NORD gratefully acknowledges David D. Weaver, MD, Professor Emeritus of Medical Genetics, Department of Medical and Molecular Genetics, Indiana University School of Medicine, for revision of this report.
Dyggve-Melchior-Clausen syndrome (DMC) 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, these authors 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 (Kandziora et al. 2002). Normally, there is growth deficiency resulting in short stature. Radiographic findings in older children and adults are pathognomonic for the disorder (Aglan at et. 2009). 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 both the intellectual disability and microcephaly (Burns et al. 2003; Neumann et al. 2006; Santos et al. 2009). SMS is also caused by mutations in DYM, and thus is allelic to DMC (Santos et al. 2009). Both are classified as osteochondrodysplasias, specifically a spondyloepimetaphyseal dysplasia; this latter category of dysplasias consists of 28 separate disorders (Lachman 2007, pp. 934-6).
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, typically is present after 18 months. Additional clinical features that may also develop include dolichocephaly (a long skull), microcephaly (a small head), coarse facial appearance, prognathism (a protruding lower jaw). Intellectual disability ranges from moderate to severe, and worsens with age (Dgyyve et al. 1977; Aglan et al. 2009. Microcephaly occurs in most individuals. Thinning of the corpus callosum has also been reported (Dupuis et al. 2015). 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 short neck and chest, pectus carinatum (protruding breastbone), flaring of the costal margins, kyphosis (excessive backward curvature of the spine), lumbar lordosis (abnormal forward curvature of the spine), scoliosis (side-to-side curvature of the spine), claw-like hands, other joint contractures especially of the elbows and hips, genu valgum and talipes equinovarus (clubbed feet) (Aglan et al. 2009). 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 shortening of the proximal portion of the limbs) may be present also. Histologically, both DMC and SMS exhibit deficient chondrocytic organization and differentiation, and columnar formation that contain populations of degenerating cells with rough endoplasmic reticulum inclusions (Horton and Scott 1982; Nakamura 1997). 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 (Engfeldt et al. 1983; El Ghouzzi et al. 2003). The above findings suggest that lack of dymeclin may lead to abnormal processing or defective synthesis of cartilage protein (El Ghouzzi et al. 2003; Kinning et al. 2005).
Other radiographic abnormalities seen in DMC have been extensively reviewed by Spranger et al. (1975) and include a small skull, hypoplastic facial bones, malformed or absent carpal bones, cone-shaped epiphyses of the phalanges, brachydactyly, fifth finger clinodactyly, accessory bones in the hands, odontoid hypoplasia (underdevelopment of the peg-like projection of the second cervical vertebra) with atlantoaxial instability (Kandziora et al. 2002; Girisha et al. 2008), 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), small femoral heads (proximal ends of the femurs), and broad metaphyses of the long bones (Aglan et al. 2009). Bone maturation (bone age) is delayed (Aglan et al. 2009). 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 is usually 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 constrictions in the middle third of the vertebral bodies (a double-humped appearance), and a lacy appearance of the upper portion of the iliac crest (hipbone) (Hall-Craggs and Chapman 1987). This latter feature because less prominent with time and disappears by adulthood (Dyggve et al. 1977).
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 (Paupe et al. 2004; Carbonell et al. 2005; Aglan et al. 2009). In most individuals with DMC, MRI analyses of the brain have been normal (Paupe et al. 2004; Aglan et al. 2009). However, one patient has been reported with cortical atrophy (Aglan et al. 2009) and another with thinning of the corpus callosum (Dupuis et al. 2015).
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 vertebral body constriction abnormalities and lacy pattern of the iliac crests appear by 3-4 years and may persist until adulthood. The vertebral body constrictions are most prominent between ages 8 and 12 years (Aglan et al. 2009). 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. The treatment of genu varum in this condition has been reported (Kenis et al. 2011). 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 (Paupe et al. 2004). Because of the of atlantoaxial instability found in DMC, cord compression is a concern. However, only a few cases have been reported with this complication (Naffah and Taleb 1974). Prenatal diagnosis of DMC has been accomplished by finding a pathogenic homozygous mutation in the DYM gene in a fetus with no detectable physical findings (Toru et al. 2015).
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 with many reported patients being from Morocco or other Mediterranean countries (Aglan et al. 2009; Santos et al. 2009).
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 et al. (1980) reported a family with apparent SMS where the condition was inherited in an X-linked mode. . Subsequently, Spranger (1981) suggested that this family had spondyloepiphyseal dysplasia tarda, a well-established X-linked disorder.
The gene that causes both DMC and SMS was first reported by Cohn et al. (2003), which they 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-q21.1), contains 17 exons and spans about 400 kb (Cahn et al. 2003; Kinning et al. 2005). The protein, dymeclin, is a protein of 669 amino acids, and is a protein involved in the Golgi apparatus (Dimitrov et at. 2009). Dymeclin’s functions in the homeostasis and organization of the Golgi apparatus, and in trafficking of vesicles and proteins into and out of this organelle (Osipovich et al. 2008). DMC appears to be produced mostly by premature truncation of the DYM product resulting in 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 (Cohn et al. 2003; Santos et al. 2009; Khalifa et al. 2011) and at least 58 different DYM mutations in multiple families from different ethnic groups have been reported (Dimitrov et al. 2009; Santos et al. 2009; Gupta et al. 2010; Khalifa et al. 2011). Some mutations in DYM appear to result in mis-localization and subsequent degradation of dymeclin with in the cell (Dimitrov et al. 2009). Interestingly, disease producing mutations in this gene are scattered throughout the gene (El Ghouzzi et al. 2003). Smith-McCort syndrome usually is the result of missense mutations in the same gene (Dimitrov et al. 2009; Khalifa et al. 2011). Mutational analysis of DYM currently is available (http://www.genetests.org).
More recently a second gene, RAB33B, has been reported to causes SMS (Alshammari et al. 2012). These investigators reported on a Saudi inbred family with six affected individuals in two sibships all of whom had clinical and radiographic features consistent with DMC/SMS. Four tested children each had the same missense mutation in the RAB33B gene. The gene encodes for a Rab protein and the mutation lead to a marked deficiency of this protein. Like dymeclin, the Rab protein plays a critical role in Golgi transport. All four of the evaluated children had normal cognitive function and head size. Thus, it appears that the siblings had SMS rather than DMC has claimed by the authors. Another individual with SMS and a mutation in RAB33B has been reported (Dupuis et al. 2012).
DMC and SMS syndromes are rare genetic disorders. As of 2007 there were over 90 individuals with DMC or SMS reported in the literature (Lachman, 2007, p 934) who were from a number of different ethnic groups (El Ghouzzi et al. 2003; Pogue et al. 2005; Aglan et al. 2009).
A diagnosis of DMC syndrome may be suspected upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic clinical 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 and 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 individuals, 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, their parents and other family.
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This disease entry is based upon medical information available through May 25, 2016. 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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