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

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DOI

  • Félixe Pelletier, McGill Univ, McGill University, McGill Space Inst
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  • Stefanie Perrier, McGill Univ, McGill University, McGill Space Inst
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  • Ferdy K Cayami, Amsterdam University Medical Centers
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  • Amytice Mirchi, McGill Univ, McGill University, McGill Space Inst
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  • Stephan Saikali, Service d'allergie, Centre Hospitalier Université Laval/Centre Hospitalier Universitaire de Québec, Québec, QC, Canada.
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  • Luan T Tran, McGill Univ, McGill University, McGill Space Inst
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  • Nicole Ulrick, The Children's Hospital of Philadelphia, Philadelphia, PA
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  • Kether Guerrero, McGill Univ, McGill University, McGill Space Inst
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  • Emmanouil Rampakakis, McGill Univ, McGill University, McGill Space Inst
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  • Rosalina M L van Spaendonk, Department of Clinical Genetics and Department of Human Genetics Leiden University Medical Centre, Leiden, The Netherlands.
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  • Sakkubai Naidu, Kennedy Krieger Inst, Kennedy Krieger Institute, Ctr Genet Disorders Cognit & Behav
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  • Daniela Pohl, Univ Ottawa, University of Ottawa, Ottawa Hospital Research Institute, Childrens Hosp Eastern Ontario, Ottawa Hosp, Div Orthopaed Surg
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  • William T Gibson, Univ British Columbia Okanagan, University of British Columbia Okanagan, University of British Columbia
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  • Michelle Demos, Univ British Columbia Okanagan, University of British Columbia Okanagan, University of British Columbia
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  • Cyril Goizet, Department of Cardiology/Hypertension, University Hospital of Bordeaux, Bordeaux, France.
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  • Ingrid Tejera-Martin, Hospital Universitario Nuestra Senora de Candelaria
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  • Ana Potic, Department of Cardiology, Clinical Center of Serbia, and Medical Faculty, University of Belgrade, Belgrade. Serbia.
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  • Brent L Fogel, Department of Dermatology, University of California, San Diego, California; Department of Pediatrics, University of California, San Diego, California; Rady Children's Hospital, San Diego, California.
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  • Bernard Brais, McGill Univ, McGill University, McGill Space Inst
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  • Michel Sylvain, Centre Mère Enfant
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  • Guillaume Sebire, McGill Univ, McGill University, McGill Space Inst
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  • Charles Marques Lourenço, Faculdade de Medicina Veterinaria
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  • Joshua L Bonkowsky, University of Utah School of Medicine, Salt Lake City, Utah; Utah Center for Advanced Imaging Research, Salt Lake City, Utah.
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  • Coriene Catsman-Berrevoets, Department of Pediatric Oncology/Hematology, Sophia Children's Hospital-Erasmus University Medical Center, Rotterdam, The Netherlands.
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  • Pedro S Pinto, Centro Hospitalar Universitário Porto
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  • Sandya Tirupathi, o The Royal Hospital for Sick Children , Belfast , N. Ireland.
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  • Petter Strømme, Department of Rheumatology and Medical Faculty, Oslo University Hospital and University of Oslo, Oslo, Norway; Norwegian National Advisory Unit on Rheumatic Diseases in Children and Adolescents, Oslo University Hospital, Oslo, Norway.
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  • Ton de Grauw, Emory University School of Medicine
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  • Dorota Gieruszczak-Bialek, Children's Memorial Health Institute
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  • Ingeborg Krägeloh-Mann, Department of General Paediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
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  • Hanna Mierzewska, Institute of Mother and Child
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  • Heike Philippi, Center of Developmental Neurology (SPZ Frankfurt Mitte)
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  • Julia Rankin, Peninsula Clinical Genetics Service
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  • Tahir Atik, Ege Univ Hosp, Ege University, Dept Pulmonol
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  • Brenda Banwell, The Children's Hospital of Philadelphia, Philadelphia, PA
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  • William S Benko, Division of Pediatric Neurology, Department of Pediatric and Adolescent Medicine, University Medical Center, Göttingen, Germany.
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  • Astrid Blaschek, Munich University Hospital
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  • Annette Bley, Tallinn Children's Hospital, Tallinn, Estonia; Tartu University Hospital, Children's Clinic, Tartu, Estonia.
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  • Eugen Boltshauser, University Children's Hospital Zurich, CHE, Zurich, Switzerland.
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  • Drago Bratkovic, KK Women's and Children's Hospital
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  • Klara Brozova, Thomayers Hospital
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  • Icíar Cimas, Hospital POVISA
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  • Christopher Clough, King's College and King's College Hospital
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  • Bernard Corenblum, University of Calgary, Calgary, Canada.
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  • Argirios Dinopoulos, National and Kapodistrian University of Athens
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  • Gail Dolan, Bristow Pediatrics
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  • Flavio Faletra, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
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  • Raymond Fernandez, Pediatric Neurology Associates
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  • Janice Fletcher, KK Women's and Children's Hospital
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  • Maria Eugenia Garcia Garcia, The Royal London Hospital
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  • Paolo Gasparini, Sincrotrone Trieste, 34149 Trieste, Italy and Department of Physics, University of Trieste, 34127 Trieste, Italy.
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  • Janina Gburek-Augustat, Department of Cardiology, Heart Center Leipzig, University of Leipzig, Leipzig.
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  • Dolores Gonzalez Moron, Hospital J.M. Ramos Mejia, Buenos Aires, Argentina.
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  • Aline Hamati, Indiana Univ Sch Med, Indiana University-Purdue University Indianapolis, Indiana University System, Indiana Alzheimer Dis Ctr
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  • Inga Harting, Heidelberg Ion Beam Therapy Center (HIT), Heidelberg University Hospital, Heidelberg
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  • Christoph Hertzberg, Department of Child Neurology, Queen Paola Child Hospital, Antwerp, Belgium.
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  • Alan Hill, Univ British Columbia Okanagan, University of British Columbia Okanagan, University of British Columbia
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  • Grace M Hobson, Nemours/ Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
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  • A Micheil Innes, University of Calgary, Calgary, Canada.
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  • Marcelo Kauffman, Hospital JM Ramos Mejia and CONICET
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  • Susan M Kirwin, Nemours/ Alfred I. duPont Hospital for Children, Wilmington, DE, 19803, USA.
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  • Gerhard Kluger, Københavns Universitet
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  • Petra Kolditz, Department of Child Neurology, Queen Paola Child Hospital, Antwerp, Belgium.
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  • Urania Kotzaeridou, University Children's Hospital Heidelberg
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  • Roberta La Piana, McGill Univ, McGill University, McGill Space Inst
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  • Eriskay Liston, The Hospital for Sick Children
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  • William McClintock, Children's National Medical Center
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  • Meriel McEntagart, St George's Vascular Institute, St George's University Hospital, London
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  • Fiona McKenzie, Univ Western Australia, University of Western Australia, Sch Plant Biol
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  • Serge Melançon, McGill University Health Centre
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  • Anjum Misbahuddin, Queen's Hospital, Romford, UK.
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  • Mohnish Suri, Nottingham University Hospitals NHS Trust
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  • Fernando I Monton, Hospital Universitario Nuestra Senora de Candelaria
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  • Sebastien Moutton, Service de Génétique Médicale
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  • Raymond P J Murphy, Tallaght University Hospital
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  • Miriam Nickel, University Medical Center Hamburg-Eppendorf
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  • Hüseyin Onay, Ege Univ Hosp, Ege University, Dept Pulmonol
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  • Simona Orcesi, Københavns Universitet
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  • Ferda Özkınay, Ege Univ Hosp, Ege University, Dept Pulmonol
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  • Steffi Patzer, Children's Hospital St. Elisabeth and St. Barbara
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  • Helio Pedro, Department of Pathology, Hackensack University Medical Center, Hackensack, New Jersey.
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  • Sandra Pekic, University of Belgrade School of Medicine, Belgrade University Medical Center, Belgrade, Serbia.
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  • Mercedes Pineda Marfa, Hospital Sant Joan de Deu, Barcelona, Spain.
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  • Amy Pizzino, MetroHealth Hospital
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  • Barbara Plecko, Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria; Center for Medical Research, Medical University of Graz, Graz, Austria.
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  • Bwee Tien Poll-The, Emma Children's Hospital/Academic Medical Center Amsterdam
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  • Vera Popovic, University of Belgrade School of Medicine, Belgrade University Medical Center, Belgrade, Serbia.
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  • Dietz Rating, Tallinn Children's Hospital, Tallinn, Estonia; Tartu University Hospital, Children's Clinic, Tartu, Estonia.
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  • Marie-France Rioux, Centre Hospitalier Universitaire de Sherbrooke - Hôpital Fleurimont
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  • Norberto Rodriguez Espinosa, Hospital Universitario Nuestra Senora de Candelaria
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  • Anne Ronan, Newcastle University, Newcastle, U.K.
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  • John R Ostergaard
  • Elsa Rossignol, Departments of Neurosciences and Pediatrics
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  • Rocio Sanchez-Carpintero, Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa 'G. Gaslini" Institute, Genova, Italy.
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  • Anna Schossig, Univ Klin Innsbruck, Medical University of Innsbruck
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  • Nesrin Senbil, Kırıkkale University Medical Faculty
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  • Laura K Sønderberg Roos, 1Copenhagen University Hospital, Copenhagen, Denmark. 2Aarhus University Hospital, Aarhus, Denmark. 3University of Copenhagen, Copenhagen, Denmark. 4Odense University Hospital, Odense, Denmark.
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  • Cathy A Stevens, University of Tennessee College of Medicine
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  • Matthis Synofzik, University Eye Clinic, University of Tübingen, Tübingen, Germany
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  • László Sztriha, Univ Szeged, Szeged University, Dept Ecol
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  • Daniel Tibussek, Heinrich Heine Univ Dusseldorf, Heinrich Heine University Dusseldorf, Heinrich Heine University Dusseldorf Hospital, Univ Hosp Dusseldorf, Dept Gynaecol & Obstet
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  • Dagmar Timmann, Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
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  • Davide Tonduti, V. Buzzi Children's Hospital
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  • Bart P van de Warrenburg, Department of Medical Oncology, Radboud university medical centre and Radboud Institute for Molecular Life Sciences, Nijmegen
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  • Maria Vázquez-López, Sección Neuropediatría. Hospital Maternoinfantil Gregorio Marañón
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  • Sunita Venkateswaran, Children's Hospital of Eastern Ontario Research Institute
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  • Pontus Wasling, Univ Gothenburg, University of Gothenburg, Gothenburg Global Biodivers Ctr
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  • Evangeline Wassmer, The Heart Unit, Birmingham Children's Hospital, Birmingham, United Kingdom.
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  • Richard I Webster, T. Y. Nelson Department of Neurology and Neurosurgery and the Institute for Neuroscience and Muscle Research
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  • Gert Wiegand, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Campus Kiel, 24105, Kiel, Germany.
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  • Grace Yoon, Toronto Western Hosp, University of Toronto, University Health Network Toronto
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  • Joost Rotteveel, Emma Children's Hospital/Academic Medical Center Amsterdam
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  • Raphael Schiffmann, Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas, USA. Electronic address: raphael.schiffmann@baylorhealth.edu.
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  • Marjo van der Knaap, Amsterdam University Medical Centers
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  • Adeline Vanderver, The Children's Hospital of Philadelphia, Philadelphia, PA
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  • Gabriel Á Martos-Moreno, Hospital Infantil Universitario Nino Jesus de Madrid
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  • Constantin Polychronakos, Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec,
  • Nicole I Wolf, Amsterdam University Medical Centers
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  • Geneviève Bernard, McGill Univ, McGill University, McGill Space Inst

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.

OriginalsprogEngelsk
TidsskriftThe Journal of clinical endocrinology and metabolism
Vol/bind106
Nummer2
Sider (fra-til)e660-e674
ISSN0021-972X
DOI
StatusUdgivet - feb. 2021

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