Abstract
Introduction: Abnormal body proportion disclosed by sitting height/height ratio for age and sex (SH/H SDS) > 2 indicates an impairment of appendicular growth. This is frequently observed in patients with skeletal dysplasia and can be the only clinical sign in nonsyndromic short stature children that harbor heterozygous defects in genes expressed in growth plate. The aim of the present study is to compare the degree of body disproportion among children with different genetic cause of growth impairment. Methods: We evaluated 75 children with short stature caused by defects in known growth plate genes, including FGFR3 gene (16 mutations in 7 patients with achondroplasia - ACH and in 9 patients with hypochondroplasia - HCH), SHOX gene (35 defects in 15 patients with Leri-weill dyschondrosteosis - DLW and in 20 patients with isolated short stature, defined as absence of Madelung deformity clinically and radiologically), NPR2 gene (8 heterozygous mutations) and IHH gene (16 heterozygous mutations). Variants in NPR2 and IHH genes were identified in children with isolated short stature or with nonspecific skeletal abnormalities. Results: At first evaluation, patients had a mean age of 8.7±4.9 years. Children with ACH were significantly shorter than those of the other groups (mean height SDS: -4.4 vs -2.5, p<0.05). All patients with clinically recognizable skeletal dysplasia (ACH, HCH and DLW) had abnormal body proportion (SH/H SDS >2). The frequency of abnormal body proportion observed in children initially classified as idiopathic short stature (ISS) was 85% for SHOX defects and 56% for IHH mutations (p = 0.073). None children with heterozygous mutations in NPR2 presented abnormal body proportion, though 62.5% had SH/H SDS >1. Children with ACH had SH/H SDS higher than all other groups (mean: 9.9±2.8; p<0.001). The degree of abnormal body proportion observed in children with HCH was similar to that of DLW (mean: 5.7±1.1 and 4.6±2.3, respectively; p = 0.14) and was higher than in children with isolated short stature, independently of the genetic defect (p=0.003 for SHOX and p<0.001 for IHH and NPR2). The mean SH/H SDS observed in children initially classified as ISS was similar between SHOX and IHH groups (mean: 2.9 ± 0.9 and 2.3 ± 1.4, respectively; p = 0.26), which was significantly higher in comparison to NPR2 group (mean: 0.7 ± 1.3; p = 0.004 for SHOX and p=0.024 for IHH). Conclusion: All patients with ACH, HCH and DLW had abnormal body proportion and their SH/H SDS were significantly higher than that observed in ISS children with SHOX, IHH or NPR2 defects. Furthermore, among nonsyndromic children with short stature, abnormal body proportion is associated with SHOX and IHH defects, but not with NPR2 defects. The authors have nothing to disclose.
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