Dyggve-Melchior-Clausen Disease

A number sign (#) is used with this entry because Dyggve-Melchior-Clausen disease (DMC) is caused by homozygous or compound heterozygous mutation in the DYM gene (607461) on chromosome 18q21. Mutations in the same gene cause Smith-McCort dysplasia-1 (607326).

Clinical Features

Among the children from an uncle-niece marriage in Greenland, Dyggve et al. (1962) found 3 with a condition resembling Hurler syndrome (607014) and Morquio syndrome (253000) in some respects. The fingers were clawed with limitation in extension. The patients were mentally retarded, and the urine showed mucopolysaccharide. The spine showed generalized platyspondyly. Irregularities of the iliac crest gave an appearance of a lace border around it. The patient shown in family 12 (plate XII) of the Norwegian study by Hobaek (1961) is probably identical. Naffah and Taleb (1974) described spinal compression from odontoid hypoplasia, as in the Morquio syndrome.

The DMC gene may have a relatively high frequency in Lebanese (Naffah, 1976; Bonafede and Beighton, 1978). Schorr et al. (1977) described the DMC syndrome in 6 Moroccan Jews and 2 Arabs from Gaza, distributed in 2 families and ranging in age from 4 to 25 years. They drew attention to a characteristic double hump with central constriction of the vertebral bodies which is present at age 4 years and becomes more distinct in late childhood. In adult patients, the vertebral bodies become more rectangular as the appositional bone which appears during adolescence becomes fused. In a review of DMC disease, Beighton (1990) gave information on the 3 authors whose names are attached to the disorder. He emphasized prominence of the jaw and relative microcephaly. Subluxation of the hips is frequent. In South Africa, Winship and Rubin (1992) described an affected brother and sister whose parents were first cousins and whose ancestors migrated to South Africa from India in the 19th century.

Spranger et al. (1976) suggested that there is a distinct entity similar to DMC dwarfism except that the patients are not mentally retarded; they recommended the designation Smith-McCort dwarfism (607326). Spinal cord compression due to atlantoaxial instability occurs in both.

Nakamura et al. (1997) examined iliac crest biopsies from 2 patients with Smith-McCort dysplasia. The lace-like appearance of the iliac crests, which is a characteristic radiologic sign, was found to be caused by bone tissue deposited in a wavy pattern at the osteochondral junction. The growth plate showed abnormal enchondral ossification with no columnarization of chondrocytes. Electron microscopy demonstrated chondrocytes with dilated cisternae of rough endoplasmic reticulum (RER) containing fine granular or amorphous material similar to what had been reported in cases of DMC syndrome. Thus, Nakamura et al. (1997) concluded that Smith-McCort dysplasia has pathologic changes in common with DMC disease as an RER storage disorder, even though the mental condition is different.

Mapping

In a consanguineous family from Guam affected by Smith-McCort dysplasia, Ehtesham et al. (2002) performed a genomewide scan and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined 2-point lod score of 3.04 at a recombination fraction of zero for marker D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in 2 affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the mutated gene. Analysis of 3 small, unrelated families with DMC syndrome provided evidence of linkage to the same region, a result consistent with the hypothesis that the 2 disorders are allelic. By homozygosity mapping, Thauvin-Robinet et al. (2002) mapped the DMC syndrome to 18q12.

Molecular Genetics

Cohn et al. (2003) sequenced the coding exons of the DYM gene, a highly evolutionarily conserved gene located within the 18q12 region defined by linkage study, and identified mutations in both DMC (607461.0001-607461.0004) and SMC (607461.0005-607461.0006) families. The data corroborated the impression that these 2 disorders are allelic and identified a gene necessary for normal skeletal development and brain function.

Independently, using a positional cloning strategy, El Ghouzzi et al. (2003) identified the DMC gene as mutant in the DMC syndrome. They detected 7 deleterious mutations, 4 of which were nonsense, 2 splice site, and 1 frameshift, among 10 affected families (see, e.g., 607461.0007-607461.0008).

Neumann et al. (2006) reported 2 consanguineous families from Lebanon and Georgia (Caucasus), respectively, with 2 patients each with DMC confirmed by genetic analysis.