Dyggve-Melchior-Clausen Syndrome Research Articles

A novel frameshift mutation and infrequent clinical findings in two cases with Dyggve–Melchior–Clausen syndrome

Dyggve-Melchior-Clausen syndrome (DMC) (MIM #223800) is a rare autosomal-recessive type of skeletal dysplasia accompanied by variable degrees of intellectual disability (ID). It is characterized by progressive spondyloepimetaphyseal dysplasia leading to disproportionate short stature, microcephaly, and coarse facies. The radiographic appearance of generalized platyspondyly with double-humped end plates and the lace-like appearance of iliac crests are pathognomonic in this syndrome. The disorder results from mutations in the dymeclin (DYM) mapped to the 18q12-12.1 chromosomal region. Here, we report two cases with DMC: one with disproportionate short stature, developmental delay, and severe ID with a novel frameshift mutation (c.1028_1056del29) leading to a premature stop codon, and the second patient with classical clinical and radiological features of DMC with mild ID and rectal prolapse, which is very rare. The clinical diagnosis was confirmed with molecular analysis of DYM with a known mutation at c.580C>T (p.R194X). The parents and sibling of the second patient were heterozygous carriers with mild skeletal changes and short stature.

A recurrent mutation in Moroccan patients with Dyggve-Melchior-Clausen syndrome: Report of a new case and review

Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive disorder. It is a spondyloepimetaphyseal dysplasia associated with mental retardation. Clinical manifestations include coarse facies, microcephaly, short trunk dwarfism, and mental retardation. Mutations in Dymeclin gene (DYM), mapped to chromosome 18q21.1, is responsible for DMC. We report here the observation of a consanguineous Moroccan patient having DMC syndrome. The molecular studies showed a previously reported homozygous mutation at c.1878delA of DYM gene. We discuss this recurrent mutation in Moroccan patients with DMC syndrome with a review.

Dyggve–Melchior–Clausen syndrome: novel splice mutation with atlanto-axial subluxation

Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive disorder characterized by the association of a progressive spondyloepimetaphyseal dysplasia and mental retardation ranging from mild to severe. The disorder results from mutations in the dymeclin (DYM) gene in the 18q12-12.1 chromosomal region. We report two siblings with classical clinical and radiological features of DMC and asymptomatic atlanto-axial dislocation. A novel homozygous splice-site mutation (IVS15+3G>T) was detected. Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed that this mutation affects normal splicing. To the best of our knowledge, this is the first report of DMC from Saudi Arabia. The splice mutation noted in our patients was compared to the previously reported cases and supports the hypothesis that loss of DYM function is the likely mechanism of disease pathogenesis. In conclusion, distinction between this type of skeletal dysplasia and Morquio disease (MPS IV) is important for paediatricians and clinical geneticist in providing standard patient care and genetic counselling.

Dyggve-Melchior-Clausen syndrome: clinical, genetic, and radiological study of 15 Egyptian patients from nine unrelated families.

Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive type of skeletal dysplasia. It is characterized by the association of progressive spondyloepimetaphyseal dysplasia (SEMD), microcephaly, mental retardation (MR), and coarse facies. The radiographic appearance of generalized platyspondyly with double-humped end plates and the lace-like appearance of iliac crests are pathognomonic and distinctive of DMC syndrome. The disorder results from mutations in the DYM gene mapped in the 18q12-12.1 chromosomal region. In this report, we studied 15 Egyptian cases with DMC syndrome from nine unrelated families. We aimed to emphasize the characteristic clinical and radiological features in order to differentiate the condition from other SEMDs and mucopolysaccharidosis (MPS). Patients were subjected to detailed history taking, three-generation family pedigree analysis, complete physical examination, anthropometric measurements, quantitative estimation, and two-dimensional electrophoresis of glycosaminoglycans in the urine and measurement of α-l-iduronidase and galactose-6-sulfatase enzyme activities to exclude Hurler and Morquio diseases (MPS type I and MPS type IVA), respectively. Other investigations were carried out whenever indicated. All patients were the offspring of consanguineous apparently normal parents. Positive family history and similarly affected sibs were noted, confirming the autosomal recessive inheritance pattern of the syndrome. Short stature, microcephaly, variable degree of MR, and coarse facies were constant features. The frequency of characteristic orthopedic and radiological findings was reported. Orthopedic surgical intervention was carried out for two patients. The study concluded that DMC syndrome may be more frequent in Egypt than previously thought, especially due to misdiagnosis. Characteristic facial dysmorphism, body habitus, and pathognomonic radiological signs suggest the diagnosis and differentiate it from other types of SEMDs and MPS for proper genetic counseling and management.

Dyggve–Melchior–Clausen syndrome: Chondrodysplasia resulting from defects in intracellular vesicle traffic

Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia are recessive spondyloepimetaphyseal dysplasias caused by loss-of-function mutations in dymeclin (Dym), a gene with previously unknown function. Here we report that Dym-deficient mice display defects in endochondral bone formation similar to that of Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia, demonstrating functional conservation between the two species. Dym-mutant cells display multiple defects in vesicle traffic, as evidenced by enhanced dispersal of Golgi markers in interphase cells, delayed Golgi reassembly after brefeldin A treatment, delayed retrograde traffic of an endoplasmic reticulum-targeted Shiga toxin B subunit, and altered furin trafficking; and the Dym protein associates with multiple cellular proteins involved in vesicular traffic. These results establish dymeclin as a novel protein involved in Golgi organization and intracellular vesicle traffic and clarify the molecular basis for chondrodysplasia in mice and men.

Novel mutation and atlantoaxial dislocation in two siblings from India with Dyggve–Melchior–Clausen syndrome

Dyggve–Melchior–Clausen syndrome is a rare variety of spondyloepimetaphyseal dysplasia which often resembles Morquio syndrome. We describe two siblings from India with the condition and report a novel homozygous mutation in them (c.1172_1173insC). One of them had atlantoaxial dislocation.

Dyggve–Melchior–Clausen syndrome and Smith–McCort dysplasia: Clinical and molecular findings in three families supporting genetic heterogeneity in Smith–McCort dysplasia

Dyggve-Melchior-Clausen syndrome (DMC) (MIM 223800) and Smith-McCort dysplasia (SMC) (MIM 607326) are rare allelic autosomal recessive spondylo-epi-metaphyseal dysplasias (SEMDs) characterized by similar skeletal manifestations. Both phenotypes have been mapped to chromosome 18q21.1 and mutations in the DYM (dymeclin) gene were identified in 13 families with DMC and in two families with SMC. Most mutations identified in DMC predict a loss of function, while those identified in SMC are mainly missense mutations, presumably associated with residual DYM activity and a less severe phenotype. We studied three consanguineous families from Turkey, Lebanon, and Georgia, one with SMC and two with DMC and identified different homozygous DYM mutations (IVS3 194-1G > A, 938_942delTGTCT) in the DMC families. No mutation was identified in the SMC family, possibly suggesting genetic heterogeneity of this disorder.

MRI findings in Dyggve‐Melchior‐Clausen syndrome, a rare spondyloepiphyseal dysplasia

We present the case of an 8-year-old female patient with bone dysplasia as part of Dyggve-Melchior-Clausen syndrome (DMCS). MRI was used to evaluate the case. In the spine, odontoid apophysis aplasia was found with no ossification nucleus, vertebrae with central hump, disk protrusions, hypertrophy of the posterior common vertebral ligament, and hidden spina bifida at the S4 level. Morphological anomalies were found in the hips both in the proximal femoral epiphysis, which was located excentrically and laterally to the femoral neck, and in the Y-cartilage, which was greatly enlarged. In the knees, anterior crossed ligaments were not seen, although there were some indirect signs that indicated congenital absence, including hypoplasia of the femoral trochlea and the intercondylar notch. There was bilateral medial patellar plicae and asymmetry in the height of the distal femoral and proximal tibial physes, as well as dysplasia of the facets of the patella. In comparison with radiography, MRI provides a much clearer definition of the aspects of bone dysplasia that are related to DMCS, including morphological changes in the soft tissue and cartilage of the spine, hips, and knees. MRI can enhance our understanding of the pathogenesis and evolution of deformities.

Le syndrome de Dyggve-Melchior-Clausen : à propos d'une observation

Dyggve-Melchior-Clausen syndrome (DMCS) is a rare skeletal disorder, characterised by a spondyloepimetaphyseal dysplasia. DMCS associates progressive nanism and mental retardation with variable severity. Radiological features include spondyloepimetaphyseal dysplasia, platyspondyly and small iliac wings with lacy iliac crest. We report a case of DMCS in a nine-year-old child.

Gene discovery in the allelic disorders Smith–McCort Dysplasia and Dyggve–Melchior–Clausen syndrome

Gene discovery in the allelic disorders Smith–McCort Dysplasia and Dyggve–Melchior–Clausen syndrome

Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve-Melchior-Clausen syndrome.

Dyggve-Melchior-Clausen syndrome (DMC) is a rare autosomal-recessive disorder, the gene for which maps to chromosome 18q21.1. DMC is characterized by the association of a spondylo-epi-metaphyseal dysplasia and mental retardation. Electron microscopic study of cutaneous cells of an affected child showed dilated rough endoplasmic reticulum, enlarged and aberrant vacuoles and numerous vesicles. As the etiology of the disorder is unknown, we have used a positional cloning strategy to identify the DMC gene. We detected seven deleterious mutations within a gene predicted from a human transcript (FLJ20071) in 10 DMC families. The mutations were nonsense mutations (R194X, R204X, L219X, Q483X), splice site or frameshift mutations (K626N+92aa to stop). The DMC gene transcript is widely distributed but appears abundant in chondrocytes and fetal brain. The predicted protein product of the DMC gene yields little insight into its likely function, showing no significant homology to any known protein family. However, the carboxy terminal end comprises a cluster of dileucine motifs, highly conserved across species. We conclude that DMC syndrome is consequent upon loss of function of a gene that we propose to name Dymeclin, which may have a role in process of intracellular digestion of proteins.

Dyggve-Melchior-Clausen syndrome: report of seven patients with the Smith-McCort variant and review of the literature.

Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive disorder affecting skeletal development. The patients have a striking "barrel-shape" chest, shortened trunk, and various distal deformities, including genu valgum or varum, and minimal decrease in joint mobility. The most notable radiographic findings are a lacy iliac crest apophysis, hip dysplasia, double vertebral hump, and odontoid hypoplasia with atlanto-axial instability. Patients may require orthopedic femoral osteotomy, total hip arthroplasty, early meniscectomy, realignment osteotomy, or posterior cervical spine fusion. Patients with the Smith McCort variant have similar orthopaedic manifestations but are not mentally retarded. The diagnosis may be confirmed histologically, but no biochemical or developmental defect has been defined as yet. The authors report seven affected members of two families from Guam and describe their orthopaedic treatment. The authors review the historical reports, clinical findings, and diagnostic radiographic features in DMC syndrome.

Dyggve-Melchior-Clausen Syndrome: Report of Seven Patients With the Smith-McCort Variant and Review of the Literature

Dyggve-Melchior-Clausen (DMC) syndrome is a rare autosomal recessive disorder affecting skeletal development. The patients have a striking “barrel-shape” chest, shortened trunk, and various distal deformities, including genu valgum or varum, and minimal decrease in joint mobility. The most notable radiographic findings are a lacy iliac crest apophysis, hip dysplasia, double vertebral hump, and odontoid hypoplasia with atlanto-axial instability. Patients may require orthopedic femoral osteotomy, total hip arthroplasty, early meniscectomy, realignment osteotomy, or posterior cervical spine fusion. Patients with the Smith McCort variant have similar orthopaedic manifestations but are not mentally retarded. The diagnosis may be confirmed histologically, but no biochemical or developmental defect has been defined as yet. The authors report seven affected members of two families from Guam and describe their orthopaedic treatment. The authors review the historical reports, clinical findings, and diagnostic radiographic features in DMC syndrome.

Le syndrome de Dyggve-Melchior-Clausen : diagnostic différentiel de la mucopolysaccharidose de type IV ou maladie de Morquio

Dyggve-Melchior-Clausen syndrome (DMCS) is an autosomal recessive skeletal dysplasia. Clinical and radiological similarities with Morquio’s syndrome can initially lead wrongly to this diagnosis. Case report. – A nine-year-old boy had mental retardation and progressive postnatal dwarfism. Platyspondyly and dysplastic epiphyses and metaphyses resembled those of Morquio’s disease; however, clinical and radiological data led to the diagnosis of DMCS. Conclusion. – Clinical and paraclinical features allowing the differentiation of Morquio’s syndrome and DMCS are discussed. Initial clinical presentation may be similar, but the intellectual prognosis is different.