Most common of the lethal skeletal dysplasias. Presents in the second trimester.
Two subtypes exist: TD I has short curved femurs with or without a cloverleaf skull; TD II has straight, longer femurs and generally a more severe cloverleaf skull.
Sporadic inheritance with extremely small recurrence risk associated with advanced paternal age (>35 years).
Mutations in fibroblast growth factor receptor 3 (FGFR3) are the underlying basis for the disorder. There is a strong genotype–phenotype correlation. DNA diagnosis is highly accurate.
FGFR3 is also expressed in the brain. Rare survivors are uniformly severely developmentally delayed.
Thanatophoric dysplasia, a lethal chondrodysplasia, was first recognized as a unique clinical entity in 1967 (Maroteaux et al., 1967). Thanatophoric is Greek for “death bearing”. The classic clinical features include micromelic limbs, short ribs, narrow thorax, relative macrocephaly, frontal bossing, midface hypoplasia, reduced height of the vertebral bodies, and central nervous system abnormalities (Figure 90-1). It is the most common form of lethal dwarfism in the human.
Fetus at 21 weeks of gestation with thanatophoric dysplasia, demonstrating severe micromelia, narrow chest, and prominent abdomen. (Courtesy of Dr. Joseph Semple.)
Fetuses and infants affected with thanatophoric dysplasia have been classified according to radiographic differences, such as the presence or absence of a cloverleaf skull and whether the femurs are curved or straight. At one time, the two subtypes of thanatophoric dysplasia (TD), TD I and TD II, were thought to be two separate entities, with possibly two different patterns of inheritance (Young et al., 1989). As of 1995, however, it was demonstrated that mutations in the fibroblast growth factor receptor 3 (FGFR3) gene were the underlying basis for both conditions (Tavormina et al., 1995). Mutation analysis of the DNA of affected patients has revealed that individuals with TD type I have short curved femurs with or without a cloverleaf skull deformity, whereas patients with TD type II have straight, somewhat longer femurs and severe cloverleaf skull (Tavormina et al., 1995). In the developing mouse and human fetus, the highest levels of FGFR3 expression are in the skeleton and the central nervous system (Tavormina et al., 1995).
Mutations in FGFR3 are also the underlying basis for achondroplasia (Bonaventure et al., 1996) (see Chapter 89). Both TD and achondroplasia exhibit poor cellular proliferation in the growth plate of the long bone, although heterozygous achondroplasia is clinically less severe than TD. It is of interest that patients with homozygous achondroplasia manifest a more severe clinical phenotype than patients with heterozygous achondroplasia. The features in homozygous achondroplasia clearly resemble TD and result in neonatal lethality (Tavormina et al., 1995).