Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in <i>POLR3A</i>, <i>POLR3B</i>, and <i>POLR1C</i>
Félixe Pelletier, Stefanie Perrier, Ferdy Kurniawan Cayami, Amytice Mirchi, Stéphan Saïkali, 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 E. Catsman‐Berrevoets, Pedro Soares Pinto, Sandya Tirupathi, Petter Strømme, Ton de Grauw, Dorota Gieruszczak‐Białek, Ingeborg Krägeloh‐Mann, Hanna Mierzewska, Heike Philippi, Julia Rankin, Tahir Atık, Brenda Banwell, William Benko, Astrid Blaschek, Annette Bley, Eugen Boltshauser, Drago Bratkovic, Klára Brožová, Icíar Cimas, Christopher Clough, Bernard Corenblum, Argirios Dinopoulos, Gail Dolan, Flavio Faletra, Raymond Fernandez, Janice M. Fletcher, María Eugenia García, Paolo Gasparini, Janina Gburek‐Augustat, Dolores González Morón, Aline I. 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, W. McClintock, Meriel McEntagart, Fiona McKenzie, Serge B. Melançon, Anjum Misbahuddin, Mohnish Suri, Fernando Montón, Sébastien Moutton, Raymond P. Murphy, Miriam Nickel, Hüseyin Önay, Simona Orcesi, Ferda Özkınay, Steffi Patzer, Hélio Pedro, Sandra Pekić, M. Pineda, Amy Pizzino, Barbara Plecko, Bwee Tien Poll‐The, Vera Popović, D. Rating, Marie‐France Rioux, N. Rodríguez-Espinosa, Anne Ronan, John R. Østergaard, Elsa Rossignol, Rocı́o Sánchez-Carpintero, Anna Schossig, Nesrin Şenbil, Laura Roos, Cathy A. Stevens, Matthis Synofzik, László Sztriha
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.