Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Thanatophoric Dysplasia (TD) [Q77.1]

OMIM numbers: 187600 (TD1), 187601 (TD2), 134934 (FGFR3)

Dr. rer. nat. Christoph Marschall, Dipl.-Biol. Christine Schack,
Dipl.-Biol. Christina Sofeso

Scientific Background

Thanatophoric dysplasia (TD) is a disease with autosomal dominant inheritance (or caused by dominant new mutations) and has an incidence of 1:20,000–40,000. Therefore, TD is one of the more frequently occurring forms of lethal skeletal dysplasias. The disease is characterized by severe disproportionate short stature with rhizomelic shortening of limbs, a very narrow thorax and macrocephalus (possibly cloverleaf skull). Affected children usually die within the first few hours of life; however, some patients live for several years.

Thanatophoric dysplasia is divided into two subtypes:

  • Type 1 (TD1): short, curved thigh bones (telephone handle-shaped femur)
  • Type 2 (TD2): straight, relatively long femur, more or less severe cloverleaf deformation of the skull

The disease is caused by mutations in the FGFR3 gene (fibroblast growth factor receptor 3). Approximately 50% of all TD1 cases are caused by the mutation R248C in the FGFR3 gene. The second most frequent mutation FGFR3-Y373C is detected in 20% of all cases. Homozygosity for a mutation associated with achondroplasia causes the phenotype of TD as well.

The only relevant mutation concerning TD2 (FGFR3-K650E) can be detected in nearly all TD2 cases. However, the same codon of the FGFR3 gene may exhibit mutations which have been associated with a less severe form of the disease, the SADDAN dysplasia, or with the mildest form of the FGFR3 diseases, hypochondroplasia. This suggests a change of varying degree in the tyrosine kinase activity of the receptor depending on the amino acid substitution (genotype-phenotype correlation).