FeedbackPolymerase Chain Reaction/Fragment Analysis
Polymerase Chain Reaction/Fragment Analysis
Use to confirm diagnosis in a fetus with clinical suspicion of TD type 1 or type 2
See Related Tests
Thanatophoric dysplasia (TD) is a skeletal dysplasia that is often suspected based on clinical and/or radiographic findings of micromelia (marked shortening of the limbs) and dysmorphic features. There are two subtypes of TD; type 1 presents with bent femurs and rarely includes skull deformity (craniosynostosis) while type 2 is characterized by straight femurs and cloverleaf skull deformity. Targeted testing for pathogenic variants can confirm a clinical diagnosis of TD in fetuses and neonates. TD is caused by pathogenic variants in the FGFR3 gene, and the majority of pathogenic variants are de novo. The condition is almost always lethal, with death occurring due to respiratory insufficiency shortly after birth.
Disease Overview
Symptoms
- Severe shortening of the extremities (bowed femurs in TD type 1)
- Redundant skin folds on limbs
- Short ribs/narrow thorax
- Hypotonia
- Brachydactyly with trident hand
- Macrocephaly
- Dysmorphic facial features (eg, frontal bossing, flat facies, low nasal bridge, proptotic eyes)
- Craniosynostosis (cloverleaf skull) in TD type 2
Prenatal Findings
| Trimester | Ultrasound Findings |
|---|---|
|
First |
|
|
Second/third |
|
Genetics
Gene
FGFR3
Incidence
Inheritance
Autosomal dominant
Most cases are caused by de novo pathogenic variant in FGFR3; often associated with advanced paternal age.
Penetrance
100%
Test Interpretation
Sensitivity/Specificity
Analytical Sensitivity/Specificity
99%
Clinical Sensitivity
99%
Variants
| TD Type 1 | TD Type 2 |
|---|---|
|
c.742C>T (p.R248C) c.746C>G (p.S249C) c.1108G>T (p.G370C) c.1111A>T (p.S371C) c.1118A>G (p.Y373C) c.2419T>G (p. X807G) c.2419T>A (p.X807R) c.2420G>C (p.X807S) c.2420G>T (p.X807L) c.2421A>T (p.X807C) c.2421A>C (p.X807C) c.2421A>G (p.X807W) |
c.1948A>G (p.K650E) |
|
a13 pathogenic variants cause 99% of TD cases. |
|
Results
| Result | Variant Detected | Interpretive Data |
|---|---|---|
|
Positive |
One pathogenic variant detected |
Diagnosis of TD confirmed |
|
Negative |
No pathogenic variant detected |
Not predicted to be affected with TD |
Limitations
- Diagnostic errors can occur due to rare sequence variations.
- Variants other than those targeted in FGFR3 are not detected.
References
-
GeneReviews Thanatophoric Dysplasia - Skeletal Dysplasias
French T, Savarirayan R. Thanatophoric dysplasia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2022. [Last update: June 2020; Accessed: Apr 2022]
Use to confirm clinical diagnosis of TD type 1 or type 2