title: Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism.
abstract: 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.
authors.affiliation: Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Xu
authors.affiliation: Endocrinology and Diabetology Department, University Children's Hospital, Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Lang-Muritano
authors.affiliation: Endocrinology-Diabetology Unit, Department of Paediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Phan-Hug
authors.affiliation: Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland.|Institute of Higher Education and Research in Healthcare, University of Lausanne, Lausanne, Switzerland.
authors.forename: A A
authors.initials: AA
authors.lastname: Dwyer
authors.affiliation: Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: G P
authors.initials: GP
authors.lastname: Sykiotis
authors.affiliation: Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Cassatella
authors.affiliation: Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Acierno
authors.affiliation: Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mohammadi
authors.affiliation: Endocrinology, Diabetology & Metabolism Service, Lausanne University Hospital, Lausanne, Switzerland.|Endocrinology-Diabetology Unit, Department of Paediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: N
authors.identifier: http://orcid.org/0000-0003-0971-3237
authors.initials: N
authors.lastname: Pitteloud
mesh_terms: D000013:Congenital Abnormalities / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D003456:Cryptorchidism / Q000235:genetics / Q000503:physiopathology; D051524:Fibroblast Growth Factor 8 / Q000235:genetics*; D005820:Genetic Testing; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D007231:Infant, Newborn; D008297:Male; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C496456:FGF8 protein, human; D051524:Fibroblast Growth Factor 8; D007987:Gonadotropin-Releasing Hormone; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: congenital hypogonadotropic hypogonadism; exome sequencing; fibroblast growth factor receptor 1; minipuberty