Polyendocrine Disorders and Endocrine Neoplastic Syndromes (Endocrinology) [1st ed. 2021] 331989496X, 9783319894966

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Endocrinology Series Editor: Andrea Lenzi Series Co-Editor: Emmanuele A. Jannini

Annamaria Colao Marie-Lise Jaffrain-Rea Albert Beckers  Editors

Polyendocrine Disorders and Endocrine Neoplastic Syndromes

Endocrinology Series Editor Andrea Lenzi Department of Experimental Medicine Section of Medical Pathophysiology Food Science and Endocrinology Sapienza University of Rome Rome, Italy Series Co-Editor Emmanuele A. Jannini Department of Systems Medicine University of Rome Tor Vergata Rome, Roma, Italy

Within the health sciences, Endocrinology has an unique and pivotal role. This old, but continuously new science is the study of the various hormones and their actions and disorders in the body. The matter of Endocrinology are the glands, i.e. the organs that produce hormones, active on the metabolism, reproduction, food absorption and utilization, growth and development, behavior control, and several other complex functions of the organisms. Since hormones interact, affect, regulate and control virtually all body functions, Endocrinology not only is a very complex science, multidisciplinary in nature, but is one with the highest scientific turnover. Knowledge in the Endocrinological sciences is continuously changing and growing. In fact, the field of Endocrinology and Metabolism is one where the highest number of scientific publications continuously flourishes. The number of scientific journals dealing with hormones and the regulation of body chemistry is dramatically high. Furthermore, Endocrinology is directly related to genetics, neurology, immunology, rheumatology, gastroenterology, nephrology, orthopedics, cardiology, oncology, gland surgery, psychology, psychiatry, internal medicine, and basic sciences. All these fields are interested in updates in Endocrinology. The aim of the MRW in Endocrinology is to update the Endocrinological matter using the knowledge of the best experts in each section of Endocrinology: basic endocrinology, neuroendocrinology, endocrinological oncology, pancreas with diabetes and other metabolic disorders, thyroid, parathyroid and bone metabolism, adrenals and endocrine hypertension, sexuality, reproduction, and behavior. More information about this series at http://www.springer.com/series/14021

Annamaria Colao • Marie-Lise Jaffrain-Rea • Albert Beckers Editors

Polyendocrine Disorders and Endocrine Neoplastic Syndromes With 56 Figures and 35 Tables

Editors Annamaria Colao Department of Clinical Medicine and Surgery, Section of Endocrinology Neuroendocrine Unit University of Naples “Federico II” Naples, Italy

Marie-Lise Jaffrain-Rea Department of Biotechnological and Applied Clinical Sciences University of L’Aquila L’Aquila, Italy Neuroendocrinology Neuromed IRCCS Pozzilli, Italy

Albert Beckers Department of Endocrinology University of Liège, Centre Hospitalier Universitaire de Liège Liège, Belgium

ISSN 2510-1927 ISSN 2510-1935 (electronic) ISBN 978-3-319-89496-6 ISBN 978-3-319-89497-3 (eBook) ISBN 978-3-319-89498-0 (print and electronic bundle) https://doi.org/10.1007/978-3-319-89497-3 © Springer Nature Switzerland AG 2021 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 Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Series Preface

Is there an unmet need for a new MRW series in Endocrinology and Metabolism? It might not seem so! The vast number of existing textbooks, monographs, and scientific journals suggest that the field of hormones (from genetic, molecular, biochemical, and translational to physiological, behavioral, and clinical aspects) is one of the largest in biomedicine, producing a simply huge scientific output. However, we are sure that this new series will be of interest to scientists, academics, students, physicians, and specialists alike. The knowledge in endocrinology and metabolism limited to the two main (from an epidemiological perspective) diseases, namely hypo/hyperthyroidism and diabetes mellitus, now seems outdated and perhaps closer to the practical interests of the general practitioner than to those of the specialist. This has led to endocrinology and metabolism being increasingly considered as a subsection of internal medicine rather than an autonomous specialization. But endocrinology is much more than this. We are proposing this series as the manifest for Endocrinology 2.0, embracing the fields of medicine in which hormones play a major part but which, for various historical and cultural reasons, have thus far been “ignored” by endocrinologists. Hence, this MRW comprises “traditional” (but no less important or investigated) topics: from the molecular actions of hormones to the pathophysiology and management of pituitary, thyroid, adrenal, pancreatic, and gonadal diseases, as well as less usual and common arguments. Endocrinology 2.0 is, in fact, the science of hormones, but it is also the medicine of sexuality and reproduction, the medicine of gender differences, and the medicine of well-being. These aspects of endocrinology have to date been considered of little interest, as they are young and relatively unexplored sciences. But this is no longer the case. The large scientific production in these fields coupled with the impressive social interest of patients in these topics is stimulating a new and fascinating challenge for endocrinology. The aim of the MRW in Endocrinology is thus to update the subject with the knowledge of the best experts in each field: basic endocrinology; neuroendocrinology; endocrinological oncology; pancreatic disorders; diabetes and other metabolic disorders; thyroid, parathyroid, and bone metabolism; adrenal and endocrine

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Series Preface

hypertension; and sexuality, reproduction, and behavior. We are sure that this ambitious aim, covering for the first time the whole spectrum of Endocrinology 2.0, will be fulfilled in this vast Springer MRW in Endocrinology Series. Andrea Lenzi Emmanuele A. Jannini

Volume Preface

Endocrinology is a fascinating discipline embracing different fields of internal medicine because of the multifaceted systemic effects of hormones, but also due to a variety of classical and emerging new endocrine and systemic syndromes developing on the basis of common pathogenetic mechanisms. These include autoimmune dysregulation and alterations in pathways involved in endocrine tumorigenesis. In the last century, polyendocrine syndromes have been progressively recognized on the basis of peculiar associations between endocrine diseases or neoplasia, with frequent non-endocrine manifestations. Inherited predisposition was then suspected because of frequent familial clustering and/or unusual early onset of clinical manifestations, opening the way to genetic investigations. For example, the history of multiple endocrine neoplasia type 1 (MEN1) began with the first report of enlarged parathyroid glands in an acromegalic patient (Erdheim 1903) and progressed through the identification of a familial condition associating parathyroid, pituitary, and pancreatic neoplasia inherited as a dominant trait (Wermer 1954), before genetic mapping studies localized the gene on 11q13 (1988–1989), leading to MEN1 gene sequencing in 1997 by two independent groups of researchers. Identification of the MEN1 gene, encoding menin, rapidly encouraged basic research studies to elucidate the molecular pathogenesis of MEN1, as well as the development of clinical guidelines aiming to design familial screening, promote genetic counselling, and improve the management of patients and carriers of MEN mutations. Similar advances were made with the autoimmune polyendocrine syndrome type 1 (APS1), also known as autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED), which causative gene, autoimmune regulator (AIRE), was also identified in 1997, 3 years after genetic mapping on 21q22. Thereafter, the growing interest of the scientific community, together with the rapid evolution of laboratory and imaging diagnostic tools, and the revolution in clinical genetics since the diffusion of new-generation sequencing (NGS), has led to an impressive acceleration in the identification of new genetic syndromes and related scientific publications. The present volume is meant to summarize current advances in the fascinating fields of polyendocrine diseases and neoplasia. Thanks to the experience of international experts, it aims to support clinicians in the management of classical and new syndromes and encourage multidisciplinary collaborations in order to promote health in affected patients. vii

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Volume Preface

The first part of the volume is dedicated to autoimmune polyendocrine disorders (APS) – which may also be viewed as multiple autoimmune syndromes (MAS) due the high prevalence of non-endocrine manifestations – and their evolving classification. Attention is given to advances in their genetic basis, ranging from the recessive monogenic condition of APS1 to the polygenic APS2 and recent knowledge about rare complex disorders such as POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) or IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked) syndromes. In addition, the multiple causes of some single-organ endocrine dysfunctions (such as adrenal insufficiency) or inflammatory processes (such as hypophysitis) are detailed in order to facilitate their potential identification as parts of APS and consider differential diagnosis with other genetic or inflammatory conditions, which are also frequently associated with non-endocrine manifestations. The emerging role of immunotherapy for cancers as a trigger for multiple endocrine and non-endocrine autoimmune diseases is also illustrated by a clinical case. The second part is dedicated to polyendocrine neoplastic syndromes. The evolving spectrum of MEN diseases, from classical MEN1 and MEN2 to MEN1-like syndromes – such as MEN4, identified after the spontaneous rat model MENX (2006) – is reported. Syndromes based on common alterations in transduction or metabolic pathways, including the cAMP pathway – MacCune Albright syndrome and Carney complex – or the most recently identified mutations in the SDHx genes, are also reviewed. Noteworthy, these latter typically associate with neuroendocrine tumors (NETs), in particular pheochromocytoma/paraganglioma, which may also develop in classically non-endocrine syndromes such as Van Hippel Lindau (VHL) or neurofibromatosis type 1 (NF1). Syndromic and/or familial presentation, multifocality and early onset of an endocrine neoplasia should alert the clinician and suggest a genetic cause. The genetic basis of some apparently isolated endocrine neoplasia is also increasingly recognized, with a growing list of predisposing genes. Therefore, attention is also paid to conditions like pheochromocytoma/paragangliomas/NETs, primary hyperparathyroidism, and gigantism. Identifying a causative gene may be challenging but may have a dramatic impact on patient’s management and has now entered clinical practice. To address this issue, a series of representative clinical cases is proposed in order to place the reader in a real-life situation. This volume has been designed for all the physicians involved in the diagnostic and management of polyendocrine diseases and neoplasia, ranging from endocrinologists to general practitioners and a variety of specialists in pediatrics, internal medicine, immunology, oncology, surgery, laboratory medicine, imaging, and genetics. We hope that they will benefit from this book and be stimulated to improve their practice and contribute to ongoing research in the field. Annamaria Colao Marie-Lise Jaffrain-Rea Albert Beckers

Contents

Part I Polyendocrine Disorders in Autoimmune and Systemic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Autoimmune Polyendocrine Syndromes (APS) or Multiple Autoimmune Syndromes (MAS) . . . . . . . . . . . . . . . . . . . . . . . . . . . Corrado Betterle, Chiara Sabbadin, Carla Scaroni, and Fabio Presotto

2

The Natural History of APS1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anette S. B. Wolff, Bergithe E. Oftedal, and Eystein S. Husebye

3

Genetics of Autoimmune Regulator (AIRE) and Clinical Implications in Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nicola Improda, Mariacarolina Salerno, and Donatella Capalbo

1 3 51

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Autoantibodies in Autoimmune Polyendocrine Syndrome . . . . . . . Isabella Lupi, Alessandro Brancatella, and Patrizio Caturegli

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5

Genetic Heterogeneity in Adrenal Insufficiency . . . . . . . . . . . . . . . Rosario Pivonello, Chiara Simeoli, Rosario Ferrigno, Maria Cristina De Martino, Davide Menafra, Cristina De Angelis, and Annamaria Colao

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Hypophysitis and Granulomatous Pituitary Lesions in Systemic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marie-Lise Jaffrain-Rea and Silvia Filipponi

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Rare Forms of Endocrine and Systemic Autoimmune Disorders . . . Federica Guaraldi, Sofia Asioli, Valentino Marino Picciola, Diego Mazzatenta, and Giovanni Corona

Part II Endocrine Tumors in Complex and Genetic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Multiple Endocrine Neoplasia Type 1 . . . . . . . . . . . . . . . . . . . . . . . Pauline Romanet, Pierre Goudet, and Anne Barlier

143 171

193 195 ix

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Contents

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Multiple Endocrine Neoplasia-Type 2 . . . . . . . . . . . . . . . . . . . . . . . Vincent Rohmer, Delphine Prunier-Mirebeau, and Iulia Potorac

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Multiple Endocrine Neoplasia-Type 4 (MEN4) and Other MEN1-Like Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ninelia Minaskan Karabid and Natalia S. Pellegata

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Molecular Alterations of the cAMP Signaling Leading to Endocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anna Vaczlavik and Jérôme Bertherat

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Genetics of Pituitary Gigantism: Syndromic and Nonsyndromic Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Liliya Rostomyan, Iulia Potorac, Adrian F. Daly, and Albert Beckers

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Pheochromocytomas, Paragangliomas, and Pituitary Adenomas (3PAs) and Succinate Dehydrogenase Defects Andrew P. Demidowich and Constantine A. Stratakis

.......

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Pheochromocytomas in Complex Genetic Disorders . . . . . . . . . . . Giuseppe Opocher, Alfonso Massimiliano Ferrara, Stefania Zovato, Giovanni Barbon, Elisa Taschin, and Francesca Schiavi

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Hyperparathyroidism in Complex Genetic Disorders . . . . . . . . . . Francesca Marini, Francesca Giusti, and Maria Luisa Brandi

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Neuroendocrine Neoplasms (NENs) in Complex Genetic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wouter W. de Herder

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Part III

Clinical Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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McCune-Albright Syndrome in Clinical Practice . . . . . . . . . . . . . . Sylvie Salenave and Philippe Chanson

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Carney Complex in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . Filippo Ceccato and Gianluca Occhi

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Multiple Endocrine Neoplasia Type 1 in Clinical Practice . . . . . . . Pauline Delannoy, Iulia Potorac, and Albert Beckers

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Coexistence of Endocrine Side Effects of Immunotherapy in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Frederique Albarel and Frederic Castinetti

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MEN2 in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Roberta Centello, Antongiulio Faggiano, and Elisa Giannetta

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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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About the Editors

Pr. Annamaria Colao is full professor of endocrinology and chair of the Section of Endocrinology in the Department of Clinical Medicine and Surgery at the “Federico II” University of Naples. Coordinator of national and international research projects with a scientific activity characterized by publication of more than 900 full papers in international journals (h-index 117), she has published more than 100 chapters in multiauthored books and monographs. She is one of the top Italian female scientists. Prof. Colao is responsible for Italy as member the European network ENDO-ERN (European Reference Network) for the study of rare endocrine diseases in adults, and she coordinates the regional center at the Federico II University, where she is also responsible for the European center of excellence ENETS (for the study of neuroendocrine tumors) and the center of excellence for the diagnosis and treatment of obesity CIBO (accredited with SIO and EASO). Past president of the National Council of Scientific Research Guarantors at the Ministry for University and Research, she also served as a president of the European Society of Neuroendocrinology (ENEA, 2016-2018) and is the president-elect of the Italian Society of Endocrinology for a 2-year period, 2021–2023 (the first woman in the history of the Society). She is also founder and president of Campus Salute Onlus (www.campussalute.it), a non-profit association dedicated to health. Since 2019, she has been serving as a UNESCO Chairholder – Unesco Federico II Chair “Education for health and sustainable development.” In 2020, she was awarded the prestigious “Geoffrey Harris” by the European Society of Endocrinology for her life achievements in the field of neuroendocrinology. xi

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About the Editors

Pr. Marie-Lise Jaffrain-Rea is associate professor of endocrinology in the Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila (AQ), Italy, and the head of the neuroendocrinology service at the Neuromed Institute, IRCCS, in Pozzilli (IS), Italy. She obtained her medical degree and specialization in endocrinology from France (University Paris V) and a scientific “Maitrise” in biochemistry (University Paris VI). She previously worked as a researcher in general pathology at the University of L’Aquila maintaining a regular clinical activity and research in the field of endocrinology and endocrine neoplasia. Since 2011, she also serves as an invited professor of endocrinology at the University of Liège, Belgium. Her main areas of interest are pituitary diseases and sellar/parasellar neoplasia, the pathogenesis and genetic basis of pituitary neuroendocrine tumors and their clinical impact, as well as the systemic aspects of hypothalamic-pituitary diseases. She has authored or co-authored more than 90 peer-reviewed publications and book chapters and more than 230 communications at national and international scientific meetings. She is interested in teaching and promoting knowledge on endocrinology and serves as a voluntary consultant for the non-profit “Carlo Ferri” Foundation for the prevention in oncology, ONLUS, in Monterotondo (RM), Italy. She is a member of the Italian Society of Endocrinology, the European Neuroendocrine Association, the European Pituitary Pathology Group, and the European Society of Endocrinology. Prof. Albert Beckers, M.D., Ph.D., is head of the Department of Endocrinology at the University Hospital Centre, Liège, and full professor at the University of Liège, Belgium. He oversees a department with multiple clinical and research areas of interest, including pituitary tumors, thyroid disease, genetic causes of endocrine cancers, and rare inherited syndromes. Current research interests include the genetics of pituitary diseases, molecular and genetic investigation of rare disorders of endocrine development, gigantism and acromegaly, and new treatments for aggressive endocrine tumors. Research highlights include the original characterization and description of familial isolated pituitary adenomas

About the Editors

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(FIPA) and a newly described pediatric syndrome X-linked acrogigantism (X-LAG). He has published more than 300 original articles, including high-impact international journals such as The New England Journal of Medicine, Endocrine Reviews, and the Journal of Clinical Endocrinology & Metabolism. He is also involved in endocrine education, authoring a series of digital projects on pituitary diseases, and has organized many national and international congresses. He has served as president of the Belgian Endocrine Society (two mandates) and secretary of the European NeuroEndocrine Association (ENEA). In 2016, he received the 2016 Geoffrey Harris Award of the European Society of Endocrinology (ESE), the most prestigious ESE prize given in recognition of achievements by senior researchers in the field of basic and clinical neuroendocrinology. In 2017, he received the Rolf Gaillard Prize of the European NeuroEndocrine Association, the highest ENEA award given in recognition of outstanding lifetime contributions to the field of basic and clinical neuroendocrinology. He is also a member of the Royal Academy of Medicine (Belgium) and Doctor Honoris Causa at the Aix-Marseille University (France).

Contributors

Frederique Albarel Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Aix-Marseille Université, Marseille, France Assistance Publique-Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France Sofia Asioli Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy Department of Biomedical and Neuromuscular Sciences, Section of Anatomic Pathology ‘M. Malpighi’ at Bellaria Hospital, University of Bologna, Bologna, Italy Giovanni Barbon Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padova, Italy Anne Barlier Aix Marseille Univ, APHM, INSERM, MMG, Conception Hospital, Laboratory of Molecular Biology, Faculte Medecine TIMONE, Marseille, France Albert Beckers Department of Endocrinology University of Liège, Centre Hospitalier, Universitaire de Liège, Liège, Belgium Jérôme Bertherat INSERM U1016, Institut Cochin, Paris, France CNRS UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Endocrinology Department, Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France Corrado Betterle Unit of Endocrinology, Department of Medicine (DIMED), University of Padova, Padua, Italy Alessandro Brancatella Division of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Maria Luisa Brandi Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy xv

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Contributors

Frederic Castinetti Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Aix-Marseille Université, Marseille, France Assistance Publique-Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France Patrizio Caturegli Division of Immunology, Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, MD, USA Filippo Ceccato Department of Medicine - Endocrinology Unit, Padova University/Hospital, Padova, Italy Roberta Centello Department of Experimental Medicine, Policlinico Umberto I Hospital, Sapienza University, Rome, Italy Philippe Chanson Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l’Hypophyse, Le Kremlin-Bicêtre, France Université Paris-Saclay, Inserm, Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Le Kremlin-Bicêtre, France Annamaria Colao Department of Clinical Medicine and Surgery, Section of Endocrinology - Neuroendocrine Unit, University of Naples “Federico II”, Naples, Italy Giovanni Corona Endocrinology Unit, Medical Department, Azienda Usl Maggiore-Bellaria Hospital, Bologna, Italy Adrian F. Daly Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium Cristina De Angelis Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy Wouter W. de Herder Department of Internal Medicine, Sector of Endocrinology, ENETS Center of Excellence for Neuroendocrine Tumours, Erasmus MC & Erasmus MC Cancer Center, Rotterdam, The Netherlands Maria Cristina De Martino Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy Pauline Delannoy Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium Andrew P. Demidowich Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA Donatella Capalbo Department of Pediatrics, Pediatric Endocrinology Section, Federico II University of Naples, Naples, Italy

Contributors

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Antongiulio Faggiano Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University, Rome, Italy Alfonso Massimiliano Ferrara Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padova, Italy Rosario Ferrigno Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy Silvia Filipponi Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila (AQ), Italy Elisa Giannetta Department of Experimental Medicine, Policlinico Umberto I Hospital, Sapienza University, Rome, Italy Francesca Giusti Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy Pierre Goudet Department of Endocrine Surgery/INSERM, U866, Epidemiology and Clinical Research in Digestive Oncology Team/ INSERM, CIC1432, Clinical Epidemiology Unit, Clinical Investigation Center, Clinical Epidemiology/Clinical Trials Unit, University Hospital of Dijon, Hopital Francois Mitterand, Dijon, France Federica Guaraldi IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy Eystein S. Husebye KG Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway Department of Clinical Science, University of Bergen, Bergen, Norway Department of Medicine, Haukeland University Hospital, Bergen, Norway Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden Marie-Lise Jaffrain-Rea Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy Neuroendocrinology, Neuromed IRCCS, Pozzilli, Italy Isabella Lupi Division of Endocrinology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Mariacarolina Salerno Department of Medical Translational Sciences, Paediatric Endocrinology section, Federico II University of Naples, Naples, Italy Francesca Marini Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy Valentino Marino Picciola Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy

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Contributors

Diego Mazzatenta IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy Davide Menafra Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy Ninelia Minaskan Karabid Institute for Diabetes and Cancer, Helmholtz Zentrum München, Munich, Germany Nicola Improda Department of Medical Translational Sciences, Paediatric Endocrinology section, Federico II University of Naples, Naples, Italy Gianluca Occhi Department of Biology - Unit of Human Molecular Genetics and Functional Genomics, University of Padova, Padova, Italy Bergithe E. Oftedal KG Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway Department of Clinical Science, University of Bergen, Bergen, Norway Giuseppe Opocher Veneto Institute of Oncology, IRCCS, Padova, Italy Natalia S. Pellegata Institute for Diabetes and Cancer, Helmholtz Zentrum München, Munich, Germany Rosario Pivonello Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy Iulia Potorac Department of Endocrinology, CHU Liège, University of Liège, Liège, Belgium Domaine Universitaire du Sart Tilman, Liège, Belgium Fabio Presotto Unit of Internal Medicine, Ospedale dell’Angelo, Mestre-Venezia, Italy Delphine Prunier-Mirebeau Department of Endocrinology (VR), CHU Angers, Angers Cedex 9, France Department of Biochemistry-Genetics (DPM), CHU Angers, Angers Cedex 9, France Vincent Rohmer Department of Endocrinology (VR), CHU Angers, Angers Cedex 9, France Department of Biochemistry-Genetics (DPM), CHU Angers, Angers Cedex 9, France Pauline Romanet Aix Marseille Univ, APHM, INSERM, MMG, Conception Hospital, Laboratory of Molecular Biology, Faculte Medecine TIMONE, Marseille, France

Contributors

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Liliya Rostomyan Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart-Tilman, Liège, Belgium Chiara Sabbadin Unit of Endocrinology, Department of Medicine (DIMED), University of Padova, Padua, Italy Sylvie Salenave Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l’Hypophyse, Le Kremlin-Bicêtre, France Carla Scaroni Unit of Endocrinology, Department of Medicine (DIMED), University of Padova, Padua, Italy Francesca Schiavi Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padova, Italy Chiara Simeoli Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy Constantine A. Stratakis Section on Genetics and Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA Elisa Taschin Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padova, Italy Anna Vaczlavik INSERM U1016, Institut Cochin, Paris, France CNRS UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, Paris, France Anette S. B. Wolff KG Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway Department of Clinical Science, University of Bergen, Bergen, Norway Stefania Zovato Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padova, Italy

Part I Polyendocrine Disorders in Autoimmune and Systemic Diseases

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Autoimmune Polyendocrine Syndromes (APS) or Multiple Autoimmune Syndromes (MAS) An Overview Corrado Betterle, Chiara Sabbadin, Carla Scaroni, and Fabio Presotto Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Criteria for the Diagnosis of Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification of Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Natural History of Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Old Classification of APS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New Classifications of APS/MAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypothesis on the Pathogenesis of APS/MAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APS/MAS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Historical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Frequency and Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Animal Models of APS/MAS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetics of APS/MAS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Main Clinical Manifestations of APS/MAS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Minor Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New Diagnostic Criteria for APS/MAS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How to Manage Patients with ASP/MAS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . When to Investigate for AIRE Gene Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APS/MAS-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Historical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetics of APS/MAS-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Frequency and Epidemiology of APS/MAS-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Main Clinical Manifestations of APS/MAS-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autoimmune Addison’s Disease (AAD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autoimmune Thyroid Diseases (AITD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Type 1 Diabetes Mellitus (DM-I) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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C. Betterle · C. Sabbadin (*) · C. Scaroni Unit of Endocrinology, Department of Medicine (DIMED), University of Padova, Padua, Italy e-mail: [email protected]; [email protected] F. Presotto Unit of Internal Medicine, Ospedale dell’Angelo, Mestre-Venezia, Italy © Springer Nature Switzerland AG 2021 A. Colao et al. (eds.), Polyendocrine Disorders and Endocrine Neoplastic Syndromes, Endocrinology, https://doi.org/10.1007/978-3-319-89497-3_1

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Combinations of the Three Major Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incomplete or Subclinical Forms of APS/MAS-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Minor Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autoimmune Diseases and Autoantibodies in APS/MAS-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APS/MAS-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Frequency of APS/MAS-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A New Classification of APS/MAS-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetics of APS/MAS-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APS/MAS 3A: Association Between AITD and Other Autoimmune Endocrine Diseases . . . APS/MAS-3B: Association Between AITD and Other Autoimmune Diseases of the Digestive System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APS/MAS-3C: Association Between AITD and Autoimmune Diseases of the Skin, Nervous System, and Hemopoietic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APS/MAS-3D: Association Between AITD and Autoimmune Rheumatic and Cardiac Diseases or Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding Comments on APS/MAS-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APS/MAS-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Presentation of APS/MAS-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IPEX Syndrome (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked) . . . Clinical Manifestations and Autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poems Syndrome (Polyradiculoneuropathy, Organomegaly, Endocrinopathy, Monoclonal Plasma Cell Disorder, and Skin Changes) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

On the basis of the revised criteria of diagnosis of autoimmune diseases (AID), more than 80 diseases previously considered as “idiopathic” have been defined as “autoimmune” and estimated to affect about 7% of the general population. AID are classically divided into organ-specific and non-organ-specific, and their prevalence varies according to gender, geographical origin, age, and genetic predisposition. AID shows the tendency to aggregate in one individual or in a family, defining an autoimmune polyendocrine syndrome (APS), also called multiple autoimmune syndrome (MAS). In this chapter, we revised the main features of the four types of APS/MAS, of IPEX and POEMS, evaluating their history, epidemiology, genetic pattern, clinical and immunological features, management, and therapy. Keywords

AIRE gene mutations · Autoimmune polyendocrine syndromes · Multiple autoimmune syndromes · Autoimmune diseases · Autoimmune endocrinopathies · IPEX · POEMS

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Autoimmune Polyendocrine Syndromes (APS) or Multiple Autoimmune. . .

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Introduction The autoimmune polyglandular syndromes (APS) are defined by the concurrence of at least two autoimmune-mediated endocrinopathies. However, multiple disease association may be also found with other non-endocrine and nonglandular autoimmune disorders involving a great variety of organs or tissues in the body. Based on these findings, we consider more appropriate to assume the term of multiple autoimmune syndromes (MAS). Specific clustering of autoimmune diseases depends on genetic and nongenetic environmental factors and differs considerably at the time of presentation, allowing detailed distinction between major types, and even subtypes, of APS/MAS.

Criteria for the Diagnosis of Autoimmune Diseases The history of AID began in London in 1956, when Ivan Roitt and Deborah Doniach discovered autoantibodies against thyroglobulin in the Hashimoto’s disease. In the same year, in Buffalo (USA), Rose and Witebsky reproduced a thyroiditis in rabbits by immunizing them with extracts of autologous thyroid gland in Freund’s adjuvant. Meanwhile, in New Zealand, Adams and Purves demonstrated that patients with Graves’ disease had in their blood a factor other than TSH capable of stimulating thyroid function for a protracted time, and thus called long-acting thyroid stimulator (LATS). Based on these findings, the criteria for defining a disease autoimmune were established in 1957 by Witebsky et al. (1957).

Classification of Autoimmune Diseases On the basis of these criteria, more than 80 diseases previously regarded as “idiopathic” come to be defined as “autoimmune” and estimated to affect about 7% of the general population (Rose and Mackay 2019 in press). Autoimmune diseases are classically divided into organ-specific and non-organ-specific, and their prevalence varies according to gender, geographical origin, age, and genetic predisposition (Betterle 2017).

Natural History of Autoimmune Diseases After the demonstration that there are autoantibodies also in the normal population, several follow-up studies on such individuals showed that AID are generally not acute but chronic disorders with a lengthy preclinical phase. Their natural history is characterized by a series of three phases, defined as: (a) potential; (b) subclinical or latent; and (c) clinical (Betterle 2017). All the three phases are marked by the presence of autoantibodies in patients’ serum (Fig. 1). (a) Potential autoimmune disease: This applies to an individual with a high probability of developing the autoimmune diseases on the grounds of the following conditions: (a) positive family history of AID; (b) genetic

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GENETIC (HLA-DRB1/DQBA1/DQB1, PTPN22, CTLA4, IL2R4, AIRE mutations, others)

Hormonal factors Environmental factors (viruses, infections, drugs, foods, chemical, radiations, others) Seroconversion for Circulating Autoantibodies Lymphocytic infiltration of the target organs begins

Function of the target

(TCD8+,TCD4+, Macrophages, Plasmacells, Fibrosis) Presence of subclinical dysfunction of the target organs

100%

50%

Precipitating events (infections, stress, pregnancy, others) Clinical manifestations develop

Presence of lymphocytes in the target organs detectable with appropriate tests

0%

Phases POTENTIAL

of

Autoimmune SUBCLINICAL

Diseases CLINICAL

Fig. 1 Phases in the natural history of autoimmune diseases. (Modified from Betterle 2017, with the permission of the Editor)

predisposition (generally related to HLA with a relative risk more than 1); (c) circulating autoantibodies in the absence of clinical manifestations of the AID. (b) Subclinical autoimmune disease: This is characterized by the presence of circulating autoantibodies and/or lymphocytic infiltration of the target organs, with evidence of a subclinical dysfunction or alteration of the organs involved, as demonstrated by specific basal tests (TSH, ACTH, cortisol, renin, aldosterone, gastrin, glycemia, glycosylated hemoglobin, transaminases, alkaline phosphatase, etc.) or by stimulation tests (ACTH test, oral glucose tolerance test, CRH-test, TRH-test, etc.). During this phase, different precipitating events (such as stress, infections, pregnancy, or surgical procedures) can trigger the onset of clinical manifestations. (c) Clinical autoimmune disease: In this phase, the majority of the target organs are infiltrated by autoreactive lymphocytes and destroyed by the immune aggression, and therefore the disease becomes clinically overt (Betterle 2017).

Old Classification of APS One of the criteria for defining AID is the tendency for more than one autoimmune disease to aggregate in the same individual. In 1980, it was proposed a clinical classification of polyglandular autoimmune diseases (PGAD), also called autoimmune polyglandular syndromes (APS), based on four types (Table 1) (Neufeld and Blizzard 1980). In the following years, this classification of APS changed in the light of several considerations:

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Autoimmune Polyendocrine Syndromes (APS) or Multiple Autoimmune. . .

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Table 1 First classification of PGAD or APS according to Neufeld and Blizzard (1980) Type 1 2 3

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Features Candidiasis, hypoparathyroidism, Addison’s disease (two or three present) Addison’s disease + Thyroid autoimmune diseases and/or type 1 diabetes mellitus Thyroid autoimmune diseases + (3A) Type 1 diabetes mellitus (3B) Pernicious anemia (3C) Vitiligo, alopecia, and/or other organ-specific autoimmune diseases Two or more organ-specific autoimmune diseases not falling into types 1, 2, or 3

PGAD polyglandular autoimmune diseases, APS autoimmune polyglandular syndromes

1. The increased number of diseases recognized as autoimmune gave origin to more complex combinations of APS. 2. Patients with association of subclinical and/or potential AID could also be included into APS (Betterle et al. 2002). 3. The initially proposed terms of PGAD or APS were not appropriate to definite these conditions because they could include not only endocrine diseases (such as Addison’s disease, type 1 diabetes mellitus, Hashimoto’s thyroiditis), etc., but also variable combinations of endocrine and non-endocrine AID (such as Addison’s disease and autoimmune gastritis or Hashimoto’s thyroiditis and primary biliary cirrhosis), or solely non-endocrine autoimmune diseases (such as systemic lupus erythematosus and Sjögren’s syndrome, vitiligo, and autoimmune gastritis). This led to the proposal that a more appropriate term for these conditions might be multiple autoimmune syndromes (MAS) (Betterle and Presotto 2008). Another suggested proposal was overlap syndromes (OS) or polyautoimmunity (Anaya 2014). In this chapter, the term APS/MAS has been used to denote these syndromes.

New Classifications of APS/MAS The separation of APS/MAS into four types is not universally accepted by researchers. There are splitters and lumpers. The splitters accept the idea of four types (Neufeld and Blizzard 1980; Betterle et al. 2002; Betterle and Presotto 2008; White 2016), while the lumpers would prefer to have just two main syndromes: (1) APS-1, comprising the association of chronic candidiasis with chronic hypoparathyroidism and Addison’s disease (also called juvenile APS), related to autoimmune regulator (AIRE) gene mutations and (2) APS-2 (also called adult APS) which includes all the other autoimmune combinations and related to class II HLA gene (Eisenbarth and Gottlieb 2004; Kahaly 2009; Husebye et al. 2018; Kahaly and Frommer 2018). We suggest a new classification of APS/MAS which includes, in addition to the four classical types of APS/MAS, also IPEX and POEMS syndromes (Table 2). These syndromes are considered distinct entities because they differ in terms of: (a) epidemiology, (b) incidence, (c) gender, (d) main and

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Table 2 New proposed classification of APS/MAS APS/MAS-1 or APECED (autoimmune-polyendocrine-candidiasisectodermal-dystrophy)

APS/MAS-2

APS/MAS-3

APS/MAS-4 IPEX syndrome POEMS syndrome

Chronic mucocutaneous candidiasis And/or Chronic hypoparathyroidism And/or Autoimmune Addison’s disease (at least two diseases present) Autoimmune Addison’s disease (AAD) (always present) And Autoimmune thyroid diseases (AITD) And/or Type 1 diabetes mellitus (DM-1) Autoimmune thyroid diseases (AITD) And (3a) Other autoimmune endocrine diseases (excluding Addison’s disease) (3b) Other autoimmune gastrointestinal, hepatic, or pancreatic diseases (3c) Other autoimmune diseases of the skin, central nervous system, or hematopoietic system (3d) Other autoimmune rheumatic and cardiovascular diseases or vasculitis Any other autoimmune disease combination not included in the previous classifications Immune dysregulation, polyendocrinopathy, enteropathy, X-linked Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes

minor combined diseases, (e) age of onset, (f) genetic associations, (g) immunological features, (h) prognosis, (i) survival and mortality, and (j) therapy.

Hypothesis on the Pathogenesis of APS/MAS It is well known that AID stem from combinations of different genetic, epigenetic, environmental, and endogenous factors (Anaya 2014). It is not clear, however, why a patient can develop a single disease or an APS/MAS. One hypothesis to explain APS/MAS is that tissues deriving from the same germ layer may share similar germ-layer-specific antigens, which would serve as targets for autoimmune responses. This hypothesis can explain APS/MAS-3, since the thyroid and the stomach derive from the same endodermal germ layer, but not APS/MAS-2 because the thyroid and the pancreas derive from the endoderm, while the adrenal glands from the mesoderm. Furthermore, according to this hypothesis, the APS/ MAS should appear at the same time, but this rarely happens. Advances in our

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understanding of the pathogenesis of APS/MAS are hindered by the lack of animal models capable to develop spontaneously these syndromes. Following the discovery of AIRE gene mutations, the genetic etiopathogenesis of APS/MAS-1 was clarified by developing AIRE gene knockout animal models.

APS/MAS-1 Historical Features The first description of an APS/MAS-1 dates back to 1929, when a case of chronic hypoparathyroidism (CH) associated with chronic mucocutaneous candidiasis (CMC) was described. In 1943, five patients (including three brothers) were described as having chronic hypoparathyroidism (CH), and one of them also had CMC and “idiopathic” Addison’s disease (AD). The association between CH, CMC, and AD was confirmed in 1946. In 1958, a review on 50 patients with CH revealed that 16% of them had CMC, 10% had AD, and 8% had keratoconjunctivitis. In 1962, histological examination at autopsy of the glands of 11 patients with CH and AD revealed parathyroid and adrenal gland atrophy, and infiltration of both by mononuclear cells, indicating a common endocrine tissue pathogenesis. This picture has been called in various terms: type 1 polyglandular autoimmune diseases (PGAD-1) (Neufeld and Blizzard 1980), autoimmune poly-endocrinopathy-candidiasis-ectodermal dystrophy (APECED), type 1 autoimmune polyglandular syndromes (APS-1) (Betterle et al. 2002), or type 1 multiple autoimmune syndromes (MAS-1) (Betterle and Presotto 2008).

Frequency and Epidemiology APS/MAS-1 is a very rare genetic disease, inherited as an autosomal recessive trait, thus it is not gender-linked. In most countries, the estimated prevalence is less than 10/1000,000 population with a relatively higher prevalence in genetically isolated populations such as Iranian Jews (1/9000), Sardinians (1/14,400), Finns (1/25,000), and Slovenian (1/43,000). It is much less frequent in Norwegians (1/80,000), Polish (1/129,000), Irish (1/130,000), and exceptional in French (1/500,000) or Japanese (1/10,000,000) (Betterle et al. 2002; Perheentupa 2006; Guo et al. 2018; Husebye et al. 2018). In a survey performed in Italy, we estimated to have around 200 cases of APS/MAS-1, with a prevalence of about 3–3.5/1000,000 population. Three “hot areas” have been also identified: Sardinia (Olgiastra), Apulia (Salento), and Veneto (Bassano del Grappa) (Betterle et al. 2016).

Animal Models of APS/MAS-1 A murine model of APS/MAS-1 was developed and demonstrated that AIRE gene knockout animals developed multiple autoimmune diseases, with lymphocytic

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infiltration of the target organs and circulating autoantibodies. These studies contributed to the discovery of the transmission mechanisms of this gene’s signal.

Genetics of APS/MAS-1 Genetic analyses on patients with APS/MAS-1 performed in 1994 showed a link to a gene in a region of human chromosome 21q22.3 that had not been previously associated with autoimmune diseases. Twenty years ago, the AIRE gene was identified, cloned, and sequenced. This gene consists of 14 exons, and it is expressed on the thymus at the level of the antigen-presenting cells, but also on the spleen, lymph nodes, pancreas, and adrenal cortex. At thymus level, the AIRE gene is involved in central tolerance, mediating the ectopic expression of many tissue-restricted proteins. This antigen presentation is able to influence the negative selection of autoreactive T cells. If the AIRE gene is mutated, many autoreactive T cells with specificity for autoantigens can escape deletion and be able to embark on an autoimmune aggression (Husebye et al. 2018). The AIRE gene controls also immune tolerance by inducing a population of FoxP3+ regulatory T cells (Treg) in the thymus, which have the ability to suppress autoreactive T-cells. Mutations in the AIRE gene prevent the elimination of self-reactive T cells at central level resulting in a Treg defect at peripheral levels (Husebye et al. 2018). This leads to the development of multiple autoimmune diseases at a young age in the affected individuals (Bruserud et al. 2016; Husebye et al. 2018; Passos et al. 2018). Some different disease-causing mutations have been found peculiar to certain populations. The most common is R257X, a nonsense mutation localized on exon 6. This mutation is present in more than 90% of the Finnish patients with APS/MAS-1 but can be found in other European and non-European patients too, Italians included (Cervato et al. 2009; Betterle et al. 2016). R257X results in a nonfunctional AIRE protein leading to an alteration of the subcellular localization and inhibition of the transactivation function and complex formation of the AIRE gene. Another mutation, the 1094–1106 del13 (or 967-979 del-13 bp), localized on exon 8, is the most common mutation in British, Irish, North American, Norwegian, French, and northern Italian patients (Cervato et al. 2009; Betterle et al. 2016; Guo et al. 2018). The Y85C mutation is the only missense mutation found among Iranian Jews. In Italy, patients with APS/MAS-1 have revealed different mutations depending on their region of origin (Cervato et al. 2009; Betterle et al. 2016). For example, more than 90% of the patients in Sardinia had the R139X mutation on exon 3. This nonsense mutation leads to the total absence of the AIRE gene and seems to be associated with a more severe phenotype. In Apulia, the most common mutations are the missense mutation W78R on exon 2, and the nonsense mutation Q358X on exon 9 (Cervato et al. 2009; Betterle et al. 2016). In Sicily, the most often seen mutations are R203X on exon 5, and two novel mutations – S107C and Q108fs – on exon 3, but cases of R257X can also be found. The S107C mutation is a missense mutation, while Q108fs is a small deletion, and both affect the homogeneously staining region (HSR) domain of the AIRE protein, probably making it lose its homodimerization properties. In Venetian patients, the most frequent mutations are R257X on exon 6, and del-13 bp on

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exon 8, which are similar to those found in Finnish and British patients. In Campania, patients have shown various mutations, but all located on the exon/intron 1 junction. No typical mutations have been identified in Calabria, where the most frequent were those found in Apulian (W78R) and Sicilian (R203X) patients (Cervato et al. 2009; Betterle et al. 2016). Dominant mutations have rarely been described in APS/MAS-1. The first one was G228W, discovered in an Italian patient from Tuscany with CH and chronic thyroiditis without AD, but positive for 21-hydroxylase (21OHAbs). The second case was c.932G > A (p.C311Y), described in a North-African patient with adult-onset CMC, AD, enamel dysplasia, pernicious anemia, partial diabetes insipidus, and interferon-ω autoantibodies. His family history (with partner 1) revealed a daughter who had CH, enamel dysplasia, primary ovarian insufficiency (POI), autoimmune gastritis with pernicious anemia, and the same mono-allelic p.C311Y mutation, indicating a dominant inheritance. The patient had four children with a second partner, and three of them carried the p.C311Y mutation (one daughter had alopecia areata and nail dystrophy, another daughter had CH and POI, and a son had autoantibodies against tyrosine hydroxylase) (Oftedal et al. 2015). So far, more than 126 AIRE gene mutations have been identified in patients with APS/MAS-1, varying from single nucleotide mutations to large deletions distributed across the coding sequence (Bruserud et al. 2016; Guo et al. 2018). Although APS/MAS-1 is a clear example of autoimmune monogenic disease, a clear genotype-phenotype correlation is lacking. In some cases, individuals with the same mutation (even siblings) have presented with different clinical manifestations and experienced a different course of the disease (Weiler et al. 2012). A recently reported Italian family disclosed an extremely variable clinical picture despite the same AIRE gene mutation. Some authors reported few phenotype-genotype associations. CMC was much lower in patients homozygous for 967-979del13bp than in those carrying the R257X or R139X mutation. A lower prevalence of CMC and AD was found among the Iranian Jewish patients with the Y85C mutation. Alopecia was more common in individuals with the 967-979del13 deletion, and autoimmune thyroiditis was usually found in individuals carrying the G228W mutation (Weiler et al. 2012). It seems evident that the allelic heterogeneity of the AIRE gene provides insufficient insight on the different phenotypes. These observations suggest that genetic background alone is unable to explain the link between genotype and phenotype. As in other monogenic diseases, the phenotypic variability of the syndrome may depend on the interaction between number of the genetic, epigenetic, immunological, and environmental factors. As regards HLA, few studies have investigated the association between the APS/MAS1 phenotype and HLA genotypes, reporting conflicting results.

Main Clinical Manifestations of APS/MAS-1 Numerous organs may be the target of autoimmune attacks in this syndrome (Husebye et al. 2018). The three main components remain CMC, CH, and AD that generally develop in a consecutive manner, with CMC first, followed by CH and, then, by AAD that typically occurs as a third disease in the second decade of life.

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Throughout their lives, patients continue to develop other autoimmune and nonautoimmune diseases (Betterle et al. 2002; Guo et al. 2018). The three main autoimmune diseases occurred with a frequency in the range of 80–90% in the various cohorts of European patients examined and the other minor autoimmune and non-autoimmune manifestations were reported in a small minority (5–20%) (Betterle et al. 2002; Perheentupa 2006; Capalbo et al. 2013; Guo et al. 2018). However, in a limited cohort of 35 American patients, the array of AID in APS-1 was nonclassical. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren’s-like syndrome, uncommon entities in European APS/MAS-1 cohorts, affected 40–80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.4 years, and 80% of patients developed a median of three non-triad manifestations before a diagnostic dyad, with 20% of patients having their first two manifestations among the classic triad (Ferre et al. 2016). Autoantibodies against interferon-α and/or interferon-ω were found in the great majority of the patients with APS/MAS-1 from Finland, Sardinia, Norway, Britain/Ireland, and Italy (Humbert et al. 2018).

Chronic Mucocutaneous Candidiasis (CMC) Many cohort studies were published in the past, including more than 500 patients with APS/MAS-1 (Betterle et al. 2016; Guo et al. 2018). The prevalence of CMC in these cohorts varied from 17% to 100% and the lowest was among Iranian Jews (Weiler et al. 2012). In most cases, CMC is the first of the main components of APS/MAS-1 to appear, often before 5 years of age (Perheentupa 2006; Weiler et al. 2012). In the Italian survey of APS/MAS-1 patients, CMC was the first disease to appear (in isolation or associated with other diseases) in 53% of patients. It was diagnosed at a mean age of 4.4 years (range 0.5–36). By the end of a follow-up period of 24.2
14.7 years (range 1–66 years), 72% of patients had CMC (Fig. 2), and the mean age of onset was 9.3 years (range 0.5–79) (Fig. 3). CMC can affect the oral mucosa, causing intermittent angular cheilitis. More severe cases include inflammation of the oral mucosa with leukoplastic areas and a potential for evolving into squamous cell carcinoma. CMC can also cause esophageal mucositis, with stricture, retrosternal pain, and dysphagia. Intestinal candidiasis can cause abdominal pain, flatulence, and diarrhea. Females may suffer from vulvovaginitis. The skin and nails may be also involved but, in most cases, no more than 5% of the skin’s surface is affected (Betterle et al. 2002). Generalized candidiasis has only been reported in patients on immunosuppressant medication that reduces T lymphocytes, and Thelper 17 in particular, which are involved in protecting against Candida albicans (Perheentupa 2006; Weiler et al. 2012; Passos et al. 2018). There is a normal B-cell response to Candida, which prevents the onset of systemic candidiasis. The diagnosis of CMC is clinical and confirmed by cultures (Betterle et al. 2016). Chronic Hypoparathyroidism (CH) The prevalence of CH in the national cohorts of APS/MAS-1 ranged from 50% to 100% (Betterle et al. 2016; Guo et al. 2018). CH is usually the second disease to develop, and the first endocrine occurring dysfunction (Betterle et al. 2002;

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Autoimmune Polyendocrine Syndromes (APS) or Multiple Autoimmune. . . 100 90 80

Patients affected (%)

70 60 50 40 30 20 10 0

Fig. 2 Frequencies of diseases in 147 Italian patients with APS/MAS-1

50 45

Mean age of onset (years)

40 35 30 25 20 15 10 5 0

Fig. 3 Mean age at onset of diseases in 147 Italian patients with APS/MAS-1

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Perheentupa 2006; Weiler et al. 2012). In an Italian cohort of patients, CH appeared as the first disease in 26% of the cases at a mean age of 9 years (Betterle et al. 2016). By the end of the observation period of 24.2
14.7 years (range 1–66 years), CH was the most prevalent disease of the triad, affecting 87% of patients (Fig. 2). The disease developed at a mean age of 11 years (range 0.5–74) (Fig. 3). CH may develop with latent or manifest hypocalcemia (Betterle et al. 2016). Latent manifestations can be revealed by Trousseau’s or Chvostek’s signs, which are hallmarks of neuromuscular irritability. The manifest symptoms are paresthesias, perioral numbness, carpo-pedal spasms, laryngospasms, tetany, and seizures, which may sometimes simulate an epileptic attack (Betterle et al. 2014). Cardiac manifestations are common too, including a prolonged QT interval and torsades de pointes on ECG. Histopathological studies performed in the past revealed atrophy and lymphocytic infiltration of the parathyroid glands and was regarded as a typical finding of AID (Betterle et al. 2014). Laboratory tests reveal hypocalcemia, hyperphosphoremia, and low levels of parathyroid hormone (Guo et al. 2018). Autoantibodies to parathyroid cells were occasionally identified in the past, but they were not subsequently confirmed. Autoantibodies against the calcium-sensing receptor (CaSRAbs) have sometimes been variably identified, depending on the method used, in 0–87% of patients with CH, and in 0–22% of controls (Betterle et al. 2014). Autoantibodies against Nacht-Leucine-Rich-Repeat Protein 5 (NALP5Abs) have been found in 49% patients with APS/MAS-1 and long-standing CH, but not in patients with isolated CH or with other autoimmune diseases (Betterle et al. 2014). Being so specifically linked to APS/MAS-1, NALP5Abs have been included in the latest criteria for diagnosing this syndrome (Husebye et al. 2009). In 2014, however, neither CaSRAbs nor NALP5Abs emerged as specific or sensitive markers of CH in APS/ MAS-1. Further investigations are therefore required to determine the exact role of these autoantibodies in the pathogenesis of the syndrome. Given such variable results, we believe that an international standardization program will be needed to establish whether these autoantibodies can be considered serological markers of the syndrome (Betterle et al. 2014).

Autoimmune Addison’s Disease (AAD) The prevalence of AAD in national surveys ranged from 22% to 95% of cases (Betterle et al. 2016; Guo et al. 2018). AAD usually appears as the third disease, with a peak incidence around 12 years of age (Betterle et al. 2002; Perheentupa 2006; Weiler et al. 2012). In an Italian study, autoimmune AD occurred as the first disease of the syndrome in 8% of cases (Betterle et al. 2016), and by the end of a follow-up period of 24.2
14.7 years (range 1–66 years), AD was diagnosed in 81% of the patients (Fig. 2) at a mean age of 18 years (range 2–76) (Fig. 3). AD is a life-threatening condition that needs to be recognized and promptly treated, and symptoms include fatigue, weight loss, salt craving, hypotension, abdominal pain, and increased skin pigmentation. At diagnosis, AAD revealed a high frequency (>90%) of ACA/ 21OHAbs Table 3). Being in general AAD, the third disease to appear, and being the presence of adrenal cortex autoantibodies (ACA) or 21OHAbs autoantibodies

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markers of very high future clinical manifestations of AAD (Betterle et al. 2016; Naletto et al. 2019), we suggest to test for these autoantibodies all the patients with APS-1 without clinical AAD (Naletto et al. 2019). At the end of follow-up of Italian patients with APS/MAS-1, the three main diseases were present in 51%, two diseases in 44%, and one disease in 5% (7 HP and 2 CMC) of the patients (Fig. 2).

Minor Autoimmune Diseases Premature Ovarian Failure (POF) The prevalence of POF in the national surveys ranged from 0% to 71% of cases (Betterle et al. 2016; Guo et al. 2018). In our patients at the end of a long follow-up period, POF developed in 50% of females (Fig. 2), at a mean age of 23 years (range 12–39) (Fig. 3). POF can manifest as primary or secondary amenorrhea with hypergonadotropic hypogonadism. When POF was diagnosed, autoantibodies against steroid-producing cells (StCA) and/or 17α-hydroxylase (17α-OHAbs) and/ or side chain cleavage enzyme (SCCAbs) are present in 95% of cases (Betterle et al. 2016). They can also be found in 44% of cases with APS/MAS-1 without POF, in which case they indicate a potential development of the disease. If so, patients should be informed in order to arrange for the preservation of their homologous eggs. In antibody-positive cases of POF biopsy of the ovary revealed a typical pattern of lymphocytic oophoritis. In males with APS/MAS-1, StCA and/or 17α-OHAbs, and/or SCCAbs were a common finding (67%), but there was no evidence of any hypergonadotropic hypogonadism or future risk of this manifestation in antibody-positive subjects (Betterle et al. 2016). Autoimmune Gastritis (AG) AG, in isolation or associated with pernicious anemia (PA), was found in 4–32% of the APS/MAS-1 patients in the national cohorts (Betterle et al. 2016; Guo et al. 2018). In our Italian patient population, at the end of a long follow-up period, 29% had AG (Fig. 2), and the mean age of onset was 29 years (Fig. 3). This disorder may remain silent or become evident with symptoms of dyspepsia and/or anemia. Biochemical tests can reveal microcytic or macrocytic anemia, hyposideremia, hypergastrinemia, high levels of chromogranin A, low levels of pepsinogen I and vitamin B12, and positivity for antibodies against parietal cells and/or intrinsic factor. Endoscopic examination, taking biopsies from the gastric fundus and body, confirms the diagnosis of AG (Weiler et al. 2012; Betterle et al. 2016). Auto-Immune Thyroid Diseases (AITD) AITD occurred in 4–50% of the APS/MAS-1 patients considered in the national surveys (Betterle et al. 2016; Guo et al. 2018). They were mainly cases of chronic thyroiditis, with very few cases of Graves’ disease (Betterle et al. 2002; Perheentupa 2006; Weiler et al. 2012). In our population, at the end of a long follow-up period,

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29% of patients had AITD (Fig. 2), which developed when they were a median 19 years old (Fig. 3). They all had chronic thyroiditis, except for one case of Graves’ disease. AITD are characterized by the presence of autoantibodies against thyroperoxidase and/or thyroglobulin (Betterle et al. 2016).

Type 1 Diabetes Mellitus (DM-1) DM-1 was present in 3–33% of patients in national surveys, with a peak incidence in the Finnish APS/MAS-1 population (Betterle et al. 2016; Guo et al. 2018). In Italy, DM-1 appeared as the first disease in 1.3% of cases and at the end of a long followup period, 8% of the patients were affected by the disease (Fig. 2). The mean age of onset was 15 years (Fig. 3). Patients with DM-1 are positive for autoantibodies against islet cells (ICA), glutamic acid decarboxylase (GADAbs), and second islet autoantigens (IA2Abs) (Weiler et al. 2012; Fierabracci 2016; Betterle et al. 2016a). Many patients who have APS/MAS-1 without DM-1 are positive for ICA, GADAbs, and IA2Abs, but they are at low risk of future DM-1 because GADAbs in APS-1 react with epitopes different from those found in “classical” DM-1, and because they do not have the Class II HLA alleles that predispose to DM-1 (Weiler et al. 2012; Fierabracci 2016). During a long follow-up, the incidence of DM-1 in patients with pancreatic autoantibodies was 1% per year (Betterle et al. 2016). Alopecia Areata (AA) AA was found in 7–52% of the APS/MAS-1 patients considered in the national surveys (Betterle et al. 2016; Guo et al. 2018). It may appear from the first year of life, but it is more frequent after middle age (Weiler et al. 2012). AA that may progress to the universalis form, affected 35% of Italian patients (Fig. 2), starting at a mean age of 12 years (Fig. 3). It is only in APS/MAS-1 that AA is associated with autoantibodies against tyrosine-hydroxylase (THAbs). The diagnosis of AA is ascertained clinically (Weiler et al. 2012; Betterle et al. 2016). Vitiligo This condition was identified in 6–50% of the APS/MAS-1 patients studied in the national surveys (Betterle et al. 2016; Guo et al. 2018). In Italy, at the end of a long follow-up period vitiligo affected 25% of patients (Fig. 2), manifesting at a mean age of 15 years (Fig. 3). It is only in APS/MAS-1 that vitiligo is associated with autoantibodies against melanocytes or SOX9 and SOX10. The diagnosis is established clinically (Weiler et al. 2012; Betterle et al. 2016). Autoimmune Hepatitis (AH) AH was diagnosed in 4–43% of patients with APS/MAS-1 (Betterle et al. 2016; Guo et al. 2018). The clinical pattern varies considerably, from fulminant and sometimes fatal forms, to chronic forms well controlled by immunosuppressants or to asymptomatic cases that regress spontaneously (Weiler et al. 2012). Among Italian APS/ MAS-1 patients, AH at the end of a long follow-up period was found in 22% of the cases (Fig. 2), and it developed at a mean 13 years of age (Fig. 3). The diagnostic biochemical tests include transaminases, autoantibodies against cytochrome P450

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(CYP-IA2 and CYP-2A6), and aromatic l-amino acid decarboxylase (AADC) (Weiler et al. 2012).

Autoimmune Enteropathy (AE) A malabsorption affected 5–54% of patients with APS/MAS-1 in the national surveys (Betterle et al. 2016; Guo et al. 2018), and correlated with various non-autoimmune causes, such as cystic fibrosis, exocrine pancreatic insufficiency, intestinal infections (Candida, Giardia lamblia and Clostridium difficile), and intestinal lymphangiectasis (Perheentupa 2006; Weiler et al. 2012; Scarpa et al. 2013). Patients with APS/MAS-1 can also have two different forms of AE, such as celiac disease, found in 2% of the patients (detectable by transglutaminase autoantibodies of IgA or IgG classes) and another AE characterized by chronic or periodic constipation or recurrent diarrhea and malabsorption occurring in 15% of patients (Fig. 2). The mean age at onset is 15 years (Fig. 3). The latter form of AE is associated with the presence of antibodies against tryptophan hydroxylase (TPHAbs), histidine decarboxylase (HDAbs), or L-amino acid decarboxylase (AADC) (Weiler et al. 2012; Kluger et al. 2015). In this form of AE, gastrointestinal biopsies have revealed a chronic lymphocytic infiltration of the gut mucosa and the absence of serotonin-producing cells associated with low circulating serotonin levels. These data suggest a role for serotonin in regulating intestinal motility (Scarpa et al. 2013). Splenic Atrophy (SA) SA can develop as a consequence of an autoimmune process against the spleen, or a vasculitis process (Weiler et al. 2012), and may be found in 2–16% of APS/MAS1 patients in various cohorts (Betterle et al. 2016; Guo et al. 2018). SA was identified in 8% of the Italian cohort at the end of a long follow-up (Fig. 2), developing at a mean age of 23 years (Fig. 3). The presence of SA is characterized by a strong susceptibility to infection by Streptococcus pneumoniae and pneumococcal vaccination is greatly recommended. SA can be suspected in the presence of Howell-Jolly’s bodies, thrombocytosis, anisocytosis, poikilocytosis, target cells, burr cells, thrombocytosis, and lymphocytosis on peripheral blood smears (Weiler et al. 2012). Pituitary Failure (PF) PF due to lymphocytic hypophysitis is characterized by single or multiple pituitary defects. From 5% to 58% of the APS/MAS-1 patients in the national cohorts had PF. Pituitary defects can be found in 15% of our patients at the end of a long follow-up (Fig. 2) at a mean age of 14 years (Fig. 3). Growth hormone deficiency is the most commonly reported defect, but central diabetes insipidus and gonadotropin or ACTH deficiencies have also been described (Weiler et al. 2012). Autoantibodies against endothelin-converting enzyme (ECE)-2, expressed in high levels especially in the pituitary, have been detected in APS/MAS-1 patients. However, there is no correlation between immunoreactivity against ECE-2 and the known major clinical phenotypes of APS/MAS-1, including hypopituitarism (SmithAnttila et al. 2017).

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Renal Diseases Tubulointerstitial nephritis and nephrocalcinosis have been described in patients with APS/MAS-1 with progression to kidney failure and the need for organ transplantation (Weiler et al. 2012). Pulmonary Diseases (PD) APS/MAS-1 patients may sporadically have PD, such as primary pulmonary hypertension, bronchiectasis, or autoimmune bronchiolitis characterized by the presence of autoantibodies against potassium channel-regulating protein (KCNRGAb). Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) Chronic inflammatory demyelinating polyradiculoneuropathy is an acquired peripheral nervous system disease characterized by progressive or relapsing proximal and distal weakness with or without sensory loss. There is good evidence to indicate that CIDP is autoimmune in nature (Weiler et al. 2012). CIDP is heterogeneous and a number of subtypes or related conditions have emerged. Vasculitis Recurrent maculopapular, morbilliform, or urticarial erythema with fever has been seen in APS/MAS-1 patients too. Skin biopsies performed in some cases revealed lymphoplasmacytic vasculitis (Weiler et al. 2012). Ectodermal Dystrophy Components of ectodermal dystrophy were found in 4–42% of the patients in the national cohorts and included: (a) phlyctenular keratoconjunctivitis (in which the cornea shows irregular confluent sublenticular opacities, with bulbar injection of the conjunctiva, and subsequent superficial corneal neovascularization, a condition extremely rare among Iranian Jewish patients); (b) dental enamel hypoplasia of the permanent teeth; and (c) punctate nail defects. The pathogenesis remains unknown (Weiler et al. 2012). Cancer Malignancies are not uncommon in APS/MAS-1 patients and squamous cell carcinoma of the oral or oesophageal mucosa is the most common form (Bruserud et al. 2018). In our Italian population of APS/MAS-1 patients 13% were affected by one or more malignant tumors developed at a mean age of 45
12 years. Other Rare Diseases The following disases have been described in patients with APS/MAS-1 with variable frequencies: cholelithiasis, iridocyclitis, optic nerve atrophy, retinal degeneration, calcified plaques of the tympanic membranes, IgA deficiency, hypergammaglobulinemia, hemolytic anemia, hypoplastic anemia, autoimmune thrombocytopenia, scleroderma, Sjögren’s syndrome, lichen planus, hypokalemia, apparent mineralocorticoid excess syndrome, reversible metaphyseal dysplasia, progressive myopathy, exocrine pancreatic insufficiency, posterior reversible encephalopathy

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syndrome, skin rash with fever, phlyctenular keratoconjunctivitis, demyelinating autoimmune diseases and retinitis pigmentosa (Betterle et al. 2002; Perheentupa 2006: Weiler et al. 2012; Capalbo et al. 2013; Ferre et al. 2016; Husebye et al. 2018).

Total Number of Diseases in the Italian Cohort of APS/MAS-1 This syndrome is the disorder with the largest number of associated autoimmune and non-autoimmune diseases. During a lengthy follow-up of 147 Italian patients, 890 diseases were identified, with a mean of six diseases per patient and a range from 1 to 15 diseases (Betterle et al. 2016). Diseases of APS/MAS-1 and Related Autoantibodies In addition to the different autoantibodies involved in the previously described diseases, APS/MAS-1 patients from various countries (Finland, Sardinia, Norway, Britain, Ireland, and Italy) have shown a very high prevalence of autoantibodies against interferon-α and/or interferon-ω, and various cytokines (Meloni et al. 2012; Larosa et al. 2017; Guo et al. 2018). The autoantibodies involved in APS/MAS-1 patients are summarized in Table 3.

New Diagnostic Criteria for APS/MAS-1 Advances made in recent decades in our understanding of the genetics and immunology of APS/MAS-1 have enabled the old diagnostic criteria to be refined and summarized in Table 4 (Husebye et al. 2009). Some studies have confirmed the importance of apply these new criteria. The first study investigated 24 young patients with CH without CMC and/or without AAD, finding AIRE gene mutations in six of them (25%). Three of these six patients had homozygous AIRE mutations characteristic of APS-1, and all three were also positive for IFNω-autoantibodies. The other three patients had heterozygous AIRE mutations (two of them novel), and one was positive for both NACHT5Abs and IFNωAbs. Analyzing AIRE gene mutations combined with serum autoantibody profiling should be helpful in assessing young patients with isolated CH (Cervato et al. 2010). Another study found that 3/37 patients (8.1%) with isolated CH had high IFNαAbs levels, and all three revealed AIRE gene mutations positive for APS/MAS-1. Patients with idiopathic isolated CH should be considered for testing for IFNαAbs (Sahoo et al. 2016). Recently, these diagnostic criteria have been modified and patients with a clinical phenotype suggestive of APS-1 should be screened for IFNαAbs before AIRE sequencing. Since IFNαAbs screening is not currently used in routine laboratories, these patients should be directly tested for AIRE gene mutations (Husebye et al. 2018).

How to Manage Patients with ASP/MAS-1 APS/MAS-1 is a very rare disease with heterogeneous clinical manifestations where it is greatly important to consider the clinical manifestations and the age of onset.

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Table 3 Diseases involved in APS/MAS-1 and related autoantibodies Diseases APS-1 screening Fundamental diseases

Regardless of the disease(s) identified Chronic candidiasis Chronic hypoparathyroidism

Other autoimmune endocrine diseases

Addison’s disease Premature ovarian failure Autoimmune thyroid diseases Type 1 diabetes mellitus Pituitary deficiency

Other autoimmune diseases

Autoimmune gastritis with or without pernicious anemia Autoimmune enteropathy Celiac disease Exocrine pancreatic insufficiency Autoimmune bronchiolitis Pulmonary hypertension Prostatitis Asplenia Vitiligo

Hematological disorders

Nephrological diseases Ectodermal dystrophy Muscle diseases a

Alopecia Periodic fever with skin rash Hypergammaglobulinemia Bone marrow red cell aplasia IgA deficiency Hypertension with apparent mineralocorticoid excess Tubulo-interstitial nephritis Keratoconjunctivitis Dental enamel dysplasia Oral squamous carcinoma Myopathy

Depending on the method

Autoantibodies IFNωAbs, IFNα Abs, IL22 Abs, IL-17-E Abs IL-22 Abs, IFNωAbs, IFNα Abs NALP5Abs CaSR Abs (?) ACA and/or 21-OH Abs StCA, 17α-OH Abs, SCC Abs TPO Abs, Tg Abs, TSHR Abs GADAbs, ICA, IA2 Abs, ZnT8Abs Pituitary Abs, Diencephalon Abs, ECE2Abs PCA, ATPAsiH/KAbs, IFAbs TPHAbs, HDAbs, AADC TransglutaminaseIgAAbs No Abs Potassium channel regulator (KCNRG Abs) Transglutaminase-4 Abs No Abs MPCAbs, SOX9Abs, SOX10Abs THAbs No Abs No Abs No Abs No Abs No Abs No Abs No Abs No Abs No Abs

Frequency (%) ~90 ~90 70–80 0–90a 90 90 90 90 Variable

90 90 100

100 ? 100 Unknown

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Table 4 New criteria for the diagnosis of APS/MAS-1 Definite diagnosis Probable diagnosis

(a) At least two of the fundamental triad of diseases (CMC, CH, AAD) (b) One disease in the triad if a sibling has APS/MAS-1 (c) AIRE gene mutations irrespective of any presence of disease (a) One disease in the triad (developed before 30 years of age) associated with another autoimmune or non-autoimmune disease (b) One (“major” or “minor”) disease associated with autoantibodies against interferons (IFNAbs) (c) One (“major” or “minor”) disease associated with autoantibodies against: Tryptophan hydroxylase (TPHAbs); aromatic L-amino acid decarboxylase (AADC); NACHT leucine-rich protein-5 (NALP-5Abs); and tyrosine hydroxylase (THAbs)

Husebye et al. (2009)

It has been demonstrated that the diagnosis of APS/MAS-1 may be delayed by as much as 10 years, especially if the first occurring disease is not one of the classical triad. But even when the disease begins with CMC, this may not be clearly evident and thus the syndrome can be unrecognized for a long time. Bearing in mind that it usually develops sequentially (CMC ! CH ! AAD), we recommend testing all patients with CMC alone for calcemia and phosphoremia, basal ACTH and cortisol, as well as for 21-OHAbs and IFNAbs. Positivity for one or more of these autoantibodies warrants investigations to identify AIRE gene mutations (Husebye et al. 2018). In the event of tetany or paresthesias, it is again important to test for calcemia, phosphoremia, and PTH, in order to confirm the diagnosis of CH and avoiding the risk of a misdiagnosis of epilepsy or hyperventilation syndrome. After confirming CH, it is important to test for ACTH, cortisol, 21-OHAbs, and IFNAbs and check accurately for the presence of CMC by means of clinical or cultural tests. Again, if any of these tests are positive, then AIRE gene mutations should be investigated. In cases with a nonclassical clinical presentation (ectodermal dystrophy or minor autoimmune diseases at a young age), it is important to search for CMC, CH, and/ or AAD by means of clinical and serological tests, test for IFNωAbs or AIRE gene mutations. Delays in the diagnosis of APS/MAS-1 in patients and their siblings can place these individuals at high risk of life-threatening adrenal crisis. Finally, every healthy individual with a family history of APS/MAS-1 should be investigated for: (1) CMC; (2) calcemia and phosphoremia; (3) ACTH and cortisol; (4) AIRE gene mutations (5) ACA/21-OHAbs, IFNωAbs, TPHAbs, AADC, NALP-5Ab, and IFNAbs (Meloni et al. 2012; Betterle et al. 2016; Larosa et al. 2017).

When to Investigate for AIRE Gene Mutations It is mandatory to test for AIRE gene mutations in: (a) patients with two or three clear clinical diseases of APS/MAS-1, (b) patients with only one major or minor disease typical of APECED and positive for IFNAbs (Husebye et al. 2018), (c) first-degree relatives of patients with APS/MAS-1, (d) uncles/aunts of the proband and if they

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reveal the presence of a mutation also their sons, (e) the partners of the carriers with one or two mutations, (f) testing is suggested in the general populations only from “hot areas” for the disease (for example, Finland or in Italy Olgiastra, Salento, or Bassano del Grappa areas) (Betterle et al. 2016). The identification of asymptomatic carriers of mutations allows early diagnosis of the syndrome and implies genetic counseling strategies (Betterle et al. 2016).

Therapy Treatment for APS/MAS-1 depends on the diseases affecting a given patient (Husebye et al. 2009), and usually hormonal replacement, anti-infective, and immunosuppressive therapies are fundamental for the success of treatment (Guo et al. 2018). CMC treatment should include appropriate lifestyle with attention to oral hygiene, avoiding any possible causes of ulceration of the oral mucosa, withdrawing of smoking, alcohol, and spicy foods. Topical or systemic therapies with antimycotic drugs could be adopted not only for acute treatments but also as periodic prophylaxis. In the case of subungual onychomycosis from Candida spp, it is important to avoid prolonged exposure to water and manicures and apply topical treatments (Table 5). CH is treated with activated vitamin D analogs (1, 25OH-vitamin D) and calcium supplementation (Table 5). Inactivated vitamin D analogs (25 OH-vitamin D) can be added to compensate for the pleiotropic action of this hormone. The therapeutic goal is to achieve the lower limit of the reference range of serum calcium levels in order to avoid an increased renal excretion of calcium and the risk of nephrocalcinosis. Follow-up is based on routine tests (every 6 months) on serum calcium, phosphate, and magnesium levels. After the introduction of PTH analogs, a prospective multicenter open-label study investigated the effect of 6 months of PTH (1–34) treatment in 42 patients with surgically treated CH: the treatment increased their serum calcium levels, leading to a significant decrease in their calcium and 1, 25 OH vitamin D supplementation, and improving their mental and physical health (Santonati et al. 2015). Another prospective open-label study examined the effect of 6 years of PTH (1–84) treatment in 33 patients with refractory CH: 53% of patients had a reduction in their supplemental calcium requirements and 48% no longer needed 1, 25-OH vitamin D supplementation. The therapy also succeeded in keeping serum calcium concentrations stable, reducing urinary calcium excretion and increasing bone turnover markers (Rubin et al. 2016). Treatment for AAD includes hormone replacement therapy with glucocorticoids such as hydrocortisone (15–25 mg) or cortisone acetate (25–35 mg) in two or three divided oral doses a day. It is best to take the highest dose in the morning on waking, and the remainder at lunchtime and/or in the early afternoon. A once-daily, dualrelease hydrocortisone tablet has recently become available that seems to reflect the normal daily cortisol rhythm better than conventional glucocorticoid replacement. Mineralocorticoid replacement therapy includes fludrocortisone (0.05–0.2 mg), once

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Table 5 Biochemical/radiological tests, therapy, and follow-up for APS/MAS-1 patients Periodical biochemical tests

Disease Chronic mucocutaneous candidiasis Chronic Serum hypoparathyroidism calcium and phosphate, 24-h urine calcium excretion Addison’s disease Blood sodium and potassium levels, plasma renin activity or direct renin assay Premature ovarian failure Thyroid autoimmune diseases Type 1 diabetes mellitus

Autoimmune hepatitis Autoimmune gastrointestinal dysfunction Autoimmune gastritis with or without pernicious anemia

Pituitary deficiency

Hematological diseases Phlyctenular keratoconjunctivitis Cataract

Periodical instrumental investigations Gastroduodenal endoscopy

Medical specialty for follow-up Gastroenterology Otolaringology

Renal ultrasound Calcitriol, alphacalcidiol or dihydrotachysterol; cholecalciferol Calcium citrate

Endocrinology Nephrology

Bone densitometry

Hydrocortisone or cortisone acetate; fludrocortisone

Endocrinology

Bone densitometry

Estroprogestin replacement therapy L-tyroxine

Gynecology

Endocrinology

Insulin

Diabetology

TSH

Thyroid ultrasound

Glucose, HbA1c, lipid profile

Fundus oculi, echocardiogram, vascular ultrasound Liver ultrasound

AST, ALT, gGT, ALP Serotonin

Treatment Fluconazole, itraconazole

Gastroduodenal endoscopy and colonscopy Gastroduodenal endoscopy

Blood count, gastrin, ferritin, serum iron levels, vitamin B12, pepsinogen I Testosterone, Pituitary FT4, IGF-1, MR scan blood sodium and potassium levels Blood count IgA

Corticosteroids and Gastroenterology azathioprine Not defined Gastroenterology

Iron replacement therapy Oral or injected vitamin B12 supplementation

Gastroenterology

Depending on the type of insufficiency

Endocrinology

Hematology Artificial tears Surgery

Ophthalmology

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daily in the morning. Patients should monitor their blood pressure (especially in orthostatism), their weight, plasma sodium and potassium, plasma renin activity or direct renin, and daily urinary cortisol levels. They should also pay attention to their subjective state of well-being and be trained to increase their glucocorticoid doses in the event of stress, using self or lay-administered parenteral glucocorticoids in particular emergency conditions, such as fever, vomiting and diarrhea, or surgical interventions in order to prevent adrenal crises (Table 5). The treatment of POF is based on estroprogestin replacement, which should be continued until menopausal age. Given the risk of POF, young females who are positive for steroidogenic autoantibodies (StCA, 17α-OHAbs and SSCAbs) should be advised to plan appropriate strategies for future recourse to in vitro fertilization procedures, if required. The treatment and follow-up of AITD is much the same as for patients with these disorders unassociated with APS/MAS-1. The treatment of DM-1 is also no different from usual, except that diabetic patients with APS/MAS-1 are at higher risk of hypoglycemia than DM-1 patients without AD because cortisol is one of the most important hormones involved in blood glucose control, in contrast with insulin. In cases of AG, treatment depends on the presence of microcytic or macrocytic anemia, which warrant oral or intravenous iron replacement therapy and injected vitamin B12 supplementation, respectively. Follow-up includes annual blood counts, also checking gastrin, ferritin, sideremia, and vitamin B12 levels. Endoscopic surveillance should be repeated every 2–3 years to rule out the development of gastric adenocarcinoma or gastrinoma (Table 5). The treatment of gastrointestinal disorders depends on the underlying causes (infections, exocrine pancreatic insufficiency, others), while celiac disease is controlled with gluten free diet. There is no targeted therapy for AE associated with TPHAbs. AH might need immunosuppressant treatment, depending on the severity of the disease. The treatment of skin disorders, such as AA and vitiligo, are nonspecific and not very effective. A sunscreen should always be used. Treatments for phlyctenular keratoconjunctivitis or cataract may include the use of artificial teardrops, or the need for surgery. In conclusion, patients with APS/MAS-1 need to be closely followed by a multidisciplinary team of expert specialists, in order to provide a personalized therapeutic strategy in this complex syndrome (Guo et al. 2018).

APS/MAS-2 Historical Features The first case of APS/MAS-2 was described in 1926 and involved two patients with “idiopathic” AD associated with chronic thyroiditis and a normal thyroid function. The association between “idiopathic” AD, DM-1 and hyperthyroidism

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was first described in 1931, and a case of “idiopathic” AD, DM-1, and hypothyroidism was reported in 1932. After the death of this last patient due to diabetic coma, autopsy revealed lymphomonocytic infiltration of the adrenal cortex, the Langerhans’ islets and the thyroid, thus suggesting that the three glands might have been affected by the same, as yet unidentified, disease. In 1964, when 142 cases with the syndrome described by Schmidt were reexamined, most of them revealed chronic thyroiditis or idiopathic myxedema and, less frequently, Graves’ disease, but 20% of them also had DM-1. The triad of diseases was also called Carpenter’s syndrome, and subsequently defined as Type 2 polyglandular autoimmune disease (PGAD-2) (Neufeld and Blizzard 1980), autoimmune polyendocrine syndrome Type 2 (APS-2) (Betterle et al. 2002, 2004), or Type 2 multiple autoimmune syndrome (MAS-2) (Betterle and Presotto 2008). The term APS/MAS-2 is used in the present publication.

Animal Models Animal models spontaneously developing APS/MAS-2 are rare. One is the obese White Leghorn Chicken, which develops chronic thyroiditis with adrenal cortex autoantibodies, but the adrenal cortex disease occurs only at serological level. An APS/MAS-2 developed in a dog with hypothyroidism and partial adrenal insufficiency. At autopsy, thyroid atrophy and lymphocytic infiltration of the adrenal cortex came to light. Experimental animal models of APS-2 have been obtained in mice infected with cytomegalovirus, which reveal lymphocytic infiltrations of the adrenals, pancreatic islets, liver, myocardium, salivary glands, and circulating autoantibodies. Another model of APS-2 affecting the thyroid, adrenals, ovary, and pancreatic islets was induced again in mice with cyclosporine A treatment after thymectomy at birth, suggesting that a major T-cell alteration (more severe than the one required to induce a single autoimmune disease) could trigger APS.

Genetics of APS/MAS-2 It is very rare for a family to include more than one patient with APS/MAS-2 or autoimmune AD. In our survey on 561 patients with APS/MAS-2, only 11 cases (2%) had a relative with AD, and only 2 of these (0.3%) were cases of APS/MAS-2 (Betterle et al. 2015). A genetic correlation was initially found between APS/MAS-2 and HLADR3 and HLA-DR4. The genetic picture of autoimmune AD (excluding APS-1) is associated with HLA Class II antigens, particularly with the HLA-DRB1*03DQA1*0501-DQB1*0201(DR3/DQ2) and DRB1*0404-DQA1*0301-DQB1*0302 (DR4.4/DQ8) haplotypes. The presence of DR3-DQ2 and DR4-DQ8 in patients with APS/MAS-2 confer a risk of type 1 diabetes, autoimmune thyroid disease, Addison’s disease, and celiac disease. This explains why these four diseases may develop in the same patient. Other genes associated with a risk of APS/MAS-2 include those that encode CTLA-4, protein tyrosine phosphatase non receptor type

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22 (PTPN22), the transcriptional regulator protein BACH2, and the CD25–interleukin-2 receptor (Husebye et al. 2018; Kahaly et al. 2018). Compared with controls, our patients’ HLA profiles revealed significantly higher levels of HLA-DR3 and HLA-DR4, and significantly lower levels of HLA-DR1, HLADR7, and HLA-DR13, suggesting a role for HLA in predisposing to and protecting against certain autoimmune diseases (Betterle et al. 2015).

Frequency and Epidemiology of APS/MAS-2 APS/MAS-2 is a rare syndrome, but not as rare as APS/MAS-1. Its prevalence was estimated at 14–45 cases/million population (Betterle et al. 2004). Subsequently, 100–200 cases/million were detected (Kahaly 2009) but a recent publication indicated that it is as high as 1000 cases/million (Husebye et al. 2018). This increase is probably due to the fact that incomplete forms of APS/MAS-2 are currently detectable by autoantibody screening tests. APS/MAS-2 can occur at all ages, but mainly in adults. It can be found in around 10% of children with AD, in about 10% of old people with AD, and has a preference for females (F/M ratio 2.7/1).

Main Clinical Manifestations of APS/MAS-2 The main clinical manifestations of APS/MAS-2 are AD (always present) associated with an AITD such as chronic thyroiditis (CT), and/or Graves’ disease (GD), and/or with DM-1. Other minor autoimmune disorders (AG with or without pernicious anemia, POF, vitiligo, alopecia, celiac disease, thrombocytopenia, multiple sclerosis, etc.) may also occur (Betterle et al. 2015).

Autoimmune Addison’s Disease (AAD) Four main national cohorts of APS/MAS-2 patients including 543 patients were published from 1981 to 2013. In these cohorts, the prevalence of AAD ranged from 40% to 100%. The lower frequency was found in German patients because in this cohort, the presence of AAD was not required for the diagnosis of APS/MAS-2 and CH can be also included (Kahaly 2009). In our survey of 561 patients with APS/ MAS-2 followed for a mean 13.7 years, all had AD with a mean age at onset of 36 years (Table 6). AAD developed in their first decade of life in 2.1% of cases, in the second decade in 10.1%, in the third in 20.7%, in the fourth in 29.6%, in the fifth in 20.3%, in the sixth in 9.1%, in the seventh in 3%, and in the eighth decade in 1.25% (Betterle et al. 2015). In patients with AAD, ACA and/or 21-OHAbs were detected in 97% of the cases within 2 years from the diagnosis, in 91% of the cases between 3 and 10 years, and in 83% of the cases after 10 years from the diagnosis of AD (Betterle et al. 2013).

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Table 6 Frequency of autoimmune diseases in a survey of 561 APS/MAS-2 Italian patients Diseases Autoimmune AD AITD Chronic thyroiditis Graves’ disease Thyroid autoantibodies with normal TSH DM-1 Pancreatic autoantibodies with normal glycemia Premature ovarian failure (on 387 females) Steroid-autoantibodies with normal menses Autoimmune gastritis Parietal cell autoantibodies only Vitiligo Alopecia Areata Rheumatic diseases Sjogren’s syndrome Psoriasis Rheumatoid arthritis SLE Others Celiac disease Haematologic diseases Werlhof’s disease Chronic urticaria Others Neurologic diseases Multiple sclerosis Myasthenia gravis Chronic inflammatory bowel diseases

Number 561 528 422 69 37 80 41 74 26 79 100 58 19 36 9 9 7 4 7 13 8 3 3 2 4 3 1 4

% 100 93 75 12 6 15 8 19 6.7 14 18 10 3 6

Mean age 36 34 35 31 25 32 46 31 29

2 1.4

0.7

0.7

Autoimmune Thyroid Diseases (AITD) From 61% to 88% of the patients in the national cohorts had AITD. In our series, AITD was identified in 93% of the cases by the end of a 13.7-year follow-up (Table 6). CT was associated with clinical/subclinical hypothyroidism in 75%, with thyroid autoantibodies and normal thyroid function in 6%. GD was found in 12% of cases at a mean age of 31 years. One in two patients developed CT before AAD, and the remainder at the same time as AAD or afterwards. GD developed before AAD in 75% of cases, and afterwards in 25%. About 90% of the patients with CT had TPOAbs and/or TgAbs. In GD patients, TRAbs were found in about 90% of cases, and TPOAbs and/or TgAbs in about 80%. Patients who have AAD with a normal thyroid function and positive test for TPOAbs and/or TgAbs are at risk of thyroid dysfunction and should be followed annually with TSH assays (Betterle et al. 2015).

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Type 1 Diabetes Mellitus (DM-I) In the national cohorts of APS/MAS-2 patients, DM-1 was diagnosed in 23–52% of cases. In our survey DM-1 developed in 15% of cases at a mean age of 25 years; 75% of these patients developed DM-1 before AAD was diagnosed, and 25% afterwards (Table 6). The majority of these DM-1 patients had ICA, and/or GADAbs, and/or IA2Abs (Betterle et al. 2016a). An additional 8% of APS/MAS-2 patients could have ICA, and/or GADAbs, and/or IA2Abs with a normal glucose tolerance test result. Such patients should be checked periodically for glycemia and HbA1c because they are at higher risk of developing classical DM-1 and/or latent autoimmune diabetes of adulthood (LADA) (Betterle et al. 2015).

Combinations of the Three Major Diseases AAD was associated with one other major disease in 81% of cases (66% AAD + CT, 11% AAD + GD, 4% AAD + DM-1), and with the other two diseases in 11% of cases. The most common association was AAD + CT (66%), while the rarest one was AAD + GD + DM-1 (found in only 1% od cases) (Betterle et al. 2015). In 8% of cases, AAD was associated with the presence of one or more autoantibody markers without any clinical manifestations of the other major diseases.

Incomplete or Subclinical Forms of APS/MAS-2 Patients with one of the major clinical diseases involved in APS/MAS-2 associated with autoantibodies against one or the other major diseases in the syndrome can be diagnosed as having incomplete forms of APS/MAS-2. The management of these patients is summarized in Fig. 4. Patients with AAD positive for thyroid autoantibodies but with normal TSH values (about 6% of cases) can be diagnosed as incomplete form of APS/MAS-2 and should periodically control TSH levels. Patients with AAD and islet cell-antibodies (ICA, GADAbs, IA2Abs, or ZnT8Abs) with a normal oral glucose tolerance test (OGTT) (about 8% of cases) are at risk of DM-1 and should periodically be tested for OGTT or HbA1c. Among patients with DM-1 and/or AITD, 0.5–2% are positive for ACA/21-OHAbs but with normal ACTH test. These patients are at risk of clinical AAD and should periodically repeat the ACTH test (Betterle et al. 2015; Naletto et al. 2019).

Minor Autoimmune Diseases Premature Ovarian Failure (POF) In the national surveys POF was found in 3.6–10% of APS/MAS-2 syndrome. In our population, POF was found in 19% of the females (Table 6), and 90% of them were also positive for StCA, and/or 17α-OHAbs, and/or SCCAbs, and they had

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Incomplete APS/MAS-2 Autoimmune Addison’s disease GADAb and/or IA2Ab

neg

Repeat Abs every 2-3 years

Positive 8%

OGTT

TPOAb and/or TgAb

Neg

Repeat Abs every 2-3 years

Positive 6% TSH, fT4 and thyroid ultrasound

Autoimmune thyroid diseases

Type 1 diabetes mellitus

ACA or 21OHAb

ACA or 21OHAb

Neg

Positive 0.5-2%

Repeat Abs ACTH-test every 2-3 years

Neg

Repeat Abs every 2-3 years

Positive 0.5-2%

ACTH-test

Fig. 4 Frequency of incomplete APS/MAS-2 and management of the cases

lymphocytic oophoritis (Betterle et al. 2015). Among the females with APS/MAS-2 and normal menses 6.7% were found positive for StCA and/or 17-α OHAbs and/or SCCAbs. When these patients have less than 40 years they should be followed for their risk of ovarian insufficiency (hypergonadotropic hypogonadism) and should be addressed for reproductive counseling for egg preservation. POF occurred before the diagnosis of AAD in 77% of the cases, while followed the onset of AAD in the remaining 23% (Betterle et al. 2015). Although 12.5% of males with APS/MAS-2 were found positive for StCA, and/or 17α OHAbs, and/or SCCAbs, none of the patients revealed or later developed testicular failure (hypergonadotropic hypogonadism) (Betterle et al. 2015).

Autoimmune Gastritis (AG) AG, alone or associated with pernicious anemia, was reported in 5–12% of the patients with APS/MAS-2. In the Italian cohort, AG was identified in 14% of the patients (Table 6). It was characterized by anemia, high levels of gastrinemia and chromogranin A, low levels of pepsinogen I, serum iron, and vitamin B12. An additional 18% of the patients with APS/MAS-2 was positive for PCA and/or IFA, without any recognized impairment in gastric body function (Table 6). AG occurred before the diagnosis of AAD in 23% of cases or developed later in the other 77% (Betterle et al. 2015). Vitiligo Vitiligo was diagnosed in 4.5–20% of patients in the national cohorts. In our survey, 10% of the patients showed signs of vitiligo (Table 6). Unlike patients with APS/ MAS-1, those with APS/MAS-2 are negative for circulating autoantibodies to SOX9 and SOX10 or MPCAbs (Betterle et al. 2015). Alopecia Alopcia was diagnosed in 0.5–4% of patients. In our population, it was found in 3% of the patients (Table 6) (Betterle et al. 2015).

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Celiac Disease Celiac disease was quite rare in APS/MAS-2 patients, while in our Italian survey, it was identified in 2% of cases (Table 6). Similarly, patients rarely have anti-transglutaminase IgA Abs in the absence of clinical disease. Celiac disease was diagnosed before AAD in 25% of cases, and in the remaining 75% afterwards (Betterle et al. 2015). Other Autoimmune Diseases In our cohort of Italian APS/MAS-2 patients, rheumatic autoimmune diseases were diagnosed in 36 cases (6%), hematological in 8 patients (1.4%), neurological in 4 patients (0.7%) and inflammatory bowel diseases in 4 patients (0.7%). (Table 6).

Autoimmune Diseases and Autoantibodies in APS/MAS-2 The major autoimmune diseases of the classical triad and the other minor autoimmune diseases are marked by specific autoantibodies (Table 7). Only vitiligo and alopecia do not have related autoantibodies, in contrast with APS/MAS-1 (Betterle et al. 2015).

Therapy The hormonal therapy of APS/MAS 2 is characterized by the single treatment of every AID. If AAD is associated to CT or GD, adrenal insufficiency must be first treated in order to avoid adrenal crisis (Betterle et al. 2015).

Table 7 Autoimmune diseases in APS/MAS-2 with their autoantibodies Diseases Classical triad

Autoimmune Addison’s disease (AAD) Autoimmune thyroid diseases (AITD)

Type 1 diabetes mellitus (DM-1) Other endocrinopathies Other autoimmune diseases

Hypergonadotropic hypogonadism (HH) Autoimmune gastritis (AG) with or without pernicious anemia Vitiligo Alopecia Celiac disease Myasthenia gravis (MG)

Autoantibodies (%) ACA and/or 21-OHAb (90%) TPOAbs and/or TgAbs (90%) TRAbs (30%) ICA and/or GADAbs and/ or IA2Abs (90%) StCA,17alpha OHAbs, SCCAbs (95%) PCA and/or IFAbs (90%) No Abs No Abs TGAbs-IgA or IgG (90%) R-AchAbs (90%)

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APS/MAS-3 General Considerations Since 1980s, APS/MAS-3 has been characterized by the presence of AITD associated with AID other than AAD and divided into three subgroups (A, B, C) (Table 1). Some authors do not consider this as a different type and incorporate these patients into the group of APS/MAS-2 (Eisenbarth and Gottlieb 2004; Husebye et al. 2018), but we believe that this syndrome is worthy to be recognized as a separate entity. After assessing our personal data base of 288 consecutive patients with AITD, in addition to the diseases mentioned by Neufeld (Fig. 5, left column marked in normal bold font), we included other autoimmune diseases to the list (Fig. 5, left column, marked with italic font) that were found up to 17% of our patients. In addition, 20% of patients with apparently isolated AITD were positive for at least one autoantibody on screening for other autoimmune diseases (Fig. 5, central column). After completing our assessment, 63% of the patients had isolated AITD (Fig. 5, right column) (Betterle and Presotto 2009). In recent decades, many published cohorts of patients have revealed high rates of other autoimmune diseases, both in adults and children with AITD (Boelaert et al. 2010; Fallahi et al. 2016; Ruggeri et al. 2017). In a study on 3000 index cases with AITD, the frequency of another autoimmune disorder was 9.7% in patients with GD and 14.3% in AutoImmune Thyroid Diseases (AITD) 288 Paents 3.A. Type 1 Diabetes mellitus Hypergonadotropic hypogonadism Diabetes insipidus Hypophysitis Chronic hypoparathyroidism 3.B. Chronic atrophic gastris Pernicious anemia Coeliac disease Inflammatory bowel diseases Autoimmune hepatitis Primary biliary cirrhosis Autoimmune pancreatitis 3.C. Viligo Alopecia Myasthenia gravis Chronic urticaria Multiple sclerosis Stiff-man syndrome Werlhof’s disease Autoimmune haemolityc anemia 3.D. Not previously defined SLE/LED Rheumatoid arthritis Mixed connective tissue disease Reactive arthritis Sjögren’s syndrome Systemic sclerosis Dermatomyositis/Polymyositis Antiphospholipid syndrome Seronegative arthritis Polymyositis/dermatomyositis Autoimmune cardiomyopathy Vasculitis

Posive for one or more autoanbodies

Subclinical or Potenal APS-3 (58 cases, 20%)

Negave for other autoimmune diseases

Isolated AITD (180 cases, 63%)

Clinical APS-3 (50 cases, 17%)

Fig. 5 Presence of other clinical, subclinical, or potential autoimmune diseases in AITD

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those with CT (P = 0.005). Rheumatoid arthritis was the most common concomitant autoimmune disorder (in 3.15% of patients with GD and in 4.2% of those with CT). The relative risks of almost all the other autoimmune diseases were found significantly increased in GD and in CT (more than tenfold higher for pernicious anemia, systemic lupus erythematosus, autoimmune AD, celiac disease, and vitiligo). There was also evidence of “clustering” in the index cases with parental hyperthyroidism for patients with GD and with parental hypothyroidism for those with CT (Boelaert et al. 2010). A study performed on children with AITD demonstrated that alopecia, vitiligo, celiac disease, and DM-1 were frequently found (Radetti 2014). Another recent study reported that other autoimmune diseases were found in 29.4% of 500 adults and in 16.8% of 553 children affected by CT, thus confirming the higher frequency of additional AID in both adults and children with AITD (Ruggeri et al. 2017). A review examined the prevalence of other autoimmune disorders in 3069 adult patients with AITD finding a significantly increased prevalence of autoimmune gastritis, vitiligo, rheumatoid arthritis, polymyalgia rheumatica, celiac disease, DM-1, Sjögren’s syndrome, multiple sclerosis, systemic lupus erythematosus, alopecia, reactive arthritis, systemic sclerosis, and cryoglobulinemia. Also the prevalence of AAD and ulcerative colitis was increased, but not to a significant degree, similarly to other AID (Fallahi et al. 2016).

Frequency of APS/MAS-3 In a study performed on a North American normal population, hypothyroidism due to CT affected 4–21% of females and 3–16% of males, increasing with age. Another study detected thyroid autoantibodies in 12–26% of females and in 2.8–14.4% of males of different geographical origin. According to these previous studies, from one in four to one in three patients with AITD have another autoimmune disease, which would make APS/MAS-3 the most common type of APS/MAS.

A New Classification of APS/MAS-3 In the past, we subdivided the APS/MAS-3 into four subgroups (Betterle et al. 2002; Betterle and Presotto 2008). 1. Group 3A: patients with AITD associated with other autoimmune endocrine diseases (excluding AAD) 2. Group 3B: patients with AITD and autoimmune diseases of the digestive system 3. Group 3C: patients with AITD and autoimmune skin, nervous system, or hematological diseases 4. Group 3D: patients with AITD and autoimmune rheumatic and cardiac diseases or vasculitis In the present chapter, we analyze the association between AITD and other AID, splitting this syndrome into four subgroups (Table 8).

Autoimmune thyroid diseases (AITD) Chronic thyroiditis (CT), Graves’ disease (GD), Endocrine ophthalmopathy (EO) Endocrinopathies Stomach Skin DM-1 AG with or without Vitiligo Hirata’s disease pernicious anemia Alopecia Flier syndrome Intestine Pemphigous group POF Crohn’s disease Pemphigoid group Adenohypophysitis Ulcerative colitis Chronic urticaria Hypoparathyroidism Celiac disease Nervous system Lymphocytic mastopathy Liver Myasthenia gravis Neurohypophysitis Hepatitis type 1 and 2 Lambert-Eaton’s syndrome Primary biliary cirrhosis Multiple sclerosis Sclerosing cholangitis Neuromyelitis optica Pancreas Guillain-Barré syndrome Autoimmune pancreatitis Stiff-man syndrome Hematological system Hemolytic anemia Werloff’s syndrome Autoimmune leucopenia 3A 3B 3C Autoimmune endocrine diseases Autoimmune diseases of the Autoimmune diseases of the skin, (excluding AAD) digestive apparatus nervous, and hematopoietic system

Table 8 Autoimmune diseases associated with AITD in APS/MAS-3

3D Autoimmune rheumatic and cardiac diseases or vasculitis

Rheumatic diseases SLE LED Rheumatoid arthritis Systemic scleroderma Mixed connective tissue disease Sjögren’s syndrome Reactive arthritis Polymyositis/dermatomyositis Anti-phospholipid syndrome Vasculitis Various forms Cardiac diseases Atrio-ventricular cardiac block Myocarditis Rheumatic fever

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Genetics of APS/MAS-3 APS/MAS-3 may be seen in more than one member of a family, but the underlying genetic factors have yet to be clearly established. This syndrome is correlated with different HLA class II alleles, depending on the associated types of autoimmune disease. The genetic risk of the diseases overlaps and includes genes of HLA class II DR and DQ or HLA class I (MIC-A). Other genes have been associated with these APS/MAS too, including the genes encoding lymphoid tyrosine phosphatase (PTPN22) and the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) (Betterle and Presotto 2009).

APS/MAS 3A: Association Between AITD and Other Autoimmune Endocrine Diseases This paragraph concerns the main associations between AITD and autoimmune endocrine diseases other than AAD.

AITD and DM-1 A review of 114 studies on the association between DM-1 and AITD showed that TPOAbs were present in 5–46% of patients as opposed to 0–27% of controls, and that TgAbs were present in 2–40% of patients versus 0–20% of controls (Guastamacchia et al. 2015). The prevalence of these autoantibodies was higher in females and increased with age and duration of DM-1 (Presotto and Betterle 1997; Betterle et al. 2016a). Clinical or subclinical hypothyroidism was found in 6–72% of the patients with thyroid autoantibodies and in 0–25% of controls. In another review collecting more than 52,000 DM-1 patients of different ages, hypothyroidism was identified in 0–15%, hyperthyroidism in 0.07–9.3%, and subclinical thyroid dysfunction in 1–11% of the patients, while 2.5–32% of them had only thyroid autoantibodies (Betterle et al. 2016a). On the other hand, the prevalence of DM-1 in AITD was analyzed in another study to be 1–5% among patients with GD, and 3–8% among those with CT. A recent report on 3069 consecutive patients with AITD indicated a significantly increased prevalence of DM-1 compared with age- and sexmatched controls (Fallahi et al. 2016). Patients with AITD without DM-1 revealed ICA/GADAb and IA2Ab in 1–10% of cases. The risk of future DM-1 in such patients is proportional to the number of pancreatic autoantibodies (Betterle et al. 2016a). AITD and Hirata’s Disease (HD) HD was first described in 1970 as an autoimmune disease inducing hypoglycemia and is quite common in Japan where a report on 380 cases was published in 2009. The disease is much rare in other countries. HD can develop spontaneously or after using drugs containing sulfhydryl compounds like methimazole, used to treat GD, that results the most common trigger factor of HD in Japan. HD is very rare in Italy, but some of the patients also have AITD.

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AITD and Hypergonadotropic Hypogonadism (HH) A subclinical or potential AITD was identified in 18–21% of females with HH. AITD and Lymphocytic Adenohypophysitis (LAH) A review of the literature showed that AITD can be found in 9% of patients with LAH, specifically in 7.4% with CT and in 1.6% with GD. Autoantibodies against pituitary were found in 13% of 707 patients with CT, and in 7% of 254 with GD, but in none of the healthy controls. About one third of the patients with high autoantibody titers had mild or severe deficiency of GH (Betterle and Presotto 2009). AITD and Lymphocytic Neurohypophysitis (LNH) One study found that 1.2% of patients with AITD were positive for antibodies against avidin-producing cells, and that some of these patients had a partial antidiuretic hormone deficiency. Moreover, 69% of patients with idiopathic diabetes insipidus had a clinical, subclinical, or potential AITD (Betterle and Presotto 2009). AITD and Chronic Hypoparathyroidism (CH) TPOAbs were found in 16% of patients with CH compared to 9% of controls, and thyroid function was normal in the majority of the positive cases (Betterle and Presotto 2009). AITD and Lymphocytic Mastopathy In 1984, a fibrous disease of the breast was described in association with CT, cheiroarthropathy, and DM-1. In 1990, this disease was defined as lymphocytic mastopathy, based on the assumption of an autoimmune pathogenesis. Among 13 cases described in 1991, 3 had DM-1 and 2 had clinical or latent CT. In 2% of the cases in other series, the breasts of patients with CT or GD revealed a sclerosing lymphocytic lobulitis. Incomplete APS/MAS 3A An incomplete APS/MAS-3A can include patients with AITD and only autoantibodies against endocrine pancreatic and/or pituitary cells, or patients with thyroid autoantibodies associated with DM-1, hypoparathyroidism, POF, adenohypophysitis, or neurohypophysitis (Betterle and Presotto 2009).

APS/MAS-3B: Association Between AITD and Other Autoimmune Diseases of the Digestive System This paragraph describes the associations between AITD and autoimmune diseases of the digestive tract.

AITD and Autoimmune Gastritis (AG) The term “thyro-gastric syndrome,” first described in the 1960s, denotes the association between AITD and AG. CT has is associated with AG in 10–40% of patients,

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while 20–40% of patients with AG may have clinical, subclinical, or potential CT. This association has been also demonstrated in children with AITD who reveal gastric parietal cell antibodies (PCA) in 30% of cases, and half of them have also hypergastrinemia. One previous study reported PCA in 22% of patients with GD and 32% of those with CT, confirming a significantly higher frequency of AG in AITD than in controls (Fallahi et al. 2016).

AITD and Pernicious Anemia (PA) In a review on 1333 patients with GD, the prevalence of pernicious anemia was 1.7–2.3%, while it ranged from 4.2% to 12.3% on 490 patients with CT and hypothyroidism. The prevalence of intrinsic factor antibodies ranged from 2.6% to 4.7% in the GD group, and from 5% to 6.7% in patients with CT and hypothyroidism (Weetman 2005). Another study found AITD in 38% of patients with PA: 25% had clinical or subclinical hypothyroidism, and 13% had clinical or subclinical hyperthyroidism. AITD and Celiac Disease (CD) In a review on about a thousand patients with celiac disease, 0–7% had clinical hypothyroidism, 0–12% had clinical hyperthyroidism, and 1–42% had subclinical or potential CT (Collin et al. 2002). In the same review, the prevalence of CD in a cohort of 1500 patients with AITD was found to be 2–7.8%. In a study on 276 patients with AITD, we found 5.4% positive for anti-transglutaminase IgA Abs (celiac disease was clinically manifest in 1.8%, and latent or potential in 3.6%). A study on 14,021 Swedish patients with CD compared with 6068 healthy controls showed that AITD was significantly associated with hypothyroidism (HR = 4.4), CT (HR = 3.6), and hyperthyroidism (HR = 2.9). The highest risk of AITD was in children with CD (HR = 6.0 for hypothyroidism, 4.8 for hyperthyroidism, and 4.7 for CT) (Elfström et al. 2008). AITD and Autoimmune Hepatitis (AH) A Japanese study reported that 12% of patients with AH also had hypothyroidism due to CT. Another study on 38 Indian patients with AH revealed CT in 8% of cases. In a group of 46 Turkish patients with CT, anti-nuclear autoantibodies (ANA) were found in 26% of cases, smooth muscle autoantibodies (SMA) in 22%, and anti-liverkidney autoantibodies (LKMAbs) in 13% of cases. Liver biopsies performed in four patients (two with LKMAbs, two with ANA/SMA) revealed the presence of AH in all four cases. AITD and Primary Biliary Cholangitis (PBC) The association between AITD and PBC was confirmed in 95 patients with PBC: 26% were found positive for anti-thyroid antibodies (24 female and 1 male), and 13 of them (52%, all female) also had clinical or subclinical hypothyroidism. Another study on 58 patients with PBC found that 25 (43%) had AITD. This preceded PBC in 12% of cases, while hypothyroidism was diagnosed at the same time of PBC in 10% of cases. Moreover, 21% of the patients had thyroid autoantibodies with normal thyroid function. A multicenter prospective study on 180 patients with PBC revealed

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AITD in 7% of patients and, during the follow-up, 2.3% per year of patients with thyroid antibodies developed thyroid dysfunction. A Japanese study identified subclinical hypothyroidism in 5.8% of PBC patients. Other studies found anti-M2 antibodies in 0.9–2% of patients with AITD, who revealed a subclinical or potential PBC. Considering the high prevalence of AITD in PBC, it is worthwhile testing for TPOAbs and TSH all these patients (Gaches et al. 1998).

AITD and Primary Sclerosing Cholangitis (PSC) One study on 119 patients with PSC identified AITD in 7% of cases: 4.5% had GD, and 2.5% had CT with hypothyroidism (Saarinen et al. 2000). AITD and Autoimmune Pancreatitis (APa) APa has recently been added to the group of autoimmune diseases, and AITD was found in 5 of 305 patients with APa (1.6%) (Terzin et al. 2012). AITD and Inflammatory Bowel Diseases (IBD) The prevalence of ulcerative colitis in patients with hyperthyroidism is reportedly around 1.3%, while the prevalence of clinical hypothyroidism in patients with ulcerative colitis is around 0.9%. The frequency of hyperthyroidism in Crohn’s disease is not different from controls (0.3%), while the association with hypothyroidism is rare (0.5%). Thyroid antibodies were found in 12.5–14.8% of a sample of patients with Crohn’s disease (Inokuchi et al. 2005). The association between IBD and AITD seems to be limited to ulcerative colitis and GD on the one hand, and Crohn’s disease and CT on the other (Inokuchi et al. 2005). Incomplete APS/MAS-3B An incomplete APS/MAS-3B can be diagnosed in patients with AITD without clinical gastrointestinal dysfunction that are positive for PCA and/or IFA, transglutaminase IgA Abs, ANA, mitochondria, SP-100, or Saccharomyces cerevisiae. On the other side, patients with AG, celiac disease, AH, PBC, PSC, or IBD with thyroid antibodies alone are also comprised in the incomplete APS/MAS-3B form (Betterle and Presotto 2009).

APS/MAS-3C: Association Between AITD and Autoimmune Diseases of the Skin, Nervous System, and Hemopoietic System This paragraph describes the associations between AITD and vitiligo, alopecia, autoimmune urticaria, myasthenia gravis, multiple sclerosis, stiff-man syndrome, and autoimmune cytopenias.

AITD and Vitiligo The association between AITD and vitiligo is very common, with AITD reported in 14.3% of patients with vitiligo, and thyroid antibodies in 21%. On the other hand, 1–25% of CT patients, and 0.5–36% of GD patients had vitiligo. In a recent review

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on 3069 patients with AITD, the prevalence of vitiligo was significantly higher than in age- and sex-matched controls (Fallahi et al. 2016).

AITD and Alopecia Areata (AA) AA is a heterogeneous clinical disease that can occur as in the areata, total, or universalis form. Only patients with alopecia universalis had a higher prevalence of thyroid Abs (21%) than controls (7%) (Betterle et al. 1984). In a study on 584 patients with alopecia, 94.7% had AA, 3.25% had alopecia universalis, and 2.05% had total alopecia (Miller et al. 2015). They had a higher prevalence of AITD than controls (18.8% versus 7.56%, respectively). A review of the National Canadian Alopecia Areata Registry revealed that 8–28% of AA patients had AITD (Spano and Donovan 2015). AITD and Autoimmune Bullous Diseases A study on 15 patients with pemphigus vulgaris identified TPOAbs in 40% of cases. A worldwide online survey on 171 patients with pemphigus vulgaris revealed AITD in 9.4% of cases. In an Italian study on 25 patients with pemphigus vulgaris and 23 with bullous pemphigoid, the prevalence of patients with TPOAb and/or TgAb was 24% and 39%, respectively (Ameri et al. 2013). AITD and Chronic Idiopathic Urticaria (CIU) A meta-analysis on 14,203 patients with CIU and 12,339 controls showed that thyroid Abs were more common in patients with CIU than in the controls, suggesting that those with CIU were more likely to have AITD. In some cases, CIU was associated with GD, and treatment with anti-thyroid drugs also resolved the CIU. There are conflicting reports of the complete or partial remission of CIU after lthyroxine treatment in patients with CT (Pan et al. 2015). AITD and Myasthenia Gravis In one group of 47 patients with myasthenia gravis, the combined prevalence of thyroid and gastric Abs was 47%. In several studies involving a total of 286 patients with myasthenia gravis, AITD was identified in 14.7–28.5% of the cases: 4.6–25% had CT and 0–7.7% had GD (Weissel et al. 2000). AITD and Lambert-Eaton Syndrome (LES) Sera from 64 patients with LES were tested for autoimmunity and one or more thyroid, gastric, and/or skeletal muscle Abs were identified in 29 cases (45%). Abs were found in 24 out of 46 patients without tumor (52%), and in 5 out of 18 patients with paraneoplastic form (28%). These data clearly support the claim that LES is an organ-specific autoimmune disease (Lennon et al. 1982). AITD and Multiple Sclerosis Studies on 601 patients with multiple sclerosis identified a clinical CT in 1.3–6% of cases, a subclinical CT in 0–2% and a potential CT in 5.7–21.7% compared with a prevalence of 1.9–5.3% in controls (Annunziata et al. 1999). A study revealed that

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AITD were significantly more common than usual in males with multiple sclerosis (9.4% versus 1.9% of controls), but not in females (8.7% versus 9.2%). A recent review demonstrated that patients with AITD had a significantly higher prevalence of multiple sclerosis as well as other autoimmune disorders compared with age- and sex-matched controls (Fallahi 2016).

AITD and Neuromyelitis Optica (NMO) NMO (Devic’s syndrome) is an optical neuritis and myelitis, associated with acquaporin-4 Abs. In the past, it was believed to be a subform of multiple sclerosis, but now it is seen as an autoimmune disease with a distinct immunopathogenesis from that of multiple sclerosis, despite considerable overlap in their clinical presentation. In a recent study on 22 cases of NMO, 5 patients (22.7%) also had clinical or latent CT (Pereira et al. 2017). AITD and Guillain-Barré Syndrome (GBS) GBS is an autoimmune radiculoneuropathy frequently associated with infection by Helicobacter jejuni. Its association with AITD is limited to case reports. AITD and Stiff-Man Syndrome (SMS) CT has been found in 30–46% of patients with SMS, and some cases of SMS associated with GD have recently been published too. AITD and Autoimmune Cytopenias The association between AITD and autoimmune hemolytic anemia or autoimmune neutropenia is very rare and has only been described in some case reports. By contrast, the association between AITD and autoimmune thrombocytopenia is quite common, being reported in 8–13% of patients with hyperthyroidism, and in 16% of children or 18% of adults with thyroid antibodies alone. Autoimmune thrombocytopenia was detected in 4 out of 218 patients with CT (1.8%), and antibodies against thrombocytes were identified in 10% of CT patients without thrombocytopenia (Gaches et al. 1998). Incomplete APS/MAS-3C An incomplete APS/MAS-3C can be diagnosed in patients with vitiligo, alopecia, myasthenia gravis, multiple sclerosis, NMO, GBS, autoimmune hemolytic anemia, autoimmune thrombocytopenia, or autoimmune leucopenia that are positive for thyroid Abs, or in patients with TAD and Abs against acetylcholine receptors, aquaporin-4, GAD, red blood cells, or thrombocytes (Betterle and Presotto 2009).

APS/MAS-3D: Association Between AITD and Autoimmune Rheumatic and Cardiac Diseases or Vasculitis Thyroid function abnormalities and thyroid Abs have frequently been described in patients with autoimmune rheumatological diseases, such as Sjögren’s syndrome,

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rheumatoid arthritis, adult systemic lupus erythematosus, and systemic scleroderma (Punzi and Betterle 2004). Limited data are available on the prevalence of AITD in other rheumatological disorders, such as rheumatic fever, juvenile systemic lupus erythematosus, and polymyositis/dermatomyositis (Robazzi and Adan 2012).

AITD and Systemic Lupus Erythematosus (SLE) Since 1960s, it has been recognized that SLE affects 0.2–3.2% of patients with AITD (Becker et al. 1963; Gaches et al. 1998). Other studies found that 7–36% of patients with AITD had ANA without any clinical manifestations of SLE. Patients with SLE have a higher than normal frequency of AITD (CT in 4.4–21.6% of cases, and GD in 0–5%), and in 14–68% of cases they reveal thyroid antibodies (Robazzi and Adan 2012). In a sample of juvenile SLE, 9% of patients had CT and 20–34% had thyroid Abs. A meta-analysis demonstrated that the frequency of thyroid antibodies is two to three times higher in SLE patients than in controls (Pan et al. 2015a). A recent review showed a high prevalence and incidence of new cases of AITD among SLE patients, especially in females, but a limited number of GD (Fallahi et al. 2016). AITD and Rheumatoid Arthritis (RA) In the 1960s, a study on 506 patients with TAD reported RA in 4% of the cases, compared with 0.4% of controls (Becker et al. 1963). In the years that followed, studies confirmed an association between RA and the various forms of AITD (clinical, subclinical or potential) in 2–38% of cases (Punzi and Betterle 2004; Robazzi and Adan 2012). AITD and Systemic Scleroderma (SS) The link between AITD and SS was initially difficult to define because only 1 case of SS was reported in a survey performed by the Mayo Clinic on 506 patients with AITD (Becker et al. 1963). However, a prospective study demonstrated that 23% of 77 SS patients had hypothyroidism, but only four were positive for thyroid antibodies. An Italian study on 85 SS patients found that TgAb and TPOAb were positive in 12% and 19% of cases, respectively. An association of localized scleroderma or morphea with AITD has also been reported confirming the correlation (Punzi and Betterle 2004; Robazzi and Adan 2012). AITD and Mixed Connective Tissue Disease (MCTD) In a cohort of MCTD cases, 25% of patients had thyroid Abs and less than 20% had clinical hypothyroidism (Hämeenkorpi et al. 1993). AITD and Sjögren’s Syndrome (SSj) The presence of AITD in patients with SSj was first reported in the 1960s in 34% of 62 SSj patients. In an Italian study on 121 SSj patients, clinical, subclinical, or potential AITD was recognized in 29% of the patients: 13% had hypothyroidism, 10% had GD, and 7% had only thyroid Abs with normal thyroid function (Punzi and Betterle 2004). An earlier study had reported that 23% of 63 patients with AITD had antibodies against SSB. Another later study on 88 patients with GD, 40 with

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CT and 48 with hypothyroidism found that 24% of patients met the criteria for SSj, with no differences related to the type of AITD. Hypothyroidism and thyrotoxicosis were found in 14% and 1.8%, respectively, of a cohort of SSj patients. Finally, in a study involving 479 patients with SSj, CT was diagnosed in 6.3% of patients (compared with 1–2% of the general population), while there were no differences in the prevalence of GD between the two groups (Zeher et al. 2009).

AITD and Dermatomyositis/Polymyositis Although the association between dermatomyositis/polymyositis and AITD has yet to be definitively confirmed, many authors have observed a 25% prevalence of primary hypothyroidism in patients with dermatomyositis/polymyositis. AITD and Anti-Phospholipid Syndrome Anti-phospholipid syndrome is rare in patients with AITD, being described in only 2 of 218 patients (0.9%) (Gaches et al. 1998). Anti-cardiolipin antibodies have been reported in 38–55% of patients with GD, and in 38–43% of patients with CT. Patients with GD and severe thyrotoxicosis revealed higher titers of anti-cardiolipin antibodies, which disappeared after methimazole treatment. Other studies confirmed these findings, with reports of anti-phospholipid antibodies in 0–3.8% of patients with GD, and in 0–9% of patients with CT. Although none of the patients with AITD and anti-phospholipid antibodies showed any signs or symptoms of anti-phospholipid syndrome, a recent review suggested a possible role for this association in some obstetrical complications (Versini 2017). AITD and Vasculitis A significant association has been described between AITD and HCV-related cryoglobulinemic vasculitis (Fallahi et al. 2016). A study on 367 patients with rheumatic polymyalgia (RPM) and giant cell arteritis (GCA) reported hypothyroidism in 4.9% of cases. Two subsequent studies failed to confirm these findings (Wiseman et al. 1989). As regards the anti-neutrophil cytoplasmic antibodies (ANCA)-associated small vessel vasculitis related to the therapy with anti-thyroid drugs (ATD), the literature includes about 260 case reports, involving propylthiouracil (PTU) in 75% of cases, and methyl-mercapto-imidazole derivatives (MMI/TMZ) in the other 25% (Balavoine et al. 2015). Young age and duration of ATD therapy were the main factors contributing to the occurrence of ANCA. The proportion of ANCA-positive patients was 0–13% before initiating ATD and reached 20% during the treatment. Only 15% of ANCA-positive patients treated with ATD showed clinical signs of vasculitis, corresponding to 3% of all the patients given ATD. Clinical manifestations of ANCA-associated vasculitis in patients taking ATD were extremely heterogeneous. When vasculitis developed, ATD withdrawal was usually followed by a rapid clinical improvement and the prognosis was favorable (Balavoine et al. 2015). AITD and Rheumatic Fever A retrospective study on 76 patients with chronic rheumatic heart disease identified thyrotoxicosis in 9 (12%), hypothyroidism in 3 (4%), and a positive test for thyroid

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Abs in 7 (9%). More recently, an increased frequency of CT has been reported in patients with rheumatic mitral stenosis (16 of 55, 29%) compared with healthy controls. Both studies suggest an association between chronic rheumatic heart disease and AITD that warrants further study (Robazzi and Adan 2012).

AITD and Autoimmune Myocardial Diseases There are very limited data on the association between AITD and cardiomyopathy, and there is only one published report of a fatal cardiomyopathy associated with CT. Incomplete APS/MAS-3D An incomplete APS/MAS-3D can be diagnosed in patients with AITD and a positive test for ANA, rheumatoid factors, anti-citrullinated protein Abs, phospholipids, or neutrophil cytoplasmic Abs, or in patients with autoimmune rheumatological diseases or myocarditis or vasculitis and thyroid Abs alone (Betterle and Presotto 2009).

Concluding Comments on APS/MAS-3 In recent decades, researchers have identified an increasing number of AID that turn around AITD, which remains the most common autoimmune disorder in the world, in a sort of an expanding galaxy (Fig. 6). Patients with AITD often have more than one other associated AID that may develop even many years after the onset of their first autoimmune disorder. Therefore, it is important for endocrinologists and pediatricians taking care of patients with AITD to look for other clinical, subclinical, or latent AID. We would also remind to all physicians who follow patients with other autoimmune diseases that AITD is the most common associated disorder. APS/MAS-3D Systemicl lupus erythematosus Autoimmune cardiomyopathy

APS/MAS-3C Vitiligo Lupus erythematosus discoid

Autoimmune hemolytic anemia

Alopecia

Pemphigus

APS/MAS-3B Autoimmune gastritis with or without pernicious anemia

Reactive arthritis

Hirata’s disease Celiac disease

Lymphocytic adeno or neuro-hypophysitis

Chronic idiopathic urticaria

Autoimmune thrombocytopenia

Flier’s syndrome

AUTOIMMUNE THYROID DISEASES Hypergonadotropic hypogonadism

Lymphocytic lobulitis

Primary sclerosing cholangitis

Chronic hypoparathyroidism Guillain-Barrè syndrome Chronic inflammatory bowel diseases

Autoimmune Hepatitis Rheumatoid arthritis

Autoimmune pancreatitis

Myasthenia gravis

Recurrent polychondritis

Primary biliary cholangitis

APS/MAS-3A Type 1 diabetes mellitus

Bullous pemphigoid

Anti-phospholipid syndrome Stiff-man syndrome

Lambert-Eaton’s syndrome Neuromyelitis optica Multiple sclerosis Sjögren’s syndrome Vasculitis

Dermatomyositis

Systemic scleroderma Polymyositis

Fig. 6 AITD associated with other organ-specific and non-organ-specific autoimmune diseases (a galaxy on expansion). (Modified from Betterle 2017, Chap. 16, with the permission of the Editor)

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APS/MAS-4 APS/MAS-4 encompasses any other combinations of autoimmune diseases not included in the previous classifications. Some authors do not consider this subtype and comprises these into APS/MAS-2 (Eisenbarth and Gottlieb 2004; Husebye et al. 2018; Kahaly and Frommer 2018), but we think that this form could be considered separately (Fig. 7). For instance, patients with DM-1 may also suffer from different types of APS/ MAS, depending on their associated autoimmune diseases (Betterle et al. 2016a). When DM-1 is associated with CH, CMC, and/or AAD, it meets the criteria for APS/ MAS-1; when it is associated with AAD it is part of APS/MAS-2; when it is associated with a AITD, it is part of APS/MAS-3A, but when it is associated with AG, PA, celiac disease, vitiligo, alopecia, HH, myasthenia gravis, stiff-man syndrome, or other AID (Collin et al. 2002; Betterle et al. 2016a), then it meets the criteria for APS/MAS-4 (Fig. 7).

Presentation of APS/MAS-4 APS/MAS may develop at different gender, ages and in different ways. AID rarely develop all at the same time but occur sequentially over a lifetime. That is why patients with an AID should be informed that they may develop APS/MAS, and that they should be periodically screened for the most common autoantibodies associated with their corresponding first AID or based on their family history. For example, patients with CT show a higher risk of developing autoimmune gastritis, pernicious anemia, DM-1, Sjögren’s syndrome, or vitiligo, but a lower risk to develop AAD. Therefore, they could be advised to undergo periodical testing for the presence of PCA, IFA, ICA, GADAbs, IA2Abs, ENA, and of ACA and/or 21OHAbs depending on clinical suspicion or their family history (Table 9). It is also important to evaluate patients at defined intervals because some AID cannot be predicted or diagnosed on the basis of antibody assays but only on clinical evidence (e.g., CMC, vitiligo, alopecia).

SLE

Alopecia

Vitiligo

Vitiligo

DM-1

DM-1

+

+

+

+

+

+

Sjogren’s Syndrome

Autoimmune Gastritis

Celiac Disease

Fig. 7 Some examples of APS/MAS-4

Autoimmune Gastritis

Autoimmune gastritis

Celiac disease

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Table 9 Most common associations of the main autoimmune diseases (in bold) in order of frequency Chronic thyroiditis Autoimmune gastritis with or without pernicious anemia DM-1

Celiac Vitiligo disease Chronic Chronic thyroiditis thyroiditis

Addison’s disease Chronic thyroiditis

Hypoparathyroidism Chronic thyroiditis

DM-1

DM-1

Premature menopause

Addison’s disease

Sjögren’s syndrome

Vitiligo

Autoimmune gastritis with or without pernicious anemia DM-1

Chronic candidiasis

Vitiligo

Alopecia

Others

Autoimmune gastritis with or without pernicious anemia DM-1

Autoimmune gastritis with or without pernicious anemia Celiac disease

Alopecia Celiac disease Addison’s disease

Others

Vitiligo Alopecia Others

Chronic thyroiditis

Autoimmune Vitiligo gastritis with or without pernicious anemia Alopecia Alopecia Vitiligo Others Others

IPEX Syndrome (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked) Autoimmune disorders are frequently genetically determined. IPEX syndrome is caused by mutations of the FOXP3 gene on chromosome Xp11.2. This gene encodes for a forkhead/winged helix transcription factor fundamental to the development of the T regulatory lymphocytes (Treg) CD4+CD25+, and their deficiency leads to a severe autoimmunity and immune deficiency, characterized by a persistent watery diarrhea that develops early in life and proves difficult to treat. IPEX syndrome is very rare, with a prevalence calculated to be about 1 case per 1000,000 population (Husebye 2018).

Clinical Manifestations and Autoantibodies The triad characterized by enteropathy, DM-1, and dermatitis is the classical manifestation of IPEX syndrome. In a review on 39 patients, enteropathy was the first disorder to appear, affecting 97.5% of the patients within a few months of birth, and characterized

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by mucoid or bloody diarrhea with consequent malabsorption, growth deficiency, and infections. Autoantibodies against enteropathy-related 75 kDa antigen (AIE-75) expressed on the brush border of the small intestine and kidney tubules, and against an actin-binding protein, villin, and harmonin were identified as markers of enteropathy in IPEX syndrome. These autoantibodies are negative in patients with APECED suffering from gastrointestinal dysfunction, typically associated with the presence of TPHAbs (Scarpa et al. 2013; Chida et al. 2015). Diarrhea in patients with IPEX syndrome sometimes responds to a gluten-free diet, and sometimes to immunosuppressants, or parenteral nutrition, but some patients are unresponsive to any therapies and their diarrhea becomes life-threatening. DM-1 is the most common associated endocrinopathy, found in about 70% of cases. Generally, DM-1 develops in the first weeks of life. It is frequently associated with the presence of GAD Abs, ICA, and IA2 Abs, and it sometimes requires insulin therapy. Skin lesions are seen in about 65% of patients: eczema is the most common manifestation, followed by erythematous dermatitis, urticaria, and AA. AITD is present in 30% of patients with positive test for thyroid antibodies. Other possible manifestations are lymphadenopathies, cholestatic hepatitis, hepatosplenomegaly, nephropathies, hemolytic anemia, thrombocytopenia, neutropenia, and arthralgias. Infections are found in 20–50% of patients, and occur with sepsis, meningitis, osteomyelitis, or pneumonia due to Staphylococchi, Candida albicans, Cytomegalovirus, and /or Enterococchi. Patients with IPEX syndrome frequently dies within 2 years of life as a result of malabsorption or infections.

Pathology Lesions of the small bowel are characterized by partial or total villous atrophy with infiltration of lymphocytes (CD3+), plasma cells, and eosinophils. The exocrine pancreas reveals lymphocytic infiltration with exocrine and endocrine cell involvement. The thymus is atrophic with depleted levels of lymphocytes and Hassal’s corpuscles that produce lymphopoietin, controlling the differentiation of CAD4+CD25+ Foxp3+Treg cells.

Therapy Immunosuppressant therapy is based on the use of cyclosporine A, tacrolimus, sirolimus, and steroids. These drugs fail to keep the disease in remission, however, and may induce infectious complications. Hemopoietic stem cell transplantation is the best therapeutic option.

Poems Syndrome (Polyradiculoneuropathy, Organomegaly, Endocrinopathy, Monoclonal Plasma Cell Disorder, and Skin Changes) POEMS syndrome is a rare, chronic, disabling condition of unknown pathogenesis, that seems to be associated with an increased production of pro-inflammatory

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Table 10 Clinical manifestations of POEMS syndrome Mandatory Major Minor

Others

Polyneuropathy and/or monoclonal plasma cell disorder Osteosclerotic or mixed sclerotic lytic disorders, Castleman’s disease, increased plasma VEGF levels Organomegaly (splenomegaly, hepatomegaly, and lymphadenopathy), vascular volume overload (peripheral edema, pleural or peritoneal effusions), endocrinopathies, with adrenal, thyroid, pituitary, gonadal insufficiencies (the most common), parathyroid or pancreas deficiencies, skin changes (hyperpigmentation, hypertrichosis, acrocyanosis, flushing, white nails), papilledema, thrombocytosis, polycythemia Digital clubbing, weight loss, pulmonary hypertension, thrombotic diathesis, diarrhea, vitamin B12 deficiency

The presence of the two mandatory disorders plus at least one major and one minor manifestation of the syndrome suffice for its diagnosis

cytokines, such as tumor necrosis factor-α, interleukin-1, interleukin-6, and vascular endothelial growth factor (VEGF) (Dispenzieri 2014; Nozza 2017).

Diagnosis POEMS is characterized by different clinical manifestations and the diagnostic criteria are shown in Table 10. The median survival of patients with POEMS syndrome is 14 years. The prognosis is generally excellent, however, if the syndrome is diagnosed early (Dispenzieri 2014).

Therapy The treatment for POEMS syndrome depends on its clinical manifestations but may include radiotherapy in the case of isolated bone lesions, or systemic therapy with alkylating agents (melphalan or cyclophosphamide) and corticosteroids, or autologous/heterologous stem cell transplantation, and new therapies (thalidomide, lenalidomide, bortezomib, bevacimuzab), if the disease is disseminated (Dispenzieri 2014; Nozza 2017).

Conclusions In recent years, the study of APS/MAS has received great interest thanks to the growing number of the diseases recognized as autoimmune in nature and the knowledge of their natural history. Clinically overt disorders are considered only the tip of the autoimmune iceberg, since latent forms are much more frequent. Autoantibody determination in patients with a single disease undoubtedly helps in

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the identification of the autoimmune pathogenesis of the disease, but in patients with one AID, an autoantibody screening may lead to the recognition even of patients with potential or subclinical APS/MAS. This has allowed clinicians to identify patients with APS/MAS in a preclinical stage and, consequently, to start early specific treatment(s). Hopefully, advancement in understanding the inner immunologic mechanisms involved in these conditions should address common treatments to avoid, or at least dampen, progression to permanent multiple organ damage. Acknowledgments This study was supported in part by a grant from the EU Seventh Framework Programme, Euradrenal project: Pathophysiology and Natural Course of Autoimmune Adrenal Failure in Europe. Grant No. 2008-201167, and by a grant ex 60% from the University of Padua.

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The Natural History of APS1 Pathogenesis and Long-Term Follow-Up Anette S. B. Wolff, Bergithe E. Oftedal, and Eystein S. Husebye

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Definition and Diagnostic Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Major Components of APS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Mucocutaneous Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hypoparathyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Adrenal Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Endocrine Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gastrointestinal Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ectodermal Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nonclassical APS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Tools in APS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cytokine Autoantibodies in APS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Natural Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of APS-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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A. S. B. Wolff · B. E. Oftedal KG Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway Department of Clinical Science, University of Bergen, Bergen, Norway E. S. Husebye (*) KG Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway Department of Clinical Science, University of Bergen, Bergen, Norway Department of Medicine, Haukeland University Hospital, Bergen, Norway Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden e-mail: [email protected] © Springer Nature Switzerland AG 2021 A. Colao et al. (eds.), Polyendocrine Disorders and Endocrine Neoplastic Syndromes, Endocrinology, https://doi.org/10.1007/978-3-319-89497-3_2

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Abstract

Autoimmune polyendocrine syndrome type I (APS-1) is a severe autoimmune disease that is caused by mutations in the autoimmune regulator (AIRE) gene. The clinical criteria are based on at least two of the three major manifestations: chronic mucocutaneous candidiasis, autoimmune adrenal insufficiency, and hypoparathyroidism. A spectrum of other manifestations of both endocrine and ectodermal origin is common, and it is challenging to set the diagnosis because the phenotype varies a lot between patients. Diagnostic tools like autoantibodies against type 1 interferons and against targeted tissues in the syndrome have eased the diagnostic work-up, as have mutational analysis of the causative gene. We will herein describe the clinical manifestation of the syndrome, the autoantibodies that correlate to the different symptoms, and advised treatment regimes. Keywords

Autoimmune polyendocrine syndrome · Autoimmune regulator · Adrenal insufficiency · Hypoparathyroidism · Mucocutaneous candidiasis · Interferon omega autoantibodies · Thymus

Introduction Autoimmune polyendocrine syndrome type I (APS-1), also called APECED (autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy), is a monogenic disorder caused by recessive or dominant mutations in the autoimmune regulator (AIRE) gene (1997; Nagamine et al. 1997; Oftedal et al. 2015). The clinical phenotype is characterized by autoimmune destructions of various, mostly endocrine, organs, as well as chronic mucocutaneous candidiasis (CMC) (Husebye et al. 2018). APS-1 typically presents in childhood or early adolescence, and the patients gradually develop autoimmune manifestations throughout life (Perheentupa 2006; Bruserud et al. 2016; Ferre et al. 2016). Several of these manifestations can be fatal if diagnosed late or if they are inadequately treated. APS-1 is a very rare condition with an estimated prevalence of around 1:100000 (about 1: 90000 in Norway (Wolff et al. 2007)), but more common in certain populations, such as the Finnish (1:25000), Sardinian (1:14000), and among Persian Jews (1:9000) (Betterle et al. 1998). Herein, we will discuss the clinical presentation of APS-1, novel diagnostic tools and state-of-the art follow-up, and treatment of the different disease entities. We will also highlight recent progress in the understanding of disease mechanisms leading to APS-1. Other related chapters are: ▶ 1, “Autoimmune Polyendocrine Syndromes (APS) or Multiple Autoimmune Syndromes (MAS)” (Betterle), ▶ 3, “Genetics of Autoimmune Regulator (AIRE) and Clinical Implications in Childhood” (Salerno M et al.), and ▶ 4, “Autoantibodies in Autoimmune Polyendocrine Syndrome” (Lupi I et al.).

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Clinical Definition and Diagnostic Criteria To make a clinical diagnosis of APS-1, two of the three main components: primary hypoparathyroidism, autoimmune adrenocortical insufficiency (Addison’s disease), and chronic mucocutaneous candidiasis (CMC) must be present. However, one of the triad of major components is sufficient if a sibling is already diagnosed, or if mutations are found on both alleles of the disease gene autoimmune regulator (AIRE). Recently, it was shown that certain heterozygous mutations in the PHD1 and SAND domains of AIRE can exert a dominant negative effect and give rise to APS-1, albeit often with milder phenotypes (Cetani et al. 2001; Oftedal et al. 2015). Thus, we suggest to include the presence of a dominant mutation in AIRE together with at least one (major) APS-1 manifestation (Husebye et al. 2018) as part of the diagnostic criteria. APS-1 patients often display other endocrine manifestations, like primary ovarian insufficiency, type 1 diabetes, autoimmune thyroid disease, and pituitary insufficiency (Ahonen et al. 1990; Betterle et al. 1998; Perheentupa 2006). Gastrointestinal components are also common, including autoimmune enteritis, gastritis, hepatitis, and exocrine pancreatitis. Finally, ectodermal tissues are often affected such as teeth (enamel hypoplasia), skin (vitiligo, rash with fever), hair (alopecia), and cornea (keratitis) (Husebye et al. 2018). Early childhood onset of the three main components or any of the more rare manifestations (Fig. 1 and Table 1) should prompt suspicion of APS-1 (Husebye et al. 2009, 2018). It should be emphasized that because this is a rare disease, it is important to raise awareness among general clinicians, especially among pediatricians and dentists, as these are probably the first specialists to see the patients. Ferre and Lionakis introduced the term “an adjunct triad”; early components that should prompt consideration of APS-1 before the more serious components appear. These are urticarial eruption (rash with fever), enamel dysplasia, and intestinal malabsorption (Ferre et al. 2016; Constantine and Lionakis 2019).

The Major Components of APS-1 Chronic Mucocutaneous Candidiasis The first component to appear is typically chronic mucocutaneous candidiasis (CMC), often presenting within the first years of life (Perheentupa 2006; Ferre et al. 2016). Candida albicans infections of nails, skin, and mucous membranes in the mouth, esophagus, and vagina are typical. A longitudinal study of Finnish patients found that 15% were diagnosed with CMC by the age of 1 year; by the age of 30 years, almost all (98%) had had episodes of candidoses (Perheentupa 2006). The prevalence and severity seems to be less frequent in other populations such as among Persian Jews (Constantine and Lionakis 2019). Clinical manifestations include sore and red mucous membranes, often with white coatings of the mucous membranes. CMC in the esophagus can be clinically

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A. S. B. Wolff et al. Candidosis Enamel dysplasia

Alopecia Keratitis Oral squamous cell carcinoma Hypoparathyroidism

Hypthyroidism Hepatitis

Adrenocortical insufficiency

Gastritis

Asplenia Exocrine pancreatic failure + type 1 diabetes

Malabsorption Candidosis Testicular failure Vitiligo

Ovarian failure

Nail candidosis

Fig. 1 The hallmarks of classical APS-1. (Courtesy of Husebye et al. (2009))

silent, but can lead to stenosis requiring blocking. Oral CMC is thought to predispose for squamous cell carcinoma, and antifungal treatment and close monitoring for changes in the mucous membrane of the oral cavity is of outmost importance (Bruserud et al. 2018a). Exposure to additional risk factors such as high alcohol consumption and smoking should be avoided. Topical treatment is preferred if possible. Azole drugs such as fluconazole are generally effective, but there is a risk of resistance with extensive and chronic use

22–100%

Addison’s disease

4–23%

Hypothyroidism

Growth hormone deficiency

5–17%

2–28

Type 1 diabetes

Pituitary failure

7–33%

Testicular failure

High gonadotrophin and low testosterone Transglutaminase-4/SCCantibodies WHO criteria, IA2/insulin-antibodies High TSH, low FT4 TPO-antibodies TDRD6-antibodies

High gonadotrophin and low estrogen, NALP1/ SCC-antibodies

Low calcium and PHT, high phosphate, NALP1-antibodies High ACTH and low cortisol 21OH/SCC-antibodies

50–93%

Other endocrine Components Primary ovarian 20–71% insufficiency

Recurrent episodes of candidiasis

20–100%

Diagnosis

Manifestation Clinical triad Chronic mucocutaneous candidiasis Hypoparathyroidism

Prevalence in APS-1

Early

Early

Early and late Late

Late

Teens or early 20s

Childhood and teens

childhood

0–3 years of age

Age of onset

Not correlated to anti-GAD-antibodies

May present as primary amenorrhea, delayed pubertal development, secondary amenorrhea because of SCC-antibodies Hypogonadism or isolated azospermia

Cortisol and aldosterone deficiency may be dissociated

Often concomitant magnesium deficiency

Mouth, esophagus, skin, and nails. Monitor for squamous carcinoma

Disease characteristics

Table 1 Manifestations of autoimmune polyendocrine syndrome type I (APS-1)a

(continued)

Adrenal, thyroid, and gonadal hormones; optional growth hormone Growth hormone

L-thyroxine

Insulin

Estrogen and gestagen, cryopreservation of ovarian tissue

Hydrocortisone/cortisone acetate + fludrocortisone

Azole drugs (fluconazole), alternatively nystatin and/or topical amphotericin B Vitamin D analogues plus calcium and magnesium. PTH is in clinical trials

Treatment

2 The Natural History of APS1 55

8–29%

4–86%

2–37%

17–53%

13–72%

Enamel dysplasia

Vitiligo

Alopecia

Nail dystrophy

Other eye manifestations

Autoimmune 4–43% hepatitis Intestinal 5–80% malabsorption Celiac disease Ectodermal manifestations Keratokonjunctivitis 9–36%

Pernicious anemia

Prevalence Manifestation in APS-1 Gastrointestinal components Autoimmune 8–49% gastritis

Table 1 (continued)

Ortopanthogram and dental examination SOX9 and SOX10antibodies TH-antibodies

Early and late Early and late Early and late

From isolated alopecia areata to alopecia totalis Differential diagnosis, candidiasis in nail

From isolated spots to all skin

Pigmental retinitis, cataract, iridocyclitis, retinal detachment, optic atrophy All permanent teeth can be affected

Blindness can be a consequence

Eye examination

Monitor for gastric adenocarcinoma

Monitor for gastric adenocarcinoma

Disease characteristics

Diarrhea and constipation

Early

Age of onset

Increased stool fat, TPHantibodies Biopsy

Type A autoimmune gastritis/megaloblastic anemia; Duodenoscopy, IF/parietal-antibodies Functional vitamin B12 deficiency IF/parietal-antibodies High ALAT, Biopsy

Diagnosis

Optional, local tacrolimus, steroids

Regular dentist checks, treatment

Cyclosporine A, corneal transplantation, limbal stem cell transplant

Diet

Immunosuppression (steroids, azathioprine) Immunosuppression, various regimens

B12 shots

Treatment

56 A. S. B. Wolff et al.

Hemolytic anemia Pericarditis

21% in one study Rare Rare

KCNRG/BP1FB1antibodies Decreased level of secretin-stimulated lipase

CT or ultrasound Howell-Jolly bodies Visual examination or biopsy

Biopsy

Early and late

Usually early

Pulmonary hypertension, might be fatal

Hypertension in some. Renal failure can develop

Optional, cyclosporine A

Azathioprine, rituximab

Steroid treatment

Azathioprine, mycophenolate, rituximab or prednisolone; kidney transplant; antihypertensive treatment Offer vaccines, especially against pneumococcus, for all patients

References: (Ahonen et al. 1990; Friedman et al. 1991; Betterle et al. 1998; Pearce et al. 1998; Ward et al. 1999; Perheentupa 2006; Stolarski et al. 2006; Wolff et al. 2007; Bensing et al. 2008; Meloni et al. 2008; Bruserud et al. 2016; Ferre et al. 2016; Orlova et al. 2017)

a

11% in one study 7% in one study 4–43%

Metaphyseal dysplasia Ptosis

1–40%

3–10%

Periodical fever with rash and/or urticaria Bronchiolitis

Sjögren-like dryness symptoms Autoimmune pneumonitis Exocrine pancreatic insufficiency Cerebellar ataxia

2–19%

Asplenia

Other and rare manifestations Urticarial eruption 14–66% Tubulo-interstitial 4–9% nephritis

2 The Natural History of APS1 57

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(Berkow and Lockhart 2017). Oral and esophageal candidoses can be treated with nystatin and/or topical amphotericin B, for example, the swish/swallow regimen (Constantine and Lionakis 2019). Alternatively, posaconazole or voriconazole can be alternative treatments (Collins et al. 2011). In patients who rapidly re-infect, pulsed treatment, for instance, once or twice a week can keep the infection in check. Patients are often colonized with exactly the same, or very genetically related, Candida strains in subsequent episodes of infections (Siikala et al. 2010).

Hypoparathyroidism The second most prevalent feature of APS-1 is hypoparathyroidism, which typically presents in 75–90% of the patients by the age of 30 (Perheentupa 2006). Hypoparathyroidism is usually the first endocrine manifestation to appear, and is slightly more prevalent in women than in men (Gylling et al. 2003). Symptoms are related to hypocalcemia and present a wide spectrum from mild to severe muscle spasms, tingling, arrhythmias, and seizures. A hypocalcemic crisis with laryngeal spasms is potentially fatal. Hypoparathyroidism is diagnosed by finding a low serum calcium and high serum phosphate combined with an inappropriately low parathyroid hormone level and normal kidney function. In APS-1, many patients display circulating autoantibodies against NACHT leucine-rich repeat protein 5 (NALP5), a parathyroid-specific protein with unknown function (Alimohammadi et al. 2008). Some patients harbor autoantibodies against the calcium sensing receptor (CaSR), a biomarker also present in patients with so-called idiopathic hypoparathyroidism (Li et al. 1996). In a recent study of all identified hypoparathyroidism patients in Norway, 17% of the included individuals had APS-1 (Astor et al. 2016). The standard treatment is vitamin D analogues in combination with calcium and magnesium replacement aiming at calcium levels in the lower half of the reference range (Astor et al. 2016). Urinary calcium should be monitored to avoid hypercalcuria and subsequent nephrocalcinosis. Despite optimized treatment, many patients score remarkably low on self-reported health questionnaires including the Short Form 36 and Hospital Anxiety and Depression scale (Astor et al. 2016). Recently, recombinant parathyroid hormone has become available and been tested in hypoparathyroidism, including patients with APS-I. The treatment is well tolerated and might reduce long-term complications (Khan et al. 2018). Careful followup at least twice yearly and patient education including equipping patients with an emergency card is important to avoid complications (Astor et al. 2019).

Primary Adrenal Insufficiency Primary adrenal insufficiency (PAI, also called Addison’s disease) is the second main endocrinopathy seen in APS-1. It is present in about 80% of APS-1 patients and generally become apparent later than hypoparathyroidism. Lack of cortisol and aldosterone explain the main symptoms and findings including hyperpigmentation

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of skin and mucous membranes, orthostatism, and hypoglycemia. Hyponatremia and sometimes hyperkalemia is commonly seen (Perheentupa 2006). Adrenal insufficiency is easy to diagnose. Often a paired cortisol and adrenocorticotropic hormone (ACTH) test will give the diagnosis, typically revealing a subnormal serum cortisol and a plasma ACTH value exceeding twice the upper reference range (Bornstein et al. 2016). Sometimes a co-syntropin test is warranted to clarify. Outside APS-1, the prevalence of PAI is about 1:15000 individuals (Erichsen et al. 2009). The first serological sign of PAI is autoantibodies against 21-hydroxylase (21-OH), which can present up to years before any biochemical or clinical evidence of PAI. Hence, they serve as excellent predictive markers when PAI is suspected (Soderbergh et al. 2004). Early diagnosis is important, as untreated PAI is fatal (Lovas and Husebye 2005). Replacement therapy with hydrocortisone or cortisone acetate in addition to fludrocortisone largely normalizes mortality rates (Erichsen et al. 2009), but adrenal crises pose a constant danger for the Addison patient. Thus, it is important to educate the patient to vary doses in accordance with stress, e.g., heavy exercise, infections, or surgery. All patients should be equipped with an emergency card (Quinkler et al. 2015).

Other Endocrine Components Premature ovarian insufficiency is common, affecting up to 50% before the age of 30, and sometimes diagnosed as primary amenorrhea (Reato et al. 2011). Testicular failure, on the other hand, is a rarer event commencing later (Ferre et al. 2016). A number of patients experience delayed pubertal development. Autoantibodies against side-chain cleavage enzyme (SCC) correlate to the presence of premature ovarian insufficiency, as do NALP5 autoantibodies (Alimohammadi et al. 2008). Interestingly, the mouse orthologue of NALP5, called MATER (maternal antigen that embryos require) is an autoantigen in autoimmune oophoritis in a thymectomized mouse model (Tong and Nelson 1999). Ovarian insufficiency is treated with estrogen and gestagen. Recent advances in cryopreservation of ovarian tissue might constitute a means of preserving fertility in these females (Kristensen and Andersen 2018). Type 1 diabetes is present in around 8–23% in the largest APS-1 cohorts that have been reported (Perheentupa 2006; Bruserud et al. 2016; Ferre et al. 2016; Orlova et al. 2017). The reason for discrepancies could be related to varying frequencies of HLA risk alleles in different populations (Halonen et al. 2002). The serum autoantibodies common for isolated type 1 diabetes are also present in APS-1 individuals (IA2 tyrosine phosphatase like protein (IA2), glutamic acid decarboxylase (GAD) and insulin). Puzzling, autoantibodies against GAD65 do not correlate to type 1 diabetes in APS-1 patients; rather an association to intestinal malabsorption has been observed (Soderbergh et al. 2004). Treatment of type 1 diabetes in APS-1 follows the same regime as other diabetes patients, although glucose regulation can be affected by other disease components such as PAI and malabsorption. Hypothyroidism is also seen in APS-1 patients, and the prevalence increases with age as in the general population. Interestingly, the patients with the dominant G228 W mutation in the SAND domain revealed a high frequency of

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autoimmune thyroid disease (Cetani et al. 2001). Patients with hypothyroidism are treated with L-thyroxine.

Gastrointestinal Components Between 8 and 49% of APS-1 patients suffer from gastrointestinal manifestations, including hepatitis, atrophic gastritis with or without pernicious anaemia, and intestinal malabsorption (Perheentupa 2006; Orlova et al. 2010; Kluger et al. 2013; Bruserud et al. 2016; Ferre et al. 2016). Autoimmune involvement of the colon, on the other hand, is uncommon (Constantine and Lionakis 2019). The prevalence of gastric components varies between different cohorts. In chronic atrophic gastritis, an autoimmune attack against the gastric mucosa, specifically the gastric parietal cells, is found. The ability of the patient to take up vitamin B12 is lost causing pernicious anaemia, the end stage of autoimmune gastritis. Autoantibodies against the sodiumpotassium channel molecule are common, as well as antibodies against intrinsic factor and parietal cells (Di Sabatino et al. 2015). Severe autoimmune enteritis with diarrhea and/or severe obstipation is the most difficult component to handle clinically as it can lead to reduced absorption of drugs. It is present in between 9 and 26% of APS-1 patients (Perheentupa 2006; Orlova et al. 2010; Bruserud et al. 2016; Ferre et al. 2016). Tryptophan hydroxylase (TPH) autoantibodies in sera and loss of enterochromaffin cells correlate with the presence of intestinal malabsorption (Ward et al. 1999). Recently autoantibodies against defensins and Paneth cells were reported (Dobes et al. 2015). Malabsorption could interfere with steroid and vitamin D replacement therapy. In these severe cases, immunosuppressive agents are warranted. mTOR inhibitors can be used for biopsy-proven autoimmune enteritis (Constantine and Lionakis 2019). Other reports document positive effects of cyclosporine A, azathioprine, tacrolimus, and mycophenolate mofetil (Padeh et al. 1997; ProustLemoine et al. 2010; Geyer et al. 2014). For intestinal infections, antibiotics or antifungal treatment is recommended (Kluger et al. 2013). The appearance of hepatitis usually manifests in childhood and before puberty. The prevalence varies, as hepatitis was reported in 43% of American patients but only in 4% of Norwegian APS-1 patients (Bruserud et al. 2016, Ferre et al. 2016). Hepatitis is a serious condition, which can potentially be fatal. It is therefore of importance to monitor the patients closely, with measurements of alanine amino transferase (ALAT) regularly and liver biopsies if suspicions of hepatitis. Autoantibodies against CYPIA2, TPH, and aromatic L-amino acid decarboxylase (AADC) correlate with hepatitis in APS-1 (Soderbergh et al. 2000; Obermayer-Straub et al. 2001). Autoimmune hepatitis is treated with high doses of glucocorticoid therapy and azathioprine. Growth in children should be monitored closely as the steroid treatment could inhibit it.

Ectodermal Manifestations The estimated prevalence of enamel dysplasia in APS-1 patients varies substantially between different populations, probably due to differences in how well the patients

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have been investigated. Recently, we found enamel dysplasia in 72% of Norwegian APS-1 patients, and most of the other patients had bad teeth quality and suboptimal oral health making it difficult to know the exact cause (Bruserud et al. 2016). An early study from Finland concluded that enamel dysplasia was seen in 70% (Ahonen et al. 1990), and a large study from the USA found over 80% with enamel dysplasia (Ferre et al. 2016). Typically, horizontal bands of enamel hypoplasia are seen, but sometimes the whole crown is devoid of most of the enamel. Hypoparathyroidism could affect and worsen enamel damage. There is no immediate treatment for enamel dysplasia, but the patients should be seen regularly by a dentist and good oral hygiene prioritized. Whether nail dystrophy in APS-1 patients is caused by Candida albicans, other infections, or is a developmental defect is still obscure. However, the component is present in about 20% of APS-1 patients, but not always on all fingers/toes simultaneously (Ahonen et al. 1990). Most likely, this component is part of the clinical picture of CMC, although several studies have shown that candidiasis is not found in all patients with nail pitting, and that antifungals do not always clear the nail infections (Ahonen et al. 1990). APS-1 manifestations of the eye include keratokonjunctivitis, cataract, iridocyclitis, retinal detachment, optic atrophy, and Sjögrens-like dry eyes (Chang et al. 2006; Ferre et al. 2016; Oftedal et al. 2017). Keratitis is seen in about one-fourth and may in worst case lead to blindness (Perheentupa 2006). There are no known biomarker for eye components in APS-1 patients, although antibodies against α-fodrin and odorantbinding protein 1a (Kuroda et al. 2005; DeVoss et al. 2010) have been found in Aire-deficient mice. Further, supporting a connection between Aire and eye disease is the finding that loss of thymic expression of interphotoreceptor retinoid-binding protein (irbp) causes autoimmunity in Aire-knockout mice. Treatment of eye conditions varies with the condition, but in most cases a combination of steroids and cyclosporine A with or without vitamin A is used (Ward et al. 1999). In serious cases, corneal transplantation or treatment with limbal stem cells has been tried with success (Tarkkanen and Merenmies 2001; Shah et al. 2007). Vitiligo is a common autoimmune condition and prevalent also in APS-1. The extent of disease varies in different cohorts, but is about 15% in the Norwegian cohort (Bruserud et al. 2016). Autoantibodies against SOX9 and SOX10 in sera have been found to correlate with vitiligo (Hedstrand et al. 2001). Alopecia, either with only local or complete scalp hair loss, is present in different percentages in different populations. The condition correlates with autoantibodies against tyrosine hydroxylase (Hedstrand et al. 2000). There are no specific treatment for alopecia.

Other Components Asplenia is is acquired during childhood (Constantine and Lionakis 2019) and is found in about 15% of APS-1 patients but might go unrecognized (Friedman et al. 1991; Perheentupa 2006). Because the spleen has a functional role in the defense against capsule-bearing bacteria, recommendations of vaccinations against pneumococci, meningococci, and haemophilus influenzas is indicated (Husebye et al. 2018).

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Pneumonitis is a rare but a feared component that can lead to respiratory failure and death (Alimohammadi et al. 2009). Serological markers are potassium channel regulator (KCNRG) (Alimohammadi et al. 2009) and BPI fold-containing family B, member 1 (BPIFB1) (Shum et al. 2013). Immunosuppressive treatment has reported to improve the condition (Popler et al. 2012). Likewise, interstitial nephritis can potentially lead to kidney failure and need for renal transplantation. Some of these patients display autoantibodies against aquaporin 2 and transcription factors which regulate the aquaporin 2 promotor (Landegren et al. 2016a). A number of other rare components of APS-1 have been summarized in Table 1, including known biomarkers and preferred treatment.

Nonclassical APS-1 Recently a set of dominant mutations in the PHD1 and SAND domain of AIRE was described giving rise to a milder phenotype of APS-1 termed nonclassical APS-1. Many of them have one of the main components, but the classic APS-1 triad is rare (Cetani et al. 2001; Oftedal et al. 2015). Their clinical presentation is more reminiscent to the more common autoimmune polyendocrine syndrome type 2 with vitiligo, vitamin B12 deficiency/pernicious anaemia as common manifestations (Oftedal et al. 2015). Looking to public databases, the frequencies of these mutations within the general population is relatively high (>0.0008) which could suggest that autoimmunity caused or influenced by AIRE is more common than previously appreciated. Nonclassical APS-1 can be challenging to discover, as these dominant mutations often present with an incomplete penetrance and the family members often display different clinical manifestations. It is further important to exclude other genetic mutations, either within AIRE, the promoter region, or in other genes. Nevertheless, it is vital to facilitate identification of these individuals and families to prevent morbidity and mortality (Oftedal et al. 2015).

Diagnostic Tools in APS-1 Circulating autoantibodies are present in very high titers in sera from patients with APS-1. Typically, these antibodies are directed against intracellular enzymes with key roles in the tissue in which they are expressed. As the autoantibodies often present before any clinical symptoms, they can be used either as etiological markers (if disease is already present) or predictive tools of future disease in that particular organ. One example is 21OH, an etiological and predictive biomarker of autoimmune PAI (Betterle et al. 1997). In addition, autoantibodies against components of the immune system itself are highly prevalent, which makes them ideal to make the diagnosis of APS-1 (Meager et al. 2006). Autoantibodies against interferon- ω, -α and IL-22 are found in almost all patients. New technological advances have identified several novel autoantibodies in APS1 patients (Betterle et al. 1998, 2002; Eisenbarth and Gottlieb 2004; Landegren et al.

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2016b; Meyer et al. 2016; Eriksson et al. 2018), including transglutaminase 4 as a prostate-specific autoantigen. Several of the autoantibodies found in patients with APS-1 are also seen in patients with other autoimmune diseases, but then usually in lower titers.

Cytokine Autoantibodies in APS-1 The interferon and Th17 derived autoantibodies recently described in APS-1 patients have created a paradigm shift regarding autoantibodies in autoimmune endocrine diseases (Meager et al. 2006; Kisand et al. 2010; Puel et al. 2010). Several studies utilizing different methods, control groups, and including large number of patients from different countries have confirmed the presence of anti-IFN-α or-ω in close to every patient diagnosed with APS-1 (Meager et al. 2006; Meloni et al. 2008). These autoantibodies also seem to precede any clinical symptoms, and have been detected as early as 7 month of age (Toth et al. 2010). Assay of autoantibodies against IFN-ω and IFN-α provide a simple and fast screening method before encountering AIRE mutational analysis (Meloni et al. 2008) as outlined in Fig. 2 (Husebye et al. 2009). Clinical presentaon of 1 of the following:

APS-workup

• • • •

Clinical presentaon of more than 2 of the following: • Chronic mucocutaneous candidiasis • Addison’s disease • Hypoparathyroidism

Chronic mucocutaneous candidiasis, Addison’s disease (< 20 yr), Hypoparathyroidism, Primary ovarian failure < 30 years, enamel hypoplasia, periodic fever with rash, noninfectious keratitis, autoimmune hepatitis

Test for type 1 interferon antibodies (IFN-α or –ω) Yes

No

Sequence AIRE

No mutation

Two mutations

«dominant mutation»

APS-1

Non-classical APS-1

Consider image for thymoma (+/- MG), sequence RAG

Yes

No

CID, MG

“APS-1-like”

OSAD/APS-2

Fig. 2 Diagnostic approach to autoimmune polyendocrine syndrome type 1. (From N Engl J Med, Husebye, E. S., M. S. Anderson and O. Kampe, Autoimmune polyendocrine syndromes, 378(12), 1132–1141. Copyright © (2018) Massachusetts Medical Society. Reprinted with permission). Abbreviations: APS autoimmune polyendocrine syndrome, CID combined immunodeficiency, MG myasthenia gravis, OSAD organ-specific autoimmune disease

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The origin and role of these autoantibodies are still unclear, but autoantibodies against IFN-α have been shown to downregulate interferon-stimulated gene expression in blood cells from APS-1 patients (Kisand et al. 2008). The discovery of autoantibodies against the Th17-essential interleukins IL-17F and IL-22, and to some extent against IL17A, in sera from APS-1 patients indicates that there is a direct link between the autoimmune attack on the immune reaction against particularly Candida albicans and the CMC-manifestation of APS-1 (Kisand et al. 2010, Puel et al. 2010). Interestingly, patients suffering from thymoma and CMC in combination are also positive for these autoantibodies (Kisand et al. 2010). The Th17-response towards Candida albicans has been studied using peripheral blood mononuclear cells (PBMC) from APS-1 patients, where the production of IL17F and IL-22 were downregulated, while the results for IL-17A were unequivocal (Kisand et al. 2010; Ahlgren et al. 2011). Recent studies have suggested a protective role of anti-IL-17A-antibodies instead of a contributor to candidoses (Meyer et al. 2016; Weiler et al. 2018).

Natural Course APS-1 patients have increased mortality and may have a fatal outcome in young years if left undiagnosed and untreated (Bensing et al. 2008). Earlier reports found that more than 50% died before the age of 30 years of age. Even if this number has decreased to about 10% in later times (Gass 1962; Betterle et al. 1998), it is still much too high. Many of the components are potentially fatal and require follow-up within a multidisciplinary health care system. The causes of fatal outcome are multiple including squamous carcinoma of the oral mucosa, autoimmune hepatitis, renal failure, bronchiolitis, and acute adrenal crises (Perheentupa 2006; Rautemaa et al. 2007; Wolff et al. 2007; Bensing et al. 2008; Bruserud et al. 2016, 2018b). Early diagnosis, close monitoring of new disease-components, and optimized treatment are therefore essential.

Pathogenesis of APS-1 Being a monogenic disease caused by mutations in one single gene, APS-1 is a surprisingly complex disorder with a large variation in the clinical phenotypes. AIRE is a master regulator of expression of peripheral tissue antigens in the thymus, and hence crucial for the negative selection of developing T cells in the thymus (Anderson et al. 2002). APS-1 patients and the corresponding mouse models have been instrumental in teasing out not only the mechanisms behind autoimmune disease but also how the immune system develops normally (Anderson et al. 2002). AIRE is located at 21q22.3 spanning 14 exons and encodes a 545-amino-acid protein (1997, Nagamine et al. 1997). Over 100 mutations in the AIRE gene have been reported in the Human Gene Mutation Database (Liston et al. 2004), varying from single-nucleotide substitutions to large deletions. Earlier studies revealed no

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genotype-phenotype correlations in APS-1 patients. However, recent observations suggests that dominant mutations in either the SAND or PHD1 domains, and certain splice mutations, have milder phenotypes that can be explained by residual AIRE activity (Oftedal et al. 2015; Bruserud et al. 2016). AIRE is mainly expressed in the thymus where it promotes the expression of thousands of organ-specific proteins. After positive selection in the thymic cortex, T cells migrate to the thymic medulla where they are exposed to self-antigens presented on the MHC complex of AIRE positive medullary thymic epithelial cells (mTECs). In the normal situation, a developing T cell which binds too strong to its target will be deleted by apoptosis. Nonautoreactive T cells will be released as functional T cells to the blood stream. However, when AIRE is nonfunctional, autoreactive T cells will escape to the blood stream where they can give rise to autoimmune disease. AIRE may also prevent autoimmunity by promoting the development of regulatory T cells and the expression of chemokines important in mediating T cell negative selection (Zeng et al. 2013; Malchow et al. 2016).

Concluding Remarks APS-1 is a severe disease and it is critical to diagnose patients early, to follow them up regularly in the specialized health care system to monitor disease progress and new components, to provide education to patients for self-care, and to give optimized treatment for the different APS-1 manifestations. The identification and characterization of the disease gene AIRE and the hallmark autoantibodies in APSI patients have been vital for understanding of the pathogenesis of this syndrome, and has also provided vital diagnostic tools for APS-I and its components. It has further been instrumental for novel understanding of how the autoimmune system works and how tolerance is broken.

References Ahlgren KM, Moretti S, Lundgren BA, Karlsson I, Ahlin E, Norling A, Hallgren A, Perheentupa J, Gustafsson J, Rorsman F, Crewther PE, Rönnelid J, Bensing S, Scott HS, Kämpe O, Romani L, Lobell A. Increased IL-17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model. Eur J Immunol. 2011;41(1):235–45. Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322(26):1829–36. Alimohammadi M, Bjorklund P, Hallgren A, Pontynen N, Szinnai G, Shikama N, Keller MP, Ekwall O, Kinkel SA, Husebye ES, Gustafsson J, Rorsman F, Peltonen L, Betterle C, Perheentupa J, Akerstrom G, Westin G, Scott HS, Hollander GA, Kampe O. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med. 2008;358(10):1018–28.

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Genetics of Autoimmune Regulator (AIRE) and Clinical Implications in Childhood Nicola Improda, Mariacarolina Salerno, and Donatella Capalbo

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetics of Aire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aire Partners and Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Implications in Childhood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract

The Autoimmune Regulator (Aire) acts as a transcription regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens (TSAs), which are presented to potentially selfreactive thymocytes to induce their apoptosis (negative selection) or to favor the generation of FoxP3+ regulatory T cells (Tregs). The precise mechanism of action of AIRE is still unclear. AIRE seems to facilitate transcription indirectly, by interacting with chromatin (where it can recognize chromatin marks typical of silenced loci) and co-operating with numerous partners. Several evidences indicate that AIRE may act in post-initiation events of gene transcription, through elongation of RNA transcripts and splicing of target TSAs. To date, more than 130 different mutations in human Aire have been reported. Homozygous and heterozygous (dominant negative) mutations in AIRE result in the development of Autoimmune polyendocrine syndrome type 1 (APS-1), also N. Improda · M. Salerno (*) Department of Medical Translational Sciences, Paediatric Endocrinology section, Federico II University of Naples, Naples, Italy e-mail: [email protected] D. Capalbo Department of Pediatrics, Pediatric Endocrinology Section, Federico II University of Naples, Naples, Italy © Springer Nature Switzerland AG 2021 A. Colao et al. (eds.), Polyendocrine Disorders and Endocrine Neoplastic Syndromes, Endocrinology, https://doi.org/10.1007/978-3-319-89497-3_3

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called Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), a rare autoimmune syndrome, with typical onset in childhood. Recent evidences suggest that mutations or dysregulated expression of AIRE may also play a role in the pathogenesis of isolated autoimmune manifestations (like hypoparathyroidism, rheumatoid arthritis, vitiligo, alopecia areata, systemic sclerosis), in the predisposition to autoimmunity in complex syndromes (i.e., Down Syndrome) or even in cancerogenesis. Keywords

AIRE · APS-1 · APECED · Immunological central tolerance · Autoantibodies

Introduction Mutations in the Autoimmune Regulator (AIRE) gene, encoding for a key transcription factor involved in immunological central tolerance, result in the development of Autoimmune polyendocrine syndrome type 1 (APS-1), also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). Recent data also suggest a pathogenic role of dysregulated Aire expression in other conditions of interest for the pediatrician, such as isolated autoimmune manifestations (like hypoparathyroidism, rheumatoid arthritis, vitiligo, alopecia areata, systemic sclerosis), predisposition to autoimmunity of complex syndromes (i.e., Down Syndrome) or even in cancerogenesis. In this chapter, we provide an overview of the most recent advances in understanding the mechanism of action of Aire, with a focus on the relevant clinical aspects in childhood.

Genetics of Aire Aire acts as a transcription regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens (TSAs). Mutations in the AIRE gene result in the development of APS-1, a rare autoimmune syndrome, with a relatively higher prevalence in genetically isolated populations such as Iranian Jews (1:9,000), Finns (1:25,000), and Sardinians (1:14,400) (Husebye et al. 2009). Of note, this gene was the first to be located outside the human MHC locus that has been associated with autoimmunity. Recent evidences also suggest that mutations or dysregulated expression of AIRE may play a role in the pathogenesis of isolated autoimmune manifestations (like hypoparathyroidism, rheumatoid arthritis, vitiligo, alopecia areata, systemic sclerosis), in the predisposition to autoimmunity in complex syndromes (i.e., Down Syndrome) or even in cancerogenesis (Conteduca et al. 2018). The human AIRE gene, located on chromosome 21 region q22.3, is 11.9 kb long, spanning 14 exons and encodes a 545-amino-acid protein with a molecular weight of 58 kDa (Capalbo et al. 2013). The murine Aire gene has been mapped to chromosome

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10 and is structurally homologous to its human ortholog (Wang et al. 1999). Despite important differences with human APS-1, the animal models of Aire / have been helpful in improving our understanding of Aire-driven prevention of autoimmunity (Wang et al. 1999). Although the characterization of AIRE functions and mechanisms of action has dramatically improved in recent years, many aspects remain to be fully elucidated. AIRE has a strict spatiotemporal regulation, being ubiquitously transcribed during the earliest stages of embryogenesis, and then mainly restricted to medullary thymic epithelial cells (mTECs) (De Martino et al. 2016). The AIRE protein resides inside the nuclear bodies, which are known to associate with transcriptionally active and chromatin-associated proteins (De Martino et al. 2016). Such a strict regulation depends on a very intricate mechanism, rather than on the action of a single transcription factor/regulator. In mTECs, AIRE plays a key role in TSAs expression, by regulating the transcription of thousands of TSA genes in a “stochastic” and “ordered” manner (Anderson and Su 2016). Indeed, a small percentage (1–3%) of the total number of mTECs expresses a particular TSA. Different sets of TSAs are regulated by AIRE within individual mTECs but whether a particular AIRE-regulated TSA is expressed in a given mTEC seems to be highly probabilistic (De Martino et al. 2016). Moreover, the “ordered” TSA expression refers to the increased likelihood that a particular set of TSA genes will be co-expressed in an individual mTEC (Pinto et al. 2013). TSAs are in turn presented to potentially self-reactive thymocytes to induce their apoptosis (called negative selection) or to support the generation of a unique population of FoxP3+ regulatory T cells (Tregs) in the thymus that have the ability to suppress autoreactive cells (Husebye et al. 2018). Therefore, when AIRE is impaired, many autoreactive T cells with specificity for specific antigens can escape negative selection and may later be able to initiate autoimmune reaction. In Airedeficient murine model, mTECs express only a small fraction of the TSA repertoire, resulting in development of several autoimmune manifestations, mononuclear infiltrates in multiple organs, and autoantibodies against several tissues, thus resembling human APS-1 (Anderson 2002; Yano et al. 2008). Recent studies also postulated that AIRE has several functions that are independent of its promotion of TSA expression in mTECs (Gray et al. 2007). Indeed, AIRE promotes mTEC expression of the chemokine XCL1 and the expression of ligands of the chemokines CCR7 and CCR4 (Gray et al. 2007). XCL1 plays a critical role in recruitment of thymic dendritic cells, which in turn participates in thymocyte negative selection, and contributes to development of regulatory T cells within the thymus. CCR7 and CCR4 are involved in thymocyte chemotaxis and migration (Lei et al. 2011). Moreover, despite contrasting evidences, recent observations suggest that AIRE regulates terminal maturation of mTECs and thymic maturation and architecture probably through the interaction with microRNAs (miRNAs) (Matsumoto et al. 2013, Macedo et al. 2015). In addition to mTECs, AIRE is also expressed in rare stromal cells of the lymph nodes (Halonen et al. 2001), dubbed extrathymic AIRE-expressing cells (eTACs)

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(Gardner et al. 2008), thymic AIRE+ B cells (Yamano et al. 2015), and gonads (Schaller et al. 2008). The functional significance of AIRE in both eTACs and thymic B cells is still not well known. Although it has been suggested that AIRE can facilitate self-tolerance by acting in both eTACs and thymic B cells, in these cells AIRE induces only a small percentage of the large number of TSA genes expressed in mTECs (Gardner et al. 2008; Yamano et al. 2015). The AIRE gene has also been found to be expressed in the fibroblasts and keratinocytes (Clark et al. 2005), thus suggesting a possible role of the skin in immune regulation. Knowledge of AIRE’s primary structure is essential to understand the effect of mutations in the AIRE gene on its biological function and APS-1 manifestations. Starting from the amino terminus, AIRE is composed by a caspase recruitment domain (CARD)/homogeneously staining region (HSR), nuclear localization sequences (NLS), a conserved approximately 80-residue region composed by Sp100, AIRE NucP41/75, DEAF (also called SAND domain), two planthomeodomain (PHD) zinc fingers, a proline-rich region (PRR), and four LXXLL motifs (where L stays for leucine) spread among the domains (Perniola and Musco 2014). The CARD/HSR is involved in the process of AIRE homomultimerization and seems also to anchor AIRE to the chromatin (Perniola and Musco 2014; Maslovskaja et al. 2015). Formation of homo-oligomers (dimers and tetramers) is essential to allow binding to specific oligonucleotide motifs (Maslovskaja et al. 2015). The NLS has a stretch of basic amino acids at positions 131–133 important for nuclear import as they serve as a docking station for karyoperines, which mediate AIRE’s transport to the nucleus via the nuclear pore complex (NPC) (Kabachinski and Schwartz 2015). The SAND domain does not have a DNA-binding-motif, but it is important for subcellular localization and promotion of protein-protein interaction with a transcriptional repressive complex (Perniola and Musco 2014). Importantly, CARD, NLS, and SAND domain have most AIRE lysine residues, which represent sites of acetylation; this is a key process for appropriate protein localization and co-operation with multiple partners (Saltis et al. 2008). AIRE PHD1 finger domain recognizes histone 3 molecules with unmethylated lysine at position 4 (H3K4me0) as a distinct epigenetic mark, thus representing a structural system involved in the recruitment of chromatin-related proteins, essential for the epigenetic role for AIRE (Org et al. 2008). Despite a structural similarity with PHD1, PHD2 has a positively charged surface that makes it unsuitable to interact with histones and was found to be critical for interaction with protein partners (Yang et al. 2013). However, both PHD fingers are critical for AIRE’s biological function, as specific mutations in these domains result in breakdown in AIRE-dependent induction of self-tolerance (Meloni et al. 2008b). LXXLL motif and PRR are implicated in promoting gene transcription by mediating interactions with other LXXLL-containing proteins, typically including various transcriptional co-activators or co-repressors, such as CREB-binding protein (CBP) and p300 (Perniola and Musco 2014). In particular, the fourth LXXLL motif in the C-terminus is critical for AIRE properties (Meloni et al. 2008b). Finally, the 30 amino acid segment placed at the end of C-terminus acts as an autonomous domain (Meloni et al. 2008b). To date, more than 130 different mutations in human AIRE have been reported (The human gene mutation databases, www.hgmd.cf.ac.uk). Mutations in AIRE can be

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either nonsense mutations, frameshift mutations caused by deletions or insertions/ duplications or single amino acid missense mutations (Peterson and Peltonen 2005). Deletion of the entire AIRE gene has also been described in association to APS-1 (Boe Wolff et al. 2008). Most of the missense mutations are concentrated into the CARD domain, and less frequently into the PHD1 and PHD2 domains, while insertion and deletions are spread throughout the gene (Abramson and Goldfarb 2016). Each mutation results in a specific Aire dysfunction, depending on its localization. In particular, missense mutations in the HSR/CARD domain reduce the ability of AIRE to homodimerize and locate to nuclear bodies, while mutations in the PHD domains impair the ability to act as a transcriptional activator and mutations in the SAND domain result in aggregation of the polypeptide in the cytoplasm preventing proper nuclear targeting (Bruserud et al. 2016). It must be noted that pathogenic mutations can also be found outside the AIRE domains. Indeed, mutations in intronic regions can alter the splicing of AIRE mRNA, while mutations in the promoter region impair the transcriptional activity of AIRE (Bruserud et al. 2016). Some mutations have been found to be typical of specific areas. The most common mutation is the so-called Finnish major mutation (p.R257X), an early stop codon mutation within the SAND domain encoding a truncated nonfunctional protein of 256 amino acids, with high prevalence in Finland, Russia, and Eastern Europe (Bruserud et al. 2016; Orlova et al. 2017). Another frequent mutation is the 13 basepair deletion (p.C322del13) in exon 8, a frame shift mutation that generates a truncated protein without any PHD fingers, prevalent in patients from Europe (Norway, the British Isles, France) and North America (Ferre et al. 2016). Other mutations are highly prevalent in restricted populations, like the R139X mutation in Sardinians (Meloni et al. 2012) or the Y85C in Iranian Jews (Zlotogora and Shapiro 1992). Although APS-1 is classically caused by biallelic mutations, it has been recently established that there are patients carrying a unique dominant negative mutation in AIRE (Oftedal et al. 2015; Cetani et al. 2001; Abbott et al. 2018; Tazi-Ahnini et al. 2001). The G228 W mutation in the SAND domain has been the first dominant negative mutation to be reported in an Italian kindred with apparent autosomal dominant autoimmunity. In this family, hypothyroidism was frequent and some individuals exhibited only autoimmune thyroid disease, while others had a clinical picture suggestive of APS-1, although with a limited number of manifestations (Cetani et al. 2001). Thereafter, at least six additional missense mutations acting in a dominant negative manner have been reported in over 30 patients, all clustering within the PHD1 domain. These patients usually have a late presentation, incomplete penetrance, and display milder forms of the disease, often characterized by pernicious anemia, vitiligo, autoimmune thyroid disease, and type 1 diabetes (Husebye et al. 2018; Oftedal et al. 2015), so that they can be erroneously diagnosed with the more common condition APS-2, which has a complex inheritance. Therefore, this condition has been named “non-classical” APS-1 (Oftedal et al. 2015). A second variant within the SAND domain of AIRE acting in a dominant negative manner, the R247C mutation, has been recently described in a family with early-onset autoimmunity, characterized by type I diabetes from the age of 3 years in the proband and rheumatoid arthritis in his mother (Abbott et al. 2018).

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It has been demonstrated that dominant negative mutations severely suppress the AIRE-driven gene expression and thymic TSA expression. Recent experiments showed that all dominant mutations in the PHD-1 domain result in a preserved ability of the mutant Aire to co-localize into the nuclear speckles with wild type Aire protein, forming a homo-oligomer with no functional activity due to impaired PHD1 fingers (Oftedal et al. 2015). Dominant negative mutations seem to be more frequent than initially thought, with an estimated frequency of at least 1/1000 subjects. Due to the broad spectrum of autoimmune phenotypes with variable penetrance and severity, it is not surprising that in many families, nonclassical APS-1 may remain undiagnosed. The phenotypic variability could be explained by a possible residual activity of Aire tetramers containing dominant negative mutations or alternatively may depend upon the specific amino acid change (Abramson and Goldfarb 2016). Changes in amino acids essential for the three-dimensional integrity of the PHD1 domain generally revealed a more severe phenotype with the presence of interferon (IFN)-omega autoantibodies (Abramson and Goldfarb 2016). Indeed, mutations in residues 302 and 311 are more likely to result in a form that resembles classical APS1 (Oftedal et al. 2015). Recent evidences demonstrated that autoimmune diseases may paradoxically be caused by increased expression of Aire (Nishijima et al. 2018). In fact, studies in mice unexpectedly demonstrated that augmented human Aire expression, obtained with the use of the MHC-II promoter, resulted in development of muscle-specific autoimmunity, incomplete maturation of mTECs, and impaired expression of Airedependent TSAs. This led to failure of negative selection with severely reduced production of regulatory T cells in the thymus, whereas in peripheral antigen presenting cells, expression of costimulatory molecules was increased. The authors hypothesized that the levels of Aire expression must be strictly under control, in order to preserve immunological tolerance, appropriate coordination between central and peripheral tolerance and finally prevent autoimmunity (Nishijima et al. 2018). Similarly, although the expression of both AIRE and TSAs have been reported to be decreased in Down syndrome (as discussed below), it is possible that a gene-dosage effect of AIRE due to chromosome 21 trisomy may contribute to increased frequency of autoimmune diseases observed in Down syndrome (Giménez-Barcons et al. 2014).

Aire Partners and Mechanism of Action Different from other traditional factors, the transcriptional activity of AIRE in mTECs involves a large portion of the genome. In particular, Aire regulates around 20% of the genes expressed in mTECs (Perniola 2018). Although the precise molecular mechanism is still unclear, AIRE operates differently from conventional transcription factors, as it has no distinct DNA-binding motif but seems to facilitate transcription indirectly, by interacting with chromatin and co-operating with numerous partners, initially divided into four main classes based on their function: nuclear transport, chromatin binding/structure, transcription, and pre-mRNA processing

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factors (Abramson and Goldfarb 2016; Perniola 2018). More recent studies have reported new AIRE partners with a broader spectrum of proteins with different activity, for example proteins that cooperate with AIRE in recognizing and identifying target genes, release stalled RNA polymerase, and regulate AIRE transcriptional activity (Fig. 1) (Perniola 2018). Aire can recognize transcriptionally quiescent sites, like chromatin marks typical of silenced loci, thus exerting an epigenetic control. In fact, Aire’s PHD1 finger domain appears to be able to bind histone three molecules with unmethylated lysine at position 4 (H3K4me0), which is characteristic of inactive chromatin or repressed genes (Org et al. 2008; Meloni et al. 2008b). Recognition of target genes and Airemediated expression of TSA may also be dependent upon interaction via the SAND domain with another gene repression complex formed by activating transcriptionfactor-7-interacting protein (ATF7IP) and methyl-CpG-binding-domain protein 1 (MBD1) (Waterfield et al. 2014). The former acts as either co-activator or corepressor of gene transcription depending on its partners, while the latter can bind to methylated CpG dinucleotides, within the promoter of silent or poorly expressed genes (Waterfield et al. 2014).

- Elongation of AIRE-dependent transctipts - Trascription of miRNAs

Brd4 pTEFb

RNA PoIll

SIRT 1 PARP1 DNA Top 1/2

AIRE DNA PK

Ac Ac

p300 CBP

ci / ive lo spons cers e r E n AIR renha Supe

Fig. 1 Simplified scheme of Aire-dependent multimolecular machinery involved in the events of gene transcription. After recognition of marks of inactive chromatin or repressed genes (like H3K4me0) or superenhancers, Aire recruits DNA-Topoisomerase 1 (TOP1) (and secondarily TOP2), resulting in stabilization of DNA double-stranded breaks and involvement of several elements of the DNA-damage response, including DNA protein kinase (PK), poly-(ADP-ribose) polymerase 1 (PARP-1), CREB-binding protein (CBP), and RNA polymerase II (PolII). Aire also partners with positive transcription elongation factor b (P-TEFb), via a bridge formed by bromodomain-containing protein 4 (BRD4), which releases stalled RNA- PolII. The release of RNA-PolII results in elongation of RNA transcripts and transcription of miRNAs. Aire’s transcription-transactivation capacity is upregulated by protein deacetylase Sirtuin1 (Sirt1) and downregulated by CBP and p300, which can acetylate Aire. (Adapted by permission from Springer Nature: [Nature Immunology] [Sirt-ainly Aire] [Pärt Peterson], [copyright 2015])

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Recent studies relying on advanced genomic and biochemical approaches have demonstrated that Aire is located on and activates super-enhancers, defined as long chromatin traits hosting exceptionally high densities of general and cell-type-specific transcription factors (Bansal et al. 2017). Super-enhancers are associated especially with genes that regulate the activities of fully differentiated cell types and are rapidly induced upon environmental or physiologic stimulation. Dynamic looping of superenhancers along a chromosome or engagement of a super-enhancer on different chromosomes could thus provide an explanation of the strong influence exerted by AIRE on the mTEC transcriptome at the population level, in contrast with a much more restrained effect on an individual cell. Several lines of evidence demonstrate that DNA-Topoisomerase 1 (DNA-TOP1) has a primary function in the Aire-mediated activation of super-enhancers (Bansal et al. 2017). DNA-TOPs are isomerase enzymes which remove positive and negative DNA supercoils by generating transient DNA breaks, causing local chromatin relaxation that facilitates gene transcription. DNA-TOP1 results in single-stranded DNA nicks, while DNA-TOP2 causes double-stranded breaks. These discoveries have prompted a hypothetical model of action of Aire. According to this model, AIRE, by recognizing unmethylated H3K4me0, localizes to mTEC super-enhancers, where it interacts with TOP1 resulting in stabilization of DNA double-stranded breaks and recruitment of several elements of the DNAdamage response, including DNA protein kinase (PK), Ku80 protein and poly(ADP-ribose) polymerase 1 (PARP-1), as well as several transcription factors, like RNA polymerase II (PolII), CBP and bromodomain-containing protein 4 (BRD4), which constitute active multi-protein complexes (Guha et al. 2017). In this model, TOP2A and 2B, which also attracts DNA-PK and PARP1, would play a role in Airedriven induction of gene expression in downstream events (Bansal et al. 2017). In another recent study, Guha and coworkers (Guha et al. 2017) have clarified that Aire could inhibit DNA-TOP1 and TOP2 re-ligation activity, resulting in chromatin changes attributable to DNA-PK and PARP1, with activation of the transcription of poorly expressed genes. Aire also partners with positive transcription elongation factor b (P-TEFb), via a bridge formed by Brd4 (Yoshida et al. 2015), thus enabling elongation and splicing of pre-mRNA into mature mRNA through the release of stalled RNA-polymerase II, and with heterogenous nuclear ribonucleoprotein L (HnRNPL), which promotes alternative mRNA splicing (Giraud et al. 2014). Taken together, these observations support the concept that AIRE promotes TSAs expression not activating transcription directly, but rather by acting in post-initiation events of gene transcription, through elongation of RNA transcripts and splicing of target TSAs. In addition, AIRE binds to several partners that induce post-translational protein modification that regulate its biological function (Abramson and Goldfarb 2016). In particular, acetylation of Aire by CBP and p300 results in downregulation of its transcriptional activity and modification in the profile of TSAs regulated by Aire (Pitkanen et al. 2000). On the contrary, deacetylation of lysin residues in AIRE by the protein deacetylase Sirtuin1 (Sirt1) activates its transcription (Chuprin et al.

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2015). Finally, another component of chromatine-associated complex likely involved in AIRE regulation in mTECs is homeodomain-interacting protein kinase 2 (HIPK2), which phosphorylates Aire in vitro (Rattay et al. 2015). Finally, recent studies demonstrate that AIRE can interact with miRNAs, small (21–25 nucleotides) double-stranded non-protein-encoding RNAs, which join in complexes able to cause translational block and mRNA degradation. This relationship seems to be very complex as such a specific miRNA subset has been demonstrated to affect Aire mRNA translation (Ucar et al. 2013), while, conversely, Aire seems to modulate the transcription of miRNAs, thus influencing their amount and composition (Macedo et al. 2013). Moreover, Aire might be able to induce in target genes a state of refractoriness to miRNAs action (Macedo et al. 2015; Passos et al. 2015).

Clinical Implications in Childhood The first disease to be related with AIRE loss of function has been APS-1, also known as APECED, a rare disease clinically defined by the presence of two of the three major disease components, such as chronic mucocutaneous candidiasis (CMC), primary adrenal insufficiency (Addison’s disease), and hypoparathyroidism (HP). Clinical features and natural history of APS-1 are detailed in ▶ Chap. 2, “The Natural History of APS1”. Classical APS-1 typically presents in childhood or adolescence. In most cases, CMC is the first clinical manifestation to appear, before the age of 5 years. This is usually followed by HP before the age of 10 years and later by Addison’s disease before the age of 15 years. Taking into account only patients exhibiting all three major APS-1 components, more than 60% develops the triad by 25 years of age (Anderson 2002). Therefore, the presence of apparently isolated CMC or Addison’s disease or HP in children and more in general in subjects