ESPE Abstracts (2014) 82 P-D-2-1-450

aInstitute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Madrid, Spain; bCIBERER, ISCIII, Madrid, Spain; cDepartment of Pediatric Endocrinology, Hospital Universitario La Paz, Madrid, Spain; dDepartment of Pediatric Endocrinology, Hospital Universitario Principe de Asturias, Alcalá de Henares, Madrid, Spain; eDepartment of Pediatric Endocrinology, Hospital Universitario Marqués de Valdecilla, Santander, Spain

Background: Homozygous natriuretic peptide receptor-2 (NPR2) mutations cause acromesomelic dysplasia, type Maroteaux, a skeletal dysplasia with extreme disproportionate short stature and recently, heterozygous NPR2 mutations have been identified also in patients with idiopathic short stature (ISS, 2–6%). SHOX mutations are found in ~2–5% of ISS cases and ~70% of Léri-Weill dyschondrosteosis (LWD) cases, characterized by disproportionate short stature and Madelung deformity. The molecular defect is unknown in the remaining ~30%.

Objective: To determine if NPR2 mutations are present in LWD patients with no known SHOX defect.

Method: 87 Spanish patients with suspected LWD and no known SHOX defect. Mutation screening was carried out using a Skeletal Next-generation sequencing panel (Haloplex/SeqCap) on a MiSDefault (Illumina), or by High Resolution Melting and sequencing. Pathogenicity was assessed using Alamut V2.3-6.

Results: Five heterozygous NPR2 mutations were identified: c.1262C>T (p.Thr421Met), c.1641_1643del (p.Val548del); c.2759G>A (p.Gly920Asp), c.2972A>G (p.Glu991Gly) and c.3058C>T (p.Arg1020Trp). All mutations were absent or very infrequent in 1000 genomes and Exome Variant Server databases. In silico analysis indicated that the affected amino acids are highly conserved and suggested that the missense mutations are likely to be pathogenic, whilst the pathogenicity of the in frame deletion is unknown. Where possible, the mutations were shown to cosegregate, with the phenotype. Functional analysis is ongoing.

Conclusions: i) NPR2 heterozygous mutations were identified in 4.6% of patients with LWD without known SHOX defects; ii) it is plausible that NPR2 mutations may cause disproportionate short stature as homozygous defects result in severe disproportionate short stature; iii) Two of the patients with NPR2 mutations showed a good response to rhGH treatment (height increase by 1SD); iv) NPR2 mutation screening should be indicated in patients with disproportionate short stature who tested negative for SHOX defects; v) Further data are required to evaluate whether rhGH treatment is appropriate for these patients.

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