ESPE Abstracts (2015) 84 HA2

A New Syndrome Associated with Mutations in the Gene for Pregnancy-Associated Plasma Protein A2 (PAPP-A2) Causing Proportionate Short Stature, High Circulating IGF-I, IGFBP-3, and ALS, Mild Microcephaly, thin Long Bones and Decreased Bone Mineral Density in two Unrelated Families

Andrew Daubera, María T Muñoz-Calvob,c, Vicente Barriosb,c, Vardhini Desikand, Jesús Pozob,c, Radhika Muzumdare, Gabriel Á Martos-Morenob,c, Federico Hawkinsf, Horacio Domeneg, Héctor G Jasperg, Soren Kloverprish, Shoshana Yakari, Cheryl A Conoverj, John J Kopchickk, Vivian Hwaa, Julie A Chowenb,c, Claus Oxvigh, Ron G Rosenfeldl, Luis A Pérez-Juradom,n & Jesús Argenteb,c

aChildren’s Hospital Medical Center, Cincinnati, OH, USA, bHospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain, cCIBEROBN, Instituto de SaludCarlos III, Madrid, Spain, dChildren’s and Women’s Physicians of Westchester, Hawthorne, NY, USA, eChildren’s Hospital of Pittsburgh, Pittsburgh, PA, USA, fHospital Universitario 12 de Octubre and Universidad Complutense, Madrid, Spain, gRicardo Gutiérrez Children’s Hospital and CEDIE/CONICET, Buenos Aires, Argentina, hDepartment of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark, iDepartment of Basic Science, New York University College of Dentistry, New York, NY, USA, jEndocrinology Research Unit, Mayo Clinic, Rochester, MN, USA, kEdison Biotechnology Institute, Ohio University, Athens, OH, USA, lDepartment of Pediatrics, Oregon Health and Science University, Portland, OR, USA, mDepartment of Genetics, Hospital del Mar Research Institute (IMIM), University Pompeu Fabra, Barcelona, Spain, nCIBERER, Instituto de Salud Carlos III, Barcelona, Spain

Background: PAPP-A2 is a metalloproteinase that specifically cleaves IGFBPs 3 and 5. Papp-a2 knock-out (KO) mice show a reduction in body size and skeletal abnormalities.

Objective and hypotheses: Our objective is to report two affected families from Spain and USA. The Spanish family presents a homozygous frameshift mutation in exon 3 of the PAPP-A2 gene (c.1927_ 1928insAT, p.D643fs25X) resulting in a premature stop codon, with 2 of 4 siblings affected. The American family has a homozygous missense variant in exon 8 (c.3098C>T), with three of five siblings affected. We hypothesized that the lack of IGFBP-3 and -5 proteolysis might increase in their circulating levels and limit the release and access of IGF1 to its receptors.

Methods: IGF-I, IGF-II, ALS, IGFBPs 1-6, fIGF-I, insulin, PAPP-A and PAPP-A2 levels were measured in serum by RIA/ELISA. Full exome, PAPP-A2 sequencing, in vitro expression of PAPP-A2 wt and mutants and functional PAPP-A2 protease activity and ternay complex (TC) formation by cross-linking and chromatography were performed. A skeletal survey was done, as well as bone mineral density (DXA), trabecular structure (TBS) of the bones and 3D micro-CT in a tooth of one proband.

Results: The 5 affected children exhibit a constant postnatal growth failure and high circulating IGF-I, IGF-II, IGFBP-3 and ALS levels. The Spanish children present high spontaneous GH secretion/8hr. PAPP-A2 was undetectable in the Spanish patients and very low in the American children. The TCs are very high. The Spanish mutation shows lack of proteolytic activity, while the American mutation results in expression of PAPP-A2, but at a much lower level than wt and the expressed protein is cleaved, probably by autoproteolysis. BMD in the lumbar area was decreased. TBS was into the normal range. The PAPP-A2 null patient showed decreased enamel and dentin density.

Conclusions: i) A new syndrome involving PAPP-A2 mutations is described; ii) PAPP-A2 levels should be measured in patients with short stature and elevated IGF-I; iii) Lack of PAPP-A2 activity results in reduced fIGF-I; iv) PAPP-A2 is involved in short stature.

Funding: This work was supported by Fondos de Investigación Sanitaria (FIS) PI13/02195 and CIBEROBN. Instituto de Salud Carlos III. Madrid, Spain.

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