title: Monogenic polycystic ovary syndrome due to a mutation in the lamin A/C gene is sensitive to thiazolidinediones but not to metformin.
abstract: BACKGROUND
  Despite the very high prevalence of the polycystic ovary syndrome (PCOS), the underlying pathogenetic mechanism has remained obscure.
  
  
  OBJECTIVE
  To determine the cause of two sisters' PCOS associated with severe insulin resistance.
  
  
  METHODS
  Clinical case report. Methods Two sisters who presented with hyperandrogenism and menstrual disorders in the context of PCOS, and were subsequently found to be severely insulin resistant. Physical examination revealed muscular hypertrophy with a paucity of fat in the extremities, trunk and gluteal regions, in spite of excess fat deposits in the face, neck and dorsocervical region. Known genes involved in familial partial lipodystrophy were screened. At the same time, metformin (1700 mg/day) was commenced. After 2-3 years of uninterrupted therapy, lack of clinical improvement led to the introduction of pioglitazone (30 mg/day).
  
  
  RESULTS
  Both sisters were found to be heterozygous for the R482Q mutation in the lamin A/C gene (LMNA) gene, establishing the definitive diagnosis as Dunnigan-type familial partial lipodystrophy complicated by severe insulin resistance and secondary PCOS. Treatment with pioglitazone resulted in progressive amelioration of insulin resistance, hyperinsulinaemia and hyperandrogenaemia. Menses also improved, with restoration of a eumenorrhoeic pattern, and the framework of ultrasound PCO was in complete remission.
  
  
  CONCLUSIONS
  Assessment of insulin sensitivity and adipose tissue topography should be a key part of the initial evaluation of patients with PCOS. Identifying such forms of PCOS with monogenic insulin resistance as the primary pathogenic abnormality may have practical implications for therapy, since they respond to thiazolidinediones, but not to metformin.
authors: Division of Endocrinology, Department of Internal Medicine, S Orsola-Malpighi Hospital, University Alma Mater Studiorum, Via Massarenti 9, 40138 Bologna, Italy.
authors: A
authors: A
authors: Gambineri
authors: R K
authors: RK
authors: Semple
authors: G
authors: G
authors: Forlani
authors: S
authors: S
authors: Genghini
authors: I
authors: I
authors: Grassi
authors: C S S
authors: CS
authors: Hyden
authors: U
authors: U
authors: Pagotto
authors: S
authors: S
authors: O'Rahilly
authors: R
authors: R
authors: Pasquali
mesh_terms: D000293:Adolescent; D000328:Adult; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D034904:Lamin Type A / Q000235:genetics*; D024821:Metabolic Syndrome / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D008687:Metformin / Q000627:therapeutic use*; D017354:Point Mutation; D011085:Polycystic Ovary Syndrome / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D034904:Lamin Type A; D045162:Thiazolidinediones; C440308:lamin C; D008687:Metformin