The Human Hypothalamus: Neuroendocrine Disorders (Volume 181) (Handbook of Clinical Neurology, Volume 181) 0128206837, 9780128206836

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THE HUMAN HYPOTHALAMUS: NEUROENDOCRINE DISORDERS

HANDBOOK OF CLINICAL NEUROLOGY Series Editors

MICHAEL J. AMINOFF, FRANÇOIS BOLLER, AND DICK F. SWAAB VOLUME 181

THE HUMAN HYPOTHALAMUS: NEUROENDOCRINE DISORDERS Series Editors

MICHAEL J. AMINOFF, FRANÇOIS BOLLER, AND DICK F. SWAAB

Volume Editors

DICK F. SWAAB, RUUD M. BUIJS, PAUL J. LUCASSEN, AHMAD SALEHI, AND FELIX KREIER VOLUME 181 3rd Series

ELSEVIER Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2021 Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-820683-6 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

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Handbook of Clinical Neurology 3rd Series Available titles Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol.

81, Pain, F. Cervero and T.S. Jensen, eds. ISBN 9780444519016 82, Motor neurone disorders and related diseases, A.A. Eisen and P.J. Shaw, eds. ISBN 9780444518941 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed, eds. ISBN 9780444519009 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed, eds. ISBN 9780444528933 85, HIV/AIDS and the nervous system, P. Portegies and J. Berger, eds. ISBN 9780444520104 86, Myopathies, F.L. Mastaglia and D. Hilton Jones, eds. ISBN 9780444518996 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo, eds. ISBN 9780444518965 88, Neuropsychology and behavioural neurology, G. Goldenberg and B.C. Miller, eds. ISBN 9780444518972 89, Dementias, C. Duyckaerts and I. Litvan, eds. ISBN 9780444518989 90, Disorders of consciousness, G.B. Young and E.F.M. Wijdicks, eds. ISBN 9780444518958 91, Neuromuscular junction disorders, A.G. Engel, ed. ISBN 9780444520081 92, Stroke – Part I: Basic and epidemiological aspects, M. Fisher, ed. ISBN 9780444520036 93, Stroke – Part II: Clinical manifestations and pathogenesis, M. Fisher, ed. ISBN 9780444520043 94, Stroke – Part III: Investigations and management, M. Fisher, ed. ISBN 9780444520050 95, History of neurology, S. Finger, F. Boller and K.L. Tyler, eds. ISBN 9780444520081 96, Bacterial infections of the central nervous system, K.L. Roos and A.R. Tunkel, eds. ISBN 9780444520159 97, Headache, G. Nappi and M.A. Moskowitz, eds. ISBN 9780444521392 98, Sleep disorders Part I, P. Montagna and S. Chokroverty, eds. ISBN 9780444520067 99, Sleep disorders Part II, P. Montagna and S. Chokroverty, eds. ISBN 9780444520074 100, Hyperkinetic movement disorders, W.J. Weiner and E. Tolosa, eds. ISBN 9780444520142 101, Muscular dystrophies, A. Amato and R.C. Griggs, eds. ISBN 9780080450315 102, Neuro-ophthalmology, C. Kennard and R.J. Leigh, eds. ISBN 9780444529039 103, Ataxic disorders, S.H. Subramony and A. Durr, eds. ISBN 9780444518927 104, Neuro-oncology Part I, W. Grisold and R. Sofietti, eds. ISBN 9780444521385 105, Neuro-oncology Part II, W. Grisold and R. Sofietti, eds. ISBN 9780444535023 106, Neurobiology of psychiatric disorders, T. Schlaepfer and C.B. Nemeroff, eds. ISBN 9780444520029 107, Epilepsy Part I, H. Stefan and W.H. Theodore, eds. ISBN 9780444528988 108, Epilepsy Part II, H. Stefan and W.H. Theodore, eds. ISBN 9780444528995 109, Spinal cord injury, J. Verhaagen and J.W. McDonald III, eds. ISBN 9780444521378 110, Neurological rehabilitation, M. Barnes and D.C. Good, eds. ISBN 9780444529015 111, Pediatric neurology Part I, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444528919 112, Pediatric neurology Part II, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444529107 113, Pediatric neurology Part III, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444595652 114, Neuroparasitology and tropical neurology, H.H. Garcia, H.B. Tanowitz and O.H. Del Brutto, eds. ISBN 9780444534903 115, Peripheral nerve disorders, G. Said and C. Krarup, eds. ISBN 9780444529022 116, Brain stimulation, A.M. Lozano and M. Hallett, eds. ISBN 9780444534972 117, Autonomic nervous system, R.M. Buijs and D.F. Swaab, eds. ISBN 9780444534910 118, Ethical and legal issues in neurology, J.L. Bernat and H.R. Beresford, eds. ISBN 9780444535016 119, Neurologic aspects of systemic disease Part I, J. Biller and J.M. Ferro, eds. ISBN 9780702040863 120, Neurologic aspects of systemic disease Part II, J. Biller and J.M. Ferro, eds. ISBN 9780702040870 121, Neurologic aspects of systemic disease Part III, J. Biller and J.M. Ferro, eds. ISBN 9780702040887 122, Multiple sclerosis and related disorders, D.S. Goodin, ed. ISBN 9780444520012 123, Neurovirology, A.C. Tselis and J. Booss, eds. ISBN 9780444534880 124, Clinical neuroendocrinology, E. Fliers, M. Korbonits and J.A. Romijn, eds. ISBN 9780444596024 125, Alcohol and the nervous system, E.V. Sullivan and A. Pfefferbaum, eds. ISBN 9780444626196 126, Diabetes and the nervous system, D.W. Zochodne and R.A. Malik, eds. ISBN 9780444534804 127, Traumatic brain injury Part I, J.H. Grafman and A.M. Salazar, eds. ISBN 9780444528926 128, Traumatic brain injury Part II, J.H. Grafman and A.M. Salazar, eds. ISBN 9780444635211 129, The human auditory system: Fundamental organization and clinical disorders, G.G. Celesia and G. Hickok, eds. ISBN 9780444626301 130, Neurology of sexual and bladder disorders, D.B. Vodušek and F. Boller, eds. ISBN 9780444632470 131, Occupational neurology, M. Lotti and M.L. Bleecker, eds. ISBN 9780444626271

vi Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol. Vol.

AVAILABLE TITLES (Continued) 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146,

Neurocutaneous syndromes, M.P. Islam and E.S. Roach, eds. ISBN 9780444627025 Autoimmune neurology, S.J. Pittock and A. Vincent, eds. ISBN 9780444634320 Gliomas, M.S. Berger and M. Weller, eds. ISBN 9780128029978 Neuroimaging Part I, J.C. Masdeu and R.G. González, eds. ISBN 9780444534859 Neuroimaging Part II, J.C. Masdeu and R.G. González, eds. ISBN 9780444534866 Neuro-otology, J.M. Furman and T. Lempert, eds. ISBN 9780444634375 Neuroepidemiology, C. Rosano, M.A. Ikram and M. Ganguli, eds. ISBN 9780128029732 Functional neurologic disorders, M. Hallett, J. Stone and A. Carson, eds. ISBN 9780128017722 Critical care neurology Part I, E.F.M. Wijdicks and A.H. Kramer, eds. ISBN 9780444636003 Critical care neurology Part II, E.F.M. Wijdicks and A.H. Kramer, eds. ISBN 9780444635990 Wilson disease, A. Członkowska and M.L. Schilsky, eds. ISBN 9780444636003 Arteriovenous and cavernous malformations, R.F. Spetzler, K. Moon and R.O. Almefty, eds. ISBN 9780444636409 Huntington disease, A.S. Feigin and K.E. Anderson, eds. ISBN 9780128018934 Neuropathology, G.G. Kovacs and I. Alafuzoff, eds. ISBN 9780128023952 Cerebrospinal fluid in neurologic disorders, F. Deisenhammer, C.E. Teunissen and H. Tumani, eds. ISBN 9780128042793 Vol. 147, Neurogenetics Part I, D.H. Geschwind, H.L. Paulson and C. Klein, eds. ISBN 9780444632333 Vol. 148, Neurogenetics Part II, D.H. Geschwind, H.L. Paulson and C. Klein, eds. ISBN 9780444640765 Vol. 149, Metastatic diseases of the nervous system, D. Schiff and M.J. van den Bent, eds. ISBN 9780128111611 Vol. 150, Brain banking in neurologic and psychiatric diseases, I. Huitinga and M.J. Webster, eds. ISBN 9780444636393 Vol. 151, The parietal lobe, G. Vallar and H.B. Coslett, eds. ISBN 9780444636225 Vol. 152, The neurology of HIV infection, B.J. Brew, ed. ISBN 9780444638496 Vol. 153, Human prion diseases, M. Pocchiari and J.C. Manson, eds. ISBN 9780444639455 Vol. 154, The cerebellum: From embryology to diagnostic investigations, M. Manto and T.A.G.M. Huisman, eds. ISBN 9780444639561 Vol. 155, The cerebellum: Disorders and treatment, M. Manto and T.A.G.M. Huisman, eds. ISBN 9780444641892 Vol. 156, Thermoregulation: From basic neuroscience to clinical neurology Part I, A.A. Romanovsky, ed. ISBN 9780444639127 Vol. 157, Thermoregulation: From basic neuroscience to clinical neurology Part II, A.A. Romanovsky, ed. ISBN 9780444640741 Vol. 158, Sports neurology, B. Hainline and R.A. Stern, eds. ISBN 9780444639547 Vol. 159, Balance, gait, and falls, B.L. Day and S.R. Lord, eds. ISBN 9780444639165 Vol. 160, Clinical neurophysiology: Basis and technical aspects, K.H. Levin and P. Chauvel, eds. ISBN 9780444640321 Vol. 161, Clinical neurophysiology: Diseases and disorders, K.H. Levin and P. Chauvel, eds. ISBN 9780444641427 Vol. 162, Neonatal neurology, L.S. De Vries and H.C. Glass, eds. ISBN 9780444640291 Vol. 163, The frontal lobes, M. D’Esposito and J.H. Grafman, eds. ISBN 9780128042816 Vol. 164, Smell and taste, Richard L. Doty, ed. ISBN 9780444638557 Vol. 165, Psychopharmacology of neurologic disease, V.I. Reus and D. Lindqvist, eds. ISBN 9780444640123 Vol. 166, Cingulate cortex, B.A. Vogt, ed. ISBN 9780444641960 Vol. 167, Geriatric neurology, S.T. DeKosky and S. Asthana, eds. ISBN 9780128047668 Vol. 168, Brain-computer interfaces, N.F. Ramsey and J. del R. Millán, eds. ISBN 9780444639349 Vol. 169, Meningiomas, Part I, M.W. McDermott, ed. ISBN 9780128042809 Vol. 170, Meningiomas, Part II, M.W. McDermott, ed. ISBN 9780128221983 Vol. 171, Neurology and pregnancy: Pathophysiology and patient care, E.A.P. Steegers, M.J. Cipolla and E.C. Miller, eds. ISBN 9780444642394 Vol. 172, Neurology and pregnancy: Neuro-obstetric disorders, E.A.P. Steegers, M.J. Cipolla and E.C. Miller, eds. ISBN 9780444642400 Vol. 173, Neurocognitive development: Normative development, A. Gallagher, C. Bulteau, D. Cohen and J.L. Michaud, eds. ISBN 9780444641502 Vol. 174, Neurocognitive development: Disorders and disabilities, A. Gallagher, C. Bulteau, D. Cohen and J.L. Michaud, eds. ISBN 9780444641489 Vol. 175, Sex differences in neurology and psychiatry, R. Lanzenberger, G.S. Kranz, and I. Savic, eds. ISBN 9780444641236 Vol. 176, Interventional neuroradiology, S.W. Hetts and D.L. Cooke, eds. ISBN 9780444640345 Vol. 177, Heart and neurologic disease, J. Biller, ed. ISBN 9780128198148 Vol. 178, Neurology of vision and visual disorders, J.J.S. Barton and A. Leff, eds. ISBN 9780128213773 Vol. 179, The human hypothalamus: Anterior region, D.F. Swaab, F. Kreier, P.J. Lucassen, A. Salehi and R.M. Buijs, eds. ISBN 9780128199756 Vol. 180, The human hypothalamus: Middle and posterior region, D.F. Swaab, F. Kreier, P.J. Lucassen, A. Salehi and R.M. Buijs, eds. ISBN 9780128201077 All volumes in the 3rd Series of the Handbook of Clinical Neurology are published electronically, on Science Direct: http://www.sciencedirect.com/science/handbooks/00729752.

Foreword

Few areas of neuroscience have received so much attention and yielded so many new and important findings in recent years as the hypothalamus and related structures. Earlier series of the Handbook of Clinical Neurology included over 100 entries under the keyword “hypothalamus,” dispersed within all 75 volumes. The current third series started with two volumes dedicated entirely to basic and clinical aspects of the hypothalamus, the first (Volume 79) dealing with the hypothalamic nuclei and the second (Volume 80) with its neuropathology. They were authored by Professor Dick Swaab and were published almost 20 years ago (in 2003 and 2004). As series editors, we felt that the number of new developments since that time required that the entire topic be reviewed once more. These new developments include a better understanding of the anatomy and connections of the human hypothalamus based on novel imaging techniques and the accumulating molecular information on the hypothalamus. Also, it is now apparent that the hypothalamus regulates more hormones than previously recognized and is the key structure in clinical neuroendocrinology. Above all, the hypothalamus is now seen to relate to a large number of neurologic domains—including memory, sleep, epilepsy, Parkinson disease and other neurodegenerative disorders, and headaches, as well as behavioral issues such as eating behavior, depression, and aggression. Last but not least, the hypothalamus plays a crucial role in reproduction and shows sexual dimorphisms in various nuclei. These advances and the associated vast expansion of knowledge that has resulted have required an increase in coverage from two to four volumes of the Handbook. We thank and congratulate Dick Swaab who is the Chief Editor of these four new multiauthored volumes. They were prepared in collaboration with four other highly experienced neuroscientists. Ruud Buijs is in the Institute for Biomedical Investigation, Universidad Nacional Autónoma de Mexico, Mexico City; Felix Kreier is in the Department of Pediatrics, OLVG hospital, Amsterdam; Paul Lucassen is at the Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam; and Ahmad Salehi is in the Department of Psychiatry and Behavioral Sciences, Stanford Medical School, California. Together they have gathered a remarkable group of contributing authors, thus assuring the right mix of continuity and highly updated information about the human hypothalamus. As series editors, we reviewed all the chapters in the volumes and made suggestions for improvement, but we are delighted that the volume editors and chapter authors produced such scholarly and comprehensive accounts of different aspects of the topic. We hope that the volumes will appeal to clinicians as a state-of-the-art reference that summarizes the clinical features and management of the many neurologic, neuroendocrine, and psychiatric manifestations of hypothalamic dysfunction. We are also sure that basic researchers will find within them the foundations for new approaches to the study of the complex issues involved. In addition to the print version, the volumes are available electronically on Elsevier’s Science Direct website, which is popular with readers and will improve the books’ accessibility. Indeed, all of the volumes in the present series of the Handbook are available electronically on this website. This should make them more accessible to readers and facilitate searches for specific information. As always, it is a pleasure to thank Elsevier, our publisher, and in particular Michael Parkinson in Scotland, Nikki Levy and Kristi Anderson in San Diego, and Punithavathy Govindaradjane at Elsevier Global Book Production in Chennai, for their assistance in the development and production of the Handbook of Clinical Neurology. Michael J. Aminoff Franc¸ois Boller

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Preface

I know very well that the reader has no great need to know all this; it is I who have a need to tell him J.J. Rousseau

THE HCN VOLUMES ON THE HUMAN HYPOTHALAMUS More than 20 years ago, I (DFS) had written a monograph on the human hypothalamus, meant as a starting point for my PhD students and the students of my former students, my scientifically gifted children and grandchildren. Traditionally the hypothalamus was considered to be a neuroendocrine structure of limited interest to neurologists. In addition, this extremely complex structure, which consists of a large number of very different functional nuclei, was not included in the standard neuropathologic investigation of the human brain. Neuropathologists were trained to cut right through the optic chiasma, thereby destroying the hypothalamus. During the period in which I wrote the monograph, it became clear, however, that the hypothalamus not only regulates hormone levels but also contributes to the memory and attention deficits in the dementias; that a disorder of the orexin/hypocretin system is the cause of narcolepsy; that hypothalamic hamartomas are responsible for gelastic epilepsy; that the subthalamic nucleus is a good target to place depth electrodes in parkinsonian patients; and that the source of cluster headache may be situated in the posterior hypothalamus. Moreover, the hypothalamus appeared to be the basis of many signs and symptoms of disorders situated on the border between neurology and psychiatry, such as depression, eating disorders, aggression, and mental retardation. As a consequence, the hypothalamus became a meeting point for neuroscientists, neurologists and psychiatrists, neuropathologists, endocrinologists, and pediatricians. It was the vision of my friend Professor George Bruyn that my monograph would be a starting point for a new (third) series of the Handbook of Clinical Neurology (HCN). The monography was published in two HCN volumes, 79 and 80. Together with my fellow series editors Michael J. Aminoff and Franc¸ois Boller and the staff of Elsevier, more than 100 additional volumes in this new series have since been published. The other two series editors have asked me repeatedly to consider a follow-up of my two earlier HCN volumes. Since they were published, there has indeed been great progress in the field, e.g., in deep brain stimulation, molecular biology (including gene and cell therapy, the various omics, transgenic animal models, and generation of hypothalamic neurons from human-induced pluripotent stem cells), molecular genetics, advanced scanning techniques (e.g., functional connectivity of hypothalamic nuclei), central effects of neuropeptides in health and disease, human brain donation, and brain banking (e.g., putative confounding factors for hypothalamic research). Other topics were simply not dealt with in Volumes 79 and 80, such as the history of neuroendocrinology/hypothalamic research, or are absolutely necessary to place the other chapters in perspective, such as microscopic neuroanatomy of the hypothalamus, borders, and markers of nuclei. Only after my friends and excellent colleagues Paul Lucassen, Ruud Buijs, Felix Kreier, and Ahmad Salehi agreed to participate as covolume editors did I feel that we could face this challenge. From the start, the Covid-19 pandemic interfered with the composition of the volumes. We are very grateful for the authors that managed to deliver their chapters, in spite of the often extremely difficult circumstances. We are also grateful for the continuous and essential help and support of Michael J. Aminoff and Franc¸ois Boller and Michael Parkinson during the entire process. The new volumes are again subdivided into a basic part (The Nuclei of the Hypothalamus) and a clinical part (Neuropathology, Neuropsychiatric disorders), but now as multiauthored volumes, consisting of in-depth reviews of topics that were novel, had progressed markedly since the earlier volumes, or needed to be reviewed in a critical way. Because of the large number of crucial topics, four volumes emerged. They are in many aspects still complementary to HCN volumes 79 and 80, as is indicated later.

The hypothalamus: Arbitrary borders The exact borders of the hypothalamus are rather arbitrary and the exact terminology has often been controversial (see HCN volume 79 for references and details). As stated by Crosby et al. (1962): Nomenclature is man-made; there is

x

PREFACE

strictly speaking no correct and no incorrect way of designating nuclear groups of a region, except as certain names are sanctioned by usage. The borders are generally considered to be: rostrally, the lamina terminalis, and caudally, the plane through the posterior edge of the mamillary body or mamillothalamic tract or the bundle of Vicq d’Azyr. The hypothalamic sulcus is generally looked upon as the dorsal border. However, the paraventricular nucleus is often found partially dorsally of the hypothalamic sulcus. Cells do not respect hypothalamic boundaries. The anterior commissure has also been mentioned as a dorsal border of the hypothalamus, but this structure might penetrate the third ventricle on different levels and the central nucleus of the bed nucleus of the stria terminalis is partly situated dorsally and partly ventrally of the anterior commissure. The ventral border of the hypothalamus includes the floor of the third ventricle that blends into the infundibulum of the neurohypophysis. The exact location of the lateral boundaries, i.e., the nucleus basalis of Meynert, striatum/nucleus accumbens, amygdala, the posterior limb of the internal capsule and basis pedunculi, and, more caudodorsally, the border of the subthalamic nucleus is not a matter of clear-cut certainty either. Finally, there is great variability: no two hypothalami are alike as Gr€ unthal remarked earlier (1950). Since I (DFS) founded the Netherlands Brain Bank in 1985, the brain has been dissected fresh in more than 100 pieces along anatomical borders. The Netherlands Brain Bank has provided more than 100,000 clinically and neuropathologically well-characterized brain samples from more than 4500 rapid autopsies to research projects in 25 countries. My own main interest was the hypothalamus. Because of this personal focus and the delineation problems mentioned previously, we did not deal with the question of which structure does or does not belong to the hypothalamus sensu stricto or sensu lato based on their embryology or adult hypothalamic borders. The way we dissected the hypothalamus en bloc during an autopsy (Fig. 1)

Fig. 1. A block of tissue (frontal cut) containing the hypothalamus and adjacent structures; OC, optic chiasm; OVLT, organum vasculosum lamina terminalis (note that the third ventricle is shining through the thin lamina terminalis); ac, anterior commissure, on top of which the septum with the fornix at both sides is located. The lateral ventricles containing plexus choroids are present and both sides of the septum and under the CC, corpus callosum.

PREFACE

xi

resulted in a hypothalamus and surrounding structures that are also included for pragmatic reasons in these volumes and provides a basis for neurobiological and neuropathological research of this brain region. This means that we include in these HCN volumes structures that are not traditionally considered to be components of the hypothalamus but are surrounding and often strongly interconnected to the core hypothalamic nuclei. An example is the basal cholinergic nuclei that are included in spite of the fact that the diagonal band of Broca and the nucleus basalis of Meynert are telencephalic. In addition, the bed nucleus of the stria terminalis is included, although it is only partly localized below the anterior commissure. Others introduce the concept of a wider hypothalamic region that includes parts of the former mesencephalic ventral thalamus such as the zona incerta and the subthalamic nucleus, based upon the fact that these structures have few common anatomic and developmental features with the thalamus. Moreover, the preoptic area that originates from the telencephalon is included since it has an intimate relationship with the anterior and other portions of the hypothalamus, with which it forms a functional unit. Dick F. Swaab Ruud M. Buijs Paul J. Lucassen Ahmad Salehi Felix Kreier

REFERENCES Crosby EC, Humphrey T, Lauer EW (1962). Correlative Anatomy of the Nervous System. MacMillan, NY, 310. Gr€ unthal E (1950). In: WR Hess (Ed.), Symposion €uber das Zwischenhirn. Helv Physiol Pharm Acta. Suppl VI: 1–80.

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Contributors

N.C. Adams Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, United States

Instituto de Investigaciones Biom
edicas, Universidad Nacional Autónoma de M
exico (UNAM), Ciudad de M
exico, Mexico

S.L. Asa Department of Pathology, Case Western University and University Hospitals, Cleveland, OH, United States; Department of Pathology, University Health Network, Toronto, ON, Canada

D. Cai Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States

S. Bacigaluppi Department of Neurosurgery, E.O. Ospedali Galliera, Genova, Italy A.-M. Bao Department of Neurobiology and Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine; NHC and CAMS Key Laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, China A. Bernal Department of Psychobiology, and Mind, Brain and Behavior Research Center, University of Granada, Granada, Spain A. Bianchi Pituitary Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy E.G. Bochukova Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom N.L. Bragazzi Laboratory for Industrial and Applied Mathematics, Department of Mathematics and Statistics, York University, Toronto, ON, Canada R.M. Buijs Hypothalamic Integration Mechanisms Laboratory, Department of Cellular Biology and Physiology,

Z. Cardona Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States S. Chiloiro Pituitary Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy S. Cudlip Department of Neurosurgery, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom L. De Marinis Pituitary Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy R. de Souza Santos Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles; Cedars-Sinai Biomanufacturing Center, West Hollywood, CA, United States G. Diene Centre de R
ef
erence du Syndrome de Prader-Willi, H^opital des Enfants, CHU Toulouse, Toulouse, France Y. Eisenberg Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States J. Epelbaum UMR 7179 CNRS/MNHN, Brunoy, France

xiv CONTRIBUTORS S. Ezzat A.R. Isles Department of Medicine, University Health Network, Neuroscience and Mental Health Research Institute, University of Toronto, Toronto, ON, Canada School of Medicine, Cardiff University, Cardiff, United Kingdom I.S. Farooqi J. Jayamohan Wellcome–MRC Institute of Metabolic Science, Department of Neurosurgery, Oxford University University of Cambridge, Cambridge, United Kingdom Hospitals NHS Foundation Trust, Oxford, T.P. Farrell United Kingdom Division of Neuroradiology, Thomas Jefferson G. Kaltsas University Hospital, Philadelphia, PA, United States Endocrinology Unit, First Department of Propaedeutic M. Ganau and Internal Medicine, National and Kapodistrian Department of Neurosurgery, Oxford University Universtiy of Athens, Medical School, LAIKO General Hospitals NHS Foundation Trust, Oxford, Hospital of Athens; Department of Medical Research, United Kingdom LCH Adult Clinic, Hellenic Air Force and VA General Hospital, Athens, Greece A. Giampietro Pituitary Unit, Fondazione Policlinico Universitario K. Kamperis A. Gemelli IRCCS, Università Cattolica del Sacro Department of Paediatrics and Adolescent Medicine, Cuore, Rome, Italy Aarhus University Hospital, Aarhus, Denmark S.M. Gold Department of Psychiatry and Medical Department, Campus Benjamin Franklin, Charit
e— Universit€atsmedizin Berlin, Berlin; Institute for Neuroimmunology and Multiple Sclerosis, Universit€atsklinikum Hamburg-Eppendorf, Hamburg, Germany

F. Kelestimur Department of Endocrinology, Yeditepe University, _ Istanbul, Turkey

C.H. Gravholt Department of Molecular Medicine; Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark

B.R. Kornum Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark

A.R Gross Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles; Cedars-Sinai Biomanufacturing Center, West Hollywood, CA, United States A.J. Holland Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom I. Huitinga Department of Neuroimmunology, Netherlands Institute for Neuroscience; Brain Plasticity Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands R. Iorio Neurology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, and Università Cattolica del Sacro Cuore, Rome, Italy

S. Khor Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States

V. Kothari Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States F. Kreier Department Pediatrics, OLVG Hospitals, Amsterdam, The Netherlands S. Looby Department of Neuroradiology, Beaumont Hospital, Dublin, Ireland P.J. Lucassen Brain Plasticity Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands J. Mahía Department of Psychobiology, and Mind, Brain and Behavior Research Center, University of Granada, Granada, Spain

CONTRIBUTORS xv N. Makita Center, West Hollywood; Department of Biomedical Department of Nephrology and Endocrinology, Sciences, Cedars-Sinai Medical Center, Los Angeles; Graduate School of Medicine, University of Tokyo, iPSC Core, David and Janet Polak Foundation Stem Cell Tokyo, Japan Core Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, United States K. Manaka I. Sataite Department of Nephrology and Endocrinology, Department of Neurosurgery, Oxford University Graduate School of Medicine, University of Tokyo, Hospitals NHS Foundation Trust, Oxford, Tokyo, Japan United Kingdom J. Melief J. Sato Department of Oncology-Pathology, Karolinska Department of Nephrology and Endocrinology, Institute, Stockholm, Sweden Graduate School of Medicine, University of Tokyo, C. Papi Tokyo, Japan Neurology Unit, Fondazione Policlinico Universitario W.A. Scherbaum A. Gemelli IRCCS, and Università Cattolica del Sacro Department of Endocrinology, Heinrich-HeineCuore, Rome, Italy University, Duesseldorf, Germany J.M. Pascual A. Skakkebæk Department of Neurosurgery, La Princesa University Department of Molecular Medicine; Department of Hospital, Madrid, Spain Clinical Genetics, Aarhus University Hospital, Aarhus, T.M. Plant Denmark Department of Obstetrics, Gynecology and D.F. Swaab Reproductive Sciences, University of Pittsburgh, Department Neuropsychiatric Disorders, Netherlands Pittsburgh, PA, United States Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, R. Prieto The Netherlands Department of Neurosurgery, Puerta de Hierro University Hospital, Madrid, Spain G. Tamma Department of Biosciences, Biotechnologies, and N. Ramoz Biopharmaceutics, University of Bari, Bari, Italy INSERM U1266, Paris, France C. Robba Anaesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Genova, Italy G.L. Robertson Department of Medicine, Northwestern University School of Medicine, Chicago, IL, United States M. Rosdolsky Independent Medical Translator, Jenkintown, PA, United States A. Salehi Department of Psychiatry and Behavioral Sciences, Stanford Medical School, Palo Alto, CA, United States D. Sareen Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles; Cedars-Sinai Biomanufacturing

T. Tartaglione Department of Radiology and Diagnostic Imaging, Istituto Dermatopatico dell’Immacolata IRCCS; Institute of Radiology, Catholic University of the Sacred Heart, Rome, Italy M. Tauber Centre de R
ef
erence du Syndrome de Prader-Willi, H^opital des Enfants, CHU Toulouse, Toulouse, France V. Tolle INSERM U1266, Paris, France M. Tsoli Endocrinology Unit, First Department of Propaedeutic and Internal Medicine, National and Kapodistrian Universtiy of Athens, Medical School, LAIKO General Hospital of Athens; Department of Medical Research, LCH Adult Clinic, Hellenic Air Force and VA General Hospital, Athens, Greece

xvi

CONTRIBUTORS

G. Valenti Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, Bari, Italy A.M. van Opstal Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands A. Voutetakis Department of Pediatrics, School of Medicine, Democritus University of Thrace, Alexandroupolis, Thrace, Greece

S.F. Witchel Pediatric Endocrinology, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States S.E.C. Wolff Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands

M. Wallentin Center of Functionally Integrative Neuroscience, Aarhus University Hospital; Center for Semiotics, Aarhus University, Aarhus, Denmark

M.P. Yavropoulou Endocrinology Unit, First Department of Propaedeutic and Internal Medicine, National and Kapodistrian Universtiy of Athens, Medical School, LAIKO General Hospital of Athens; Department of Medical Research, LCH Adult Clinic, Hellenic Air Force and VA General Hospital, Athens, Greece

J.E. Whittington Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom

S. Zahova Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom

Contents Foreword vii Preface ix Contributors xiii 1. Introduction: The human hypothalamus and neuroendocrine disorders D.F. Swaab, R.M. Buijs, P.J. Lucassen, A. Salehi, and F. Kreier (Amsterdam, The Netherlands, Ciudad de Mexico, Mexico and Palo Alto, United States) SECTION 15

1

Structural disorders of the hypothalamo-pituitary region

2. Pituitary stalk interruption syndrome A. Voutetakis (Thrace, Greece)

9

3. Empty sella syndrome: Multiple endocrine disorders S. Chiloiro, A. Giampietro, A. Bianchi, and L. De Marinis (Rome, Italy)

29

4. Pituitary dysfunction after aneurysmal subarachnoidal hemorrhage S. Bacigaluppi, C. Robba, and N.L. Bragazzi (Genova, Italy and Toronto, Canada)

41

5. Septo-optic dysplasia I. Sataite, S. Cudlip, J. Jayamohan, and M. Ganau (Oxford, United Kingdom)

51

SECTION 16

Tumors of the hypothalamus

6. Hypothalamic hormone-producing tumors S.L. Asa and S. Ezzat (Cleveland, United States and Toronto, Canada)

67

7. Craniopharyngiomas primarily affecting the hypothalamus J.M. Pascual, R. Prieto, and M. Rosdolsky (Madrid, Spain and Jenkintown, United States)

75

SECTION 17

Neuroimmunological disorders

8. The stress-axis in multiple sclerosis: Clinical, cellular, and molecular aspects J. Melief, I. Huitinga, and S.M. Gold (Stockholm, Sweden, Amsterdam, The Netherlands and Berlin and Hamburg, Germany)

119

9. Neuroendocrine manifestations of Langerhans cell histiocytosis M.P. Yavropoulou, M. Tsoli, and G. Kaltsas (Athens, Greece)

127

10. Neuroendocrine manifestations of Erdheim–Chester disease K. Manaka, J. Sato, and N. Makita (Tokyo, Japan)

137

11. Hypothalamitis and pituitary atrophy S. Chiloiro, T. Tartaglione, A. Giampietro, and A. Bianchi (Rome, Italy)

149

xviii

CONTENTS

12. Narcolepsy Type I as an autoimmune disorder B.R. Kornum (Copenhagen, Denmark)

161

13. Neuromyelitis optica, aquaporin-4 antibodies, and neuroendocrine disorders R. Iorio and C. Papi (Rome, Italy)

173

14. Antibodies against the pituitary and hypothalamus in boxers F. Kelestimur (İstanbul, Turkey)

187

15. Autoimmune diabetes insipidus W.A. Scherbaum (Duesseldorf, Germany)

193

SECTION 18

Drinking disorders

16. Neuroimaging of central diabetes insipidus T.P. Farrell, N.C. Adams, and S. Looby (Philadelphia, United States and Dublin, Ireland)

207

17. Differential diagnosis of familial diabetes insipidus G.L. Robertson (Chicago, United States)

239

18. The vasopressin–aquaporin-2 pathway syndromes G. Valenti and G. Tamma (Bari, Italy)

249

19. Adipsic diabetes insipidus V. Kothari, Z. Cardona, and Y. Eisenberg (Chicago, United States)

261

20. Animal models for diabetes insipidus J. Mahía and A. Bernal (Granada, Spain)

275

21. Nocturnal enuresis in children: The role of arginine–vasopressin K. Kamperis (Aarhus, Denmark)

289

SECTION 19

Eating disorders

22. Monogenic human obesity syndromes I.S. Farooqi (Cambridge, United Kingdom)

301

23. Hypothalamic microinflammation D. Cai and S. Khor (Bronx, United States)

311

24. Glucose and fat sensing in the human hypothalamus A.M. van Opstal (Leiden, The Netherlands)

323

25. Hypothalamus and neuroendocrine diseases: The use of human-induced pluripotent stem cells for disease modeling R. de Souza Santos, A.R Gross, and D. Sareen (Los Angeles and West Hollywood, United States)

337

26. Prader–Willi syndrome: Hormone therapies M. Tauber and G. Diene (Toulouse, France)

351

27. Transcriptomics of the Prader–Willi syndrome hypothalamus E.G. Bochukova (London, United Kingdom)

369

CONTENTS 28. Disorders of hypothalamic function: Insights from Prader–Willi syndrome and the effects of craniopharyngioma J.E. Whittington and A.J. Holland (Cambridge, United Kingdom)

xix 381

29. Animal models for Prader–Willi syndrome S. Zahova and A.R. Isles (Cardiff, United Kingdom)

391

30. Is there a hypothalamic basis for anorexia nervosa? V. Tolle, N. Ramoz, and J. Epelbaum (Paris and Brunoy, France)

405

SECTION 20

Reproduction, olfaction and sexual behavior

31. Sexual differentiation of the human hypothalamus: Relationship to gender identity and sexual orientation D.F. Swaab, S.E.C. Wolff, and A.-M. Bao (Amsterdam, The Netherlands and Hangzhou, China)

427

32. Klinefelter syndrome or testicular dysgenesis: Genetics, endocrinology, and neuropsychology A. Skakkebæk, M. Wallentin, and C.H. Gravholt (Aarhus, Denmark)

445

33. Neurobiology of puberty and its disorders S.F. Witchel and T.M. Plant (Pittsburgh, United States)

463

Index

497

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Contents of related volumes Volume 179 (The Human Hypothalamus: Anterior Region) Volume 180 (The Human Hypothalamus: Middle and Posterior Region) Volume 182 (The Human Hypothalamus: Neuropsychiatric Disorders)

Contents of Volume 179 Foreword vii Preface ix Contributors xiii SECTION 1

Introduction

1. Introduction: The anterior hypothalamus D.F. Swaab, R.M. Buijs, F. Kreier, P.J. Lucassen, and A. Salehi (Amsterdam, The Netherlands, Ciudad de M
exico, Mexico and Palo Alto, United States)

3

2. History of hypothalamic research: “The spring of primitive existence” F. Kreier and D.F. Swaab (Amsterdam, The Netherlands)

7

3. Anatomy and cytoarchitectonics of the human hypothalamus B. Dudás (Erie, United States and Szeged, Hungary)

45

4. Morphology and distribution of hypothalamic peptidergic systems B. Dudás and I. Merchenthaler (Erie and Baltimore, United States and Szeged, Hungary)

67

5. MRI maps, segregation, and white matter connectivity of the human hypothalamus in health J.-J. Lemaire and A. De Salles (Clermont-Ferrand, France, Los Angeles, United States and São Paulo, Brazil)

87

6. Magnetic resonance imaging of the hypothalamo–pituitary region M. Perosevic, P.S. Jones, and N.A. Tritos (Boston, United States)

95

7. Resting-state functional connectivity of the human hypothalamus S. Kullmann and R. Veit (T€ ubingen and Neuherberg, Germany)

113

8. Neurogenesis in the adult hypothalamus: A distinct form of structural plasticity involved in metabolic and circadian regulation, with potential relevance for human pathophysiology 125 A. Sharif, C.P. Fitzsimons, and P.J. Lucassen (Lille, France and Amsterdam, The Netherlands) 9. Matching of the postmortem hypothalamus from patients and controls D.F. Swaab and A.-M. Bao (Amsterdam, The Netherlands and Hangzhou, China)

141

xxii SECTION 2

CONTENTS OF RELATED VOLUMES CONTINUED The basal forebrain cholinergic system

10. Spatial topography of the basal forebrain cholinergic projections: Organization and vulnerability to degeneration T.W. Schmitz and L. Zaborszky (London, Canada and Newark, United States)

159

11. The diagonal band of Broca in health and disease A.K.L. Liu and S.M. Gentleman (London, United Kingdom)

175

12. Nucleus basalis of Meynert degeneration predicts cognitive impairment in Parkinson's disease H. Wilson, E.R. de Natale, and M. Politis (London, United Kingdom)

189

13. Enlargement of early endosomes and traffic jam in basal forebrain cholinergic neurons in Alzheimer's disease A. Fahimi, M. Noroozi, and A. Salehi (Los Angeles and Palo Alto, United States) 14. Gene and cell therapy for the nucleus basalis of Meynert with NGF in Alzheimer's disease M. Eriksdotter and S. Mitra (Stockholm and Huddinge, Sweden) SECTION 3

207

219

The circadian system

15. The circadian system: From clocks to physiology R.M. Buijs, E.C. Soto Tinoco, G. Hurtado Alvarado, and C. Escobar (Ciudad de M
exico, Mexico)

233

16. Development of the circadian system and relevance of periodic signals for neonatal development C. Escobar, A. Rojas-Granados, and M. Angeles-Castellanos (Ciudad de M
exico, Mexico)

249

17. Disrupted circadian rhythms and mental health W.H. Walker II, J.C. Walton, and R.J. Nelson (Morgantown, United States)

259

18. Diurnal and seasonal molecular rhythms in the human brain and their relation to Alzheimer disease 271 A.S.P. Lim (Toronto, Canada) 19. Circadian changes in Alzheimer's disease: Neurobiology, clinical problems, and therapeutic opportunities K. Toljan and J. Homolak (Cleveland, United States and Zagreb, Croatia)

285

20. The circadian system in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy K. Fifel and T. De Boer (Ibaraki, Japan and Leiden, The Netherlands)

301

21. Retina and melanopsin neurons C. La Morgia, V. Carelli, and A.A. Sadun (Bologna, Italy and Los Angeles, United States)

315

22. Melatonin and the circadian system: Keys for health with a focus on sleep P. Pevet, E. Challet, and M.-P. Felder-Schmittbuhl (Strasbourg, France)

331

23. Melatonin receptors, brain functions, and therapies A. Oishi, F. Gbahou, and R. Jockers (Paris, France)

345

24. Chronotherapy D.P. Cardinali, G.M. Brown, and S.R. Pandi-Perumal (Buenos Aires, Argentina and Toronto, Canada)

357

CONTENTS OF RELATED VOLUMES CONTINUED 25. The use of melatonin to mitigate the adverse metabolic side effects of antipsychotics F. Romo-Nava, R.M. Buijs, and S.L. McElroy (Mason and Cincinnati, United States and Ciudad de M
exico, Mexico) SECTION 4

xxiii 371

Bed nucleus of the stria terminalis and the fear circuit

26. Chemoarchitecture of the bed nucleus of the stria terminalis: Neurophenotypic diversity and function S.E. Hammack, K.M. Braas, and V. May (Burlington, United States)

385

27. Functional anatomy of the bed nucleus of the stria terminalis–hypothalamus neural circuitry: Implications for valence surveillance, addiction, feeding, and social behaviors I. Maita, A. Bazer, J.U. Blackford, and B.A. Samuels (Piscataway and Nashville, United States)

403

28. Roles of the bed nucleus of the stria terminalis and amygdala in fear reactions A.M. Hulsman, D. Terburg, K. Roelofs, and F. Klumpers (Nijmegen and Utrecht, The Netherlands and Cape Town, South Africa) SECTION 5

419

Preoptic area

29. The median preoptic nucleus: A major regulator of fluid, temperature, sleep, and cardiovascular homeostasis M.J. McKinley, G.L. Pennington, and P.J. Ryan (Parkville, Australia) 30. The neuroendocrinology of the preoptic area in menopause: Symptoms and therapeutic strategies M. Modi and W.S. Dhillo (London, United Kingdom)

435

455

31. The intermediate nucleus in humans: Cytoarchitecture, chemoarchitecture, and relation to sleep, sex, and Alzheimer disease C.B. Saper (Boston, United States)

461

Index

471

Contents of Volume 180 Foreword vii Preface ix Contributors xiii 1. Introduction: The middle and posterior hypothalamus D.F. Swaab, F. Kreier, P.J. Lucassen, A. Salehi, and R.M. Buijs (Amsterdam, The Netherlands, Palo Alto, United States and Ciudad de México, Mexico) SECTION 6

1

Supraoptic and paraventricular nucleus more than a neuroendocrine system

2. Vasopressin and oxytocin beyond the pituitary in the human brain M. Møller (Copenhagen, Denmark) 3. Central and peripheral release of oxytocin: Relevance of neuroendocrine and neurotransmitter actions for physiology and behavior F. Althammer, M. Eliava, and V. Grinevich (Atlanta, United States and Mannheim, Germany)

7

25

xxiv

CONTENTS OF RELATED VOLUMES CONTINUED

4. Organization of the neuroendocrine and autonomic hypothalamic paraventricular nucleus A. Kalsbeek and R.M. Buijs (Amsterdam, The Netherlands and Ciudad de M
exico, Mexico)

45

5. Sex differences of oxytocin and vasopressin in social behaviors Q. Lu and S. Hu (Hangzhou, China)

65

6. Oxytocin, eating behavior, and metabolism in humans L. Kerem and E.A. Lawson (Boston, United States)

89

7. The supraoptic and paraventricular nuclei in healthy aging and neurodegeneration C.A. Stewart and E.C. Finger (London, Canada)

105

8. Perinatal stress and epigenetics M. Szyf (Montreal, Canada)

125

9. The hypothalamus in anxiety disorders S. Fischer (Zurich, Switzerland)

149

10. Congenital isolated central hypothyroidism: Novel mutations and their functional implications A. Boelen, A.S.P. van Trotsenburg, and E. Fliers (Amsterdam, The Netherlands) SECTION 7

Zona incerta

11. The zona incerta system: Involvement in attention and movement S. Chometton, M. Barbier, and P.-Y. Risold (Los Angeles and New York, United States and Besanc¸on, France) SECTION 8

173

Ventromedial nucleus and dorsomedial nucleus

12. The role of the dorsomedial and ventromedial hypothalamus in regulating behaviorally coupled and resting autonomic drive L.A. Henderson and V.G. Macefield (Sydney and Melbourne, Australia) SECTION 9

161

187

Circumventricular organs of the hypothalamus

13. The subfornical organ and organum vasculosum of the lamina terminalis: Critical roles in cardiovascular regulation and the control of fluid balance W.M. Fry and A.V. Ferguson (Winnipeg and Kingston, Canada)

203

14. Lamina terminalis fenestration: An important neurosurgical corridor C. Giussani and A. Di Cristofori (Milan and Monza, Italy)

217

15. Arcuate nucleus, median eminence, and hypophysial pars tuberalis H.-W. Korf and M. Møller (D€ usseldorf, Germany and Copenhagen, Denmark)

227

16. Tanycytes in the infundibular nucleus and median eminence and their role in the blood–brain barrier 253 V. Prevot, R. Nogueiras, and M. Schwaninger (Lille, France, Santiago de Compostela, Spain and L€ ubeck, Germany) 17. The human hypothalamic kisspeptin system: Functional neuroanatomy and clinical perspectives
Rumpler, and K. Skrapits (Budapest, Hungary) E. Hrabovszky, S. Takács, E.

275

CONTENTS OF RELATED VOLUMES CONTINUED 18. Kisspeptin and neurokinin B expression in the human hypothalamus: Relation to reproduction and gender identity J. Bakker (Liège, Belgium)

xxv 297

19. The infundibular peptidergic neurons and glia cells in overeating, obesity, and diabetes M.J.T. Kalsbeek and C.-X. Yi (Amsterdam, The Netherlands)

315

20. Hypothalamus and weight loss in amyotrophic lateral sclerosis R.M. Ahmed, F. Steyn, and L. Dupuis (Sydney and Brisbane, Australia and Strasbourg, France)

327

SECTION 10

Lateral tuberal nucleus

SECTION 11

Lateral hypothalamic area, perifornical area

21. The orexin/hypocretin system in neuropsychiatric disorders: Relation to signs and symptoms R. Fronczek, M. Schinkelshoek, L. Shan, and G.J. Lammers (Leiden, Heemstede and Amsterdam, The Netherlands)

343

22. Pleasure, addiction, and hypocretin (orexin) R. McGregor, T.C. Thannickal, and J.M. Siegel (Los Angeles, United States)

359

SECTION 12

Tuberomamillary complex

23. Histamine receptors, agonists, and antagonists in health and disease P. Panula (Helsinki, Finland)

377

24. The tuberomamillary nucleus in neuropsychiatric disorders L. Shan, R. Fronczek, G.J. Lammers, and D.F. Swaab (Leiden, Heemstede and Amsterdam, The Netherlands)

389

SECTION 13

Subthalamic nucleus

25. Imaging of the human subthalamic nucleus A. Alkemade and B.U. Forstmann (Amsterdam, The Netherlands)

403

26. Neuropsychiatric effects of subthalamic deep brain stimulation P.E. Mosley and H. Akram (Brisbane, Australia and London, United Kingdom)

417

27. The subthalamic nucleus and the placebo effect in Parkinson's disease E. Frisaldi, D.A. Zamfira, and F. Benedetti (Turin, Italy and Plateau Rosà, Switzerland)

433

SECTION 14

Corpora mamillaria, fornix, and mamillothalamic tract

28. Electrical stimulation of the fornix for the treatment of brain diseases S. Hescham and Y. Temel (Maastricht, The Netherlands) 29. The contribution of mamillary body damage to Wernicke's encephalopathy and Korsakoff's syndrome N.J.M. Arts, A.-L. Pitel, and R.P.C. Kessels (Venray, Wolfheze, and Nijmegen, The Netherlands and Caen and Paris, France) Index

447

455

477

xxvi

CONTENTS OF RELATED VOLUMES CONTINUED

Contents of Volume 182 Foreword vii Preface ix Contributors xiii 1. Introduction: The human hypothalamus and neuropsychiatric disorders D.F. Swaab, R.M. Buijs, F. Kreier, P.J. Lucassen, and A. Salehi (Amsterdam, The Netherlands, Ciudad de M
exico, Mexico and Palo Alto, United States) SECTION 21

Trauma and iatrogenic disorders

2. Chronic traumatic encephalopathy and the nucleus basalis of Meynert E.J. Mufson, C. Kelley, and S.E. Perez (Phoenix, United States) SECTION 22

1

9

Neurobehavioral disorders

3. Hypothalamic stress systems in mood disorders F. Holsboer and M. Ising (Munich, Germany)

33

4. Light therapy for mood disorders B. Bais, W.J.G. Hoogendijk, and M.P. Lambregtse-van den Berg (Rotterdam, The Netherlands)

49

5. Neurobiology of peripartum mental illness J.L. Pawluski, J.E. Swain, and J.S. Lonstein (Rennes, France and Stony Brook and East Lansing, United States)

63

6. The hypothalamo–pituitary–adrenal axis and the autonomic nervous system in burnout A. Sj€ ors Dahlman, I.H. Jonsdottir, and C. Hansson (Gothenburg, Sweden)

83

7. Posterior hypothalamus as a target in the treatment of aggression: From lesioning to deep brain stimulation M. Rizzi, O. Gambini, and C.E. Marras (Milan and Rome, Italy) 8. The implications of hypothalamic abnormalities for schizophrenia H.-G. Bernstein, G. Keilhoff, and J. Steiner (Magdeburg, Germany) 9. The promiscuity of the oxytocin–vasopressin systems and their involvement in autism spectrum disorder A.M. Borie, C. Theofanopoulou, and E. Andari (Atlanta, New York, and Toledo, United States) SECTION 23

95

107

121

Epilepsy

10. Gelastic seizures and the hypothalamic hamartoma syndrome: Epileptogenesis beyond the lesion? J. Scholly and F. Bartolomei (Marseille, France)

143

11. The interactions between reproductive hormones and epilepsy E. Taubøll, J.I.T. Isoj€ arvi, and A.G. Herzog (Oslo, Norway, Oulu, Finland and Boston, United States)

155

SECTION 24

Neurodegenerative disorders

12. Alternative splicing in aging and Alzheimer's disease: Highlighting the role of tau and estrogen receptor a isoforms in the hypothalamus T.A. Ishunina (Kursk, Russia)

177

CONTENTS OF RELATED VOLUMES CONTINUED 13. Cholinergic neurodegeneration in Alzheimer disease mouse models A. Shekari and M. Fahnestock (Hamilton, Canada)

xxvii 191

14. Autonomic disorders in Parkinson disease: Disrupted hypothalamic connectivity as revealed from resting-state functional magnetic resonance imaging E. Dayan and M. Sklerov (Chapel Hill, United States)

211

15. Hypothalamic a-synuclein and its relation to autonomic symptoms and neuroendocrine abnormalities in Parkinson disease E. De Pablo-Fernández and T.T. Warner (London, United Kingdom)

223

16. Lewy bodies in the olfactory system and the hypothalamus 235 M.G. Cersosimo, E.E. Benarroch, and G.B. Raina (Buenos Aires, Argentina and Rochester, United States) 17. Hypothalamic pathology in Huntington disease D.J. van Wamelen and N.A. Aziz (London, United Kingdom, Nijmegen, The Netherlands and Bonn, Germany)

245

18. Endocrine dysfunction in adrenoleukodystrophy M. Engelen, S. Kemp, and F. Eichler (Amsterdam, The Netherlands and Boston, United States)

257

19. Hypothalamic symptoms of frontotemporal dementia disorders R.M. Ahmed, G. Halliday, and J.R. Hodges (Sydney, Australia)

269

SECTION 25

Olfactory system

20. The vomeronasal organ: History, development, morphology, and functional neuroanatomy G.S. Stoyanov, N.R. Sapundzhiev, and A.B. Tonchev (Varna, Bulgaria)

283

21. Pheromone effects on the human hypothalamus in relation to sexual orientation and gender Y. Ye, Z. Lu, and W. Zhou (Beijing and Shenzhen, China)

293

22. Kallmann syndrome and idiopathic hypogonadotropic hypogonadism: The role of semaphorin signaling on GnRH neurons A. Cariboni and R. Balasubramanian (Milan, Italy and Boston, United States) 23. Olfaction as an early marker of Parkinson's disease and Alzheimer's disease I.M. Walker, M.E. Fullard, J.F. Morley, and J.E. Duda (Philadelphia and Aurora, United States) SECTION 26

307

317

Autonomic and sleep disorders

24. The hypothalamus and its role in hypertension V.D. Goncharuk (Moscow, Russia and Amsterdam, The Netherlands)

333

25. The heart is lost without the hypothalamus S. Pyner (Durham, United Kingdom)

355

26. Sleep disorders and the hypothalamus S. Overeem, R.R.L. van Litsenburg, and P.J. Reading (Heeze, Eindhoven, Utrecht, and Amsterdam, The Netherlands and Middlesbrough, United Kingdom)

369

xxviii SECTION 27

CONTENTS OF RELATED VOLUMES CONTINUED Addiction and pain

27. Molecular genetics of neurotransmitters and neuropeptides involved in Internet use disorders including first insights on a potential role of hypothalamus’ oxytocin hormone C. Sindermann, R. Sariyska, J.D. Elhai, and C. Montag (Ulm, Germany and Toledo, United States) 28. The neurobiology of cluster headache M. Leone, S. Ferraro, and A.P. Cecchini (Milan, Italy) SECTION 28

389

401

Critical care and brain-death

29. Endocrine interventions in the intensive care unit A. T
eblick, L. Langouche, and G. Van den Berghe (Leuven, Belgium)

417

30. Hypothalamic function in patients diagnosed as brain dead and its practical consequences M. Nair-Collins and A.R. Joffe (Tallahassee, United States and Edmonton, Canada)

433

Index

447

Handbook of Clinical Neurology, Vol. 181 (3rd series) The Human Hypothalamus: Neuroendocrine Disorders D.F. Swaab, R.M. Buijs, P.J. Lucassen, A. Salehi, and F. Kreier, Editors https://doi.org/10.1016/B978-0-12-820683-6.00001-4 Copyright © 2021 Elsevier B.V. All rights reserved

Chapter 1

Introduction: The human hypothalamus and neuroendocrine disorders DICK F. SWAAB1*, RUUD M. BUIJS2, PAUL J. LUCASSEN3, AHMAD SALEHI4, AND FELIX KREIER5 1

Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands

2

Hypothalamic Integration Mechanisms Laboratory, Department of Cellular Biology and Physiology, Instituto de Investigaciones Biom
edicas, Universidad Nacional Autónoma de M
exico (UNAM), Ciudad de M
exico, Mexico 3

Brain Plasticity Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands 4

Department of Psychiatry and Behavioral Sciences, Stanford Medical School, Palo Alto, CA, United States 5

Department Pediatrics, OLVG Hospitals, Amsterdam, The Netherlands

SECTION 15#: STRUCTURAL DISORDERS OF THE HYPOTHALAMO–PITUITARY REGION Pituitary stalk interruption syndrome (PSIS) is identified by MRI and characterized by a thin, interrupted, attenuated, or absent pituitary stalk, hypoplasia or aplasia of the adenohypophysis, and an ectopic posterior pituitary. Recently a wide variety of PSIS-associated candidate genes were found, mostly related to the Wnt, Notch, and Shh signaling pathways that regulate pituitary growth and development during embryogenesis. A multigenic origin and inheritance pattern of PSIS is presumed. PSIS is currently viewed as a mild form of an expanded holoprosencephaly spectrum. The clinical manifestations include pituitary hormone deficiencies. Most patients are referred later in childhood for growth retardation. Empty sella is a pituitary disorder characterized by the herniation of the subarachnoid space in the sella turcica and a variable degree of flattening of the pituitary gland. Primary empty sella is an idiopathic disease that may be associated with idiopathic intracranial hypertension. Secondary empty sella instead is due to pituitary disorders. Empty sella is in the majority of cases only a neuroradiological

finding, without clinical implications. However, in the empty sella syndrome may be accompanied by pituitary hormonal dysfunction and/or neurological symptoms and should be managed by a multidisciplinary approach. Vascular supply and vascular disorders of the hypothalamus and pituitary are discussed in Swaab (2004, Chapter 17). Neuroendocrine dysfunction has a high prevalence in aneurysmal subarachnoid hemorrhage patients. Septooptic dysplasia or de Morsier’s syndrome is characterized by a classic triad of optic nerve hypoplasia, agenesis of septum pellucidum and corpus callosum, and hypoplasia of the hypothalamic–pituitary axis. It is caused by a combination of prenatal exposure to environmental factors while genetic predisposition plays a major role. Typically, these patients may show abnormalities of the hypothalamo-neurohypophysial system and other hypothalamic nuclei (see Swaab, 2004, Chapter 18 section 3 for a case description). Many aspects of this syndrome can be improved through a tailored multidisciplinary approach consisting in hormonal replacement, corrective ophthalmological surgery, management of epileptic seizures, and active neuropsychological support.

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Continued from the previous volume.

*Correspondence to: Prof. Dr. Dick F. Swaab, Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. Tel: +31-20-566-5500, Fax: +31-20-566-6121, E-mail: [email protected]

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D.F. SWAAB ET AL. For anencephaly, optic nerve hypoplasia, optic chineurons and the number of active MS lesions in the asm disorders, growth hormone disorders, Noonan synhypothalamus. drome, hydrocephalus, and cavum septum pellucidum, Langerhans cell histiocytosis is an inflammatory see Swaab (2004, Chapter 18). myeloid neoplasia that affects the hypothalamus in approximately 40% of the cases. This results in deficienSECTION 16: TUMORS OF cies in both anterior and posterior pituitary function, THE HYPOTHALAMUS including central diabetes insipidus (CDI). In the majority of cases, these deficiencies are permanent and require Patients with hypothalamic endocrine tumors suffer specific hormone replacement regimes. mass effects including headaches, visual disturbances, Erdheim–Chester disease (ECD) is a non-Langerhans and endocrine dysfunction due to structural damage to form of histiocytosis with multisystemic infiltration. The hypothalamic nuclei, which regulate appetite, temperainvolvement of hypothalamo–pituitary axis is common ture, diurnal rhythms, and emotions. In addition, these and central diabetes insipidus is one of the most common tumors can secrete hormones that may cause acromegaly, endocrine manifestation in ECD. Suprasellar region cushing disease, hyperprolactinemia, or the syndrome of extension, due to infiltration of ECD lesion, can cause inappropriate antidiuresis. Morphologic classification of neurologic manifestations by mass effects, such as headthese tumors shows two classes of tumors, gangliocytoache, visual disturbance, and cranial nerve palsies. In mas that are composed of large neurons and neurocytoaddition, disorders affecting anterior pituitary hormones mas that are comprised of small cells, resembling the are common. Some anterior pituitary dysfunctions such variants of magnocellular and parvocellular neurons in as ACTH and/or TSH deficiencies can be life-threatening the hypothalamic nuclei. Surgery remains the main therwithout adequate hormone supplementation therapies. apy. In patients with acromegaly long-acting somatoHwypothalamitis is an inflammatory disorder involvstatin analogues are used with some success, and ing the hypothalamus. It is considered to be an autoimpeptide receptor radiotherapy may be used for patients mune disorder due to the lymphocytic and plasma cell with residual symptomatic disease. infiltration in the hypothalamic region It is classified as Infundibulo-tuberal craniopharyngiomas (CPs) primary, or isolated, and secondary hypothalamitis. Secdevelop within the infundibulum and tuber cinereum ondary hypothalamitis may occur in patients affected by affecting primarily the hypothalamus. This subgroup of autoimmune diseases such as autoimmune hypophysitis, CPs largely occupies the third ventricle. They cause a systemic autoimmune diseases, infective diseases in wide range of hypothalamic symptoms, such as adiposoimmunocompromised patients, in paraneoplastic encephgenital dystrophy (Babinski–Fr€ ohlich’s syndrome), diaalitis, or in patients treated with immune-check point betes insipidus, abnormal diurnal somnolence, and a inhibitors. The main symptoms may include various complex set of cognitive (dementia-like, Korsakoffdegrees of hypopituitarism, neuropsychiatric, and behavlike), emotional (rage, apathy, depression) and behavioral disorders, and disturbances of autonomic and metaioral (autism-like, psychotic-like) disturbances. The vast bolic regulation. Magnetic resonance images play a majority is of the squamous-papillary type and most of crucial role in the diagnosis of hypothalamitis and in these tumors have extensive and strong gliotic adhesions exclusion of neoplastic lesions. Therapeutic management to the surrounding hypothalamus and are associated with should be oriented according to the disease etiology. In high surgical morbidity and mortality risk. most cases, after ruling out infective hypothalamitis, the For other tumors of the hypothalamus and pineal mainstay of therapy includes immunosuppressive treatgland see Swaab (2004, Chapter 19). ment and hormone replacement therapy. Narcolepsy Type 1 (NT1) is hypothesized to be an autoSECTION 17: NEUROIMMUNOLOGICAL immune disease targeting the hypocretin/orexin neurons in DISORDERS the lateral hypothalamus. However, NT1 does still not fully Altered activity of the hypothalamus–pituitary–adrenal meet all the criteria for being classified as a genuine auto(HPA) stress axis and glucocorticoids have been impliimmune disease. Many autoantibodies have been detected cated in the pathogenesis and progression of multiple in blood samples from NT1 patients, but none in a consissclerosis (MS) and linked to the development of specific tent manner. Importantly, T cells directed toward hypocresymptoms and comorbidities such as mood disorders, tin/orexin neurons have been detected in peripheral samples fatigue or cognitive dysfunction. Overall, the HPA axis from NT1 patients. However, it remains to be seen if these is activated or hyperresponsive in MS, though a hyporepotentially autoreactive T cells are also present in the hyposponsive HPA axis has been observed in a subgroup of thalamus and if they are pathogenic. The autoimmune MS patients that has a more severe course of the disease. hypothesis has led to attempts at slowing or stopping disIn addition, an inverse correlation was found between the ease progression with immunomodulatory treatment, but number of corticotropin-releasing hormone expressing so far the overall results have not been very encouraging.

INTRODUCTION 3 Neuromyelitis optica (NMO) is an autoimmune disorsurgery, and head trauma. Central DI may also be caused der that preferentially affects the optic nerve and the spiby processes affecting the osmoreceptors (adipsic diabenal cord. In around 80% of the patients, autoantibodies tes insipidus (see later), affecting; (ii) impaired renal binding to aquaporin-4 (AQP4) are detected. AQP4effects of AVP (nephrogenic DI, NDI); (iii) reduced IgG unifies a spectrum of disorders (NMOSD) that AVP secretion due to excessive water intake (primary include not only optic neuritis, longitudinally extensive polydipsia); (iv) degradation of AVP by placental vasotransverse myelitis but also syndromes caused by lesion pressinase (gestational DI); and (v) autoimmune DI (see of the diencephalic region and the circumventricular before). Hypothalamic and nephrogenic DI can also be organs in the dorsal hypothalamic area, dorsomedial caused by mutation of the gene that encodes the AVP hypothalamic nucleus, and suprachiasmatic nucleus, prohormone or the AVP-2 receptors in the collecting where AQP4 expression is concentrated. In patients with ducts of the kidney that cause antidiuresis by increasing NMOSD, several inflammatory neuroendocrine disorwater permeability through aquaporin-2 water channel ders have been described, including the syndrome of redistribution to the luminal membrane. Altered AVPinappropriate antidiuresis, sleep disorders, and other aquaporin-2 pathway can be present in some diseases endocrinopathies caused by hypothalamic injury. associated with water balance disorders such as congenThe prevalence of hypopituitarism after traumatic ital nephrogenic diabetes insipidus, syndrome of inapbrain injury (TBI) is about 30%, GH is the most common propriate antidiuretic hormone secretion, nephrogenic hormone lost. The positivity of antipituitary and syndrome of inappropriate antidiuresis, and autosomal antihypothalamic antibodies is a significant risk factor dominant polycystic kidney disease. The pituitary MRI in the development of neuroendocrine abnormalities signal is diminished in both types of familial DI. The after TBI. Autoimmune reaction may be responsible determination of plasma AVP and/or the response to for the reduction in pituitary volume in boxers with desmopressin therapy plus gene sequencing provides hypopituitarism. the best basis for effective management and family Autoimmune central diabetes insipidus is caused by counseling. autoantibodies directed to hypothalamic vasopressinAdipsic diabetes insipidus (ADI) is mostly caused by producing cells. The major autoantigen for autoimmune damage of osmolar-responsive neuroreceptors, localized CDI is rabphilin-3A, a protein of secretory vesicles of the primarily within the supraoptic and paraventricular neurohypophyseal system. The radiological and mornuclei. This results in impaired production and release phological correlate of autoimmune diabetes insipidus of AVP. Patients with central diabetes insipidus with (DI) is lymphocytic infundibulon-eurohypophysitis as impaired thirst response, defined as ADI, suffer from detected by MRI and biopsies that show massive infiltrawide swings of plasma osmolality resulting in repeated tion of the posterior pituitary and the infundibulum with hospitalization, numerous associated comorbidities, lymphocytes and some plasma cells, and fibrosis in the and significant mortality. Acute disease management later stages of the disease. Autoimmune CDI may disapfocuses on fixed dosing of antidiuretic hormone anapear either spontaneously or on treatment with immune logues and calculated prescriptions of obligate daily checkpoint inhibitors. water intake. For neurosarcoidosis of the hypothalamus, see Swaab There are different animal models for DI. The AVP (2004, Chapter 21) and for hypothalamic infections, see mutant (Brattleboro) rat is the principal animal model Swaab (2004, Chapter 20). of hereditary CDI, while neurohypophysectomy, pituitary stalk compression, hypophysectomy, and mediobasal hypothalamic lesions produce acquired CDI. In SECTION 18: DRINKING DISORDERS animals, hereditary nephrogenic DI is mainly caused Arginine–vasopressin (AVP) is synthesized by the hypoby mutations in AVP2R or AQP2 genes, while acquired thalamic supraoptic and paraventricular nuclei and NDI is most frequently induced by lithium. Depending secreted from the posterior pituitary into the bloodstream. on the cause there are different drugs for DI such as AVP binds to AVP receptor 2 (AVPR2) in the kidney AVP analogues and sildenafil, a compound that increase to activate aquaporin channels (AQP2) and so induces the expression and function of AQP2 channels in animal the antidiuretic response. Diabetes insipidus is a syndrome models and humans with NDI. characterized by polydipsia and polyuria. It can be Nocturnal enuresis is the involuntary pass of urine caused by any of five fundamentally different disorders: during sleep beyond the age of 5 years. An excess urine (i) secondary to deficient synthesis or secretion of AVP production during sleep is a common finding in children due to any pathology affecting the hypothalamic supraopwith enuresis, and disturbances in the circadian rhythm tic or paraventricular nuclei, median eminence, infundibof arginine–vasopressin are found in the majority of chilulum, stalk, or the posterior pituitary gland. The most dren with nocturnal polyuria. Children with enuresis and common causes of “central/hypothalamic DI” are tumors, nocturnal polyuria lack the physiologic increase in AVP

4 D.F. SWAAB ET AL. levels during sleep, and treatment with the AVP analogue neurons that are fat specific. Subsequently, fats signal desmopressin can restore this rhythm and lead to dry the long-term metabolic status and energy availability nights. Not all children with enuresis and nocturnal polyin the form of fat storage. Both glucose and fats are also uria can be successfully treated with desmopressin sugsensed indirectly by the hypothalamus via gut-derived gesting that factors beyond renal water handling can be signals that have an anorectic effect. Excessive intake implicated such as natriuresis, hypercalciuria, and sleep of long-chain saturated fatty acids is held responsible disordered breathing. for hypothalamic inflammation, especially when conFor inappropriate secretion of vasopressin and sumed in combination with high levels of refined carboWolfram syndrome, see Swaab (2004, Chapter 22 sechydrates. Diet-induced hypothalamic inflammation, tions 6 and 7, respectively). which leads to hypothalamic dysfunction and a loss of regulation of energy balance, is emerging as a potential driver of obesity. SECTION 19: EATING DISORDERS Human-induced pluripotent stem cells (hiPSCs) are a Neural circuits in the hypothalamus play a key role in the novel model for neuroendocrine disorders that is used regulation of human energy homeostasis. At least 10% of for instance to model extreme obesity in a dish. They are children with severe obesity have rare chromosomal generated by reprogramming adult human somatic cells abnormalities and/or highly penetrant genetic mutations such as skin fibroblasts and peripheral blood mononuclear that drive their obesity. A critical circuit involves leptincells. These hiPSCs can give rise to any desired cell type of responsive neurons in the infundibular nucleus of the body when exposed to specific combinations of small the hypothalamus expressing the appetite-suppressing molecules, transcription factors, and growth factors, which neuropeptide proopiomelanocortin (POMC) and the drive the differentiation of pluripotent stem cells into appetite-stimulating Agouti-related peptide. In the fed defined organ-specific cells. hiPSCs-derived hypothalamic state, the POMC-derived melanocortin peptide a-melaneurons can provide a powerful platform to study obesity nocyte-stimulating hormone stimulates melanocortin-4 and gene–environment interactions in vitro. receptors (MC4Rs) expressed on neurons in the paravenPrader–Willi syndrome (PWS) is due to the lack of tricular nucleus of the hypothalamus. Disruption of this expression of maternally imprinted genes located in hypothalamic circuit by inherited mutations in the genes the chromosomal region 15q11-q13. It is characterized encoding leptin, the leptin receptor, POMC, and MC4R by impaired hypothalamic development and functions can lead to severe obesity in humans. Multiple other including hyperphagia and severe obesity. The endocrine genes have now been found that cause obesity. There dysfunctions involve growth hormone deficiency and are a number of drugs in clinical trials targeted specifihypogonadism, central hypothyroidism, and precocious cally at patients with genetic obesity syndromes, such adrenarche. In addition, the oxytocin and ghrelin systems as Setmelanotide, a MC4R agonist. are impaired resulting in hyperphagia with food addicMicroinflammation is recently appreciated as a core tion, poor social skills, and emotional dysregulation. mechanism involved in the advancement of metabolic Current hormonal replacement treatment is recombinant syndrome and aging. Studies have causally linked these human growth hormone. In addition, oxytocin and oxychanges to activation of proinflammatory pathways tocin analogue treatments are currently investigated as especially NF-kB signaling, which leads to hypothawell as new molecules targeting the ghrelin system. lamic neuronal dysregulation, astrogliosis, microgliosis, Genome-wide gene expression analysis (transcripand loss of adult hypothalamic neural stem/progenitor tomics) confirmed in PWS hypothalamus a decreased cells. Inhibiting hypothalamic microinflammation expression of oxytocin. In addition, it showed that the through targeting proinflammatory signaling pathways marked hypothalamic neurodegeneration and neuronal may be beneficial. loss in PWS may be mediated by reduced expression The hypothalamus can sense glucose and fats trough of the neurotrophin BDNF and its receptor. This raises different pathways. At the blood–brain barrier glucose is the question whether potential interventions at the level bound by glucose transporters and can be sensed by of BDNF/TrkB pathway offer therapeutic options. glucose-excited and glucose-inhibited neurons in the The impact of physical damage due to craniopharynhypothalamus. Subsequently downstream signals will gioma and/or surgery to remove a craniopharyngioma is be sent via the autonomic nervous system to regulate gluquite comparable with the impact resulting from the cose homeostasis, energy homeostasis, and feeding genetic abnormalities associated with Prader–Willi synbehavior accordingly. Free fatty acids cross the blood– drome and both show the functions of the hypothalamus. brain barrier either via diffusion or via fatty acid transloThis comparison holds for hyperphagia and weight gain, case. Fats can be sensed by hypothalamic neurons that low growth hormone levels, low bone density in adults, also sense glucose, but also by distinct populations of hypogonadism, disturbed temperature regulation,

INTRODUCTION disturbed sleep and daytime sleepiness, memory difficulties, and problems with behavior and with peer relationships. Differences between the two conditions include higher ghrelin levels in PWS, complete absence of pituitary hormones in many cases of craniopharyngioma, higher incidence of thyroid dysfunction in craniopharyngioma, “growth without growth hormone” in obese children with craniopharyngioma, different types of diabetes (diabetes insipidus in craniopharyngioma and diabetes mellitus in PWS), and evidence of developmental delay and low IQ in people with PWS. The similarity of the Prader–Willi syndrome genetic interval on chromosome 15q11-q13 in human, with a cluster of genes on mouse chromosome 7, has allowed the development of mouse models for PWS. Some models mimic the loss of all gene expression from the paternally inherited PWS genetic interval, whereas others target smaller regions or individual genes. These models have provided insight into the mechanisms underlying the core symptoms of PWS, including growth retardation, hyperphagia and metabolism, reproductive maturation, and endophenotypes that are relevant for behavioral and psychiatric problems. Anorexia nervosa is a serious disorder characterized by abnormal feeding behavior and food aversion. It is, in addition, characterized by a number of neuroendocrine alterations. However, little is known concerning the possible cause of this hypothalamic disorder. It should be emphasized that human hypothalamus neuropathological studies in the course of anorexia nervosa are strikingly lacking. For bulimia nervosa and the ciliopathies Laurence– Moon/Bardet–Biedl syndrome and Alstr€ om’s syndrome, see Swaab (2003, Chapter 23).

SECTION 20: REPRODUCTION AND SEXUAL BEHAVIOR Gender identity (an individual’s perception of being male or female) and sexual orientation (heterosexuality, homosexuality, or bisexuality) are programmed into our brain during the second half of pregnancy by a testosterone surge that masculinizes the male fetal brain. If such a testosterone surge does not occur, this will result in a feminine brain. Structural and functional differences are present in the hypothalamus, relating to gender

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dysphoria (transsexuality) and sexual orientation. A multitude of mechanisms and factors is involved in sexual differentiation of the brain that are responsible for variation in all aspects of sexual differentiation of the brain and behavior. However, all research supports the neurobiological theory about the intrauterine origin of gender identity and sexual orientation. There is no evidence that one’s postnatal social environment plays a crucial role in the development of these characteristics. Klinefelter syndrome (47,XXY) is often presenting with hypergonadotropic hypogonadism, small, firm testicles, low testosterone level, and high levels of gonadotropins and infertility due to gonadal dysgenesis, metabolic disorders, neurocognitive challenges, and increased height. Neurological disorders such as epilepsy, seizures, and tremor as well as psychiatric disorder are also seen. The neurocognitive deficits are present in many areas of cognition, typically affecting general cognitive abilities, language and executive functioning. In addition, social dysfunction is frequent. Dyslexia is present in more than half of all patients. Recent studies have described pervasive changes in the methylome and the transcriptome. Postmortem hypothalamic alterations have so far not sufficiently been studied. Puberty is characterized by gonadarche, adrenarche, the occurrence of menarche in girls, and voice breaking in boys. Gonadarge is triggered at the level of the hypothalamus by the pulsatile discharge of gonadotropinreleasing hormone (GnRH) into the hypophysial portal circulation. The neurobiological mechanisms underlying the pubertal increase in hypothalamic GnRH release and its timing, the hypothalamic disorders affecting the onset of puberty, and contemporary therapies for their treatment are reviewed.

REFERENCES Swaab DF (2003). The human hypothalamus. basic and clinical aspects. Part I: nuclei of the hypothalamus. In: MJ Aminoff, F Boller, DF Swaab (Eds.), Handbook of clinical neurology. vol. 79. Elsevier, Amsterdam. Swaab DF (2004). The human hypothalamus. basic and clinical aspects. Part II: neuropathology of the hypothalamus and adjacent brain structures. In: MJ Aminoff, F Boller, DF Swaab (Eds.), Handbook of clinical neurology. vol 80. Elsevier, Amsterdam.

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Section 15 Structural disorders of the hypothalamo-pituitary region

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Handbook of Clinical Neurology, Vol. 181 (3rd series) The Human Hypothalamus: Neuroendocrine Disorders D.F. Swaab, R.M. Buijs, P.J. Lucassen, A. Salehi, and F. Kreier, Editors https://doi.org/10.1016/B978-0-12-820683-6.00002-6 Copyright © 2021 Elsevier B.V. All rights reserved

Chapter 2

Pituitary stalk interruption syndrome ANTONIS VOUTETAKIS* Department of Pediatrics, School of Medicine, Democritus University of Thrace, Alexandroupolis, Thrace, Greece

Abstract Pituitary stalk interruption syndrome (PSIS) is a distinct developmental defect of the pituitary gland identified by magnetic resonance imaging and characterized by a thin, interrupted, attenuated or absent pituitary stalk, hypoplasia or aplasia of the adenohypophysis, and an ectopic posterior pituitary. The precise etiology of PSIS still remains elusive or incompletely confirmed in most cases. Adverse perinatal events, including breech delivery and hypoxia, were initially proposed as the underlying mechanism affecting the hypothalamic–pituitary axis. Nevertheless, recent findings have uncovered a wide variety of PSIS-associated molecular defects in genes involved in pituitary development, holoprosencephaly (HPE), neural development, and other important cellular processes such as cilia function. The application of whole exome sequencing (WES) in relatively large cohorts has identified an expanded pool of potential candidate genes, mostly related to the Wnt, Notch, and sonic hedgehog signaling pathways that regulate pituitary growth and development during embryogenesis. Importantly, WES has revealed coexisting pathogenic variants in a significant number of patients; therefore, pointing to a multigenic origin and inheritance pattern of PSIS. The disorder is characterized by inter- and intrafamilial variability and incomplete or variable penetrance. Overall, PSIS is currently viewed as a mild form of an expanded HPE spectrum. The wide and complex clinical manifestations include evolving pituitary hormone deficiencies (with variable timing of onset and progression) and extrapituitary malformations. Severe and life-threatening symptomatology is observed in a subset of patients with complete pituitary hormone deficiency during the neonatal period. Nevertheless, most patients are referred later in childhood for growth retardation. Prompt and appropriate hormone substitution therapy constitutes the cornerstone of treatment. Further studies are needed to uncover the etiopathogenesis of PSIS.

INTRODUCTION The pituitary gland is composed of three lobes: anterior, intermediate (which is underrepresented in adult humans), and posterior. The anterior lobe (adenohypophysis) is derived from the oral ectoderm, which produces Rathke’s pouch, and the posterior lobe (neurohypophysis) is derived from the neural ectoderm (Zhu et al., 2007; Davis et al., 2013). Pituitary development is a complex embryonic process initially orchestrated by the overlapping, temporal, and spatial patterns and interactions of a variety of transcription factors such as the bone

morphogenetic protein and fibroblast growth factors (BMP2, BMP4, FGF8, and FGF10), Pax6, and sonic hedgehog (Shh) (Kelberman et al., 2009). Moreover, pituitary development (including Rathke’s pouch stratification and cell-type determination) mainly involves three signaling pathways: Wnt (affecting BMP and FGF expression and acting as the processes’ organizer), SHH (regulating pituitary growth and transcription factors), and Notch (driving anterior lobe cell specification) (Rizzoti, 2015). The hypophysis contains specialized cell types that produce hormones such as growth hormone

*Correspondence to: Prof. Antonis Voutetakis, Department of Pediatrics, University General Hospital of Alexandroupolis, Democritus University of Thrace, 68 100 Alexandroupolis, Thrace, Greece. Tel: +30-6972-123670, E-mail: [email protected]

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A. VOUTETAKIS

(GH), thyroid-stimulating hormone (TSH), and adrenocorticotrophic hormone (ACTH) that are involved in the regulation of all basic physiological human functions. Therefore, failure of embryonic pituitary development results in various forms of congenital hypopituitarism, most often combined pituitary hormone deficiency (CPHD) (Mehta and Dattani, 2008; Parks, 2018; Alatzoglou et al., 2020). Pituitary stalk interruption syndrome (PSIS) is a developmental defect of the pituitary gland identified by magnetic resonance imaging (MRI). PSIS is manifested as isolated or (most commonly) CPHD with variable timing of onset and progression of hormone deficiencies and symptoms (Bar et al., 2015; Voutetakis et al., 2016). Moreover, PSIS may constitute an isolated morphological abnormality or be part of a syndrome. To this extent, in a subset of patients, not only neuroimaging may reveal other accompanying brain abnormalities but also various extracerebral midline defects may be identified, resulting in diverse clinical manifestations and a wide phenotypic spectrum (Vergier et al., 2019). Overall, although PSIS is a rare abnormality in the general population, it is a relatively frequent defect in the cohort of patients with CPHD (Parks, 2018). In this chapter, etiology, genetics, clinical presentation, and evolution of pituitary dysfunction, diagnosis, and management of PSIS will be outlined and discussed.

EPIDEMIOLOGY The exact prevalence of PSIS in the general population is unknown. Nevertheless, the increasing availability and use of MRIs in the investigation of a variety of disorders (including short stature, hypopituitarism, and congenital malformations) have increased the number of patients diagnosed with PSIS. Interestingly, patients may be identified many years after the initial diagnosis of pituitary hormone deficiencies even while being well into adulthood (i.e., diagnostic reclassification of idiopathic disorders; Maghnie et al., 2013; Wang et al., 2015). In a postmarketing database analysis of treated GH deficient patients with an available MRI, 6.8% were diagnosed with PSIS (Maghnie et al., 2013). Moreover, retrospective analysis of 577 GH deficient patients with short stature caused by pituitary lesions revealed that 7.8% of those had PSIS (Xu et al., 2017). With respect to a cohort of adult patients with hypopituitarism, PSIS was present in 11.2% (Fernandez-Rodriguez et al., 2011). Male preponderance is observed with a male to female ratio close to 2:1 (Reynaud et al., 2011; Deal et al., 2013; Guo et al., 2013). Most PSIS patients are sporadic with few familial cases (5% of all cases) having been reported to date (Simon et al., 2006; Reynaud et al., 2011; Guo et al., 2013; Bar et al., 2015; Vergier et al., 2019). Ethnic

differences have been noted since Chinese patients appear to have lower rates of midline malformations and a higher frequency of breech delivery compared to other large cohorts (Guo et al., 2013; Yang et al., 2013; Wang et al., 2017).

MAGNETIC RESONANCE IMAGING FINDINGS PSIS is a distinct developmental defect characterized by a thin, interrupted, attenuated or absent pituitary stalk, hypoplasia or aplasia of the adenohypophysis, and an ectopic posterior pituitary (Fujisawa et al., 1987; Pinto et al., 1997). Nevertheless, besides this classic triad, the definition of PSIS has widened to include patients with a subset of these features such as isolated lack of a visible pituitary stalk or an ectopic posterior pituitary “bright spot” (i.e., outside the sella turcica). However, we must underline that isolated absence of a visible posterior pituitary with a normal pituitary stalk may not be considered as PSIS since the “bright spot” may be absent in 10% of normal individuals (Di Iorgi et al., 2012). Although this developmental pituitary disorder may be clinically and hormonally suspected, it is identified and diagnosed through MRI (Maghnie et al., 1991a,b, 1996; Argyropoulou and Kiortsis, 2005; Di Iorgi et al., 2012).

CLINICAL MANIFESTATIONS PSIS disrupts the anatomical integrity, coherence, and function of the hypothalamic–pituitary axis and leads to pituitary hormone deficiencies. The age at diagnosis of PSIS depends not only upon the severity of the developmental and hormonal defect but also on the clinical awareness of the caring physician. Patients have been reported as born full-term, with a birth weight within the normal range and birth length in the lower normal range (with SGA found in about 10% of neonates). The incidence of adverse perinatal events such as breech delivery, cesarean section, and neonatal distress is significantly higher compared to the general population nevertheless, showing ethnic variability (Bar et al., 2015; Han et al., 2016a,b). Overall, patients may be initially referred at the neonatal age for hypoglycemia (15%), later on for growth retardation (70%) or at any time due to existing malformations (15%; Bar et al., 2015). The phenotype during the neonatal period may include micropenis, cryptorchidism, hypoglycemia, and jaundice of various degrees (Tauber et al., 2005; Pham et al., 2013; Bar et al., 2015). The presenting phenotype and symptomatology of PSIS patients diagnosed as neonates is severe due to the coexistence of already established multiple pituitary hormone deficiencies (in most cases, complete), including GH and ACTH

PITUITARY STALK INTERRUPTION SYNDROME deficiency leading to severe hypoglycemia and symptoms of adrenal insufficiency. To this extent, such PSIS patients seem to be more frequently admitted to neonatal ICUs than those with isolated GH deficiency (Murray et al., 2008). Obviously, male patients with LH and FSH deficiency have a higher incidence of micropenis and cryptorchidism than patients with a normal gonadotropic axis (Rottembourg et al., 2008; Bar et al., 2015). In this subcohort of early-diagnosed patients, not only the hormonal profile is more affected but also imaging findings point to severe divergence from normal pituitary development (compared to patients diagnosed later, on the basis of growth retardation) with more than 30% having a nonvisible anterior pituitary. Nonetheless, neonates with PSIS and transient or mild symptomatology may escape detection. Indeed, retrospective evaluation of patients with PSIS diagnosed later in childhood for growth retardation reveals underappreciated clinical signs of hypopituitarism in the neonatal period in up to 30% (Tauber et al., 2005; Bar et al., 2015). Therefore, clinicians should be more attentive and able to adequately validate combined symptoms including hypoglycemia, jaundice, and/or micropenis during the neonatal period and infancy (especially, when accompanied by midline malformations) considering that in this developmental stage, growth retardation is not evident. As previously mentioned, most patients with PSIS are diagnosed during evaluation for growth retardation in early childhood (70%; median age at diagnosis 4 years) and most of them (66%) have isolated GH deficiency (Bar et al., 2015). In these patients, initial clinical presentation may be observed even in the second decade of life (i.e., in adolescence or early adulthood) and in some extreme or unattended cases well into adulthood without that meaning that hormonal deficits actually started that late (Fernandez-Rodriguez et al., 2011; Ioachimescu et al., 2012). Interestingly, retrospective evaluation of growth curves usually reveal growth trajectories showing subnormal growth velocity at a far younger age compared to the age at diagnosis (Bar et al., 2015). The latter underlines the importance of meticulous pediatric clinical assessment and regular follow-up of growth during childhood as simple (nevertheless, effective) tools for early diagnosis. It must be underlined that subnormal growth velocity and growth deficit may not be apparent up to the age of 2 years of life even in severe PSIS forms since growth after birth is initially predominantly GH independent and gradually changes to GH dependant (Ogilvy-Stuart, 2003; Voutetakis et al., 2016). As previously mentioned, retrospective analysis reveals transient clinical signs of hypopituitarism (e.g., hypoglycemia) in the neonatal period in about one-third of the patients. Such findings should prompt earlier evaluation of the pituitary through dynamic testing and imaging.

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Furthermore, it must be noted that in Chinese patients with a very late PSIS diagnosis (at 22–28 years of age) the most common presenting symptom (or trigger to seek medical advice) is not short stature but the absence of pubertal development due to hypogonadism (Wang et al., 2015). Developmental defects and malformations may be the presenting symptom and the reason for referral in a relatively small number of patients compared to growth retardation. Nevertheless, thorough clinical investigation reveals congenital extrapituitary malformations in up to 50% of patients with PSIS in some cohorts. Such malformations (classifying patients as syndromic) include both central nervous system (e.g., septo-optic dysplasia, partial agenesis of the corpus callosum, Arnold–Chiari malformations) and craniofacial structures, especially midline such as cleft lip or palate, and dental anomalies such as single central incisor. Distinct facial features may also include broad forehead with frontal bossing, hypotelorism, anteverted helix, bulbous nasal tip, deep philtrum with a thin upper lip, etc., such as observed in GH deficient patients. Moreover, abnormalities in other organs such as skin, heart, skeleton, gastrointestinal tract, urinary tract, etc., are also reported as well as association of PSIS with various syndromes such as CHARGE, Pallister–Hall syndrome, etc. (Simon et al., 2006; Kulkarni et al., 2012; Deal et al., 2013; Guo et al., 2013; Maghnie et al., 2013; Tatsi et al., 2013; Bar et al., 2015). The presence of extrapituitary malformations has been associated with more severe hormonal and radiological characteristics but not consistently (Pinto et al., 1997; Simon et al., 2006; Reynaud et al., 2011; Pham et al., 2013; Bar et al., 2015). Importantly, treating physicians should methodically investigate for potential associated malformations in patients with PSIS. Finally, we need not forget that PSIS should always be considered and systematically screened for in all patients with malformations (syndromic cases) and short stature.

HORMONAL PROFILE AND EVOLUTION OF HORMONE DEFICIENCIES All patients with PSIS have GH deficiency at diagnosis, manifesting either as isolated GH deficiency or as part of CPHD (Kikuchi et al., 1988; Fernandez-Rodriguez et al., 2011; Reynaud et al., 2011; Bar et al., 2015; Wang et al., 2015). CPHD is usually observed in all patients diagnosed as neonates and is less frequent in patients investigated for growth retardation (i.e., at diagnosis; for example 34% as reported by Bar et al., 2015). Additional hormone deficiencies (with respect to GH) include TSH, ACTH, gonadotropins, and ADH in order of diagnostic frequency in childhood (Deal et al., 2013; Bar et al., 2015). Nevertheless, actual frequency of other hormone

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deficiencies at diagnosis varies among different series and age groups. Progressive insufficiency in additional pituitary hormones gradually develops in all patients. Within 3 years of follow up, almost 15% of patients initially diagnosed with isolated GH deficiency have CPHD and eventually all patients with PSIS suffer from combined (two or more pituitary hormone deficiencies) to complete hypopituitarism, actual percentages depending on the age of diagnostic testing (Tauber et al., 2005; Fernandez-Rodriguez et al., 2011; Deal et al., 2013; Guo et al., 2013; Bar et al., 2015; Han et al., 2016a,b). Specifically, it has been documented that 81% of patients with PSIS have CPHD at completion of growth and up to 96% as adults with long-term follow up, of which 46% have panhypopituitarism (Fernandez-Rodriguez et al., 2011; Bar et al., 2015). Severity of hormonal impairment has been associated with MRI findings such as the nonvisible stalk (vs thin or intersected) and the nonvisible anterior pituitary and with the presence of extrapituitary malformations such as in syndromic patients nevertheless, not consistently (Chen et al., 1999; Simon et al., 2006; Melo et al., 2007; Reynaud et al., 2011; Wang et al., 2014, 2015; Bar et al., 2015). These observations seem to follow the general rule that complex MRI abnormalities of the hypothalamic–pituitary region are usually associated with the presence or development of combined pituitary hormone deficiencies (Hamilton et al., 1998; Kornreich et al., 1998; Di Iorgi et al., 2012). Therefore, such MR images can contribute to the prediction of the pattern and evolvement of additional hormone deficiencies and severity of hypopituitarism (Bozzola et al., 1996; Maghnie et al., 2004, 2013). In a broader view, given the usual early onset of hormone deficiencies in patients with PSIS, we need to underline that MRI has even been proposed as an attractive first-line tool for the diagnosis of pituitary hormone deficiencies during infancy and early childhood (i.e., below the age of 4 years) given the practical difficulties, unsafe nature, lack of normative data, and unreliability of hormone stimulation tests in this age group (Pampanini et al., 2015). Nevertheless, we need not forget that although severe GH deficiency is more strongly associated with severe brain MRI findings, the severity of GH deficiency based on peak GH levels on stimulation tests does not predict the presence or absence of brain abnormalities. Practically, the presence of partial GH deficiency should not act reassuringly for the treating physician (Zimmermann et al., 2007; Alba et al., 2020). Whenever GH deficiency is diagnosed, it is imperative to always perform a pituitary MRI. GH deficiency is considered permanent and severe in the vast majority of PSIS cases (Maghnie et al., 1999; Di Iorgi et al., 2012, 2016). Among patients diagnosed with

GH deficiency, patients with the classical triad of PSIS have a more severe phenotype (lower age at diagnosis, greater height deficit compared to target height as well as bone age delay, etc.) and endocrine findings (lower GH peak response, IGF-I, and IGFBP-3 levels) and better response to GH treatment as indicated by first-year change in height SDS and height velocity (Coutant et al., 2001; Louvel et al., 2009; Deal et al., 2013; Grimberg et al., 2016; Murray et al., 2016; Grimberg and Allen, 2017; Collett-Solberg et al., 2019). Patients with GH deficiency and congenital hypothalamic–pituitary abnormalities do not generally require reevaluation of GH secretion after reaching adult height (i.e., at the transition period toward adult care; Loche et al., 2018). Nevertheless, nonpersistent GH deficiency has been reported in patients with isolated GH deficiency (documented in childhood) and a “mild” version of PSIS (including thin pituitary stalk, hypoplastic anterior pituitary, and an ectopic posterior lobe located at different levels of the pituitary stalk) after reaching adult height (L
eger et al., 2005). However, long-term follow-up data of these specific patients is not available. In contrast, 2-year follow up and reinvestigation of anterior pituitary function in young adults with congenital childhoodonset GH deficiency associated with (a) less severe structural hypothalamic–pituitary abnormalities and (b) a normal GH response at the time of first reassessment of GH secretion, documented deterioration of GH response and the presence of additional pituitary defects. (Di Iorgi et al., 2007). MRI findings of the hypothalamic–pituitary area may be the most important criterion upon which the decision to reevaluate the patient (or not) should be based, rather than response to pharmacological stimulation or IGF-I and IGFBP3 levels (Adan et al., 1994; Di Iorgi et al., 2012; Loche et al., 2018). Moreover, discordant response with a “normal” GH peak after stimulation tests accompanied by low IGF-I levels pointing to severe GH deficiency has been documented (Maghnie et al., 1999). In summary, classical PSIS leads to permanent GH deficiency. Nonpersistent GH deficiency observed during reevaluation in early adulthood (in less severe structural PSIS defects) should not defer the caring physician from long-term follow up and reassessment of pituitary function as GH and additional hormone deficiencies develop in most patients. We need not forget that adult GH treatment has proven beneficial metabolic effects (Ho, 2007; Molitch et al., 2011; Díez et al., 2018; Yuen et al., 2019). Gonadotropin (LH and FSH) insufficiency seems to be present in most PSIS patients with severe symptoms diagnosed in the neonatal period (up to 90%), about half of the patients diagnosed due to growth retardation (up to 57%) and 75%–98% of adults, being in the vast majority of cases part of CPHD rather than isolated

PITUITARY STALK INTERRUPTION SYNDROME (Rottembourg et al., 2008; Fernandez-Rodriguez et al., 2011; Guo et al., 2013; Bar et al., 2015; Wang et al., 2015; Han et al., 2016a,b). Hypogonadism can be clinically suspected in the neonatal period only in boys with micropenis and/or undescended testes. Later on, gonadotropin insufficiency must be suspected if secondary sex characteristics (breast development Tanner stage 2 in girls or testicular size >4mL in boys) are not present in girls more than 13 and boys more than 14 years of age. Although the majority of patients (80%) have complete or partial pubertal deficiency, a number of PSIS patients enter puberty spontaneously and have normal pubertal development (Rottembourg et al., 2008; Corvest et al., 2020). Interestingly, reversible gonadotrope deficiency has been reported in a patient with PSIS and Kallmann syndrome (Sarfati et al., 2015). The gonadotropic axis may be evaluated (by dynamic testing) only in neonates and infants (during “mini-puberty”) and in patients of (theoretical) postpubertal age (in between, the physiological quiescence stage of the hypothalamic–pituitary–gonadal axis is observed). It has been suggested that underrange inhibin B concentrations (or similar markers) in prepubertal patients with PSIS might be suggestive of complete hypogonadism and act as a simple first-line predictive test, especially in boys (Corvest et al., 2020). Overall, hypogonadism encountered in patients with PSIS presents with high clinical variability from cryptorchidism and micropenis present at birth, partial pubertal development, primary amenorrhoea after normal pubertal development with normal gonadotrophin values (pointing to subtle disturbances of gonadotrophin pulsatility) to complete gonadotrophin deficiency leading to absence of pubertal initiation (Rottembourg et al., 2008; Bar et al., 2015; Corvest et al., 2020). ACTH deficiency may cause neonatal cholestasis, adrenal insufficiency, and recurrent hyponatremia (Guo et al., 2013; Bar et al., 2015; Mauvais et al., 2016; Jang and Ko, 2017). Secondary adrenal insufficiency, such as in the case of PSIS, may be predicted based on the coexistance of preceding signs pointing toward pituitary hormone deficiency (such as micropenis, hypoglycemia, etc.). Moreover, we need not forget that hormone deficiencies gradually evolve over time in patients with PSIS and, therefore, previously unrecognized or partial adrenal insufficiency may surface during periods of illness or stress. Depending on the age at testing, the prevalence of corticotropin deficiency may be as high as 90% in PSIS patients (Guo et al., 2013; Wang et al., 2015) and is more frequently encountered among patients with nonvisible stalk (Wang et al., 2015). With respect to cholestasis in the neonate, it is a rather frequent finding pointing toward various forms of hypopituitarism (Voutetakis et al., 2004b). Indeed, in almost one

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in three PSIS patients diagnosed during the neonatal period or infancy, cholestasis was the initial presenting sign (Mauvais et al., 2016). Cholestasis and elevated liver enzymes are mainly attributed to the hypofunction of the pituitary–adrenal axis leading to cortisol deficiency and growth hormone deficiency, respectively, along with hypothyroidism (Binder et al., 2007; Karnsakul et al., 2007; Voutetakis et al., 2016). Thyrotropin deficiency is almost always present in patients with PSIS diagnosed in the neonatal period or infancy. With respect to the rest of the patients (e.g., those referred for short stature), the prevalence of TSH insufficiency gradually increases with age from 20% to 80% in adults (Fernandez-Rodriguez et al., 2011; Guo et al., 2013; Yang et al., 2013; Bar et al., 2015; Zhang et al., 2018). Often, pituitary insufficiency (i.e., secondary hypothyroidism) may not present with low TSH values but as inappropriately low TSH values with respect to thyroid hormone levels (with actual values being slightly over the normal TSH limit), thus mimicking the diagnosis of primary hypothyroidism and potentially misleading the treating physician (Voutetakis et al., 2016; Zhang et al., 2018). Moreover, isolated sparing of the pituitary–thyroid axis despite the deficiency of the remaining anterior pituitary hormones has been described (Nawaz et al., 2018). Conflicting reports exist with respect to the association of TSH levels and potential deficiency with MRI findings. For example, no correlation with pituitary stalk status has been documented by Zhang et al. and significant association with pituitary stalk visibility (or not) has been acknowledged by Wang et al. (Wang et al., 2015; Zhang et al., 2018). With respect to prolactin, levels seem inconsistently affected and do not follow the general trend of pituitary hormone deficiency since they have been reported as normal, low, increased, and varying even between subsets of patients within the same cohort (for example, low in 12% and increased in 44% of patients as documented by Bar et al). Effect on prolactin levels depends on the degree and type of dopaminergic pathway disconnection, and most findings are suggestive of a loss of normal dopaminergic inhibition of prolactin secretion (Fernandez-Rodriguez et al., 2011; Reynaud et al., 2011; Guo et al., 2013; Bar et al., 2015; Han et al., 2016a,b). Interestingly, despite the abnormality of the neurohypophysis, diabetes insipidus is clinically evident in a relatively low number of patients ranging from none to 15.4% in various cohorts (Fernandez-Rodriguez et al., 2011; Yang et al., 2013; Bar et al., 2015; Wang et al., 2015). Such findings are expected since the anterior and posterior lobes have different embryonic origins. Nevertheless, the prevalence of posterior pituitary hypofunction seems to be affected by the mode of diagnostic assessment (i.e., if using only clinical criteria such as

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polydipsia and polyuria as a trigger for dynamic testing vs diligently testing all patients for AVP deficiency). For example, Wang et al. report ADH deficiency in over 60% of patients after thoroughly testing their entire PSIS cohort (Wang et al., 2014). Analogous data have been reported by Lukezic et al. in a cohort of patients with congenital hypopituitarism and posterior pituitary ectopia who showed a high prevalence (>80%) of subnormal (but clinically silent) vasopressin response to an osmolar stimulus (Lukezic et al., 2000). Therefore, it seems possible that a significant number of PSIS patients have subclinical or unappreciated ADH deficiency. With respect to imaging data, patients with PSIS and an absent posterior lobe on MRI seem to have overt diabetes insipidus or intractable nocturnal enuresis (Kikuchi et al., 1988; Yamanaka et al., 1990; Wang et al., 2017). On the other hand, it has been reported that patients with a large ectopic posterior lobe (greater than 5 mm) at the proximal stump of the transected stalk seem to be unaffected, whereas a number of patients with a small posterior lobe (less than 5 mm) seem to have subnormal vasopressin response to the osmolar stimulus (i.e., via water deprivation or the hypertonic saline infusion test) and an impairment of thirst appreciation (Yamanaka et al., 1990). It has been suggested that such differences maybe be due to the integrity (or not) of the vascular component or hypothalamic dysfunction (i.e., in more complex midline brain abnormalities) involving damage to the osmoreceptors that regulate AVP synthesis and possibly the posterior lobe (Genovese et al., 1997; Secco et al., 2011).

TREATMENT Prompt and appropriate hormone substitution therapy constitutes the cornerstone of treatment for all patients with PSIS. Depending on the specific hormone deficiencies uncovered and age, patients may receive a combination of GH, Levothyroxin, cortisol, testosterone or estrogens, and desmopressin. We need to underline that the hormone profile at diagnosis is not stable and longterm follow-up is imperative since, as previously mentioned, additional pituitary hormone deficiencies gradually develop in all patients. We need not forget that patients with pituitary hormone deficiencies are at excess risk of morbidity and mortality (especially from hypoglycemia and adrenal insufficiency) and therefore prompt identification, early intervention and aggressive treatment of panhypopituitarism is of the outmost importance (Mills et al., 2004). With respect to response to GH treatment, substitution therapy in PSIS patients is considered very effective and significantly improves growth rate and final height with individual gains depending on height, chronological age, and bone age at GH initiation (Hilczer et al., 2005;

Tauber et al., 2005; El Chehadeh et al., 2010; Bar et al., 2015; Wang et al., 2020). In general, patients with PSIS respond better to GH treatment in comparison to other GH deficient patients, as demonstrated by various growth indicators (Coutant et al., 2001). The latter follows the broader observation that height gain in patients with developmental abnormalities of the hypothalamic–pituitary axis on magnetic imaging (such as PSIS) is significantly higher compared to those with a normal MRI (Hilczer et al., 2005). Evaluation and comparison after 3 years of GH treatment seems to be a relatively accurate measure that adequately reflects overall treatment effectiveness (Zenaty et al., 2003). It is worth noting that growth under GH treatment seems to be similar between various PSIS subgroups (e.g., neonates vs patients with growth retardation and syndromic vs nonsyndromic patients) and is independent of the spectrum of pituitary MRI findings classified as PSIS (Bar et al., 2015). Treatment leads to a significant total height gain SDS and normal adult height within the target height (based on the midparental height) when initiated at the appropriate age (Coutant et al., 2001; Tauber et al., 2005; Louvel et al., 2009; Bar et al., 2015; Wang et al., 2020). Both shorter height at baseline and growth velocity during the first year of GH treatment seem to be significant predictive factors of GH response (Zenaty et al., 2003; Bar et al., 2015; Wang et al., 2020). Interestingly, some patients with PSIS without GH or sex hormone substitution therapy reach normal height (according to ethnic growth charts) probably due to slow bone maturation (attributable to hypogonadism) and incomplete GH deficiency that allows for linear growth beyond the usual age of growth arrest (Wang et al., 2015). To this extent, a patient with PSIS and “normal growth beyond target height without GH” has been reported (Lee et al., 2017). Hypocortisolemia should be recognized promptly, based on symptoms and biochemical data, and treated appropriately without delay (especially in neonates) since low cortisol levels represent an eminent lifethreatening derangement (Charmandari et al., 2014). Substitution therapy with estrogens in girls and testosterone in boys should be initiated in patients with hypogonadism at the appropriate age followed by the necessary dose adjustments (Boehm et al., 2015; Sultan et al., 2018; Young et al., 2019). If started too soon, it will negatively affect final height, if inappropriately postponed beyond the normal age range of pubertal onset may influence peak growth velocity and growth, bone mineralization, and lead to problems of social adjustment, self-esteem, and psychological well-being. Management of hypothyroidism, especially during the neonatal period, should be given promptly in order to preserve normal psychomotor development and normal height velocity. Initiation of therapy, dosing, and follow up should be

PITUITARY STALK INTERRUPTION SYNDROME based on thyroid hormone (FT4) levels that need to be maintained in the upper half of the age-specific reference range (L
eger et al., 2014). Diabetes insipidus should be investigated through appropriate dynamic testing and managed accordingly (Dabrowski et al., 2016; Robertson, 2016). It must be noted that successful pregnancies and deliveries in a patient with evolving hypopituitarism due to PSIS have been reported (Yoshizawa et al., 2017). With respect to quality of life (QoL), Kao et al. reported that noncancer patients with childhood-onset hypopituitarism (19 out of 22 with congenital hypopituitarism, rest with traumatic) described significantly more behavioral problems during childhood than physically healthy peers. Moreover, a nonsignificant trend to score lower in all QoL domains and a nonsignificant trend for lower female sexual functioning scores in all aspects except female sexual desire was documented; the latter being significantly lower than in controls. Nevertheless, patients showed no significant differences in employment rate, income, household status, relationship status, marital status, or number of children with respect to controls despite the fact that they were less educated (Kao et al., 2015). Therefore, apart from hormone substitution therapy, psychological support adjusted to the child’s needs and ability to compensate must be strongly considered in patients with PSIS. Importantly, GH therapy in adults provides sustained improvement in QoL measures (Mo et al., 2014).

PATHOGENESIS OF PITUITARY STALK INTERRUPTION SYNDROME The precise etiology of PSIS still remains elusive or incompletely confirmed in most cases. Nevertheless, recent advances in biomedical technologies and analysis and especially, the broad application of whole exome sequencing (WES) in large cohorts have prompted a significant change of view with respect to the underlying mechanism of PSIS: from theories pointing to adverse perinatal events, we have gradually moved toward pinpointing a broad spectrum of proven and probable genetic causes that continuously expand (Kulkarni et al., 2012). Adverse perinatal events leading to head trauma, ischemia, hypoxia, or even mechanical rupture of the pituitary stalk and/or affecting the hypothalamus had been suspected in the past as the causative mechanism of PSIS (and in a broader view, pituitary deficiency), based on the increased incidence of dystocia, breech presentation, cesarean section delivery, and potential neonatal distress in patients with PSIS (Demura et al., 1975; Shizume et al., 1977; Maghnie et al., 1991a,b; Aci
en, 1995; Pinto et al., 1997; Bar et al., 2015; Wang

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et al., 2017). Indeed, breech delivery is significantly increased among PSIS patients (observed in over 60% in some cohorts) with respect to the 4% observed in the general population (Cruikshank, 1986; Maghnie et al., 1991a,b; Wang et al., 2017). However, the reality of patients without perinatal trauma or events, familial cases, and the frequent association with extrapituitary malformations do not fit this hypothesis. It must be noted that Chinese patients appear to have an even higher frequency of breech delivery (over 80%) compared to other published cohorts (Wang et al., 2010, 2014; FernandezRodriguez et al., 2011; Guo et al., 2013; Yang et al., 2013; Han et al., 2016a,b). Nevertheless, ethnic differences may be due to lack of regular prenatal follow up leading to a higher incidence of perinatal complications in specific populations. Such epidemiological observations confirm a close relationship between breech delivery and patients with PSIS, however, do not verify an undisputable, one-way cause–effect relationship. Indeed, it seems that this theory may be reversed since it may in turn be that antenatal pituitary hormone deficiencies (possibly due to existing molecular aberrations) lead to abnormal delivery and perinatal adverse effects and not vice versa (Despert et al., 1993; Pinto et al., 1997; Kulkarni et al., 2012; Voutetakis et al., 2016). To this extent, recent large WES studies in Chinese patients with PSIS have unsurfaced a high overall incidence of various molecular alterations in patients with a history of breech delivery and dystocia (Guo et al., 2017; Fang et al., 2020). Yet, hypoxia or mechanical rupture per se may still underlie a subcohort of PSIS patients. Overall, current data support the view that PSIS constitutes an antenatal developmental event of multifactorial genetic etiology belonging to an expanded spectrum of holoprosencephaly (HPE) and midline defects (Tatsi et al., 2013; Voutetakis et al., 2016).

GENETICS OF PITUITARY STALK INTERRUPTION SYNDROME Most PSIS cases are sporadic and rarely familial (5%), with incomplete or variable penetrance of the underlying molecular alteration leading to a wide clinical and hormonal spectrum even in the case of family members harboring the same genetic variant; phenotype ranging from unaffected parents to severely affected individuals (Voutetakis et al., 2016; Wang et al., 2017; Vergier et al., 2019). PSIS may be observed as a single morphological abnormality or accompanied by a wide variety of manifestations and developmental mishaps (i.e., as part of syndromes) due to a continuously growing pool of molecular candidates. Initial studies, mostly on patients born to consanguineous parents, familial cases, and syndromic forms, revealed that germline mutations in genes

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important for pituitary development may be responsible for PSIS. A variety of animal models have confirmed the essential and determining role of such molecular defects (Kelberman et al., 2009; Davis et al., 2013; Alatzoglou et al., 2020). Later on, the spectrum of PSIS-associated genes expanded in order to include holoprosencephaly related genes, genes involved in neural development as well as other important processes. However, all of these mutations are identified in a few isolated cases, and molecular defects in sporadic patients (who account for the vast majority of cases) still remain to be revealed (Guo et al., 2013; Wang et al., 2017). Recent data, mostly obtained through the application of WES in relatively large cohorts, have refocused our interest toward multigenic inheritance of the disorder. Still, the majority of identified genes are related to the Wnt, Notch and Shh signaling pathways that regulate pituitary growth and development during embryogenesis and therefore PSIS may be viewed as a mild form of an expanded HPE spectrum (Tatsi et al., 2013). Molecular disorders associated with PSIS may be categorized as transcription factors known to be involved in pituitary organogenesis (e.g., HESX1, LHX4), HPErelated genes (e.g., TGIF, GLI2), genes related to the Wnt (e.g., LHX3, OTX2), Notch (e.g., PROP1), Shh (e.g., GPR161, CDON), and other signaling pathways (e.g., PROKR2 belonging to the prokineticin pathway) (Geng and Oliver, 2009; MacDonald et al., 2009; Bray, 2016; Castinetti et al., 2016; Fang et al., 2016; Rizzoti, 2015; Carballo et al., 2018; Roessler et al., 2018; Gregory and Dattani, 2020). Obviously, specific genes may be classified to more than one of the suggested subgroups.

Genes involved in pituitary organogenesis Pituitary organogenesis is a complex process that depends on and is regulated by a cascade of transcription factors, such as PROP1, PIT1 (POU1F1), HESX1, LHX3, and LHX4 that interact in a highly sensitive temporal and spatial pattern. Mutations in such genes may not only result in different combinations of hormone deficiencies but also in structural abnormalities of the anterior and posterior pituitary gland and therefore cause PSIS (Reynaud et al., 2006; Kelberman et al., 2009; de Moraes et al., 2012). PROP1 gene encodes a pituitary-specific transcription factor required for the determination of most pituitary hormone secreting cells (somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs), and pathogenic molecular alterations are the most frequent cause of congenital combined pituitary hormone deficiency (Wu et al., 1998). Since PROP1 acts late in the cascade of pituitary organogenesis, MR images are not expected to be reminiscent of PSIS (Fang et al., 2016). Indeed, patients with PROP1

gene mutations are associated with pituitary hypoplasia or, in some cases, transient enlargement (Voutetakis et al., 2004a). Interestingly, a PROP1 gene mutation has only been identified in two familial cases with PSIS born from a consanguineous union (homozygous 301302delAG, i.e., the most frequently encountered PROP1 mutation). Nevertheless, authors recognize that they cannot rule out that the unusual imaging data encountered in these two PROP1 patients (pituitary stalk absence and ectopic posterior pituitary) might be related to mutations in other genes involved in pituitary development that were not analyzed (Fernandez-Rodriguez et al., 2011). HESX1 is a homeobox gene expressed in the prospective forebrain that plays a role in the development of the optic nerves, hypothalamus, and Rathke’s pouch (Fang et al., 2016). Missense variants of HESX1 are associated with septo-optic dysplasia (SOD, including optic nerve hypoplasia, pituitary abnormalities, and midline brain defects) as well as various pituitary phenotypes without optic nerve involvement (Dattani et al., 1998; Thomas et al., 2001; Sobrier et al., 2006; Webb and Dattani, 2010). A HESX1 variant was uncovered in a patient with PSIS (i.e., hypoplastic anterior pituitary gland, ectopic posterior lobe, and interrupted pituitary stalk without SOD) (Reynaud et al., 2011). Nevertheless, HESX1 mutations causing PSIS are infrequently encountered. To this extent, OTX2, a transcription factor that has a transactivation function for the promoters of HESX1, POU1F1, and IRBP, has also been investigated (Hever et al., 2006). Although OTX2 is primarily involved in ocular development, it is also expressed in the pituitary and is involved in pituitary development and function (Dateki et al., 2008). It has been shown that OTX2 variants are associated with variable pituitary phenotypes (pituitary hypoplasia and ectopic posterior pituitary) in patients with ocular involvement (anophthalmia or microphthalmia) (Dateki et al., 2010). PAX6 is a transcriptional regulator known for its involvement in oculogenesis and required for the development of the olfactory system, brain, spinal cord, pancreas, and anterior pituitary (Simpson and Price, 2002; Zhu et al., 2007). Therefore, PAX6 mutations are associated with diverse clinical features ranging from severely impaired ocular (e.g., aniridia) and pituitary development with PSIS features (including anterior pituitary hypoplasia, ectopic posterior pituitary, and invisible stalk) to an apparently normal phenotype (Takagi et al., 2015). LHX4 plays important roles as a transcriptional regulator during embryogenesis by directing, along with LHX3, the development of the pituitary gland and specifically by controlling the formation of the definitive Rathke’s pouch (Sheng et al., 1996; Mullen et al., 2007). LHX4 variants have been associated with PSIS with

PITUITARY STALK INTERRUPTION SYNDROME poorly developed sella turcica and inconstant pituitary hypoplasia and ectopic neurohypophysis along with brain malformations (Castinetti et al., 2008). Moreover, two LHX4 mutations were present in familial PSIS with discordant MRI findings between two brothers: one with poorly developed sella turcica and pituitary hypoplasia, associated with a hypoplastic corpus callosum, thin pituitary stalk, and invisible posterior pituitary and the other with ectopic posterior pituitary and normal corpus callosum (Reynaud et al., 2011). A presumably lethal LHX4 variant was also identified in two deceased male patients with severe panhypopituitarism associated with anterior pituitary aplasia and posterior pituitary ectopia despite early hormone replacement therapy (Gregory et al., 2015a,b). Nevertheless, such LHX4 molecular findings remain rare when screening relatively large cohorts of patients with CPHD and midline brain malformations (Castinetti et al., 2008; Cohen et al., 2017). ARNT2 is a transcription factor with restricted expression in the developing brain, pituitary gland, and kidneys. Mutations in ARNT2 have been identified as the cause of the Webb–Dattani syndrome, which is characterized by dysgenesis of the pituitary and the hypothalamus, postretinal blindness, and renal abnormalities. The molecular defect has been uncovered in multiple members of a single consanguineous family with a thin pituitary stalk, hypoplastic anterior pituitary gland, and a missing posterior pituitary bright spot (Webb et al., 2013). CHD7 is a transcriptional regulator that is expressed in cranial nerves and ganglia, and auditory, pituitary, and nasal tissues as well as in the neural retina (Sanlaville et al., 2006). Molecular alterations of CHD7 are associated with the CHARGE syndrome (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) but have also been found in patients with Kallmann syndrome or normosmic-isolated hypogonadotropic hypogonadism (Vissers et al., 2004; Kim et al., 2008). Structural pituitary abnormalities such as anterior pituitary hypoplasia and an ectopic posterior pituitary have been associated with CHARGE syndrome and CHD7 (Gregory et al., 2013). Interestingly, as previously discussed, a variety of PSIS-related genes are associated with ophthalmic malformations such as in the case of HESX1, OTX2, PAX6, LHX4, ARNT2, CHD7, and ROBO1.

Genes involved in neural development ROBO1 defines a novel and highly conserved among species subfamily of proteins involved in neurogenesis, axon guidance (by controlling axon crossing of the CNS

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midline), and branching (Kidd et al., 1998). Heterozygous mutations in the ROBO1 gene were recently associated with five cases of PSIS also presenting with ocular anomalies (including hypermetropia with strabismus and ptosis) (Bashamboo et al., 2017). Further, a ROBO1 mutation was identified in a patient with pituitary dysgenesis (including invisible pituitary stalk, anterior pituitary hypoplasia, and ectopic posterior pituitary) accompanied by thinning of the corpus callosum, and hypoplasia of the pons and midbrain (Dateki et al., 2019). Interestingly, a ROBO1 deletion was uncovered in a young girl with anterior pituitary hypoplasia and pituitary stalk duplication. Her father had a similar pituitary phenotype, characterized by anterior pituitary hypoplasia combined with ectopic posterior pituitary (Scala et al., 2019). These findings widen the spectrum of the phenotypes associated with ROBO1 and further support a role in PSIS. Prokineticin 2 (PROK2) and its receptor PROKR2 are implicated in several important physiological functions, including neurogenesis and neuronal migration, angiogenesis, circadian rhythm regulation, reproduction, and gastrointestinal smooth muscle contraction (Zhao et al., 2019). Of most importance are their involvement and role in the migration of olfactory neurons and gonadotropin-releasing hormone-secreting cells during development (Ng et al., 2005). PROKR2 alterations have been identified as one of the molecular defects underlying Kallmann syndrome (characterized by hypogonadism and anosmia) and hypogonadotropic hypogonadism without anosmia (Dod
e et al., 2006; Cangiano et al., 2021). Recently, heterozygous mutations in PROKR2 have been identified in patients with PSIS (Reynaud et al., 2012; Han et al., 2016a,b; McCormack et al., 2017).

Holoprosencephaly (HPE)-related genes HPE is a developmental disorder classically defined as incomplete cleavage of the forebrain. The extent of the brain malformations varies and characterizes the disorder’s degree of severity. HPE is often associated with midline facial anomalies that are also of varying severity ranging from cyclopia to milder signs such as cleft lip and/or palate, philtrum aberrations, and characteristic tooth abnormalities such as the single central incisor (Dubourg et al., 2007). Nevertheless, relevant molecular studies have identified that HPE-related gene alterations may also underlie midline facial defects and pituitary anomalies without any of the typical brain malformations that were initially thought as the cornerstone of this developmental disorder (Roessler and Muenke, 2010). Such cases are now defined as HPE microforms, further extending the HPE clinical spectrum and our understanding of head and brain development. To the same extent,

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A. VOUTETAKIS

HPE has been progressively redefined from what was initially thought as an autosomal dominant disease to a disorder of a highly complex genetic background, affected by gene–environment interactions, of variable (and challenging) penetrance and expressivity, and oligogenic inheritance (Dubourg et al., 2018; Grinblat and Lipinski, 2019). Molecular alterations in HPE-related genes were uncovered in patients with PSIS, eventually leading to the theory that PSIS may be classified as a mild form of an expanded HPE spectrum (Franc¸a et al., 2010; Tatsi et al., 2013). Since their initial report such genetic associations continue to expand (albeit, along with their genetic complexity and challenging inheritance pattern), currently including a variety of relevant factors that will further be addressed. The Sonic hedgehog (Shh) signaling pathway is essential for CNS, early pituitary and ventral forebrain development and is considered the most prominent HPE-related factor (Roessler and Muenke, 2010; Xavier et al., 2016; Carballo et al., 2018). TGIF, a component of the Wnt signaling pathway, is expressed in the developing midline structures, is required for appropriate Shh signaling during forebrain development, and acts as a transcriptional repressor and corepressor for retinoid X receptor targets (Taniguchi et al., 2012; Wotton and Taniguchi, 2018). Therefore, reduced TGIF levels may mimic increased retinoid acid levels and result in increased retinoid responsive gene expression (Nanni et al., 1999). Nevertheless, retinoic acids have teratogenic effects (i.e., leading to HPE-like phenotypes) in animal models (Sulik et al., 1995; Billington et al., 2015). The latter may explain the underlying mechanism leading to HPE in patients with TGIF variants as well as the potential contribution of environmental factors (e.g., exposure to certain chemical compounds) in the severity of the observed HPE phenotype (nevertheless, starting from a majority of unaffected carriers). Indeed, TGIF has been associated with HPE and up to 1%–2% of individuals with a family history of HPE have TGIF variants (Gripp et al., 2000; Roessler and Muenke, 2010). Importantly, a heterozygous nonsense TGIF variant and a TGIF deletion, as part of an 18p( ) syndrome, have been associated with PSIS and a single central incisor in two patients, respectively (Tatsi et al., 2013). Nevertheless, only a small percent of damaging TGIF variants lead to developmental malformations (10%) and variable inter- and intrafamilial variability and penetrance is often observed, as with the majority of other HPE and PSISassociated genes (Nanni et al., 1999; Dubourg et al., 2018). It has been hypothesized that variants in such essential developmental genes act as predisposing factors that need to combine with additional more subtle genetic alterations (in a variety of protective or compromising molecular components) and environmental

factors in order to deviate from what is considered as normal development (i.e., the unaffected individual) to the spectrum of the HPE phenotype (Roessler et al., 2012). CDON, a member of the neural cell adhesion molecule family, acts as an Shh coreceptor and has been associated with HPE patients presenting with a broad range of phenotypic severity (Bae et al., 2011; Xavier et al., 2016). Moreover, a nonsense mutation in the CDON gene has been reported in a familial case of PSIS without HPE (Bashamboo et al., 2016). Interestingly, phenotypic discordance and variable penetrance are once more present since the mutation was inherited from the patient’s asymptomatic mother. Importantly, as in the case of TGIF, environmental factors may again play a synergistic or modifying role since mice lacking CDON and exposed to ethanol in utero have variable HPE phenotypes, which are not seen when either one of these factors are missing (Hong and Krauss, 2012). The GLI family of transcription factors act as mediators of the Shh signaling pathway during CNS, pituitary, and ventral forebrain development (Gregory et al., 2015a, 2015b). Mutations in GLI2 have been described in patients with a distinctive phenotype whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia (Roessler et al., 2003). With respect to non-HPE patients with hypopituitarism and heterozygous alterations in GLI2, the phenotype of affected individuals includes a small anterior pituitary lobe and an ectopic/ undescended posterior pituitary lobe on MR imaging. The inheritance pattern is autosomal dominant with incomplete penetrance since the variant is frequently inherited from an asymptomatic parent (Franc¸a et al., 2010; Arnhold et al., 2015).

Cilia-related genes Primary cilia are microtubule-based cellular organelles that protrude from the cell surface and are responsible for two major physiologic functions: locomotion or fluid flow and detection of extracellular signals and environments. Importantly, cilia are essential for development since they play key roles in transducing or regulating several signaling pathways, including Shh and Wnt (Mukhopadhyay and Rohatgi, 2014; Park et al., 2019). Abnormal ciliary function leads to a heterogeneous group of syndromic disorders called ciliopathies that can adversely affect development of the brain, kidneys, eyes, and liver (Suciu and Caspary, 2021). GPR161 is an orphan member of the ciliary G proteincoupled receptor family that acts as a key negative regulator of Shh signaling through GLI2 and GLI3, all of

PITUITARY STALK INTERRUPTION SYNDROME which have been associated with midline defects and HPE-spectrum phenotypes (Roessler and Muenke, 2010; Mukhopadhyay et al., 2013). Gpr161 mRNA is expressed in pituitary gland and hypothalamus of both mouse and human. Interestingly, Gpr161 knockout results in extensive craniofacial abnormalities in mice and is embryonic lethal (Mukhopadhyay et al., 2013). A homozygous missense mutation in the GPR161 gene was associated with PSIS in two affected siblings from a consanguineous family. Both parents and two unaffected children had this variant in the heterozygous state and one healthy sister was wild-type. The phenotype also included midline facial defects, short fifth finger, two to three toe syndactyly, hypopituitarism, and intellectual disability (Karaca et al., 2015). Primary cilia contain a transport machinery of both structural components and signaling proteins that is called intraflagellar transport (IFT; Broekhuis et al., 2013). TTC26 is an atypical component of the IFT-B complex, and its deficiency has been shown to cause defective ciliary function in several model organisms (Ishikawa et al., 2014; Swiderski et al., 2014). Bi-allelic mutations in TTC26 have been described in the context of a syndromic ciliopathy presenting with severe neonatal cholestasis and polydactyly, with brain, kidney, and heart involvement. Cilia in TTC26mutated patient cells display dysregulated Shh signaling (Shaheen et al., 2020). Importantly, PSIS was diagnosed in four patients with TTC26 ciliopathy, highlighting an important role of TTC26 in pituitary development (David et al., 2020).

PSIS associated with microdeletions or duplications PSIS has been diagnosed not only in patients with gene variants but also in individuals having chromosomal microdeletions or duplications. Koolen-De Vries syndrome, characterized by intellectual disability, hypotonia, friendly demeanor, and highly distinctive facial features, can be caused by a microdeletion on chromosome 17q21.31 including several genes or by a heterozygous mutation in the KANSL1 gene, which resides in that area (Koolen et al., 2006, 2012). A patient with a de novo 493kb microdeletion on chromosome 17q21.31 and partial PSIS has been reported (El ChehadehDjebbar et al., 2011). A very rare and complex chromosomal rearrangement (distal 2p25 duplication and 2q37.1-qter deletion) has also been identified in a patient with severe psychomotor delay and PSIS (Vetro et al., 2014). Interestingly, both submicroscopic duplication of Xq27.1 containing SOX3 (leading to overdosage) and an expansion of a polyalanine tract within the transcription factor SOX3 (leading to underdosage) are

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associated with hypopituitarism and PSIS (Woods et al., 2005; Bauters et al., 2014; Arya et al., 2019). SOX3 is a key player in many developmental processes, is expressed throughout the developing central nervous system, and is involved in the early steps of pituitary organogenesis (Alatzoglou et al., 2009; Xatzipsalti et al., 2019). Moreover, a variety of chromosomal aberrations has been described in patients with extrapituitary malformations belonging to syndromic forms of PSIS such as a 15q24 microdeletion, tetrasomy 22pterq11.1, and trisomy 12 mosaicism (Bar et al., 2015). As previously described, PSIS has also been associated with an 18p deletion including TGIF in a patient with a single central incisor (Tatsi et al., 2013). Finally, a broadened genomic approach in CPHD patients identified copy number imbalances (copy number variants, CNVs) in three patients with PSIS; detecting gains encompassing LHX4 and OTX2 in two of the patients, respectively (Budny et al., 2020).

Digenic and polygenic inheritance and the application of next generation sequencing Genotype–phenotype discordance, intrafamilial clinical variability with mildly affected or unaffected mutationcarrying relatives, and inconsistent penetrance of identified molecular defects comprise core characteristics of PSIS and point away from what is considered as a classic Mendelian inheritance pattern (Voutetakis et al., 2016; Wang et al., 2017; Vergier et al., 2019). Theoretically, such complex inheritance features may be attributed to modifications of the expressivity of a given genetic defect by other factors or necessity for synergistically acting alterations in more than one gene (Roessler et al., 2012; Fang et al., 2016; Dubourg et al., 2018). In other words, coexistence of variants in contingent factors (members of the same or interacting pathways) may be a prerequisite for the abnormal PSIS phenotype to emerge in most cases. Such an inheritance pattern may well explain the observed difficulty in uncovering the molecular etiology in the vast majority of PSIS patients. Digenic inheritance, defined as the association of a phenotype with coexisting molecular alterations in two different (in most cases, functionally related) genes in the same patient, has been described with respect to PSIS. For example, the association between a PROKR2 mutation and a rare HESX1 polymorphism or a WDR11 variant has been documented in PSIS patients, respectively (Reynaud et al., 2012; McCormack et al., 2017). With respect to the latter, WDR11, a transcription factor that interacts with EMX1 (which in turn is involved in the development of olfactory neurons and pubertal development), has been associated with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome (Kim et al., 2010).

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A. VOUTETAKIS

Recently, application of WES and a variety of next generation sequencing (NGS) panels (e.g., for pituitary development, holoprosencephaly, and midline abnormalities) allowed meticulous molecular screening of large cohorts of PSIS patients (Bamshad et al., 2011; Guo et al., 2017; Zwaveling-Soonawala et al., 2018; Fang et al., 2020). These high-throughput techniques helped associate a relatively large number of novel potential candidate genes with the PSIS phenotype. Importantly, a number of affected genes have been identified to exist in the same patient; therefore, introducing the idea of multigenic inheritance as a plausible explanation of inconsistent penetrance observed in PSIS. Nevertheless, in most cases, these novel candidate genes and their potential interactions (or cumulative impact) have not been thoroughly tested and validated through functional studies or with the use of animal models. Instead, tools such as bioinformatics analysis, in silico prediction, allele frequency in controls, and effect on protein (truncation) have been applied nevertheless, following established guidelines for their interpretation (Richards et al., 2015). This is not surprising and does not limit the merit and importance of such efforts but underlines the volume of data produced by these powerful tools and the difficult task that follows with respect to their proper interpretation. Nevertheless, novel approaches, tools, and analyses might help us to better interpret and understand PSIS and other complex genetic disorders in the future (Kim et al., 2019; Alatzoglou et al., 2020). Guo et al. performed WES on 24 sporadic PSIS Han Chinese patients and identified 41 heterozygous variants in 22 of the participants in members of (or associated with) the Notch, SHH, and Wnt signaling pathways. Importantly, 83% of patients harbored multiple (from 2 to 5) of these variants, suggestive of polygenic involvement. Interestingly, no mutations were found in genes known to be associated with pituitary malformations or previously identified in familial cases with PSIS. The most frequently encountered genes were NCOR2 (of the Notch pathway), NKD2 (of the Wnt pathway), and ZIC2 (of the SHH pathway). Moreover, 46% of these patients experienced breech delivery and 9% perinatal events including dystocia or suffocation. Based on these results, authors concluded that familial and sporadic PSIS may be driven by a different set of gene mutations, respectively. Moreover, they suggested that compound mutations in multiple genes synergistically contribute to the PSIS phenotype in sporadic cases, with familial cases being attributed to single gene alterations (Guo et al., 2017). Likewise, Zwaveling-Soonawala et al. applied WES (as well as specific NGS panels) in 20 PSIS patients and identified five novel candidate genes: DCHS1 (implicated in neuronal migration), ROBO2 (participating in

axon guidance in the CNS), CCDC88C (which is a negative regulator of the Wnt signaling pathway), KIF14 (a cause of ciliopathies), and KAT6A (implicated in a form of syndromic developmental delay). In addition, pathogenic mutations were found in NR0B1 and PROK2 (in the hypogonadotropic hypogonadism panel) as well as in DHCR7 and CC2D2A (in the absent corpus callosum panel) along with several potentially pathogenic variants in genes involved in midline brain formation, pituitary development, HPE, hypogonadotropic hypogonadism, and absent corpus callosum. Overall, pathogenic or likely pathogenic variants were identified in 8 out of the 20 patients included in the study. Interestingly, all mutations found in the target panels were inherited from an unaffected parent. Importantly, 13 out of the 20 patients carried more than one variant (from two to four, in a single patient). Authors concluded that these data are suggestive of a polygenic etiology of isolated PSIS (ZwavelingSoonawala et al., 2018). Finally, when Fang et al. applied WES in 59 patients with PSIS, relevant molecular alterations were identified in a total of 59 genes, with 14 clustering to the Hedgehog pathway (i.e., in 50 out of the 59 participants). Of these, PTCH2, HHAT, MAPK3, EGR4 (combined with LHX4), SPG11, GLI2 (combined with PTCH2), and CDON (combined with GLI2) were considered as the most credible pathogenic and likely pathogenic variants associated with the PSIS phenotype (with PTCH2, HHAT, MAPK3, EGR4, SPG11 being novel heterozygous null variants). Genetic alterations in PTCH1, PTCH2, GLI2, TCTN1, and ATR were most frequently encountered in the cohort. By contrast, well-documented published pathogenic variants associated with PSIS were not identified. Interestingly, in 31 out of the 50 patients, variants in more than one candidate gene coexisted (ranging from two to five genes in a single patient), suggesting a polygenic inheritance pattern for PSIS (Fang et al., 2020). Importantly, perinatal adverse events were reported for the majority of the patients reported by Fang et al.: dystocia in 83.1%, abnormal fetal position in 71.2%, and history of hypoxia in 28.8% (Fang et al., 2020). Such data imply that our understanding of PSIS etiology (as either being genetic or due to perinatal adverse events) might be misconceived since one would not expect to find pathogenic variants in patients supposedly affected by environmental adversities. Such data offer proof that in most cases PSIS leads to a deficient pituitary hormonal milieu in the embryo that in turn increases susceptibility for adverse perinatal events and not vice versa.

ENVIRONMENTAL FACTORS AND PSIS As described previously in detail, PSIS is rarely familial (5% of all cases) and variable inter- and intrafamilial

PITUITARY STALK INTERRUPTION SYNDROME variability and penetrance is often observed with respect to associated alterations in important developmental genes. Therefore, it has been postulated that these specific genetic variants may act as predisposing factors that need to combine with additional molecular changes, epigenetic modifications, and environmental factors in order to lead to the various clinical forms of PSIS (Roessler et al., 2012). These types of interactions have been hypothesized to underlie and potentially explain a variety of complex disorders including HPE, in the extended spectrum of which PSIS has been recently “classified” (Ming and Muenke, 2002; Hunter, 2005; van Loo and Martens, 2007; Liu et al., 2008; Gohlke et al., 2009; Petryk et al., 2015). With respect to potential environmental influences, experimental data have shed some light in a scientific domain that is quite challenging to explore in humans. Potential HPE-related conditions, exposures, substances, and teratogens include maternal (and gestational) diabetes, ethanol, retinoic acid, cocaine (as well as other similar substances), and defective cholesterol biosynthesis (Dominguez et al., 1991; Ming and Muenke, 2002; Rogers et al., 2004; Billington et al., 2015; Petryk et al., 2015; Hong and Krauss, 2012). Interestingly, some of these harmful chemical effects necessitate a specific genetic background in order to occur and affect development, such as in the case of Twsg1 mutant mice and retinoic acid exposure as well as Cdon mutations and fetal ethanol exposure (Billington et al., 2015; Hong and Krauss, 2012). With respect to the latter, a broad range of phenotypic severity has been reported in loss-offunction mutations of the CDON gene in six patients with HPE as well as phenotypic discordance and variable penetrance in a familial case of PSIS without holoprosencephaly associated with a nonsense mutation in the CDON gene (Bae et al., 2011; Bashamboo et al., 2016). Whether such phenotypic differences observed in humans, are indeed due to the presence of other genetic or environmental factors (as in the case of experimental animals), remains to be proven. Overall, such data suggest that for certain complex genetic disorders that originate during early embryogenesis, such as PSIS, multifactorial synergy (including environmental factors as well as alterations in more than one gene) may modify or dictate the clinical phenotype observed.

CONCLUSIONS AND PERSPECTIVES PSIS is a heterogeneous and complex disorder characterized by high phenotypic variability and incomplete penetrance, diagnosed with MRI. It is currently considered an antenatal developmental defect and classified as a mild form of an expanded HPE spectrum. Specifically, PSIS has been associated with an expanding pool of

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molecular defects in genes involved in pituitary development, holoprosencephaly, neural development, and other important cellular processes. Importantly, digenic and multigenic inheritance has been revealed through the application of WES in large cohorts, with most candidate genes related to the Wnt, Notch, and Shh signaling pathways. Clinical symptoms and signs include evolving pituitary hormone deficiencies (leading to complete CPHD in most adult patients) and extrapituitary malformations, mostly affecting brain, eyes, and craniofacial structures. Of particular importance, a subset of patients manifesting with severe (and therefore life threatening) CPHD during the neonatal period. Nevertheless, the most common presentation of PSIS is growth retardation during early childhood. Follow-up of all patients throughout life is necessary due to the progressive development of endocrine deficiencies and the need for substitution therapy. PSIS seems to be a window overlooking basic developmental processes. Therefore, future studies need to focus not only in uncovering and reporting new candidate genes but also offering functional evidence and proving pathogenicity as well as potential interactions through the use of novel approaches, tools, and analyses including sophisticated software, a variety of animal models, the generation of stem cells derived from the patient’s fibroblasts and using CRISPR-Cas9 gene editing to generate knockout cell lines. Such an approach will help to elucidate genotype–phenotype discordances, explore gene–environment interactions, expand our understanding of development and make us able to offer genetic counseling. Since PSIS is a rare disorder, building strong worldwide collaborations and combining cohorts, databases, and efforts might help to achieve such a goal.

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Handbook of Clinical Neurology, Vol. 181 (3rd series) The Human Hypothalamus: Neuroendocrine Disorders D.F. Swaab, R.M. Buijs, P.J. Lucassen, A. Salehi, and F. Kreier, Editors https://doi.org/10.1016/B978-0-12-820683-6.00003-8 Copyright © 2021 Elsevier B.V. All rights reserved

Chapter 3

Empty sella syndrome: Multiple endocrine disorders SABRINA CHILOIRO, ANTONELLA GIAMPIETRO, ANTONIO BIANCHI, AND LAURA DE MARINIS* Pituitary Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy

Abstract Empty sella is a pituitary disorder characterized by the herniation of the subarachnoid space within the sella turcica. This is often associated with a variable degree of flattening of the pituitary gland. Empty sella has to be distinguished in primary and secondary forms. Primary empty sella (PES) excludes any history of previous pituitary pathologies such as previous surgical, pharmacologic, or radiotherapy treatment of the sellar region. PES is considered an idiopathic disease and may be associated with idiopathic intracranial hypertension. Secondary empty sella, however, may occur after the treatment of pituitary tumors through neurosurgery or drugs or radiotherapy, after spontaneous necrosis (ischemia or hemorrhage) of chiefly adenomas, after pituitary infectious processes, pituitary autoimmune diseases, or brain trauma. Empty sella, in the majority of cases, is only a neuroradiological finding, without any clinical implication. However, empty sella syndrome is defined in the presence of pituitary hormonal dysfunction (more frequently hypopituitarism) and/or neurological symptoms due to the possible coexisting of idiopathic intracranial hypertension. Empty sella syndrome represents a peculiar clinical entity, characterized by heterogeneity both in clinical manifestations and in hormonal alterations, sometimes reaching severe extremes. For a proper diagnosis, management, and follow-up of empty sella syndrome, a multidisciplinary approach with the integration of endocrine, neurological, and ophthalmological experts is strongly advocated.

INTRODUCTION Empty sella is a disorder due to the herniation of the subarachnoid space into the sella turcica, with a consequent compression and flattening of the pituitary gland and stretching of the pituitary stalk. In 1951, Busch defined “empty sella” for the first time as “a peculiar anatomical condition, observed in 40 of 788 human cadavers, particularly women, characterized by a sella turcica with a diaphragma sellae incomplete or that forms only a small peripheral rim, with a pituitary gland not absent, but flattened in such a manner as to form a thin layer of tissue at the bottom of the sella turcica” (Busch, 1951). In the following years, more details were reported. In particular, Kaufman, in 1968, described that “…empty sella is a distinct anatomical

and radiographic entity, function of an incompleteness of the diaphragma sellae and of the cerebrospinal fluid (CSF) pressure, normal or elevated…The role of the normal fluctuations of CSF pressures and the effect of a superimposed prolonged increase in CSF pressure were related to the anatomic changes involving the bony wall of the ” (Kaufman, 1968).

CLASSIFICATION Empty sella is typically classified as primary or secondary (Maira et al., 2005), as summarized in Fig. 3.1. Primary empty sella (PES) is defined after the exclusion of any history of previous pituitary pathologies such as previous surgical, pharmacologic, or radiotherapy treatment of the sellar region (Maira et al., 2005).

*Correspondence to: L. De Marinis, Pituitary Unit, Dipartimento di Medicina e Chirurgia traslazionale, Università Cattolica del Sacro Cuore, A. Gemelli Hospital IRCCS, Rome, Italy. Tel: +39-06-30158294, Fax: +39-06-30158294, E-mail: [email protected]

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Fig. 3.1. Schematic representation of the pathogenic mechanisms of the empty sella. Adjusted from Chiloiro, S., Giampietro, A., Bianchi, A., et al., 2017. Diagnosis of endocrine disease: primary empty sella: a comprehensive review. Eur J Endocrinol 177, R275–R285.

However, secondary empty sella (SES) can occur after the treatment of pituitary tumors in any of the following situations: through neurosurgery, drugs, radiotherapy, after spontaneous necrosis (ischemia or hemorrhage) of chiefly adenomas, after pituitary infectious processes, pituitary autoimmune disease such as hypophysitis (Hodgson et al., 1972; Chiloiro et al., 2018, 2019), or brain trauma (Hodgson et al., 1972). Moreover, SES can develop in patients with slow-growing and large intracranial neoplasia that may induce a progressive increase of intracranial pressure. The occurrence of SES was also reported in patients with brain tumors not located in the pituitary sella (Kim et al., 2009); patients who have undergone surgical procedures, radiotherapy, and pharmacologic treatments; and particularly in older patients affected by larger brain neoplasia and meningiomas (Kim et al., 2009).

EPIDEMIOLOGY Epidemiology data of empty sella are strongly influenced by collection methods. The first epidemiologic data were derived from an autopsy series and suggested an incidental finding of empty sella in approximately 5.5%–12% of cases (Busch, 1951; Kaufman, 1968). However, more recently neuroradiological studies have suggested an overall incidence of empty sella of 12%. In clinical practice, according to different series, PES is reported in around 8%–35% of the general population (Degli Uberti et al., 1989; Foresti et al., 1991; De Marinis

et al., 2005; Maira et al., 2005), with a female-to-male ratio of 5:1 (De Marinis et al., 2005). The high prevalence of PES in women may be explained by the history of at least one completed pregnancy and/or lactation (Guitelman et al., 2013). In fact, the pituitary volume increased during pregnancy and lactation, representing a risk factor for a subsequent development of PES in cases with a defect of sellar diaphragm. The peak incidence of PES occurs between 30 and 40 years of age, being sometimes earlier in women than in men. PES in children occurs less frequently than in adults and is frequently associated with hypothalamic–pituitary dysfunction, genetic disorders, or perinatal complications, such as Turner syndrome, moyamoya disease, Bartter syndrome, nevoid basal cell carcinoma syndrome, Hunter syndrome, Prader–Willi syndrome, Alstr€om syndrome, Meniere’s disease, and Erdheim–Chester disease (Linnemann et al., 1999; Takanashi et al., 2000; Ertekin et al., 2003; Lin et al., 2005; Catrinoiu et al., 2009; Loh et al., 2015; Nour et al., 2016; Tawfik et al., 2017). SES, on the other hand, is much more common than primary forms (Ucciferro and Anastasopoulou, 2019).

PATHOGENESIS OF EMPTY SELLA The pathogenesis of empty sella is not completely clarified. Numerous etiopathogenetic mechanisms seem to be involved. Table 3.1 summarizes a schematic representation of the actually recognized pathogenic mechanism of PES and SES.

EMPTY SELLA SYNDROME: MULTIPLE ENDOCRINE DISORDERS Table 3.1 Schematic representation of empty sella classification and etiology Primary empty sella

✓ Idiopathic etiology that required the exclusion of a history of previous pituitary pathologies or therapies, as previous surgical, pharmacologic, or radiotherapy treatment of the disease of the sellar region ✓ It may or may not be associated with idiopathic or benign intracranial hypertension

Secondary empty sella

May occur: ✓ in patients who underwent treatment for pituitary tumors through neurosurgery, drugs, or radiotherapy ✓ after spontaneous necrosis (ischemia or hemorrhage) of chiefly adenomas ✓ after pituitary infectious processes or pituitary autoimmune diseases ✓ after brain trauma ✓ in patients carrying slow-growing and large intracranial neoplasia, which may induce a progressive increase of intracranial pressure

The main determinant of the development of empty sella seems to be the presence of a congenital or acquired defect of the sellar diaphragm. This may facilitate the herniation of the subarachnoid space into the sella, which is determined in cases of the occurrence of upper-sellar risk factors, associated with an intracranial hypertension (as alteration of CSF’s pulsatility, a stable or intermittent increase in intracranial pressure) or in cases of the occurrence of pituitary risk factors, associated with the variation of pituitary volume (as in pregnancy, lactation) (Chiloiro et al., 2017). The sellar diaphragm is a deflection of the dura mater which separates the suprasellar cistern from the pituitary fossa, also called sella turcica. Incompetence of the sellar diaphragm is considered crucial in the formation of empty sella and has been demonstrated in 22%–77% of cases, while a total absence of diaphragm sella has been reported in 20.5% of normal subjects (DelgadoHernández et al., 2015). When the sellar diaphragm is incomplete, an unobstructed pathway exists between the chiasmatic cistern and the pituitary fossa, allowing the unopposed brisk pulsatile movements of the CSF to enter the sella turcica. These pulsations slowly flatten the pituitary gland into the floor of the sella and may occasionally erode through the bony wall of the sella into the sphenoid sinus, producing CSF rhinorrhea (Mortara

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and Norrel, 1970). However, most of these defects alone do not result in herniation of the subarachnoid space, and this confirms that the anomaly of the sellar diaphragm is essential for the development of PES, although other factors seem to be relevant as well. The role of intracranial hypertension in the genesis of PES has been proposed by many authors. Various intracranial conditions with elevated CSF pressure are associated with PES, such as hydrocephalus, thrombosis, meningitis, brain tumors, and Arnold-Chiari malformations (Friedman and Jacobson, 2002). Specifically, in over 94% of patients with intracranial idiopathic hypertension (IIH), empty sella was also described (Maira et al., 2005). IIH, also known as pseudotumor cerebri, is a syndrome characterized by elevated intracranial pressure, in the absence of intracranial mass lesion or hydrocephalus. Different etiologic mechanisms have been proposed for justifying the physiopathology of IIH, such as impaired CSF absorption, increased CSF secretion, increased cerebral hemodynamics, and, finally, increased cerebral capillary permeability (Friedman and Jacobson, 2002). In particular, impaired CSF absorption at the arachnoid villi was the most frequent alteration of the dynamics of CSF that occurred in over 80%–84% of patients with PES syndrome (Maira et al., 2005), followed by the impaired circulation and dynamics of CSF that occurred in over 77% of cases (Maira et al., 2005). PES syndrome may also occur in patients with abnormal pulsations of CSF, as in intracranial hypertension during sleeping. In fact, this condition may be sufficient to produce the empty sella in the presence of a deficient diaphragm sella (Maira et al., 2005). The spectrum of intracranial hypertension probably begins with a silent and intermittent form that gradually evolves into an empty sella and in severe forms of IIH, with papilledema, severe headache, and visual field symptoms. This would explain why only in some cases (from 8% to 15%) does empty sella progress to develop IIH, but conversely up to 94% of IIH-affected patients already carried an empty sella. Interestingly, obese female patients seem to be frequently affected by PES syndrome (Brisman et al., 1969). In various series of PES syndrome, the percentage of obese hypertensive women was 70%–80% (Kesler et al., 2001). The correlation between obesity, systemic hypertension, and PES syndrome is not clear. In obese patients, intermittent or persistent elevation of intracranial pressure was described, associated with hypercapnia and obstructive sleep apnea syndrome. Some authors, moreover, suggested a correlation between body mass index values and the occurrence of IIH (Daniels et al., 2007). Moreover, abdominal obesity may also raise intraabdominal pressure, with a consequent increase of both pleural and cardiac filling pressures. This obstructs

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venous return from the brain, leading to increased intracranial venous pressure and intracranial pressure (Newton and Bone, 1979; Sugita et al., 1985; Kirkpatrick et al., 1994). One other mechanism proposed is that obesity, directly or through cytokines and adipokines, can induce the activation of the 11beta-HSD1 enzyme, which increases cortisol production. Cortisol excess increases the intracranial pressure through the increment of CSF production and through a reduction of CSF drainage (Sinclair et al., 2008). Moreover, obesity is associated with thrombophilic–ipofibrinolytic coagulator disorders, which could induce microvascular thrombosis and, consequently, the reduction of CSF resorption and the increase of intracranial pressure (Romano et al., 2003; Wellen and Hotamisligil, 2003; Dunkley and Johnston, 2004). In summary, potential alterations of the sellar diaphragm and the presence of stable or intermittent increase of intracranial pressure may play an etiologic role in the development and maintenance of PES syndrome, particularly in obese patients. Additionally, the changes of pituitary volume may favor the occurrence of empty sella, in the presence of defects of the sellar diaphragm and/or in cases of CSF hypertension. An increase in the size of the pituitary gland is observed during pregnancy and lactation, when the pituitary gland volume can double, enlarging the sella turcica (Neelon et al., 1973). However, in women in the fourth decade of life, pituitary involution is associated with menopause, which explains why PES syndrome predominates in middle-aged women. On occasion, in cases of primary hormonal deficiency (such as primary hypothyroidism, primary hypoadrenalism, and primary hypogonadism), a compensatory pituitary hypertrophy occurs (Delgado-Hernández et al., 2015). In these cases, an enlargement of the pituitary gland occurs with a concomitant reduction of the suprasellar subarachnoid space. When the pituitary gland restores its volume, if there is not a corresponding reduction of both pituitary gland and sella turcica volume, this can create a space that can allow a suprasellar chiasmatic cistern herniation, as in hypoplastic diaphragm sella and in CSF hypertension, even if this is moderate and only temporary. Similar pathogenic mechanisms can be postulated in the case of SES. In fact, the presence of pituitary tumors or inflammatory disorders of the pituitary gland (Komatsu et al., 1988) induces an increase in the volume of the pituitary gland. The therapeutic management of these pituitary disorders through drugs, neurosurgery, or radiotherapy induces a reduction of the pituitary volume. Once again, the changes of the pituitary volume, associated with congenital or acquired diaphragma sellae defect or CSF hypertension, may induce the occurrence of empty sella.

PRESENTING CLINICAL MANIFESTATIONS The clinical presentation of empty sella is very variable. In the majority of cases, the empty sella remains a radiological finding, in the absence of clinical manifestations. Empty sella in fact is often incidentally discovered and represents a relatively common finding in autopsies (5%–23%) (Busch, 1951; Chynn, 1966; Kaufman, 1968; Foresti et al., 1991) and in radiological imaging (8%–35% in the general population) (Caplan and Dobben, 1969; Sage and Blumbergs, 2000). Empty sella is present in approximately 70% of patients with IIH (Brodsky and Vaphiades, 1998), representing the most commonly described imaging sign in the setting of IIH. In contrast, the incidence of IIH is relatively rare, estimated at approximately 1 case per 100,000 individuals. Therefore most patients showing an empty sella turcica on imaging will not have IIH. Consequently, empty sella can be an incidental radiological finding and does not usually present symptoms (Ambrosi and Faglia, 2002). However, the occurrence of endocrine, neurological, or ophthalmological symptoms associated with the radiological signs of empty sella characterizes the “empty sella syndrome” (De Marinis et al., 2005). The most common symptoms of empty sella syndrome are headache, menstrual irregularities, galactorrhea, hirsutism, and sterility (De Marinis et al., 2005). Specifically, headache and obesity are considered the most common clinical manifestations, respectively, in men and in women (Maira et al., 2005).

Endocrine symptoms The clinical picture in patients with PES is often quite complex. It is not always possible to differentiate symptoms and biochemical findings that are the consequences of the empty sella from those that are found due to a medical referral. However, in patients affected by SES, the clinical assessment is more easily recognized, due to the presence of a previous history of pituitary disorders. Irregular menses (hypo-, hyper-, oligo-, or polymenorrhea, anovular cycles, or short luteal phases, etc.) are present in 40%, galactorrhea in 26%, and hypertrichosis in 18% of female patients affected by PES (De Marinis et al., 2005). Overweight and obesity involve, respectively, 73% and 14% of PES-affected patients. Approximately 50% of women with PES present with obesity (6). On the other hand, among male patients, sexual disturbances occurred in around 53% and gynecomastia in around 12% of cases (6).

EMPTY SELLA SYNDROME: MULTIPLE ENDOCRINE DISORDERS Hypopituitarism is found in approximately 19% of patients (De Marinis et al., 2005). It is more readily recognized in patients affected by SES, due to damage caused by surgery, radiation therapy, or other pathologic causes (Ucciferro and Anastasopoulou, 2019). Insufficient glandular secretion can be caused by the compression of the pituitary parenchyma against the sellar cavity wall. This is associated with the stretching of the pituitary stalk that is flattened down to the thin residual pituitary. This insufficiency can be of varied degrees, ranging from panhypopituitarism with a prolactin (PRL) deficit, to hypopituitarism or isolated hormonal deficit, with an increased or normal PRL value. The most frequent pituitary deficit is growth hormone deficit that occurs, both in the adult and pediatric population, in 4%–57.1% of PES syndrome patients (Bianconcini et al., 1999; Cannavò et al., 2002; Gasperi et al., 2002; De Marinis et al., 2005; Maira et al., 2005; Del Monte et al., 2006; Ghatnatti et al., 2012; Guitelman et al., 2013). In addition, a secondary hypoadrenalism, hypothyroidism, and hypogonadism may occur in 2.3%–32% of PES syndrome cases. Hyperprolactinemia is documented in at least 7%–10% of PES syndrome-affected patients. Almost half of the patients have a PRL value of between 50 and 100 mg/L (median prolactin level, 31 mg/L) (De Marinis et al., 2005). Furthermore, it must be noted that menstrual irregularities (hypo-, hyper-, oligo-, or polymenorrhea, anovular cycles, or short luteal phases) may also occur while there is a normal PRL level; this can be explained by a hypersensitivity to normal PRL values or transient hyperprolactinemia periods that are not possible to observe with a single basal blood sample. In fact, an alteration of PRL circadian rhythm has been described in patients affected by empty sella syndrome, associated with a chronic or intermittently altered intracranial pressure. In patients affected by intracranial hypertension, the nightly PRL increment is reduced or completely lacking, in particular during the REM phase (Maira et al., 1984, 1990). Rarely, a pituitary hypersecretion condition was described in patients with empty sella, associated with ectopic GH and ACTH secreting pituitary adenomas (Mancini et al., 1990; Arzamendi et al., 2016), located within the midline in the intersphenoidal septum. Endocrine disturbances may also derive from an alteration in CSF dynamics and immune system reactions that may interfere with the release of hypothalamic neurotransmitters. These factors highlight a complex network of primary and secondary effects resulting from the initial anatomic alteration. In patients with increased CSF pressure, the dopamine inhibition is altered, as suggested by the PRL response to dynamic tests. It has been hypothesized that the original neuroanatomic alteration can

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influence neuronal dopamine reuptake. In fact, intracranial hypertension interferes with dopamine reuptake, strengthening the dopamine’s action at the pituitary level and lowering PRL’s reaction to nomifensine, an indirect dopaminergic agonist (Barbarino et al., 1987). In empty sella cases with normal PRL values, the increased dopaminergic tone induces a response to a single thyrotropin releasing hormone (TRH) and metoclopramide (MCP) test similar to that observed in the normal subjects. However, in empty sella subjects, there is a higher and more prolonged PRL release and an inferior increment of PRL after stimulation with MCP, as compared to normal subjects. Moreover, there is an inverse correlation between basal PRL levels and the post-MCP administration peak increment (De Marinis et al., 1988). In PES syndrome with moderate hyperprolactinemia, the laboratory differential diagnosis with PRL-secreting pituitary adenoma represents a great challenge, in which pituitary neuroimaging plays a crucial role. In fact, an increased central dopaminergic activity with respect to TSH secretion is characteristic of prolactinomas and, when a reaction to TSH and MCP is not present, it is possible to exclude a PRL-secreting pituitary adenoma (Barbarino et al., 1978). At least, in pre- and postmenopausal patients affected by empty sella, the PRL dynamics differ, as estrogen-mediated dopamine activation is presumably less than in postmenopausal women. Consequently, in postmenopausal PES-affected patients, PRL response to TRH is often greater than in normal subjects and, in premenopausal PES-affected patients, PRL response to TRH is similar to that in normal women (De Marinis et al., 1986). In young fertile women affected by PES with normal PRL levels, the increase of a high nightly value and the reestablishment of PRL’s circadian rhythm were observed in patients on treatment with tryptophan, suggesting an alteration of the serotoninergic system, which in physiologic conditions stimulates PRL secretion through central mechanisms (De Marinis et al., 1993). In conclusion, multiple factors can influence PRL dynamic tests in PES, such as intracranial pressure, the integrity of the pituitary stalk, the basal PRL value, and the gonadal status. Pituitary hormone alterations in patients affected by SES may be influenced also by previous pituitary disorders, such as secreting pituitary adenomas or other causes of hypopituitarism, such as radiotherapy.

Neurological and ophthalmological symptoms Neurological and opthalmological signs of empty sella syndrome are predominantly due to the presence of intracranial hypertension. In fact, an intracranial pressure

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higher than 14 mm/Hg is sufficient to maintain the neurological symptomatology of empty sella syndrome, such as headache and visual disturbances. Headache in empty sella syndrome is typically lateral, persistent, and present for years and may occur in 84%– 88% of cases (De Marinis et al., 2005; Maira et al., 2005). In about 20% of cases, headache is accompanied by symptoms of intracranial hypertension, such as papilledema and visual disturbances (Chiloiro et al., 2018; Ucciferro and Anastasopoulou, 2019). Neurological disturbances such as dizziness, syncope, cranial nerve disorders, convulsions, or depression occurred in about 40% of patients (Maira et al., 2005). Rarely, CSF rhinorrhea may occur in combination with the empty sella syndrome, increasing the risk of retrograde meningitis. Ophthalmological signs include the worsening of visual acuity (13%–37%), blurred vision (29%), diplopia (2%), defects in the oculomotor nerve (1%), and optical neuritis (1%) (De Marinis et al., 2005; Maira et al., 2005).

DIAGNOSIS Empty sella may be diagnosed in most cases incidentally by a neuroradiologist, during a brain MRI or computerized tomography (CT) (Chiloiro et al., 2017). In this case, the patient should be addressed to an endocrinologist, ophthalmologist, and neurosurgeon for diagnosing or excluding, respectively, the occurrence of hypopituitarism, ophthalmology disorder, and intracranial hypertension. Similarly, if empty sella syndrome is diagnosed by a pituitary MRI test conducted for: -

-

-

hypopituitarism, the patient should be addressed to the ophthalmologist and/or the neurosurgeon for diagnosing or excluding the occurrence of intracranial hypertension; ophthalmological disorders, the patient should be addressed to the neuroendocrinologist for diagnosing/excluding hypopituitarism and to the neurosurgeon for the evaluation of intracranial hypertension; symptoms of intracranial hypertension, the patient should be addressed to the neuroendocrinologist for diagnosing/excluding hypopituitarism and to the ophthalmologist for diagnosing/excluding visual field disorders.

In conclusion, empty sella and empty sella syndrome require a multidisciplinary management, for diagnosis, treatment, and follow-up, with the integration of neuroendocrine, neurological, and ophthalmological experts.

performed, in particular for TSH, fT4, prolactin, ACTH, cortisol, IGF-I, LH, FSH, testosterone in male, and estradiol in premenopausal women. Moreover, if indicated, dynamic tests are also suggested, for confirming the presence of pituitary hormonal deficits. In the very rare cases of secreting pituitary adenomas of the midline intersphenoidal septum, pituitary hormonal hypersecretion can occur and should be properly investigated.

Ophthalmological assessment In recent years, ophthalmic echography has taken up a primary role in the diagnosis of intracranial hypertension and in patients affected by empty sella syndrome. Ophthalmic echography is a brief, noninvasive, extremely specific diagnostic tool, able to provide an indirect evaluation through the observation of the optic nerves’ morphology and dimensions as well as the observation of the periotic subarachnoid spaces. In fact, optic nerve diameters have a direct, biphasic, positive correlation with diastolic intracranial pressure and with the intracranial absorptive reserve (Tamburrelli et al., 1990). Moreover, optic nerve diameters rapidly change in response to a variation in intracranial pressure (Tamburrelli et al., 1990). In cases of ophthalmic echography suggestive of intracranial hypertension, a computerized visual field view and visual evoked potential should be performed to detect possible neurological damage. These examinations should be performed at PES diagnosis and during follow-up, according to the clinical features, for surveillance and for evaluating possible treatment efficacy.

Radiological assessment Empty sella can be diagnosed through MRI or CT study of the sellar and suprasellar region. CT should be limited to patients with absolute contraindications to the MRI. As previously discussed, empty sella is diagnosed at neuroradiological examinations in the majority of cases. In more selected cases, PES syndrome is detected during MRI studies conducted for the analysis of hypopituitarism and symptoms or signs of intracranial hypertension. The diagnosis of SES is frequently found during the radiological follow-up of pituitary diseases. As shown in Fig. 3.2, the typical findings of PES are (Osborn et al., 2016) -

Endocrinological assessment

-

Hormonal tests are required in patients affected by empty sella to identify hypopituitarism. In all empty sella patients, basal pituitary hormonal dosage should be

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the intrasellar CSF filling in continuity with overlying subarachnoid spaces; the residual pituitary gland, with a semilunate morphology, flattened against the sellar floor; the enlarged bony sella; the pituitary stalk usually thinned, located in the midline; the optic chiasm and the anterior 3rd ventricle can occasionally herniate into the sella.

EMPTY SELLA SYNDROME: MULTIPLE ENDOCRINE DISORDERS

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Fig. 3.2. Primary empty sella MRI study: (A and B) Sagittal and coronal postcontrast T1w images. The (*) represents the intrasellar CSF filling in continuity with overlying subarachnoid spaces; the arrow represents the residual pituitary gland, with a semilunate morphology, flattened against the sellar floor and the enlarged bony sella; the (#) represents the pituitary stalk thinned and located on midline.

Sagittal and coronal T1-weighted (T1W) contrastenhanced images and coronal T2-weighted (T2W) images are strongly recommended for an accurate MRI study of empty sella. T1W and T2W images particularly show a fluid signal within the sella similar to that of CSF. On FLAIR sequences intrasellar fluid is completely suppressed and it then presents without restriction in DWI sequences. After contrast, T1W images show a normal enhancement of the residual pituitary gland and stalk, without any abnormalities. Fig. 3.3 represents a case of a male patient affected by PES syndrome with secondary hypoadrenalism, due to Arnold-Chiari syndrome. MR imaging can also focalize indirect signs of intracranial hypertension, such as the flattening of the posterior sclera, prominent subarachnoid spaces along the optic nerves, vertical tortuosity of the optic nerve sheath complex, protrusion or enhancement of the prelaminar optic nerve (Saindane et al., 2013), and nerve sheath volumes >201.30 mm3 with pituitary volumes >>>>>>>>>>>> Set point >>>>> Set point