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      Management of progressive genu varum in a patient with Dyggve-Melchior-Clausen syndrome Translated title: Management einer ausgeprägten Genu varum-Fehlstellung bei einem Patienten mit Dyggve-Melchior-Clausen Syndrom

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          Abstract

          We describe the orthopaedic management of progressive genu varum in a child who manifested the full phenotypic characterization of Dyggve-Melchior-Clausen syndrome.

          Translated abstract

          Wir beschreiben das orthopädische Management einer schweren Genu varum-Fehlstellung am Fall eines Kindes mit voller phänotypischer Ausprägung eines Dyggve-Melchior-Clausen Syndroms.

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          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.
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            Recent advances in Dyggve-Melchior-Clausen syndrome.

            Dyggve-Melchior-Clausen (DMC) is a rare autosomal-recessive disorder characterized by the association of a progressive spondylo-epi-metaphyseal dysplasia and mental retardation ranging from mild to severe. Electron microscopy studies of both DMC chondrocytes and fibroblasts reveal an enlarged endoplasmic reticulum network and a large number of intracytoplasmic membranous vesicles, suggesting that DMC syndrome may be a storage disorder. Indeed, DMC phenotype is often compared to that of type IV mucopolysaccharidosis (Morquio disease), a lysosomal disorder due to either N-acetylgalactosamine-6-sulphatase or beta-galactosidase deficiency. To date, however, the lysosomal pathway appears normal in DMC patients and biochemical analyses failed to reveal any enzymatic deficiency or accumulated substrate. Linkage studies using homozygosity mapping have led to the localization of the disease-causing gene on chromosome 18q21.1. The gene was recently identified as a novel transcript (Dym) encoding a 669-amino acid product (Dymeclin) with no known domains or function. Sixteen different Dym mutations have now been described in 21 unrelated families with at least five founder effects in Morocco, Lebanon, and Guam Island. Smith-MacCort syndrome (SMC), a rare variant of DMC syndrome without mental retardation, was shown to be allelic of DMC syndrome and to result from mutations in Dym that would be less deleterious to the brain. The present review focuses on clinical, radiological, and cellular features and evolution of DMC/SMC syndromes and discusses them with regard to identified Dym mutations and possible roles of the Dym gene product.
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              Mental retardation and abnormal skeletal development (Dyggve-Melchior-Clausen dysplasia) due to mutations in a novel, evolutionarily conserved gene.

              Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function.
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                Author and article information

                Journal
                Ger Med Sci
                GMS Ger Med Sci
                GMS German Medical Science
                German Medical Science GMS Publishing House
                1612-3174
                20 September 2011
                2011
                : 9
                Affiliations
                [1 ]Pediatric Orthopedic Institute n.a. H. Turner, Department of Foot and Ankle Surgery, Neuroorthopaedics and Systemic Disorders, Saint-Petersburg, Russia
                [2 ]Orthopaedic Hospital of Speising, Paediatric Department, Vienna, Austria
                [3 ]Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, First Medical Department, Hanusch Hospital, Vienna, Austria
                Author notes
                *To whom correspondence should be addressed: Ali Al Kaissi, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, First Medical Department, Hanusch Hospital, Heinrich Collin Str. 30, A-1140, Vienna, Austria, E-mail: ali.alkaissi@ 123456osteologie.at
                Article
                000148 Doc25 urn:nbn:de:0183-0001489
                10.3205/000148
                3182029
                21966286
                Copyright © 2011 Kenis et al.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free to copy, distribute and transmit the work, provided the original author and source are credited.

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                Medicine

                radiographs, genu varum, dyggve-melchior-clausen syndrome

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