@article{3076336,
    title = "Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C",
    author = "Pelletier, F. and Perrier, S. and Cayami, F.K. and Mirchi, A. and Saikali, S. and Tran, L.T. and Ulrick, N. and Guerrero, K. and Rampakakis, E. and Van Spaendonk, R.M.L. and Naidu, S. and Pohl, D. and Gibson, W.T. and Demos, M. and Goizet, C. and Tejera-Martin, I. and Potic, A. and Fogel, B.L. and Brais, B. and Sylvain, M. and Sébire, G. and Lourenço, C.M. and Bonkowsky, J.L. and Catsman-Berrevoets, C. and Pinto, P.S. and Tirupathi, S. and Strømme, P. and De Grauw, T. and Gieruszczak-Bialek, D. and Krägeloh-Mann, I. and Mierzewska, H. and Philippi, H. and Rankin, J. and Atik, T. and Banwell, B. and Benko, W.S. and Blaschek, A. and Bley, A. and Boltshauser, E. and Bratkovic, D. and Brozova, K. and Cimas, I. and Clough, C. and Corenblum, B. and Dinopoulos, A. and Dolan, G. and Faletra, F. and Fernandez, R. and Fletcher, J. and Garcia Garcia, M.E. and Gasparini, P. and Gburek-Augustat, J. and Gonzalez Moron, D. and Hamati, A. and Harting, I. and Hertzberg, C. and Hill, A. and Hobson, G.M. and Innes, A.M. and Kauffman, M. and Kirwin, S.M. and Kluger, G. and Kolditz, P. and Kotzaeridou, U. and La Piana, R. and Liston, E. and McClintock, W. and McEntagart, M. and McKenzie, F. and Melançon, S. and Misbahuddin, A. and Suri, M. and Monton, F.I. and Moutton, S. and Murphy, R.P.J. and Nickel, M. and Onay, H. and Orcesi, S. and Özklnay, F. and Patzer, S. and Pedro, H. and Pekic, S. and Pineda Marfa, M. and Pizzino, A. and Plecko, B. and Poll-The, B.T. and Popovic, V. and Rating, D. and Rioux, M.-F. and Rodriguez Espinosa, N. and Ronan, A. and Ostergaard, J.R. and Rossignol, E. and Sanchez-Carpintero, R. and Schossig, A. and Senbil, N. and Sønderberg Roos, L.K. and Stevens, C.A. and Synofzik, M. and Sztriha, L. and Tibussek, D. and Timmann, D. and Tonduti, D. and Van De Warrenburg, B.P. and Vázquez-López, M. and Venkateswaran, S. and Wasling, P. and Wassmer, E. and Webster, R.I. and Wiegand, G. and Yoon, G. and Rotteveel, J. and Schiffmann, R. and Van Der Knaap, M.S. and Vanderver, A. and Martos-Moreno, G.Á. and Polychronakos, C. and Wolf, N.I. and Bernard, G.",
    journal = "JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM",
    year = "2021",
    volume = "106",
    number = "2",
    pages = "E660-E674",
    publisher = "Endocrine Society",
    issn = "0021-972X",
    doi = "10.1210/clinem/dgaa700",
    keywords = "corticotropin;  estradiol;  follitropin;  growth hormone;  hydrocortisone;  luteinizing hormone;  prolactin;  somatomedin C;  testosterone;  thyrotropin;  DNA directed RNA polymerase;  DNA directed RNA polymerase III;  POLR1C protein, human;  POLR3A protein, human;  POLR3B protein, human, Article;  body height;  corticotropin blood level;  cross-sectional study;  descriptive research;  disease classification;  endocrine disease;  estradiol blood level;  female;  follitropin blood level;  gene;  genetic analysis;  genetic variability;  genotype;  growth disorder;  growth hormone blood level;  head circumference;  human;  leukodystrophy;  luteinizing hormone blood level;  major clinical study;  male;  multicenter study;  phenotype;  POLR3A gene;  POLR3B gene;  POLR3C gene;  prolactin blood level;  retrospective study;  testosterone blood level;  thyroid function;  thyrotropin blood level;  thyroxine blood level;  adolescent;  adult;  biological variation;  child;  clinical trial;  cohort analysis;  complication;  demyelinating disease;  disorders of mitochondrial functions;  endocrine disease;  genetic heterogeneity;  genetics;  growth disorder;  hypogonadism;  infant;  mutation;  newborn;  preschool child;  young adult, Adolescent;  Adult;  Biological Variation, Population;  Child;  Child, Preschool;  Cohort Studies;  Cross-Sectional Studies;  DNA-Directed RNA Polymerases;  Endocrine System Diseases;  Female;  Genetic Heterogeneity;  Growth Disorders;  Hereditary Central Nervous System Demyelinating Diseases;  Humans;  Hypogonadism;  Infant;  Infant, Newborn;  Male;  Mitochondrial Diseases;  Mutation;  Retrospective Studies;  RNA Polymerase III;  Young Adult",
    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. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society."
}