Inter- and intrafamilial variability in premature pubarche and polycystic ovary syndrome.

Objective: To ascertain the extent of phenotypic heterogeneity for premature pubarche and polycystic ovary syndrome between and within families.

Design: Association study.

Setting: Academic research environment.

Patient(s): Three families in which the propositus had presented with either premature pubic hair or adolescent hyperandrogenism.

Intervention(s): Detailed medical histories, hormone determinations, and genotype analyses.

Main Outcome Measure(s): Clinical phenotype. Genotypes for CYP21, HSD3B2, G972R variant of IRS-1, N363S variant of GRL, W64R variant of ADRB3, CAG repeat in exon 1 of AR, MspAI polymorphism in CYP17, and R264C variant of CYP19.

Result(s): Significant phenotypic and genetic heterogeneity was observed both within and between families. In one family, CYP21 and IRS-1 variants were observed to co-segregate with symptoms of androgen excess and obesity. No genetic markers were consistently noted to associate with clinical features of hyperandrogenism in the other two families.

Conclusion(s): The difficulties in classifying female family members as clearly affected or unaffected and lack of definitive male phenotype complicate the use of linkage analysis to identify the polycystic ovary syndrome genes. Each family is best considered on an individual basis to identify genetic markers that segregate with the clinical features of androgen excess.