FSHβ Gene Mutations in a Female with Partial Breast Development and a Male Sibling with Normal Puberty and Azoospermia

FSH is a dimeric pituitary glycoprotein hormone that regulates gonadal function. Human mutations in the FSHβ gene have been shown to produce complete deficiency states in which pubertal development and reproductive capacity are inhibited. To date, no patients with partial or complete pubertal development due to FSHβ mutations have been documented in humans. We describe and characterize affected siblings, a male and a female, with evidence of pubertal development due to homozygosity for a Tyr76X nonsense mutation in the FSHβ gene. In vitro analysis of this mutant demonstrates unmeasurable FSH by immunoassay and by two different bioassays, using either cAMP (homologous FSH bioassay) or estradiol (rat granulosa cell assay) as the endpoints. In additional in vitro analyses, mutants previously found in patients with a phenotype of complete FSH deficiency (Cys51Gly and Val61X) and the Tyr76X were compared in the same immuno- and bioassays. All mutations failed to produce measurable FSH by all assays. Unexpectedly, these siblings with isolated FSH deficiency due to a nonsense FSHβ mutation had some evidence of puberty, suggesting that other factors might preserve gonadal steroidogenesis in the absence of FSH or that current bioassays cannot discriminate among very low FSH levels.