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.

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).

The incidence of TD ranges from 0.27 in 10,000 to 0.4 in 10,000 livebirths (Martínez-Frías et al., 1988; Rasmussen et al., 1996). In a large series of 126,000 deliveries occurring at one institution, TD was the most common osteochondrodysplasia observed (Rasmussen et al., 1996).

In individuals affected with TD, the mean paternal age is elevated as compared with unaffected controls (Martínez-Frías et al., 1988; Orioli et al., 1995). In 50% of cases of TD, the father is >35 years of age (Orioli et al., 1995). There is approximately a threefold increased risk for having a fetus with TD when the father is between the ages of 35 and 39 (Martínez-Frías et al., 1988).

To date, most cases of TD have occurred sporadically. The small number of familial cases reported reveals a paucity of well-documented sibling pairs, except in the case of monozygous twins. There is no evidence for parental consanguinity in affected fetuses (Martínez-Frías et al., 1988).

The sonographic findings in cases affected by TD include severe micromelia with limited limb mobility and narrow chest (Figure 90-2A to 90-2C). Although the femur is classically described as curved and resembling a telephone receiver (Figure 90-3), affected fetuses can also have straight femurs. Additional sonographic findings include short, broad ribs, a narrowed chest circumference with consequent pulmonary hypoplasia, and hypoplastic vertebral bodies. The pelvic bones are characteristically small. Polyhydramnios is frequently present (Burrows et al., 1984; Stamm et al., 1987). In one report, an associated cardiac abnormality consisting of an atrioseptal defect and a bicuspid aortic valve was also described (Isaacson et al., 1983).

The kleeblattschädel (cloverleaf) deformity was first described in 1960 (Holtermüller and Wiedemann, 1960). This cloverleaf shape of the skull is due to early fusion of the lambdoidal and coronal sutures. This results in a towering calvarium and lateral bulges of the temporal lobes, which form three leaves of the cloverleaf when the head is viewed from the face (Figure 90-4). Because the lambdoidal and coronal sutures are fused, subsequent brain growth results in bulging in the regions of least resistance (Isaacson et al., 1983). The cloverleaf skull is present in only 14% of cases of TD (Iannaccone and Gerlini, 1974). Hydrocephalus is frequently associated with the cloverleaf skull (Shaff et al., 1980; Isaacson et al., 1983). To diagnose the cloverleaf skull deformity, a coronal scan that shows the temporal lobes is recommended (Stamm et al., 1987).

In the literature, multiple reports exist of the second trimester diagnosis of TD on the basis of the severe micromelia (Camera et al., 1984; de Elejalde and de Elejalde, 1985; Loong, 1987; Meizner et al., 1990; Schild et al., 1996). More recent studies report on the molecular diagnostic findings as well (De Biasio et al., 2000; Chen et al., 2001). These reports all describe fetuses with a long bone length of less than the third percentile for gestational age, an extremely narrow chest, a protruberant abdomen, and vertebral bodies of reduced height.

First trimester diagnosis has also been reported (Benacerraf et al., 1988). Benacerraf et al. described a 13-week-old fetus with a narrow chest and foreshortened and bowed femurs. A repeat sonographic examination performed at 15 weeks again demonstrated the abnormalities. The pregnancy was electively terminated. In contrast, another group has described a fetus that appeared normal at 15 weeks of gestation and was subsequently diagnosed at 32 weeks of gestation with TD (Macken et al., 1991). Three-dimensional sonography is considered to be advantageous for evaluation of the midface hypoplasia that is seen in TD (Krakow et al., 2003).

The differential diagnosis includes other skeletal dysplasias that manifest as severe micromelia, such as campomelic dysplasia (see Chapter 92), Ellis van–Creveld syndrome (see Chapter 94), and short-rib polydactyly syndrome (see Chapter 95). Polydactyly is absent in TD. In achondrogenesis, the bones are usually less mineralized than in TD.

The cloverleaf skull is occasionally mistaken for an encephalocele (Chervenak et al., 1983; Mahony et al., 1985; Weiner et al., 1986; Stamm et al., 1987). Any soft tissue bulge in the head or neck must be evaluated for its exact position. Encephalocele and cystic hygroma occur in the midline and most often are posterior. The cloverleaf skull is bilateral, with enlargement of the temporal lobes. The standard teaching that the skull is not intact in encephalocele is not helpful to distinguish between encephalocele and cloverleaf skull. This is because the bony calvarium may be expanded, thinned, or partially absent in the cloverleaf skull deformity, and conversely, in cases of encephalocele, the osseous defect in the skull may be very small (Stamm et al., 1987). A cloverleaf skull may also be noted in Apert, Carpenter, Crouzon, and Pfeiffer syndromes as well as in homozygous achondroplasia.

The underlying defect in TD is in the formation of bone from a cartilage model. There is generalized disruption and decrease in endochondral ossification, with membranous ossification being less affected (Lemyre et al., 1999). Fetuses affected with TD show a progressive decrease in the growth rate of the long bones throughout gestation. While sometimes early in the second trimester, the femur length can be in the normal range, the bones become progressively shortened and curved (Burrows et al., 1984).