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-müllerian 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 .

Diseases
Validation

Diseases presenting "first time" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

adrenomyeloneuropathy

alpha-thalassemia

aniridia

aromatase deficiency

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

classical phenylketonuria

congenital adrenal hyperplasia

congenital toxoplasmosis

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dentin dysplasia

dentinogenesis imperfecta

dracunculiasis

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

fabry disease

familial mediterranean fever

gm1 gangliosidosis

harlequin ichthyosis

heparin-induced thrombocytopenia

hirschsprung disease

hodgkin lymphoma, classical

holt-oram syndrome

hydrocephalus with stenosis of the aqueduct of sylvius

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

malignant atrophic papulosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

omenn syndrome

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

phenylketonuria

primary effusion lymphoma

primary hyperoxaluria type 1

severe combined immunodeficiency

sneddon syndrome

triple a syndrome

trochlear dysplasia

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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