Dysspondyloenchondromatosis: Another COL2A1-Related Skeletal Dysplasia

Dysspondyloenchondromatosis (DSC) is a rare skeletal dysplasia, which was proposed as a distinctive entity by Freisinger et al. [1993]. So far, 12 affected individuals have been reported [Mainzer et al., 1971; Spranger et al., 1978; Azouz, 1987; Lerman-Sagie et al., 1987; Freisinger et al., 1993; Kozlowski et al., 1994; Haga et al., 1998], and the radiologic images of 3 cases were illustrated in standard textbooks of bone dysplasias [Spranger et al., 2002; Lachman, 2007]. All cases are sporadic, and the etiology has not been elucidated up to date. The hallmark features of DSC are irregularly shaped vertebral bodies (anisospondyly) and enchondroma-like lesions in the metaphyseal and diaphyseal parts of the long tubular bones. The former may cause progressive kyphoscoliosis, and the latter may result in asymmetric limb shortening [Freisinger et al., 1993; Kozlowski et al., 1994]. DSC was once considered to be a form of generalized enchondromatosis, but the disorder has currently been classified into the group of spondylometaphyseal dysplasias [Warman et al., 2011].

Heterozygous mutations in the type II collagen gene (COL2A1) induce a wide spectrum of skeletal dysplasias collectively termed type II collagenopathies [Spranger et al., 1994; Nishimura et al., 2005]. The most constant radiographic features of type II collagenopathies are spondylar and epiphyseal involvement of the skeleton. However, a subset of type II collagenopathies shows predominant metaphyseal involvement with only mild epiphyseal changes [Walter et al., 2007], such as in spondyloepimetaphyseal dysplasia Strudwick type (SEMD-S) [Anderson et al., 1982; Tiller et al., 1995]. In some cases with SEMD-S, the metaphyseal anomalies impair physeal growth and lead to limb asymmetry [Walter et al., 2007]. Craniofacial involvement with cleft palate, vitreoretinal degeneration, severe myopia, and hearing impairment are characteristic clinical features of type II collagenopathies. Cleft palate and minor facial dysmorphism have been reported in DSC as well [Kozlowski et al., 1994].

Given the phenotypic overlap between DSC and the type II collagen disorders (especially SEMD-S), both at the radiographic and clinical level, we were interested to investigate the possibility of COL2A1 mutation in a boy with DSC.

The boy is the third child of a Japanese father and a Thai mother. The parents and his 2 siblings did not have a bone disease. He was delivered uneventfully at 37 weeks of gestation. Fetal ultrasonography apparently showed delayed bone maturation. Birth length was 41.0 cm (–3.1 SD) and birth weight 2,648 g (–0.5 SD). Cleft palate was noted at birth. He failed to thrive and underwent medical care in a community hospital until he was 6 months old. Motor development was delayed: he achieved head control at the age of 8 months and sat alone at the age of 18 months. He started walking at the age of 2 years and 3 months. However, then he started to develop gait disturbances and was wheelchair-bound when he was 4 years old. Language and mental development was normal. His IQ was 108 at the age of 10 years. At the age of 14 years and 8 months, his height was 103.0 cm (–9.8 SD) and his weight was 21.0 kg (–3.4 SD).

At the age of 3 years, he was diagnosed as having DSC. He had a flat midface with low-set ears and an everted lower lip. The radiological findings included severe thoracic scoliosis with misshapen vertebral bodies and enchondroma-like metaphyseal changes with metaphyseal expansion and unequal length of the legs (fig. 1). The right proximal femoral epiphysis was ossified, while the left was not. The radiological manifestations at the age of 10 years were essentially the same as those at the early age of 3 years. However, scoliosis was progressive. Metaphyseal expansion of the femora was less conspicuous than previously seen, while metaphyseal radiolucencies extended deeply into the diaphysis of the right femur (fig. 2). The proximal femoral epiphyses were now well ossified, but coxa vara was seen bilaterally. The proximal humeral metaphyses were expanded with enchondroma-like lesions. The ulnae and radii were bowed. The distal radial and distal ulnar metaphyses were irregular. Spinal CT at the age of 13 years revealed asymmetric ossifications of the vertebral bodies (fig. 3).

DNA was extracted from the boy’s blood, his siblings and the parents after informed consent. A sequence analysis of COL2A1 was performed as described by Walter et al. [2007]. This revealed heterozygosity for a novel COL2A1 mutation, c.2258 G>A (p.Gly753Asp) in exon 34. The mutation was present in the boy, but not in the other family members.

The manifestations of previously reported cases with DSC are summarized in table 1. Affected individuals usually present with short length at birth. Kyphoscoliosis and limb length discrepancy usually become apparent later on in life but can be present at birth. The metaphyseal changes are scooped-out ossification defects reminiscent of perinatally hypophosphatasia. They evolve into longitudinally oriented radiolucencies, deeply extending into the diaphyses and resembling enchondromata. The vertebral changes are also peculiar. The vertebral bodies are irregularly ossified (anisospondyly) which mimics segmentation defects of the spine. Kozlowski et al. [1994] meticulously discussed the spinal deformity in DSC and raised the possibility that the vertebral abnormalities rather reflect ossifications defects than true malsegmentation. This was supported by the spinal CT findings in the boy we report here.

As is well known, missense mutations in COL2A1 that substitute a bulky amino acid for a glycine residue in the triple-helical region of the type II collagen chain lead to a broad spectrum of type II collagenopathies including SEMD-S [Spranger et al., 1994; Nishimura et al., 2005]. Metaphyseal involvement in SEMD-S is generally mild but sometimes conspicuous, with disruption of growth plate development and resulting in limb length discrepancy [Walter et al., 2007]. It is likely that the COL2A1 mutation (p.Gly753Asp) in the present boy is responsible for his DSC phenotype. This mutation clearly interferes with metaphyseal and vertebral ossification to a greater degree than that seen in SEMD-S. Mutations previously reported in SEMD-S are shown in figure 4 [Tiller et al., 1995; Kaitila et al., 1996; Tysoe et al., 2003; Walter et al., 2007]. Patients with the Gly283Arg or V783del mutations have limb asymmetry, but vertebral involvement was mild in these cases.

In conclusion, our data suggest that DSC is yet another member of the large family of type II collagen disorders. Study of additional cases with DSC is warranted to confirm this observation. It remains to be determined why glycine substitutions within the triple-helical domain of the type II collagen molecule can result in such a broad spectrum of diseases, ranging from lethal phenotypes (achondrogenesis type II, hypochondrogenesis) to surviving short-stature phenotypes (spondyloepiphyseal dysplasia congenital, SEMD-S, DSC) with variable spondylo-epi-metaphyseal involvement on radiographs.