IMPAIRED GROWTH IN RABSON-MENDENHALL SYNDROME - LACK OF EFFECT OF GROWTH-HORMONE AND INSULIN-LIKE GROWTH-FACTOR-I

Mutations in the insulin receptor gene cause the severe insulin-resist ant syndromes leprechaunism and Rabson-Mendenhall syndrome. There is n o accepted therapy for these inherited conditions. Here we report the results of recombinant human GH (rhGH) and recombinant human insulin-l ike growth factor-I (rhIGF-I) treatment of a male patient, Atl-2, with Rabson-Mendenhall syndrome. The patient was small for gestational age , had premature dentition, absence of sc fat, acanthosis nigricans, fa sting hypoglycemia and postprandial hyperglycemia, and extremely high concentrations of circulating insulin (up to 8500 mu U/mL). Fibroblast s and lymphoblasts established from this patient had reduced insulin b inding, which was 20-30% of the control value. Binding of epidermal gr owth factor, IGF-I, and GH to the patient's fibroblasts was normal. Th e growth of fibroblasts cultured from patient Atl-2 in vitro was inter mediate between that of fibroblasts from patients with leprechaunism a nd control values. The patient's growth curve in vivo was far below th e fifth percentile despite adequate nutrition. To stimulate growth, th erapy with rhGH was initiated, the rationale being to stimulate hepati c IGF-I production and IGF-I receptor signaling, and bypass the inheri ted block in insulin receptor signaling. Therapy with rhGH (up to 0.5 mg/kg.week) did not improve growth and failed to increase the levels o f circulating IGF-I and IGF-binding protein-3 over a 14-month period. As rhGH could not stimulate growth, rhIGF-I (up to 100 mu g/kg.day) wa s given by daily sc injection. No increase in growth velocity was obse rved over a 14-month period. These results indicate that both GH and I GF-I fail to correct growth in a patient with severe inherited insulin resistance. The lack of efficacy of IGF-I treatment may be related to multiple factors, such as the poor metabolic state of the patient, th e deficiency of serum carrier protein for IGF-I, an increased clearanc e of the growth factor, IGF-I resistance in target cells at a receptor or postreceptor level, or an inhibitory action of the mutant insulin receptors on IGF-I receptor signaling.