Congenital syndromes of severe insulin resistance

Rare syndromes of severe insulin resistance (IR), caused by genetic defects in canonical insulin signalling or adipose tissue development, place patients at high, early risk of adverse clinical complications but are clinically challenging to manage. Prompt evaluation and diagnosis of these individuals not only facilitates more appropriate intervention but, together with identification of the underlying genetic defects, may provide valuable mechanistic insights into the pathogenesis of rare as well as common, obesity-associated IR. Although diagnosis of these syndromes is complicated by the variability of their natural history, several presenting features are common to all severe IR syndromes including disturbed glucose metabolism (either hypoglycaemia or hyperglycaemia), acanthosis nigricans and severe ovarian dysfunction in lean individuals. These features may be evident at birth, or appear during childhood or adolescence, so their recognition by paediatricians is essential. Here we review the general and specific features of syndromes of severe IR, summarise their classification, and recommend strategies for their subsequent investigation.