CONICET | Buscador de Institutos y Recursos Humanos

CONTEXT: IGF-I deficiency may result from impairment of GH secretion or action,or from defects in IGF-I synthesis, transport, or action. Complete deficiency of the acid-labile subunit (ALS), previously described in two male patients, theonly known inherited alteration in IGF-I transport, is characterized by severecirculating IGF-I and IGF binding protein (IGFBP)-3 deficiency with only mildgrowth retardation. OBJECTIVE: Our objective was to study the characterization,at biochemical and molecular levels, of the cause for severe circulating IGF-Iand IGFBP-3 deficiency in a male patient with mild growth retardation. PATIENTS: We report an adolescent male with delayed growth and pubertal development (Tannerstage I, -2.00 sd score for height at the age of 15.3 yr), profound circulatingIGF-I and IGFBP-3 deficiency, and poor response to GH treatment. RESULTS: Theindex case, as well as one of his brothers, and his sister were found to becompound heterozygotes for two novel IGFALS gene mutations: C540R, a missensepoint mutation; and S195_197Rdup, a 9-bp duplication. The parents and youngestbrother were found to be carriers for one of these two mutations. The threeaffected siblings had marked reduction of IGF-I and IGFBP-3 levels, undetectable serum levels of ALS, inability to form ternary complexes, and moderate insulinresistance. All of them attained a normal near-adult height (between -1.0 and-0.5 sd score), which was nonetheless lower than that of their heterozygousbrother. The IGF system was only modestly affected in the heterozygous carriers. CONCLUSIONS: This study confirms the critical role of ALS in forming ternarycomplexes and the maintenance of normal levels of IGF-I and IGFBP-3. Insulinresistance, pubertal delay in male patients, and poor GH responsiveness seem tobe frequent findings in ALS deficiency. However, haploinsufficiency of the IGFALSgene has no discernible clinical effects with only modest impact on the IGFsystem.