title: Impaired growth in Rabson-Mendenhall syndrome: lack of effect of growth hormone and insulin-like growth factor-I.
abstract: Mutations in the insulin receptor gene cause the severe insulin-resistant syndromes leprechaunism and Rabson-Mendenhall syndrome. There is no accepted therapy for these inherited conditions. Here we report the results of recombinant human GH (rhGH) and recombinant human insulin-like 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, fasting hypoglycemia and postprandial hyperglycemia, and extremely high concentrations of circulating insulin (up to 8500 microU/mL). Fibroblasts and lymphoblasts established from this patient had reduced insulin binding, which was 20-30% of the control value. Binding of epidermal growth factor, IGF-I, and GH to the patient's fibroblasts was normal. The growth of fibroblasts cultured from patient Atl-2 in vitro was intermediate between that of fibroblasts from patients with leprechaunism and control values. The patient's growth curve in vivo was far below the fifth percentile despite adequate nutrition. To stimulate growth, therapy with rhGH was initiated, the rationale being to stimulate hepatic IGF-I production and IGF-I receptor signaling, and bypass the inherited 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 of circulating IGF-I and IGF-binding protein-3 over a 14-month period. As rhGH could not stimulate growth, rhIGF-I (up to 100 micrograms/kg.day) was given by daily sc injection. No increase in growth velocity was observed over a 14-month period. These results indicate that both GH and IGF-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, the deficiency of serum carrier protein for IGF-I, an increased clearance 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.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia 30322.
authors.forename: N
authors.initials: N
authors.lastname: Longo
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.forename: L D
authors.initials: LD
authors.lastname: Griffin
authors.forename: S D
authors.initials: SD
authors.lastname: Langley
authors.forename: J S
authors.initials: JS
authors.lastname: Parks
authors.forename: L J
authors.initials: LJ
authors.lastname: Elsas
mesh_terms: D000052:Acanthosis Nigricans / Q000209:etiology; D000273:Adipose Tissue; D001786:Blood Glucose / Q000378:metabolism; D003817:Dentition; D005347:Fibroblasts / Q000378:metabolism; D006130:Growth Disorders / Q000188:drug therapy* / Q000209:etiology; D013006:Growth Hormone / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D011994:Recombinant Proteins / Q000627:therapeutic use; D013577:Syndrome
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone