A case report of congenital idiopathic hypogonadotropic hypogonadism caused by novel mutation of GNRHR gene

Abstract

Rationale: This study aimed to investigate the genetic mutation characteristics of congenital idiopathic hypogonadotropic hypogonadism (IHH) through the clinical features and genetic analysis of 2 patients with IHH in 1 pedigree. Patient concerns: A 23-year-old girl presented with primary amenorrhea, sparse pubic hair, lack of breast development, and delayed sexual development. Diagnoses: Combined with the clinical characteristics, auxiliary examinations, and molecular genetic analysis, the patient was diagnosed as IHH. Interventions: Whole exome and Sanger sequencing were performed to validate the mutation in family members. Outcomes: A novel homozygous missense mutation c.521A > G (p.Q174R) in the GNRHR gene was identified in the 2 affected sisters. Familial segregation showed that the homozygous variant was inherited from their parents respectively and the eldest sister was the carrier without correlative symptom. Lessons: We reported a novel GNRHR mutation in a pedigree with congenital idiopathic hypogonadotropic hypogonadism. Glutamine at amino acid position 174 was highly conserved among various species. The molecular structure of GNRHR protein showed that p.Q174R mutation brought in a new stable hydrogen bond between position 174 and 215, may impede conformational mobility of the TMD4 and TMD5. It suggests that the missense mutation c.521A > G related to congenital idiopathic hypogonadotropic hypogonadism was probably a causative factor for both sisters. Through high-throughput sequencing and experimental verification, we had basically determined the patient's pathogenic mutation and inheritance, which could better guide doctors for treatment.

Causas poco frecuentes de amenorrea debida a hipogonadismo hipogonadotrópico

“…Se han descrito cerca de 8 mutaciones diferentes que pueden afectar a este receptor. En los casos de mutaciones con cambio de sentido, homocigotas heredadas de ambos padres, las pacientes se presentan con un desarrollo puberal variable pero la mayoría presenta amenorrea primaria (10,21). También se han reportado casos donde el receptor sufre una mutación sin sentido, la cual lleva a diferentes niveles de secreción de estradiol, explicando así la variabilidad fenotípica.…”