Heterozygous NPR2 Mutation in Two Family Members with Short Stature and Skeletal Dysplasia.

Marianne Jacob,Ian Marshall,Christina Botti,Surabhi Menon

doi:10.1155/2018/7658496

Marianne Jacob, Ian Marshall + Show 2 more

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https://doi.org/10.1155/2018/7658496

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Abstract

Endochondral ossification at the level of the growth plate, an essential process involved in longitudinal growth, is regulated by hormonal and local factors including C-type natriuretic peptide and its receptor, natriuretic peptide receptor B. Biallelic loss-of-function mutations in the NPR2 gene, which encodes this receptor, cause acromesomelic dysplasia, Maroteaux type (AMDM), a skeletal dysplasia characterized by severe short stature and disproportionate shortening of limbs. Heterozygous NPR2 mutations have been reported in patients previously classified with idiopathic short stature (ISS). We report the presentation of a 7-year-old girl and her mother with short stature, both of whom were identified with the same NPR2 mutation, and who demonstrated clinical and radiological features consistent with a skeletal dysplasia. We also report the patient's response to recombinant human growth hormone (rhGH) over a 2-year period. We encourage clinicians who evaluate children with ISS to consider genetic testing, particularly when the presentation is associated with features suggestive of a skeletal dysplasia.

Highlights

Idiopathic short stature (ISS) has classically been defined as a height more than 2 standard deviation scores (SDS) below the mean height for age and sex without evidence of systemic, endocrine, nutritional, or chromosomal abnormalities [1]
Due to the presence of skeletal dysplastic features in Leri-Weill dyschondrosteosis (LWD) which is classically characterized by disproportionate short stature, mesomelia, and Madelung deformity [13], Hisado-Oliva et al [11] investigated whether NPR2 mutations could account for a proportion of cases with suspected LWD in whom short homeobox (SHOX) testing was negative
We describe a patient and her mother whose clinical and radiological evaluation for short stature revealed certain skeletal dysplastic features, with genetic testing confirming NPR2 heterozygosity

Summary

Introduction

Idiopathic short stature (ISS) has classically been defined as a height more than 2 standard deviation scores (SDS) below the mean height for age and sex without evidence of systemic, endocrine, nutritional, or chromosomal abnormalities [1]. In growth plate chondrocytes, binding of CNP to NPR-B stimulates chondrocyte differentiation and hypertrophy, and an increase in matrix synthesis [5]. This interaction plays an important role in endochondral ossification at the level of the growth plate, an important component of longitudinal bone growth [6]. Biallelic NPR2 mutations cause acromesomelic dysplasia, Maroteaux type (AMDM) [7]. Subsequent studies identified heterozygous NPR2 mutations as the cause of short stature in unrelated patients previously classified with ISS [5, 6, 10, 11]. We report the patient’s response to recombinant human growth hormone (rhGH)

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Conflicts of Interest