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Last updated: June 01, 2015
Years published: 2015
NORD gratefully acknowledges Giedre Grigelioniene, MD, PhD, Consultant in Pediatrics and Clinical Genetics, Department of Clinical Genetics,
Karolinska University Hospital, Stockholm, Sweden for assistance in the preparation of this report.
Summary
Recessive multiple epiphyseal dysplasia (rMED) is a rare genetic disorder characterized by abnormal skeletal development mainly affecting the growth zones of the long tubular bones (dysplasia) including those affecting bones of the hands, hips, knees and feet. Joint pain, particularly of the hips and/or knees, is also common and develops during childhood. Affected individuals may exhibit additional abnormalities such as mild sideways curvature of the spine (scoliosis). Certain malformations such as clubfoot or cleft palate can be present at birth (congenital). rMED is caused by mutations in the SLC26A2 gene. This gene is also known as the diastrophic dysplasia sulfate transport or DTDST gene. The term โrecessiveโ in the disorderโs name refers to the how the disorder is inherited (autosomal recessive inheritance). rMED is a form of skeletal dysplasia (osteochondrodysplasia), a broad term for a group of disorders characterized by abnormal growth or development of cartilage and bone. The disorder is also known as multiple epiphyseal dysplasia type 4.
Introduction
Multiple epiphyseal dysplasia is a general term for a group of disorders characterized by abnormal development of the bone and cartilage of the epiphyses, which are the rounded ends or โheadsโ of the long bones. In the past, the disorder was subdivided into the milder Ribbing type and the more severe Fairbank type. According to new classification, multiple epiphyseal dysplasia represents a group of disorders and these disorders are classified according to mutations in different genes, and the types of MED are classified according to the causative gene. However, not all genes behind MED have been identified yet. Most subtypes are inherited in an autosomal dominant manner. rMED belongs to a family of skeletal diseases with a variable severity of phenotype caused by different mutations in the same gene. This group includes the following diagnoses from the most severe to the mildest end of the spectrum: achondrogenesis type 1B, atelogenesis type 2, diastrophic dysplasia and rMED is the mildest form.
The specific symptoms and physical findings may vary from one person to another. Affected individuals may develop relatively mild symptoms and, in some cases, individuals reach adulthood without ever receiving a diagnosis of recessive multiple epiphyseal dysplasia. However, most individuals are diagnosed with a skeletal dysplasia at some point during childhood. Other individuals may have more severe complications.
Approximately 50% of affected infants have a skeletal malformation that is present at birth such as clubfoot, fingers may be fixed or โlockedโ in a bent position (clinodactyly), or abnormal closure of the roof of the mouth (cleft palate).
Affected children will usually display symptoms or signs of abnormal bone and cartilage development (skeletal dysplasia) that can include short, stubby fingers and toes (brachydactyly), broadening of the space between the first and second toes, and mild, abnormal sideways curvature of the spine (scoliosis). Clubfoot, clinodactyly or cleft palate may also first become apparent during childhood. In some children, ears may get swollen in infancy as in diastrophic dysplasias. Diminished muscle tone (muscular hypotonia) may be significant but improves with physical therapy. Also attention has to be paid to the cervical spine especially if an operation is needed with general anesthesia.
Affected individuals also experience early onset pain and stiffness in affected joints (early-onset arthritis) that can develop in chronic joint pain (arthralgia) and damage to the joints. The hips and the knees are commonly affected. Affected individuals often develop misalignment or malformation of the hips (hip dysplasia). Some affected individuals develop a waddling manner of walking (abnormal gait), and mild short stature can occur, but is not a frequent finding. Multiple joints may be affected, particularly in adolescents. Joint pain is usually worse after physical exercise. Some individuals develop deformity or rigidity of affected joints due to shortening or hardening of muscles, tendons or other tissue (contractures).
A specific finding associated with rMED is a double-layered or partitioned patella. The patella, or the kneecap, is the triangular bone that protects the front of the knee joint. A double patella has two bony (osseous) layers instead of one with cartilage in between. A double patella may not be associated with any symptoms (asymptomatic) or may lead to frequent dislocations, knee pain, and potentially functional disability of the knee. In some cases, a double patella resolves on its own in adulthood.
Recessive multiple epiphyseal dysplasia is caused by a mutation in the SLC26A2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene 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. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
The SLC26A2 gene is located on the long arm (q) of chromosome 5 (5q32). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated โpโ and a long arm designated โqโ. Chromosomes are further sub-divided into many bands that are numbered.
The protein production of the SLC26A gene is required for efficient cellular transport of certain cartilage proteins needed to build skeleton and other tissues. The protein is a sulfate transporter that is involved in the proper development and function of molecules that build cartilage. Cartilage is the specialized tissue that serves as a buffer or cushion at joints.
Recessive multiple epiphyseal dysplasia affects males and females in equal numbers. The exact incidence or prevalence of the disorder is unknown, but multiple epiphyseal dysplasia, collectively, has been estimated to occur in approximately 1 in 20,000 people in the general population. rMED is estimated to account for approximately 25% of all cases of multiple epiphyseal dysplasia. Because some cases go undiagnosed or misdiagnosed, determining the true frequency these disorders in the general population is difficult.
A diagnosis of recessive multiple epiphyseal dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with joint pain, particularly in the hips and knees, skeletal malformation of the hands, feet and knees, and scoliosis.
Clinical Testing and Workup
Basic x-rays (radiographs) can help to establish a diagnosis of rMED by revealing abnormal epiphyses, brachydactyly, and a double patella.
Molecular genetic testing can support a diagnosis of multiple epiphyseal dysplasia. Molecular genetic testing can detect mutations in the SLC26A gene known to cause the disorder, but it is only available as a diagnostic service at specialized laboratories. The test is often expensive and often not necessary to confirm a diagnosis of rMED.
Treatment
The treatment of rMED is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, geneticists, orthopedic surgeons, rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect childโs treatment. Genetic counseling may be of benefit for affected individuals and their families.
Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), is beneficial. Pain management can be challenging. Cautious use of pain (analgesic) medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) is recommended.
In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery may be necessary. Surgical procedures may be recommended to correct clubfoot or abnormalities of the knee.
A registry for skeletal dysplasias has been set up at the University of California Los Angeles. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials into specific treatment options. For more information, contact:
International Skeletal Dysplasia Registry
UCLA
615 Charles E. Young Drive, South RM 410
Los Angeles CA 90095-7358
Phone: 310-825-8998
Website: https://isdr.csmc.edu/
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 web site.
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: [email protected]
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Mankin HJ, Mankin KP, eds. Multiple Epiphyseal Dysplasias. In: Rare Genetic Disorders that Affect the Skeleton. AuthorHouse, LLC, Bloomington, IN; 2013:88-95.
Jones KL, Jones MC, del Campo Casanelles, eds. Multiple Epiphyseal Dysplasia. In: Smithโs Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:494-495.
JOURNAL ARTICLES
Makitie O, Geiberger S, Horemuzova E, et al. SLC26A disease spectrum in Sweden โ high frequency of recessive multiple epiphyseal dysplasia (rMED). Clin Genet. 2014; [Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/24598000
Warman ML, Cormier-Daire V, Hall C, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011;155:943-968. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166781/
Hinrichs T, Superti-Fruga A, Scheiderer WD, et al. Recessive multiple epiphyseal dysplasia (rMED) with homozygosity for C653S mutation in the DTDST gene โ phenotype, molecular diagnosis and surgical treatment habitual dislocation of multilayered patella: case report. BMC Musculoskelet Disord. 2010;11:110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902411/
Goebel S, Steinert AF, Barthel T. Surgical management of a double-layered patella: a case report. Arch Orthop Trauma Surg. 2009;129:1071-1075. https://www.ncbi.nlm.nih.gov/pubmed/18677496
Ballhausen D, Bonafe L, Terhal P, et al. Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W. J Med Genet. 2003;40:65-71. https://www.ncbi.nlm.nih.gov/pubmed/12525546
Makitie O, Savarirayan R, Bonafe L, et al. Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign. Am J Med Genet. 2003;122A:187-192. https://www.ncbi.nlm.nih.gov/pubmed/12966518
Briggs MD, Chapman KL. Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat. 2002;19:465-478. https://www.ncbi.nlm.nih.gov/pubmed/11968079/
Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SCL26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001;17:159-171. https://www.ncbi.nlm.nih.gov/pubmed/11241838
INTERNET
Bonafรฉ L, Mittaz-Crettol L, Ballhausen D, et al. Multiple Epiphyseal Dysplasia, Recessive. 2002 Aug 29 [Updated 2014 Jan 23]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1306/ Accessed June 1, 2015.
Ranade AS. McCarthy JJ. Multiple Epiphyseal Dysplasia.Medscape, August 2, 2013. Available at: https://emedicine.medscape.com/article/1259038-overview Accessed June 1, 2015.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:226900; Last Update:01/13/2011. Available at: https://www.omim.org/entry/226900 Accessed June 1, 2015.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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