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Dyggve Melchior Clausen syndrome

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Copyright 1992, 1999, 2005, 2009, 2012

NORD is very grateful to David D. Weaver, MD, Professor Emeritus of Medical Genetics, Department of Medical and Molecular Genetics, Indiana University School of Medicine, for assistance in the preparation of this report.

Synonyms of Dyggve Melchior Clausen syndrome

Disorder Subdivisions

General Discussion

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.

Symptoms

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.

Causes

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.

Affected Populations

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.

Related Disorders

Features in the following disorders can be similar to those found in DMC. Comparisons may be useful for a differential diagnosis:

Morquio syndrome (mucopolysaccharidosis type IV; MPS IV) exists in two forms (Morquio syndromes A and B) and occurs because of a deficiency of the enzymes, N-acetylgalactosamine-6-sulfatase and beta-galactosidase, respectively. A deficiency of either enzyme leads to the accumulation of mucopolysaccharides in the body, cloudy corneas, deafness, abnormal skeletal development, and other features. In most cases, individuals with Morquio syndrome have normal intelligence. The clinical features of Morquio syndrome type B are usually fewer and milder than those associated with Morquio syndrome type A. Findings in both types may also include growth retardation, mildly course facial appearance, glaucoma, a prominent lower face, an abnormally short neck, pectus carinatum (a prominent breast bone), kyphoscoliosis (abnormal backward and sideways curvatures of the spine), platyspondyly, irregular epiphyses (ends of the long bones), broad metaphyses (segments underneath the epiphyses), genu valgum (bowed legs), and flat feet. In some cases, hearing loss, leg weakness, and/or additional abnormalities also occur. In contrast to Morquio syndrome, individuals with DMC have normal hearing and teeth, lack cloudy corneas and lack the urinary mucopolysaccharides, but do have mental retardation. (For more information, choose "Morquio syndrome" as a search term in the Rare Disease Database.)

Pseudoachondroplasia is a rare, inherited disorder characterized by skeletal malformations resulting in short legs and mild to moderate short stature (short-limbed dwarfism). Affected individuals also may have brachydactyly (short, stubby fingers), genu varum, and/or genu valgum. Often there are spinal abnormalities including lumbar lordosis and kyphosis. In some cases, ulnar deviation of the wrists (abnormal bending of the hand toward the fifth finger side of the hand), and limited flexibility the elbows and hips may occur. Pseudoachondroplasia is due to mutations of the cartilage oligomeric matrix protein (COMP) gene, and as such, is allelic to some cases of multiple epiphyseal dysplasia (i.e., caused by different mutations of the same disease gene). Pseudoachondroplasia is inherited as an autosomal dominant trait. (For more information, choose "pseudoachondroplastic dysplasia" as a search term in the Rare Disease Database.)

Spondyloepiphyseal dysplasia congenital is also a rare genetic disorder characterized by growth deficiency before birth (prenatally); spinal, hips, knees and other joint abnormalities; and/or abnormalities affecting the eyes. As affected individuals age, growth deficiency results in short stature (dwarfism), in part, due to a disproportionately short neck and trunk, and coxa vara (a hip deformity in which the femur [thigh bone] is angled toward the midline of the body). In most cases, affected individuals also have hypotonia (diminished muscle tone), kyphoscoliosis, lumbar lordosis, and pectus carinatum. Affected individuals also have abnormalities affecting the eyes including myopia (nearsightedness) and, in approximately 50 percent of cases, retinal detachment. Although there usually is normal intelligence, there may be delay in waking and a waddling gait. Spondyloepiphyseal dysplasia congenital is inherited as an autosomal dominant trait and is produced by a mutation in the collagen II (COL2A1) gene. This gene is involved in the production of type 2 collagen, a connective tissue protein, which is essential for the normal development of bones and other connective tissues. Changes in the composition of this collagen lead to abnormal skeletal growth in this and related disorders. (For more information, choose "spondyloepiphyseal dysplasia congenital" as a search term in the Rare Disease Database.)

Spondyloepiphyseal dysplasia tarda, an X-linked inherited disorder, is also a rare genetic disorder that primarily affects males, and is characterized by short stature, kyphoscoliosis, and lumbar lordosis. Individuals with this condition are normal at birth with onset of features between ages 5 and 10 years. Affected individuals may also have flat facies, a short neck and barrel-shaped chest (a rounded, bulging chest) with pectus carinatum. With time, pain and stiffness of the shoulders, cervical and lumbar vertebrae, and hips develops. (For more information, choose "spondyloepiphyseal dysplasia tarda" as a search term in the Rare Disease Database.)

Metatropic dysplasia I is also a rare genetic disorder with major findings including extremely short stature with short arms and legs. Other features are a narrow thorax, short ribs, and kyphoscoliosis, the latter contributing to the short trunk typical for this condition. The cause of the disorder is a mutation in the TRPV4 gene.
(For more information, choose "metatropic dysplasia I" as a search term in the Rare Disease Database.)

Kniest dysplasia features include cleft palate, short stature, and enlarged joints. The cleft palate is present at birth but other characteristics may not appear for two or three years. Other features may include flat facies, myopia progressing to retinal detachment, kyphoscoliosis and platyspondyly. Kniest dysplasia is also caused by mutations in the COL2A1 gene. (For more information, choose "Kniest dysplasia" as a search term in the Rare Disease Database.)

Spondylometaphyseal dysplasia, Kozlowski type, is a rare disorder characterized by short stature with a short neck and trunk, scoliosis or kyphoscoliosis, short hands and feet, and limited joint movement associated with an abnormal gait. Radiographically, there is severe and generalized platyspondyly, widened and irregular metaphyses of the tubular bones, coxa vara, and delayed bone maturation. The condition is inherited in an autosomal dominant mode. The cause of the disorder also is produced from mutations in the TRPV4 gene.

Standard Therapies

Diagnosis
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
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.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

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.

Dyggve Melchior Clausen syndrome Resources

Organizations:

References

TEXTBOOKS
Lachman RS. Taybi and Lachman's Radiology of Syndromes. Metabolic Disorders, and Skeletal Dysplasias. 5th ed. Philadelphia, PA: Mosby Elsevier; 2007.

Jones KL, Smith's Recognizable Patterns of Human Malformation. 6th ed. Philadelphia, PA:Elsevier Saunders; 2006:412-413.

Weaver DD., Dyggve-Melchior-Clausen Syndrome. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins;2003:180.

Magalini SI, Magalini SC, eds. Dictionary of Medical Syndromes. 4th ed. New York, NY: Lippincott-Raven Publishers; 1996:245.

Hennekam RCM, Krantz ID, Allanson JE, eds. Gorlin's Syndromes of the Head and Neck. 4th ed. New York, NY : Oxford University Press; 1990:342-345.

JOURNAL ARTICLES
Khalifa O, Imtiaz F, Al-Sakati N, et al., Dyggve-Melchior-Clausen syndrome: novel splice mutation with atlanto-axial subluxation. Eur J Pediatr 2011;170:121-6.

Gupta V, Kohli A, Dewan V, Dyggve-Melchior-Clausen syndrome. Indian Pediat. 2010;47:973-5.

Dimitrov A, Paupe V, Gueudry C, et al., The gene responsible for Dyggve-Melchior-Clausen syndrome encodes a novel peripheral membrane protein dynamically associated with the Golgi apparatus. Hum Mol Genet. 2009;18:440-53.

Santos HG, Fernandes HC, Nunes JL, et al., Portuguese case of Smith-McCort syndrome caused by a new mutation in the Dymeclin (FLJ20071) gene. Clin Dysmorph. 2009;18:41-4.

Osipovich AB, Jennings JL, Lin Q, et al., Dyggve-Melchior-Clausen syndrome: Chondrodysplasia resulting from defects in intracellular vesicle traffic. Proc Nat Acad Sci. 2008;105:16171-6.

Carbonell PG, Fernandez PD, Vicente-Franqueira JR., MRI findings in Dyggve-Melchior-Clausen syndrome, a rare spondyloepiphyseal dysplasia. J Magnet Reson Imag. 2005;22:572-576.

Kinning E, Tufarelli C, Winship WS, et al., Genomic duplication in Dyggve-Melchior-Clausen syndrome, a novel mutation mechanism in an autosomal recessive disorder. J Med Genet 2005;42:e70.

Paupe V, Gilbert T, Le Merrer M, et al., Recent advances in Dyggve-Melchior-Clausen syndrome. Mol Genet Metab. 2004;83:51-9.

Burns C, Powell BR, Hsia YE, et al., Dyggve-Melchior-Clausen syndrome: report of seven patients with the Smith-McCort variant and review of the literature. J Pediatr Orthop. 2003;23:88-93.

Cohn DH, Ehtesham N, Krakow D, et al., Mental retardation and abnormal skeletal development (Dyggve-Melchior-Clausen dysplasia) due to mutations in a novel, evolutionary conserved gene. Am J Hum Genet. 2003;72:419-28.

El Ghouzzi V, Dagoneau N, Kinning E, et al., Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve-Melchior-Clausen syndrome. Hum Mol Genet. 2003;12:357-64.

Kandziora F, Neumann L, Schnake KJ, et al., Atlantoaxial instability in Dyggve-Melchior-Clausen syndrome. Case report and review of the literature. J Neurosurg Spine. 2002;96:112-7.

Nakamura K, Kurokawa T, Nagano A, et al., Dyggve-Melchior-Clausen syndrome without mental retardation (Smith-McCort dysplasia): Morphological findings in the growth plate of the iliac crest. Amer J Med Genet 1997;72:11-7.

Engfeldt B, Bui T.-H, Eklof O, et al., Dyggve-Melchior-Clausen dysplasia: Morphological and biochemical findings in cartilage growth zone. Acta Paediatr Scand. 1983;72:269-74.

Horton WA, Scott CI, Dyggve-Melchior-Clausen syndrome: A histological study of the growth plate. J Bone Joint Surg. 1982;64-A;408-15.

Spranger J, X-linked Dyggve-Melchior-Clausen syndrome. Clin Genet. 1981;19:304.

Yunis E, Fontalvo J, Quintero L, X-linked Dyggve-Melchior-Clausen syndrome. Clin Genet 1980;18:284-90.

Dyggve HV, Melchior JC, Clausen J, et al., The Dyggve-Melchior-Clausen (DMC) syndrome. A 15 year follow-up and a survey of the present clinical and chemical findings. Neuropadiatrie 1977;8:429-42.

Dyggve HV, Melchior JC, Clausen J, Morquio-Ullrich's disease: an inborn error of metabolism. Arch Dis Childh. 1962;37:525-34.

Smith R, McCort JJ, Osteochondrodystrophy (Morquio-Brailsford type): Occurrence of three siblings. Calif Med. 1958;88:55-9.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Dymeclin; DYM. Entry No: 607461. Last Edited September 9, 2010. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed February 23, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Smith-McCort Dysplasia; SMC. Entry No: 607326. Last Edited September 24, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed February 23, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Dyggve-Melchior-Clausen Disease; DMC. Entry No: 223800. Last Edited October 1, 2008. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed February 23, 2012.

Report last updated: 2012/03/13 00:00:00 GMT+0