eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
Thanatophoric Dysplasia
Updated: Sep 21, 2007
Introduction
Background
Thanatophoric dysplasia (TD) is the most common form of skeletal dysplasia that is lethal in the neonatal period. The term thanatophoric derives from the Greek word thanatophorus, which means "death bringing". Characteristics of TD include severe shortening of the limbs, a narrow thorax, macrocephaly, and a normal trunk length. TD is divided into 2 clinically defined subtypes. TD type 1 (TD1), the most common subtype, is characterized by a normal-shaped skull and curved long bones (shaped like a telephone receiver); the femurs are most affected. TD type 2 (TD2) is associated with a cloverleaf-shaped skull and straight femurs. Some clinical overlap exists between the 2 subtypes. Autosomal dominant mutations in the fibroblast growth factor receptor 3 gene (FGFR3), which has been mapped to chromosome band 4p16.3, results in both subtypes. The vast majority of cases are due to de novo mutations. Gonadal mosaicism has not been definitivelydocumented.
Pathophysiology
The FGFR3 gene is a member of the tyrosine kinase receptor family. Ligand binding induces receptor homodimerization, as well as heterodimerization, that results in activation of tyrosine kinase function and potentiates many effects on cell growth and differentiation. Some authors suggest that mutations in FGFR3 lead to the formation of cysteine residues that create disulfide bonds between the extracellular domains of mutant monomers. Activation of the homodimer receptor complex increases its stability and promotes translocation of the complex into the nucleus, where it may interfere with terminal chondrocyte differentiation.
Patients with TD2 have a single recurrent mutation (A-to-G) in the tyrosine kinase domain of FGFR3, but patients with TD1 have different mutations that affect either the extracellular or intracellular domains of FGFR3. The most common TD1 mutation is a C-to-T transition, which results in a change of arginine to cysteine (R248C) in the extracellular domain of FGFR3.Frequency
United States
TD has an prevalence of 1 per 10,000-35,000 live births.
International
Frequency in Spain is 2.7 per 100,000.
Mortality/Morbidity
Although the literature documents several reports of survival into childhood, TD is virtually always lethal in the neonatal period. Respiratory insufficiency secondary to reduced thoracic capacity or compression of the brainstem leads to death.
Sex
Males and females are equally affected.
Age
TD is lethal in neonates; however, long-term survival has been reported.
Clinical
History
Most cases of thanatophoric dysplasia (TD) are diagnosed using ultrasonography during the second or third trimester of pregnancy.
- Typical ultrasonography findings include curved or straight short femurs, symmetric micromelia, a narrow chest with short ribs, and a protuberant abdomen.
- Polyhydramnios is often observed.
Physical
- Severe growth deficiency with an average length of 40 cm at term
- A macrocephalic head with a frontal bossing, a flattened nasal bridge, and proptotic eyes
- In TD2, a cloverleaf-shaped skull due to premature closure of the cranial sutures
- Narrow thorax with small ribs
- Micromelic limbs with brachydactyly
- Protuberant abdomen
- Hydrocephalus and other cerebral parenchymal abnormalities
Causes
TD is an autosomal dominant disorder that results from sporadic de novo mutations in the FGFR3 gene. Gonadal mosaicism has been suggested as a possibility but has not been convincingly documented.
The following mutations that affect distinct domains of FGFR3 cause the TD subtypes:
- TD1: Amino acid substitutions in the extracellular domain of FGFR3 have resulted in TD1. The most common mutation in TD1 is arg248cys, which is present in approximately 50% of patients.
- TD2: In patients with TD2, lys650blu is the only reported gene mutation.
More on Thanatophoric Dysplasia |
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| Treatment & Medication: Thanatophoric Dysplasia |
| Follow-up: Thanatophoric Dysplasia |
| References |
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References
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Further Reading
Keywords
thanatophoric dysplasia, TD, skeletal dysplasia, dwarfism, fatal skeletal dysplasia, TD type 1, TD1, TD type 2, TD2, FGFR3, narrow thorax, cloverleaf skull, curved femurs, short femurs, symmetric micromelia, polyhydramnios, macrocephalic head, severe growth deficiency, brachydactyly
