A case report of a novel homozygote mutation causing severe Leydig cell hypoplasia: insights in the coexistence of nonsense mutation and polymorphism in the same LHCGR gene locus

Abstract

Introduction: Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with normal development of male external genitalia in 46,XY individuals. It is mediated by mutations in the lutropin/choriogonadotropin receptor (LHCGR) gene, resulting in impairment of either hormone binding or signal transduction. Case report: We report a 32-year-old female patient who presented with primary amenorrhoea, female external genitalia and 46,XY karyotype. Breast and pubic hair development were of B2 and PH2 respectively. Magnetic resonance imaging revealed at both sides inguinal testicles (cryptorchidism) with microcalcification in the absence of uterus and ovaries. At first presentation, serum luteinizing hormone was about 3-fold above the normal limit, while testosterone was in the normal female adult range. Estradiol was low and the serum follicle-stimulating hormone was unremarkable. Dehydroepiandrosterone sulphate, 17-hydroxyprogesterone and sex hormone-binding globulin were normal. Anti-Mullerian hormone and inhibin B were elevated. Mutation or deletion of the sex-determining region Y-, androgen receptor- and steroid 5-alpha-reductase-gene could be excluded. Finally, sequencing of the lutropin-choriogonadotropic hormone receptor gene revealed a homozygote nonsense mutation in exon 10 (c.907C>T, p.Gln 303Trm). Interestingly, a second a second polymorphism was found (c.935A>G, p.Asn312Ser) downstream of the disruption of the gene sequence. We therefore concluded to the diagnosis of severe Leydig cell hypoplasia. A hormone replacement therapy with estradiol was inducted and the further operative removal of the inguinal testicles as well as the genetic analysis of the parents is planned. Conclusions: We report a phenotypically female patient with 46,XY disorder of sexual development with a novel homozygote nonsense mutation (p.Gln303Trm) accompanied by a second homozygote polymorphism (p.Asn312Ser) in the LHCGR gene. Our case expands the genotypic spectrum of LHCGR mutations and underlines the importance of thorough molecular analysis.