Thanatophoric Dysplasia Clinical Presentation

Updated: Sep 18, 2018
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
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Presentation

History

Most cases of a severe fetal skeletal dysplasia can be diagnosed by prenatal ultrasonography during the second or third trimester of pregnancy. However, making the conclusive diagnosis of thanatophoric dysplasia (TD) using only this imaging tool can be difficult.

Key ultrasonography findings include the following:

  • Growth deficiency with limb length of less than 5% (by 20 weeks' gestation)

  • Macrocephaly

  • Ventriculomegaly 

  • Cloverleaf-shaped skull or kleeblattschädel (indicates TD-II, but also seen in TD-I) [7]

  • Well-ossified skull and spine

  • Platyspondyly of the vertebrae

  • Narrow chest cavity with shortened ribs

  • Micromelia

  • Bowed femurs with metaphyseal flaring, described as having a "telephone receiver' appearance (usually indicates TD-I)

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Physical

Salient phenotypic features in an affected newborn are cited below:

  • Severe growth deficiency with an average length of 40 cm (about 16 in) at term

  • Generalized hypotonia

  • Macrocephalic head with frontal bossing and large anterior fontanel

  • Cloverleaf-shaped skull due to premature closure of the cranial sutures

  • Flat facies with low nasal bridge and proptotic eyes

  • Narrow, bell-shaped thorax with short ribs

  • Normal trunk length

  • Protuberant abdomen

  • Micromelia (marked bilateral shortening of the limbs) with redundant skin folds

  • Brachydactyly with a trident hand configuration

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Causes

Thanatophoric dysplasia (TD) is an autosomal dominant disorder that results from sporadic de novo point mutations in the FGFR3 gene. Sequence and targeted mutation DNA analyses of FGFR3 are available to assist with diagnosis when clinical concerns are present. Germline mosaicism has been suggested as another possible cause, but has not been clearly documented.

The following mutations that affect distinct domains of FGFR3 cause the TD subtypes, TD-I and TD-II:

  • TD-I: Amino acid substitutions in the extracellular domain of FGFR3 have resulted in TD-I. The more common mutation occurring in TD-I is R248C (p.Arg248Cys), which is confirmed in approximately 50% of patients.
  • TD-II: K650E (p.Lys650Glu) is the only reported gene mutation and is present in more than 99% of patients with TD-II.

TD-I occurs more often than TD-II. TD-I and TD-II do not share common FGFR3 gene mutations. 

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