Case of the Month: January

FGFR3-Related Thanatophoric Dysplasia Type II: A Fully Penetrant, De Novo Lethal Skeletal Dysplasia

Clinical Background

A non-consanguineous couple with no family history of congenital anomalies experienced an adverse outcome in their first pregnancy.

Antenatal Findings and Pregnancy Outcome

Antenatal ultrasonography at approximately 18 weeks’ gestation revealed severe fetal abnormalities, including marked rhizomelic shortening of all four limbs, a significantly narrowed thoracic cavity, fetal growth restriction, lateral angulation of the heart with tricuspid regurgitation, and echogenic bowel. Given the lethal nature of the findings, the pregnancy resulted in loss. Routine prenatal screening, including non-invasive prenatal testing (NIPT), was reported as low risk for common aneuploidies, prompting further genetic evaluation due to discordance between imaging findings and screening results.

Genetic Testing and Molecular Diagnosis

Whole exome sequencing of products of conception identified a heterozygous pathogenic variant c.742C>T (p. Arg248Cys) in exon 7 of the FGFR3 gene. This well-established gain-of-function mutation is causative of Thanatophoric Dysplasia type II, an autosomal dominant, fully penetrant, and lethal skeletal dysplasia characterized by severe limb shortening, thoracic hypoplasia, and perinatal lethality due to pulmonary hypoplasia. All individuals carrying pathogenic FGFR3 variants associated with classic Thanatophoric Dysplasia are expected to manifest the disease, with no reported cases of reduced or variable penetrance. Maternal cell contamination was excluded, confirming the fetal origin of the variant. The molecular findings were highly concordant with the antenatal phenotypic features.

Parental Segregation and Recurrence Risk

Parental segregation analysis did not detect the variant in either parent, indicating a de novo occurrence. Although Thanatophoric Dysplasia follows an autosomal dominant inheritance pattern, most cases arise sporadically. Consequently, the recurrence risk for future pregnancies is low, though a small residual risk remains due to the rare possibility of germline mosaicism.

Genetic Counseling and Future Reproductive Planning

The couple received comprehensive genetic counseling regarding the diagnosis, prognosis, recurrence risk, and available reproductive options. Early targeted prenatal testing in future pregnancies was discussed to facilitate timely diagnosis and informed decision-making.

Conclusion

This case highlights the importance of advanced genomic testing, particularly whole exome sequencing, in pregnancies with severe fetal anomalies when routine prenatal screening is non-informative. Establishing a definitive molecular diagnosis enables accurate recurrence risk assessment and supports personalized reproductive counseling.