Premium
Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism
Author(s) -
Xu C.,
LangMuritano M.,
PhanHug F.,
Dwyer A.A.,
Sykiotis G.P.,
Cassatella D.,
Acierno J.,
Mohammadi M.,
Pitteloud N.
Publication year - 2017
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12996
Subject(s) - micropenis , hypogonadotropic hypogonadism , endocrinology , kallmann syndrome , medicine , luteinizing hormone , testosterone (patch) , delayed puberty , hormone , biology , fibroblast growth factor receptor 1 , receptor , genetics , fibroblast growth factor , disease , covid-19 , hypospadias , infectious disease (medical specialty)
Neonatal micropenis and cryptorchidism raise the suspicion of congenital hypogonadotropic hypogonadism ( CHH ), a rare genetic disorder caused by gonadotropin‐releasing hormone deficiency. Low plasma testosterone levels and low gonadotropins during minipuberty provide a clinical diagnostic clue, yet these tests are seldomly performed in general practice. We report a male neonate with no family history of reproductive disorders who was born with micropenis and cryptorchidism. Hormonal testing at age 2.5 months showed low testosterone (0.3 nmol/L) and undetectable gonadotropins (luteinizing hormone and follicle‐stimulating hormone both <0.5 U/L), suggestive of CHH . Genetic testing identified a de novo , heterozygous mutation in fibroblast growth factor receptor 1 ( FGFR1 p. L630P ). L630 resides on the ATP binding cleft of the FGFR1 tyrosine kinase domain, and L630P is predicted to cause a complete loss of receptor function. Cell‐based assays confirmed that L630P abolishes FGF8 signaling activity. Identification of a loss‐of‐function de novo FGFR1 mutation in this patient confirms the diagnosis of CHH , allowing for a timely hormonal treatment to induce pubertal development. Therefore, genetic testing can complement clinical and hormonal assessment for a timely diagnosis of CHH in childhood.