TY - JOUR
T1 - Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
AU - Orcesi Simona
AU - Pelletier, Félixe
AU - Perrier, Stefanie
AU - Cayami, Ferdy K
AU - Mirchi, Amytice
AU - Saikali, Stephan
AU - Tran, Luan T
AU - Ulrick, Nicole
AU - Guerrero, Kether
AU - Rampakakis, Emmanouil
AU - van Spaendonk, Rosalina M L
AU - Naidu, Sakkubai
AU - Pohl, Daniela
AU - Gibson, William T
AU - Demos, Michelle
AU - Goizet, Cyril
AU - Tejera-Martin, Ingrid
AU - Potic, Ana
AU - Fogel, Brent L
AU - Brais, Bernard
AU - Sylvain, Michel
AU - Sebire, Guillaume
AU - Lourenço, Charles Marques
AU - Bonkowsky, Joshua L
AU - Catsman-Berrevoets, Coriene
AU - Pinto, Pedro S
AU - Tirupathi, Sandya
AU - Strømme, Petter
AU - de Grauw, Ton
AU - Gieruszczak-Bialek, Dorota
AU - Krägeloh-Mann, Ingeborg
AU - Mierzewska, Hanna
AU - Philippi, Heike
AU - Rankin, Julia
AU - Atik, Tahir
AU - Banwell, Brenda
AU - Benko, William S
AU - Blaschek, Astrid
AU - Bley, Annette
AU - Boltshauser, Eugen
AU - Bratkovic, Drago
AU - Brozova, Klara
AU - Cimas, Icíar
AU - Clough, Christopher
AU - Corenblum, Bernard
AU - Dinopoulos, Argirios
AU - Dolan, Gail
AU - Faletra, Flavio
AU - Gasparini, Paolo
AU - Orcesi, Simona
AU - Tonduti, Davide
N1 - © The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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 2015-2016. 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 three predominant centers.PATIENTS: 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-1, prolactin, ACTH, cortisol, TSH, and T4), 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 under-investigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
AB - 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 2015-2016. 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 three predominant centers.PATIENTS: 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-1, prolactin, ACTH, cortisol, TSH, and T4), 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 under-investigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
U2 - 10.1210/clinem/dgaa700
DO - 10.1210/clinem/dgaa700
M3 - Article
C2 - 33005949
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
ER -