Campomelic dysplasia is a distinct clinical and radiologic entity characterized by symmetric bowing of the long bones of the lower extremities, phenotypic sex reversal in some chromosomally male infants, and associated abnormalities including cleft palate, flat facies, micrognathia, hydrocephalus, and renal abnormalities. The term campomelia comes from the Greek camptos, meaning bent and melos, meaning limbs. Despite the name of the condition, campomelia is not obligatory for a diagnosis of campomelic dysplasia (Ninomiya et al., 1995). MacPherson et al. (1989) described two newborn infants with respiratory distress who demonstrated all of the clinical and radiologic manifestations of campomelic dysplasia except the bent lower extremities. This rare clinical variant is now known as acampomelic campomelia dysplasia (Thong et al., 2000). The various skeletal and extraskeletal manifestations of campomelic dysplasia, including sex reversal, are part of a contiguous gene syndrome that maps to chromosome 17 and is caused by mutations in the transcription factor, SOX9.

Classic campomelic dysplasia was first described by Maroteaux et al. (1971) and Bianchine et al. (1971) in independent reports. In a review of 43 affected patients, Hall and Spranger (1980) described four major radiologic features in patients with campomelic dysplasia: characteristic lower-limb bowing, absent or hypoplastic scapulas, nonmineralization of the thoracic pedicles, and narrow, vertical iliac bones (Figure 92-1A). They described other useful diagnostic features of the condition that included hypoplastic cervical vertebrae, widely spaced ischial bones, and absent ossification of the distal femoral and proximal tibial epiphyses. Khajavi et al. (1976) described campomelic dysplasia as a distinct entity consisting of short-limbed dwarfism with pretibial skin dimples, a peculiar facies, cleft palate, hypotonia, absent olfactory bulbs, and respiratory distress ending in neonatal death. These authors suggested that the condition could be classified into three varieties: a long-limbed type, a short-limbed type with craniosynostosis, and a short-limbed type with normocephaly. The long-limbed variety is considered to be the most common (Khajavi et al., 1976).

A unique aspect of this condition is the phenotypic sex reversal. Over half of the apparently female infants have a male, XY, karyotype (Figure 92-2). In one study of 121 reported cases of campomelic dysplasia, 74 individuals had been karyotyped. Of these, 24 were 46, XX and phenotypically female. Of the remaining 50 who were 46, XY, 36 (72%) of them had normal female external genitalia, although a minority of them had some degree of ambiguity (Figure 92-3) (Foster et al., 1994).

Over the past few years, much progress has been made with regard to understanding the underlying molecular mechanisms in campomelic dysplasia. The chromosomal location of the gene has been mapped, the gene involved in the condition has been identified as SOX9, and the inheritance pattern has been clarified.

The incidence of campomelic dysplasia is 0.05 to 1.6 per 10,000 livebirths (Normann et al., 1993). There is no association between the incidence of campomelic dysplasia and advanced maternal or paternal age (Hall and Spranger, 1980; Mansour et al., 1995).

Fetuses affected with campomelic dysplasia have a varietyof anomalies. The most characteristic is the acute femoral angulation, which typically occurs at the junction of the upper third and lower third of both femora, with resulting symmetrical shortening (Figure 92-4). The femoral angulation is always anterior in the tibia and anterolateral in the femur (Pazzaglia and Beluffi, 1987). Other typical abnormalities include marked micrognathia, a small bell-shaped chest, mild bilateral hydronephrosis, hydrocephalus, cystichygroma (Foster et al., 1994; Mansour et al., 1995), and clubfeet (Sanders et al., 1994) (Figure 92-1B). Polyhydramnios has been described in 25% to 48% of affected cases (Slater et al., 1985; Mansour et al., 1995). The associated hydrocephalus is thought to be due to atlanto-occipital occlusion (Deschamps et al., 1992). Approximately one fourth of patients may have associated cardiac malformations, which are always of the mild variety (Hall and Spranger, 1980; Mansour et al., 1995). The associated genitourinary anomalies may include hydronephrosis, hydroureter, renal hypoplasia, or renal cysts (Slater et al., 1985; Argaman et al., 1993). The association of hypoplastic scapulae, nonmineralized thoracic pedicles, and vertically narrow iliac bones is unique for this syndrome (Tongsong et al., 2000).

The first successful prenatal diagnoses for this condition occurred in families with a previously affected child. In 1981, Fryns et al. described such a family and successfully diagnosed recurrence of the campomelic dysplasia in a fetus with short, bowed limbs and hydrocephalus at 17 weeks of gestation. Sonographic examination revealed poorly ossified long tubular bones that were not bowed and massive hydrocephaly. At autopsy the infant was also shown to have a high forehead and micrognathia (Fryns et al., 1981). In families not at risk for campomelic dysplasia, affected infants have been identified by a discrepancy between upper- and lower-limb lengths (Gillerot et al., 1989). Cordone et al. (1989) described a fetus at 26 weeks of gestation with a normal amniotic fluid volume that demonstrated symmetrical anterior bowing of the lower extremities with hypoplasia of the fibulas and talipes equinovarus, hypoplastic scapulas, a bell-shaped chest, and facial abnormalities including a flat nasal bridge and micrognathia.

As in other skeletal dysplasias, an increased nuchal translucency measurement has been demonstrated at 13 weeks’ gestation in a fetus that was subsequently shown to have campomelic dysplasia (Michel-Calemard et al., 2004). Three-dimensional ultrasound examination has aided in the diagnosis of campomelic dysplasia (Seow et al., 2004). Surface rendering 3-D studies demonstrate skin dimpling over a convex surface at the point of maximal deformity as well as the characteristic flat face and mid-facial hypoplasia.

A prenatal diagnostic overlap occurs between campomelic dysplasia and osteogenesis imperfecta type II (see Chapter 91). This is due to the presence of bowing in the lower limbs, which can be a manifestation ofosteogenesis imperfecta. The tibial bowing, however, is more pronounced in campomelic dysplasia (Sanders et al., 1994). Campomelic dysplasia is also accompanied by mild bowing of the femurs. In one report, the authors described three cases of osteogenesis imperfecta in which tibial bowing was present without apparent fractures. They also described two cases of campomelic dysplasia misdiagnosed as osteogenesis imperfecta because the femurs showed an acute angulation that was suggestive of a fracture (Sanders et al., 1994). The presence of additional fetal anomalies – including clubfeet, micrognathia, and hydronephrosis – is more consistent with a diagnosis of campomelic dysplasia than osteogenesis imperfecta.

Other conditions that should be included in the differential diagnosis include diastrophic dysplasia (see Chapter 93). Both campomelic and diastrophic dysplasia share cervical vertebral anomalies, cleft palate, joint dislocations, bilateral talipes equinovarus, and laryngotracheal abnormalities, as well as abnormal ears, micrognathia, and brachy-dactyly (Hall and Spranger, 1980). Individuals with Larsen syndrome also manifest many of these abnormalities as well as a flat nasal bridge and apparent hypertelorism. Hall and Spranger (1980) recommended comparison of the scapulas, thoracic pedicles, and iliac bones to allow a specific diagnosis of campomelic dysplasia. The following major features of campomelic dysplasia occur with greater than 50% frequency in affected individuals: hypoplastic scapulas, nonmineralized thoracic pedicles, and vertically narrow iliac bones. These are rare findings when seen individually, but pathognomonic for campomelic dysplasia when found in combination (Hall and Spranger, 1980).