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Thanatophoric Dysplasia: Causes, Symptoms and Treatment

  • Published: 2010-04-03 (Revised/Updated 2018-05-19) : Author: Thomas C. Weiss : Contact: Disabled World
  • Synopsis: Thanatophoric dysplasia occurs in approximately one in every 20 to 50 thousand newborns.

Quote: "A chromosome analysis, as well as molecular testing for FGFR3 with targeted and sequence mutation analysis can help to achieve a diagnosis of thanatophoric dysplasia."

Main Document

Defining Thanatophoric Dysplasia - Thanatophoric Dysplasia is a form of severe skeletal disorder that is characterized by very notably short limbs as well as redundant skin on the person's arms and legs. Additional features of the condition include short ribs, a narrowing of the person's chest, enlargement of the person's head, lungs that are underdeveloped, and eyes that are prominent and wide-spaced. The term, 'thanatophoric is Greek and means, 'death bearing.' Infants who have thanatophoric dysplasia are often stillborn or perish shortly after they are born due to respiratory failure. There are; however, a few people who survive into childhood with extensive medical assistance.

Thanatophoric dysplasia is a severe skeletal disorder characterized by a disproportionately small ribcage, extremely short limbs and folds of extra skin on the arms and legs. Infants with type 1 thanatophoric dysplasia also have curved thigh bones, flattened bones of the spine (platyspondyly) and shortened thoracic ribs. An unusual head shape called kleeblattschadel ("cloverleaf skull") can be seen with type 2 thanatophoric dysplasia. Thanatophoric dysplasia affects about 1 in 60,000 births.

Thanatophoric dysplasia occurs in approximately one in every twenty-to-fifty thousand newborns.

Medical researchers have described two major forms of the condition; Type I and II.

Causes of Thanatophoric Dysplasia

Type I and II thanatophoric Dysplasia are caused by mutations in the FGFR3 gene. The gene provides instructions for the production of a protein that is involved in the development and maintenance of a person's brain tissue and bone. Mutations in the FGFR3 gene cause the protein to become over-active, leading to severe disturbances in the person's bone growth which are characteristic of the condition. Medical science does not know how mutations to the FGFR3 gene cause the abnormalities related to the condition and a person's skin and brain.

Thanatophoric dysplasia is considered by the medical community to be a form of autosomal dominant disorder because one mutated copy of the FGFR3 gene in each of a person's cells is enough to cause the condition. Nearly every person with thanatophoric dysplasia has the disorder due to new mutations in the FGFR3 gene; it happens in people with no history of the disorder in their family. There are no people with thanatophoric dysplasia who are known to have had children. The disorder must therefore have not been passed between generations. Thanatophoric dysplasia is also known by the names:

Symptoms of Thanatophoric Dysplasia

Unfortunately, newborns with thanatophoric dysplasia are many times stillborn or die shortly after they are born. Death in the neonatal period is often due to severe respiratory distress caused by a reduced thoracic capacity and Hypoplastic lungs, or respiratory failure caused by brain stem compression. There are some rare reports of newborns with thanatophoric dysplasia surviving into early childhood. Female and male newborns are affected equally by the condition. Additional symptoms of thanatophoric dysplasia include:

Diagnosing Thanatophoric Dysplasia

The types of thanatophoric dysplasia may be diagnosed by the features each type presents. The appearance of either curved or straight bones in the person are an indicator of the disorder, for example. Thanatophoric dysplasia type I is the more common of the two types and is characterized by an average-shaped skull and curved long bones with the person's femurs being most affected. Thanatophoric dysplasia type II is associated with the presence of a cloverleaf shaped skull and straight femurs. The is observation of clinical overlap between the two subtypes.

The pathophysiology of thanatophoric dysplasia is notable. FGFR3 is a part of the tyrosine kinase receptor family. Usually, FGFR3 is a negative regulator of bone growth. Mutations in thanatophoric dysplasia that code for FGFR3 cause a gain in function, sending negative signals to the person's cartilage cells. This happens when ligand binding within the chondrocytes induces receptor homodimerization and heterodimerization. This in turn activates tyrosine kinase function, which then potentiates a number of effects on the person's cell growth and differentiation.

Medical researchers suggest that mutations in FGFR3 lead to the formation of cysteine residues that create disulfide bonds between extracellular domains of mutant monomers. Activation of the homodimer receptor complex increases its stability, promoting translocation of the complex into the nucleus where it can interfere with terminal chondrocyte differentiation. Because of this, generalized disorganization of Endometrial ossification at the person's bone growth plate occurs, something that is readily identifiable.

The majority of people who experience severe fetal skeletal dysplasia may achieve a prenatal diagnosis through ultrasonography during the second or third trimester of pregnancy. Unfortunately, making a diagnosis of thanatophoric dysplasia using only ultrasonography can be difficult. The key findings of ultrasonography include:

A chromosome analysis, as well as molecular testing for FGFR3 with targeted and sequence mutation analysis can help to achieve a diagnosis of thanatophoric dysplasia. Two-dimensional ultrasonography can reveal polyhydramnios, ventriculaomegaly, growth deficiency, narrowing of the person's thorax, micromelia, and flattening of the person's vertebrae. Three-dimensional ultrasonography can reveal scapular anomalies, the fetal face, as well as chest hyperplasia.

Postnatal radiographs and additional imaging studies may reveal irregular metaphyses of the person's long bones and rhisomelic shortening of bones. These studies can also reveal platyspondyly, wide intervetebral spacing, skull enlargement and a small foramen magnum, brain stem compression, hydrocephalus, temporal lobe malformations, brainstem hypoplasia, or neuronal migration abnormalities. Histologic evaluation of the person's long bone structure can show disruption of endochondral ossification.

Treatment of Thanatophoric Dysplasia

Inpatient care is something that is needed for newborns with thanatophoric dysplasia. Intubation may be needed as a form of aggressive treatment for respiratory distress; admission to a neonatal unit is required. If aggressive treatment is deferred, palliative treatment is something that consists of keeping the newborn comfortable, warm, and nourished. At this time, medication therapy is not a part of the care provided in association with thanatophoric dysplasia directly, although medications might be indicated for treatment of concurrent medical conditions that are associated with the disorder.


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