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

Thanatophoric Dysplasia (TD) [Q77.1]

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

Scientific Background

Thanatophoric dysplasia (TD) is a disease with autosomal dominant inheritance (or caused by dominant new mutations) and an incidence of 1:20,000–40,000 making TD 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 in 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, cloverleaf deformation of the skull of varying severity

The disease is caused by mutations in the FGFR3 gene (fibroblast growth factor receptor 3). TD1 can be caused by amino acid substitutions in the extracellular and intracellular domain of the protein. Examples of extracellular domains are the two common variants R248C and Y373C. There are also reports of affected stop codon variants leading to protein extension. Homozygosity for a mutation associated with achondroplasia also leads to a TD phenotype.

The only relevant change in TD2 (FGFR3-K650E) can be detected in nearly all TD2 cases. However, variants in the same codon of the FGFR3 gene can occur that are associated with a less severe form of the disease: SADDAN dysplasia, or with the mildest form of the FGFR3 diseases: hypochondroplasia. This implies  that the severity of the change in the tyrosine kinase activity of the receptor is dependant on the amino acid substitution (genotype-phenotype correlation).

Literature

Wainwright 2016, S Afr Med J 106:S50  / Xue et al. 2014, Mol Genet Genomic Med 2:497 / Foldynova-Trantirkova et al. 2012, Hum Mutat 33:29 / Martinez-Frias et al. 2009, Am J Med Genet Part A 152A:245 / Lievens et al. 2004, J Biol Chem 279:43254 / Zabel 2004, medgen 16:8 / Van Esch et al. 2004, Genet Counsel 15:375 / Wilkin 2001 in: The Metabolic & Molecular Basis of Inherited Disease 5379 / Vajo et al. 2000, Endocr Rev 21:23 / Perez-Castro et al. 1997, Genomics 41:10 / Tavormina et al. 1995, Nature Genet. 9:321