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.
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 ‘locked’ 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 “p” and a long arm designated “q”. 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.
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 child’s 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
615 Charles E. Young Drive, South RM 410
Los Angeles CA 90095-7358
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:
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.
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: Smith’s Recognizable Patterns of Human Malformation. 7th ed. Elsevier Saunders, Philadelphia, PA; 2013:494-495.
Makitie O, Geiberger S, Horemuzova E, et al. SLC26A disease spectrum in Sweden – high frequency of recessive multiple epiphyseal dysplasia (rMED). Clin Genet. 2014; [Epub ahead of print]. http://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. http://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 – phenotype, molecular diagnosis and surgical treatment habitual dislocation of multilayered patella: case report. BMC Musculoskelet Disord. 2010;11:110. http://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. http://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. http://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. http://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. http://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. http://www.ncbi.nlm.nih.gov/pubmed/11241838
Bonafé 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: http://www.ncbi.nlm.nih.gov/books/NBK1306/ Accessed June 1, 2015.
Ranade AS. McCarthy JJ. Multiple Epiphyseal Dysplasia.Medscape, August 2, 2013. Available at: http://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: http://www.omim.org/entry/226900 Accessed June 1, 2015.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100