Dyggve-Melchior-Clausen (DMC) syndrome is a rare, progressive genetic disorder characterized by abnormal skeletal development, microcephaly and intellectual disability. The condition was first reported by Dyggve, Melchior and Clausen in 1962 in three of eight siblings where the father was the mother's paternal uncle. Because of physical appearance and the present of acid mucopolysaccharides in the urine, Dyggve believed that their affected patients had Morquio-Ullrich disease (now Morquio syndrome). Skeletal abnormalities in this condition may include a barrel-shaped chest with a short truck, partial dislocation of the hips, genu valgum (knocked knees) or varum (bowed legs), and decreased joint mobility. In 11% of patients, there is atlantoaxial (upper neck vertebrae) instability that can lead to spinal cord compression, weakness and paralysis. Normally, there is growth deficiency resulting in short stature. Radiographic findings in older children and adults are pathognomonic for the disorder. DMC results from mutations in the DYM (dymeclin) gene and is inherited in an autosomal recessive mode.
A variant of DMC syndrome, Smith-McCort syndrome (SMS), which was first described by Smith and McCort in 1958, has identical skeletal abnormalities, but lacks the intellectual disability. SMS is also caused by mutations in DYM, and thus is allelic to DMC. Both are classified as osteochondrodysplasias, specifically a spondyloepimetaphyseal dysplasia; this latter category of dysplasias consists of 28 separate disorders.
Affected newborns may be small at birth, but otherwise appear normal. With age, other characteristics develop. For instance, chest deformities, feeding difficulties and developmental delay usually are manifest by or before 18 months. Disproportionate short stature, with the arms and legs being disproportionately too long for the torso, normally is present after 18 months. Additional features that may also develop include dolichocephaly (a long skull), coarse facial appearance, prognathism (a protruding jaw), microcephaly, i.e., a smaller than expected head size for the age and sex of the affected individual, and claw-like hands. Intellectual disability occurs in 82% of cases, ranges from moderate to severe, and worsens with age. The overall health of an affected person is generally good and survival into adulthood is usual.
In addition to the skeletal abnormalities listed above, affected individuals can also develop a protruding sternum (breastbone), kyphosis (excessive backward curvature of the spine), lordosis (abnormal forward curvature of the spine), scoliosis (side-to-side curvature of the spine), and joint contractures especially of the elbows and hips. Further, the metacarpals (bones in the middle of the hand) and phalanges (other bones in the fingers and toes) are shortened. The carpal bones (bones of the wrist) may also be small and irregularly shaped. Rhizomelic shortening of the limbs (disproportionate upper limb shortening) may be present also. Histologically, both DMC and SMS exhibit deficient chondrocyte organization and differentiation, and columnar structures formation that contain populations of degenerating cells with rough endoplasmic reticulum inclusions. On electron microscopic exam, the chondrocytes contain widened cisternae of the rough endoplasmic reticulum, and the vesicles are coated with a smooth single-layered membrane. The above findings suggest that lack of dymeclin may lead to abnormal processing or defective synthesis of cartilage protein.
Other radiographic abnormalities seen include small skull; hypoplastic facial bones; small and malformed, or absent carpal bones; cone-shaped epiphyses of the phalanges; accessory bones in the hands; odontoid hypoplasia (underdevelopment of the peg-like projection of the second cervical vertebra) with atlantoaxial instability; platyspondyly (flattened vertebral bodies); irregular superior and inferior edges of the vertebral bodies; anterior pointing of the vertebral bodies; hypoplastic ilia (small hipbones); narrow sacrosciatic notch; widen pubic symphysis; dysplastic acetabulum (malformation of the hip socket); and small femoral heads (proximal ends of the femurs). Bone maturation (bone age) is delayed. Individuals with Smith-McCort syndrome have similar skeletal findings as those associated with DMC.
Secondary problems resulting from the skeletal abnormalities associated with DMC may include spinal compression, dislocated hips, and restricted joint mobility. These problems may in turn cause a waddling gait. When it occurs, spinal cord compression in the neck usually is caused by the hypoplasia of the odontoid process and to hyperlaxity of the longitudinal ligament of the upper cervical spine. The pathognomonic radiographic findings for DMC and SMS include double-humped appearance with central notching in the superior and inferior end plates of the vertebral bodies, and a lacy appearance of the upper portion of the iliac crest (hipbone). This later feature because less prominent or disappears by adulthood.
MRI findings in DMC include hypoplasia of the odontoid process, posterior disk protrusions in the lumbar vertebrae and the enlargement of the posterior common vertebral ligament. In most individuals with DMC, a MRI analysis of the brain is normal.
Both DMC and SMS are progressive disorders. With the exception of reduced length, affected individuals usually are normal at birth. Skeletal findings often are recognized first between 1 and 18 months. The double-humped vertebral abnormality and lacy pattern of the iliac crests appear by 3-4 years and may persist until adulthood. The microcephaly in DMC and short stature in both appear during childhood. Throughout childhood and as adults, thoracic kyphosis, scoliosis, lumbar lordosis, subluxation (partial dislocation) and frank dislocation of the hips, wide-based and waddling gait, genu valgum or varum, and restricted joint mobility appear and may worsen. Adult height is severely reduced with height ranging from 82 cm to 128 cm (32 in to 50 in). Neurologic and behavioral complications in DMC may include hyperactivity, autistic-like behavior, lack of speech and mild to severe intellectual disability with IQ scores ranging from 25 to 65.
Dyggve-Melchior-Clausen syndrome is inherited as an autosomal recessive trait. Normally, autosomal genes come in pair with an individual receiving one gene of the paired genes from his or her father, and the other from the mother. Recessive genetic disorders occur when an individual inherits an abnormal or mutated gene for the same trait from each parent. In autosomal recessive conditions, if an individual receives one normal gene and one gene for the disease, the person is a carrier for the disease, but usually will not have any clinical manifestations of the condition. The risk for two carrier parents to both pass on their defective genes to an offspring, and therefore have an affected child, is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. And the chance for a child to receive two normal genes from his or her parents and be genetically normal for that particular trait is 25%. Many children with DMC and SMS are offspring of consanguineous parents and many are from Morocco or other Mediterranean countries.
Smith-McCort syndrome is allelic to DMC, and also is inherited as an autosomal recessive trait. There has been some confusion about the inheritance of SMS because Yunis reported a family which these authors denoted as SMS and the condition was inherited in an X-linked fashion. Subsequently, Spranger (1981) suggested that this family had spondyloepiphyseal dysplasia tarda, an X-linked inherited disorder.
The gene that causes both DMC and SMS was originally called FLJ90130. Subsequently, others proposed changing the gene’s name, and the protein it produces, to dymeclin (abbreviated from Dyggve-Melchior-Clausen). The gene now most commonly is referred to as DYM. The gene is located on the long arm (q) of chromosome 18 (18q12-21.1), contains 17 exons and spans about 400 kb. The protein, dymeclin, is a protein of 669 amino acids, and appears to be a protein of the Golgi apparatus. Dymeclin’s function involves trafficking of vesicles and proteins into and out of the Golgi apparatus. DMC appears to be produced by complete or nearly complete absence of dymeclin production from both DYM genes. Alternatively, there may be little or no production from one gene and production of a partially functioning protein from the other. A number of different types of mutations, i.e., frameshift, nonsense, missense mutations and etc., cause DMC and at least 58 different DYM mutations in multiple families from different ethic groups have been reported. Mutations in DYM appear to result in mis-localization and subsequent degradation of dymeclin and these mutations are scattered throughout the gene. Smith-McCort syndrome is the result of other mutations of the same gene.
DMC and SMS syndromes are rare genetic disorders. There are now over 90 individuals with DMC or SMS reported in the literature from a number of different ethnic groups.
A diagnosis of DMC syndrome may be suspected upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic findings, e.g., barrel chest, and disproportionate short stature. Radiographs may confirm specific skeletal abnormalities and findings consistent with DMC syndrome and includes notching of the vertebral bodies, lacy appearance of the iliac crest, and small malformed carpal bones. Alternatively, gene testing for mutations in DYM can be done.
Treatment of individuals with DMC syndrome is symptomatic and supportive. When there is hypoplasia of the odontoid process and partial dislocation of the cervical vertebrae (the segments of the spinal column at the top of the spine), spinal fusion of these vertebrae or other means of vertebral stabilization normally is indicated. These procedures should be done in order to prevent damage to the cervical spinal cord, which can result in cord-related weakness or paralysis. Additionally, surgical techniques may be used to correct various other skeletal abnormalities such as subluxation or dislocation of the shoulder and hip joints. In some cases, hip replacement is required.
Children with DMC syndrome may benefit from early intervention and special educational programs. Genetic counseling may be of benefit for affected individuals and their families.
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This disease entry is based upon medical information available through February, 2012. Since NORD’s resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.
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