Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Félixe Pelletier; Stefanie Perrier; Ferdy K Cayami; Amytice Mirchi; Stephan Saikali; Luan T Tran; Nicole Ulrick; Kether Guerrero; Emmanouil Rampakakis; Rosalina M L van Spaendonk; Sakkubai Naidu; Daniela Pohl; William T Gibson; Michelle Demos; Cyril Goizet; Ingrid Tejera-Martin; Ana Potic; Brent L Fogel; Bernard Brais; Michel Sylvain; Guillaume Sébire; Charles Marques Lourenço; Joshua L Bonkowsky; Coriene Catsman-Berrevoets; Pedro S Pinto; Sandya Tirupathi; Petter Strømme; Ton de Grauw; Dorota Gieruszczak-Bialek; Ingeborg Krägeloh-Mann; Hanna Mierzewska; Heike Philippi; Julia Rankin; Tahir Atik; Brenda Banwell; William S Benko; Astrid Blaschek; Annette Bley; Eugen Boltshauser; Drago Bratkovic; Klara Brozova; Icíar Cimas; Christopher Clough; Bernard Corenblum; Argirios Dinopoulos; Gail Dolan; Flavio Faletra; Raymond Fernandez; Janice Fletcher; Maria Eugenia Garcia Garcia; Paolo Gasparini; Janina Gburek-Augustat; Dolores Gonzalez Moron; Aline Hamati; Inga Harting; Christoph Hertzberg; Alan Hill; Grace M Hobson; A Micheil Innes; Marcelo Kauffman; Susan M Kirwin; Gerhard Kluger; Petra Kolditz; Urania Kotzaeridou; Roberta La Piana; Eriskay Liston; William McClintock; Meriel McEntagart; Fiona McKenzie; Serge Melançon; Anjum Misbahuddin; Mohnish Suri; Fernando I Monton; Sebastien Moutton; Raymond P J Murphy; Miriam Nickel; Hüseyin Onay; Simona Orcesi; Ferda Özkınay; Steffi Patzer; Helio Pedro; Sandra Pekic; Mercedes Pineda Marfa; Amy Pizzino; Barbara Plecko; Bwee Tien Poll-The; Vera Popovic; Dietz Rating; Marie-France Rioux; Norberto Rodriguez Espinosa; Anne Ronan; John R Ostergaard; Elsa Rossignol; Rocio Sanchez-Carpintero; Anna Schossig; Nesrin Senbil; Laura K Sønderberg Roos; Cathy A Stevens; Matthis Synofzik; László Sztriha; Daniel Tibussek; Dagmar Timmann; Davide Tonduti; Bart P van de Warrenburg; Maria Vázquez-López; Sunita Venkateswaran; Pontus Wasling; Evangeline Wassmer; Richard I Webster; Gert Wiegand; Grace Yoon; Joost Rotteveel; Raphael Schiffmann; Marjo S van der Knaap; Adeline Vanderver; Gabriel Á Martos-Moreno; Constantin Polychronakos; Nicole I Wolf; Geneviève Bernard

doi:10.1210/clinem/dgaa700

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

J Clin Endocrinol Metab. 2021 Jan 23;106(2):e660-e674. doi: 10.1210/clinem/dgaa700.

Authors

Félixe Pelletier^{1

2

3

4

5

6}, Stefanie Perrier^{1

4}, Ferdy K Cayami^{7

8}, Amytice Mirchi^{1

2

3

4

5}, Stephan Saikali⁹, Luan T Tran^{1

2

3

4}, Nicole Ulrick¹⁰, Kether Guerrero^{1

2

3

4}, Emmanouil Rampakakis², Rosalina M L van Spaendonk¹¹, Sakkubai Naidu¹², Daniela Pohl¹³, William T Gibson¹⁴, Michelle Demos¹⁵, Cyril Goizet¹⁶, Ingrid Tejera-Martin¹⁷, Ana Potic¹⁸, Brent L Fogel¹⁹, Bernard Brais^{1

3

20}, Michel Sylvain²¹, Guillaume Sébire^{2

22}, Charles Marques Lourenço²³, Joshua L Bonkowsky²⁴, Coriene Catsman-Berrevoets²⁵, Pedro S Pinto²⁶, Sandya Tirupathi²⁷, Petter Strømme²⁸, Ton de Grauw²⁹, Dorota Gieruszczak-Bialek^{30

31}, Ingeborg Krägeloh-Mann³², Hanna Mierzewska³³, Heike Philippi³⁴, Julia Rankin³⁵, Tahir Atik³⁶, Brenda Banwell³⁷, William S Benko³⁸, Astrid Blaschek³⁹, Annette Bley⁴⁰, Eugen Boltshauser⁴¹, Drago Bratkovic⁴², Klara Brozova⁴³, Icíar Cimas⁴⁴, Christopher Clough⁴⁵, Bernard Corenblum⁴⁶, Argirios Dinopoulos⁴⁷, Gail Dolan⁴⁸, Flavio Faletra⁴⁹, Raymond Fernandez⁵⁰, Janice Fletcher⁵¹, Maria Eugenia Garcia Garcia⁵², Paolo Gasparini⁵³, Janina Gburek-Augustat⁵⁴, Dolores Gonzalez Moron⁵⁵, Aline Hamati⁵⁶, Inga Harting⁵⁷, Christoph Hertzberg⁵⁸, Alan Hill⁵⁹, Grace M Hobson⁶⁰, A Micheil Innes⁶¹, Marcelo Kauffman⁶², Susan M Kirwin⁶³, Gerhard Kluger⁶⁴, Petra Kolditz⁶⁵, Urania Kotzaeridou⁶⁶, Roberta La Piana⁶⁷, Eriskay Liston⁶⁸, William McClintock^{69

70}, Meriel McEntagart⁷¹, Fiona McKenzie^{72

73}, Serge Melançon⁷⁴, Anjum Misbahuddin⁷⁵, Mohnish Suri⁷⁶, Fernando I Monton¹⁷, Sebastien Moutton⁷⁷, Raymond P J Murphy⁷⁸, Miriam Nickel⁷⁹, Hüseyin Onay⁸⁰, Simona Orcesi⁸¹, Ferda Özkınay⁸², Steffi Patzer⁸³, Helio Pedro⁸⁴, Sandra Pekic⁸⁵, Mercedes Pineda Marfa⁸⁶, Amy Pizzino^{87

88}, Barbara Plecko⁸⁹, Bwee Tien Poll-The⁹⁰, Vera Popovic⁹¹, Dietz Rating⁹², Marie-France Rioux⁹³, Norberto Rodriguez Espinosa¹⁷, Anne Ronan⁹⁴, John R Ostergaard⁹⁵, Elsa Rossignol⁹⁶, Rocio Sanchez-Carpintero⁹⁷, Anna Schossig⁹⁸, Nesrin Senbil⁹⁹, Laura K Sønderberg Roos¹⁰⁰, Cathy A Stevens¹⁰¹, Matthis Synofzik¹⁰², László Sztriha¹⁰³, Daniel Tibussek¹⁰⁴, Dagmar Timmann¹⁰⁵, Davide Tonduti¹⁰⁶, Bart P van de Warrenburg¹⁰⁷, Maria Vázquez-López¹⁰⁸, Sunita Venkateswaran¹⁰⁹, Pontus Wasling¹¹⁰, Evangeline Wassmer¹¹¹, Richard I Webster¹¹², Gert Wiegand^{113

114}, Grace Yoon¹¹⁵, Joost Rotteveel¹¹⁶, Raphael Schiffmann¹¹⁷, Marjo S van der Knaap^{7

118}, Adeline Vanderver^{10

119}, Gabriel Á Martos-Moreno^{120

121

122}, Constantin Polychronakos¹²³, Nicole I Wolf⁷, Geneviève Bernard^{1

2

3

4

5}

Affiliations

¹ Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
² Department of Pediatrics, McGill University, Montreal, QC, Canada.
³ Department of Human Genetics, McGill University, Montreal, QC, Canada.
⁴ Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
⁵ Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada.
⁶ Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada.
⁷ Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁸ Center of Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
⁹ Department of Pathology, Centre Hospitalier Universitaire de Québec, Québec City, QC, Canada.
¹⁰ Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹² Department of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
¹³ Division of Neurology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.
¹⁴ Department of Medical Genetics, University of British Columbia, BC Children's Hospital Research Institute, Vancouver, BC, Canada.
¹⁵ Division of Neurology, Department of Pediatrics, University of British Columbia, BC Children's Hospital, Vancouver, BC, Canada.
¹⁶ Centre de Référence Neurogénétique, Service de Génétique Médicale, Bordeaux University Hospital, and Laboratoire MRGM, INSERM U1211, Université de Bordeaux, Bordeaux, France.
¹⁷ Department of Neurology, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Canary Islands, Spain.
¹⁸ Department of Neurology, Clinic for Child Neurology and Psychiatry, Medical Faculty University of Belgrade, Belgrade, Serbia.
¹⁹ Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
²⁰ Montreal Neurological Institute, Montreal, QC, Canada.
²¹ Centre Mère Enfant, CHU de Québec, Québec City, QC, Canada.
²² Department of Pediatrics, Université de Sherbrooke, Sherbrooke, QC, Canada.
²³ Faculdade de Medicina, Centro Universitario Estácio de Ribeirão Preto, Ribeirão Preto, SP, Brazil.
²⁴ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
²⁵ Department of Paediatric Neurology, Erasmus University Hospital - Sophia Children's Hospital, 3015 CN Rotterdam, The Netherlands.
²⁶ Neuroradiology Department, Centro Hospitalar do Porto, Porto, Portugal.
²⁷ Department of Paediatric Neurology, Royal Belfast Hospital for Sick Children, Belfast, UK.
²⁸ Division of Pediatrics and Adolescent Medicine, Oslo University Hospital, Ullevål, 0450 Oslo, and University of Oslo, Oslo, Norway.
²⁹ Department of Pediatrics, Emory School of Medicine, Atlanta, GA, USA.
³⁰ Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
³¹ Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland.
³² Department of Child Neurology, University Children's Hospital Tübingen, Tübingen, Germany.
³³ Department of Child and Adolescent Neurology, Institute of Mother and Child, Warsaw, Poland.
³⁴ Center of Developmental Neurology (SPZ Frankfurt Mitte), Frankfurt, Germany.
³⁵ Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
³⁶ Division of Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey.
³⁷ Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
³⁸ Division of Pediatric Neurology, Department of Neurology, UC Davis Health System, Sacramento, CA, USA.
³⁹ Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany.
⁴⁰ University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴¹ Department of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
⁴² Metabolic Clinic, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
⁴³ Department of Child Neurology, Thomayers Hospital, Prague, Czech Republic.
⁴⁴ Department of Neurology, Povisa Hospital, Vigo, Spain.
⁴⁵ Department of Neurology, King's College Hospital, London, UK.
⁴⁶ Division of Endocrinology & Metabolism, Department of Medicine, University of Calgary, Calgary, AB, Canada.
⁴⁷ Third Department of Pediatrics, National and Kapodistrian University of Athens, "Attikon" Hospital, Athens, Greece.
⁴⁸ Bristow Pediatrics, Bristow, VA, USA.
⁴⁹ Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy.
⁵⁰ Pediatric Neurology Associates, Tampa, FL, USA.
⁵¹ Genetics and Molecular Pathology, Women's and Children's Hospital, Adelaide, South Australia, Australia.
⁵² Department of Neurology, The Royal London Hospital, London, UK.
⁵³ Institute for Maternal and Child Health, IRCCS Burlo Garofolo, 34100 Trieste, and University of Trieste, Trieste, Italy.
⁵⁴ Division of Neuropaediatrics, Hospital for Children and Adolescents, University Leipzig, Leipzig, Germany.
⁵⁵ Neurogenetics Unit, Department of Neurology, Hospital JM Ramos Mejia, ADC, Buenos Aires, Argentina.
⁵⁶ Department of Child Neurology, Indiana University, Indianapolis, IN, USA.
⁵⁷ Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
⁵⁸ Department of Child Neurology, Vivantes Klinikum, Berlin, Germany.
⁵⁹ Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
⁶⁰ Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
⁶¹ Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
⁶² Neurogenetics Unit, Department of Neurology, Hospital JM Ramos Mejia and CONICET, ADC, Buenos Aires, Argentina.
⁶³ Molecular Diagnostics Laboratory, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
⁶⁴ PMU Salzburg, 5020 Salzburg, Austria; Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.
⁶⁵ Department of Child Neurology, Kantonsspital Luzern, Luzern, Switzerland.
⁶⁶ Department of Child Neurology, University Children's Hospital Heidelberg, Heidelberg, Germany.
⁶⁷ Department of Neuroradiology, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
⁶⁸ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
⁶⁹ Pediatric Specialists of Virginia, Fairfax, VA, USA.
⁷⁰ Department of Neurology, Children's National Medical Center, Washington, DC, USA.
⁷¹ South West Thames Regional Genetics Service, St. George's Hospital, London, UK.
⁷² Genetic Services of Western Australia, Subiaco, WA, Australia.
⁷³ School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.
⁷⁴ Department of Medical Genetics, McGill University Health Centre, Montreal Children's Hospital, Montreal, QC, Canada.
⁷⁵ Essex Centre for Neurological Sciences, Queen's Hospital, Romford, UK.
⁷⁶ Nottingham Clinical Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁷⁷ Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France.
⁷⁸ Department of Neurology, Tallaght University Hospital, Tallaght, Ireland.
⁷⁹ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸⁰ Department of Medical Genetics, Ege University, Izmir, Turkey.
⁸¹ Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.
⁸² Department of Pediatrics, Subdivision of Pediatric Genetics, Faculty of Medicine, Ege University, Izmir, Turkey.
⁸³ Children's Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany.
⁸⁴ Department of Pediatrics, The Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, NJ, USA.
⁸⁵ Clinic for Endocrinology, Diabetes and Diseases of Metabolism, University Clinical Center, Belgrade & School of Medicine, University of Belgrade, Belgrade, Serbia.
⁸⁶ Hospital Sant Joan de Deu, Passeig de Sant Joan de Deu nº2, Barcelona, Spain.
⁸⁷ Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸⁸ Department of Genetics, MetroHealth Hospital, Cleveland, OH, USA.
⁸⁹ Department of Pediatrics and Adolescent Medicine, Division of General Pediatrics, Medical University of Graz, Graz, Austria.
⁹⁰ Department of Pediatric Neurology, Emma Children's Hospital, 1105 Amsterdam, The Netherlands.
⁹¹ Medical Faculty, University of Belgrade, Belgrade, Serbia.
⁹² Department of Paediatric Neurology, University Children's Hospital, Heidelberg, Germany.
⁹³ Centre Hospitalier Universitaire de Sherbrooke - Hôpital Fleurimont, Sherbrooke, QC, Canada.
⁹⁴ Hunter New England LHD, University of Newcastle, NSW, Australia.
⁹⁵ Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
⁹⁶ Departments of Neurosciences and Pediatrics, CHU-Sainte-Justine, Université de Montréal, Montreal, QC, Canada.
⁹⁷ Pediatric Neurology Unit, Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain.
⁹⁸ Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
⁹⁹ Department of Child Neurology, Kırıkkale University Medical Faculty, Kırıkkale, Turkey.
¹⁰⁰ Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
¹⁰¹ Department of Pediatrics, Division of Medical Genetics, University of Tennessee College of Medicine, Chattanooga, TN, USA.
¹⁰² Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
¹⁰³ Department of Paediatrics, University of Szeged, Szeged, Hungary.
¹⁰⁴ Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
¹⁰⁵ Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.
¹⁰⁶ Child Neurology Unit, V. Buzzi Children's Hospital, Milano, Italy.
¹⁰⁷ Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
¹⁰⁸ Sección Neuropediatría. Hospital Maternoinfantil Gregorio Marañón, Madrid, Spain.
¹⁰⁹ Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
¹¹⁰ Department of Neuroscience and Rehabilitation, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹¹¹ Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK.
¹¹² T. Y. Nelson Department of Neurology and Neurosurgery and the Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
¹¹³ Department of Pediatric Neurology, University Hospital Kiel, Germany.
¹¹⁴ Neuropediatrics Section of the Department of Pediatrics, Asklepios Clinic Hamburg Nord-Heidberg, Hamburg, Germany.
¹¹⁵ Division of Clinical and Metabolic Genetics, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹¹⁶ Emma Children's Hospital, Amsterdam UMC, Pediatric Endocrinology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹¹⁷ Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA.
¹¹⁸ Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
¹¹⁹ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹²⁰ Department of Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain.
¹²¹ Department of Pediatrics, Universidad Autónoma de Madrid, 28049 Madrid, Spain.
¹²² CIBER de Fisiopatologia de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
¹²³ Division of Endocrinology, Montreal Children's Hospital and the Endocrine Genetics Lab, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

Abstract

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main outcome measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Keywords: 4H leukodystrophy; POLR3-related leukodystrophy; hypogonadotropic hypogonadism; hypomyelination.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Biological Variation, Population
Child
Child, Preschool
Cohort Studies
Cross-Sectional Studies
DNA-Directed RNA Polymerases / genetics*
Endocrine System Diseases / epidemiology
Endocrine System Diseases / etiology
Endocrine System Diseases / genetics*
Female
Genetic Heterogeneity
Growth Disorders / epidemiology
Growth Disorders / etiology
Growth Disorders / genetics*
Hereditary Central Nervous System Demyelinating Diseases / complications
Hereditary Central Nervous System Demyelinating Diseases / epidemiology
Hereditary Central Nervous System Demyelinating Diseases / genetics*
Humans
Hypogonadism / epidemiology
Hypogonadism / etiology
Infant
Infant, Newborn
Male
Mitochondrial Diseases / complications
Mitochondrial Diseases / epidemiology
Mitochondrial Diseases / genetics*
Mutation
RNA Polymerase III / genetics
Retrospective Studies
Young Adult

Substances

DNA-Directed RNA Polymerases
POLR1C protein, human
POLR3A protein, human
POLR3B protein, human
RNA Polymerase III

Supplementary concepts

Leukodystrophy, Hypomyelinating, 4

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding