Abstract 505 Poster Session II, Sunday, 5/2 (poster 205)

Mutations in the insulin gene cause the autosomal recessive disorders Leprechaunism and Rabson-Mendenhall syndrome. Here we report a child who presented at 4 weeks of age with hyperglycemia and extreme hyperinsulinemia (2776 µU/ml). Other features included intrauterine growth retardation (birth weight 2.16 kg at term), post-natal failure to thrive, acanthosis nigricans, dysplastic teeth, thick hair, absent subcutaneous fat, and large genitalia, all findings consistent with a diagnosis of Rabson-Mendenhall syndrome. He also developed chronic hip arthralgia, felt to represent a variant of idiopathic toxic synovitis. During the first three years of life, his blood glucose levels ranged from normal to ∼400 mg/dL while his hemoglobin (Hb) A1C ranged from 5.8% to 8.1%. At 3.7 years of age he was started on glipizide 2.5 mg/day. Metformin was added subsequently for worsening glycemic control. Despite this regimen maintaining HbA1C values of 8-9%, he developed unexpected sequelae, including microalbuminuria, persistent ketonuria, and progressive decline in weight gain and linear growth. During the last 3 years, he had normal to low values for IGF-1 (36-50 ng/ml), IGF-BP3 (0.9-1.8 mg/l). and IGF-BP1 (60-62 ng/ml). Currently he is 7.2 years old with a height at -3.5 SD for age. He is on a trial of growth hormone (GH), which seems to aggravate hyperglycemia (HbA1C of 10.6%), without yet affecting growth velocity. IGF-1 therapy will be considered following completion of the GH trial.

Sequencing of the insulin receptor gene indicated that he is a compound heterozygote for two novel missense mutations in the β-subunit. The paternal mutation is P970T, substituting a conserved Proline in the NPEY consensus sequence in the 16th exon that is a major binding site for IRS-1 (Insulin-Receptor Substrate 1) and Shc (Src Homology 2 Containing Protein). Mutations in this area are known to affect insulin-stimulated IRS-1 and Shc phosphorylation. The maternal mutation, R1131W, reported in another patient with the same syndrome, affects a conserved amino acid in the core of the catalytic loop of the tyrosine kinase domain of 19th exon of the insulin receptor. These mutations likely impair insulin effect on growth and metabolism through a variety of mechanisms, including interference with the IGF-1 receptor. Site-directed mutagenesis is underway to determine whether the novel P970T mutation affects not only insulin, but also IGF-1 signaling, explaining the progressive deterioration of growth.