Evaluation of clinical, radiological and molecular findings in patients with hypochondroplasia

Hypochondroplasia (HCH) is an autosomal dominant genetic skeletal disorder characterized by short stature with a relatively long trunk and short extremities. The diagnosis of HCH is primarily based on clinical findings. About 60-70% of patients with clinical and radiographic findings of HCH have recurrent c.1620C>A and c.1620C>G; p.(Asn540Lys) variants in the FGFR3 gene. Other less frequent pathogenic variants have also been described. However, not all patients with presumed HCH have demonstrable FGFR3 pathogenic variants. Along with skeletal findings, intellectual disability and seizures have also been described. Bilateral temporal lobe dysgenesis has been demonstrated in these patients. It is unknown whether such structural abnormalities exist in patients without neurological symptoms. In the present study the clinical, radiological, and molecular findings of 17 patients diagnosed with hypochondroplasia, based on clinical and/or molecular findings, were evaluated. After a retrospective evaluation of medical records, patients were divided into two main groups; Group 1: Patients with FGFR3 pathogenic variants associated with HCH (53%; n = 9/17); Group 2: Patients without FGFR3 pathogenic variants (47%; n = 8/17). The most common findings were short stature and body disproportions. Relative macrocephaly, shortening of the long tubular bones, and moderate narrowing of the interpedincular distances were more frequently observed in Group 1. Temporal lobe dysgenesis was observed in all patients in Group 1 (100%, n=9/9). Of all patients with a pathogenic FGFR3 variant, 66,7% carried the p.Asn540Lys variant while 33,3% carried the p.Arg200Cys variant. Mental development was normal in 57% of patients with bilateral temporal lobe dysgenesis, while 43% had varying degrees of intellectual impairment. Moderate intellectual disability and seizure were observed in only one patient. In addition to hypochondroplasia, this patient was also diagnosed with ERF-related craniosynostosis. Temporal lobe dysgenesis was not observed in Group 2. Clinical and radiological findings of HCH can be confused with other conditions that cause short stature. Confirming the clinical diagnosis with genetic testing is an appropriate approach. Bilateral temporal lobe dysgenesis is common in HCH patients with FGFR3 pathogenic variants and can be observed in individuals without neurological symptoms. More comprehensive studies are needed to determine the genotype-phenotype relationship in HCH and to elucidate the mechanism by which FGFR3 pathogenic variants lead to similar neuroradiological findings.