The term achondrogenesis refers to a diverse group of generally lethal chondrodysplasias characterized by a short trunk, severe micromelia, and a disproportionately large cranium. Achondrogenesis is the second most common lethal short-limb dysplasia. The term achondrogenesis is actually a misnomer, as it implies that cartilage is not made. In this condition, cartilage is made but it is profoundly abnormal. A more correct term would be chondrogenesis imperfecta (Eyre et al., 1986).

Subclassification of the different conditions included under the term achondrogenesis has been confusing. Historically, two types of achondrogenesis have been described: type I is referred to in the literature as Parenti–Fraccaro syndrome. This subtype accounts for 20% of cases and is the more severe of the two. Type II achondrogenesis—termed Langer–Saldino syndrome—accounts for 80% of cases. In 1983, Whitley and Gorlin reviewed 79 cases that presented with a lethal neonatal chondrodysplasia. Affected infants had a short trunk, extreme micromelia, and a disproportionately large cranium. Radio-graphically, they were demonstrated as having deficient spine ossification, short ribs with cupped and flared ends, and absent pubic and ischial ossification. On the basis of this study, they identified four subtypes. These included type I (Parenti–Fraccaro), which was characterized by multiple rib fractures and the most marked limb shortening. Within the type II category (Langer–Saldino), they identified three subtypes, characterized by differences in the severity of the micromelia and ossification of the vertebrae. Although type I achondrogenesis was traditionally called Parenti–Fraccaro syndrome, a review by Borochowitz et al. (1988) revealed that the original case described by Parenti had a well-ossified skull and ossification of the vertebral bodies. This original case, therefore, was more likely to represent a more mildly affected case of achondrogenesis type II.

Borochowitz et al. (1988) attempted to more accurately classify the subtypes of achondrogenesis (Figure 97-1). In this report, they divided achondrogenesis into three subtypes: the most severely affected is lethal achondrogenesis, type IA (Houston–Harris). This condition is characterized by a poorly ossified skull, multiple rib fractures, and a completely unossified spine (Figure 97-2). Type I also includes lethal achondrogenesis, type IB (Fraccaro), which follows the original case description of Fraccaro. These patients are characterized by a poorly ossified skull, absence of rib fractures, and some ossification of the posterior pedicles of the spine (Figure 97-3). The third subtype is known as lethal achondrogenesis, type II (Langer–Saldino), which is characterized by a normally ossified skull and some ossification of the vertebral bodies, which may make the spine appear flat and ovoid. All three types of achondrogenesis are lethal and they are distinguished from a rare nonlethal form, known as Grebe dysplasia that has been described in Brazilian patients.

The molecular basis of the achondrogenesis syndromes affirm the rationale behind the classification of Borochowitz et al. Achondrogenesis type IB is caused by an inborn error of cartilage metabolism and achondrogenesis type II is caused by a defect in type II collagen (Rimoin, 1996). The underlying basis for achondrogenesis type IA is currently unknown.

Achondrogenesis is part of the group of disorders known as osteochondrodysplasias, which highlights the fact that abnormalities of cartilage or bone growth and development are present (Rimoin, 1978). Autopsy studies performed on all patients with achondrogenesis reveal disorganization of the chondrocytes. In some cases, the cartilage matrix stains irregularly for mucopolysaccharides (Jimenez et al., 1973). For all cases of achondrogenesis, chondro-cytes fail to align in columns and they are very irregularly distributed. In type IA, intracellular acid Schiff–positive inclusion bodies are seen with vacuolization of cytoplasm of chondrocytes of the growth plate (Jaeger et al., 1994). These intracytoplasmic inclusion bodies are pathognomonic of achondrogenesis type IA. Type IB is characterized by a decrease in type II collagen, with a peculiar arrangement of fibers in the cartilage matrix that form unique or multiple rings around the chondrocytes (Freisinger et al., 1994). In type II achondrogenesis, there are structural abnormalities present in the type II collagen. This results in an abnormal, poorly secreted type II collagen molecule. Ultrastructural studies have shown intracellular retention of type II collagen within vacuolar structures, probably existing within dilated rough en-doplasmic reticulum observed in all chondrocytes by electron microscopy (Godfrey et al., 1988). Patients with type II achondrogenesis have increased amounts of type I and type III collagen (Feshchenko et al., 1989). Therefore, definitive diagnosis of the subtype of achondrogenesis is possible with histopathologic studies.

The incidence of achondrogenesis is 1 in 40,000 to 1 in 50,000 livebirths (Smith et al., 1981; Orioli et al., 1986; Lachman and Rappaport, 1990). Achondrogenesis accounts for 1 in 650 perinatal deaths (van der Harten et al., 1988).

The major sonographic findings in achondrogenesis are that of a severe short-limb dwarfism with lack of vertebral ossification (Table 97-1). Typically, a large head is seen with either normal or decreased ossification of the calvarium. Additional findings include a small thorax, protuberant abdomen, and polyhydramnios or generalized edema (Figure 97-4) (Wenstrom et al., 1989). Large cystic hygromas have been described in association with types I (Özeren et al., 1999) and II (Won et al., 1999). To distinguish between types IA and IB and type II, a specific notation must be made of the degree of skull ossification. Type I is characterized by decreased or absent skull ossification. In addition, type IA is characterized by the presence of rib fractures, which can be visualized sonographically (see Figure 97-2) (Graham et al., 1983). In one report, the most specific finding for the diagnosis of achondrogenesis in a case of short-limb dysplasia was a transverse view of the fetus demonstrating less than three ossification centers per spinal segment (Pretorius et al., 1986). Interestingly, approximately one-third of cases with achondrogenesis are associated with hydrops fetalis. It is postulated that this may be due to the primary collagen defect in type II, which may damage subcutaneous tissue as well as bone and cartilage (Soothill et al., 1993).