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 beta 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 alpha and beta 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.