ESPE Abstracts

Background: Donohue syndrome is a rare congenital syndrome of insulin-resistance and abnormal glucose homeostasis, caused by mutations in the insulin receptor (INSR) gene. It is characterized by specific phenotypic and clinical features and the diagnosis is based on clinical, biochemical and genetic criteria.

Case reports: We report two siblings with Donohue syndrome with typical dysmorphic features and multiple clinical and biochemical characteristics. Genetic analysis detected a homozygous sequence variant in exon 4 of the INSR gene in both patients, predicted to result in an abnormal INSR protein, p.(Gly365Trp). Both patients presented with intra-uterine growth restriction, failure to thrive during the neonatal and infantile period, fasting hyperinsulinaemic hypoglycaemia and episodic post-prandial hyperglycaemia. Less common clinical features were also present, such as atrial septal defect (ASD) with left to right shunt and heart dilatation, abnormal clotting and liver function tests, and nephrocalcinosis. Of unknown cause were clinical signs, such as respiratory distress with prolonged oxygen requirement, intermittent fever and muscular hypotonia (case 2). Interestingly, two previously unrecognised possible manifestations of the syndrome were also identified: gastrointestinal dysmotility (case 1), that resulted in the patient’s death at the age of 10 months, and pancreatic exocrine insufficiency (case 2).

Conclusion: The co-existence of all the above clinical features makes these cases extremely rare. Gastrointestinal dysmotility should always be considered a potentially fatal feature in patients with Donohue syndrome, due to the complexity of the possible co-morbidities. In addition, our clinical experience for the first time suggests that exocrine pancreatic insufficiency may offer a possible explanation for the growth retardation seen in the syndrome. Our finding that replacement with pancreatic enzymes improved weight gain (case 2), indicates that failure to thrive may be treatable, hence we recommend that all patients with syndromes of insulin resistance should be investigated for exocrine pancreatic insufficiency.