Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis

A Hisado-Oliva, AI Garre-Vázquez… - The Journal of …, 2015 - academic.oup.com
A Hisado-Oliva, AI Garre-Vázquez, F Santaolalla-Caballero, A Belinchón, AC Barreda-Bonis…
The Journal of Clinical Endocrinology & Metabolism, 2015academic.oup.com
Context: SHOX mutations have been detected in approximately 70% of Léri-Weill
dyschondrosteosis (LWD) and approximately 2.5% of idiopathic short stature (ISS) cases,
suggesting the implication of other genes or loci. The recent identification of NPR2 mutations
in ISS suggested that NPR2 mutations may also be involved in disproportionate short
stature. Objective: The objective of the study was to investigate whether NPR2 mutations can
account for a proportion of the cases referred for LWD and ISS in whom no SHOX mutation …
Context
SHOX mutations have been detected in approximately 70% of Léri-Weill dyschondrosteosis (LWD) and approximately 2.5% of idiopathic short stature (ISS) cases, suggesting the implication of other genes or loci. The recent identification of NPR2 mutations in ISS suggested that NPR2 mutations may also be involved in disproportionate short stature.
Objective
The objective of the study was to investigate whether NPR2 mutations can account for a proportion of the cases referred for LWD and ISS in whom no SHOX mutation was detected.
Patients and Methods
We undertook NPR2 mutation screening in 173 individuals referred for suspected LWD and 95 for ISS, with no known defect in SHOX or its enhancers. Intracellular localization and natriuretic peptide precursor C-dependent guanylate cyclase activity were determined for the identified NPR2 variants.
Results
Eight NPR2 variants were identified in nine individuals, seven referred for suspected LWD and two for ISS. Six were demonstrated to affect NPR-B cell trafficking and/or its ability to synthesize cyclic GMP (cGMP) under response to natriuretic peptide precursor C/brain natriuretic peptide stimulation. All pathogenic mutations were detected in the suspected LWD referral group (∼3%). Interestingly, one of these patients is currently being treated with recombinant human GH and in contrast to previous reports is showing a positive response to the treatment.
Conclusions
NPR2 mutations account for approximately 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.
Oxford University Press