Endocrine Abstracts

Isolated hypogonadotrophic hypogonadism (IHH) is defective secretion of luteinizing hormone (LH) and follicular stimulating hormone (FSH) resulting in incomplete or absent pubertal development and infertility. Several genetic defects underlying IHH have been identified, including in the gonadotrophin releasing hormone receptor (GnRH-R) gene. Here we report a case of two sisters, with clinical phenotypes of IHH, presenting with poor breast development, primary amenorrhoea and a rudimentary uterus. Peripheral blood samples were obtained from both the effected sisters along with a third sister and mother who were phenotypically normal. Genomic DNA was extracted from leukocytes and the sequences of the three exons of the GnRH-R and splice sites were analysed. Both of the affected sisters were found compound heterozygotes for Arg¹³⁹His and Arg²⁶²Gln, while the mother was found heterozygous for the Arg²⁶²Gln. The unaffected sister displayed a normal genotype.

The Arg¹³⁹His mutation is situated in the highly conserved DRS motif at the junction of the third intracellular domain and second intracellular loop of the GnRH-R and has been previously demonstrated to affect GnRH ligand binding capacity and intracellular signalling. Arg²⁶²Gln, one of the most commonly identified mutations resulting in IHH, affects the expression of the α- and β- components of the gonadotrophins.

This current genotype-phenotype correlation of the GnRH-R mutation Arg¹³⁹ His compares well with previously reported homozygous pedigrees. The Arg²⁶² Gln is associated with significantly variable phenotypes in both homozygous and heterozygous states. Identified here is the first time these two point mutations appear in a compound heterozygous state. In conclusion, we have identified a novel compound heterozygous mutation in the GnRH-R, inherited on separate alleles in an autosomal recessive fashion, resulting in complete IHH.