Thanatophoric dysplasia is a severe skeletal disorder characterized by severe dysproportional short stature, shortened extremeties, a narrow thorax and macrocephalus. It is typically fatal during the perinatal period. Thanatophoric dysplasia has two forms, type I and type II. The main symptoms are extremely short limbs and folds of extra skin on the arms and legs. The disease is caused by pathogenic variants in the FGFR3 gene.
Also called
Thanatotropic dysplasia is also known as:
- Dwarf, thanatophoric
- Thanatophoric dwarfism
- Thanatophoric short stature
- TD
Symptoms
In type I thanatophoric dysplasia, curved thigh-bones and flattened bones of the spine (platyspondyly) are observed. Type II thanatophoric dysplasia is distinguished by straight thigh-bones and a cranial abnormality known as cloverleaf skull, ranging from moderate to severe.
Other symptoms of TD may include:
- Short limbs
- Fold of extra skin on the arms and legs
- Narrow chest
- Short ribs
- Underdeveloped lungs
- Enlarged head
- Wide-spaced eyes
Frequency
The frequency of TD is estimated to be 1 in 20,000 to 40,000 newborns. Type I thanatophoric dysplasia is the most prevalent form of this condition.
Causes
TD is caused by mutations in the FGFR3 gene, whereby different variants can cause different manifestations of the disease.
TD1 can be caused, for example, by amino acid substitutions in the extracellular or intracellular domain of the protein. Examples of the extracellular domain are the two common variants R248C and Y373C. However, variants affecting the stop codon have also been reported, which lead to an elongation of the protein. Homozygosity for a variant associated with achondroplasia also leads to the TD phenotype.
The only relevant change in TD2 (FGFR3-K650E) is detectable in almost all TD2 cases. However, variants can also occur in the same codon of the FGFR3 gene that are associated with a less severe form of the disease, SADDAN dysplasia, or with the mildest form of FGFR3 disease, hypochondroplasia. This suggests that there is a different degree of change in the tyrosine kinase activity of the receptor depending on the amino acid exchange (genotype-phenotype relationship).
Inheritance
TD syndrome is inherited in an autosomal dominant pattern, meaning that if one parent carries one mutated copy of the FGFR3 gene, it can cause TD syndrome in the offspring. It can also be caused by dominant new mutations.
Differential diagnosis
Syndromes with similar symptoms to TD include Achondroplasia, Hypochondroplasia, Crouzon syndrome, Familial acanthosis nigricans, Muenke syndrome, LADD syndrome, Camptodactyly, tall stature and hearing loss syndrome.
Treatment
Currently, there is no cure for thanatotropic dysplasia, and most affected individuals usually die in the first few hours of life due to the disorder's multisystem complications. However, there are patients who live to be several years old. Long-term survivors will require long-term respiratory support, neurological surveillance as well as developmental, orthopedic, and audiology evaluations.
References
“Thanatophoric Dysplasia: MedlinePlus Genetics.” Medlineplus.gov, www.medlineplus.gov/genetics/condition/thanatophoric-dysplasia/ Accessed 13 Dec. 2023.
French, Tegan, and Ravi Savarirayan. “Thanatophoric Dysplasia.” PubMed, University of Washington, Seattle, 1993, www.ncbi.nlm.nih.gov/books/NBK1366/#td.Differential_Diagnosis
