Role of Pregnancy-Associated Plasma Proteins (PAPP A and PAPP A2) and Insulin-Like Growth Factor-Binding Proteins in Children with Idiopathic Short Stature

Background: Idiopathic short stature (ISS) is a poorly understood growth disorder in children who have normal growth hormone secretion but remain significantly shorter than their peers. This review synthesises current evidence on the roles of pregnancy‑associated plasma proteins (PAPP‑A and PAPP‑A2) and insulin‑like growth factor-binding proteins (IGFBPs) in the pathophysiology of ISS, and evaluates their potential as diagnostic biomarkers and therapeutic targets. Main Body: We performed a narrative review of peer‑reviewed literature published up to 2024, focusing on the biochemical regulation of the growth hormone–insulin‑like growth factor (GH–IGF) axis, with special emphasis on PAPP‑A, PAPP‑A2, and IGFBPs. Genetic, diagnostic, and treatment studies in children with ISS were also examined. PAPP‑A and PAPP‑A2 are metalloproteinases that cleave IGFBP‑3 and IGFBP‑5, thereby increasing free IGF‑1 bioavailability and promoting chondrocyte proliferation and linear bone growth. Disrupted activity of these proteins leads to relative IGF‑1 resistance and impaired growth. Several genetic variants in the GH–IGF axis (GHR, IGFALS) and in growth‑plate regulators (SHOX, NPR2, FGFR3, ACAN) have been identified in ISS children, although routine testing for PAPP‑A/A2 is not yet standard. GH therapy remains the only FDA‑approved treatment for ISS, but its efficacy is variable and long‑term safety data are limited. Conclusion: PAPP‑A, PAPP‑A2, and IGFBPs are key modulators of IGF bioavailability. Their measurement may improve diagnostic accuracy in ISS and open avenues for targeted therapy. Future research should focus on standardised assays and clinical trials of PAPP‑A/A2 modulators.