Gastrointestinal dysmotility and pancreatic insufficiency in 2 siblings with Donohue syndrome

Abstract

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. We report 2 siblings with Donohue syndrome (cases 1, 2) with multiple clinical and biochemical characteristics. Both patients shared the same mutation and presented with intra-uterine growth restriction, failure to thrive, fasting hyperinsulinaemic hypoglycaemia and episodic post-prandial hyperglycaemia. Less common clinical features were also present, such as atrial septal defect and biventricular hypertrophy, clotting disorders, abnormal liver function tests and nephrocalcinosis. Interestingly, 2 previously unrecognized manifestations of the syndrome were also identified: severe gastrointestinal dysmotility (case 1) and exocrine pancreatic insufficiency (case 2). The co-existence of all the above clinical features makes these cases extremely rare. Gastrointestinal dysmotility should always be considered as a potentially fatal feature in patients with the syndrome, due to the complexity of the possible co-morbidities. In addition, our clinical experience for the first time suggests that pancreatic exocrine insufficiency may offer a possible explanation for the growth retardation observed in some patients with this syndrome. Our finding that replacement treatment with pancreatic enzymes improved weight gain (case 2) implies that all patients with Donohue syndrome should be investigated for exocrine pancreatic insufficiency.

Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β‐subunit of the insulin receptor (INSR) gene

“…To evaluate the effect of insulin signaling defects during the fetal period, we compared the SDSs of birth weight between patients with Donohue syndrome (DS), Rabson–Mendenhall syndrome (RMS), and Type A IR. In addition to the present cases, we collected perinatal information for 12 Japanese patients (five with Type A IR and seven with DS or RMS) and 28 patients from other countries (two with Type A IR, 15 with DS, and 11 with RMS) based on previous studies . All birth weight SDSs for all nine patients with Type A IR were < 0 (mean [±SD] –1.65 ± 0.85; range from −0.72 to −3.28).…”

“…Birth weight SDSs were calculated based on Japanese standards . (b) Birth weight SDS of the reported 40 patients with genetically proven severe IR . A, Type A IR; R, Rabson–Mendenhall syndrome; D, Donohue syndrome.…”

“…To assess correlations between phenotype severity and birth weight, perinatal information was collected for patients with genetically proven SIR from previous reports . Birth weight SDSs were calculated based on a Japanese reference and international standard .…”

Enteroinsular hormones in two siblings with Donohue syndrome and complete leptin deficiency

“…The full clinical features of these 2 patients were reported before with genetically confirmed DS (homozygous INSR mutation; c.1093G>T, in exon 4).…”

“…Our group previously published 2 sisters with DS with new associated gastrointestinal (GI) and pancreatic complications: GI dysmotility and pancreatic exocrine insufficiency . We now report on the enteroinsular hormone concentrations in these patients.…”