Thanatophoric Dysplasia, Types 1 and 2 (FGFR3), 13 Mutations

Use to confirm clinical diagnosis of TD type 1 or type 2

Use to confirm diagnosis in a fetus with clinical suspicion of TD type 1 or type 2

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

  • Increased nuchal translucency
  • Reverse flow in ductus venosus
  • Long bone shortening

Second/third

  • Limb shortening <5%; recognizable on ultrasound by ~18 wks gestation
  • Bent femurs in TD type 1
  • Cloverleaf skull in TD type 2
  • Narrow thorax
  • Polyhydramnios
  • Well-ossified skull and spine

Genetics

Gene

FGFR3

Incidence

1/20,000 

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

Disease Type/Pathogenic Varianta
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