Absent or Minimal Vertebral Ossification

► [Unossified or poorly ossified vertebrae]

Defective ossification occurs in a selected group of skeletal dysplasias. Although the defect is usually widespread, some target areas in the skeleton may be involved to a greater extent, providing important clues to the diagnosis. Vertebral ossification can be defective in the body or posterior arches, or in the entire vertebra. Typically, ossification of the vertebral bodies and sacrum is absent or severely defective in achondrogenesis type IA and IB (OMIM 200600, 600972) and achondrogenesis type II (Langer-Saldino, OMIM 200610) (Jaeger et al. 1994) (Fig. 3.40). Ossification is also absent or markedly retarded in the pubic and ischial bones in both types. Other anomalies include severe micromelia with bowed bones, bony spurs projecting from concave metaphyses, barrel-shaped thorax, small ilia, and short trunk with prominent abdomen and hydropic appearance. Moreover, in both types death occurs in utero or during the early neonatal period. Compared with type I, achondrogenesis type II is characterized by fewer stillbirths, longer survival, longer gestation period, less severe micromelia, a very peculiar crescent-shaped inner and inferior margins of the iliac bones, and characteristic craniofacial features (prominent forehead, flat face, micrognathia) (Chen et al. 1981). Moreover, the ribs are thinner in type I, and often fractured. Lack of vertebral ossification is important as a means of differentiating achondrogenesis, of either type I or type II, from other lethal dysplasias with similar features,including short rib-polydactyly syndromes and thanatophoric dysplasia. Based on radiographic and microscopic analysis, achondroge-nesis type I has been subclassified into two distinct disorders, type IA (Houston-Harris type, OMIM 200600) and type IB (Fraccaro type, OMIM 600972) (Borochowitz et al. 1988). Cases of type IA correspond to those originally described by Houston et al. (1972) and Harris et al. (1972), whereas those with type IB correspond to the original report of Fraccaro (1952). Parenti's original case was considered to be an example of achondrogenesis type II (Langer-

Achondrogenesis

Fig. 3.40. Achondrogenesis, type II, in a stillborn at 32 weeks' gestation. Note severely deficient or absent vertebral ossification. The ischia and pubic bones are unossified. The inner border of the ilia is crescent shaped. The ribs are short, thin, and horizontally oriented. The tubular bones are very short, bowed, with cupped ends

Fig. 3.40. Achondrogenesis, type II, in a stillborn at 32 weeks' gestation. Note severely deficient or absent vertebral ossification. The ischia and pubic bones are unossified. The inner border of the ilia is crescent shaped. The ribs are short, thin, and horizontally oriented. The tubular bones are very short, bowed, with cupped ends

Saldino), while the nonlethal form of short-limbed dwarfism originally termed achondrogenesis by Grebe (1952) is now referred to as Grebe dysplasia. Hypochondrogenesis (OMIM 200610) may be an allelic variant of the Langer-Saldino type of achondrogenesis (Hendrickx et al. 1983). As in achondrogenesis type II, all cases of hypochondrogenesis represent new autosomal dominant mutations in the COL2A1 gene (Sanford et al. 1989; Horton et al. 1992; Mortier et al. 2000). The phenotype in hypochondrogenesis is milder than that in achondrogenesis type II, but clear-cut differentiation of these two forms is not always possible on clinical and radiographic grounds alone (Godfrey et al. 1988; Whitley and Gorlin 1983). Evidence also exists for a phenotypic continuum between achondrogenesis II-hypochondrogenesis and lethal spondylo-epiphyseal dysplasia congenita, with a link between the amount of type I collagen in the cartilage and the severity of the phenotype (Mortier et al. 2000). Schneckenbecken dysplasia (OMIM 269250), a lethal condition that has been confused with achondrogenesis type I, shows decreased ossification in the cervical spine and flat and hypoplastic vertebral bodies, with relatively well-preserved posterior arches, a finding distinctively different from achondrogenesis, in which the vertebrae are virtually

Parenti Fraccaro
Fig. 3.41. Schneckenbecken dysplasia in a male fetus at 22 weeks of gestation. Observe marked reduction of vertebral ossification, extreme shortening of the long bones, narrow thorax, and typical snail-like appearance of the ilia. (From Nikkels et al. 2001)
Fig. 3.42. Opsismodysplasia in a 10-year-old child. Note absence of vertebral body ossification, with relative preservation of the posterior elements. Note also C1-2 subluxation. (From Lachman 1997)

unossified (Knowles et al. 1986; Nikkels et al. 2001) (Fig. 3.41). Opsismodysplasia (OMIM 258480),a non-lethal skeletal dysplasia characterized by marked delay in bone maturation, shows a high degree of ossification deficiency of the vertebral bodies and severe platyspondyly (Lachman 1997). Absence of cervical spine ossification leads to severe C1-2 instability and dislocation. The posterior elements are only mildly affected (Fig. 3.42). Vertebral ossification is defective in metatropic dysplasia (OMIM 250600), resulting in flattened, anteriorly wedged, diamond-shaped vertebrae in early infancy (Kozlowski et al. 1976). In atelosteogenesis type I (OMIM 108720) various bones are poorly ossified, and vertebrae are no exception, especially at the thoracic level. Coronal clefts of the thoracolumbar vertebrae are a constant finding in this disorder. Vertebral ossification is grossly preserved in atelosteogenesis type II (OMIM 256050), and vertebral anomalies, including flattened verte-

brae with coronal clefts, are fewer and less severe than in type I (Maroteaux et al. 1982; Sillence et al. 1997).Additional features in this early lethal disorder include marked shortening of the limbs, with a unique triangular configuration of fibula and ulna, hypoplastic chest, scoliosis, talipes equinovarus, abducted thumbs and great toes, and cleft palate. The distal humerus is typically bifid, and the distal femur is rounded. The generalized joint dysplasia, including talipes equinovarus, abducted thumbs and great toes, and kyphoscoliosis, are features resembling those of diastrophic dysplasia, the least severe disorder caused by DTDST mutations (Rossi et al. 1996). Boomerang dysplasia (OMIM 112310), a disorder sharing similarities with atelosteogenesis type I, possibly including a common defect in cartilage and bone formation (Greally et al. 1993), is also characterized by generalized ossification deficiency, resulting in hypoplasia/aplasia of several bones, including the vertebrae, radius, fibula, ilia, and pubic bones (Tenconi et al. 1983). Poor to absent ossification of the cervical spine is encountered in chondrodysplasia punctata, rhizomelic type (OMIM 215100) and tibial-metacarpal type (OMIM 118651), and in osteogenesis imperfecta type IIA (OMIM 166210).

Hypophosphatasia Images Bony Spur
Fig. 3.43. Hypophosphatasia congenita in a newborn.Note absent ossification of the vertebral bodies and neural arches. The ossification process is also severely impaired at the level of the skull and facial bones. (From Lachman 1997)

In hypophosphatasia congenita (OMIM 241500) (Fig. 3.43), defective skeletal mineralization results in very poor or absent vertebral ossification, especially involving the neural arches. Either several contiguous vertebral bodies or individual vertebrae may be affected. Other features in this disorder include un-ossified calvarium, tubular bones in the hands, and pelvic bones; short and thin ribs; and fragile long bones, resembling those of osteogenesis imperfecta (Fallon et al.1984).

Studies in animals have shown that some drugs, such as chlorpromazine hydrochloride, may induce intrauterine and extrauterine impairment of skeleto-genesis, resulting in defective or delayed ossification of the axial and appendicular skeleton (Singh and Padmanabhan 1979).

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