Thanatophoric dysplasia syndrome

What is Thanatophoric dysplasia syndrome?

It is a rare skeletal disorder that presents with very short limbs as well as folds of skin on the arms and legs. The syndrome is severe and most infants with the syndrome are stillborn or die very soon after birth from respiratory failure. Very few survive into childhood and those that do require considerable medical assistance.

What gene changes cause Thanatophoric dysplasia syndrome?

Mutations in the FGFR3 gene are responsible for causing the syndrome. These mutations cause the gene to be overactive which in turn causes the issues with bone growth that present with the syndrome.

The syndrome can be inherited in an autosomal dominant pattern but to date most cases of the syndrome have been caused by de novo or new gene mutations.

What are the main symptoms of Thanatophoric dysplasia syndrome?

The main symptoms of the syndrome affect the development of the skeletal system and bone growth.

Physical features of the syndrome include very short limbs and folds of extra skin on the limbs. These features also include a narrow chest, short ribs and a large head with a large forehead and widely spaced eyes.

The symptoms are so severe with the syndrome that most infants do not survive birth and are born stillborn.

There are currently two recognized forms of the syndrome-
Type 1 generally presents with curbed thigh bones and flattened bones of the spine
Type 2 presents with straight thigh bones and a skull abnormality, that can range from moderate to severe, known as a cloverleaf skull.

How does someone get tested for Thanatophoric dysplasia syndrome?

The initial testing for Thanatophoric dysplasia syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Thanatophoric dysplasia syndrome

Syndrome Overview:
Thanatophoric dysplasia is a neonatal lethal skeletal dysplasia that features shortened limbs and a narrowed thorax. Thanatophoric dysplasia, Type I is characterized by curved ""telephone receiver"" femurs with or without cloverleaf skull, whereas Type II is characterized by straight femurs and moderate-to-severe cloverleaf skull. Thanatophoric dysplasia is an autosomal dominant condition caused by heterozygous mutations in the FGFR3 gene.

Clinical Description:
The classic features of this disorder are micromelia and a narrow thoracic cage with short ribs. Macrocephaly, distinctive facial features, brachydactyly, hypotonia and redundant skin folds along the limbs are common features. The limbs are extremely short with rolls of redundant skin, and the fingers are short with a trident configuration. The chest is very narrow, and most infants die within a few hours of birth from respiratory failure. The head is large with a prominent forehead and a depressed nasal bridge.

Thanatophoric dysplasia is among the most common lethal skeletal dysplasias in the neonatal period. Its prevalence is estimated at approximately 1:12,000-1:20,000 prenatal cases and 1:33,000-1:47,000 live births.

Chen et al., (2017) reviewed the main characteristics of thanatophoric dysplasia. Sargar et al., (2017) reviewed the imaging in thanatophoric dysplasia in comparison with other skeletal disorders caused by fibroblast growth factor receptor gene mutations, whereas Bondioni et al., (2017) made the comparison with osteogenesis imperfecta II.

Prenatal Presentation:
As early as 14 weeks gestation, shortened femurs below the 5th percentile and a narrow chest with short ribs may be observed. Increased nuchal translucency, macrocephaly, cloverleaf skull, bowed femurs and frontal bossing may also be present by the first trimester.

Khalil et al., (2011) review the prenatal diagnosis of skeletal dysplasias.

Age of Onset:
Thanatophoric dysplasia presents during the prenatal period.


Molecular genetics:
Wilcox et al., (1998) studied 91 cases. FGFR3 mutations were identified in every case. Cases with a Lys650Glu mutation had straight femora and craniosynostosis. In all other cases, the femora were curved, and craniosynostosis was infrequent. Cases with the Tyr373Cys substitution tended to have more severe radiographic manifestations than the Arg248Cys cases, but with overlap.

The data suggested that thanatophoric dysplasia could be subdivided into two groups (Type I and Type II) based on the presence or absence of curved femora. Craniosynostosis can occur in both types but is more common in Type II.

The cases with the c.742C>T (p.Arg248Cys) substitution could either have cloverleaf or normal skulls, representing variable expressivity. Rousseau et al., (1995) reported three separate mutations in the stop codon of FGFR3 in five out of 15 Type I patients without cloverleaf skull. The mutations were expected to give rise to a protein elongated by 141 amino acids.

Rousseau et al., (1996) and Nerlich et al., (1996) further define the mutational spectrum and phenotypic/genotypic correlation in Thanatophoric dysplasia, Type 1.

Specific Mutations:
Several pathogenic mutations in the FGFR3 gene have been linked to Thanatophoric dysplasia, Type I. The c.742C>T (p.Arg248Cys) and c.1118A>G (p.Tyr373Cys) are the two most common mutations in Type I.

A single missense mutation, c.1948A>G (p.Lys650Glu), has been identified in all cases of Thanatophoric dysplasia, Type II.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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