Severe insulin resistance in disguise: A familial case of reactive hypoglycemia associated with a novel heterozygous INSR mutation

Aim Hypoglycemia in childhood is very rare and can be caused by genetic mutations or insulin-secreting neoplasms. Postprandial hypoglycemia has previously been associated with insulin receptor (INSR) gene mutations. We aimed to identify the cause of postprandial hypoglycemia in a 10-year-old boy. Subjects We studied the symptomatic proband and his apparently asymptomatic mother and elder brother. All of them were lean. Methods Metabolic screening of the proband included a 5-hour oral glucose tolerance test (OGTT), angio-magnetic resonance imaging, and 18F-dihydroxyphenylalanine positron emission tomography/computed tomography imaging of the pancreas. INSR gene sequencing and in vitro functional studies of a novel INSR mutation were also undertaken. Results Fasting hyperinsulinemia was detected during metabolic screening, and 5-hour OGTT showed hypoglycemia at 240′ in the proband, his mother, and brother. Pancreatic imaging showed no evidence of neoplasia. Acanthosis nigricans with high fasting insulin levels in the proband suggested severe insulin resistance and prompted INSR gene sequencing, which revealed the novel, heterozygous p.Phe1213Leu mutation in the patient and his family members. In vitro studies showed that this mutation severely impairs insulin receptor function by abolishing tyrosine kinase activity and downstream insulin signaling. Conclusions The identification of etiological cause of hypoglycemia in childhood may be challenging. The combination of fasting hyperinsulinemia with acanthosis nigricans in a lean subject with hypoglycemia suggests severe insulin resistance and warrants INSR gene screening.