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Thanatophoric Dysplasia (Type I & II)

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information

Background

Thanatophoric dysplasia (TD) is one of the most common lethal skeletal dysplasias. TD is characterized by extremely short ribs, tubular bones and macrocephaly, a small chest which crowds the respiratory system, and compression of the brain due to deformations of the skull. Two subtypes of TD exist, based on the presence (type II) or absence (type I) of cloverleaf skull, and the shape of the femur (curved, type I; straight, type II).

TD is an autosomal dominant disorder caused by mutations in the fibroblast growth factor receptor 3 gene (FGFR3) located on chromosome 4 (4p16.3). Eleven different mutations in this gene leading to TD type 1 have been identified. TD type II is caused almost exclusively by one type of mutation in the FGFR3 gene: a substitution at nucleotide 1948.

Who should be tested

• individuals clinically suspected of being affected with thanatophoric dysplasia
• pregnancies at risk due to abnormal ultrasound findings or a family history of TD

Testing Methodology

Direct Mutation Analysis:

Samples submitted for TD type I testing are analyzed using direct sequencing for the known mutations in the FGFR3 gene associated with type I disorder: c.742C>T (p.Arg248Cys); c.746C>G (p.Ser249Cys); c.1108G>T (p.Gly370Cys); c.1111A>T (p.Ser371Cys); c.1118A>G (p.Tyr373Cys); c.2416T>G (p.X807Glyext141); c.2416T>A (p.X807Argext141); c.2417G>T (p.X807Leuext141); c.2418A>T (p.X807Cysext141); c.2418A>(p.X807Cysext141) and c.2418A>G (p.X807Trpext141).
Samples submitted for TD type II testing are analyzed using a PCR-restriction enzyme analysis for the most common FGFR3 gene mutation associated with type II disorder: c.1948A>G (p.Lys650Glu).

Potential Outcomes & Interpretation of Test Results

Cautions

• Current molecular testing will not detect all possible mutations causing thanatophoric dysplasia. A negative result does not rule out the possibility that the individual has a rare mutation not included in the assay and is affected with TD.
• Test results should be interpreted in the context of clinical findings, family history and other laboratory data.
• This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

For More Information:

• Online Mendelian Inheritance in Man - Item #187600
• Understanding Gene Testing
• Thompson LM, Raffioni S, Zhu Y-Z, et al (1996) Biological studies of mutations in FGFR3 which cause skeletal dysplasias. American Journal of Human Genetics 59:A161.
• Bonaventure J, Rousseau F, Legeai-Mallet L, Le Merrer M, Munnich A, Maroteaux P (1996) Common mutations in the gene encoding fibroblast growth factor receptor 3 account for achondroplasia, hypochondroplasia and thanatophoric dysplasia. Acta Paediatrica Supplement 417: 33-8.
• To locate a genetics center near you, please visit Canadian Association of Genetic Counsellors website.