A family with type A insulin resistance syndrome caused by a novel insulin receptor mutation

Abstract

Summary: A 17-year-old boy was referred to our endocrinology clinic for a clinical investigation of hyperinsulinemia. An oral glucose tolerance test showed plasma glucose concentrations in the normal range. However, insulin concentrations were considerably elevated (0 min: 71 μU/mL; 60 min: 953 μU/mL), suggesting severe insulin resistance. An insulin tolerance test confirmed that he had insulin resistance. There was no apparent hormonal or metabolic cause, including obesity. The patient had no outward features of hyperinsulinemia, including acanthosis nigricans or hirsutism. However, his mother and grandfather also had hyperinsulinemia. Genetic testing showed that the patient (proband), his mother, and his grandfather had a novel p.Val1086del heterozygous mutation in exon 17 of the insulin receptor gene (INSR). Although all three family members have the same mutation, their clinical courses have been different. The onset of the mother's diabetes was estimated at 50 years, whereas the grandfather developed diabetes at 77 years.

Learning points: Type A insulin resistance syndrome is caused by mutations in the insulin receptor (INSR) gene and results in severe insulin resistance. Genetic evaluation should be considered in adolescents or young adults with dysglycemia when an atypical phenotype, such as severe insulin resistance, or a relevant family history is observed. Clinical courses may differ even if the same genetic mutation is found in a family.

Figure 1

Pedigree of the family. The arrow shows the proband. The gray square and gray circle indicate family members found to have the mutation, and the numbers in the figure represent age in years.

Figure 2

Sequencing results of genomic DNA (A–D) and cDNA (E, F) of the insulin receptor gene (INSR). The proband, his mother, and his grandfather have a heterozygous GTG deletion at the 3′ end of exon 17. Sequencing of genomic DNA could not distinguish between this mutation and a GTG deletion next to it at the 5′ end of the intron. Sequencing of cDNA confirmed the mutation as p.Val1086del in exon 17.