Objective: To screen for mutations in the GnRH receptor gene in a case of complete hypogonadotropic hypogonadism (HH) with GnRH resistance.
Design: Case report.
Setting: A university hospital.
Patient(s): A male patient with the complete form of HH without anosmia.
Intervention(s): Physical examination and laboratory and genetic studies.
Main outcome measure(s): Gonadotropins at the basal state and after GnRH administration and GnRH receptor DNA sequencing.
Result(s): A novel missense mutation, localized in the first amino acid of the extracellular loop found in the heterozygous state, and another mutation, Arg(139)His (R139H), located in the conserved aspartate-arginine-serine motif at the junction of the third transmembrane and second intracellular loop of the GnRH receptor, were identified in the homozygous state. Pedigree studies reveal that both parents were heterozygous for R139H, while the mother carried the missense mutation at codon 1(M1T).
Conclusion(s): GnRH receptor mutations may account for a larger proportion of cases of HH than previously thought. The phenotypic spectrum of HH seems to vary, and this heterogeneity may be related, at least in part, to the degree of impaired biological activity of the mutated GnRH receptor caused by the allelic type of mutations.