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.

3rd Department of Pediatrics National and Kapodistrian University of Athens Attikon Hospital Athens Greece

Applied Human Molecular Genetics Kennedy Center Copenhagen University Hospital Rigshospitalet Glostrup Denmark

Bristow Pediatrics Bristow VA USA

Center of Biomedical Research Faculty of Medicine Diponegoro University Semarang Indonesia

Center of Developmental Neurology Frankfurt Germany

Centre de Référence Neurogénétique Service de Génétique Médicale Bordeaux University Hospital and Laboratoire MRGM INSERM U1211 Université de Bordeaux Bordeaux France

Centre for Rare Diseases Aarhus University Hospital Aarhus Denmark

Centre Hospitalier Universitaire de Sherbrooke Hôpital Fleurimont Sherbrooke QC Canada

Centre Mère Enfant CHU de Québec Québec City QC Canada

Child Health and Human Development Program Research Institute of the McGill University Health Centre Montreal QC Canada

Child Neurology and Psychiatry Unit IRCCS Mondino Foundation Pavia Italy

Child Neurology Unit 5 Buzzi Children's Hospital Milano Italy

Children's Hospital St Elisabeth and St Barbara Halle Germany

CIBER de Fisiopatologia de la Obesidad y Nutriciόn Instituto de Salud Carlos 3 Madrid Spain

Clinic for Endocrinology Diabetes and Diseases of Metabolism University Clinical Center Belgrade and School of Medicine University of Belgrade Belgrade Serbia

Department of Child and Adolescent Neurology Institute of Mother and Child Warsaw Poland

Department of Child Neurology Amsterdam Leukodystrophy Center Emma Children's Hospital Amsterdam University Medical Centers and Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam The Netherlands

Department of Child Neurology Indiana University Indianapolis IN USA

Department of Child Neurology Kantonsspital Luzern Luzern Switzerland

Department of Child Neurology Kırıkkale University Medical Faculty Kırıkkale Turkey

Department of Child Neurology Thomayers Hospital Prague Czech Republic

Department of Child Neurology University Children's Hospital Heidelberg Heidelberg Germany

Department of Child Neurology University Children's Hospital Tübingen Tübingen Germany

Department of Child Neurology University Children's Hospital Zurich Zurich Switzerland

Department of Child Neurology Vivantes Klinikum Berlin Germany

Department of Clinical Genetics Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands

Department of Functional Genomics Center for Neurogenomics and Cognitive Research VU University Amsterdam The Netherlands

Department of General Pediatrics Neonatology and Pediatric Cardiology University Children's Hospital Heinrich Heine University 40225 Düsseldorf Germany

Department of Genetics MetroHealth Hospital Cleveland OH USA

Department of Human Genetics McGill University Montreal QC Canada

Department of Medical Genetics and Alberta Children's Hospital Research Institute University of Calgary Calgary AB Canada

Department of Medical Genetics Children's Memorial Health Institute Warsaw Poland

Department of Medical Genetics Ege University Izmir Turkey

Department of Medical Genetics McGill University Health Centre Montreal Children's Hospital Montreal QC Canada

Department of Medical Genetics University of British Columbia BC Children's Hospital Research Institute Vancouver BC Canada

Department of Neurodegeneration Hertie Institute for Clinical Brain Research and Centre of Neurology German Research Center for Neurodegenerative Diseases University of Tübingen Tübingen Germany

Department of Neurogenetics Kennedy Krieger Institute Johns Hopkins Medical Institutions Baltimore MD USA

Department of Neurology and Neurosurgery McGill University Montreal QC Canada

Department of Neurology Children's Hospital of Philadelphia Philadelphia PA USA

Department of Neurology Children's National Medical Center Washington DC USA

Department of Neurology Clinic for Child Neurology and Psychiatry Medical Faculty University of Belgrade Belgrade Serbia

Department of Neurology Donders Institute for Brain Cognition and Behaviour Radboud University Medical Centre Nijmegen The Netherlands

Department of Neurology Essen University Hospital University of Duisburg Essen Essen Germany

Department of Neurology Hospital Universitario Nuestra Señora de Candelaria 38010 Santa Cruz de Tenerife Canary Islands Spain

Department of Neurology King's College Hospital London UK

Department of Neurology Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

Department of Neurology Povisa Hospital Vigo Spain

Department of Neurology Tallaght University Hospital Tallaght Ireland

Department of Neurology The Royal London Hospital London UK

Department of Neuroradiology Montreal Neurological Institute and Hospital McGill University Montreal QC Canada

Department of Neuroradiology University Hospital Heidelberg Heidelberg Germany

Department of Neuroscience and Rehabilitation The Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Department of Paediatric Neurology Erasmus University Hospital Sophia Children's Hospital 3015 CN Rotterdam The Netherlands

Department of Paediatric Neurology Royal Belfast Hospital for Sick Children Belfast UK

Department of Paediatric Neurology University Children's Hospital Heidelberg Germany

Department of Paediatrics University of Szeged Szeged Hungary

Department of Pathology Centre Hospitalier Universitaire de Québec Québec City QC Canada

Department of Pediatric Endocrinology Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Madrid Spain

Department of Pediatric Neurology and Developmental Medicine Dr v Hauner Children's Hospital University Hospital LMU Munich Munich Germany

Department of Pediatric Neurology Emma Children's Hospital 1105 Amsterdam The Netherlands

Department of Pediatric Neurology University Hospital Kiel Germany

Department of Pediatrics and Adolescent Medicine Division of General Pediatrics Medical University of Graz Graz Austria

Department of Pediatrics Division of Medical Genetics University of Tennessee College of Medicine Chattanooga TN USA

Department of Pediatrics Emory School of Medicine Atlanta GA USA

Department of Pediatrics McGill University Montreal QC Canada

Department of Pediatrics Medical University of Warsaw Warsaw Poland

Department of Pediatrics Subdivision of Pediatric Genetics Faculty of Medicine Ege University Izmir Turkey

Department of Pediatrics The Joseph M Sanzari Children's Hospital Hackensack University Medical Center Hackensack NJ USA

Department of Pediatrics Universidad Autónoma de Madrid 28049 Madrid Spain

Department of Pediatrics Université de Sherbrooke Sherbrooke QC Canada

Department of Pediatrics University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Pediatrics University of British Columbia Vancouver BC Canada

Department of Pediatrics University of Utah School of Medicine Salt Lake City UT USA

Department of Specialized Medicine Division of Medical Genetics McGill University Health Centre Montreal QC Canada

Departments of Neurology and Human Genetics David Geffen School of Medicine University of California Los Angeles CA USA

Departments of Neurosciences and Pediatrics CHU Sainte Justine Université de Montréal Montreal QC Canada

Division of Child Neurology Department of Pediatrics CHU Sainte Justine Université de Montréal Montreal QC Canada

Division of Clinical and Metabolic Genetics Division of Neurology Department of Pediatrics The Hospital for Sick Children University of Toronto Toronto ON Canada

Division of Clinical and Metabolic Genetics The Hospital for Sick Children Toronto ON Canada

Division of Endocrinology and Metabolism Department of Medicine University of Calgary Calgary AB Canada

Division of Endocrinology Montreal Children's Hospital and the Endocrine Genetics Lab Research Institute of the McGill University Health Centre Montreal QC Canada

Division of Genetics Department of Pediatrics School of Medicine Ege University Izmir Turkey

Division of Neurology Children's Hospital of Eastern Ontario University of Ottawa Ottawa ON Canada

Division of Neurology Children's Hospital of Philadelphia Philadelphia PA USA

Division of Neurology Department of Pediatrics Children's Hospital of Eastern Ontario Ottawa ON Canada

Division of Neurology Department of Pediatrics Children's Hospital of Philadelphia Philadelphia PA USA

Division of Neurology Department of Pediatrics University of British Columbia BC Children's Hospital Vancouver BC Canada

Division of Neuropaediatrics Hospital for Children and Adolescents University Leipzig Leipzig Germany

Division of Pediatric Neurology Department of Neurology UC Davis Health System Sacramento CA USA

Division of Pediatrics and Adolescent Medicine Oslo University Hospital Ullevål 0450 Oslo and University of Oslo Oslo Norway

Emma Children's Hospital Amsterdam UMC Pediatric Endocrinology Vrije Universiteit Amsterdam Amsterdam The Netherlands

Essex Centre for Neurological Sciences Queen's Hospital Romford UK

Faculdade de Medicina Centro Universitario Estácio de Ribeirão Preto Ribeirão Preto SP Brazil

Genetic Services of Western Australia Subiaco WA Australia

Genetics and Molecular Pathology Women's and Children's Hospital Adelaide South Australia Australia

Hospital Sant Joan de Deu Passeig de Sant Joan de Deu nº2 Barcelona Spain

Hunter New England LHD University of Newcastle NSW Australia

Institute for Maternal and Child Health IRCCS Burlo Garofolo 34100 Trieste and University of Trieste Trieste Italy

Institute for Maternal and Child Health IRCCS Burlo Garofolo Trieste Italy

Institute of Human Genetics Medical University Innsbruck Innsbruck Austria

Institute of Metabolic Disease Baylor Scott and White Research Institute Dallas TX USA

Medical Faculty University of Belgrade Belgrade Serbia

Metabolic Clinic Women's and Children's Hospital North Adelaide South Australia Australia

Molecular Diagnostics Laboratory Nemours Alfred 1 duPont Hospital for Children Wilmington DE USA

Montreal Neurological Institute Montreal QC Canada

Nemours Biomedical Research Nemours Alfred 1 duPont Hospital for Children Wilmington DE USA

Neurogenetics Unit Department of Neurology Hospital JM Ramos Mejia ADC Buenos Aires Argentina

Neurogenetics Unit Department of Neurology Hospital JM Ramos Mejia and CONICET ADC Buenos Aires Argentina

Neuropediatrics Section of the Department of Pediatrics Asklepios Clinic Hamburg Nord Heidberg Hamburg Germany

Neuroradiology Department Centro Hospitalar do Porto Porto Portugal

Nottingham Clinical Genetics Service City Hospital Campus Nottingham University Hospitals NHS Trust Nottingham UK

Paediatric Neurology Birmingham Children's Hospital Birmingham UK

Pediatric Neurology Associates Tampa FL USA

Pediatric Neurology Unit Department of Pediatrics Clinica Universidad de Navarra Pamplona Spain

Pediatric Specialists of Virginia Fairfax VA USA

Peninsula Clinical Genetics Service Royal Devon and Exeter NHS Foundation Trust Exeter UK

PMU Salzburg 5020 Salzburg Austria; Clinic for Neuropediatrics and Neurorehabilitation Epilepsy Center for Children and Adolescents Schön Klinik Vogtareuth Vogtareuth Germany

School of Paediatrics and Child Health University of Western Australia Perth WA Australia

Sección Neuropediatría Hospital Maternoinfantil Gregorio Marañón Madrid Spain

Service de Génétique Médicale CHU de Bordeaux Bordeaux France

South West Thames Regional Genetics Service St George's Hospital London UK

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

University Children's Hospital University Medical Center Hamburg Eppendorf Hamburg Germany

Zobrazit více v PubMed

Vanderver A, Prust M, Tonduti D, et al. ; GLIA Consortium . Case definition and classification of leukodystrophies and leukoencephalopathies. Mol Genet Metab. 2015;114(4):494-500. PubMed PMC

van der Knaap MS, Bugiani M. Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017;134(3):351-382. PubMed PMC

Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72(8):750-759. PubMed PMC

Steenweg ME, Vanderver A, Blaser S, et al. . Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain. 2010;133(10):2971-2982. PubMed PMC

Parikh S, Bernard G, Leventer RJ, et al. ; GLIA Consortium . A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Mol Genet Metab. 2015;114(4):501-515. PubMed PMC

Bernard G, Vanderver A. POLR3-related leukodystrophy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, eds. GeneReviews. Seattle, WA: University of Washington Seattle; 2017. PubMed

Wolf NI, Vanderver A, van Spaendonk RM, et al. ; 4H Research Group . Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology. 2014;83(21):1898-1905. PubMed PMC

La Piana R, Cayami FK, Tran LT, et al. . Diffuse hypomyelination is not obligate for POLR3-related disorders. Neurology. 2016;86(17):1622-1626. PubMed PMC

Vanderver A, Tonduti D, Bernard G, et al. . More than hypomyelination in Pol-III disorder. J Neuropathol Exp Neurol. 2013;72(1):67-75. PubMed PMC

Billington E, Bernard G, Gibson W, Corenblum B. Endocrine aspects of 4H leukodystrophy: a case report and review of the literature. Case Rep Endocrinol. 2015;2015:314594. PubMed PMC

Potic A, Brais B, Choquet K, Schiffmann R, Bernard G. 4H syndrome with late-onset growth hormone deficiency caused by POLR3A mutations. Arch Neurol. 2012;69(7):920-923. PubMed

Potic A, Popovic V, Ostojic J, et al. . Neurogenic bladder and neuroendocrine abnormalities in Pol III-related leukodystrophy. BMC Neurol. 2015;15:22. PubMed PMC

La Piana R, Tonduti D, Gordish Dressman H, et al. . Brain magnetic resonance imaging (MRI) pattern recognition in Pol III-related leukodystrophies. J Child Neurol. 2014;29(2):214-220. PubMed

Vrij-van den Bos S, Hol JA, La Piana R, et al. . 4H leukodystrophy: a brain magnetic resonance imaging scoring system. Neuropediatrics. 2017;48(3):152-160. PubMed

Bernard G, Chouery E, Putorti ML, et al. . Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011;89(3):415-423. PubMed PMC

Tétreault M, Choquet K, Orcesi S, et al. . Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet. 2011;89(5):652-655. PubMed PMC

Thiffault I, Wolf NI, Forget D, et al. . Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nat Commun. 2015;6:7623. PubMed PMC

Dorboz I, Dumay-Odelot H, Boussaid K, et al. . Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation. Neurol Genet. 2018;4(6):e289. PubMed PMC

Delemarre-van de Waal HA. Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism--diagnostic and therapeutic aspects. Eur J Endocrinol. 2004;151Suppl 3:U89-U94. PubMed

Orcesi S, Tonduti D, Uggetti C, Larizza D, Fazzi E, Balottin U. New case of 4H syndrome and a review of the literature. Pediatr Neurol. 2010;42(5):359-364. PubMed

Grimberg A, DiVall SA, Polychronakos C, et al. ; Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society . Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr. 2016;86(6):361-397. PubMed

Abuelo D. Microcephaly syndromes. Semin Pediatr Neurol. 2007;14(3):118-127. PubMed

Sells CJ. Microcephaly in a normal school population. Pediatrics. 1977;59(2):262-265. PubMed

Jurkiewicz E, Dunin-Wąsowicz D, Gieruszczak-Białek D, et al. . Recessive mutations in POLR3B encoding RNA polymerase III subunit causing diffuse hypomyelination in patients with 4H leukodystrophy with polymicrogyria and cataracts. Clin Neuroradiol. 2017;27(2):213-220. PubMed PMC

Hunter I, Greene SA, MacDonald TM, Morris AD. Prevalence and aetiology of hypothyroidism in the young. Arch Dis Child. 2000;83(3):207-210. PubMed PMC