Clinical Manifestations and Outcomes of 20 Korean Hypochondroplasia Patients with the FGFR3 N540K variant

Abstract

Abstract Background Hypochondroplasia is a skeletal dysplasia caused by activating pathologic variants of FGFR3. The N540K variant accounts for 60–70% of reported cases and is associated with severe manifestations. Here, we analyze the clinical manifestations and outcomes of Korean patients with hypochondroplasia harboring the FGFR3 N540K variant. Methods Medical records of 20 unrelated patients with genetically confirmed N540K-related hypochondroplasia were retrospectively reviewed. All individuals were diagnosed with hypochondroplasia by Sanger sequencing for FGFR3, or target-panel sequencing for skeletal dysplasia. The effectiveness of growth hormone therapy was analyzed in 16 patients treated with growth hormones. Results Among 20 patients (7 men, 13 women), the mean age at first visit was 3.5±1.0 years, and the mean follow-up duration was 6.8±0.6 years. The patients presented with a short stature and/or short limbs. Genu varum, macrocephaly, and developmental delay were observed in 11 (55.0%), 9 (45.0%), and 5 (25.0%) patients, respectively. Of the 12 patients who underwent neuroimaging, five (41.7%) showed abnormal findings (one required operation for obstructive hydrocephalus). Among 16 growth-hormone-treated patients (two were growth-hormone deficient), the increase in height standard deviation scores was significant after a mean 5.4±0.7 years of treatment (+0.6 and+1.8 using growth references for healthy controls and achondroplasia children, respectively). Four patients underwent surgical limb lengthening at a mean age of 8.8±3.3 years. Conclusions Neurodevelopmental abnormalities are frequently observed in patients with N540K-related hypochondroplasia. Close monitoring of skeletal manifestations and neurodevelopmental status is necessary for hypochondroplasia.