We report of two sisters with hyperandrogenism, menstrual abnormalities, and severe insulin resistance. The elder sister was seen after puberty at age 21 and she was referred for the evaluation of hirsutism and polymenorrhoea; the younger was seen earlier in life, at age 15, for the evaluation of secondary amenorrhoea. In both of them, we performed the diagnosis of polycystic ovary syndrome (PCOS) in accordance to the Rotterdam criteria. They also presented a lipodystrophic phenotype, characterized by loss of fat from the extremities, trunk and gluteal regions and excess fat deposition in face, neck, axillae and back. The two sisters started an oral treatment with metformin (1700 mg/day), that was continued uninterruptedly for 2 years. Because of the lack of improvement in clinical and metabolic pattern, pioglitazone (30 mg/day) was added to metformin, with progressive amelioration of hyperandrogenism, insulin resistance and hyperinsulinemia. Menses also improved, with restoration of a eumenorrhoeic pattern, but weight and waist circumference remained unchanged. The characteristic phenotype and the marked insulin resistance induced us to screen them for candidate genes involved in insulin signalling pathway. We detected a heterozygous missense mutation in codon 482 (R482Q) of the lamin A/C gene consistent with the diagnosis of Dunnigan-type familial partial lipodystrophy. Notwithstanding the autosomal dominant inheritance of the disease, LMNA genotyping showed that none of the alive members of the family was carrier of the R482Q mutation (father and grandmother were not screened because deceased). At the end of the analysis, we reformulated the diagnosis into PCOS secondary to Dunnigan-type familial partial lipodystrophy. This form widens the knowledge of the monogenic forms of PCOS, gives new insights into the relationships between insulin resistance and PCOS, with practical consequences on therapeutic choices.
03 - 07 May 2008
European Society of Endocrinology