Disorders caused by genetic defects associated with GH-dependent genes: PAPPA2 defects.

Growth hormone (GH) and its mediator, insulin-like growth factor-1 (IGF-1), have long been recognized as central to human growth physiology. IGF-1 is known to complex with IGF binding proteins as well as with the acid labile subunit (ALS) in order to prolong its half-life in circulation. Factors regulating the bioavailability of IGF-1 (i.e. the balance between free and bound IGF-1) were less well understood. Recently, pregnancy-associated plasma protein-A2 (PAPP-A2) was discovered as a protease which specifically cleaves IGF-binding protein (IGFBP)-3 and -5. PAPP-A2 deficient patients present with characteristic findings including growth failure, elevated total IGF-1 and -2, IGFBPs, and ALS, but decreased percentage of free to total IGF-1. Additionally, patients with PAPP-A2 deficiency have impairments in glucose metabolism and bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) improved height SD scores, growth velocity, body composition, and dysglycemia. Mouse models recapitulate many of the human findings of PAPP-A2 deficiency. This review summarizes the function of PAPP-A2 and its contribution to the GH-IGF axis through an examination of PAPP-A2 deficient patients and mouse models, thereby emphasizing the importance of the regulation of IGF-1 bioavailability in human growth.