eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
Thanatophoric Dysplasia
Updated: Nov 6, 2009
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" or "death bearing." Some salient phenotypic features of thanatophoric dysplasia include macrocephaly, narrow bell-shaped thorax, normal trunk length, and severe shortening of the limbs.
Infant with thanatophoric dysplasia. Note short-limbed dysplasia, large head, short neck, narrow thorax, short and small fingers, and bowed extremities. Radiographs demonstrate thin flattened vertebrae, short ribs, small sacrosciatic notch, extremely short long tubular bones, and markedly short and curved femora (telephone receiver–like appearance).
Thanatophoric dysplasia is divided into 2 clinically defined subtypes: thanatophoric dysplasia type I (TDI or TD1) and thanatophoric dysplasia type II (TDII or TD2). The clinical subtypes of thanatophoric dysplasia are defined by the curved or straight appearance of the long bones. TDI, the more common subtype, is characterized by a normal-shaped skull and curved long bones (shaped like a telephone receiver); the femurs are most affected. TDII is associated with a cloverleaf-shaped skull and straight femurs. However, clinical overlap is observed between these subtypes.
TDI and TDII are caused by an autosomal dominant mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, which has been mapped to chromosome band 4p16.3. Penetrance of this mutation is 100%. Currently, all cases of thanatophoric dysplasia are due to de novo mutations in FGFR3. Germline mosaicism has not been clearly documented but remains a theoretical possibility.
Pathophysiology
FGFR3 is part of the tyrosine kinase receptor family. Normally, FGFR3 is a negative regulator of bone growth. The mutations in thanatophoric dysplasia that code for FGFR3 cause a gain in function, sending negative signals to the cartilage cells (chondrocytes). This occurs when ligand binding within the chondrocytes induces receptor homodimerization and heterodimerization. This, in turn, activates tyrosine kinase function, which potentiates many effects on cell growth and differentiation.
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 and promotes translocation of the complex into the nucleus, where it may interfere with terminal chondrocyte differentiation. Hence, generalized disorganization of endochondral ossification at the bone growth plate occurs.
TDI is caused by several different mutations that affect either the extracellular or intracellular domains of FGFR3. The two missense mutations, R248C and Y373C, account for as much as 80% of TDI cases. The more common of these two TDI mutations, R248C (known as p.Arg248Cys), is a C-to-T nucleotide transition and impacts the extracellular domain of FGFR3.
To date, all patients with TDII have a single point mutation, p.Lys650Glu, with an A → G nucleotide transition in the tyrosine kinase domain of FGFR3, also known as K650E.
Frequency
United States
Thanatophoric dysplasia has an incidence of 1 per 20,000-50,000 births.
International
Incidence in Spain is reported as 1 per 37,000 births.
Mortality/Morbidity
Newborns with thanatophoric dysplasia are stillborn or die shortly after birth. Death in the neonatal period is due to severe respiratory insufficiency from reduced thoracic capacity and hypoplastic lungs or respiratory failure due to brainstem compression. Very rare reports of survival into early childhood have been cited.
Sex
Males and females are equally affected.
Age
Thanatophoric dysplasia is lethal in neonates; however, survival beyond the neonatal period has been rarely reported.
Clinical
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 diagnosis of thanatophoric dysplasia (TD) using only this imaging tool can be difficult. Key ultrasonography findings are the following:
- Growth deficiency with limb length of less than 5% (by 20 weeks' gestation)
- Ventriculomegaly
- Macrocephaly
- Cloverleaf-shaped skull or kleeblattschãdel (indicates thanatophoric dysplasia type II [TDII], also seen in thanatophoric dysplasia type I [TDI])1
- Well-ossified skull and spine
- Platyspondyly of the vertebrae
- Micromelia
- Bowed femurs (usually indicates TDI)
- Narrow chest cavity with shortened ribs
- Polyhydramnios
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
- Flat facies with low nasal bridge and proptotic eyes
- Cloverleaf-shaped skull due to premature closure of the cranial sutures
- Narrow, bell-shaped thorax with short ribs
- Normal trunk length
- Protuberant abdomen
- Marked bilateral shortening of the limbs (micromelia) with redundant skin folds
- Brachydactyly with a trident hand configuration
Causes
- Thanatophoric dysplasia is an autosomal dominant disorder that results from sporadic de novo mutations in the FGFR3 gene. Sequence and targeted mutation analysis of FGFR3 is available to assist with diagnosis when clinical concerns are present. Germline mosaicism has been suggested as a possibility but has not been clearly documented.
- The following mutations that affect distinct domains of FGFR3 cause the thanatophoric dysplasia subtypes:
- TDI: Amino acid substitutions in the extracellular domain of FGFR3 have resulted in TDI. The most common mutation in TDI is p.Arg248Cys (R248C), which is present in approximately 50% of patients.
- TDII: p.Lys650Glu (K650E) is the only reported gene mutation and is present in more than 99% of patients with TDII.
- TDI occurs more often than TDII. TDI and TDII do not share common FGFR3 mutations within the gene.
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| References |
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References
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Further Reading
Keywords
thanatophoric dysplasia, TD, skeletal dysplasia, thanatophoric dwarfism, fatal skeletal dysplasia, short limb dwarfism, TD type I, TD type 1, TDI, TD1, TD type II, TD type 2, TDII, TD2
