Surgical Atlas of Cleft Palate and Palatal Fistulae 9811581231, 9789811581236

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Ghulam Qadir Fayyaz Editor

Surgical Atlas of Cleft Palate and Palatal Fistulae

Surgical Atlas of Cleft Palate and Palatal Fistulae

Ghulam Qadir Fayyaz Editor

Surgical Atlas of Cleft Palate and Palatal Fistulae With 1725 Figures and 50 Tables

Editor Ghulam Qadir Fayyaz Department of Plastic Surgery Services Institute of Medical Sciences/ CLAPP Hospital Lahore, Pakistan Adjunct Faculty University of Health Sciences Lahore, Pakistan

ISBN 978-981-15-8123-6 ISBN 978-981-15-8124-3 (eBook) https://doi.org/10.1007/978-981-15-8124-3 © Springer Nature Singapore Pte Ltd. 2022, corrected publication 2022 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

This book is Dedicated to Intense hard days and long hours have been spent to produce the book , present in your hands, which I dedicate to multiple inspiring sources. Notable among them are My father, Late Muhammad Siddique, who guided me to be a good human being, My friend, Haji Muhammad Hanif Tayyab, who helped me to become a plastic surgeon, My mentor, Late Prof. Kahlid Mehmood Durrani, who trained me in plastic surgery, My Grand-Teacher in cleft craft, Late Prof. Samuel Noordhoff, My patients who motivated me to do better and better every day of life, and lastly My friends and family members who sacrificed their time and had faith in me. Ghulam Qadir Fayyaz

Foreword

Prof. Dr. Hermann F. Sailer, MD, DDS Dr. med., Dr. h.c. mult., Dr. sc. h.c. mult. FDSRCS (Engl.), FRCS (Edinb.) Founding President Cleft-Children International CCI Chairman Sailer Clinic, Zurich, Switzerland Cleft lip and palate is one of the major craniofacial anomalies and is prevalent worldwide – its incidence varies from 1:550 to 1:1,500 live births around the globe. Management of cleft lip and palate patients needs comprehensive cleft care programs, which can only be run in wellorganized hospital settings. As most of the workload involves cleft patients in South Asia and the Pacific, Africa, and South America, government hospitals in these regions are unable to cater to such a huge patient workload. The majority of the population in these regions cannot afford the cost of management of cleft lip and palate patients in private hospitals. Even the private hospitals do not have all the facilities needed to help these cleft patients from birth to adulthood. Charity organizations around the world have helped communities in underprivileged countries to provide free cleft surgery, as well as associated ancillary services such as nasoalveolar molding, cleft orthodontics, and speech therapy. Cleft-Children International (CCI), Switzerland, was founded in 2001 with the same initiative to help poor cleft patients in many parts of the world under a well-designed and guided program. CCI has always emphasized the multidisciplinary management of cleft lip and palate patients under compassionate, consistent, and well-organized services in most of the major cities. I met with Prof. Ghulam Qadir Fayyaz in mid-May 2013, when he visited the office of CleftChildren International CCI at Zurich. He asked me to make his organization CLAPP (Cleft Lip & Palate Association of Pakistan) a partner of CCI. As chairperson of CCI Foundation, I am always very eager to look into the management of cleft patients provided by our partners around the globe. Over the years, I have seen Dr. Fayyaz’s commitment to help his cleft patients in a very comprehensive and integrated way. Dr. Fayyaz’s hospital is one of the most active cleft centers in the world. His team operates on 2,500 to 3,000 cleft patients every year, in partnership with CCI. He has extensive experience in the management of both primary and previously operated cleft lip and palate vii

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patients. Fortunately, he is quite active in documenting his results for publications. His papers have won various international awards as well. Dr. Fayyaz and his team have operated on more than 43,500 cleft patients so far and have very extensive experience in managing difficult and complicated cases of palatal fistulae. He has shared many of the palatal fistula patients with me that could not fit into any of the presently used classification schemes for palatal fistula. Accordingly, he has developed and published a new classification of palatal fistulae and dehiscence, and also an algorithm for managing these. I am very happy that one of CCI’s partner surgeons, Dr. Fayyaz, is writing this book, Surgical Atlas of Cleft Palate and Palatal Fistulae. As this is the first book that comprehensively covers different types of techniques for repair of cleft palate as well as palatal fistulae and dehiscence, this publication will become an ideal reference for all difficult and complicated cleft palate cases. His classification of palatal fistulae into midline, lateral, and subtotal cases is very helpful for designing a workable management plan. He has given us a practical and reproducible algorithm for the management of these fistulae. Each clinical chapter is dedicated to a specific type of problem, describes a management plan, and then provides step-by-step pictures during surgery with late postoperative follow-up. I would be very keen to see this book published at the earliest opportunity so that cleft surgeons around the world will be able to help all their difficult palate patients in a much better way.

William P. Magee Jr., DDS, MD Co-founder and CEO, Operation Smile Global Headquarters Norfolk, Virginia, USA What began back in 1982 as an opportunity for my wife and myself, along with the oldest of our five children, to take care of children with cleft lips and cleft palates in the Philippines has now evolved into one of the largest volunteer-based nonprofit organizations today. This would not have been possible without the thousands of good-hearted human beings who also recognized the opportunity that existed to help children around the world. Today, over 6,000 enthusiastic volunteers are willing to travel the globe and spend countless hours sharing their skills and talents with others. From the beginning, we realized that education and training would be critical if our work was to be sustainable. We also understood that surgery is certainly not just the surgeon, but the cumulative knowledge of anesthesiologists, nurses, pediatricians, speech pathologists, child psychologists, dentists, and nutritionists, in addition to many other allied specialties. Change never occurs because of one individual or one particular specialty, yet it is the merging of these talents that is crucial. We also realized early on that the need for cleft care is significant and we needed to enable a global network of talented individuals in order to reach more people earlier in their lives. Using

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an integrated team approach to help improve the health and dignity of patients with cleft conditions in underserved areas, our dedicated volunteers have catalyzed the growth of Operation Smile over the years and improved our ability to provide comprehensive cleft care, while developing safe and effective surgical standards, thereby elevating the surgical infrastructure in the countries we serve. This enables patients to begin a new life with a lifted outlook from within. This also elevates the attitude of surrounding family and other members of their society. By sharing our time, talent, and treasures, we not only create a lasting change for the child and their family, but also for society as a whole. One cleft surgery can transform a child’s life in as little as 45 min, allowing them to breathe better, eat, speak, and live a life of greater quality and confidence. Operation Smile is committed to providing patients with health that lasts by being there to offer additional comprehensive services when needed. Thirty-one comprehensive cleft care centers in 19 countries across the globe now provide year-round medical services. In taking care of the cleft child, there is always the possibility that a fistula may develop after the palate is repaired. This can significantly affect the functional results associated with cleft surgery. Management of the fistula is quite difficult, and excellent secondary care is essential. This requires careful planning and good execution to produce the desired results. Up until now, books providing guidelines and management of palatal fistulae issues were limited. The knowledge, talent, and determination Prof. Ghulam Qadir Fayyaz has put into his book titled Surgical Atlas of Cleft Palate and Palatal Fistulae are remarkable. He has been an ally of Operation Smile since 2013, when we first met at a cleft congress in Orlando, Florida. Since then, he has volunteered with Operation Smile on many missions all over the world, setting a positive example for others. His expertise in managing difficult palatal fistulae adds a wonderful dimension not only to international missions but to the organization as a whole, and I am certain his book will be a valuable asset for thousands of cleft surgeons, and their patients, around the globe for years to come.

Joseph E. Losee, MD, FACS, FAAP Dr. Ross H. Musgrave Endowed Chair in Pediatric Plastic Surgery Associate Dean for Faculty Affairs, University of Pittsburgh School of Medicine Professor and Executive Vice Chair, Department of Plastic Surgery Division Chief, Pediatric Plastic Surgery, Children’s Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania, USA I was both thrilled and honored to be asked by Prof. Ghulam Qadir Fayyaz, from Lahore, Pakistan, to write a Foreword to his textbook titled Surgical Atlas of Cleft Palate and Palatal Fistulae. I was privileged to meet Prof. Fayyaz recently in July 2021 at the International Cleft Palate Master Course in Amsterdam (virtual) for the symposium “Palatal Fistulas: Prevention, Classification, and Treatment.” As someone who has maintained a long-term interest in the

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subject of palatoplasty, and specifically palatal fistulas, I, along with the other international experts in attendance, was nothing short of mesmerized by Prof. Fayyaz’s presentations and overwhelmed by his experience treating palatal fistulae, which is likely one of the greatest – if not the greatest – in the world. He lectured on his incredible experience with successfully treating exceptionally complicated palatal fistulas, and, no doubt, this experience led to his classification system and successful therapeutic protocols. This textbook, Surgical Atlas of Cleft Palate and Palatal Fistulae, is most certainly birthed from that massive personal experience, containing 109 chapters, 56 personally written by him. The remaining 53 chapters are penned by global experts from around the world. The exhaustive table of contents contains a comprehensive tour of palatoplasty from prenatal diagnosis to secondary surgery. All topics and procedures are covered, including alveolar, skeletal, and speech surgery, with chapters including wonderful illustrations and high-quality intraoral photographs. I can personally attest to the massive effort of “birthing” such a work – to the sacrifice and dedication that it takes. It is nothing short of a labor of love – dedicated to those children born with orofacial clefts. For those of us who have committed our professional lives to the treatment of children born with cleft palate, this comprehensive encyclopedic tome of palatoplasty will benefit us all and be an invaluable resource and reference guide. We are indebted to Prof. Fayyaz for his significant contribution to our field.

Robert Mann Associate Clinical Professor of Surgery and Pediatrics College of Human Medicine, Michigan State University, USA Greatness always requires inspiration. For Prof. Fayyaz, inspiration came in the person of Prof. Ralph Blocksma, a plastic surgeon from Grand Rapids, Michigan, who moved to Pakistan in 1949, stayed there till 1954, and established United Christian Hospital in Lahore. Dr. Blocksma returned to Grand Rapids where he began a plastic surgery training program; the first trainee was Dr. Samuel Noordhoff, who in turn devoted his life in service of the people of Taiwan, where he established one of the most respected cleft programs in the world, another inspiration to Prof. Fayyaz. This was the center where Dr. Fayyaz was extensively trained in cleft surgeries at Chang Gung Memorial Hospital, Taiwan. I was privileged to train with Dr. Blocksma and to count Dr. Noordhoff as my friend. When I first met Dr. Fayyaz, I saw a gentleman who was an extension of these two giants, not simply a surgeon, but a teacher and mentor, always going the extra mile to share his knowledge and skills. Cleft care began with treatments for the adult cleft patients 150 years ago. These surgeries were deemed too risky for infants. Over the years, anesthesia improved and cleft care treatment was begun with progressively younger patients, finally including infants.

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During this evolution, treatments that were developed for adults were used to treat younger and younger patients. We were taught to reconstruct the cleft palate defect by releasing tissue adjacent to the cleft, pulling the tissue together to close the gap, and using secondary healing to make up any tissue deficit. Because the infant face is immensely more compressible than the adult face, this seemed logical and more or less worked. Thus, for 15 decades, cleft palate care remained unchanged at its core. Over the many years, Prof. Fayyaz has treated some of the most complex problems associated with the cleft palate defect. Critically, he has also invested the time to document his work so it could be shared. All professions would be better off if the innovators documented and shared their learnings in this manner. Professor Fayyaz remains a willing teacher and, as with all great teachers, remains open minded to his own learning process. This textbook is a vital collection of cases encompassing all aspects of cleft palate care. In each chapter the cases are analyzed, the problems studied to determine possible causation, and treatment plans established. It is said that textbooks are quick to be outdated, but the process of presurgical analysis so clearly documented by Prof. Fayyaz will stand the test of time. He gives us a fascinating look at the results of surgeries done using traditional repairs, including, but not limited to, infants. The book begins with the compressive (comprehensive) techniques used in treating the infant patient, moving on to describe other techniques used later in life to repair the resultant effects of undue facial compression. He includes compelling chapters on orthognathic surgery, which has been regularly required to repair midface hypoplasia. But Prof. Fayyaz gives us so much more, as he extensively covers treatments for older children and adults. Studies of large tissue gaps closed in older patients using the traditional treatments give us an unprecedented look at the historic roots of the cleft repair philosophy, still very much dominant today. The amazing results that were achieved are a direct reflection of Dr. von Langenbeck’s brilliant use of relaxing incisions and secondary healing. It was, of course, Dr. von Langenbeck who initially saw that the bones of the mature face had sufficient strength to hold a large space open, long enough for epithelialization to close the tissue deficit. Thank you, Prof. Fayyaz, for putting together such a marvelous collection of cases. The question of the compressive power of healing by secondary intention in infants versus older patients has troubled cleft care practitioners for generations. This landmark book brings the answer alive before our eyes. And this is just one example of the myriad of issues waiting to be discovered with a deep dive into this eye-opening book. This beautiful textbook is a reflection of Prof. Fayyaz, as well as his and my inspirations, Dr. Blocksma and Dr. Noordhoff. It offers a gateway to the future of cleft palate care.

Philip Kuo-Ting Chen, MD Professor in Surgery, Taipei Medical University Director, Craniofacial Center, Taipei Medical University Hospital, Taipei, Taiwan Parents of cleft lip and palate babies usually pay more attention to the result of lip repair than palate repair simply because everyone can easily appreciate it. Moreover, if the change after lip

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repair is dramatic, the result of palate repair can only be assessed after several years. Likewise, cleft surgeons concentrate more on lip repair, and most of the textbooks on plastic surgery or cleft care provide more chapters on lip repair than palate repair, not to mention how few are those on the management of palatal fistula. However, the result of cleft palate repair affects many areas of child development: speech, hearing, maxillary growth, and the process of swallowing. A poorly executed palate repair will have serious consequences, with the worst scenario of tissue necrosis and a huge fistula. It takes great efforts to reverse these complications, whereas only little can be found in the literature on their management. Edited by Prof. Fayyaz, this book is a comprehensive textbook on all the knowledge about cleft palate repair, including primary and secondary treatment and postoperative care. Such detailed review on the classification and management of palatal fistula cannot be found in any other textbooks. I have known Prof. Fayyaz since 2002 and have visited his centers in Faisalabad and Lahore many times. I have witnessed his effort to improve cleft care in Pakistan. I would like to thank him for his willingness to share his precious experience in cleft palate surgery and fistula management. This work is especially beneficial for surgeons in well-established centers who seldom have the chance to deal with these complications. It is my honor to write this foreword, and I will recommend this book to all cleft surgeons around.

Mohamed El-Shazly, MBBCh, MSc, PhD, MD Professor of Plastic Surgery, Assiut University, Egypt Co-founder, CEO, Operation Smile, Egypt What an amazing professional experience it is to become a physician and surgeon and what a glorious career to practice as a plastic and reconstructive surgeon! It is both rewarding yet demanding, interesting yet perplexing, and you should be willing to delve into the challenges of reconstructive surgery to complement aesthetic and cosmetic interventions. Profound changes in the landscape of healthcare and medical education are providing challenges as well as opportunities to the plastic surgery specialty to develop an international perspective and a global outreach and to address growing needs. Cleft surgery is not a simple subspecialty. The techniques to repair and reconstruct the deformities are very complex, and the outcomes are both functional and cosmetic. It is also very critical because it is a matter of fate for the patients. Each cleft surgery means a different fate for the shape, the smile, the voice, the tone, and the consequent engagement in the community. It is not a “cut as you go” surgery. It is in your eyes, mind, and hands and through your scalpel that the fate is sealed. Please be careful. I encourage all my colleagues at all levels of experience to be proud of our calling and our mission to serve as plastic and reconstructive surgeons. We practice the surgery for changing

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shapes and changing lives. Do your best to master one or two techniques during your career learning from the masters. This would help improve your results and be better for your patients than trying to know and acquire all the techniques published and taught. Be keen to know more to ideally serve your patients. Include yourself in a cleft group or a charity cleft team, and volunteer your time and experience to help those patients in need and present them the humanitarian access to safe surgery. Cleft surgeries are very crucial to the patients and their families, and they put their trust and fate in your hands and on your expertise. Always remember the feelings of a mother waiting 9 months and the disappointment she feels during the first ever look at the face and mouth of her baby. Always remember that it is not a usual surgery in your hands; it is a surgery of fate. What a gift to work as a cleft surgeon and what a glorious opportunity to be included in a cleft team working side by side with others who share the common sense of helping people and serving patients with no attention to color, race, or religion. There is no other surgical discipline that combines a comprehensive care team spanning so many committed professionals. I was lucky to be a member of the Operation Smile team. I was fortunate to gain extensive experience and acquire knowledge through the years. I shared in the writing and editing of nine chapters in this distinguished book through my interest in cleft surgery, which I developed through this team. Through the Operation Smile team, I met Dr. Ghulam Qadir Fayyaz, the editor of this invaluable book. A learned professor as well as a kind and gentleman! He dedicated his life to serve his mission and his patients. On a daily basis, he spends hours performing surgery, reading to enhance his knowledge, writing to help others learn from his experience, communicating with colleagues and students helping develop future scholars, and transferring his knowledge to others. A scholarly professor.

David K. Chong, MBBS, FRACS Plastic and Reconstructive Surgeon Royal Children’s Hospital, Flemington Rd, Melbourne, Australia I was having a chat with Billy Magee Jr. He has become a close friend. Close enough that we can disagree about things and still like each other easily. We were thinking for a term to describe surgeons who were leaders, who advocate for a region, and dedicate themselves to cleft care through education and service. These surgeons seemed to have a common denominator, being motivated by a currency that is not financial, and we wanted to coin a title to recognize their contribution. Billy came up with the word champion. I didn’t like it. I thought it sounded elitist. Could there possibly be these surgeons that are appropriately described in this way? I thought we could find a better name. Being stubborn, I mumbled that I thought there were other options. We wrestled awkwardly and then deferred the conversation. As I begun to write this foreword, I got that familiar feeling of being wrong. I realized that there really are champions. Because it describes my friend Ghulam Qadir Fayyaz perfectly.

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How else could one describe a colleague who has done over 202 cleft missions and led a team that has operated on over 43,000 cleft patients in Pakistan and Afghanistan, patients who otherwise would have little access to care? The depth of his experience, his dedication to patients with clefts, and his willingness to share his techniques with others have left me in awe of him. When he told me he was going to do an atlas on palate surgery and fistulas, I was sure it would be done. I had previously been exposed to his passion and determination, and it has not surprised me to see him galvanize 38 authors (including many learned colleagues from his region) over the last 3 years to produce this atlas, as well as writing over half the chapters himself. Ghulam champions cleft care, his country, his colleagues, and education. We know the best time to repair a palate is the first time. The problem of a poorly done primary repair sets the patient on a journey which is difficult to recover from. Even the small fistula is challenging, with its scarred tissue and propensity to recur, let alone the massive defects that Ghulam closes with his infectiously humorous demeanor, accompanied with straightforward instruction. I am sure you will share my opinion that his prowess dealing with large fistulas is unsurpassed. Thanks to this atlas, we all have a copy of his road map to some of the most difficult problems in cleft surgery. Thank you for taking the time to gather these pearls for us, Ghulam. This atlas will fill a hole that is sorely required in cleft literature and will benefit many surgeons around the world and, most importantly, the patients they treat. Oh, and I messaged my friend Billy to tell him that he was right. . . again.

Foreword

Preface

The first ever cleft workshop I attended was in 2002 at Chang Gung Memorial Hospital, Linkou, Taiwan. I met legendary Prof. Noordhoff and Profs. Yu-ray Chen, Philip Chen, and Lun-jou Lo for the first time. It was a three-day workshop with lectures and live surgery sessions. On the last day, I asked Prof. Philip Chen about the concluding ceremony. “What? ( as they don’t have any formal concluding ceremony)”, he responded. I told him that I would like to present some gifts from Pakistan to the faculty members of this workshop. He agreed to my request, and when the last lecture was finished, Prof. Philip Chen called me to the podium. I gave my camera to Prof. Myong Chul Park (from South Korea) to take pictures. I started as “Whenever anybody goes to a teacher (in the Indo-Pak region) to learn some art or procedure, they (as a tradition) usually take some gifts as a token of ‘submission to the teacher’ (the gifts may be a turban, a cap, or other items or some kilos of delicious sweet food items). I am presenting these gifts (on behalf of all the participants of this workshop) to the faculty members.” Instead of just three days at Linkou, Taiwan, I extended my stay and observed different cleft surgeries for an entire month. When I returned to Faisalabad, Pakistan, three new operating rooms (OR) at Punjab Medical College, Allied Hospital Faisalabad, were almost ready. I established these ORs by fundraising from the city of Faisalabad and made these functional by the end of 2002. In 2003, I founded a nonprofit organization, CLAPP (Cleft Lip & Palate Association of Pakistan), with the single purpose of providing free cleft surgeries to all deserving patients. Smile Train started supporting free surgeries (332 in 2003 and 617 in 2004). On my promotion as Associate Professor of Plastic Surgery in 2005, I was transferred to the Services Institute of Medical Sciences, Lahore, and so the cleft program was shifted to Lahore as well. We established a small facility at Lahore in January 2008, dedicated to cleft lip and palate patients where we provide audiology, speech therapy, and cleft orthodontic services and cleft surgeries, totally free for all deserving patients. We were able to organize one of the busiest cleft programs in the world, where we operated 2800(2008), 3000(2009), 3600(2010) and 4222 (2011) cleft patients in a year’s time. Our capacity building helped us to reach this level. In 2004, we started cleft missions in remote areas of Pakistan, to provide free surgeries to the patients at their doorstep. We trained our surgeons, anesthesiologists, and supporting staff at our main center, CLAPP Hospital in Lahore, so that we could help hundreds of cleft patients in each of our cleft missions. In the first mission in 2004, we were two surgeons and two OR staff members; now we have grown to a 48-membered strong team. So far, we have conducted 193 cleft missions in Pakistan and Afghanistan. We published our experience in the paper “A Model Humanitarian Cleft Mission: 312 Cleft Surgeries in 7 Days” in PRS Global Open in 2015 (this paper won the Best International Collaboration Gold Award in 2016). Overall, CLAPP’s team (since 2003 till date) has operated more than 43,500 cleft lip and palate patients. Since 2013, we are working in collaboration with Cleft-Children International (CCI), Zurich, Switzerland. Most of my chapters describe the patients whose surgeries were sponsored by CCI.

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We organized eight symposiums for the management of cleft lip and palate in Pakistan in 2004, 2005, 2007, 2009, 2011, 2013, 2015, and 2018. Professors Philip Chen and Lun-jou Lo were the most important faculty members and have contributed largely to the development of the cleft program in Pakistan. Over the years, we gained extensive experience with handling cleft palate patients (and complications after palate surgery). All difficult palatal fistula patients from all over Pakistan and even Afghanistan ultimately landed in CLAPP Hospital, Lahore. We were able to innovate some methods to close difficult palatal fistula by simple techniques. We were operating more than 1500 cleft palate patients every year, both unoperated and previously operated patients (with fistula). We described our techniques of “Radical Dissection of Greater Palatine Artery” and “Continuous Versus Interrupted Sutures for Primary Cleft Palate Repair” (both papers were published in PRS Global Open and won awards). We tried to classify palatal fistulae as per prevalent classification systems; however, quite a good number of them could not be categorized properly. Over the years, we became more and more experienced and confident to handle a wide variety of palatal fistulae (not described previously), so we developed a new classification for them and devised an algorithm to close different and difficult palatal fistulae. We then Published our classification in PRS in January 2019. Professor Philip Chen once told me that a cleft surgeon from the USA wanted to visit Taiwan for training in the management of palatal fistula. He told the American surgeon that we have extremely low fistula rate and even those are very minor fistulae. I then searched the Internet for any book on the management of palatal fistula, and to my utter surprise, I could not find even a single book solely focused on closure of palatal fistula. At that time, it occurred to me that I should try to organize our extensive experience on closure of different types of palatal fistulae into a book. Although the initial planning of the book was done in 2016, the overwhelming response to our paper in PRS (January 2019) fueled our passion to write this book, and we thought to include everything related to the management of palatal fistula. When I was trying to compile the list of chapters for the management of palatal fistula, it came to my mind that we should also include chapters on different types of palate repair, where we can share (with the readers) how to do a good repair of cleft palate and thus avoid complications of palate repair. To build a good foundation for primary palate repair, I then included chapters on the anatomy and physiology of normal and cleft palate. Later, I included everything related to cleft palate, namely, chapters on the etiology, genetics, psychosocial aspects, and antenatal diagnosis of cleft palate. This was a huge undertaking on my part, and I could not do it single-handedly. I contacted many of my friends in Pakistan and abroad to contribute to this atlas. I was assisted by friends from the Cleft WhatsApp group, created by Edwar Alvarez from Ecuador. Many friends from Taiwan, India, the Philippines, Indonesia, Australia, Egypt, Ecuador, Nicaragua, Guatemala, Peru, Paraguay, Brazil, the UK, Netherlands, Italy, and the USA were very supportive and contributed 33 chapters. Our colleagues from the Pakistan Association of Plastic Surgeons and allied disciplines were very helpful and have contributed 20 chapters. The rest of the chapters were written by me. When I started to write the book, it was estimated to have around 50 chapters; later, the number kept on increasing, and finally the book has swollen to 109 chapters. There are a good number of articles published on the management of palatal fistula. However, there are limitations for the research articles: there is a word limit, and the number of figures is also limited. The idea of writing this book was to provide readers a detailed account of the management of each and every type of palatal fistula. To organize data of hundreds of patients having palatal fistula into a book was an uphill task. We tried to include those cases for which we had pictures of each and every step of the procedure. We also tried our level best to include those cases where we had very late follow-up for at least 3–6 months. It is the late follow-up which confirms the validity of a certain approach or invalidity otherwise. We routinely take multiple pictures during surgery for every difficult and interesting case. It took many months to select the cases which can be included in this atlas. There were many cases for each type of palatal fistula, and we selected the case which can better help the reader to

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understand the most appropriate procedure for a particular type of palatal fistula. Once the cases were selected, we arranged the pictures in a sequence, from preoperative, perioperative to postoperative, and lastly, good follow-up minimum of three months. Then I started writing legends/captions for each picture. The description of the entire scenario was written and relevant references added. We selected more than one cases for each type of palatal fistula or primary palate cases, and in the end, we finalized the better among those cases for publication in this book. We contacted Springer Nature in September 2018 to publish this book, and after many months of negotiations, we entered into a formal contract. What should be the name of the book? Initially, it was named Surgical Atlas of Secondary Repair of Cleft Palate, but it did not reflect the contents of the book. Then, we changed it to Surgical Atlas of Palate Repair, but even then there was no mention of palatal fistulae. Finally, after many consultations and deliberations, it was titled Surgical Atlas of Cleft Palate and Palatal Fistulae. I am thankful to Naren Aggarwal of Springer India and many other persons who have contributed to the development of this book. Writing a book has never been an easy job. Sometimes, we can make a list of topics for chapters in the book and ask many colleagues to write one or two chapters from the given list. If the editor has one or two chapters of his own, the job becomes quite easier and the whole book can be compiled in about 6 months or so. The scenario here was quite different. I had to write 56 chapters on my own. It took me quite a long time to write each chapter, read it, reread it, and then rewrite it. Many of the authors sent their chapters in early 2020, but I was unable to review and edit their chapters as I was busy with my own chapters. But all is well that ends well. I am very happy and satisfied that we were able to compile a book which will enable thousands of cleft surgeons around the globe to manage their patients amicably. June 2022

Ghulam Qadir Fayyaz

Contents

Part I

Basics of Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Anatomy of the Normal Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Muhammad Ashraf Ganatra and Diaa Othman

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2

Anatomy of Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Muhammad Sohail and Muhammad Mustehsan Bashir

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3

Physiology of Normal Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amina Asif Siddiqui

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4

Pathophysiology of the Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Amina Asif Siddiqui

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5

Global Incidence of Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mohamed El-Shazly, Yasser Helmy, Lobna Abdelsalam, and Tasnim Ali

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6

Etiology of Cleft Lip and Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tahmeedullah and Waqas Hayat

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7

Antenatal 2-D, 3-D, and 4-D Sonographic Evaluation of Cleft Lip and Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Safdar Ali Malik and Muhammad Bin Zulfiqar

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8

Genetic Factors Responsible for Cleft Lip and Palate . . . . . . . . . . . . . . . . . . . Xiaoqian Ye and Mairaj K. Ahmed

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9

Prevalent Classification Scheme of Cleft Lip and Palate . . . . . . . . . . . . . . . . . Mirza Shehab Afzal Beg and Mehtab A. Solangi

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Part II

Management of Cleft Palate Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71

10

Psycho-social Aspects of Cleft Palate Patient . . . . . . . . . . . . . . . . . . . . . . . . . . Tahmeedullah and Waqas Hayat

73

11

Timeline of Management of Cleft Palate Patient . . . . . . . . . . . . . . . . . . . . . . . Muhammad Ashraf Ganatra and Muhammad Aslam

77

12

Role of Orthodontist in Cleft Palate Patient . . . . . . . . . . . . . . . . . . . . . . . . . . Erum Minhas

83

13

Feeding Protocol in Cleft Palate Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Farooq Shahzad and Paymon Sanati-Mehrizy

99

14

Management of Cleft Palate in Pierre Robin Syndrome . . . . . . . . . . . . . . . . . 113 Yoshiko Toyoda and Jordan W. Swanson

xix

xx

Contents

15

The Science and Art of Anesthesia: A Look at a Glance for Plastic Surgeons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Adrián Villalba Egas, Fernando Córdova Lopez, and Zafar Hussain

16

Rationale of Cleft Palate Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Christopher Hill and Serena Martin

17

History of Cleft Palate Repair: Regional Influences of Technique Variations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Priyanka Naidu, Aaron C. Van Slyke, and David K. Chong

18

Telemedicine in Cleft Surgery: Overcoming Geographical Barriers and Improving Health Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Mohamed El-Shazly and Tarek Raief

19

Education Modules and Methodologies in Training of Cleft Palate Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 Domenico Scopelliti, Mohamed El-Shazly, and Giulia Amodeo

Part III

Techniques of Cleft Palate Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

20

Tips and Tricks in Cleft Palate Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Mohamed El-Shazly, Ahmed Taha, and Ghulam Qadir Fayyaz

21

Radical Dissection of Greater Palatine Vessels . . . . . . . . . . . . . . . . . . . . . . . . 175 Ghulam Qadir Fayyaz and Muhammad Daiem

22

Continuous Running Sutures for Palate Repair . . . . . . . . . . . . . . . . . . . . . . . 191 Ghulam Qadir Fayyaz and Priyanka Naidu

23

Langenbeck Repair for Incomplete Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . 199 Mirza Shehab Afzal Beg and Ghulam Qadir Fayyaz

24

Modified Langenbeck Repair for Soft Palate Cleft: Right Incision Only . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Ghulam Qadir Fayyaz

25

Soft Palate Repair with No lateral incisions . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Divya Narain Upadhyaya and Abhijat Mishra

26

Double Opposing Furlow’s Z Plasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Gaurav Deshpande

27

Modified Furlow Palatoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Philip Kuo-Ting Chen and Vikram Pandit MDS

28

The Usage of Vomer Flap in Cleft Palate Repair . . . . . . . . . . . . . . . . . . . . . . . 249 Philip Kuo-Ting Chen and Biader Bilal

29

Early Soft Palate Repair with Delayed Hard Palate Repair . . . . . . . . . . . . . . 259 Luca Autelitano, Tarek Raief, Ahmed Taha, and Mohamed El-Shazly

30

Bardach Two Flap Palatoplasty for Unilateral Cleft Palate . . . . . . . . . . . . . . . 269 Ghulam Qadir Fayyaz and Muhammad Daiem

31

Bilateral Complete Cleft Palate for Two-Flap Palatoplasty . . . . . . . . . . . . . . . 285 Ghulam Qadir Fayyaz and Fahad Nazir

32

Submucous Cleft Palate for Langenbeck Repair . . . . . . . . . . . . . . . . . . . . . . . 293 Ghulam Qadir Fayyaz and Nauman Ahmad Gill

Contents

xxi

33

Submucous Cleft Palate for Langenbeck Repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309 Ghulam Qadir Fayyaz and Farrakh Mahmood

34

Incomplete Cleft Palate Repair with Pharyngeal Flap in an Adult Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Ghulam Qadir Fayyaz and Tajammal Ahmed Chaudhry

35

Repair of Wide Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 Ghulam Qadir Fayyaz and Muhammad Aslam

36

Cleft Palate Repair in Adult Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 Gary R. Parker, David K. Chong, and Priyanka Naidu

37

One-Flap Palatoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347 Matthew Fell, Per N. Hall, and Percy Rossell-Perry

38

Repair of Asymmetric Soft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 Ghulam Qadir Fayyaz and Kamran Khalid

39

Use of Buccal Fat Pad Flap in Palate Repair . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Muhammad Ashraf Ganatra

40

Dorsally Based Tongue Flap for Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . . 365 Muhammad Ashraf Ganatra

41

Ventrally Based Tongue Flap for Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . 373 Edwar Alvarez, David Alvarez, Andrea Iñiguez, and Miguel E. Farina

42

How We Do pharyngeal Flap for a Short Palate . . . . . . . . . . . . . . . . . . . . . . . 381 Ghulam Qadir Fayyaz and Moazzam Nazeer Tarar

43

Sphincter Pharyngoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393 Peter D. Witt

44

Management of Anomalies Associated with Cleft Palate . . . . . . . . . . . . . . . . . 403 Mohamed El-Shazly, Ahmed Taha, Tarek Raief, and Yasser Helmy

45

Alveolar Bone Grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 Syed Mahmood Haider

46

Tissue Engineering Strategies in Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . 429 Yasser Helmy Ali, Mohamed El-Shazly, Ahmed Taha, Tasnim Ali, and Sayed Bakri

Part IV

Postoperative Management and Speech Therapy . . . . . . . . . . . . . . . . . 439

47

Postoperative Management of Cleft Palate Repair . . . . . . . . . . . . . . . . . . . . . 441 Rachel A. McKenna, Christopher L. Kalmar, and Jordan W. Swanson

48

The Benefit of Honey After Cleft Palate Repair . . . . . . . . . . . . . . . . . . . . . . . 449 Gentur Sudjatmiko and Mohamad Rachadian Ramadan

49

Speech Therapy Protocol After Palate Repair . . . . . . . . . . . . . . . . . . . . . . . . . 457 Amina Asif Siddiqui

50

The Speech Score: A New Concept for Evaluation of Functional Result After Cleft Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467 Edwar Alvarez, David Alvarez, Andrea Iñiguez, and Cleidys Pereira

xxii

Contents

Part V

Complications of Cleft Palate Repair and Their Management . . . . . . . . 473

51

The Red Code: Management of Bleeding During or After Cleft Palate Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 Edwar Alvarez, David Alvarez, and Andrea Iñiguez

52

Hanging Palate: Anterior Detachment of Mucoperiosteal Flaps . . . . . . . . . . . 483 Muhammad Ashraf Ganatra

53

Mucoperiosteal Flap Necrosis After Primary Palatoplasty in Patients with Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487 Percy Rossell-Perry

54

Palatal Fistula and Dehiscence: Its Etiology and Consequences . . . . . . . . . . . 507 Gaurav Deshpande

55

History of Repair of Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 Renato da Silva Freitas, Fabiola Grigoletto Lupion, and Flávia Davi Joāo de Masi Nassif

56

Short Palate: Its Etiology and Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . 519 Moazzam Nazeer Tarar and Farrukh Aslam Khalid

57

Methods of Lengthening of Short Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 Miguel E. Farina and Ghulam Qadir Fayyaz

58

Velopharyngeal Incompetence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 Muhammad Mustehsan Bashir and Saadia Nosheen Jan

59

Fat Grafting for Velopharyngeal Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . 547 Armando Siu Bermúdez and Nicholas Webster

60

Use of Conchal Cartilage and Acellular Dermal Matrix in Repair of Palatal Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555 Ahmed Taha, Mohamed El-Shazly, and Yasser Helmy

61

FAMM-Flap: The Facial Artery Myo Mucosal Flap in Palatal Fistulae Reconstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 J. W. Nolte and C. C. Breugem

62

Cleft Orthognathic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575 Frank Chun-Shin Chang and Lee Seng Khoo

Part VI

Classification Systems for Palatal Fistulae . . . . . . . . . . . . . . . . . . . . . . . 589

63

Previous Classifications for Palatal Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . 591 Saadia Nosheen Jan

64

Pakistan Comprehensive Fistula Classification . . . . . . . . . . . . . . . . . . . . . . . . 595 Ghulam Qadir Fayyaz and Mohamed Elshazly

65

Midline Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607 Nauman Ahmed Gill, Ghulam Qadir Fayyaz, and Farhan Gohar

66

Lateral Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613 Miguel E. Farina, Ghulam Qadir Fayyaz, and Muhammad Azam

67

Subtotal Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619 Ghulam Qadir Fayyaz and Muhammad Younas Mehrose

Contents

xxiii

Part VII

Management of Midline Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . . 627

68

M5 for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629 Ghulam Qadir Fayyaz, Muhammad Azam, and Muhammad Daiem

69

M2 for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633 Ghulam Qadir Fayyaz and Muhammad Daiem

70

M3 for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639 Ghulam Qadir Fayyaz

71

M3 for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . . . . . . 645 Ghulam Qadir Fayyaz and Farhan Gohar

72

M4 for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . . . . . . 651 Ghulam Qadir Fayyaz and Muhammad Azam

Part VIII

Management of Lateral Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . . 657

73

La Fistula for Palate Re-repair by Unfolding of Distal Portion of Mucoperiosteal Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659 Ghulam Qadir Fayyaz

74

La Fistula for Palate Re-repair by Contralateral Mucoperiosteal Flap . . . . . . 667 Ghulam Qadir Fayyaz and Muhammad Daiem

75

La Fistula for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . 677 Ghulam Qadir Fayyaz

76

Rb Fistula for Palate Re-repair by Contralateral Mucoperiosteal Flap and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685 Ghulam Qadir Fayyaz, Muhammad Daiem, and Muhammad Azam

77

Lb Fistula for Palate Re-repair by Contralateral Mucoperiosteal Flap . . . . . . 699 Ghulam Qadir Fayyaz, Muhammad Daiem, and Muhammad Azam

78

Rc Fistula for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . 705 Ghulam Qadir Fayyaz and Marco Aurélio Lopes Gamborgi

79

La and Ra for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713 Ghulam Qadir Fayyaz and Muhammad Daiem

Part IX

Management of Subtotal Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723

80

Subtotal Left Fistula for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725 Ghulam Qadir Fayyaz

81

Subtotal Right Fistula for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . 735 Ghulam Qadir Fayyaz and Muhammad Daiem

82

Subtotal Right Fistula for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . 743 Ghulam Qadir Fayyaz and Muhammad Azam

83

Large Subtotal Right Fistulae for Palate Re-repair, Buccal Sulcus Mucosal Flap, and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753 Ghulam Qadir Fayyaz and Marvee Turk

84

Very Large Subtotal Right Fistula for Palate Re-repair . . . . . . . . . . . . . . . . . 767 Ghulam Qadir Fayyaz

xxiv

85

Contents

SubTotal Bilateral Fistula for Tongue Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . 779 Ghulam Qadir Fayyaz

Part X

Management of Multiple Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787

86

M1-2 and M3 for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789 Ghulam Qadir Fayyaz and Muhammad Azam

87

M2 and M5 for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . 799 Ghulam Qadir Fayyaz and Marvee Turk

88

M2, M2, and M3 with D2 for Palate Re-repair and Pharyngeal Flap . . . . . . . 805 Ghulam Qadir Fayyaz and Muhammad Daiem

89

M2, M3, M5 and D1 for Palate Re-Repair and Pharyngeal Flap . . . . . . . . . . . 817 Ghulam Qadir Fayyaz, Muhammad Daiem, and Muhammad Azam

90

StB, M3, and Rc for Tongue Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 829 Ghulam Qadir Fayyaz

Part XI

Management of Fistula Adjacent Regions (FAR) . . . . . . . . . . . . . . . . . . 841

91

M1-2 for Buccal Sulcus Mucosal Flap (BSMF) . . . . . . . . . . . . . . . . . . . . . . . . 843 Ghulam Qadir Fayyaz and Miguel E. Farina

92

M1-2, for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . . . . 849 Ghulam Qadir Fayyaz and Muhammad Daiem

93

M2-3 and D1 for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859 Ghulam Qadir Fayyaz and Muhammad Aslam

94

M3-4 for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . . . . . 869 Ghulam Qadir Fayyaz and Muhammad Azam

95

M4-5 for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881 Ghulam Qadir Fayyaz and Farrakh Mahmood

96

M3-4-5 for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . . . . . . . . . . 889 Ghulam Qadir Fayyaz and Muhammad Daiem

97

M2-3-4-5 for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 895 Ghulam Qadir Fayyaz

Part XII

Dehiscence/Almost Total Loss of Palatal Tissue . . . . . . . . . . . . . . . . . . 901

98

Management of D2 for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903 Ghulam Qadir Fayyaz and Muhammad Daiem

99

Management of D2 for Palate Re-repair and Pharyngeal Flap . . . . . . . . . . . . 907 Ghulam Qadir Fayyaz and Muhammad Azam

100

Management of D3-L for Palate Re-repair and Pharyngeal Flap . . . . . . . . . 911 Ghulam Qadir Fayyaz and Muhammad Daiem

101

Management of D3-R for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . 921 Ghulam Qadir Fayyaz and Muhammad Daiem

102

Management of D4-L for Palate Re-repair . . . . . . . . . . . . . . . . . . . . . . . . . . 929 Ghulam Qadir Fayyaz and Farhan Gohar

Contents

xxv

103

Management of D4-R for Palate Re-repair and Pharyngeal Flap . . . . . . . . . 939 Ghulam Qadir Fayyaz, Nauman Ahmed Gill, and Muhammad Daiem

Part XIII

Difficult to Repair Secondary Palate Patients . . . . . . . . . . . . . . . . . . . 951

104

Management of Almost Total Loss of Palate, Buccinator Myomucosal Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953 Fernando Henrique Almas de Carvalho and Ghulam Qadir Fayyaz

105

Lengthening of the Anterior Palate by Unfolding of Mucosalized Undersurface of the Distal Portion of Mucoperiosteal Flap in Anterior Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967 Ghulam Qadir Fayyaz and Nauman Ahmed Gill

106

Management of Palatal Flaps Having No Pedicle During Palate Revision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977 Ghulam Qadir Fayyaz and Muhammad Azam

107

Use of Free Flaps in Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987 Abraham Zavala and Wieslawa De Pawlikowski

Part XIV

Nonsurgical Management of Palatal Fistula . . . . . . . . . . . . . . . . . . . . 999

108

Use of Orthopedic and Orthodontic Appliances for Management of Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1001 Nydia Ivette Paredes Amenábar

109

Nonsurgical Management of a Palatal Fistula . . . . . . . . . . . . . . . . . . . . . . . . 1025 Eric Pius J. Cembrano

Correction to: Management of Almost Total Loss of Palate, Buccinator Myomucosal Flap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fernando Henrique Almas de Carvalho and Ghulam Qadir Fayyaz

C1

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035

About the Editor

Ghulam Qadir Fayyaz Born in Multan in 1959, Ghulam Qadir Fayyaz graduated from Punjab Medical College, Faisalabad, in 1984. Then he completed postgraduate diploma in plastic surgery in 1988 from Vienna University, Austria. He obtained an MS (Master in Surgery) in plastic surgery from Dow Medical College, affiliated with the University of Karachi, in 1991. He was appointed Assistant Professor Plastic Surgery at Punjab Medical College, Faisalabad, in 1995. He started the Department of Burns and Plastic Surgery at Allied Hospital, Faisalabad, in June 1999. He raised funds from the business community of Faisalabad and installed multiple air conditioners in the Burn Unit to facilitate the burn patients. He raised funds from philanthropists of Faisalabad and abroad to construct three operating rooms (ORs) for the Department of Burns and Plastic Surgery. The three ORs were completed and equipped at a cost of 6 million Pakistani rupees. in 2002. Dr. Fayyaz founded a nonprofit organization, Cleft Lip & Palate Association of Pakistan (CLAPP), in 2003, which was registered with the Government of Punjab, Pakistan. The CLAPP Foundation was registered in New York in 2012, and the Internal Revenue Service granted income tax exemption for it in 2016. Dr. Fayyaz was transferred from Punjab Medical College, Faisalabad, to the Services Institute of Medical Sciences, Lahore, and retired in January 2019 as Professor of Plastic Surgery from the same institution. He was trained in cleft surgeries at Chang Gung Memorial Hospital, Linkou and Taoyuan, Taiwan. He has actively participated in cleft workshops arranged by Chang Gung Memorial Hospital, Taiwan, in 2002, 2004, 2006, 2008, 2010, 2012, 2014, 2016, 2019, and 2021. He was an integral part of cleft congresses held in Durban, South Africa (2005); Fortaleza, Brazil (2009); and Orlando, USA (2013). Late Abdul Sattar Edhi donated 5 million Pakistani rupees to start a dedicated cleft hospital in Lahore, at 932-C, Faisal Town, Lahore. This hospital is the only cleft center in Pakistan where cleft lip and palate patients are provided cleft surgeries, audiology, cleft orthodontics, and speech therapy, all free under one roof. Since January 2008, this hospital has operated more than 15,000 cleft lip and palate patients from all across Pakistan and even from Afghanistan. Cleft surgeons from Germany, the UK, and Afghanistan have been trained in cleft surgeries at CLAPP Hospital, Lahore, in 2014, 2016, and 2019. xxvii

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About the Editor

Over a period of 17 years, team CLAPP has conducted 193 surgical cleft missions – 187 in Pakistan and 6 in Kabul, Afghanistan. The team of Dr. Fayyaz has operated more than 21,600 cleft patients in these missions. Working since 2003, so far CLAPP has operated more than 44,000 cleft patients. Team CLAPP has organized awareness seminars in collaboration with Daily Jang & Geo TV in 2010, 2014, 2016, and 2020. One seminar was conducted at Estiqlal Hospital, Kabul, Afghanistan, in May 2013. Dr. Fayyaz’s foundation, CLAPP, is going to start the construction of a 300-bedded charitable hospital at Main Ferozepur Road, Lahore. He has written many research articles which have been published in local and international journals. Three of his papers received International Collaboration awards in 2016, 2018, and 2019 from the USA. He has written one chapter in Global Cleft Care in Low-Resource Settings published by Springer in 2021. He is the chief editor of this book, titled Surgical Atlas of Cleft Palate and Palatal Fistulae, a 1,000-page book being published by Springer Nature. He has written 56 chapters, while 53 chapters have been written by other authors from around the globe. He is the most sought-after speaker during international conferences on repair of palatal fistula. He is an international volunteer surgeon for Operation Smile and has operated in Rwanda, Malawi, Egypt, Morocco, Paraguay, the Philippines, and Mexico. He has organized eight symposiums in cleft lip and palate surgeries in 2004, 2005, 2007, 2009, 2011, 2013, 2015, and 2018 in Pakistan. He has served as President-Elect of the Pakistan Association of Plastic Surgeons (PAPS) from 2018 to 2020 and President of PAPS from 2020 to 2022. Currently he is Chairman Board of Trustees of PAPS (2022-2024). At above 60 years of age, he is still a force in the international arena of cleft care.

Contributors

Lobna Abdelsalam University of North Carolina, Chapel Hill, NC, USA Mairaj K. Ahmed Department of Dentistry, Montefiore Medical Center / Albert Einstein College of Medicine, Bronx, NY, USA Department of Dentistry/Oral Maxillofacial Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Surgery, Division of Plastic and Reconstructive Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA Tasnim Ali Faculty of Biotechnology, Nile University, Cairo, Egypt Yasser Helmy Ali Plastic Surgery Department & Director of International Excellence Bureau, Al-Azhar University, Cairo, Egypt Volanteer Middle East & North Africa – Operation Smile International, Virginia, VA, USA David Alvarez Reconstructive and Aesthetic Plastic Surgery Service, Continental Basic Hospital, Latacunga, Ecuador Operation Smile Paraguay, Fernando de la Mora, Paraguay Edwar Alvarez Reconstructive and Aesthetic Plastic Surgery Service, Continental Basic Hospital, Latacunga, Ecuador Operation Smile Paraguay, Fernando de la Mora, Paraguay Operation Smile Paraguay, Virginia, VA, USA Operation Smile Ecuador, Latacunga, Ecuador Giulia Amodeo Maxillofacial Surgery Department, San Filippo Neri Hospital – Smile House Roma San Filippo Neri Hospital, Rome, Italy Muhammad Aslam Department of Plastic Surgery, Services Hospital and CLAPP Hospital, Lahore, Pakistan Services Institute of Medical Sciences and CLAPP Hospital, Lahore, Pakistan Luca Autelitano Clinical Coordinator, Cleft Lip & Palate Regional Center Milan, San Paolo University Hospital, Milan, Italy Muhammad Azam Head of department of Speech & Language Therapy, CLAPP Hospital, Lahore, Pakistan Sayed Bakri Dean of Faculty of Science & Director of Centre of Tissue Engineering & Stem Cell Research, Al-Azhar University, Cairo, Egypt

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Muhammad Mustehsan Bashir Division of Plastic Surgery, King Edward Medical University, Lahore, Pakistan FCPS Surgery; FCPS Plastic Surgery; PhD Plastic Surgery, Kind Edward Medical University, Lahore, Pakistan Mirza Shehab Afzal Beg Department of plastics, reconstructive & hand surgery, Liaquat National Hospital, Karachi, Pakistan Armando Siu Bermúdez Plastic and Reconstructive surgery, Center for Reconstructive and Microsurgery, Hospital Vivian Pellas, Managua, Nicaragua Biader Bilal Plastic reconstructive surgeon, Craniofacial fellow, Taipei Medical University Hospital, Taipei, Taiwan C. C. Breugem Plastic and Reconstructive surgeon, Department of Plastic and Reconstructive Surgery, Amsterdam University Medical Centers, Emma Children’s Hospital, President Interplast Holland, Amsterdam, The Netherlands Eric Pius J. Cembrano Department of Clinical Sciences, Davao Medical School Foundation, Inc., College of Dentistry, Davao City, Philippines Private Practice, Cembrano Dental Clinic, Davao City, Davao del Sur, Philippines Volunteer, Operation Smile, Davao City, Philippines Fernando Córdova Lopez Anesthesiologist, Clínica Santa Lucia, Quito, Ecuador Clínica Continental, Latacunga, Ecuador Frank Chun-Shin Chang Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan Tajammal Ahmed Chaudhry Department of Plastic Surgery, Hameed Latif Hospital, Lahore, Pakistan Philip Kuo-Ting Chen Craniofacial Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan David K. Chong Department of Plastic and Maxillofacial Surgery, Royal Children’s Hospital, Melbourne, VIC, Australia Muhammad Daiem Agha Khan University, Karachi, Pakistan Renato da Silva Freitas Plastic Surgery Unit, Hospital de Clínicas of Federal University of Parana, Curitiba, Parana, Brazil Center for Cleft Lip and Palate (CAIF), Curitiba, Parana, Brazil Fernando Henrique Almas de Carvalho Department of craniofacial Deformities, Saint Lucas Hospital, Goiânia, Goiás, Brazil Flávia Davi Joāo de Masi Nassif Center for Cleft Lip and Palate (CAIF), Curitiba, Parana, Brazil Wieslawa De Pawlikowski Department of Plastic and Reconstructive Surgery, Instituto Nacional de Salud del Niño – San Borja, Lima, Peru Gaurav Deshpande “Maaya” Cleft and Craniofacial Unit, MGM Institute of Health Sciences, Navi Mumbai, India MGM Dental College and Hospital, Navi Mumbai, India Penn State Hershey School of Medicine, Hershey, PA, USA

Contributors

Contributors

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Mohamed El-Shazly Plastic Surgery Department, Assiut University, Assiut, Egypt Middle East & North Africa, Operation Smile International, Virginia Beach, VA, USA Operation Smile, Virginia, VA, USA Miguel E. Farina Plastic Surgery, Centro Medico Guaireno, Villarrica, Guaira, Paraguay Edificio Coompecipar 4to piso, Rio de Janeiro, Asuncion, Paraguay Ghulam Qadir Fayyaz Department of Plastic Surgery, Services Institute of Medical Sciences/ CLAPP Hospital, Lahore, Pakistan Adjunct Faculty, University of Health Sciences, Lahore, Pakistan Matthew Fell Southmead Hospital, Bristol, UK Marco Aurélio Lopes Gamborgi R. Visc. do Rio Branco, Centro, Curitiba, Brazil Muhammad Ashraf Ganatra Plastic Surgery Department, Dow University of Health Sciences, Karachi, Pakistan Nauman Ahmed Gill Plastic Surgery, King Edward Medical University, Lahore, Pakistan Farhan Gohar Department of Paediatric Plastic Surgery, Children Hospital, Lahore, Pakistan Syed Mahmood Haider Karachi Medical and Dental College, University of Karachi, Karachi, Pakistan Per N. Hall Addenbrookes Hospital NHS Foundation Trust, Cambridge, UK Waqas Hayat Burn and Plastic Surgery Center, Peshawar, Pakistan Yasser Helmy Al-Azhar University, Cairo, Egypt Christopher Hill Plastic Surgery, Northern Ireland Plastic and Maxillofacial Service, Belfast, UK Andrea Iñiguez Reconstructive and Aesthetic Plastic Surgery Service, Continental Basic Hospital, Latacunga, Ecuador Saadia Nosheen Jan FRCSEd; FCPS Plastic Surgery, Services Institute of Medical Sciences, Lahore, Pakistan Christopher L. Kalmar Cleft and Craniofacial Program, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Farrukh Aslam Khalid Jinnah Burn & Reconstructive Surgery Centre, Allama Iqbal Medical College, Lahore, Pakistan Kamran Khalid Plastic Surgery, Jinnah Burn & Reconstructive Surgery Center, Lahore, Pakistan Lee Seng Khoo Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan Fabiola Grigoletto Lupion Craniofacial Surgery at CAIF, Curitiba, Parana, Brazil Farrakh Mahmood Department of Pediatric Surgery, Children Hospital, Lahore, Pakistan Safdar Ali Malik Services Institute of Medical Sciences, Tamgha-e-Imtiaz Alnoor Institute of Radiology (Alnoor Diagnostic Centre), Lahore, Pakistan Serena Martin Plastic Surgery, Northern Ireland Plastic and Maxillofacial Service, Belfast, UK

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Rachel A. McKenna Cleft and Craniofacial Program, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Vikram Pandit MDS Consultant Oral and Maxillofacial Surgeon, Pune, India Muhammad Younas Mehrose Plastic Surgery, Jinnah Burns & Reconstructive Surgery Center, Lahore, Pakistan Erum Minhas Consultant orthodontist CLAPP hospital, Lahore, Pakistan Abhijat Mishra Department of Plastic and Reconstructive Surgery, King George’s Medical University, Lucknow, India Priyanka Naidu Department of Research, Education, and Innovation, Operation Smile Incorporated, Virginia Beach, VA, USA Fahad Nazir CLAPP Hospital, Lahore, Pakistan J. W. Nolte Oral and Maxillofacial surgeon, Department of Oral and Maxillofacial Surgery, Amsterdam University Medical Centers, Emma Children’s Hospital, Amsterdam, The Netherlands Diaa Othman Dr. Sulaiman Al Habib Takhassusi Hospital, Riyadh, Saudi Arabia Nydia Ivette Paredes Amenábar Orthodontist and Pediatric Dentist Orthogt, Guatemala City, Guatemala Gary R. Parker Hospital Ship m/v Africa Mercy, Rotterdam, The Netherlands Cleidys Pereira Phonoaudiology Service of the Operation Smile Ecuador Foundation, Quito, Ecuador Tarek Raief Plastic Surgery, Plastic Surgery Department, Assiut University, Assiut, Egypt Mohamad Rachadian Ramadan Division of Plastic Surgery, Dr. Ciptomangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia Percy Rossell-Perry Plastic Surgeon Assistant from Plastic Surgery Service, E. Rebagliati Martins Hospital ESSALUD, Lima, Peru Paymon Sanati-Mehrizy Plastic and Reconstructive Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA Domenico Scopelliti Maxillofacial Surgery Department, San Filippo Neri Hospital – Smile House Roma San Filippo Neri Hospital, Rome, Italy Farooq Shahzad Plastic Surgery, Memorial Sloan-Kettering Cancer Center, Weill Medical College of Cornell University, New York, NY, USA Amina Asif Siddiqui College of Speech Language & Hearing Sciences, Ziauddin University, Karachi, Pakistan Muhammad Sohail Division of Plastic Surgery, King Edward Medical University, Lahore, Pakistan Mehtab A. Solangi Department of plastics, reconstructive & hand surgery, Liaquat National Hospital, Karachi, Pakistan Gentur Sudjatmiko Division of Plastic Surgery, Dr. Ciptomangunkusumo Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia

Contributors

Contributors

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Jordan W. Swanson The Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA, USA Cleft and Craniofacial Program, Children’s Hospital of Philadelphia, Philadelphia, PA, USA Ahmed Taha Plastic Surgery, Plastic Surgery Department, Al-Azhar University, Cairo, Egypt Tahmeedullah Plastic and Reconstructive Surgery, Burn and Plastic Surgery Center, Peshawar, Pakistan Moazzam Nazeer Tarar Jinnah Burn & Reconstructive Surgery Centre, Allama Iqbal Medical College, Lahore, Pakistan Yoshiko Toyoda The Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, PA, USA Marvee Turk Department of Plastic Surgery, University of South California, Los Angeles, USA Divya Narain Upadhyaya Department of Plastic and Reconstructive Surgery, King George’s Medical University, Lucknow, India Aaron C. Van Slyke Department of Plastic and Maxillofacial Surgery, Royal Children’s Hospital, Melbourne, VIC, Australia Adrián Villalba Egas Anesthesiologist, Hospital Hernán Henríquez Aravena, Temuco, Chile Nicholas Webster Department of Surgery, Division of Plastic Surgery, Baylor Scott and White Health, Temple, TX, USA Peter D. Witt Pediatric Plastic Surgery, Valley Children’s Hospital, Madera County, CA, USA Xiaoqian Ye Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA Zafar Hussain Consultant Anesthesiologist, Services Institute of Medical Sciences & CLAPP Hospital, Lahore, Pakistan Abraham Zavala Department of Plastic and Reconstructive Surgery, Instituto Nacional de Salud del Niño – San Borja, Lima, Peru Muhammad Bin Zulfiqar Radiology SIMS/Alnoor Institute of Radiology (Alnoor Diagnostic Centre), Lahore, Pakistan

Part I Basics of Cleft Palate

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Anatomy of the Normal Palate Muhammad Ashraf Ganatra and Diaa Othman

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Anatomy of the Hard Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Anatomy of the Soft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Blood Supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Innervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 The Muscles of the Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Abstract

Craniofacial anomalies, in particular cleft lip and/or palate, are major human birth defects with a worldwide frequency of 1 in 700, and significant clinical sequelae. The normal palate is composed of the hard and soft palates and divides the oropharynx and nasopharynx. Development of the palate is the result of organized events at the cellular level, influenced by growth factors, receptors, and signaling pathways playing an important role in the growth, elevation, and fusion of the palatal shelves. Cleft palate results from failed midline fusion of these paired palatine shelves. Embryologic errors of formation leading to cleft palate include inadequate growth of the palatine shelves (e.g., failed neural crest cell migration), failed shelf elevation and fusion, and secondary degradation after fusion. This chapter reviews the normal palate M. A. Ganatra Plastic Surgery Department, Dow University of health Sciences, Karachi, Pakistan D. Othman (*) Dr. Sulaiman Al Habib Takhassusi Hospital, Riyadh, Saudi Arabia e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2022 G. Q. Fayyaz (ed.), Surgical Atlas of Cleft Palate and Palatal Fistulae, https://doi.org/10.1007/978-981-15-8124-3_2

development, with the relevant palatal embryology, anatomy, and physiology, with illustrative figures to enhance the understanding of its normal development and pathogenesis.

Introduction Isolated cleft lip (CL) comprises about 25% of all clefts, isolated cleft palate (CP) is around 30% while combined cleft lip and palate (CL/P) cases account for about 45% of all cleft cases (Allam and Stone 2014). CL/P occurs more frequently and more severe in boys than in girls. Unilateral clefts are more common than bilateral clefts with a ratio of 4: 1, and for unilateral clefts, about 70% occur on the left side of the face (Allam and Stone 2014). CL/P is frequently associated with other developmental abnormalities, and majority of cases are presented as part of a syndrome. Syndromic clefts account for about 50% of the total cases in some reports with about 300 syndromes described. Although the percentage of cases directly linked to genetic factors is estimated to be about 40%, all clefts appear to show a familial tendency. It 3

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affects around 1.5 per 1,000 live births (about 220,000 new cases per year), with wide variation across geographic areas and ethnic groups, with substantial evidence of both health inequality and inequity (IPDTOC Working Group 2011; Mossey et al. 2011).

Anatomy The palate forms the roof of the mouth and floor of the nasal cavities. It separates oral cavity from nasal cavity, paired maxillary sinuses as well as with nasopharynx. It consists of two portions, the hard palate in front, and the soft palate behind (Fig. 1). The superior (nasal) surface of the palate is covered with respiratory mucosa, and the inferior (oral) surface is covered with oral mucosa, densely packed with glands. The normal palate divides the oropharynx and nasopharynx and is composed of the hard and soft palates (Allam and Stone 2014).

Embryology Normal lip development occurs between weeks 4 and 8 of gestation. The mesoderm involved in facial development is believed to be a separate tissue similar to the primary germ cell types and of ectodermal origin. This specialized tissue begins to differentiate on or about day 21 of gestation as the ectoderm in the vicinity of the neural plate folds on itself to form the neural tube. Embryo is roughly 3 mm long. As the neural tube takes shape, neural crest cells differentiate from the ectoderm and effectively separate the neuroectoderm of the neural tube from the covering cutaneous ectoderm. These special neural crest cells, although of ectodermal origin, exhibit most of the properties associated

Fig. 1 (a, b) General outline of oral cavity

M. A. Ganatra and D. Othman

with mesenchyme, so that the tissue they form is termed “ectomesenchyme” (Fig. 2). The normal hard palate is covered with a dense mucous membrane that adheres closely to the underlying periosteum, creating a mucoperiosteal covering of the oral bony surface (Aalst et al. 2008). The mucosa of the hard palate is tightly bound to the underlying bone; consequently, submucous injections here are extremely painful. The superior lingual gingiva, the part of the gingiva covering the lingual surface of the teeth and the alveolar process, is continuous with the mucosa of the palate; therefore, injection of an anesthetic agent into the gingiva of a tooth anesthetizes the adjacent palatal mucosa (Moore et al. 2014). Deep to the mucosa, are mucus-secreting palatine glands. The openings of the ducts of these glands give the palatine mucosa a pitted (orange-peel) appearance. In the midline, posterior to the maxillary incisor teeth, is the incisive papilla. This elevation of the mucosa lies directly anterior to the underlying incisive fossa. Radiating laterally from the incisive papilla, are several parallel transverse palatine folds or rugae. These folds assist with manipulation of food during mastication. Passing posteriorly in the midline of the palate from the incisive papilla is a narrow whitish streak, the palatine raphe. It may present as a ridge anteriorly and a groove posteriorly. The palatine raphe marks the site of fusion of the embryonic palatal processes (palatal shelves) which can be felt with the tongue (Moore et al. 2014). The ectomesenchyme migrates along the natural cleavage planes between the mesoderm, ectoderm, and endoderm. In migration from their site of formation, the neural crest cells have no predetermined pattern of travel. The migration of this ectomesenchyme over and around the head is essential to the development of the facial processes (Fig. 2a, b, c, d, e, f). By the end of week 4, the frontonasal prominence is formed from migrating neural crest cells of the first pharyngeal arch. Nasal

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Fig. 2 (a–f) Different stages of development of palate

placodes, representing ectodermal thickening, develop at the caudal end of this structure and divide the paired medial and lateral nasal processes. The primary palate forms from the fusion of the paired medial nasal processes by week 6, giving rise to the premaxilla: central upper lip, maxillary alveolar arch and four incisor teeth, and hard palate anterior to the incisive foramen. The secondary palate develops after the primary palate during weeks 6–12. The medial projections of the maxillary processes form palatal shelves which rise above the tongue, fusing medially at the midline, anteriorly with the primary palate, and superiorly with the septum. The incisive foramen marks the anterior extent of the secondary palate. Formation of the primary and secondary palates completes the separation of nasal and oral cavities, permitting simultaneous respiration, and mastication.

Development Normal development occurs sequentially; thus, cleft lip may or may not be associated with cleft palate. Similarly, isolated cleft palate may arise independently of cleft lip. Deformities of the lip, palate, and nose are a result of the disruption of normal development. The severity is dictated by the timing, the severity of the insult, and amount of disruption.

Anatomy of the Hard Palate The hard palate maintains the width and anterior projection of the maxillofacial architecture, whereas the soft palate works as an active muscular valve, referred to as the velopharyngeal sphincter (Marks and Marks 1997; Aalst et al. 2008). This sphincter raises the soft palate toward the posterior pharyngeal wall, dynamically separating the nose from the mouth.

The soft palate’s intrinsic muscular function aids in proper breathing, swallowing, blowing, and phonation. Five pairs of muscles constitute the soft palate: the levator veli palatini (LVP), tensor veli palatini (TVP), mucularis uvulas (MU), palatopharyngeus (PP), and palatoglossus (PG) muscles (Strong and Buckmiller 2001; Aalst et al. 2008). The primary palate includes all structures anterior to the incisive foramen (the premaxilla), whereas the secondary palate includes the hard palate, posterior to the incisive foramen, along with the soft palate. The muscular soft palate (velum) is found posterior to the hard palate (Friedman et al. 2005). Hard palate is bounded in front and at the sides by the alveolar arches and gums; behind, it is continuous with the soft palate. It is concave in order to accommodate the tongue when at rest. Hard palate is made up of two types of bones. Anterior two-thirds consist of palatine process of maxilla and posterior one-third consists of horizontal plate and pyramidal process of palatine bone, and they represent the posterior edge of the hard palate. Incisive foramen, greater palatine foramen, and lesser palatine foramen are present on the oral surface of the hard plate (Fig. 3). Incisive foramen is a slight depression behind the central incisor teeth. Nasopalatine nerves pass from the nose into the palate from this foramen. Greater palatine foramen is present medial to the third molar tooth at the lateral border of the hard palate. Greater palatine artery emerges from this foramen and is the main supply of mucoperiosteal flap raised for palate repair. Lesser palatine foramen is posterior to greater palatine foramen and pierces the pyramidal process of palatine bone. These foramina transmit the lesser palatine nerves and vessels to the soft palate and adjacent structures (Moore et al. 2014). Nerve supply of the palate is by greater palatine nerve which is a branch of third division of the trigeminal nerve,

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M. A. Ganatra and D. Othman

Fig. 3 Bony framework of the palate

Fig. 4 Soft palate

that is, maxillary division. After arising from maxillary division, it passes through sphenopalatine ganglion and emerges with artery from greater palatine foramen. Hard palate is covered by a dense structure, formed by the periosteum and mucous membrane of the mouth, which are intimately adherent. Along the middle line is a linear raphe. It is covered with stratified squamous epithelium, and furnished with numerous palatal glands, which lie between the mucous membrane and the surface of the bone.

Anatomy of the Soft Palate The other name of soft palate is “Velum.” The soft palate is a movable fold of posterior one-third of the palate, suspended from the posterior border of the hard palate. It forms an incomplete septum between the mouth and pharynx (Fig. 4). Soft palate has no bony skeleton. It consists of two surfaces, oral and nasal. The mucous membrane on oral side

consists of stratified squamous epithelium and on nasal side consists of columnar ciliated epithelium. It is made up of anterior aponeurotic layer and posterior muscular layer. When occupying its usual position, i.e., relaxed and pendent (hanging down), its anterior surface is concave, continuous with the roof of the mouth, and marked by a median raphe. Its posterior surface is convex and continuous with the mucous membrane covering the floor of the nasal cavities. Its upper border is attached to the posterior margin of the hard palate, and its sides are blended with the pharynx. Its lower border is free. The soft palate is the movable posterior third of the palate and is suspended from the posterior border of the hard palate. Its anterior aponeurotic part is strengthened by the palatine aponeurosis, which attaches to the posterior edge of the hard palate. The aponeurosis is thick anteriorly and thin posteriorly, where it blends with a posterior muscular part. Posteroinferiorly, hanging from the middle of its lower border is a small, conical, pendulous process called uvula, and arching

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Anatomy of the Normal Palate

lateralward and downward from the base of the uvula on either side are two curved folds of mucous membrane, containing muscular fibers, called the Palatoglossal (PG) and Palatopharyngeal (PP) arches. When a person swallows, the soft palate initially is tensed to allow the tongue to press against it, squeezing the bolus of food to the back of the mouth. The soft palate is then elevated posteriorly and superiorly against the wall of the pharynx, thereby preventing passage of food into the nasal cavity. Laterally, the soft palate is continuous with the wall of the pharynx and is joined to the tongue and pharynx by the PG and PP arches, respectively. A few taste buds are located in the epithelium covering the oral surface of the soft palate, the posterior wall of the oropharynx, and the epiglottis. The isthmus of the fauces is the short-constricted space that establishes the connection between the oral cavity proper and oropharynx. The isthmus is bounded anteriorly by the palatoglossal folds and posteriorly by the palatopharyngeal folds. The palatine tonsils, often referred to as “the tonsils,” are masses of lymphoid tissue, one on each side of the oropharynx. Each tonsil is in a tonsillar sinus (fossa), bounded by the palatoglossal and palatopharyngeal arches and the tongue (Moore et al. 2014).

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Veins of the palate are tributaries of the pterygoid venous plexus which converge on its anterior end, to form the maxillary vein which then drains into retromandibular vein.

Innervation The sensory nerves of the palate are branches of the maxillary nerve (CNV2), which branch from the pterygopalatine ganglion (Moore et al. 2014). The greater palatine nerve supplies the gingivae, mucous membrane, and glands of most of the hard palate. The nasopalatine nerve supplies the mucous membrane of the anterior part of the hard palate, whereas the lesser palatine nerves supply the soft palate. The palatine nerves accompany the arteries through the greater and lesser palatine foramina, respectively. All muscles of the soft palate (derived from the fourth branchial arch) are supplied through the pharyngeal plexus of nerves formed by the Glossopharyngeal nerve (CN 9) and vagus nerve (CN 10), except for the TVP (derived from the first branchial arch) which is supplied by medial pterygoid nerve, a branch of the mandibular nerve (CN 3) (Moore et al. 2014).

The Muscles of the Palate Blood Supply There are five muscles in the soft palate (Figs. 7 and 8): The palate has a rich blood supply, chiefly from the greater palatine artery on each side, a branch of the descending palatine artery, which is a branch of internal maxillary artery (Figs. 5 and 6). The greater palatine neurovascular bundles emerge from the palatine canals; the artery is located between mucoperiosteum and bone, along the posterolateral edge of the hard palate. The greater palatine artery passes through the greater palatine foramen and runs anteromedially. The lesser palatine artery, a smaller branch of the descending palatine artery, enters the palate through the lesser palatine foramen. Ascending palatine artery, a branch of the facial artery (Moore et al. 2014), travels along the levator muscles into the soft palate and then anastomoses with lesser palatine artery. Fig. 5 Blood and nerve supply of the palate

1. 2. 3. 4. 5.

Tensor veli palatini (TVP) Levator veli palatini (LVP) PalatogGlossus (PG) PalatoPharyngeus (PP) Musculus Uvulae (MU)

The TVP and LVP both originate from the eustachian tube and constitute the key anatomical landmarks of the palate repair. Both TVP muscles originate from the medial pterygoid plate and become tendinous as they wrap laterally around the pterygoid hamulus before ultimately inserting medially into the soft palatal aponeurosis near the junction

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of the soft and hard palates, occupying the anterior 25% of the velum. Consequently, they play a key role in aerating the middle ear, and their dysfunction results in recurrent otitis media (Mesa et al. 2019). On the other hand, both LVP muscles originate from the petrous portion of the temporal bone at the skull base and from the medial lamina of the cartilage of the auditory tube, coursing inferomedially, and interdigitating at the midline to form the bulk of the anterior portion of the “levator sling,”

Fig. 6 Normal blood supply of the palate: 1. branches from infraorbital artery; 2. superior alveolar artery; 3. branches from superior labial artery; 4. anterior palatine artery; 5. greater palatine artery; 6. descending palatine artery; 7. ascending palatine artery. (a) Vascular anastomosis between descending palatine artery and ascending palatine artery through lesser palatine vessels. (b) Vascular anastomoses between greater palatine artery and anterior palatine artery Fig. 7 Muscles of the soft palate

M. A. Ganatra and D. Othman

with their contraction causing the soft palate to move superiorly and posteriorly, contacting the posterior pharyngeal wall for velar closure, usually at the level of the adenoid pad, with this action forming the characteristic “genu” seen on lateral views of the palate in motion (Strong and Buckmiller 2001; Aalst et al. 2008). The palatoglossus is a small fleshy fasciculus, narrower in the middle than at either end, forms anterior tonsillar pillar with the mucous membrane covering its surface. It arises from the anterior surface of the soft palate, where it is continuous with the muscle of the opposite side, and passing downward, forward, and lateralward in front of the palatine tonsil, is inserted into the side of the tongue, some of its fibers spreading over the dorsum, and others passing deeply into the substance of the tongue to intermingle with the transversus linguæ. Palatopharyngeus is a longitudinal muscle which extends from the palate to the pharynx. It belongs to both the soft palate and pharyngeal muscle groups. PalatoPharyngeus (PP) muscle arises from the posterior border of the hard palate and palatine aponeurosis. The levator veli palatini muscle divides PP into anterior and posterior layers, which intermingle with each other to form a compact muscle belly at the posterolateral border of the soft palate. The muscle then goes posterolaterally along the pharyngeal wall, to form the palatopharyngeal arch. In the oropharynx, the muscle fibers, then, insert to the posterior border of thyroid cartilage, while some cross the midline and blend with fibers of the contralateral palatopharyngeus muscle. Palatopharyngeus muscle helps in deglutition as it shortens the pharynx by elevating it superiorly, anteriorly, and medially, so as to close the laryngeal airway and prevent aspiration of food. The posterior layer of palatopharyngeus and superior constrictor of the pharynx contract together to form the palatopharyngeal sphincter (Passavant’s muscle). This sphincter seals the nasopharynx during swallowing, thus

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Fig. 8 Another way of depicting the muscles of the soft palate

preventing food from passing, from the oropharynx into the nasopharynx. The musculus uvulae (MU) arises from the posterior nasal spine of the palatine bones and from the palatine aponeurosis. It then courses posteriorly along with the musculus uvula from the opposite side and inserted into the uvula (Friedman et al. 2005). The normal soft palate may be divided into three sections: anterior 25%, middle 50%, and posterior 25%. • The anterior 25% of the soft palate is relatively static. • In the normal palate, the levator forms a muscular sling that facilitates a cranial, posterior, and lateral pull on the soft palate during velopharyngeal closure. In the normal state, the levator muscles take a transverse course, running horizontally within the middle 50% of the velum. • The PG, PP, and U muscles compose the posterior 25% of the soft palate. The submucous cleft palate presents with classic triad of bifid uvula, midline notching of the posterior hard palate, and diastasis of the velar musculature (Fisher and Sommerlad 2011). Sommerlad et al. (2004) have described a scoring system to further describe the spectrum of submucous cleft palate.

References Aalst J et al (2008) MOC-PSSM CME article: nonsyndromic cleft palate. PRS J 121(1):1–14 Allam and Stone (2014) Cleft lip and palate: etiology, epidemiology, preventive and intervention strategies. Anat Physiol 4:3 Fisher D, Summerlad B (2011) Cleft lip, cleft palate, and velopharyngeal insufficiency. Plast Reconstr Surg 128(4):342e–360e Friedman O, Wang TD, Milczuk HA (2005) Cleft lip and palate. In: Cummings CW (ed) Otolaryngology: head and neck surgery. Saunders Elsevier, Philadelphia, pp 4052–4082 IPDTOC Working Group (2011) Prevalence at birth of cleft lip with or without cleft palate: data from the International Perinatal Database of Typical Oral Clefts (IPDTOC). Cleft Palate Craniofac J 48:66–81 Marks MW, Marks C (1997) Cleft lip and palate. In: Fundamentals of plastic surgery. Saunders, Philadelphia, p 156 Mesa J et al (2019) Atlas of operative craniofacial surgery. Thieme Medical Publishers, Inc. Lippincott Williams and Wilkins Moore K et al (2014) Moore clinically oriented anatomy, 7th edn. Lippincott Williams and Wilkins Mossey PA, Shaw WC, Munger RG, Murray JC, Murthy J et al (2011) Global oral health inequalities: challenges in the prevention and management of orofacial clefts and potential solutions. Adv Dent Res 23:247–258 Sommerlad BC, Fenn C, Harland K et al (2004) Submucous cleft palate: a system of grading and a review of a consecutive series of 40 submucous cleft palate repairs. Cleft Palate Craniofac J 2004(41):114–123 Strong EB, Buckmiller LM (2001) Management of the cleft palate. Facial Plast Surg Clin North Am 9(15):2001

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Anatomy of Cleft Palate Muhammad Sohail and Muhammad Mustehsan Bashir

Contents Anatomy of Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Submucous Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Abstract

A gap, split, or defect in the midline of roof of mouth communicating both oral and nasal cavities at birth is referred to as cleft palate. Many genetic factors and environmental teratogens (maternal usage of corticosteroids, tretenoins, alcohol, anticonvulsants, and smoking during pregnancy) are assumed to be linked with development of cleft palate (LaRossa et al. 2010; Dixon 2011; Kosowski et al. 2012; Leslie and Marazita 2013). It is categorized as anterior and posterior cleft palate depending upon lack of fusion anterior or posterior to incisive foramen. Cleft of posterior palate may also present as bifid uvula, cleft of soft palate, and cleft of soft and hard palate. A complete cleft involves both anterior and posterior palate. Patients of cleft palate may present with difficulty in feeding coupled with reflux of food through the nose. Babies are often malnourished as they are unable to suck milk adequately. If not repaired timely, child will M. Sohail (*) Division of Plastic Surgery, King Edward Medical University, Lahore, Pakistan e-mail: [email protected] M. M. Bashir Division of Plastic Surgery, King Edward Medical University, Lahore, Pakistan FCPS Surgery; FCPS Plastic Surgery; PhD Plastic Surgery, Kind Edward Medical University, Lahore, Pakistan e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2022 G. Q. Fayyaz (ed.), Surgical Atlas of Cleft Palate and Palatal Fistulae, https://doi.org/10.1007/978-981-15-8124-3_3

develop delayed and improper speech, recurrent ear infection, and dental problems.

Anatomy of Cleft Palate Cleft palate refers to a gap, split, or defect in the midline of roof of mouth between the oral and nasal cavities. Following cardiac anomalies, cleft palate is the major cause of congenital deformities (LaRossa et al. 2010). Prevalence of cleft palate is observed to differ between different populations. Many genetic factors and environmental teratogens (maternal usage of corticosteroids, tretenoins, alcohol, anticonvulsants, and smoking during pregnancy) are assumed to be linked with development of cleft palate (LaRossa et al. 2010; Kosowski et al. 2012; Leslie and Marazita 2013). Cleft palate may manifest as a part of syndromes resulting from chromosomal abnormalities, for instance velocardiofacial syndrome, stickler syndrome, and Van der Woude syndrome (Venkatesh 2009). Gestational development of palate starts during the 4th week and the two medial nasal prominences fuse together to form median palatine process. Around 6th week the lateral palatal process outgrows from the maxillary prominence. Fusion of median palatine process with both lateral palatine processes form the anterior (primary) palate whereas fusion of two lateral palatine processes together forms the posterior (secondary) palate. Halt in the process of fusion may occur

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due to lack of mesenchymal delivery and proliferation leading to cleft of palate (Hopper et al. 2007; Weissler et al. 2016). Traditionally in literature the cleft palate is categorized embryologically with reference to the incisive foramen into primary and secondary cleft palate (Odunze 2020; Allori et al. 2017). However, the terms primary and secondary confound with preoperative and postoperative cases and here the terms anterior and posterior are used for clarity. The various types of palatal clefts are categorized as follows: 1. Cleft of the anterior palate It manifests as gap in the midline of the roof of the mouth starting anterior to incisive foramen. The condition occurs due to failure of fusion between the median palatine process (formed by fusion of medial nasal prominences) and the lateral palatine processes (of maxillary prominences) anterior to incisive foramen. In isolated cleft of anterior palate, the two lateral palatine processes posterior to incisive foramen completely fuse with each other. It is always associated with cleft of the lip, and infants are brought with disfigured face with either unilateral or bilateral cleft determined by lack of fusion on one or both sides (Fig. 1a, b). 2. Cleft of the posterior palate (incomplete cleft palate) The cleft presents as gap in the midline of the roof of the mouth posterior to incisive foramen. It occurs due to arrest of fusion between the two lateral palatine processes of the maxillary prominences posterior to the incisive foramen. Commencing from uvula, it may remain limited to soft palate or may reach the incisive foramen. Furthermore it is observed that in isolated cleft of posterior palate the alveolar arch remain normal as it lies anterior to incisive foramen. The vascularity of palate in these cases is derived mainly from greater and lesser palatine arteries, branches of descending palatine artery which is branch of maxillary artery. The ascending palatine artery (branch of facial artery) also supplies the palate and forms anastomosis with lesser palatine artery. Branches from superior alveolar artery, superior labial artery, and anterior palatine artery also supply anterior palate (Rossell-Perry 2015) (Fig. 4a). Patients with cleft of posterior palate presents with more functional problems than esthetic. Posterior or incomplete cleft palate is further subclassified into various types depending upon the length of arrest of fusion, which are as follows: I. Bifid Uvula: also called cleft uvula, usually present as a small asymptomatic notch or split of the uvula. It is mostly found incidentally and represents an underlying submucous cleft palate (Fig. 2a, b). II. Cleft of Soft Palate: such cases may show up as mild form in which the gap commences from the uvula and partly traverse into the soft palate or severe form with

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the gap in soft palate moving up to junction with hard palate. In these cases, the levator muscle fibers are maloriented and abnormally inserted into the hard palate. Patients with this variety of cleft presents with difficulty in feeding coupled with reflux of food through nose. Babies are often malnourished as they are unable to suck milk adequately. If not repaired timely, child will develop delayed and improper speech (Figs. 1c and 2c, d). III. Cleft of Soft and Hard Palate: This is seen as a gap in the mid line of palate which commences at uvula, traverses the entire soft palate, and involves part of the hard palate that may or may not reach up to the incisive foramen. The maloriented Levator muscle fibers in this variety are also abnormally attached to posterior border of hard palate. Such cases also present as undernourished infants with compromised feeding and will develop speech defects if not operated timely. It is further observed that babies born with palatine clefts are more prone to develop respiratory tract infections and aspiration pneumonia. Depending upon arrest of fusion on one or both sides the patient will have unilateral or bilateral cleft. Furthermore the bilateral involvement may appear symmetric or asymmetric (Figs. 1d and 2e–g). 3. Cleft of anterior and posterior palate (complete cleft palate) This variety of cleft is noticed as gap in the roof of mouth traversing complete length of anterior and posterior palates. It occurred following arrest of fusion between the median palatine process and the lateral palatine processes both anterior and posterior to incisive foramen. Cleft commences at uvula, involves soft and hard palate, and extends into the alveolar ridge. It is always associated with cleft of lip. Patients are born with either unilateral or bilateral cleft associated with distorted face. Furthermore, the bilateral involvement may be symmetric (complete cleft on both sides) or asymmetric (complete cleft on one side and incomplete cleft on other side). Patients with this variety have both functional and aesthetic issues. They not only have difficulty in feeding but the appearance of face is also distorted. Those who were left untreated may develop recurrent ear infection leading to hearing loss, speech abnormalities, and also dental problems (Figs. 1e, f and 3). The vascular supply of complete cleft is shown in Fig. 4b, c (Rossell-Perry 2015).

Pierre Robin Sequence Infant with this condition presents as inverted U or horseshoe-shaped gap in midline of roof of palate. It is thought to result from mechanical obstruction in the process

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Fig. 1 Types of cleft palate. (a) Unilateral anterior cleft palate, (b) bilateral anterior cleft palate, (c) cleft of soft palate, (d) cleft of hard and soft palate, (e) complete unilateral cleft palate, (f) complete bilateral cleft palate. a Alveolus, H hard palate, S soft palate, P premaxilla

of fusion of paired lateral palatal processes. The mandibular hypoplasia coupled with glossoptosis is considered the cause of mechanical obstruction. Patients with severe involvement may present with airway compromise requiring immediate management. Repair of the palate in such cases is often performed somewhat late.

Submucous Cleft Palate It is a form of cleft palate which relatively appears intact. However, there is lack of fusion of levator muscle fibers and bones in the roof of mouth under the transparent intact

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Fig. 2 Types of incomplete cleft palate. (a) Bifid uvula, (b) mild form of cleft soft palate, (c) cleft soft palate reaching up to the junction of soft and hard palate, (d) cleft palate extending to hard palate, (e) cleft palate involving posterior half of hard palate, (f) cleft palate extending to

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incisive foramen, (g) incomplete asymmetric cleft palate. Right side is limited to posterior part of hard palate while left side extending to incisive foramen

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Fig. 3 Types of complete cleft palate (involving both anterior and posterior palate). (a) Unilateral complete cleft palate and lip. (b) Bilateral complete cleft palate and lip

mucosa (zona pellucida). It is defined as triad of deformities which include (1) bony defect manifesting as notch in hard palate, (2) muscular deficit in the soft palate with normal looking intact mucosa, and (3) bifid uvula. Majority of patients with this condition usually remain asymptomatic with around 15% developing abnormal speech. Further details will be discussed in relevant section (Geneser and Allareddy 2019).

Summary Babies born with cleft palate may present with variety of clefts of the palate and often are undernourished infants due to compromised feeding. Proper knowledge of anatomy and timely management will help to manage feeding, speech, hearing, and dental problems.

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Fig. 4 Vascular anatomy of cleft palate

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Anatomy of Cleft Palate

References Allori AC, Mulliken JB, Meara JG, Shusterman S, Marcus JR (2017) Classification of cleft lip/palate: then and now. Cleft Palate Craniofac J 54(2):175–188 Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011) Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 12(3):167 Geneser MK, Allareddy V (2019) Cleft lip and palate. Pediatr Dent 22: 77–87 Hopper RA, Cutting C, Grayson B (2007) Cleft lip and palate. In: Grabb and Smith’s plastic surgery, 6th edn. Lippincott Williams and Wilkins, Philadelphia, p 201 Kosowski TR, Weathers WM, Wolfswinkel EM, Ridgway EB (2012) Cleft palate. Semin Plast Surg 26:164–169

17 LaRossa D, Randall P, Cohen MA, Afifi GY (2010) Cleft palate. In: Plastic surgery secrets plus. Mosby, St. Louis, pp 151–156 Leslie EJ, Marazita ML (2013) Genetics of cleft lip and cleft palate. Am J Med Genet C Semin Med Genet 163(4):246–258 Odunze M (2020) Different types of cleft palates. https://www. verywellhealth.com/what-is-a-cleft-palate-2709801. Updated 3 Apr 2019, medically reviewed by William Truswell, MD on 3 Aug Rossell-Perry P (2015) Flap necrosis after palatoplasty in patients with cleft palate. Biomed Res Int 2015:Article ID 516375. 14 pages. https://doi.org/10.1155/2015/516375 Venkatesh R (2009) Syndromes and anomalies associated with cleft. Indian J Plast Surg 42(Suppl):S51 Weissler EH, Paine KM, Ahmed MK, Taub PJ (2016) Alveolar bone grafting and cleft lip and palate: a review. Plast Reconstr Surg 138 (6):1287–1295

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Physiology of Normal Palate Amina Asif Siddiqui

Contents Brief Clinical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Introduction to Physiology of the Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Phonological Development or the Development of Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 The Physiology of Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Structure of the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology of the Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Respiration, Phonation, Resonance, and Articulation of Speech Sounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Production of Vowels in Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Production of Consonants in Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Abstract

It is essential to understand the physiology of the palate before discussing any pathological condition, which in this case is the congenital malformation of the hard and/or soft palate within the mouth. The palate is also known as the roof of the mouth or the oral cavity. It separates the nose or nasal cavity from the mouth. In the front and on both sides, the hard palate is lined by teeth; it extends at the back as a soft movable muscular potion, called the soft palate or velum, that ends in a short dangling uvula. The palate plays a crucial role in both eating and drinking as well as in the production of speech. A structural deformity of the palate, known as cleft palate, can cause a deviancy or impairment in its functioning, manifest as a difficulty in eating and/or swallowing of food and liquid, as well as trouble in speaking clearly. This chapter sheds light on the importance of the shape, size, and appearance of the hard and soft palate, for optimal performance along with other structures for the functions of speech, feeding, and swallowing. A. A. Siddiqui (*) College of Speech Language & Hearing Sciences, Ziauddin University, Karachi, Pakistan e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2022 G. Q. Fayyaz (ed.), Surgical Atlas of Cleft Palate and Palatal Fistulae, https://doi.org/10.1007/978-981-15-8124-3_4

Brief Clinical History Amina Siddiqui has been a practicing speech and language therapist in Karachi, Pakistan, for nearly the last three decades. Her interest lies in the acquisition of speech and language and its stages in the development of young children. This draws her towards working with children having a congenital cleft palate. Amina also works with children and adults having speech, language, feeding and swallowing disorders of neurogenic origin.

Introduction to Physiology of the Palate The mouth or oral cavity has a dual function of feeding and swallowing (Matsuo and Palmer 2008). Since birth, the newborn baby suckles for milk at the mother’s breast reflexively (Batacan 2010). As the baby grows older, they acquire the ability to eat and swallow different textures and consistencies of food and liquid with ease. The act of speech is superimposed on some of the same structures that are used for eating. A baby typically acquires the native language, and all the speech sounds used in it completely, around the age of 6 years, and is able to communicate verbally like an adult 19

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using the same language in the surroundings (Kuhl 2000). This period is also known as the age of speech and language maturation. The baby’s auditory apparatus must also function normally during this entire age range, as the auditory feedback loop plays the most significant role in the acquisition of receptive and expressive verbal communication skills (Pallier et al. 1997). The critical period for speech and language acquisition is birth to 3 years, when there is maximal development of the baby’s neurological system (Kuhl et al. 2005). Verbal communication is a characteristically distinctive human ability. We always speak on an exhaled airstream (Pešák 1990). The vocal chords in the larynx vibrate along the exhaled airstream for the production of voice, or phonation. As the vocal column arises out, it resonates in the oral and nasal cavities. The size and shape of the two cavities is determined by the position of the articulators within, and the type and extent of closure formed by any two articulators together, during speech production. This closure determines the manner in which the column of the exhaled air stream must exit during speech production (Hixon et al. 2018).

Phonological Development or the Development of Speech During the critical period for speech and language development in human babies, we see the rapid development of cognitive skills of attention, memory, perception, and judgment (Levinson and Bowerman 2001). Metalinguistic and metaphonological skills are crucial to the development of language and speech, respectively, as the child is able to match his own utterances to those of others around him, through his auditory feedback loop, and naturally correct his errors (Wasserman 2007), thus having adult like communication skills around the age of 6 years, which also marks the end of early childhood. Normal speech, hearing, and a neurological apparatus are crucial along with a healthy and stimulating environment for the development of typical verbal communication skills in children. (Macias and Twyman 2011). Babies naturally make several typical errors in their spoken utterances as they progress toward speech and language maturation. These are called natural processes or phonological processes (Archibald 2014), universally, among all languages spoken around the world. Any impairment or disorders in the ability to communicate verbally can be detrimental to the child’s academic and vocational careers in later life (Im-Bolter and Cohen 2007).

The Physiology of Speech Human beings use the oral cavity for both functions of speech and eating. This twofold function warrants optimal structure and movement of the entire oral motor mechanism to

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correctly perform the acts of biting, chewing, sucking, sipping, and swallowing, as well as speaking and even blowing. These functions encompass phonation, articulation of speech sounds, and respiratory functions as well as oral and nasal resonance. Speech is produced on the expiratory airstream (Dromey and Ramig 1998). Sounds produced during speech can be classified under the categories of vowels and consonants.

Structure of the Oral Cavity In the oral cavity or mouth, we have the bony hard palate which is immobile, with the teeth lining the upper jaw semicircularly, extending symmetrically from the midline on each side. The alveolar ridge is the narrow bump at the anterior of the hard palate just behind the upper front maxillary teeth. Anterior two-thirds of the palate is bony and hard, arching in the middle, and continuing as the soft palate posteriorly. Also known as the velum, the soft palate is soft, muscular, and mobile ending with the short, elongated dangling piece of tissue called uvula hanging at the posterior end (Mueller and Callanan 2007). The nasal cavity opens into the posterior part of the mouth when the velum is hanging downward, at rest. This connection between the nose and mouth, called the velopharyngeal port, remains open as it is the airway for breathing. It can be transiently blocked or closed by the upward and backward movement of the velum toward the pharyngeal walls forming a velopharyngeal closure (Dickson and Dickson 1972). The palatopharyngeal and palatoglossal arches extend from the soft palate on either sides within the mouth, posteriorly, and symmetrically (Rubesin et al. 1987). Anteriorly, the mouth closes with the coming together of the lower lip in the movable lower jaw or mandible with the upper lip in the stationary upper jaw. The lateral inner walls of our oral cavity are our left and right cheeks. The very soft, flexible, and mobile muscular structure called the tongue lies on the floor of the mouth. The lower jaw or mandible is mobile and is lined by the teeth in a similar symmetrical semicircular shape that just fits snugly with the teeth in the upper jaw (Green et al. 2002).

Physiology of the Palate One of the important functions of the palate is to separate the nasal and oral cavity from one another, during the acts of eating and speaking (Hiiemae and Palmer 2003). Each cavity performs its respective jobs of breathing, and the very complex tasks of eating (biting, cutting, crushing, chewing, sucking, sipping, and licking) as well as swallowing of food, or liquid independently. This separation is also very essential for the prevention of upper respiratory tract infections, because the nose, mouth, throat, and ears are connected to one another

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in close proximity through the eustachian tubes in the posterior part of the oral cavity, which open into the right and left middle ear chamber of the ears (Hickok 2001).

Respiration, Phonation, Resonance, and Articulation of Speech Sounds To understand phonation and resonance, one may consider the pharynx to be a three tiered chamber (Lin 1991). The lowest tier is that of the larngopharynx housing the vocal chords which vibrate to provide phonation or voice on the expiratory airstream that emerges from our lungs, when we speak. Above the laryngopharynx is the oropharynx housing the posterior and the lateral pharyngeal walls which establish a closure with the soft palate or velum as the latter moves upward and backward with a knee-like movement toward the posterior pharyngeal wall, with the simultaneous inward movements of the lateral pharyngeal walls preventing escape of the airstream into the topmost tier of the pharynx called nasopharynx. This allows the air to move into the oral cavity or mouth, for oral resonance. When we are breathing quietly, the velum remains in rest position and is hanging downward resting on the back of the tongue, and the air is allowed to move into the nasopharynx and the nasal cavity. This little region, known as the velopharyngeal port, and the velum along with the pharyngeal walls form the velopharyngeal valve. When the expiratory airstream moves out through the nasal cavity during speech production, it provides space for nasal resonance of speech sounds. The velopharyngeal valve is closed for oral sounds and opens for nasal sounds, as it controls the passage of air coming from the larynx into the appropriate cavity with the simultaneous production of resonance for audibility of the speech sounds in the utterance. Appropriate resonance during connected speech is thus Fig. 1 The oral cavity showing articulators for speech

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determined by the velopharyngeal competence (Wójcicki and Wójcicka 2008). The resonance in the pharyngeal (oropharyngeal and nasopharyngeal), oral, and nasal cavities varies with the size and shape of the cavities. Both, nasal or oral resonance, provide the unique characteristic or acoustic features to the speech of each human being, as perceived by their listeners (Wilhelms-Tricarico 1995). The speech mechanism, beginning from the lips to the vocal chords and extending below to the lungs (that provide the expiratory airstream for phonation), synchronously performs one of the most complex behaviors known as “articulation of speech” (Mermelstein 1973). During phonation, as the airstream ejects upward from the laryngeal vestibule toward the oropharynx, the velum must play the most important role of either opening the velopharyngeal port for passage of air through the nasopharynx and letting it into the nasal cavity and out through the nostrils as we would speak the consonants [m,n,ŋ], or keeping the nasopharynx closed by establishing a closure with the posterior and lateral pharyngeal walls, allowing the airstream only to be released via the oral cavity, as appropriate of all other consonants and vowels (Raphael et al. 2007). The articulators of speech namely the vocal chords in the larynx, the uvula, the soft and hard palate with the alveolar ridge and teeth as well as tongue in the oral cavity, and the lower jaw or mandible are all used for the production or articulation of speech sounds across the many languages spoken in the world. Only some of the articulators are moving ones such as the lower jaw, uvula, soft palate, tongue, lips, and vocal chords, while the hard palate, alveolar ridge, and teeth in the upper jaw do not move. The type of contact made between the articulators characterizes each consonant of a given language. The articulators make no contact with one another in the production of vowel sounds (see Fig. 1).

Upper lip Teeth in upper jaw Alveolar ridge Hard palate So palate Uvula Tongue Teeth in lower jaw Lower lip

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Speech sounds are produced with fine precision through the rapid, harmonious, and dexterously synchronized movements among the mobile, and immobile, articulators of speech (Hacioglu et al. 2004). The maxillary teeth are predominantly used for biting and cutting of food, and when the tongue articulates with them, several speech sounds among most languages spoken across the world can be produced, such as [t,d,s,z,ʃ,tʃ,dʒ,n] to list a few. The incisors, premolars, and molars are predominantly used for biting, crushing, and mastication of food, as well as for the production of a few speech sounds in some languages, for example, [l,ȴ]. The tongue and soft palate together produce sounds such as [k,ɡ], while the tongue and uvula produce [ɋ,ɡ,ɣ] and the lips together produce [p,b,m]. There arises the need of shutting the nasal cavity’s connection posteriorly with the oral cavity to provide passage to the exhaled air stream through the mouth, for all vowels and a majority of consonants within any language (Toro et al. 2008). This passage is required to remain open for those consonants which are spoken with the exhaled airstream being emitted through the nose, such as [n], [m], and [ŋ] which have a nasal quality (Ball and Muller 2014). The orally emitted airstream provides oral resonance in the mouth to the speech sounds being vocalized, while the nasally emitted airstream provides nasal resonance in the nose, to the vocalization (Smith and Kuehn 2007). This unique function of the soft palate and pharyngeal walls or velopharynx not only demarcates the boundaries of oral and nasal speech sounds but also gives a distinct vocal quality to every individual’s speech (Caramazza et al. 2000). There are several words that have a combination of oral and nasal sounds, which requires rapid changes in the status of the velopharyngeal closure (Peterson-Falzone et al. 2001).

Production of Vowels in Speech Vowels are characterized by phonation or laryngeal vibration, and an open vocal tract in which there is no obstruction created by any of the articulators coming together. However, the height or hump of the tongue in the mouth, and the rounding of lips, gives each vowel its typical acoustic features. They are categorized as close, mid, and open vowels and front, central, and back vowels, based upon the size of the oral cavity while speaking them, and height of the hump of the tongue within (Marchal 2010). Close vowels are produced with a high hump of the tongue and the mandible in a high position such as the vowels in the words bee, boot, bit and bell, bull, and ball. Open vowels are produced with tongue having a lower hump and the mandible in a lowered position such as in the words bar, bear, bud, and bad, bade, and aboard (see Fig. 2) (Ball 2010).

A. A. Siddiqui

Fig. 2 Placement of production of vowel sounds in the oral cavity

Production of Consonants in Speech Production of consonants partakes the obstruction of the expiratory airstream at different points in the vocal tract namely in the laryngeal, pharyngeal, and oral cavities categorizing them by characteristics of (a) voicing, (b) manner of articulation, and (c) place of articulation in the vocal tract (Vihman 1996). The expiratory airstream exits the oral cavity for most sounds in any given language. At this point, the velum is elevated to form a closure with the posterior and lateral pharyngeal walls, preventing the airstream to exit from the nose. The velum lies at rest when not in the elevated position. It also remains this way when we require the airstream to exit from the nose to produce nasal consonants such as in the word [name]. (a)Voicing Voiced consonants are consonants that involve vibration of vocal folds; they are /b,g,d,ɗ,v,n,m,ŋ, r,l,z,dz./. Voiceless consonants are consonants that involve no laryngeal vibration; they are /p,k,t,f,s,ʃ,Ɵ,tʃ/. (b)Manner of Articulation Manner of articulation for consonants characterizes them by the type of closure or obstruction of expiratory airstream in the vocal tract during sound production. Plosives are sounds produced with a sudden release or explosion of the oral airstream after being completely blocked behind the closure created by any two articulators. Some of the plosive sounds are /b,p,g,k,d,t, t,d,ţ,ɖ/. Fricatives are sounds released with partial obstruction of oral airstream, i.e., under friction. Some of the sounds are /s,z,ʃ/.

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Physiology of Normal Palate

Affricates are sounds that are completely obstructed at first, and then released under friction or partial obstruction of the oral airstream; they are /dʒ,tʃ, ɗ,Ɵ/. Laterals are sounds in which the oral air stream is released laterally (from either side of the tongue); they are /l/. Nasal sounds are those in which the airstream is released via the nose as the velum moves downward, creating a pathway for the nasal air stream and nasal resonance. The sounds are /n,m,ŋ/. (c)Place of Articulation The place of articulation of consonants characterizes them by the place of production of sound in the vocal tract. Most sounds are produced in the front part of the oral cavity, except the velars, uvulars, and glottal consonants. Bilabials are produced by the complete closure of lips together /m.b.p/. Labio-dentals are produced by the upper front teeth and the lips /f,v/. Linguo-dentals or inter-dentals are produced by the tongue and upper front teeth /ɗ,Ɵ, t,d/. Linguo-alveolars are produced by the tongue near the alveolar ridge /d,ţ,n,r,s,z,l/. Palatals or retroflex are produced by the tongue turning backward and the hard palate / t,ɖ,r/. Velar are sounds produced by the tongue at the velum /k,g, Υ,X/. Uvular are sounds produced by the tongue and the uvula / Ġ, ɋ/. Glottal sound produced at the glottis /h, Ɂ/. (International Phonetic Alphabet Chart Revised 2015; Available online https://www.internationalphone ticassociation.org/sites/default/files/IPA_Kiel_2015.pdf)

References Archibald J (2014) Phonological acquisition and phonological theory. Psychology Press Ball MJ (2010) “My client’s using non-English sounds! A tutorial in advanced phonetic transcription. Part 2: Vowels and diacritics,” contemporary issues In communication science and disorders; Volume 37, 103–110, Fall, NSSLHA, 1092-5171/10/3702-0103; ResearchGate. Available online on https://www.researchgate.net/ profile/Martin_Ball/publication/280245811_My_client%27s_ using_non-English_sounds_A_tutorial_in_advanced_phonetic_tran s c r i p t i o n _ P a r t _ 2 _ Vo w e l s _ a n d _ D i a c r i t i c s / l i n k s / 55af69ea08aee0799220ff63/My-clients-using-non-English-sounds-

23 A-tutorial-in-advanced-phonetic-transcription-Part-2-Vowels-andDiacritics.pdf?origin¼publication_detail Ball MJ, Muller N (2014) Phonetics for communication disorders. Psychology Press Batacan J (2010) A new approach: biological nurturing and laid-back breastfeeding. Int J Childbirth Educ 25(2):7 Dickson DR, Dickson WM (1972) Velopharyngeal anatomy. J Speech Hear Res 15(2):372–381 Dromey C, Ramig LO (1998) The effect of lung volume on selected phonatory and articulatory variables. J Speech Lang Hear Res 41 (3):491–502 Green JR, Moore CA, Reilly KJ (2002) The sequential development of jaw and lip control for speech. J Speech Lang Hear Res 45:66–79 Hacioglu K, Pellom B, Ward W (2004) Parsing speech into articulatory events. In: Proceedings of the 2004 IEEE international conference on acoustics, speech, and signal processing. IEEE, vol 1, pp 925–928 Hickok G (2001) Functional anatomy of speech perception and speech production: psycholinguistic implications. J Psycholinguist Res 30 (3):225–235 Hiiemae KM, Palmer JB (2003) Tongue movements in feeding and speech. Crit Rev Oral Biol Med 14(6):413–429 Hixon TJ, Weismer G, Hoit JD (2018) Preclinical speech science: anatomy, physiology, acoustics, and perception. Plural Publishing Im-Bolter N, Cohen NJ (2007) Language impairment and psychiatric comorbidities. Pediatr Clin N Am 54(3):525–542 Kuhl PK (2000) A new view of language acquisition. Proc Natl Acad Sci 97(22):11850–11857 Kuhl PK, Conboy BT, Padden D, Nelson T, Pruitt J (2005) Early speech perception and later language development: implications for the “critical period”. Lang Learn Dev 1(3–4):237–264 Levinson SC, Bowerman M (2001) Language acquisition and conceptual development (no. 3). Cambridge University Press Lin Q (1991) Speech production theory and articulatory speech synthesis. J Acoust Soc Am 90(4):2203–2203 Macias MM, Twyman KA (2011) Speech and language development and disorders. Dev Behav Pediatr 201–220 Matsuo K, Palmer JB (2008) Anatomy and physiology of feeding and swallowing: normal and abnormal. Phys Med Rehabil Clin N Am 19 (4):691–707 Mueller DT, Callanan VP (2007) Congenital malformations of the oral cavity. Otolaryngol Clin N Am 40(1):141–160 Pallier C, Bosch L, Sebastián-Gallés N (1997) A limit on behavioral plasticity in speech perception. Cognition 64(3):B9–B17 Pešák J (1990) Complex mechanism of laryngeal phonation. Folia Phoniatr Logop 42(4):201–207 Peterson-Falzone SJ, Hardin-Jones MA, Karnell MP, McWilliams BJ (2001) Cleft palate speech. Mosby, St. Louis, pp 266–291 Rubesin SE, Jessurun J, Robertson D, Jones B, Bosma JF, Donner MW (1987) Lines of the pharynx. Radiographics 7(2):217–237 Smith BE, Kuehn DP (2007) Speech evaluation of velopharyngeal dysfunction. J Craniofac Surg 18(2):251–261 Toro JM, Nespor M, Mehler J, Bonatti LL (2008) Finding words and rules in a speech stream: functional differences between vowels and consonants. Psychol Sci 19(2):137–144 Wasserman LH (2007) The correlation between brain development, language acquisition, and cognition. Early Childhood Educ J 34 (6):415–418

4

Pathophysiology of the Cleft Palate Amina Asif Siddiqui

Contents Brief Clinical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Pathophysiology of the Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Impact of Cleft Palate on Eating and Swallowing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Impact of the Cleft Palate on Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Abstract

Having understood the structure and functioning of the palate, it becomes easier to recognize its implicit defects and dysfunctions which manifest as a disorder of feeding, swallowing and impairment in the speech of individuals with a cleft palate. The degree and severity of disordered functioning is directly proportional to the size and type of defect in the palate. A disorder of eating, drinking, and swallowing challenges the nutritional intake, affecting the physical and mental health as well as social wellbeing of the child. The development of orally and nasally spoken speech sounds, require resonance within their respective cavities, to enhance the audibility of the sounds to the listener. Disorder of speech is evident through hypernasality, hyponasality, or mixed nasality, and inappropriate or displaced resonance accompanied by misarticulation of speech sounds. It may be said here that a cleft palate causes more concern than the cleft lip, as the latter poses a bigger cosmetic problem, than the one pertaining to malfunctioning of the speech mechanism.

A. A. Siddiqui (*) College of Speech Language & Hearing Sciences, Ziauddin University, Karachi, Pakistan e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2022 G. Q. Fayyaz (ed.), Surgical Atlas of Cleft Palate and Palatal Fistulae, https://doi.org/10.1007/978-981-15-8124-3_5

Brief Clinical History Amina Siddiqui has been a practicing speech and language therapist in Karachi, Pakistan, for nearly the last three decades. Her interest lies in the acquisition of speech and language and its stages in the development of young children. This draws her towards working with children having a congenital cleft palate. Amina also works with children and adults having speech, language, feeding and swallowing disorders of neurogenic origin.

Introduction Then We made this drop into a clot, then We made the clot into a lump, then We made the lump into bones, then We clothed the bones with flesh, and then We caused it to grow into another creation. Thus Most Blessed is Allah, the Best of all those that create. (Al Quran, Surah 23 - Al Muminoon, Ayat 14)

Pathophysiology of the Cleft Palate A child born with a cleft palate is predisposed to having communication and feeding disorders, along with the scars of facial deformity that affects personal and social well-being of the little child, as the new born bundle of joy seeks a happy

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acceptance within the family. Another one of the initial challenges that the new born faces, is that of receiving the required nutritional intake for normal physical growth and development (Pandya and Boorman 2001). Since the oral and nasal cavities cannot be disconnected from one another, the normal “suckle-swallow-suckle-swallow-suckle” pattern for milk is impaired. A compensatory strategy must be put in place immediately to ensure that the baby has good oral intake and achieves normal physical growth in preparation of the surgical reconstruction of the cleft lip at first followed by the repair of the cleft palate. The first three years of life are known as the critical period for speech and language development in human babies. A baby is born with a cleft lip and/or cleft palate when there is incomplete development, or non-fusion of the human fetus’ natural bony structures that form before birth. The baby born with only a cleft lip presents with little or no difficulty in feeding, and swallowing at birth or after that. The cleft lip primarily impairs the face cosmetically. However, a cleft lip with the cleft palate can be of major concern with respect to these functions. The size, type, and position of the cleft of the palate affects the functions of feeding, swallowing, and speaking to varying degrees.

Impact of Cleft Palate on Eating and Swallowing To understand the pathophysiology of the palate, it is essential to understand the process of eating and swallowing for both solid and liquid foods. The process consists of biting, chewing, or masticating food to soften and mix it with saliva in the mouth, making it easier for the individual to swallow. It also involves the sucking and sipping of liquids. To understand the mechanics of eating and swallowing, it is divided into three phases which are the oral, pharyngeal, and esophageal phases. In babies and children with cleft palate our concern primarily lies in the oral and pharyngeal phases. In the oral phase, the mandible moves up toward the upper jaw, bringing the lips to close together to prevent anterior spillage, as the food is held inside the mouth. The lower jaw and tongue perform a rotational movement with the food in the mouth, as it is chewed and mixed with saliva to form a softened bolus. At the initiation of swallowing, the tip of the tongue forms a closure with the anterior part of the hard palate at the alveolar ridge; and the dorsal surface forms a hump against the arch of the hard palate, holding the bolus in between and moving it backwards toward the oropharynx. Here starts the pharyngeal phase, as the soft palate is raised upwards against the posterior pharyngeal wall at the Passavant’s ridge which is formed by the contraction of inferior fibers of superior constrictor muscle; and simultaneously the lateral pharyngeal walls also squeeze in toward

A. A. Siddiqui

the soft palate, making a velopharyngeal closure and blocking the passage into the nasopharynx and preventing the food from going into the nasal cavity. At this point the posterior dorsum of the tongue forms a tight closure with the soft palate blocking off the oral cavity, preventing the food from returning into the mouth. The bolus gets pushed downwards by the back of the tongue, and the epiglottis closes safeguarding the airway to prevent the food from going into it. The bolus of food is pushed further down toward the upper esophageal sphincter, beginning the esophageal phase. Liquids may be sucked or sipped into the mouth, because of a low pressure being created inside the oral cavity, with the lateral ridges of the tongue turning toward with the molar and premolar teeth in the upper jaw, forming a central groove in the tongue. As the liquid is sucked, or sipped into the mouth, the soft palate forms the velopharyngeal closure, as it moves up against the nasopharyngeal wall, blocking the passage of the liquid into the nasal cavity. It is again swallowed just like a soft bolus of food. The baby born with a cleft palate faces the biggest challenge at birth, with an inability or difficulty to feed and swallow milk (Reid 2004). His/her oral and nasal cavities cannot be separated from one another. S/he must first latch on to the breast to suckle milk, in the oral phase but the cleft itself makes it very challenging to be able to draw or suck milk as the low pressure required within the oral cavity, to be able to do so does not get established, since the nasal cavity is open constantly (Mitchell and Wood 2000). In the pharyngeal phase the velopharyngeal port is constantly open because either there is no soft palate or it is very short, making it impossible for it to make contact with the posterior or lateral pharyngeal walls. The impaired structure of the palate may lead to nasal drainage of the liquid causing loss of dietary intake (Goyal et al. 2012). Increased effort to suckle milk may cause ingestion of air in the stomach, this dysfunctional suckle making baby feel full, but not actually having a full stomach. Cleft palate babies are unable to fulfill their body’s nutritional requirements, and present with malnourishment, low weight gain, and poor growth (Ize-Iyamu and Saheeb 2011). Babies with a cleft palate having difficulty with swallowing, may be at the risk of aspiration or even choking. These babies are also at risk of upper respiratory tract infection, chest infections, and ear infections. A study by Turner et al. (2001) suggests the education of the mother of the new born with a cleft on positioning the baby as such to obdurate the cleft with the breast, causing milk to flow into the correct food pipe and not drain into the nasal cavity to be wasted. Similarly using a prosthetic appliance (palatal plate) covering the gap in the cleft palate during feeding, may be taught to the mother of the new born. Both methods require training and support provided to the mother before she is left alone at home to manage the baby (Devi et al. 2012).

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Pathophysiology of the Cleft Palate

Impact of the Cleft Palate on Speech A child with a cleft palate may present with delayed development of speech and language skills; and have unclear speech, despite having normal neurodevelopment for speech and language skills. As a result these children often tend to speak late, and in short sentences which lack speech intelligibility (Frederickson et al. 2006). Speech disorders resulting because of a cleft palate are characterized by mis-articulation of sounds, inappropriate resonance, and inappropriate nasality (Hardin-Jones and Jones 2005). The articulation of speech sounds has a binary classification, by describing the manner of articulation firstly and secondly naming the place of articulation of the sound being uttered. The manner of articulation describes the release of the exhaled air stream, while place of articulation names the position in the speech tract from where the sound is uttered. The palate plays the most important role in the utterance of speech sounds, which requires the controlled release of the exhaled air stream through the oral cavity for all vowels and consonants except [m,n,ŋ] which are released through the nasal cavity. Some sounds require the air stream to be released as a soft explosion, created by blocking the airstream behind a tight closure of the lips or a lip seal. A large number of sounds are uttered by releasing the airstream from between the tongue and hard palate at different points, these are called plosives [p,b,k,ɋ, g,Ɂ, t,d,ɖ,ţ,t,d]. While others require the air stream to be released slowly and consistently as the sound is being uttered, such sounds are called continuants, which include fricatives [s,z,f,v,ʃ,ʐ], affricates [ts,dz], laterals [l,] and trills [r,Υ], as well as the nasal sounds [m,n,ŋ]. For all continuants and plosives, the tongue forms a relationship with the palate at different points, starting from the maxillary teeth at the front edge of the hard palate, and moving backwards to the alveolar ridge, the mid-section at the arch of the hard palate, the soft palate, and the uvula (Salas-Provance et al. 2003). For the production of vowel sounds in any language of the world, the soft palate must be raised upwards and backwards toward the pharyngeal walls, blocking off the nasal cavity from the oral cavity completely, so that all vowels always have an oral escape of the exhaled airstream, during speech production (Perry et al. 2011). This is called the velopharyngeal port where we see the velopharyngeal closure, and it is one of the most crucial areas that must be surgically repaired with precision. An instrumental or videofluroscopic assessment may be required to be done by the speech language therapist to ascertain the insufficiency versus the incompetence of the velopharyngeal closure, to decide the line of treatment to be surgical intervention or speech therapy alone (Chapman et al. 2001).

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In babies with cleft palate, there is no separation between the oral and nasal cavities, which pre-disposes them to ear infections, in early life (Paliobei et al. 2005). It also hampers the mastery of the speech sounds, often leading to misarticulations such as omission of sounds in a word, substitution of incorrect sounds in place of the correct ones, and even addition of sounds that a word does not have. In effect a hearing loss is likely to compound the speech defects seen in children with a cleft palate (Nagarajan et al. 2009). A delay in the surgical intervention is likely to cause not only delayed development of verbal communication skills but also several errors in the production of speech sounds. The child uses compensatory strategies (Chapman et al. 2001) in the production of consonant and vowel sounds in his repertoire, making speech unintelligible and causing dependency on nonverbal means of communication such as gestures to augment it. The erroneous speech sounds, among the consonants and vowels learnt, can only be corrected through very intensive listening exercises complementing speech therapy (Hortis-Dzierzbicka et al. 2012). Remediation may be sought by a dentist, orthodontist or prosthodontist depending upon the degree to which the child benefits from surgical repair and speech therapy (Robin et al. 2006). A speech prostheses or speech bulb may be given as an obturator for a palate that cannot be surgically repaired completely. However maximal intelligibility of speech would only be achieved through intensive speech therapy that teaches the child the optimal use of the obturator or prostheses by wearing it all day, and auditorily discriminating between acceptable versus unacceptable production of vocal resonance (Hardin-Jones and Jones 2005). Early intervention, both surgery and speech therapy (Hardin-Jones et al. 2006), is the only key to alleviation of speech and language disorders, in children born with a cleft palate.

References Chapman KL, Hardin-Jones M, Schulte J, Halter KA (2001) Vocal development of 9-month-old babies with cleft palate. J Speech Lang Hear Res 44(6):1268. https://doi.org/10.1044/1092-4388 (2001/099) Devi ES, Sai Sankar AJ, Manoj Kumar MG, Sujatha B (2012) Maiden morsel-feeding in cleft lip and palate infants. J Int Soc Prev Commun Dent 2(2):31 Frederickson MS, Chapman KL, Hardin-Jones M (2006) Conversational skills of children with cleft lip and palate: a replication and extension. Cleft Palate Craniofac J 43(2):179–188 Goyal A, Jena AK, Kaur M (2012) Nature of feeding practices among children with cleft lip and palate. J Indian Soc Pedod Prev Dent 30(1):47 Hardin-Jones MA, Jones DL (2005) Speech production of preschoolers with cleft palate. Cleft Palate Craniofac J 42(1):7–13 Hardin-Jones M, Chapman K, Scherer NJ (2006) Early intervention in children with cleft palate. ASHA Leader 11(8):8–32 Hortis-Dzierzbicka M, Radkowska E, Fudalej PS (2012) Speech outcomes in 10-year-old children with complete unilateral cleft lip and

28 palate after one-stage lip and palate repair in the first year of life. J Plast Reconstr Aesthet Surg 65(2):175–181 Ize-Iyamu IN, Saheeb BD (2011) Feeding intervention in cleft lip and palate babies: a practical approach to feeding efficiency and weight gain. Int J Oral Maxillofac Surg 40(9):916–919 Mitchell JC, Wood RJ (2000) Management of cleft lip and palate in primary care. J Pediatr Health Care 14(1):13–19 Nagarajan R, Savitha VH, Subramaniyan B (2009) Communication disorders in individuals with cleft lip and palate: an overview. Indian J Plast Surg 42(Suppl):S137 Paliobei V, Psifidis A, Anagnostopoulos D (2005) Hearing and speech assessment of cleft palate patients after palatal closure: long-term results. Int J Pediatr Otorhinolaryngol 69(10):1373–1381 Pandya AN, Boorman JG (2001) Failure to thrive in babies with cleft lip and palate. Br J Plast Surg 54(6):471–475

A. A. Siddiqui Perry JL, Kuehn DP, Sutton BP, Goldwasser MS, Jerez AD (2011) Craniometric and velopharyngeal assessment of infants with and without cleft palate. J Craniofac Surg 22(2):499–503 Reid J (2004) A review of feeding interventions for infants with cleft palate. Cleft Palate Craniofac J 41(3):268–278 Robin NH, Baty H, Franklin J, Guyton FC, Mann J, Woolley AL, Grant J (2006) The multidisciplinary evaluation and management of cleft lip and palate. South Med J 99(10):1111–1121 Salas-Provance MB, Kuehn DP, Marsh JL (2003) Phonetic repertoire and syllable characteristics of 15-month-old babies with cleft palate. J Phon 31(1):23–38 Turner L, Jacobsen C, Humenczuk M, Singhal VK, Moore D, Bell H (2001) The effects of lactation education and a prosthetic obturator appliance on feeding efficiency in infants with cleft lip and palate. Cleft Palate Craniofac J 38(5):519–524

5

Global Incidence of Cleft Palate Mohamed El-Shazly, Yasser Helmy, Lobna Abdelsalam, and Tasnim Ali

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Descriptive Global Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gender Ratio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laterality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30 30 30 30

Geographical Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Incidence Variations of Syndromic and Non-syndromic Cleft Palate Worldwide . . . . . . . . . . . . . . . . . . . . . . . 31 African Americans, Africans, Caucasian, and Mestizo Americans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 East-Mediterranean Region . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Possible Interpretation for the Global Differences in Cleft Palate Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Factors in Cleft Palate Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnicity and Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Environmental Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33 33 33 33

Could a Cleft Palate and Lip Be Prevented? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Abstract

M. El-Shazly (*) Plastic Surgery Department, Assiut University, Assiut, Egypt Middle East & North Africa, Operation Smile International, Virginia Beach, VA, USA Operation Smile, Virginia, VA, USA e-mail: [email protected]; [email protected] Y. Helmy Al-Azhar University, Cairo, Egypt e-mail: [email protected] L. Abdelsalam University of North Carolina, Chapel Hill, NC, USA T. Ali Faculty of Biotechnology, Nile University, Cairo, Egypt e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2022 G. Q. Fayyaz (ed.), Surgical Atlas of Cleft Palate and Palatal Fistulae, https://doi.org/10.1007/978-981-15-8124-3_129

Background: Worldwide rates of cleft palate could vary based on ethnicity and geography. Orofacial clefts are the most common craniofacial malformation of the newborn that may occur due to environmental factors and socioeconomic conditions, with variability across geographic origin, race, and ethnic groups. Objectives: to review trends in the rate of cleft lip and palate (CLP) patients in many countries across several world regions to find out any possible socioeconomic, genetic factors that could affect the cleft palate incidence. The chapter will review the reported annual rates per 10,000 live births calculated worldwide that will be grouped according to World Health Organization (WHO) regions (North and south America, Europe, South and East Asia, Western Pacific, Africa, and Eastern Mediterranean). 29

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M. El-Shazly et al.

Conclusion: CL/P prevalence is highest in the Asian and American populations and lowest in African populations. The gender distribution of cleft lip and palate is not equal in general. The incidence of CL/P is 2 times higher in men than in women, whereas that of CP is higher in women.

1. Asian populations showed the highest prevalence worldwide which exists (0.82–4.04 per 1000 live births), followed by 2. Caucasian populations, that showed intermediate rates (0.9–2.69 per 1000 live births) 3. But the lowest rates have been reported in the African populations (0.18–1.67 per 1000 live births)

Introduction Cleft lip and palate or cleft palate (only) is a frequently seen congenital abnormality which is prevalent in each country around the world (Peterson-Falzone et al. 2001). Cleft palate alone (C/P) shows a prevalence rate of 5.5–6.6 per 10,000 births in USA, while that prevalence varies when C/P is associated with cleft lip (C/L) to reach 2.2 to 11.7 per 10,000 births (Forrester and Merz 2004). Cleft palate and lip have a birth prevalence rate ranging from 1/1000 to 2.69/1000 among different parts of the world (McLeod et al. 2004). According to most recent data across 55 countries, A. The highest rates of CL/P were reported in Venezuela (38 cases/10,000 births) B. Iran (36 cases/10,000 births) and Japan (30 cases/10,000 births). Preliminary analysis of temporal trends was assessed within WHO regions from 1990 to 2013 (Allam et al. 2014). C. The Americas reported significant increases in the rate of CL
P from 10.3 cases/10,000 births to 12.37 cases/10,000 births (P ¼ 0.01) and total CL/P from 13.5 cases/10,000 births to 15.3 cases/10,000 births (P ¼ 0.02). No other WHO region demonstrated a significant change in CL/P rate. D. Countries at higher elevation (>1000 m) reported significantly higher rates of cleft lip
palate than countries at lower elevation (mean rate of 12.4 versus 8.4 cases/ 10,000 births; P ¼ 0.02). E. In contrast, countries at higher elevation had significantly lower rates of cleft palate than countries at lower elevation (mean rate of 3.5 versus 5.2 cases/10,000 births; P ¼ 0.03) (Watkins et al. 2014) (Brito et al. 2011; Mossey and Modell 2012).

Descriptive Global Epidemiology Prevalence The overall prevalence of orofacial clefts (OFC) is nearly 1 in 700 live births, that accounts for 50% of all craniofacial anomalies. According to World Health Organization (WHO) reports, the overall prevalence of OFC varies worldwide from 3.4–22.9 per 10,000 births for CL/P and 1.3–25.3 per 10,000, for cleft palate only presentation. However, literature review shows heterogenicity in the incidence, parameters, inclusion criteria, and data sources.

Interestingly, Study conducted by Forrester, showed lower rates of prevalence of overall Orofacial Clefts (OFC) in sub-Asian groups (Far East Asians compared to Filipinos) (Forrester and Merz 2004).

Gender Ratio Gender ratio has a different impact on cleft palate and lip prevalence. A. Male predominance has been reported in cleft lip, that showed a male/female sex ratio of 1.81 (CI 95%: 1.75–1.86). B. However, cleft palate has shown an opposite sex ratio female/male of 0.93 (CI 95%: 0.89–0.96) This observation is not explained clearly in literature and some authors attribute it to possible bias in study’s design. Danish study reported nonsignificant value in term of a male/female sex ratio in both groups, that have been surgically treated and non-surgically treated (Christensen et al. 1992).

Laterality Cleft Palate may present as unilateral or bilateral. I. The proportion of bilateral presentation of cleft lip without palate is 10.3% for cleft lip (CL) and 30.2% for cleft lip with palate. II. Nevertheless, the proportion of unilateral cases is 36.9% of cleft lip (CL) and 41.1% of cleft lip with palate (CLP), occur on the right side, proposing that unilateral presentation of cleft lip with palate (CLP) occurs more frequently on the left side (Mastroiacovo et al. 2011).

Geographical Distribution The World Health Organization (WHO) divides the world into six WHO regions, for the purposes of reporting, analysis, and administration.

5

Global Incidence of Cleft Palate

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Incidence Variations of Syndromic and Non-syndromic Cleft Palate Worldwide In a study conducted by the International Perinatal Database of Typical Orofacial Clefts, established in 2003, through the Human Genetics Program of World Health Organization (WHO), on the basis of the records evaluated according to geographical regions, CL
P incidence was determined in Japan, Mexico, Western Europe, Canada, the United States, Australia, British Isles, Eastern Europe, United Arab Emirates, South Mediterranean Europe, and South Africa; the incidence was the highest in Japan and the lowest in South Africa (Fig. 1) (Ağaçayak et al. 2014; IPDTOC 2011). Generally, the accepted incidence of non-syndromic(ns) CL/P (nsCL/P) cases across the world is 1 in 1000 births. However, the incidence varies depending on ethnic background, geographical origin, and socioeconomic level. 1. The incidence of nsCL/P is 0.3 in 1000 births in African populations 2. 0.7–1.3 in 1000 births in European populations 3. 1.4–2.1 in 1000 births in Asian populations 4. 3.6 in 1000 births in American populations (Stuppia et al. 2011; Allam et al. 2014) In a study conducted in a population of 30,665,615 live births, 45,193 patients with orofacial clefts (OFCs) were found. 1. According to continents, the OFC birth prevalence (95% confidence interval) from Asia, North America, Europe, Oceania, South America, and Africa were 1.57 (1.54–1.60), 1.56 (1.53–1.59), 1.55 (1.52–1.58), 1.33 (1.30–1.36), 0.99 (0.96–1.02), and 0.57 (0.54–0.60) per 1000 live births, respectively.

2. The American Indians had the highest prevalence rates of 2.62 per 1000 live births, followed by the Japanese, the Chinese, and the Whites of 1.73, 1.56, and 1.55 per 1000 live births, respectively (Watkins et al. 2014; Allam et al. 2014). 3. The Blacks had the lowest rate of 0.58 per 1000 live births. The prevalence of nsCL/P and nsCP in Europe according to EUROCAT registration data, which is widely used in the classification of congenital malformations, are presented in (Fig. 2) (Mossy PA, Modell B 2012). Due to its unique geographical location that connects Middle East, Europe, and Asia, Turkey has been exposed to a high degree of immigration. Variability, along with the increase in population, led to the formation of a complex heterogeneous ethnic picture in Turkey and resulted in a diverse set of important genetic variations in the current population. Thus, epidemiological studies on cleft lip and palate in Turkey are important for establishing a resource for researchers and clinicians.

African Americans, Africans, Caucasian, and Mestizo Americans The prevalence rates of clefts in different cultures are quite interesting when it comes to the origins. For example (i) In the USA, the African Americans have a lower prevalence rate of cleft lip with or without palate (CL+/P) compared to Caucasian. (ii) One/2500 African Americans are born with a cleft (Suleiman et al. 2005).

Japan Mexico & South America Western Europe Canada United States Australia - Victoria British Isles Eastern Europe United Arab Emirates South - Mediterranean Europe South Africa 0.00

Fig. 1 Prevalence of CL/P by geographical area (per 10,000)

5.00

10.00

15.00

20.00

25.00

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M. El-Shazly et al.

2.5

Affected / 1.000

2.0

1.5 Cleft palate non-chr /1,000

1.0

0.5

Portugal

Italy

Spain

Ireland

Bulgaria

France

Hungary

Croatia

Reunion

Switzerland

Malta

Poland

Austria

Ukraine

Norway

Belgium

Netherlands

Denmark

Germany

0.0

Finland UK

Cleft lip (& palate) non-chr /1,000

Fig. 2 Prevalence of non-syndromic (CL(P) and CP) in Europe

(iii) A prevalence rate of 0.61 per 1000 and 1.05 per 1000 live births was reported in African American and Caucasian respectively (Croen et al. 1998). (iv) In Malawi there is a reported low prevalence rate for cleft lip and/or palate, 0.7 per 1000 live births (Msamati et al. 2000). (v) Study conducted in Sudan found that the prevalence rate of cleft palate/ lip Sudanese subgroups hospital in Khartoum city is 0.9 per 1000 live births (Suleiman et al. 2005). Mestizo Americans are defined as people of mixed origins of European and Native American origins (Mexico, Central America and South America, and the Caribbean) (Meyerson 1990). (vi) The prevalence of cleft lip with or without palate (CL+/P) in Mestizo Americans is lower than that of Caucasians and Native Americans. However, prevalence is still higher than African Americans (Croen et al. 1998). (vii) Mestizo populations have a prevalence of cleft lip with or without palate about 9.7 per 10,000 live births (Kirby et al. 2000). (viii) In Sucre city, which is the constitutional capital of Bolivia, the prevalence rate of CL+/P is shown 1.23 per 1000 live births (McLeod et al. 2004). (ix) Hawaii is an extremely diverse population belonging to US consisting of 73% people of Asian and Pacific origin. Study showed that the prevalence rate of cleft lip with or without palate (CL+/P) was 10 and 16 per 10,000 live births in Caucasians and Far East Asian Hawaii, respectively. The prevalence is 14.5 per 10,000 live births in Hawaii population of Filipino descent (Forrester and Merz 2004).

East-Mediterranean Region This area includes most of Arab countries, north Africa, and middle east. Studies that have examined the prevalence of cleft lip with or without palate (CL+/P) in other Arab populations. 1. In Jordan and found an overall rate of 1.39 per 1000 live births for cleft lip with or without palate (CL+/P). Al Omari and Al-Omari 2004). 2. Study by showed in a sample size of 25,440, 60 liveborn infants, that prevalence of facial clefts was 2.4/1000; 33% of them were presented with cleft lip, 25% with cleft palate, and 42% with both. In Egypt, the average birth rate is approximately 30/1000 population. There are no updated comprehensive registries in Egypt, that allows accurate assessment of the prevalence of Cleft palate. 3. Study conducted by Abulezz et al. (2018) is expected to have >3000 new cleft cases per year (considering the total population at that time was around 90,000,000 and the incidence of cleft is 1/750 live birth. 4. Another study conducted in 2019 has shown that the prevalence value of CL
P in the four Egyptian governorates included in the study was 0.40/1000. The highest type of incidence was cleft lip and palate, then cleft lip, and isolated cleft palate, respectively (Alswairki et al. 2019). The epidemiological Population-based data in northern Pakistan, has shown that the incidence of cleft lip and palate were obtained from birth registry information in Abbottabad, northern city of Pakistan.

5

Global Incidence of Cleft Palate

1. Number of cases of cleft lip with or without palate were 117 cases out of 61,156 live births. 2. The incidence of cleft lip with or without palate was 1.91 per 1000 births (one per 523 births). 3. Cleft lip alone was noted more frequently in 42% of cases than isolated cleft palate which was noted in 24% and the combined cleft lip with palate deformities were 34%. 4. Males have more of cleft lip and cleft lip with cleft palate, while females have presented mainly with cleft palate only (Elahi et al. 2004).

Possible Interpretation for the Global Differences in Cleft Palate Incidence The multifactorial inheritance model, which involves the interaction of genetic and environmental factors, is a good example for the epidemiological findings of non-syndromic CL/P (nsCL/P). The risk of cleft lip and palate in a family varies depending on many factors. Risk factors and factors increasing the severity of cleft lip and palate are determined based on the number of family members with cleft lip and palate (positive family history), degree of relationship, gender of the affected individual, and type of cleft. If there is a child with cleft lip and palate in a family, the risk that the next child will be affected is 2–5%; however, the risk increases to 10–12% if the family has more than one child with cleft lip and palate. If a recurrent syndrome is also present in the family, the risk increases to 50%. Studies had shown that the prevalence of nsCL/P is significantly higher in maternal “identical monozygotic” twins (40–60%) than in fraternal “dizygotic” twins (3–5%). Elahi’s study in 2004 showed that the Consanguineous parents’ marriages were observed in 32% versus 18% in matched controls. Studies showed that 32% of cleft mothers received prenatal counseling and laboratory testing during the pregnancy. Nutritional and vitamin supplements were reported in 28% of mothers of cleft children compared with 59% in matched controls.

Genetic Factors in Cleft Palate Incidence Approximately 70% of cleft lip and palate cases are non-syndromic. The etiology of syndromic clefts, constituting approximately 30% of the cases, includes more than 300 defined Mendelian syndromes, teratogens, and uncategorized syndromes. The geneticist evaluates every new patient to determine if the cleft is isolated or part of an underlying syndrome. This is not due to a single gene abnormality but rather many genes working together along with other factors. If a genetic syndrome, such as 22q deletion syndrome, is identified, the infant may have several other physical disorders that will occur as well (Carinci et al. 2007; Beaty et al. 2016).

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Ethnicity and Gender Although cleft lip with or without cleft palate can occur in any race, there is a higher incidence in people of Asian, Native American, or Hispanic descent. There is a lower incidence in African American individuals.

Environmental Factors Most cleft palates seem to be caused by environmental factors that increase a mother’s risk of giving birth to a child with a cleft palate. These factors include: • • • • •

Exposure to German measles (Rubella) or other infections. Certain medications. Alcohol and drug usage. Cigarette smoking. Certain vitamin deficiencies, especially during early pregnancy.

Since the baby’s face develops so early in the pregnancy, even when these factors are minimized through proper prenatal care, the damage may have already occurred to the child before the mother was even aware that she was pregnant (Dixon et al. 2011).

Could a Cleft Palate and Lip Be Prevented? Major issues in prevention of cleft palates are: • Public education about possible environmental and genetic dangers to children. • Increased access to prenatal care for mothers. • Efforts to decrease teen pregnancies. • Women older than 35 must be counseled regarding the maternal age risk factors because older women are more likely to give birth to a child with a birth defect. Also, families with a history of cleft palate should seek genetic counseling to determine their relative risks for giving birth to a child with a cleft palate.

Conclusion In conclusion, the rate of CL/P has remained stable throughout much of the world, with an increase noted in the Americas. Geographical variables may influence incidence rates. In addition, observed differences may also be of ethnic origin, genetic, environmental factors, and methods of ascertainment. Future efforts to develop comprehensive registries will allow more accurate assessment of the global burden of CLP.

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References Abulezz TA, Elsherbiny AK, Mazeed AS (2018) Management of cleft lip and palate in Egypt: a national survey. Indian J Plast Surg 51(3): 290–295 Ağaçayak KS, Ağaçayak E, Coşkun S, Aksoy O (2014) Congenital orofacial clefts: etiology and frequency. Dicle Med J 41:429–433 Al Omari F, Al-Omari IK (2004) Cleft lip and palate in Jordan: birth prevalence rate. Cleft Palate Craniofac J 41(6):609–612 Allam E, Windsor J, Stone C (2014) Cleft lip and palate: etiology, epidemiology, preventive and intervention strategies. Anatom Physiol Current Res 4:1–6 Alswairki H, Abd El-Sayed FA, Fouda MY (2019) Incidence of Egyptian live births of cleft lip and/or palate in Cairo, Luxor, Aswan, and New Valley governorates: a survey study in 237,783 children. Pesquisa Brasileira em Odontopediatria e Clínica Integrada 19: 1519–0501 Beaty TH, Marazita ML, Leslie EJ (2016) Genetic factors influencing risk to orofacial clefts: today’s challenges and tomorrow’s opportunities. F1000Research 30(5):2800 Brito LA, Cruz LA, Rocha KM, Barbara LK, Silva CBF et al (2011) Genetic contribution for non-syndromic cleft lip with or without cleft palate (NS CL/P) in different regions of Brazil and implications for association studies. Am J Med Genet A 155: 1581–1587 Carinci F, Scapoli L, Palmieri A, Zollino I, Pezzetti F (2007) Human genetic factors in nonsyndromic cleft lip: an update. Int J Pediatr Otorhinolaryngol 71:1509–1519 Christensen K, Holm NV, Olsen J, Kock K, Fogh-Andersen P (1992) Selection bias in genetic-epidemiological studies of cleft lip and palate. Am J Hum Genet 51:654–659 Croen L, Shaw GM, Wasserman CR, Tolarova M (1998) Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983–1992. Am J Med Genet 79:42–47 Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011) Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 12:167–178

M. El-Shazly et al. Elahi M, Jackson IT, Elahi O, Khan AH et al (2004) Epidemiology of cleft lip and cleft palate in Pakistan. Plast Reconstr Surg 113(6): 1548–1555 Forrester MB, Merz RD (2004) Descriptive epidemiology of oral clefts in a multiethnic population, Hawaii, 1986–2000. Cleft Palate Craniofacial J 41(6):622–628 IPDTOC Working Group (2011) Prevalence at birth of cleft lip with or without cleft palate: data from the International Perinatal Database of Typical Oral Clefts (IPDTOC). Cleft Palate Craniofac J 48:66–81 Kirby R, Petrini J, Alter C (2000) Collecting and interpreting birth defects surveillance data by Hispanic ethnicity: a comparative study. Teratology 61:21–27 Mastroiacovo P, Maraschini A, Leoncini E et al (2011) Prevalence at birth of cleft lip with or without cleft palate: data from the International Perinatal Database of Typical Oral Clefts (IPDTOC). Cleft Palate Craniofac J 48:66–81 McLeod NM, Arana-Urioste ML, Saeed NR (2004) Birth prevalence of cleft lip and palate in Sucre, Bolivia. Cleft Palate Craniofac J 41(2): 195–198 Meyerson MD (1990) Cultural considerations in the treatment of Latinos with craniofacial malformations. Cleft Palate J 27(3):279–288 Mossey PA, Modell B (2012) Epidemiology of oral clefts 2012: an international perspective. Front Oral Biol 16:1–18 Msamati BC, Igbibi PS, Chisi JE (2000) The incidence of cleft lip. Cleft palate, hydrocephalus, and spina bifida at Queen Elizabeth Central Hospital, Blantyre, Malawi. Central Africa J Med 46(11):292–296 Peterson-Falzone SJ, Hardin-Jones MA, Karnell MP (2001) Cleft palate speech, 3rd edn. Mosby, Inc, St. Louis Stuppia L, Capogreco M, Marzo G et al (2011) Genetics of syndromic and nonsyndromic cleft lip and palate. J Craniofac Surg 22:1722–1726 Suleiman AM, Hamzah ST, Abusalab MA, Samaan KT (2005) Prevalence of cleft lip and palate in a hospital-based population in Sudan. Int J Paediatr Dent 15:185–189 Watkins SE, Meyer RE, Strauss RP, Aylsworth AS (2014) Classification, epidemiology, and genetics of orofacial clefts. Clin Plast Surg 41: 149–163

6

Etiology of Cleft Lip and Palate Tahmeedullah and Waqas Hayat

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Epidemiology of Cleft Lip and Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Development of the Lip and Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Spectrum of Cleft Lip and Palate Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Environmental Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Associated Genetic Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interferon Regulatory Factor 6 (IRF-6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wnt Signaling Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FOXE1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VAX1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABCA4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37 37 37 37 37 37

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Abstract

Introduction

Cleft lip and palate are one of the most common congenital anomalies. This anomaly occurs during the organogenesis period from 4th week to 10th week of gestation because the frontonasal prominence fails to fuse with the maxillary prominence. Pathophysiology of the cleft lip and palate is multifactorial. Several genetic mutations and environmental factors are associated with cleft lip and palate.

Infant mortality has been reduced to a record low level in the modern world. Nowadays, the focus is shifting to many intricate problems like the congenital anomalies. The prevalence of congenital anomalies is on the rise. To improve the quality of life of these patients, importance of prevention and treatment of these anomalies cannot be overemphasized.

Epidemiology of Cleft Lip and Palate

Aims and Scope: This chapter presents a brief overview of the etiology and the etiopathology of the cleft lip and palate. Tahmeedullah (*) Plastic and Reconstructive Surgery, Burn and Plastic Surgery Center, Peshawar, Pakistan W. Hayat Burn and Plastic Surgery Center, Peshawar, Pakistan © Springer Nature Singapore Pte Ltd. 2022 G. Q. Fayyaz (ed.), Surgical Atlas of Cleft Palate and Palatal Fistulae, https://doi.org/10.1007/978-981-15-8124-3_1

Cleft lip and palate are one of the most commonly occurring congenital anomalies. These can occur in isolation, referred to as the nonsyndromic cleft lip with or without palate (NSCL/P). It can also be associated with a number of syndromes. The prevalence of the orofacial clefts varies widely, depending on the region and ethnicity. The reported incidence of cleft lip is 0.9 per 1000 live births. The incidence of cleft palate is, however, much less and stands at 0.56 per 1000 live births in the United States 35

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(Bird et al. 2006). The incidence of cleft lip and palate in UK is 1.4 per 1000 live births (Slator et al. 2009). The incidence is more in the northern Europe as compared to the Southern European countries (Mossey and Modell 2012). Elahi et al. (2004) did a survey in the northern city of Pakistan. Birth and population data was collected from the provincial birth registries. These registries reported 61,156 live births in 4.5 years. The incidence of cleft lip and palate was 1.91/1000 live births. The incidence of cleft lip was 0.80 per 1000 live births. Primary palate cleft was reported as 1.65 per 1000 per live births. The incidence of cleft lip with palate was 0.65 per 1000 live births.

Development of the Lip and Palate Development of the lip and palate occurs during the organogenesis period. Neural crest cells migrate to create the maxillary prominences. These prominences advance toward the medial side and fuse with the frontonasal process. The frontonasal process forms the nasal placodes which develops into a nasal pit and medial and lateral nasal prominences. The frontonasal prominence also develops into the philtrum, columella, premaxilla, central incisors, and the primary hard palate. The advancing maxillary processes fuse with the structures developed from the frontonasal processes. This development takes place from fourth to tenth week of gestation. Any interruption/ insult during this phase of development will cause failure of fusion and will lead to different types of congenital anomalies. The failure of fusion has a temporal relationship with the development of the resultant congenital anomaly. The following is a brief overview of the cardinal events during the development of lip and palate: • • • •

Day 28: Development of the nasal placode. Day 30: Nasal pit develops. Day 33: Medial and lateral nasal prominences develop. Day 48: The two medial nasal prominences fuse with each other and with the medially advancing maxillary prominences. • 10th – 14th week: Development of philtrum by the frontonasal prominence. The secondary palate develops from the palatine shelves of the maxillary processes. These develop and elongate in inferomedial direction. At 7-8th week, the palatine shelves change their orientation and come to lie in a horizontal plane above the tongue. These palatine processes fuse with each other and with the primary palate before the 12th week.

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Spectrum of Cleft Lip and Palate Disorders The cleft lip and palate is a spectrum of disorders. These can occur in isolation or can be associated with a number of syndromes. Historically, the nonsyndromic cleft lip and palate are treated as an isolated event. For years, researchers have tried to pinpoint the specific genetic mutation responsible for the nonsyndromic cases, but consensus cannot be made over a mutation in a specific locus of genes. Now it is theorized that the nonsyndromic cleft lip and/or palate (NSCL/P) might be the milder form of the syndromic variants (Seto-Salvia and Stanier 2014). These can present as cleft lip, as cleft palate, and as cleft lip and palate. The exact etiology of these types is multifactorial. Several environmental factors and genes have been implicated.

Environmental Risk Factors • Maternal smoking can increase the risk of cleft in the child. The risk is more in infants when the mother smokes during the peri-conceptual period. • Alcohol consumption is associated with increased risk of cleft lip and palate. The odds of having children with orofacial clefts in women drinking more than 6 days a week is 1.6 times the normal population. Taking a higher dose is more harmful as compared to frequent consumption. In women who consume more than five drinks in one sitting, the odds of having a child with cleft lip and palate is 2.4 as compared to the general population (DeRoo et al. 2008). • Valproic acid: Using valproic acid as a monotherapy during the first trimester increases the risk of cleft lip and palate by 5–6 times (Jentink et al. 2010). Valproic acid is also associated with other anomalies such as spina bifida, hypospadias, atrial septal defect, polydactyly, and craniosynostosis (Jentink et al. 2010). • Stress. • Obesity. • Exposure to radiation. • Febrile events in the first trimester can increase the risk of cleft lip and/or palate. The increased risk is not associated with any specific infections. This risk is significantly reduced with the use of antipyretic medications (Shahrukh Hashmi et al. 2010). • Zinc deficiency: Some studies have found an association between the low plasma zinc levels and orofacial clefts. A severe deficiency of zinc can increase the risk of these orofacial clefts significantly (Krapels et al. 2004; Munger et al. 2009).

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• Folate deficiency: is considered to be a risk factor by some researchers. Folate supplementation is known to decrease the incidence of cleft lip and palate.

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NSCL/P. It also plays a role in the hair follicle development and the organogenesis of the thyroid gland (Beaty et al. 2013).

VAX1

Associated Genetic Mutations Interferon Regulatory Factor 6 (IRF-6) IRF-6 gene mutation was first associated with the orofacial clefts in Van der Woude Syndrome. These mutations were later on discovered in the nonsyndromic clefts as well. More than 200 single nucleotide polymorphisms(SNPs) in the IRF6 locus have been attributed to the formation of cleft lip and palate (de Lima et al. 2009). So far, IRF-6 mutation has shown the most consistent associations with the NSCL/P across the different populations in the genome-wide association studies (GWAS). The risk of recurrence increases by 9% in the family if one child is diagnosed with these mutations (Zucchero et al. 2004). During the orofacial development, all the developing structures are surrounded by a single layer nonstratified squamous epithelium called the periderm. The function of periderm is to prevent abnormal fusion of structures such as the tongue, palate, and the mandible. The periderm is anchored to the basal lamina by a basal layer of cuboidal cells. After migration of the palatal shelves to the horizontal position, the periderm on the medial edges of the palatal shelves is lost, thus allowing the palatal shelves to fuse. Due to SNPs in the IRF-6 locus, there is overexpression of the IRF-6 and the medial edges of the palate fail to fuse (Dixon et al. 2011; Kousa and Schutte 2016).

Located on the 10q25 locus, mutations on the VAX1 gene were found in the European populations. These mutations are also associated with colobomas, mcirophthalmia, and brain anomalies (Mangold et al. 2010). Other loci with SNPs associated with NSCL/P, identified by Mangold et al., are NOG, THADA, SPRY2, and GERM1 (Mangold et al. 2010).

ABCA4 ATP binding cassette subfamily A member 4 (ABCA4) gene is located on the short arm of chromosome 1 (1p22.1). It has also shown an association with the orofacial clefts in the genome-wide association studies (GWAS) in the European and the Asian populations. These genes are also responsible for the synthesis of a protein in the photoreceptor cells of the retina. SNPs of this gene are also associated with retinal dystrophies (Beaty et al. 2010). Orofacial clefts are multifactorial processes. These cannot be explained by a single genetic mutation. Epigenetics also plays a role in the pathogenesis of these anomalies. With better understanding of the workings of these mutations, along with the epigenetic changes that are responsible, it might be possible to explain the pathogenesis of these congenital orofacial clefts more clearly.

References Wnt Signaling Pathway Wnt (Wingless-related Integration Site) signaling pathways are a group of morphogenic proteins used for signal transduction. They play a role in cellular differentiation, mobility, and differentiation in an embryo by cell to cell communication. Wnt signaling pathway plays a role in the fusion of lip during development (Vijayan et al. 2018). Mutation of genes in the Wnt signaling pathway is associated with the orofacial clefts in several studies (Dixon et al. 2011; Vijayan et al. 2018). The exact mechanism of action is not clear and needs further studies to elaborate the exact role of these mutations.

FOXE1 FoxE1 gene located on the 9q22.33 locus was discovered in the European and Asian populations to be associated with the

Beaty TH et al (2010) A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4. Nat Genet 42(6):525–529 Beaty TH et al (2013) Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study. Hum Genet 132 (7):771–781 Bird TM et al (2006) National rates of birth defects among hospitalized newborns. Birth Defects Res A Clin Mol Teratol 76 (11):762–769 de Lima RL et al (2009) Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome. Genet Med 11(4):241–247 DeRoo LA et al (2008) First-trimester maternal alcohol consumption and the risk of infant oral clefts in Norway: a population-based casecontrol study. Am J Epidemiol 168(6):638–646 Dixon MJ, Marazita ML, Beaty TH, Murray JC (2011) Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 12(3):167–178 Elahi MM, Jackson IT, Elahi O, Khan AH, Mubarak F, Tariq GB, Mitra A (2004) Epidemiology of cleft lip and cleft palate in Pakistan. Plast Reconstr Surg 113(6):1548–1555

38 Jentink J et al (2010) Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 362(23):2185–2193 Kousa YA, Schutte BC (2016) Toward an orofacial gene regulatory network. Dev Dyn 245(3):220–232 Krapels IP et al (2004) Maternal nutritional status and the risk for orofacial cleft offspring in humans. J Nutr 134(11):3106–3113 Mangold E et al (2010) Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet 42(1):24–26 Mossey PA, Modell B (2012) Epidemiology of oral clefts 2012: an international perspective. Front Oral Biol 16:1–18 Munger RG et al (2009) Plasma zinc concentrations of mothers and the risk of oral clefts in their children in Utah. Birth Defects Res A Clin Mol Teratol 85(2):151–155

Tahmeedullah and W. Hayat Seto-Salvia N, Stanier P (2014) Genetics of cleft lip and/or cleft palate: association with other common anomalies. Eur J Med Genet 57(8): 381–393 Shahrukh Hashmi S et al (2010) Maternal fever during early pregnancy and the risk of oral clefts. Birth Defects Res A Clin Mol Teratol 88 (3):186–194 Slator R et al (2009) Understanding cleft lip and palate. 1: an overview. J Fam Health Care 19(3):101–103 Vijayan V et al (2018) Association of WNT pathway genes with nonsyndromic cleft lip with or without cleft palate. Cleft Palate Craniofac J 55(3):335–341 Zucchero TM et al (2004) Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med 351 (8):769–780

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Antenatal 2-D, 3-D, and 4-D Sonographic Evaluation of Cleft Lip and Palate Safdar Ali Malik and Muhammad Bin Zulfiqar

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification of Cleft Lip (With and Without Palate) and Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Basic Sonographic (2-D and 3-D) Oronasal Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . First Trimester Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Second and Third Trimester Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Abstract

Cleft lip and cleft palate are two of the most commonly encountered congenital anomalies. The key to diagnosing these facial anomalies on antenatal ultrasound is hidden in the complete understanding of embryogenesis of fetal face. On a routine anomaly scan (18–21 weeks) a well-experienced radiologist can detect and categorize these anomalies. With the advent of high-resolution ultrasound machines, having 3-D and 4-D tools, we can now detect signs of cleft lip and palate as early as 12–13 weeks (NT scan) of gestation. We can now classify and categorize the severity of orofacial cleft with associated anomalies. This provides a complete roadmap for postnatal facial reconstruction.

S. A. Malik (*) Services Institute of Medical Sciences, Tamgha-e-Imtiaz Alnoor Institute of Radiology (Alnoor Diagnostic Centre), Lahore, Pakistan M. B. Zulfiqar Radiology SIMS/Alnoor Institute of Radiology (Alnoor Diagnostic Centre), Lahore, Pakistan © Springer Nature Singapore Pte Ltd. 2022 G. Q. Fayyaz (ed.), Surgical Atlas of Cleft Palate and Palatal Fistulae, https://doi.org/10.1007/978-981-15-8124-3_115

Introduction Cleft lip (with or without palatal involvement) and cleft palate are among the most commonly encountered congenital anomalies. Antenatal diagnosis of cleft lip and palate not only helps in reducing psychological trauma faced by parents but also sequentially aids in the antenatal surgical planning for repair. An accurate diagnosis and characterization of cleft lip and palate are very important to detect associated anomalies and to tailor the precise mode of surgery. In the antenatal period, complete midline fusion of lips and alveolar ridges is seen by six weeks and soft and hard palates are fused by 10–12 weeks. The fetal face is studied using two-dimensional (2-D), three-dimensional (3-D), and real-time four-dimensional (4-D) ultrasound. Facial survey of the fetus starts as early as the first trimester. In the first trimester (11–13 weeks gestation), we look for the “Maxillary gap” sign on a standard midsagittal view of the face and retro-nasal triangle by using 3-D technique. In the second and third trimesters, gray scale ultrasound is used to visualize the face in both coronal and sagittal planes for any anatomical defect in lips, alveolar ridges, and intermaxillary segment or midline protruded mass. For

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evaluation of any soft and hard palate abnormalities, volume rendering, multiplanar reconstruction, and “reverse-face” or “flipped-face” 3-D techniques are used.

Epidemiology Orofacial cleft is one of the most common congenital anomalies. Incidence varies from 1 in 600 births to 1 in 1000 births in different parts of the world (Mernagh et al. 1999; Abramson et al. 2015; Smarius et al. 2017) with risk increasing by 4% and 10% if there is a previous family history of a single child or two previous children with cleft lip and palate, respectively (Nyberg et al. 1995). Variable racial predilection has also been observed with cases being more prevalent in Asians (1.5–2/1000) followed by Caucasians (1/1000) and Africans (0.3/1000) (Tolerova and Cervenka 1998). Isolated cleft palate is more commonly encountered in the female population. Global distribution of cleft lip and cleft palate is estimated to be 40–50% followed by isolated cleft palate (30–35%) and isolated cleft lip (20–25%). Ratio on the basis of laterality is 6:3:1 for unilateral left, unilateral right, and bilateral cleft, respectively (Fakhim et al. 2016).

Embryogenesis Development of Lips At 5 weeks of gestation, five facial prominences develop including one frontonasal prominence, two maxillary, and two mandibular prominences. The frontonasal prominence lies in front of the fetal brain. Nasal placodes develop at the lower end of the frontonasal prominence that invaginate to

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form the nasal pit and split the frontonasal prominence into medial and lateral nasal plates as shown in Fig. 1. At 6 weeks of gestation, the medial nasal plates grow towards the midline and fuse resulting in the formation of the midline nose, medial parts of the upper lip, philtrum, columella, tip of the nose, incisor teeth, and the primary palate as shown in Fig. 2. In embryogenesis, the palate is divided into a primary and secondary palate. Primary palate is located in front of the foramen incisivum while secondary palate develops posterior to the foramen incisivum. Lateral nasal plates form the nasal alae and alar base. The maxillary processes grow forward and medially to fuse with medial nasal processes resulting in the formation of the lateral part of upper lip, maxilla, and the secondary palate during 6 weeks of embryogenesis. The lower lips and mandible are formed by the fusion of the mandibular processes. By the end of 6 weeks, the upper, philtrum, nasal prominences, maxilla, lower lips, and the mandible are fused with each other. Any halt in the embryogenesis of frontal prominences at 5–6 weeks may lead to unilateral or bilateral facial clefts with involvement of the primary palate as well.

Development of Palate 1. The palate can be divided into the primary and secondary palate. 2. Primary palate develops from the posterior part of the intermaxillary segment and gives rise to four incisor teeth and extends posteriorly up to the foramen incisivum. 3. Embryogenesis of the primary palate starts at 5 weeks and finishes by 6–7 weeks. 4. The secondary palate develops from the medial margins of the maxilla as an outgrowth in the form of palatine shelves

Fig. 1 Fetal embryogenesis at 5 weeks of gestation showing frontonasal prominences and paired maxillary and mandibular prominences

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Fig. 2 Coronal image of a fetal face at 6 weeks showing well-developed medial and lateral nasal plates

Fig. 3 Axial image of the fetal face at 7–8 weeks showing fusion of the medial and nasal plates and upper lip. Primary palate develops from the posterior part of the intermaxillary segment and secondary palate develops from the medial part of the maxilla

and fuses in the midline in anteroposterior direction as shown in Fig. 3. 5. Some parts of the anterior and posterior palate remain unossified and give rise to the primary palate and uvula respectively, while the intervening part is ossified and gives rise to the hard palate as shown in Fig. 4. 6. Secondary palate embryogenesis is completed by 10–12 weeks of gestation. 7. In parallel with the downward and forward growth of the mandible, the tongue descends as well and helps in the fusion of the palate. Since development of the upper lip, philtrum, intermaxillary segment, and primary palate precedes the secondary palate,

failure of fusion at 9–12 weeks can result in an isolated cleft palate. As growth of the secondary palate is from the foramen incisivum towards the uvula, an intact soft plate suggests an intact hard palate except fenestration. A failure in embryogenesis starting from 6 weeks is associated with both cleft lip and palate.

Classification of Cleft Lip (With and Without Palate) and Cleft Palate Cleft lip (with and without palatal involvement) and cleft palate are considered as two different entities on the basis of underlying genetic malformation, syndromes, and

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Fig. 4 Schematic axial images showing complete development of the palate between 9 and 12 weeks

Associations Cleft lip and palate are associated with a myriad of anomalies and syndromes with prevalence ranging from 21% to 38% (Johnson et al. 2000; Liu et al. 2008). According to the Nyberg classification, type IV and V are associated with the highest rate of associated anomalies followed by Type I, II, and III (Milerad et al. 1997). Antenatal prevalence of concomitant anomalies has been found to be highest in isolated cleft palate (22.2–78.3%) followed by cleft lip and palate (21.1–61.2%) and isolated cleft lip (7.6–41.4%). The most common associated congenital anomalies are: • Congenital heart disease (60%) (atrial septal defect being the most common) • Micrognathia (15%) • Hydrocephalus (5%) Most commonly encountered non-aneuploidic syndromes are: Fig. 5 Nyberg classification

prognosis (Hadadi et al. 2017). Classification of cleft is either based on laterality as unilateral, bilateral, and midline or location as isolated cleft lip, cleft lip with palatal involvement, and isolated cleft palate. Several classification systems exist but the Nyberg 1995 antenatal ultrasound classification is widely accepted because of its notable correlation with the severity of defect and its outcomes. Nyberg classified the defect into five types (Fig. 5): • • • • •

Type I. Isolated cleft lip alone Type II. Unilateral cleft lip and palate Type III. Bilateral cleft lip and palate Type IV. Median/midline cleft lip and palate Type V. Cleft associated with amniotic band syndrome and limb body wall complex

The main drawback of the Nyberg classification is that it does not include isolated cleft palate.

• • • • •

Pierre Robin syndrome Apert syndrome Popliteal pterygium syndrome Turner syndrome and Van der Woude syndrome Most common aneuploidic syndromes are:

• Patau syndrome (trisomy 13) • Edwards syndrome (trisomy 18)

Basic Sonographic (2-D and 3-D) Oronasal Anatomy 2-D Gray Scale Ultrasound On gray scale 2-D ultrasound at 12–13 weeks, a midsagittal view of the face is taken and major landmarks are identified, important among which are the nose, upper lip, and the intervening area between the aforementioned two landmarks as shown in Fig. 6. 2-D ultrasound

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To visualize the hard palate, special 3-D techniques such as reverse 3-D face review and “flipped face” techniques are used as shown in Figs. 9 and 10. The fetal lip and palate morphology is completed by 10–12 weeks making it possible to scrutinize for any cleft in lip and/or palate. By 18–20 weeks, almost all varieties of facial cleft can be identified and diagnosed. Diagnosis of an isolated cleft lip with or without palatal involvement is straightforward while the identification of an isolated cleft palate is often missed on gray scale ultrasound thus rendering 3-D ultrasound more appropriate for defining the palatal anomalies. Associated anomalies which can be identified are:

Fig. 6 Sagittal view of the fetal head during first-trimester aneuploidy screening purposes (measuring the nuchal translucency (NT) thickness and assessing the nasal bone (NB)). The facial structures that are clearly visualized at this gestational age are: 1. frontal bone; 2. prefrontal and prenasal subcutaneous tissue; 3. nasal skin; 4. tip of the nose; 5. upper lip; 6. lower lip; 7. chin; 8. palate; 9. oral cavity and tongue; 10. mandibular bone

1. 2. 3. 4. 5. 6.

Increased Nuchal Translucency (NT) Micrognathia Cardiac defects Polyhydramnios Nasal bone abnormalities Lateral ventricular dilatation

First Trimester Ultrasound In the first trimester three important soft tissue landmarks exist: • Maxillary gap • Retronasal triangle • Premaxillary protrusion

Fig. 7 Annotated coronal view of the fetal face in the first trimester. MS: metopic suture; FB: frontal bone; O: orbit; RNT: retronasal triangle (alveolar ridge and frontal processes of the maxilla with the nasal bones on the top); M, mouth; MB, mandibular bone; MG, mandibular gap. Right panel and calipers delineating the mandibular gap

screening has a lower detection rate in low-risk populations but is associated with fewer false-positive results (Maarse et al. 2010).

3-D Ultrasound Important landmarks such as the retronasal triangle, maxilla, nasal bone, alveolar ridge, and mandible can also be identified using 3-D imaging at 12–13 weeks (Fig. 7) (Ghi et al. 2009). 2-D and 3-D ultrasound can be utilized at 18–20 weeks to identify the fetal nose, nostrils, upper and lower lips, philtrum, and the intermaxillary segment (Fig. 8).

Maxillary Gap In the first trimester ultrasound, we usually take a midsagittal view of the face to look for NT by using a transabdominal and transvaginal approach (for suspicious cases). With this view, we can measure the maxillary gap which is an area between the intermaxillary segment and echogenic soft palate as shown in Fig. 8 (Chaoui et al. 2015). This gap may be present in a normal fetus as well, owing to the incomplete ossification of the maxilla and palatine bone, thereby setting the upper normal limit for this gap at 1.5 mm (Chaoui et al. 2015). When the maxillary bone and palatine shelves have completely ossified, an echogenic line can be seen extending from the intermaxillary segment towards the posterior limit of the oral cavity. This line acts as a partition between the nasal and oral cavities (Fig. 10). When the maxillary gap is present, a clear gap can be appreciated in the echogenic line as shown in Fig. 11, which compares a normal fetus and a fetus with a maxillary gap. Normally, this gap extends in an anteroposterior manner, and in certain cases, there is complete absence of this gap. Henceforth, maxillary gap serves as one of the very initial and important soft tissue markers for the evaluation of the growth of the orofacial compartment. In Fig. 12, we compare a normal maxilla with the variable severity levels of a

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Fig. 8 Gray scale and 3-D images of the fetus at 23 weeks of gestation showing normal morphology of the nostrils, upper and lower lips, intermaxillary segment, cheeks, and chin

Fig. 9 Reverse facial view technique described by Campbell et al. (Moss 2001; Gillham et al. 2009) in which the cut plane (green arrows) is directed from the back of the skull towards the front. When the 3-D volume is rendered, the transverse hard palate can be identified

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Fig. 10 By using the 3-D “flipped face” technique, both hard and soft palate are visualized

Fig. 11 Midsagittal and coronal view of a normal fetus is seen in both gray scale and 3-D images with normal appearance of the maxillary line, nasal bone, and upper lip

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Fig. 12 Schematic diagram showing the midsagittal view of the face at 11–13 weeks. (a) Normal fetus with a normal maxillary and palatine bone; (b) fetus with a “maxillary gap” sign

maxillary gap to almost complete absence (Chaoui et al. 2015; Lachman et al. 2018).

Retronasal Triangle Retronasal triangle is also one of the very important landmarks for the evaluation of a fetal palate. Both transabdominal and transvaginal scans are done to characterize its presence. 3-D and multiplanar ultrasound images are used for delineation of the boundaries of the triangle. A midsagittal image of the face is selected and by using multiplanar technique, a simultaneous coronal view of the face is obtained as shown in Fig. 13. On coronal images, anterolateral paired echogenic lines show frontal processes of the maxilla and the horizontal inferior echogenic lines show the alveolar ridges and palate as we go before backward as illustrated in Figs. 7 and 13. As we move further, posteriorly, in the coronal plane, the hard palate is visualized and other parts of retronasal triangle start to fade out. Any disparity in the horizontal part of the retronasal triangle raises the suspicion of a cleft palate (Sepulveda et al. 2010). As shown in Fig. 14, transabdominal ultrasound of a fetus at 12.2 weeks of gestation shows a deficient horizontal segment of the retronasal triangle on coronal view. Additionally, increased NT and generalized body wall edema is also appreciated. This case was later proved to be bilateral cleft lip and palate. Figure 15 shows a malformed horizontal segment of the retronasal triangle and this case later proved to be having holoprosencephaly and cleft palate (Sepulveda et al. 2010; Li et al. 2015; Suresh et al. 2006). Premaxillary Soft Tissue Mass Premaxillary soft tissue mass is another very important landmark in first trimester ultrasound. It is formed due to the migration of the hard palate, teeth, and malformed upper lip

Fig. 13 Midsagittal gray scale ultrasound images of the fetal face at 12–13 weeks of gestation shows a maxillary gap in the maxillary line shown by arrow

(Nyberg et al. 1993). It appears as a protuberant paranasal soft tissue mass between the tip of the nose and the upper lip and in front of the palate in the midsagittal view. Premaxillary protrusion warrants a complete anatomical survey of the fetus to rule out any associated anomalies and conduct cytogenetic sampling if indicated (Suresh et al. 2006; Nyberg et al. 1993; Ghi et al. 2009). Figure 16 shows multiplanar and 3-D surface rendered images of a fetus in the first trimester with premaxillary

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Fig. 14 Retronasal triangle: Midsagittal view of the face is taken that shows the nasal bone, intermaxillary segment, and palate. Using multiplanar, oblique view technique, a simultaneous coronal image at the level of the reference line (dotted line) is obtained

Fig. 15 On Transabdominal midline sagittal image at 12–13 weeks’ gestation. (a) Midsagittal and (b) coronal views show abnormal configuration of the retronasal triangle with premaxillary protrusion on

midsagittal view and a bilateral gap in alveolar ridge on coronal view. This fetus later proved to have bilateral cleft lip and palate

protrusion in gray scale simultaneous midsagittal, coronal, axial images (Fig. 17). Presence of any one or more primarily raises strong suspicion of a cleft palate and secondarily gives hints toward cleft lip or cleft of both components. These landmarks warrant a more detailed survey of the fetus to detect any associated anomalies.

First trimester is the best time for cytogenetic sampling of the fetus and this can serve as adjunct to rule out aneuploidic and non-aneuploidic syndromic sequences. In cases of highrisk pregnancies such as advanced maternal age, maternal alcohol use or smoking, history of congenital anomalies, and cleft lip and palate detailed counseling of the parents is advised (Nyberg et al. 1993; Ten et al. 2012).

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Fig. 16 Schematic diagram of the face showing premaxillary protrusion compared with normal face. It is due to the migration of hard palate, incisors teeth, and part of malformed upper lip

Fig. 17 Multiplanar simultaneous midsagittal and coronal images of a fetus at 12–13 weeks of gestation show midline premaxillary protrusion indicative of bilateral cleft lip and palate. Coronal 3-D image of the fetus confirm premaxillary protrusion

Second and Third Trimester Ultrasound Second trimester ultrasound between 18 and 22 weeks is a gateway to detect almost all important fetal anomalies including isolated cleft lip and cleft palate. Soft tissue details are most obvious at this stage and ossification of the palate is good enough to detect all palate-related anomalies. Diagnosing cleft lip with and without palate is very straightforward on careful evaluation of fetal face. 2-D transabdominal scan can easily detect cleft lip and palate. Isolated cleft palate is one of the commonly missed fetal anomalies on 2-D ultrasound. Whenever there is a

suspicion, we use a 3-D ultrasound technique to detect the cleft lip and palate, for better pre-surgical planning and providing parents assurance. Multiple techniques of 3-D ultrasound are employed, such as: • Multiplanar oblique reconstruction (Ten et al. 2012) • 3-D surface rendering (Platt 2006) • 3-D “reverse face” view (Campbell et al. 2005; Mak and Leung 2019) • 3-D “reverse face” flipped view (Ten et al. 2012) as well as different types of filters

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Antenatal 2-D, 3-D, and 4-D Sonographic Evaluation of Cleft Lip and Palate

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Fig. 19 2-D ultrasound (second trimester) of a fetus shows fetal nose, upper and lower lips. An anechoic cleft dividing the right side of fetus’ upper lip with slight impaired morphology of the fetal nose. (Abramson et al. 2015) Fig. 18 2-D (second trimester) ultrasound showing fetal nose and mouth; an anechoic line is seen partially involving the fetus’ upper lip (arrowhead). (Mak and Leung 2019)

Gray Scale 2-D Ultrasound On 2-D gray scale ultrasound, an anechoic cleft or line is seen in the line of cleft. This anechoic line may be partially involving the lip or palate (Abramson et al. 2015; Platt 2006). It may be complete, unilateral, or bilateral. It may be midline or there may be a premaxillary mass in case of a bilateral cleft lip or palate. In Fig. 18, fetal nose and upper lip can be appreciated with a cleft partially dividing the fetus’ upper lip. It is not involving the fetal nose as evidenced by the normal nostrils and normal outline of the nasal ala suggesting partial, unilateral cleft lip. Figure 19 shows another fetal face with an anechoic cleft completely dividing the fetal lip and causing slight morphological impairment of fetal nose suggesting a complete, right sided, unilateral cleft lip. Two anechoic clefts appearing in the fetal lip without a significant premaxillary mass suggest bilateral, complete cleft lip. Figure 20 shows a fetus with nostrils, upper lip, and part of the lower lip as well as two anechoic clefts completely dividing the fetus’ upper lip suggestive of bilateral, complete cleft lip. A premaxillary protrusion seen in the second trimester is also a sign of bilateral, complete cleft lip and palate as mentioned previously, in the first trimester (Fig. 21). 3-D and 4-D Ultrasound While 2-D ultrasound can diagnose almost all types of oronasal clefts (except isolated cleft palate), 3-D and realtime 4-D ultrasound have many added benefits over conventional 2-D ultrasound as discussed in the tabulated form.

Fig. 20 2-D ultrasound of a fetal face showing fetal nostrils, upper lip, and part of the lower lip. Bilateral anechoic lines are seen completely partitioning the fetal lip. (Mak and Leung 2019) Advantages of 3-D ultrasound • We can see the real face of fetus • Facial expressions can be seen • Hard-to-see structures can be imaged, for example, alveolar ridge and hand palate • Parents can see the simulated true appearance of the fetus • Counseling by other non-imaging physicians is facilitated • Bedside or off-line analysis – Date sharing for expert opinion and data is reevaluated and compared on next session • Short processing time

Multiplanar, 3-D reconstructed images in a second trimester fetus in Fig. 17 shows bilateral anechoic clefts seen extending through the upper lip and palate with a

50

premaxillary protrusion suggesting complete cleft lip and palate. By using 3-D surface rendering technique, the fetal face is better visualized and anomalies are more easily picked up (as shown by the left-sided unilateral cleft in Fig. 22). When a cleft palate cannot be visualized on a conventional 2-D ultrasound, “reverse face” view 3-D technique may be used to visualize the face from backwards. The palate as well as other defects can be easily visualized in a coronal view section using the 3-D technique.

Fig. 21 Ultrasound in midsagittal view of a second trimester fetus shows fetal nose, lower lip, and chin. A premaxillary mass is seen protruding anteriorly giving the appearance of premaxillary protrusion highly suggestive of a bilateral, complete cleft lip and palate

Fig. 23 3-D frontal view shows left-sided cleft lip; with the umbilical cord crossing the chin and left cheek. Reverse face view shows a narrow cleft of the secondary palate

S. A. Malik and M. B. Zulfiqar

In Fig. 23, a case is shown by using reverse 3-D face technique. Initially, the cleft palate is not clearly visualized on coronal surface rendered images but after moving posteriorly from the lip, the cleft becomes visualized. The main drawback of this technique is that the palate is not seen in the axial view (Campbell et al. 2005). This drawback can be

Fig. 22 3-D surface rendered image of a fetus showing a cleft in left side of upper lip also mildly distorting the fetal nose

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Antenatal 2-D, 3-D, and 4-D Sonographic Evaluation of Cleft Lip and Palate

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Fig. 24 3-D reverse flipped face views. In this case, a cleft is seen on the right side of the fetus’ upper lip with extension into the hard palate. (Platt et al. 2006)

Fig. 25 Surface rendered 3-D images showing a left sided, unilateral cleft in right panel, bilateral cleft lip in the mid panel and, premaxillary protrusion in the left panel

overcome by using a reverse 3-D flipped face view with simultaneous visualization of the axial, coronal, and sagittal planes of the face and superadded by surface rendered 3-D images of the fetus (as shown in Fig. 24).

In Fig. 25, surface rendered images of different fetal faces are seen with increasing severity of cleft from left unilateral cleft lip to bilateral cleft lip and premaxillary protrusion (bilateral complete cleft lip and palate).

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Conclusion Prenatal ultrasound is the most comfortable way to diagnose cleft lip alone or cleft lip and palate as early as 16 weeks of gestation. Precise and timely diagnosis is particularly important in the counselling of parents along with the involvement of a multidisciplinary team for further management.

References Abramson ZR et al (2015) Radiology of cleft lip and palate: imaging for the prenatal period and throughout life. Radiographics 35: 2053–2063 Campbell S et al (2005) Ultrasound antenatal diagnosis of cleft palate by a new technique: the 3D ‘reverse face’ view. Ultrasound Obstet Gynecol 25:12–18 Chaoui R et al (2015) Maxillary gap at 11–13 weeks’ gestation: marker of cleft lip and palate. Ultrasound Obstet Gynecol 46:665–669 Fakhim SA et al (2016) Prevalence of associated anomalies in cleft lip and/or palate patients. Iran J Otorhinolaryngol 28(2):Serial No. 85 Ghi T et al (2009) Three-dimensional sonographic imaging of fetal bilateral cleft lip and palate in the first trimester. Ultrasound Obstet Gynecol 34:119–121 Gillham JC et al (2009) Antenatal detection of cleft lip with or without cleft palate: incidence of associated chromosomal and structural anomalies. Ultrasound Obstet Gynecol 34:410–415 Hadadi AI et al (2017) Congenital anomalies associated with syndromic and non-syndromic cleft lip and palate. JPRAS Open 14:5e15 Johnson DD et al (2000) Fetal lip and primary palate: three-dimensional versus two-dimensional US. Radiology 217(1):236–239 Lachman R et al (2018) Isolated cleft lip and palate: maxillary gap sign and palatino-maxillary diameter at 11–13 weeks. Fetal Diagn Ther 44:241–246

S. A. Malik and M. B. Zulfiqar Li WJ et al (2015) Clinical significance of first-trimester screening of the retronasal triangle for identification of primary cleft palate. Fetal Diagn Ther 38:135–141 Liu Y, Freitas Rda S, Magriples U et al (2008) Fetal diagnosis of cleft lip: natural history and outcomes. J Craniofac Surg 19(5):1195–1198 Maarse W, Bergé SJ, Pistorius L et al (2010) Diagnostic accuracy of transabdominal ultrasound in detecting prenatal cleft lip and palate: a systematic review. Ultrasound Obstet Gynecol 35(4):495–502 Mak ASL, Leung KY (2019) Prenatal ultrasonography of craniofacial abnormalities. Ultrasonography 38:13–24 Mernagh JR, Mohide PT, Lappalainen RE et al (1999) US assessment of the fetal head and neck: a state-of-the-art pictorial review. Radiographics 19 Spec No:S229–S241 Milerad J, Larson O, Hageberg C, Ideberg M (1997) Associated malformations in infants with cleft lip and palate: a prospective, population- based study. Paediatrics 100:180–186 Moss A (2001) Controversies in cleft lip and palate management. Ultrasound Obstet Gynecol 18:420–421 Nyberg DA et al (1993) Premaxillary protrusion: a sonographic clue to bilateral cleft lip and palate. J Ultrasound Med 12:331–335 Nyberg DA, Sickler GK, Hegge FN, Kramer DJ, Kropp RJ (1995) Fetal cleft lip with and without cleft palate: US classification and correlation with outcome. Radiology 195:677–684 Platt LD et al (2006) Improving cleft palate/cleft lip antenatal diagnosis by 3-dimensional sonography the “flipped face” view. J Ultrasound Med 25:1423–1430 Sepulveda W et al (2010) Retronasal triangle: a sonographic landmark for the screening of cleft palate in the first trimester. Ultrasound Obstet Gynecol 35:7–13 Smarius B et al (2017) Accurate diagnosis of prenatal cleft lip/palate by understanding the embryology. World J Methodol 7(3):93–100 Suresh S et al (2006) The premaxillary triangle: clue to the diagnosis of cleft lip and palate. J Ultrasound Med 25:237–242 Ten PM et al (2012) First-trimester diagnosis of cleft lip and palate using three-dimensional ultrasound. Ultrasound Obstet Gynecol 40:40–46 Tolerova M, Cervenka J (1998) Classification and birth prevalence of orofacial clefts. Am J Med Genet 75(2):126–137

8

Genetic Factors Responsible for Cleft Lip and Palate Xiaoqian Ye and Mairaj K. Ahmed

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Syndromic Orofacial Cleft (SOFC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Common Syndromes Associated with Orofacial Cleft . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Non-Syndronic Orofacial Cleft (NSOFC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Genetic Studies of NSOFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Linkage Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chromosomal Aberrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Candidate Gene Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genome-Wide Association Studies (GWAS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Next Generation Sequencing (NGS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Genes and Genetic Loci Involved in Nonsyndromic Orofacial Clefts . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60 60 60 61 61 61 63

Recurrence Risk of NSOFC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Abstract

Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), are one of the most common birth defects with an estimated prevalence of 1: 1000 live births. On the basis of association with other anomalies, OFCs can be classified as X. Ye Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA M. K. Ahmed (*) Department of Dentistry, Montefiore Medical Center / Albert Einstein College of Medicine, Bronx, NY, USA Department of Dentistry/Oral Maxillofacial Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Surgery, Division of Plastic and Reconstructive Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2022 G. Q. Fayyaz (ed.), Surgical Atlas of Cleft Palate and Palatal Fistulae, https://doi.org/10.1007/978-981-15-8124-3_95

syndromic (30%) and nonsyndromic (70%). To date, the major causes of OFCs remain largely unknown. Chromosomal abnormalities, Mendelian single gene mutations, and teratogenic effects, as well as uncharacterized interactions between genetic and environmental factors are reported to be involved. Recently, various genetic approaches such as linkage analysis, case-control studies, genome-wide association studies (GWAS), candidate gene studies, and whole exome or whole genome sequencing have identified multiple genes/loci involved in the etiology of OFCs. Here, we briefly review the multiple genes/loci and molecular pathways that have been implicated in OFCs during the last few decades. The aim of this review is to provide a better understanding of the molecular pathogenesis of OFCs and to help with a more accurate diagnosis, genetic counseling, and personalized treatment decisions for better clinical care and prevention of OFCs.

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Introduction Orofacial clefts (OFCs) are one of the most common human birth defects with an incidence of 1 in 500 to 1000 (Lidral and Murray 2004). The etiology is highly complex and multifactorial involving both genetic and environmental factors. Orofacial clefts are generally categorized into clefts affecting the lip only (CL), the palate only (CP), or both the lip and palate (CLP). CL and CLP have traditionally been considered variants of the same defect; however, recent epidemiological and biological data suggest unique genetic etiologies may exist (Grosen et al. 2010; Rahimov et al. 2008). OFCs are additionally classified into nonsyndromic (isolated) cleft lip and/or palate and syndromic cleft lip and/or palate based on additional physical and/or cognitive anomalies. Multiple genes are associated with both nonsyndromic and syndromic cleft lip and/or cleft palate. The etiology of nonsyndromic clefts appears to be more complex and multifactorial, likely resulting from gene-gene and geneenvironmental interactions, whereas syndromic cleft lip and palate have a stronger documented pattern of hereditary (Stuppia et al. 2011). Studies have implicated multiple genes involved in the genesis of cleft lip and palate (Marazita et al. 2002; Field et al. 2004). Identification of such key genes and characterization of both gene-environment and gene-gene interactions will help in early diagnosis, risk counseling, and possibly in the development of adjunctive preventive therapies.

Syndromic Orofacial Cleft (SOFC) Over 400 syndromes have been identified in which orofacial cleft is a primary feature (http://www.ncbi.nlm.nih.gov/ OMIM). 75% of these described syndromes have a known genetic cause and are caused by Mendelian inheritance of mutation at a single gene, genetic locus, chromosomal abnormalities, or teratogens (Leslie and Marazita 2013). Table 1 summarizes selected oral cleft syndromes with their genetic cause.

Common Syndromes Associated with Orofacial Cleft Monogenic Disorders Van der Woude Syndrome (VWS) Van der Woude syndrome (VWS, OMIM #119300) is the most common form of syndromic oral clefts, accounting for 2% of all orofacial cases, with a birth prevalence rate of approximately 1 in 35,000. VWS is inherited in an autosomal dominant mode with high penetrance (96.7%) and variable

X. Ye and M. K. Ahmed

manifestations. In VWS patients, lower lip pits and/or sinuses are considered to be the main characteristic features, which vary from a single barely evident depression to bilateral fistulae. Lip pits are present in 75–80% of VWS cases and are the only visible defect in 64% VWS patients. The other frequently associated phenotypes with VWS include cleft lip with or without cleft palate, cleft palate only, and hypodontia. Another syndrome closely mimicking VWS is popliteal pterygium syndrome (PPS, OMIM # 119500). It combines VWS signs and symptoms with popliteal and oral webs, unusual nails, syndactyly, ankyloblepharon, and genital anomalies (Peyrard-Janvid et al. 2005). To date, over 300 mutations causing 70% of families with VWS and PPS have been reported in different populations across the world, and these include missense, nonsense, and frameshift, microdeletions, and splice-site mutations. These mutations are nonrandomly distributed and observed to be enriched in exon 4, which is in the highly conserved DNA-binding domain. Exon 7 and 9, which are in the lessconserved mutations that add a termination codon into IRF6, were reported to be found more often in families with VWS than with PPS (Yeetong et al. 2009). IRF6 belongs to a family of transcription factors. The families share a conserved helixturn-helix DNA-binding domain (DBD) and a less conserved Smad-interferon regulatory factor-binding domain (SMIR). While coding mutations of IRF6 can cause syndromic orofacial clefts, polymorphisms near IRF6 are over transmitted in patients with nonsyndromic orofacial clefting. Additional evidence including linkage analyses, candidate gene analyses, and genome-wide association studies have confirmed the relationship between IRF6 and NSOFC as well. In 2004, by using a combination of whole-exome and Sanger sequencing methods, a second causative gene GRHL3 was identified in eight families with VWS who were negative in IRF6 mutation, confirming locus heterogeneity for this syndrome. Individuals with GRHL3 mutations were more likely to have CP and less likely to have CL/P than individuals with IRF6 mutations, and like IRF6, common variants in GRHL3 may also be associated with isolated forms of orofacial clefting (Peyrard-Janvid et al. 2014) (Fig. 1). Treacher Collins Syndrome Treacher Collins Syndrome (TCS, OMIM #154500), also named Franceschetti–Zwahlen–Klein syndrome, is a rare congenital birth disorder (1 in 50,000 live births). TCS belongs to a clinically and genetically heterogeneous group of craniofacial development disorders involving particularly the first and second branchial arches. It is characterized by a combination of malar and mandibular hypoplasia, downward slanting of the palpebral fissures, coloboma of the lower eyelids, sparse eyelashes, and cleft lip with or without cleft palate. Malformations of the external and the middle ears are responsible for bilateral conductive hearing loss. The most

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Table 1 Selected CL/P syndromes with known genetic cause. (Adapted from Beaty et al. 2016) Phenotype OMIM number 106,260

Inheritance mode AD

Location 3q28

Cleft phenotype observed CL/P

Identified gene TP63

101,200 241,850 263,650 113,620 114,290

AD AR AR AD AD

10q26.13 9q22.33 21q22.3 6p24.3 17q24.3

CP CP CL/P CL/P CP

FGFR2 FOXE1 RIPK4 TFAP2A SOX9

214,800 214,800 225,060 122,470 300,590 610,759 614,701 300,882 123,500 188,400 604,292

AD AD AR AD XLD AD AD XLD AD AD AD

8q12.2 7q21.11 11q23.3 5p13.2 Xp11.22 10q25.2 8q24.11 Xq13.1 10q26.13 22q11.21 3q28

CP CL/P CP CP CP CP CP CP CP CL/P

CHD7 SEMA3E PVRL1 NIPBL SMC1A SMC3 RAD21 HDAC8 FGFR2 TBX1 TP63

137,215 109,400 109,400 109,400 610,829 142,945 157,170 142,946 609,637 610,828 612,313 147,920 300,867 147,950 265,000 609,192 610,168 263,750 300,166 300,000 145,410 175,700 311,200 311,300 261,800

AD AD AD AD AD AD AD AD AD AD AD AD XLD AD AR AD AD AR XLD XLR AD AD XLD XLD AR

CL/P CL/P CL/P CL/P CL/P CL/P CL/P CL/P CL/P CL/P CP CL/P CL/P CL/P CP CP CP CP CP CL/P CL/P CL/P CL/P CP CP

CDH1 PTCH1 PTCH2 SUFU GLI2 SHH SIX3 TGIF1 ZIC2 PTCH1 SATB2 MLL2 KDM6A FGFR1 CHRNG TGFBR1 TGFBR2 DHODH BCOR MID1 SPECC1L GLI3 OFD1 FLNA SOX9

Popliteal pterygium Saethre-Chotzen Siderius X-linked mental retardation Stickler type 1 Stickler type 2

119,500 101,400 300,263 108,300 604,841

AD AD XLR AD AD

16q22.1 9q22.32 1p34.1 10q24.32 2q14.2 7q36.3 2p21 18p11.31 13q32.3 9q22.32 2q33.1 12q13.12 Xp11.3 8p11.23 2q37.1 9q22.33 3p24.1 16q22.2 Xp11.4 Xp22.2 22q11.23 7p14.1 Xp22.2 Xq28 17q24.3q25.1 1q32.2 7p21.1 Xp11.22 12q13.11 1p21.1

CL/P CP CL/P CP CP

Tetra-amelia with CLP

273,395

AR

17q21

CL/P

IRF6 TWIST1 PHF8 COL2A1 COL11A1, COL11A2 WNT3 (continued)

Syndrome Ankyloblepharon-ectodermal dysplasia-clefting Apert Bamforth-Lazarus Bartsocas-Papas Branchio-oculo-facial Campomelic dysplasia, Pierre Robin sequence CHARGE CHARGE CLP ectodermal dysplasia Cornelia de Lange Cornelia de Lange Cornelia de Lange Cornelia de Lange Cornelia de Lange Crouzon DiGeorge Ectrodactyly-ectodermal dysplasiaclefting Familial gastric cancer and CLP Gorlin Gorlin Gorlin Holoprosencephaly Holoprosencephaly Holoprosencephaly Holoprosencephaly Holoprosencephaly Holoprosencephaly Isolated cleft palate Kabuki Kabuki Kallmann Lethal and Escobar multiple pterygium Loeys-Dietz Loeys-Dietz Miller Oculofaciocardiodental Opitz G/BBB Opitz G/BBB Orofacial-digital Orofacial-digital type 1 Otopalatodigital types 1 and 2 Pierre Robin

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Table 1 (continued) Syndrome Tooth agenesis with or without cleft Treacher Collins Treacher Collins Treacher Collins Treacher Collins Van der Woude Van der Woude X-linked cleft palate and ankyloglossia

Phenotype OMIM number 106,600 154,500 613,717 248,390 618,939 119,300 606,713 303,400

Inheritance mode AD AD AD, AR AR AD AD AD XLR

Location 4p16 5q32-q33 13q12.2 6p21.1 2q14.1 1q32.2 1p36 Xq21.1

Cleft phenotype observed CL/P CP CP CP CP CL/P CL/P CP

Identified gene MSX1 TCOF1 POLR1D POLR1C POLR1B IRF6 GRHL3 TBX22

AD: autosomal dominant; AR: autosomal recessive; XLD: X-linked dominant; XLR: X-linked recessive

a

b

c

d

Fig. 1 Variable phenotypes of VWS syndrome patients within a large family: (a) Proband’s grandmother has a bilateral cleft lip (repaired), unilateral asymmetric lower lip pits, and cleft palate; (b) Proband’s father has affected bilateral symmetric lower lip pits, cleft lip (repaired),

and cleft palate; (c) Proband’s uncle has unilateral lower lip pits, cleft lip (repaired), and cleft palate; and (d) Proband has bilateral lower lip pits, cleft lip (repaired), and cleft palate

frequent dental anomalies are tooth agenesis predominantly affecting the mandibular second premolars, and enamel opacities. Together, these features contribute to speech and

language difficulties, visual impairment or loss, conductive hearing loss, breathing difficulty, and obstructive sleep apnea (Dixon 1996).

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Genetic Factors Responsible for Cleft Lip and Palate

To date, TCS has been proven to be genetically heterogeneous, and four genes have been involved with a dominant (TCOF1, POLR1D) or a recessive (POLR1D, POLR1C) autosomal mode of inheritance. Among known causative genes, TCOF1 is the major gene and is responsible for approximately 80–85% autosomal dominant cases. TCOF1 involves and encodes the nucleolar phosphoprotein Treacle, acting in ribosomal RNA transcription by interacting with upstream binding factor and RNA polymerase I. TCOF1 is also involved in the proliferation and differentiation of neural crest cells in the first and second branchial arches during early embryogenesis (Dixon 1996). POLR1C and POLR1D mutations account for a small subset of patients with TCS (less than 10% of patients) without TCOF1 mutations. POLR1D and POLR1C encode subunits of RNA polymerase I and III, respectively, which are involved in the synthesis of ribosomal RNA precursors and small RNAs (Dauwerse et al. 2011; Schaefer et al. 2014). By trio-exome sequencing in patients who were negative for mutation in all known mandibulofacial dysostosis-associated genes, heterozygous missense mutations in the POLR1B gene were identified in 2 probands with TCS (Sanchez et al. 2020). X-Linked Cleft Palate with Ankyloglossia X-linked cleft palate (CPX, OMIM # 303400) is characterized by X-linked Mendelian inheritance. The cleft phenotype predominantly affects males, with considerable variation ranging from a complete cleft of the secondary palate, submucous cleft, or bifid uvula to high arched palate. Ankyloglossia is frequently seen in affected patients and carrier females. CPX is caused by mutations in TBX22 (Braybrook et al. 2001). Many mutations of TBX22 have been reported, including nonsense, frameshift, splice site, or missense mutation (Marçano et al. 2004). In addition to familial cases with well-defined CPX, TBX22 mutations have also been found in many sporadic nonsyndromic cleft palate cases, as well as cleft lip and palate, hypodontia, and limb anomaly (Suphapeetiporn et al. 2007). TBX22 encodes a T box containing transcription factor that shares a highly conserved DNA-binding domain which encodes 180 amino acids. It is part of the TBX1 subfamily and shares a close evolutionary origin with TBX15 and TBX18. Members of this gene family (Tbx1, Tbx15, Tbx10, Tbx18 and Tbx22) are all expressed in the craniofacial area, and mutation of Tbx1 and Tbx10 results in cleft palate phenotypes. Additionally, haploinsufficiency of the TBX1 gene is the major gene responsible for DiGeorge syndrome, which includes cleft palate as a presenting feature (DGS; OMIM # 188400). Expression of Tbx22 in mouse and chicken is seen in the posterior palate, caudal tongue, nasal mesenchyme, extraocular mesenchyme, and early somites. This pattern correlates well with the phenotypic characteristics found in CPX patients but suggests additional roles for TBX22 in

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development (Pauws et al. 2013). Although the defects associated with mutations in TBX22 are obvious at birth, the underlying developmental pathogenesis remains unclear. TP63 Syndrome Ectrodactyly-Ectodermal-Dysplasia-Clefting syndrome (EEC, OMIM # 604292) is a rare autosomal-dominantly inherited condition characterized by split hands and feet, ectodermal dysplasia, and cleft lip and/or cleft palate. Additional EEC features include lacrimal duct anomalies, urogenital defects, conductive hearing loss, chronic respiratory infections, ventricular cardiomyopathy, and developmental delay. Limb-Mammary syndrome (LMS, OMIM # 603543) is an EEC-like syndrome with two major symptoms: ectrodactyly, and hypoplastic mammary glands and nipples. In contrast to EEC, LMS patients rarely have hair and skin involvement, and if facial clefting is present, it is limited to the palate (Maas et al. 1996). Most cases (> 80%) of classic EEC and LMS are caused by TP63 gene mutations. Mutations of TP63 are also responsible for the following syndromic malformations, AnkyloblepharonEctodermal dysplasia-Clefting (AEC, OMIM # 106260), AcroDermato-Ungual-Lacrimal-Tooth (ADULT, OMIM # 103285, an LMS-like syndrome with ectrodactyly, and mammary hypoplasia plus excessive freckling, but without facial clefting), and Rapp-Hodgkin ectodermal dysplasia (RHS, OMIM # 129400, an AEC-like syndrome with characteristic midfacial hypoplasia). In addition, two nonsyndromic human disorders are associated with TP63 mutations: isolated split hand/foot malformation type IV (SHFM-IV, OMIM # 605289) and nonsyndromic cleft lip/palate. The term “TP63 syndromes” is therefore suggested for these related disorders featured by overlapping phenotype spectrums. Analysis of large amounts of data has demonstrated distinct TP63 mutation patterns and locations for each of these syndromes. The apparent genotype-phenotype relationship is partially attributed to the various biochemical structures of TP63. An unusual phenomenon with TP63 is the differential mutation of the gene which can influence the cleft phenotype. Missense mutation of the conserved DNA-binding domain region results in cleft lip and palate while C-terminal mutations give cleft lip or palate. Mutation at the N-terminal end outside of the conserved domains gives rise to cleft palate or no clefting at all (Celli et al. 1999; Yin et al. 2010). TP63 encodes a transcription factor, which is a master regulator of epithelial lineage commitment during and after development. Mutations are dispersed in all functional domains of TP63, with a well-established genotype-phenotype correlation. Penetrance is incomplete and variable expressivity is observed. EEC point mutations cluster in the DNA-binding domain (DBD) and have a disruptive effect on DNA-binding characteristics of all expressed isoforms. The effects of these mutations on the counterpart wild-type allele are thought to be dominant negative (Maclean et al. 2007) (Fig. 2).

58 Fig. 2 Clinical features of three affected subjects with EEC and LMS: (a) bilateral complete cleft lip (repaired) and cleft palate; (b, c) severe ectrodactyly and clinodactyly anomaly of both hands and feet; (d) radiograph of bilateral ectrodactyly and complete unilateral fusion of phalanges 1 and 2 on the left hand; (e, f) typical “lobster-claw” malformations on both hands and feet in patient 2. Note syndactyly of both toes with dystrophic nails; (g, h) cutaneous syndactyly of the 2, 3, and 4 digits on both feet, and partial absence of phalange 2 on the left foot, and (i) panoramic radiograph of 13-year-old female with multiple congenitally missing permanent teeth in the maxillary and mandibular arches

X. Ye and M. K. Ahmed

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Genetic Factors Responsible for Cleft Lip and Palate

Cleft Lip/Palate-Ectodermal Dysplasia Syndrome Autosomal recessive CLP with ectodermal dysplasia (CLPED1, OMIM # 225060), also referred to as ZlotogoraOgur syndrome or Margarita Island ectodermal dysplasia, is characterized by cleft lip/palate, hidrotic ectodermal dysplasia, developmental defects of the hands, and in some cases mental retardation. CLPED1 occurs with a frequency of approximately 1 per 2,000 among the Indigenous population of Margarita Island (north of Venezuela). Mutations were identified in the CLPED1 gene as PVRL1, encoding Nectin1, an immunoglobulin-related transmembrane cell-cell adhesion molecule that is part of the NAP cell adhesion system and is expressed in the developing face and palate (Suzuki et al. 2000). Being that Nectin-1 is the principle cell surface receptor for herpesvirus, it is speculated that the high frequency of heterozygotes might have resulted from relative resistance to infection by viruses such as HSV1and HSV2. In Margarita Island patients, CLPED1 is generally caused by homozygosity of a nonsense mutation W185X in the PVRL1 gene, while heterozygosity is high in the unaffected population. A highly significant association was detected between heterozygosity of the same W185X mutation and sporadic, nonsyndromic cleft lip with or without cleft palate in northern Venezuela, which could be a significant risk factor for nonsyndromic cleft lip/palate (Sözen et al. 2001). Whether PVRL1 mutations contribute to nonsyndromic clefts in other geographical locations remains to be seen.

Chromosomal Abnormalities Pierre Robin Sequence (PRS) Pierre Robin sequence (PRS, OMIM # 261800) was first described by Robin (1923) and is an autosomal recessive craniofacial anomaly. It is characterized by the triad of airway obstruction, micrognathia, and glossoptosis, leading to feeding and respiratory difficulties during the early postnatal period (Jakobsen et al. 2006). The reported incidence varies between 1 in 8500 to 14,000. A wide U-shaped cleft palate is commonly associated with this condition. Family members of individuals with PRS have been found to have a higher incidence of cleft lip and palate, and there is a higher incidence of twins with PRS. Cleft palate is associated with deletions on 2q and 4p, and duplications on 3p, 3q, 7q, 78q, 10 p, 14q, 16p, and 22q. Micrognathia is associated with deletions in 4p, 4q, 6q, and 11q, and duplications on 10q and 18q (Jakobsen et al. 2006).

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J. Shprintzen. It is caused by a submicroscopic deletion on the long arm of chromosome 22 in the q11 region (deletion22q11). Its incidence is approximately 1 in 2000 live births. Over 180 phenotypic features have been reported, the most common of these being cleft palate, cardiac anomalies, speech and feeding difficulties, characteristic facial appearance, and compromised immune system (Shprintzen 2008). TBX1 maps to 22q11.2, a region frequently deleted in humans (~1/4000 live births). It is associated with DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS) (OMIM # 192430/188400). It regulates a number of genes via epigenetic modifications. TBX1 mutations manifest with pharyngeal arch-related developmental defects, affecting the heart, thymus, and parathyroid gland. TBX1 mutations cause a recognizable spectrum of craniofacial anomalies such as CP, or VPI with typical facies and a predilection to develop neuropsychiatric disorders. Trisomy 13 Trisomy 13, also known as Patau syndrome, is associated with three copies of chromosome 13, or unbalanced Robertsonian translocations involving chromosome 13. Infants typically die in the neonatal period, with only 5–10% living beyond their first year. Clinical features include cleft lip and palate, severe intellectual disability, severe central nervous malformations (including holoprosencephaly), microcephaly, micropthalmia, iris coloboma, absence of the eyes, malformed ears, polydactyly, clenched fists, rocker bottom feet, congenital heart defects, and urogenital defects (McCaffrey 2016). Trisomy 18 Trisomy 18, also known as Edwards syndrome, is associated with three distinct copies of chromosome 18. Clinical features include cleft lip and palate, intellectual disability, failure to thrive, congenital heart disease, hypertonia, micrognathia, short sternum, low-set malformed ears, clenched hands, rocker bottom feet, and hypoplastic nails. Like Trisomy 13, this is a severe diagnosis as evidenced by the 5–10% 1-year infant survival rate (McCaffrey 2016). In conclusion, the majority of syndromes associated with clefts of the lip and palate are rare. Identification of genes causing these syndromes has been successful and has been further facilitated by progress in sequencing technology.

Non-Syndronic Orofacial Cleft (NSOFC) Velocardiofacial Syndrome or 22q11.2 Deletion Syndrome Velocardiofacial syndrome (VCFS, OMIM # 192430) is an autosomal dominant anomaly described by Dr. Robert

Nonsyndromic orofacial clefts are generally subtyped into cleft lip only (CLO), cleft lip with palate (CLP), and cleft palate only (CPO) based on anatomical sites. Both CLO and

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CLP are sometimes combined into a subgroup, namely cleft lip with or without cleft palate (CL/P), as they share similar epidemiological feature and embryonic origin (Leslie and Marazita 2013). Epidemiologic data suggest that CPO may have unique etiologic features. Among CL/P, the rate of CLP is higher than CLO. CLP accounted for 62.0% and CLO accounted for 29.6% of orofacial cleft cases. Geographic, racial, and ethnic data have found the highest prevalence of NSOFC among Asian and Native American ancestry populations, followed by European ancestry populations, with African ancestry populations having the lowest prevalence rates at about 1/2500 (Dixon et al. 2011). 80% of nonsyndromic cases are sporadic while 20% are multiplex (familial) cases. The frequency of nonsyndromic oral cleft also differs by sex and laterality. There is a 2:1 male to female ratio for cleft lip and approximately a 1:2 male to female ratio for cleft palate only, and there is a 2:1 ratio of left- to rightsided clefts among unilateral cleft lip cases. NSOFC has a complex multifactorial etiology with both genetic factors and environmental risk factors contributing to the pathogenesis. In the past few decades, numerous studies have identified genes and loci associated with NSOFC; however, known variants account for a minority of the estimated heritability at risk for this disorder, with the mechanisms underlying the pathogenesis of NSOFC still largely unknown and yet to be explained. It has been very difficult to identify specific etiologic factors for this disorder due to the fact that such defects arise during early embryological development, and recurrence is common and unpredictable. Moreover, NSOFC lacks traditional Mendelian inheritance pattern and is highly genetically heterogeneous involving multiple genes, gene-gene interactions, and several environmental risk factors which may cause gene-environment interactions. Study design limitations and unrecognized bias such as size and number of patient samples, poorly controlled studies, and other factors can also lead to false positive results (Beaty et al. 2016).

X. Ye and M. K. Ahmed

in a meta-analysis of linkage data. In the genomics era, next generation sequencing techniques have led to the identification of potential NSOFC susceptibility variants in Cadherin 1 (CDH1) and a small number of other genes. Variants detected thus far via exome sequencing have been dominant heterozygous and can be important for the respective family as carriers of such variants. However, these are rare findings and currently explain only a small portion (