Delayed dental development and short stature associated with a novel homozygous PAPPA2 variant

Abstract

Normal human linear growth depends on intact growth hormone (GH) signaling and insulin-like growth factor-I (IGF-I) bioavailability. In the circulation, IGF-I is largely bound to IGF-binding proteins (IGFBPs), predominantly IGFBP-3 and IGFBP-5, which, together with the acid-labile subunit form a ternary complexes that prolong its half-life. Pregnancy-associated plasma protein-A2 (PAPP-A2) cleaves IGFBP-3 and IGFBP-5, releasing bioactive IGF-I. Pathogenic PAPPA2 variants impair this process, reducing IGF-I bioavailability despite elevated total IGF-I concentrations. We report a 12.3-year-old Jordanian girl with short stature and delayed dental development. Biochemical evaluation demonstrated markedly elevated serum IGF-I and high-normal IGFBP-3. Comparative genomic hybridization microarray and targeted sequencing of genes associated with postnatal growth failure, including IGF1R, were unremarkable. A 6-month trial of recombinant human GH produced no measurable growth acceleration; however, interpretation was limited because treatment was commenced when skeletal maturity was advanced. Extended genetic analysis subsequently identified a novel homozygous PAPPA2 frameshift variant, c.1223delT (p.L408Rfs*49). This case expands the molecular spectrum of PAPP-A2 deficiency and highlights the importance of PAPPA2 testing in children with short stature, persistently elevated total IGF-I, and negative IGF1R genetic analysis. Delayed dental development may provide an additional clinical clue and help distinguish PAPP-A2 deficiency from other causes of short stature.