- Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Luis O Rohena, MD more...
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." Salient phenotypic features of thanatophoric dysplasia include macrocephaly, narrow bell-shaped thorax with shortened ribs, normal trunk length, and severe shortening of the limbs. See the image below.
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 either a 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 the old-fashioned telephone receivers); the femurs are most affected. TDII is associated with a cloverleaf-shaped skull and straight femurs. In addition, reported cases have cited clinical overlap between these subtypes.
Both TDI and TDII are caused by an autosomal dominant point mutation in the fibroblast growth factor receptor 3 (FGFR3). The gene, FGFR3, is mapped to the short-arm of chromosome 4(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.[1, 2]
Fibroblast growth factor receptor 3, known as FGFR3, is part of the tyrosine kinase receptor family. Normally, FGFR3 is a negative regulator of bone growth. Point mutations within FGFR3 causing thanatophoric dysplasia initiate a gain in function by sending negative signals to the cartilage cells (chondrocytes). These signals occur when ligand binding within the chondrocytes induces receptor homodimerization and heterodimerization. Subsequently, activation of tyrosine kinase function potentiates many effects on cell growth and differentiation.
Researchers believe 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. Two missense mutations, R248C and Y373C, account for about 80% of TDI cases. The more common of these two TDI point mutations, R248C (known as p.Arg248Cys), is a C→T pyrimidine nucleotide transition and impacts the extracellular domain of FGFR3.
To date, all patients with TDII have a single point mutation, K650E (known as p.Lys650Glu), with an A→G purine nucleotide transition in the tyrosine kinase domain of FGFR3.
Thanatophoric dysplasia has an incidence of 1 per 20,000 to 1 per 50,000 live births.
Incidence in Spain is reported as 1 per 37,000 live births.
Newborns with thanatophoric dysplasia are stillborn or die shortly after birth. Death occurs usually within 48 hours and is due to severe respiratory insufficiency from a reduced thoracic capacity and hypoplastic lungs and/or respiratory failure due to brainstem compression. Survival into early childhood has been rarely reported.[3, 4]
Males and females are equally affected.
Thanatophoric dysplasia is lethal in neonates. Although extremely rare, survival beyond the neonatal period has been described in the medical literature.
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