Severe phenotype of a heterozygous with variant on FGFR3 in the second trimester: a case report

Background: Achondroplasia is a congenital skeletal system malformation caused by missense mutation of FGFR3 gene with an incidence of 1 per 20,000–30,000 newborns, which is an autosomal dominant inheritance disease. Despite similar imaging features, the homozygous achondroplasia is absolutely lethal due to thoracic stenosis, whereas heterozygous achondroplasia does not lead to fetal death. Case presentation A fetus with progressive rhizomelic short limbs and overt narrow chest was detected by prenatal ultrasound in the second trimester. Gene sequencing results of amniotic fluid sample indicated a rare missense variant NM_000142.4: c.1123G > T(p.Gly375Cys), leading to a glusate-to-cysteine substitution. Re-sequencing confirmed that it was a heterozygous mutation, and thoracic stenosis was then confirmed in the corpse by radiological examination. Conclusions We identified a wild heterozygous variant of the FGFR3 gene as the rare pathogenic mutation of severe achondroplasia in a fetus. Heterozygous variants of p.Gly375Cys may have a severe phenotype similar to homozygote. It’s crucial to combine prenatal ultrasound with genetic examination to differentiate heterozygous from homozygous achondroplasia. The p.Gly375Cys mutation of FGFR3 gene may serve as a vital target for the diagnosis of severe achondroplasia.