Endocrine Abstracts

GH-secreting pituitary adenomas are by far the commonest cause of acromegalic soft tissue overgrowth. However the differential diagnosis includes pseudoacromegaly in rare patients with severe insulin resistance, with or without lipodystrophy, and some congenital overgrowth syndromes such as Sotos’ syndrome, due to mutations in the NSD1 gene. We now report the case of two siblings, born to non consanguinous, clinically unaffected Europid parents, with childhood overgrowth and progressive adult soft tissue overgrowth closely resembling acromegaly, but without any evidence of GH hypersecretion or a pituitary adenoma. Serum IGF1 levels were also repeatedly normal. Moreover, far from exhibiting severe insulin resistance, both siblings showed strikingly low insulin excursions during an oral glucose tolerance test: the male sibling, despite a body mass index of 37 kg/m², had fasting and peak insulin levels of 10 and 85 pmol/l respectively, while his sister, with a BMI of 34 kg/m², had fasting and peak insulin levels of 17 and 118 pmol/l, well below the third centile for sex, age and BMI matched control subjects. Serum adiponectin levels were also abnormal, with both siblings having elevated adiponectin relative to matched controls. NSD1 screening was normal in both siblings. In summary, both siblings present with a previously unreported syndrome of biochemically-determined insulin supersensitivity, and clinical features consistent with lifelong excess IGF1 action. We hypothesized that this disorder is caused by genetic loss of function of a negative regulator of both insulin and IGF1 action. Genetic screening to date has ruled out coding defects in the genes encoding the IGF1 receptor, protein tyrosine phosphatase 1B, and the adaptor proteins GRB10 and GRB14. Elucidating the cause of this syndrome is likely to give valuable insights into the function in vivo of a negative regulator of insulin action, and thereby to inform efforts to target it pharmacologically.