ESPE Abstracts (2015) 84 P-2-459


aInstitute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain; bCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, U753), Instituto Carlos III, Madrid, Spain; cDepartment of Pediatric Endocrinology, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain; dUnidade de Endocrinologia Genetica, Laboratorio de Endocrinologia Celular e Molecular LIM-25, Universidade de São Paulo, São Paulo, Brazil; eDepartment of Endocrinology & Nutrition, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain; fDepartment of Pediatric Endocrinology, Hospital Marqués de Valdecilla, Santander, Spain

Background: Mutations in SHOX or its regulatory regions have been detected in ~70% of Léri-Weill dyschondrosteosis (LWD) and ~2.5% of idiopathic short stature (ISS) cases, suggesting the implication of other genes or loci. Recent studies have identified NPR2 defects in ISS patients.

Objective and hypotheses: To investigate if NPR2 mutations can account for a proportion of the cases referred for LWD and ISS in whom no SHOX/PAR1 mutation was detected.

Method: We undertook NPR2 mutation screening in 173 individuals referred for suspected LWD and 95 for ISS, with no known SHOX/PAR1 defect. In silico pathogenicity analysis was undertaken using Alamut V2.6. Intracellular localization and CNP-dependent guanylate cyclase activity were determined to characterize the pathogenicity of the identified NPR2 variants. Cosegregation analysis was undertaken when possible.

Results: Eight NPR2 variants, four novel, were identified in nine individuals, seven referred for LWD and two for ISS. Seven of the eight variants were predicted to be pathogenic whilst only one was predicted to be a non-pathogenic variant. Functional analysis confirmed the pathogenicity of six of the variants, all of which were detected in the LWD referral group (~3%). The variants observed in ISS patients did not affect NPRB function.

Conclusion: NPR2 mutations account for ~3% of patients with disproportionate short stature and/or clinical or radiographic indicators of SHOX deficiency and in whom no SHOX defect has been identified. However, no patient has yet presented with Madelung deformity. Thus, NPR2 should be screened in the SHOX negative LWD referrals. Functional analyses are required as several NPR2 variants, predicted to be pathogenic, and were demonstrated to be non-pathogenic. Interestingly, one of the NPR2 mutation carriers is currently being treated with rhGH, and in contrast to previous reports is showing a positive response to the treatment.

Funding: This work was supported in part by a MINECO grant (SAF2012-30871), the Jose Igea Award by the Foundation of the Spanish Society of Pediatric Endocrinology (F-SEEP) and the EndoScreen project (IdiPAZ and UAM).

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