タナトフォリック骨異形成症

Thanatophoric dysplasia (TD) is the most common lethal skeletal dysplasia, caused by de novo fibroblast growth factor receptor 3 (FGFR3) mutations. Prenatal ultrasound may detect key features such as severe micromelia, narrow thorax, macrocephaly, and temporal lobe dysplasia, although molecular confirmation is essential. Type I TD (TD1), the most frequent subtype, shows "telephone-receiver" femur bowing, frontal bossing, and midface hypoplasia. Type II TD presents with a cloverleaf skull and straight femurs. TD is generally fatal due to pulmonary hypoplasia, narrow thorax, and brainstem compression, with survival beyond the early neonatal period being uncommon. We report a newborn with prenatal suspicion of skeletal dysplasia, confirmed postnatally as TD1 via FGFR3 p.Ter807Trp mutation, highlighting the importance of prenatal counseling, early genetic confirmation, and palliative care involvement.

Thanatophoric dysplasia (TD) is the most common lethal congenital skeletal dysplasia, characterized by severe micromelia, a narrow thorax, and frontal bossing due to activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene on chromosome 4p16.3. First described by Maroteaux and Lamy in 1967, it carries a near-uniform perinatal mortality from respiratory insufficiency. We present the case of a male newborn in whom the diagnosis of thanatophoric dysplasia was established during the antenatal period.

OBJECTIVE: To investigate the clinical application value of exome sequencing technology in fetuses with sonographically detected skeletal dysplasia. METHODS: A total of 80 pregnant women whose fetuses were diagnosed with sonographically detected skeletal dysplasia at 11⁺0 to 38⁺0 weeks of gestation in our hospital from March 2021 to January 2022 were enrolled in this study. G-banded chromosomal karyotype analysis (KA), chromosomal microarray analysis (CMA) and whole exome sequencing (WES) were simultaneously performed for all cases. Clinical data including maternal age, gestational week, prenatal ultrasound findings, results of KA, CMA and WES, and pregnancy outcomes were collected and subjected to statistical analysis. RESULTS: Limb shortening was the most common phenotypic manifestation of fetal skeletal dysplasia. The diagnostic yield of KA combined with CMA for fetal skeletal dysplasia was only 7.5% (6/80), while the additional combination with WES identified 43 positive cases, with an overall diagnostic yield of 53.75% (43/80). There was a statistically significant difference in the diagnostic yield between the two detection protocols (χ2=50.19, P<0.001), with an absolute increase of 46.25% in the diagnostic yield after the integration of WES. The most common clinical disorders caused by pathogenic genes included osteogenesis imperfecta, achondroplasia and thanatophoric dysplasia. The majority of pathogenic variants were de novo mutations, mainly involving the COL1A1, FGFR2 and FGFR3 genes. Among the 43 WES-positive cases, 34 pregnancies opted for termination of pregnancy. CONCLUSION: Whole-exome sequencing technology holds important application value in the prenatal diagnosis of fetal skeletal system diseases, and provides a more accurate evidence base for genetic counseling and clinical decision-making.