Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome.

[werner syndrome]

Laminopathies , due to mutations in LMNA , encoding A type -lamins , can lead to premature ageing and /or lipodystrophic syndromes , showing that these diseases could have close physiopathological relationships . We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN , encoding a RecQ DNA helicase .We analysed the clinical and biological features of two women , aged 32 and 36 , referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome . Cultured skin fibroblasts from one patient were studied .Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis . One of them had also diabetes . Both patients showed a peculiar , striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation . Their oral glucose tolerance tests showed extremely high levels of insulinemia , revealing major insulin resistance . Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect . Other clinical features included bilateral cataracts , greying hair and distal skin atrophy . We observed biallelic WRN null mutations in both women (p .Q 748 X homozygous , and compound heterozygous p .Q 1257 X /p .M 1329 fs ). Their fertility was decreased , with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure . However undetectable anti-mÃ¼llerian hormone and inhibin B indicated diminished follicular ovarian reserve . Insulin -resistance linked ovarian hyperandrogenism could also contribute to decreased fertility , and the two patients became pregnant after initiation of insulin -sensitizers (metformin ). Both pregnancies were complicated by severe cervical incompetence , leading to the preterm birth of a healthy newborn in one case , but to a second trimester-abortion in the other . WRN -mutated fibroblasts showed oxidative stress , increased lamin B 1 expression , nuclear dysmorphies and premature senescence .We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN -linked premature aging syndrome . Increased expression of lamin B 1 with altered lamina architecture observed in WRN -mutated fibroblasts could contribute to premature cellular senescence . Primary alterations in DNA replication and /or repair should be considered as possible causes of lipodystrophic syndromes .

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Diseases presenting "severe cervical incompetence" symptom

werner syndrome

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