Anthropometric and Radiological Findings in Patients with Hypochondroplasia. Correlation with Presence of Mutations in the Fibroblast Growth Factor Receptor 3 Gene

Abstract

Hypochondroplasia is a skeletal dysplasia with autosomic dominant inheritance characterized by short stature with short limbs, that presents a wide phenotypic variation. In 50–70% of the patients, mutations are found in the FGFR3 gene. Diagnosis is based on the clinical and radiological criteria described by Spranger. Objective: To correlate the anthropometric and radiological criteria with the molecular findings in 21 patients. Patients and Methods: In all patients we measured head circumference (HC), height, sitting height and leg length (LL), and we calculated Z scores. We also performed a blind reading of the X-Rays. The region of the FGFR3 gene that includes prevalent mutations (N540K C→A y C→G) and the majority of the rare mutations (N540T, N540S and I538V) were analyzed by sequencing and allelic specific hybridization (ASO). Median test and Fisher test were used to compare both groups according to the molecular results. We set cut off points for the significant variables with ROC analysis. Results: Whereas a mutation in FGFR3 gene was detected in 14 patients (8 N540K C→A y 6 N540K C→G) (group 1), the sequence was normal in 7 patients (group 2). We found statistically significant differences in HC and LL between both groups. The median in HC was 2.05 (0.80/3.80) (group 1) vs. –0.10 (-2.29/1.13) (group 2); (Median Test p=0,001). The median in LL was –5.15 (-7.10/ -4.00) vs –4.10 (-5.50/-3.30), respectively; (Median Test p=0,033). The cut off point that divided both groups was for HC + 1.13 SD (with a 92.3% sensitivity and 100% specificity) vs. – 5.8 SD for LL (with a 28.6% sensitivity and 100% specificity). No association was found between radiological criteria and presence of mutation or not (NS, Fisher test). Conclusion: In our study sample, while the auxologic findings (greater HC and shorter LL) permitted the anthropometric differentiation of patients with mutations in the FGFR3 gene (group 1), radiological criteria were not useful to predict the presence of such mutation.