Thanatophoric dysplasia

Thanatophoric dysplasia is inherited in an autosomal dominant manner. However, virtually all affected individuals have a de novo heterozygous FGFR3 pathogenic variant, as the condition is associated with a high rate of perinatal mortality and reproductive fitness is therefore markedly reduced. Parents are typically clinically unaffected. The recurrence risk for future pregnancies of clinically unaffected parents is low but greater than that of the general population because of the possibility of parental germline mosaicism.

The diagnosis is suspected on the basis of characteristic prenatal ultrasonographic and postnatal radiographic findings and can be confirmed by molecular genetic testing of FGFR3. Formal consensus diagnostic criteria have not been established. Findings supporting the diagnosis include rhizomelic shortening of the long bones, a narrow thorax with short ribs, platyspondyly, ventriculomegaly, polyhydramnios, bowed femurs in TD type 1, and a cloverleaf skull deformity in TD type 2.

Main differential diagnoses include:

• Homozygous achondroplasia: severe micromelia, narrow thorax, and macrocephaly with frontal bossing; caused by biallelic FGFR3 pathogenic variants.
• Perinatally lethal (OI type II): undermineralisation of the skeleton, multiple fractures, wormian bones, and blue sclerae; e.g., COL1A1, COL1A2.
• Achondrogenesis types IA, IB, and II: extreme micromelia, severe failure of vertebral and pelvic ossification, and marked shortening of the trunk; e.g., TRIP11, SLC26A2, COL2A1.
• Skeletal (including short-rib polydactyly syndromes and Jeune asphyxiating thoracic dystrophy): narrow thorax, frequent polydactyly, and variable renal, hepatic, and retinal involvement; e.g. DYNC2H1, IFT140.

• Identification of the causal FGFR3 pathogenic variant confirms the diagnosis, distinguishes thanatophoric dysplasia from other severe skeletal dysplasias with overlapping prenatal or neonatal features, and provides the basis for accurate genetic counselling.
• Once the familial pathogenic variant has been identified, targeted testing can be offered in future pregnancies. Molecular confirmation also enables counselling regarding the low but non-zero recurrence risk associated with possible parental germline mosaicism.

French T, Savarirayan R. Thanatophoric Dysplasia. 2020 Jun 18. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301540. Available from: