Delayed dental development and short stature associated with a novel homozygous PAPPA2 variant.
4 affiliations
- 1Department of Pediatric Endocrinology, Etlik City Hospital, University of Health Sciences, Ankara 06170, Turkey.
- 2Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University, London EC1M 6BQ, UK.
- 3Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, Bristol BS2 8BJ, UK.
- 4Bristol Medical School, University of Bristol, Queens Road, Bristol BS8 1QU, UK.
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.
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BibTeX
@article{kurnaz2026delayed,
title = {{Delayed dental development and short stature associated with a novel homozygous PAPPA2 variant.}},
author = {Erdal Kurnaz and Avinaash Vickram Maharaj and Afiya Andrews and Helen L Storr and Sumana Chatterjee and Dinesh Giri},
journal = {JCEM case reports},
year = {2026},
month = oct,
doi = {10.1210/jcemcr/luag317},
url = {https://europepmc.org/article/MED/42948660},
note = {CC BY},
}
RIS
TY - JOUR
TI - Delayed dental development and short stature associated with a novel homozygous PAPPA2 variant.
AU - Erdal Kurnaz
AU - Avinaash Vickram Maharaj
AU - Afiya Andrews
AU - Helen L Storr
AU - Sumana Chatterjee
AU - Dinesh Giri
PY - 2026
DA - 2026/10/27
JO - JCEM case reports
DO - 10.1210/jcemcr/luag317
UR - https://europepmc.org/article/MED/42948660
AB - 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.
SN - 2755-1520
ER -