Metaphyseal Chondrodysplasia, Schmid Type

A number sign (#) is used with this entry because of evidence that Schmid-type metaphyseal chondrodysplasia (MCDS) is caused by heterozygous mutation in the COL10A1 gene (120110) on chromosome 6q22.

Description

Schmid-type metaphyseal chondrodysplasia is characterized by short stature and bowing of the long bones; radiographic features include widening and irregularity of the growth plates, especially in the distal and proximal femora (summary by Makitie et al., 2005).

Clinical Features

Stephens (1943) reported a Mormon kindred in which over 40 members of 4 generations were affected with what he considered to be achondroplasia. The x-ray findings as demonstrated in his figures and as reviewed by Caffey and Christensen (1963) were, however, those of metaphyseal chondrodysplasia. In a 3-year-old child the interpediculate distances and greater sciatic groove were normal and the typical metaphyseal changes were demonstrated. Affected women went through vaginal deliveries successfully and were usually accompanied only by a midwife. Stephens (1943) suggested that the original mutation could be identified. The first affected ancestor, born in 1833, was said to have normal parents and 11 unaffected sibs.

Rosenbloom and Smith (1965) described 24 affected persons in 1 kindred. In a girl with metaphyseal chondrodysplasia said to be intermediate in phenotype between the Jansen (156400) and Schmid types, Cooper et al. (1973) demonstrated distention of the rough-surfaced endoplasmic reticulum cisternae of chondrocytes due to accumulation of what appeared to be a protein. Cooper and Ponseti (1973) studied an affected girl. Electron microscopy of her chondrocytes from the iliac crest area and ulnar epiphyseal plate revealed dilated rough endoplasmic reticulum (RER) cisternae containing a granular material. Cartilage matrix collagen and osteoid appeared to be normal. Osteoblasts and osteocytes showed a slight degree of RER dilatation. Gorlin (1985) suggested that the true diagnosis in the family reported by David and Palmer (1958) was oculodentoosseous dysplasia (164200).

Lachman et al. (1988) analyzed 20 cases and reviewed the literature. They suggested that the condition was often overdiagnosed. Significant radiologic features included an enlarged capital femoral epiphysis in early childhood, coxa vara, greater involvement of the distal femoral metaphysis than the proximal, anterior rib changes, and a normal spine. Chondroosseous morphology is not specific. Presentation in nonfamilial cases is no earlier than the second year of life.

Hasegawa et al. (1994) reported a Japanese family in which 5 members (3 males, 2 females) had a spondylometaphyseal dysplasia (SMD) characterized clinically by short stature and bowed legs and radiographically by severe coxa vara, moderately severe metaphyseal changes, normal hands, and mild platyspondyly. The platyspondyly was observed only in the males, and the younger 2 boys (aged 11 and 6) had greater platyspondyly than that in their 43-year-old father. Hasegawa et al. (1994) considered this a novel form of SMD, which they called the Japanese type. Ikegawa et al. (1998) identified a mutation in the COL10A1 gene (120110.0016), which had previously been found in a family with Schmid metaphyseal chondrodysplasia, in the family reported by Hasegawa et al. (1994).

Because of clinical, radiographic, and molecular similarities between the Japanese type of SMD reported by Hasegawa et al. (1994) and Schmid MCD, Savarirayan et al. (2000) reviewed 33 cases of of 'typical' MCDS and found that 3 cases had radiographic evidence of spinal involvement comprising mild platyspondyly, vertebral body abnormalities, and end-plate irregularity. Savarirayan et al. (2000) concluded that spinal changes are an uncommon but variable component of MCDS and that MCDS and the Japanese type of SMD are identical collagen type X disorders.

Elliott et al. (2005) reviewed radiographs of 15 'classic' MCDS patients and found hand involvement in 7 cases (47%). The findings were subtle and consisted of shortening of the tubular bones and metaphyseal cupping of the proximal phalanges and metacarpals; these changes were more marked in younger patients. Elliott et al. (2005) concluded that mild hand involvement that appears to resolve with age is a common feature of MCDS and should not exclude the diagnosis in young patients.

Molecular Genetics

In the Mormon kindred reported by Stephens (1943) and studied by Caffey and Christensen (1963), Warman et al. (1993) identified a 13-bp deletion in heterozygous state in COL10A1 gene (120110.0001). The mutation produced a frameshift that altered the highly conserved C-terminal domain of the alpha-1(X) chain and reduced the length of the peptide by 9 residues. Type X collagen is a homotrimeric molecule. Its restricted expression in hypertrophic chondrocytes and studies in transgenic mice with a dominant-negative mutation in type X collagen support its role in endochondral ossification (Jacenko et al., 1993).

Wallis et al. (1996) noted that at least 17 different point mutations and deletions in the region of the COL10A1 gene encoding the carboxy-terminal (NC1) domain had been reported in patients with MCDS. To determine whether mutations in other regions of the gene can cause MCDS or comparable phenotypes, Wallis et al. (1996) used PCR and SSCP techniques in the study of 5 patients with typical MCDS, 1 patient with atypical MCDS, and 9 patients with other forms of metaphyseal chondrodysplasia. Four new mutations in the NC1 domain were found in 4 patients with typical MCDS. Mutations in the COL10A1 gene were not found in 1 typical and 1 atypical case of MCDS or in cases of other metaphyseal chondrodysplasias. Wallis et al. (1996) contended that the restricted distribution of COL10A1 mutations in the region encoding the NC1 domain argues against haplotype insufficiency being the mutation mechanism in this disorder.

In 2 MCDS patients with COL10A1 nonsense mutations, trp611 to ter (120110.0019) and tyr632 to ter (120110.0015), Bateman et al. (2003) showed that the mutated alleles underwent complete nonsense-mediated mRNA decay (NMD) in cartilage, but not in lymphoblasts or bone cells. The authors suggested that novel RNA surveillance mechanisms may exist in cartilage, and that tissue specificity of NMD could be of importance in understanding the molecular pathology of nonsense mutations.

Makitie et al. (2005) reported 10 patients with MCDS and COL10A1 mutations in whom the most characteristic radiographic findings were found in the proximal femoral metaphysis, which showed metaphyseal irregularity, coxa vara, and a vertical growth plate in all the patients. One patient had a significantly milder presentation, characterized by normal height, late onset of symptoms, and lack of lower limb deformity. Makitie et al. (2005) suggested that the clinical variability in severity of COL10A1-associated skeletal dysplasia might be greater than previously thought.

In a 13-year-old boy with MCDS, Ho et al. (2007) identified heterozygosity for a nonsense mutation in the COL10A1 gene (Y663X; 120110.0020). Approximately 50% of mutant Y663X mRNA was translated into truncated alpha-1(X) chains that were misfolded, unable to assemble into trimers, and interfered with the assembly of normal alpha-1(X) chains into trimers.

Animal Model

Ho et al. (2007) studied transgenic mice bearing the equivalent of a human 1859delC frameshift mutation (120110.0005), which displayed typical characteristics of MCDS. The degree of expansion of the hypertrophic zones was transgene dosage-dependent, and transgenic chondrocytes in the lower region of the expanded hypertrophic zone expressed markers uncharacteristic of hypertrophic chondrocytes, indicating that differentiation was disrupted. Misfolded mutant alpha-1(X) chains were retained within the endoplasmic reticulum (ER) of hypertrophic chondrocytes, activating the unfolded protein response. Ho et al. (2007) suggested that a gain-of-function effect, linked to the activation of ER-stress response and altered chondrocyte differentiation, was a possible molecular pathogenetic mechanism for MCDS.

History

Schmid metaphyseal chondrodysplasia was formerly known as metaphyseal dysostosis. The disorder is not a true dysostosis (since it is not primarily a disorder of bone formation), nor is the primary defect in the metaphyses.