Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson–Mendenhall syndrome

Homozygous or compound heterozygous mutations within the insulin binding domain of the human insulin receptor (INSR) are usually associated with severe impairment of insulin binding leading to Donohue syndrome (“Leprechaunism”), which is characterized by excessive hyperglycemia with hyperinsulinism, pre- and postnatal growth retardation, distinct dysmorphism and early death. Missense mutations in the β subunits are commonly associated with a milder impairment of insulin binding and milder phenotype with prolonged survival and less dysmorphism, the so called Rabson–Mendenhall syndrome.We report on a 13-year-old girl with Donohue syndrome like dysmorphism, hyperinsulinism and prolonged survival due to two novel INSR missense mutations within the insulin binding domain. Unexpectedly, insulin binding assays and investigations of activation of central insulin signaling pathways in fibroblasts revealed no significant alterations. Instead, immunofluorescence studies showed abnormal perinuclear distribution of the INSR α and β subunits. Our data indicate that the quality of insulin binding activity is correlated with survival, not with the dysmorphic phenotype, and it is not always a valid parameter for predicting INSR mutations as proposed.