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Multiple Epiphyseal Dysplasia, Recessive

Synonyms: EDM4, rMED

, MD, PhD, , PhD, , MD, and , MD.

Author Information
, MD, PhD
Associate Professor; Head, Division of Molecular Pediatrics
Lausanne University Hospital
Lausanne, Switzerland
, PhD
Laboratory of Molecular Pediatrics
Lausanne University Hospital
Lausanne, Switzerland
, MD
Senior Lecturer, Division of Molecular Pediatrics
Lausanne University Hospital
Lausanne, Switzerland
, MD
Professor of Pediatrics, Department of Pediatrics
Lausanne University Hospital
Lausanne, Switzerland

Initial Posting: ; Last Update: January 23, 2014.

Summary

Disease characteristics. Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have an abnormal finding at birth, e.g., clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild.

Diagnosis/testing. Diagnosis of EDM4/rMED is based on clinical and radiographic findings. SLC26A2 is the only gene in which mutations are known to cause EDM4/rMED.

Management. Treatment of manifestations: Physiotherapy for muscular strengthening and maintaining mobility; cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs (NSAIDs); orthopedic surgery (joint replacement) as indicated; career counseling.

Prevention of secondary complications: Intensive physiotherapy may help in delaying joint contractures and in maintaining mobility.

Surveillance: Radiographs as indicated.

Agents/circumstances to avoid: Sports involving joint overload.

Genetic counseling. EDM4/rMED is inherited in an autosomal recessive manner. At conception, each sib of a proband with EDM4/rMED has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk is possible if both disease-causing alleles in the family are known and the carrier status of the parents has been confirmed. Requests for prenatal testing for mild conditions such as EDM4/rMED are not common.

Diagnosis

Clinical Diagnosis

The diagnosis of recessive multiple epiphyseal dysplasia (EDM4/rMED) is usually established during childhood or early adulthood. The diagnosis is suspected in individuals with the following:

Clinical features

  • Joint pain (usually in the hips and knees). Onset of pain is variable, but usually occurs in late childhood. Some individuals have no pain.
  • Deformity of hands, feet, and knees
  • Scoliosis

Radiographic findings. Skeletal radiographs establish the diagnosis in clinically suspected individuals (see Figure 1). Typical findings include the following:

Figure 1

Figure

Figure 1. Double patella

Ballhausen et al [2003]; reprinted with permission from the BMJ Publishing Group

  • Flat epiphyses with early arthritis (degenerative and painful changes in the articular cartilage of the hip joint)
  • Mild brachydactyly
  • Double-layered patella (i.e., presence of a separate anterior and posterior ossification layer) observed in approximately 60% of individuals on lateral knee radiographs. This finding appears to be age-related and may disappear in adults (Figure 1).

Molecular Genetic Testing

Gene. SLC26A2 (DTDST) is the only gene in which mutations are known to cause with EDM4/rMED.

Clinical testing.

Table 1. Summary of Molecular Genetic Testing Used in Multiple Epiphyseal Dysplasia, Recessive

Gene 1 Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
SLC26A2Targeted mutation analysisPanel of selected mutations 4 See footnote 5
Sequence analysis Sequence variants 6>90% 7
Deletion/ duplication analysis 8(Multi)exonic and whole-gene deletion/ duplicationUnknown, none reported

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. % of disease alleles detected in individuals with typical clinical, radiologic, and histologic features of ACG1B

4. Mutation panel may vary by laboratory.

5. Dependent on mutation panel and population tested. The four most common SLC26A2 mutations (p.Arg279Trp, c.-26+2T>C, p.Arg178Ter, and p.Cys653Ser) account for approximately 70% of disease alleles in all SLC26A2-related dysplasias, but only 10% of disease alleles in ACG1B.

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. 90% of alleles in individuals with radiologic and histologic features compatible with the diagnosis of sulfate transporter-related dysplasias [Rossi & Superti-Furga 2001].

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband. Clinical and radiologic features may strongly suggest the diagnosis of EDM4/rMED in a proband.

The presence of a double-layered patella at lateral x-ray of the knee is a very specific, although not highly sensitive, sign of EDM4/rMED [Makitie et al 2003].

Targeted mutation analysis for the four most common SLC26A2 mutations is indicated in probands with clinical and radiologic features very suggestive for EDM4/rMED and/or with a clinical diagnosis of MED and no evidence of autosomal dominant inheritance. This test allows identification of at least one pathogenic allele in nearly 100% of EDM4/rMED cases (80% of individuals with EDM4/rMED carry two of the most common pathogenic mutations, and another 16% of cases carry one of the most common pathogenic mutations in compound heterozygosity with another pathogenic allele).

Sequence analysis of SLC26A2 is indicated in probands with only one heterozygous SLC26A2 mutation and in probands who tested negative with targeted mutation analysis and have very specific signs of EDM4/rMED (double-layered patella and/or classic signs of sulfate transporter-related dysplasia, like clubfoot, cleft palate, and cystic swelling of the ears).

Sequence analysis of SLC26A2 may be considered in simplex cases (i.e., a single occurrence in a family) with no specific signs for a distinct autosomal dominant MED type before testing other known MED-related genes, as recessive mutations in SLC26A2 are found more frequently in simplex cases than dominant mutations in other MED-related genes [Jakkula et al 2005].

Single gene testing. One strategy for molecular diagnosis of a proband suspected of having EDM4/rMED is sequence analysis of only SLC26A2.

Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having EDM4/rMED is use of a multi-gene panel. See Differential Diagnosis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

In retrospect, approximately 50% of individuals with recessive multiple epiphyseal dysplasia (EDM4/rMED) have an abnormal finding at birth, such as clubfoot (frequently), clinodactyly, or cleft palate. However, only half of those with findings at birth are suspected of having a skeletal dysplasia.

The majority of affected individuals are diagnosed with a skeletal disorder in childhood, but some are not diagnosed until adulthood. Reasons for seeking medical assistance are mainly chronic joint pain (hips, knees, wrists, and fingers), waddling gait, hand/foot deformities (mild brachydactyly, clinodactyly, clubfoot, broadening of the space between the first and second toes), and mild scoliosis.

There is no specific timing of joint involvement or specific location of joint pain at different ages. Adolescents are usually symptomatic in multiple joints and joint pain increases after physical exercise. Brachydactyly is evident after puberty in most cases.

Habitus is unremarkable in most affected individuals, except for genu valgum in some.

Facies and body proportions are usually normal. Bowing of the extremities is not observed.

Functional disability is mild or absent [Ballhausen et al 2003] in childhood and adolescence; joint involvement progresses slightly in young adults, but hip and knee surgery is usually not needed.

Stature is usually within the normal range prior to puberty and downward crossing of the growth curve does not occur. In adulthood, stature is only slightly diminished, with the median height shifting from the 50th to the tenth centile; range of adult height is 150-180 cm. Approximately one third of affected adults have stature below 2 SD for age.

Genotype-Phenotype Correlations

Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in a spectrum that goes from lethal achondrogenesis 1B (ACG1B) to mild EDM4/rMED.

  • Homozygosity or compound heterozygosity for mutations predicting stop codons or structural mutations in transmembrane domains of the sulfate transporter are associated with ACG1B.
  • Mutations located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene result in less severe phenotypes [Superti-Furga et al 1996a, Karniski 2001, Rossi & Superti-Furga 2001, Karniski 2004].

Mutation p.Arg279Trp, the most common SLC26A2 mutation outside Finland (45% of alleles) is a mild mutation resulting in the EDM4/rMED phenotype when homozygous and mostly in the diastrophic dysplasia (DTD) phenotype when compounded.

Mutation p.Arg178Ter is the second-most common mutation (9% of alleles) and is associated with a more severe DTD phenotype or even the perinatal-lethal AO2 phenotype, particularly when combined in trans with the p.Arg279Trp mutation. It has also been found in some cases of more severe rMED and of ACG1B, making it one of two mutations identified in all four SLC26A2-related dysplasias.

Mutations p.Cys653Ser and c.-26+2T>C are the third most common mutations (8% of alleles for each).

c.-26+2T>C is sometimes referred to as the "Finnish" mutation because it is much more frequent in Finland than in the remainder of the world population. It produces low levels of correctly spliced mRNA and results in DTD when homozygous and in rMED when compounded with another mild mutation (p.Arg279Trp, p.Cys653Ser).

Together with p.Arg178Ter, c.-26+2T>C is the only mutation that has been identified in all four SLC26A2-related dysplasias, in compound heterozygosity with mild (rMED and DTD) or severe (AO2 and ACG1B) alleles [Dwyer et al 2010; Bonafé, unpublished results].

Mutation p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other mutations.

The same mutations associated in some individuals with the ACG1B phenotype can be found in individuals with a milder phenotype (AO2 and DTD) if the second allele is a relatively mild mutation. Indeed, missense mutations located outside the transmembrane domain of the sulfate transporter are often associated with a residual activity that can "rescue" the effect of the null allele [Rossi & Superti-Furga 2001].

Nomenclature

Multiple epiphyseal dysplasia is a disorder with clinical and genetic heterogeneity. In the past, the disorder was clinically subdivided into the milder Ribbing type, with flattened epiphysis and normal or near-normal stature; the more severe Fairbank type, with round, small epiphyses and short stature; and the unclassified types [International Working Group on Constitutional Diseases of Bone 1998].

The genetic dissection of this heterogeneous group of conditions in recent years has provided a molecular-pathogenic classification of the different subtypes according to the gene involved:

  • EDM4/rMED is classified in the "sulfation disorders group" in the revised Nosology and Classification of Genetic Skeletal Disorders of Bone [Warman et al 2011]. It accounts for about 25% of cases of MED.
  • The other autosomal dominant subtypes of MED are classified in the "multiple epiphyseal dysplasia and pseudoachondroplasia group" in the revised Nosology. The most frequent form of MED is caused by dominant mutations in COMP (~50% of cases). The remaining 20%-25% of cases are split between MATN3, COL9A1, COL9A2, and COL9A3.
  • Some cases of MED are not caused by mutations in a known gene [Zankl et al 2007, Unger et al 2008] and remain unclassified.

Prevalence

Exact data about the prevalence of MED and its subtypes are not available. Based on the number of cases seen in growth clinics, rheumatology clinics, or genetics clinics, and compared to conditions whose incidences are more precisely known (e.g., achondroplasia, osteogenesis imperfecta), it seems reasonable to estimate an overall prevalence of 1:20,000 [Unger et al 2008]. This prevalence is most probably an underestimation as several simplex cases (i.e., a single occurrence in a family) may remain undiagnosed. EDM4/rMED is indeed one of the most frequent forms, accounting for almost 25% of all cases of MED [Jackson et al 2012].

Differential Diagnosis

See Epiphyseal Dysplasia, Multiple: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Recessive multiple epiphyseal dysplasia (EDM4/rMED) needs to be distinguished from other multiple epiphyseal dysplasia (MED) types [Unger & Hecht 2001, Ballhausen et al 2003]. Clinical and radiographic differences between the genetically distinct forms of these skeletal dysplasias may allow clinicians to distinguish between them. In contrast to other MED types, prepubertal children with EDM4/rMED usually do not show short stature.

Autosomal dominant forms of MED and their associated proteins and genes:

  • Cartilage oligomeric matrix protein, a glycoprotein of the cartilage extracellular matrix that belongs to the family of extracellular calcium-binding proteins. Mutations in COMP occur in different autosomal dominant forms of MED (EDM1, OMIM 132400) as well as in the more severe disorder, pseudoachondroplasia. Individuals with MED and COMP mutations usually have significant involvement at the capital femoral epiphyses and irregular acetabuli [Unger et al 2001].
  • Type IX collagen, a structural component of the extracellular matrix, is a heterotrimer composed of three different chains (alpha-1, alpha-2, and alpha-3) encoded by COL9A1, COL9A2, and COL9A3. Mutations in individuals with MED have been identified in COL9A2 (EDM2) [Muragaki et al 1996, Holden et al 1999], COL9A3 (EDM3) [Paassilta et al 1999], and COL9A1 [Czarny-Ratajczak et al 2001]. These forms of MED appear to have more severe knee involvement but relative sparing of the hip, resulting in a milder course than the MED associated with COMP or SLC26A2 mutations [Unger et al 2001].
  • Matrilin 3 (EDM5), an oligomeric protein in the cartilage extracellular matrix. Different missense mutations in MATN3 were identified in two unrelated families with autosomal dominant MED [Chapman et al 2001]. While it appears to be the mildest form of MED identified to date; EDM5 is associated with a high degree of intrafamilial variability [Makitie et al 2004, Zankl et al 2007, Unger et al 2008].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with recessive multiple epiphyseal dysplasia (EDM4/rMED), the following evaluations are recommended:

  • Height measurement
  • Radiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral)
  • Medical genetics consultation

Treatment of Manifestations

Symptomatic individuals should be seen by a physical therapist and an orthopedist in order to assess the possibility of treatment (physiotherapy for muscular strengthening and maintaining mobility, cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs [NSAIDs]) and the optimal time for surgery (joint replacement), if indicated.

Career counseling is recommended.

Prevention of Secondary Complications

Intensive physiotherapy may help in delaying joint contractures and in maintaining mobility.

Surveillance

Radiographic surveillance by an orthopedist is appropriate.

Agents/Circumstances to Avoid

Sports involving joint overload are to be avoided.

Evaluation of Relatives at Risk

Presymptomatic testing of at-risk relatives is not indicated because no preventive measures or therapeutic interventions to reduce morbidity are available

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women affected by EDM4/rMED may suffer from chronic joint pain which may be increased during pregnancy due to maternal weight gain. Appropriate pain management should be offered and physical therapy should be intensified.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Recessive multiple epiphyseal dysplasia (EDM4/rMED) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation in SLC26A2. Note: Parental testing is always recommended when mutations are identified in a proband, in order to confirm the segregation of mutations in the family and confirm the carrier status of both parents. Results should always be discussed with the family in the context of a genetic counseling consultation.
  • Heterozygous carriers are asymptomatic and have normal stature.
  • No evidence that carriers are at increased risk of developing degenerative joint disease has been presented.
  • To date, de novo mutations in a proband and germline mosaicism in the parents have not been reported.

Sibs of a proband

  • At conception, each sib of a proband with EDM4/rMED has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband. The offspring of an individual with EDM4/rMED are obligate heterozygotes (carriers) for a disease-causing mutation in SLC26A2.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the family.

Carrier detection in reproductive partners of heterozygous individuals is available on a clinical basis. The partners can be screened for the four most common pathogenic alleles: p.Arg279Trp, p.Arg178Ter, c.-26+2T>C, and p.Cys653Ser. The risk of carrying a SLC26A2 mutation is reduced from the general population risk of 1:100 to approximately 1:400 when these four alleles are excluded. If a reproductive partner of a carrier also has an SLC26A2 mutation, information about genotype-phenotype correlations should be provided to the couple.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Biochemical testing. No data exist on prenatal functional biochemical testing (sulfate incorporation test on chorionic villus or fibroblasts).

Requests for prenatal testing for conditions which (like EDM4/rMED) are mild and do not affect intellect are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Multiple Epiphyseal Dysplasia, Recessive: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SLC26A25q32Sulfate transporterFinnish Disease Database (SLC26A2)SLC26A2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Multiple Epiphyseal Dysplasia, Recessive (View All in OMIM)

226900EPIPHYSEAL DYSPLASIA, MULTIPLE, 4; EDM4
606718SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 2; SLC26A2

Molecular Genetic Pathogenesis

Mutations in SLC26A2 (DTDST) are responsible for the family of chondrodysplasias including EDM4/rMED, DTD, ACG1B, and AO2 [Hastbacka et al 1996, Superti-Furga et al 1996a, Superti-Furga et al 1999]. Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans that are not sulfated or are insufficiently sulfated [Superti-Furga 1994, Rossi et al 1997, Rossi et al 1998, Satoh et al 1998], most probably because of intracellular sulfate depletion [Rossi et al 1996]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impairment of proteoglycan deposition, which is necessary for proper enchondral bone formation [Corsi et al 2001]. A correlation exists between the mutation, the predicted residual activity of the sulfate transporter, and the predicted severity of the phenotype [Cai et al 1998, Rossi & Superti-Furga 2001, Karniski 2004].

Gene structure. The coding sequence of SLC26A2 is organized in two coding exons separated by an intron of approximately 1.8 kb [Hastbacka et al 1994]. A further untranslated exon is located 5' relative to the two coding exons; it probably has regulatory functions, [Hastbacka et al 1999]. SLC26A2 is expressed in developing cartilage in human fetuses but also in a wide variety of other tissues [Haila et al 2001]. The size of the predominant mRNA species is greater than 8 kb, indicating the existence of significant untranslated sequences [Hastbacka et al 1994, Hastbacka et al 1999]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. The p.Thr689Ser allele has been frequently observed in the heterozygous or homozygous state in several controls of different ethnicity and is thus a common benign variant [Cai et al 1998, Rossi & Superti-Furga 2001].

There is evidence that p.Arg492Trp is a rare benign variant found in seven out of 200 Finnish control individuals and in five out of 150 non-Finnish individuals [Bonafé et al 2008]. This allele may have been erroneously considered pathogenic in previous reports [Rossi & Superti-Furga 2001].

Pathogenic allelic variants. Four pathogenic alleles of SLC26A2 appear to be recurrent: p.Arg279Trp, p.Arg178Ter, c.-26+2T>C, and p.Cys653Ser. Together they represent approximately 70% of the pathogenic variants in SLC26A2.

Most mutations associated with EDM4/rMED are amino acid substitutions outside transmembrane domains of the sulfate transporter. The p.Arg279Trp mutation is the most common mutation in persons of northern European origin. When homozygous, it results in an EDM4/rMED phenotype; when heterozygous, the phenotype depends on the severity of the mutation of the second allele (f compounded with a mild mutation it results in EDM4/rMED, while if compounded with a truncated allele or an amino acid substitution in a transmembrane domain, it results in DTD). Apart from homozygosity for p.[Arg279Trp]+[Arg279Trp] (55% of all EDM4/rMED cases) or for p.[Cys653Ser]+[Cys653Ser] (10%), compound heterozygosity for c.[835C>T] + [-26+2T>C] (10%) and c.[1957T>A ] +[-26+2T>C] (5%) are also common in EDM4/rMED. Other compound heterozygous mutation combinations are also found in EDM4/rMED, most of which include one of the four most common SLC26A2 mutations (less than 5% of all EDM4/rMED cases do not have at least one of the four common SLC26A2 mutations). There are a few other recurrent mutations in individuals with EDM4/rMED, including p.Phe256Ser and p.Phe595Leu (neither of which is found in other SLC26A2-related dysplasias).

Distinct phenotypes known to be allelic to EDM4/rMED are diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and achondrogenesis 1B (ACG1B).

Table 2. SLC26A2 Variants Discussed in This GeneReview

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Benignc.1474C>Tp.Arg492TrpNM_000112​.3
NP_000103​.2
c.2065A>Tp.Thr689Ser
Pathogenicc.-26+2T>C
(IVS1+2T>C)
--
c.532C>Tp.Arg178Ter
c.767T>Cp.Phe256Ser
c.835C>Tp.Arg279Trp
c.1783T>Cp.Phe595Leu
c.1957T>Ap.Cys653Ser

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. SLC26A2 encodes a sulfate transporter protein of 739 amino acids that is predicted to have 12 transmembrane domains and a carboxy-terminal, cytoplasmic, moderately hydrophobic domain [Hastbacka et al 1994]. This protein transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. The sulfate transporter protein belongs to the family of sulfate permeases. The overall structure with 12 membrane-spanning domains is shared with two other human anion exchangers: PDS (OMIM 274600), a chloride-iodide transporter involved in Pendred syndrome, and CLD, which is responsible for congenital chloride diarrhea. The function of the carboxy-terminal hydrophobic domain of the sulfate transporter is not yet known.

Abnormal gene product. Most of the SLC26A2 mutations either predict a truncated polypeptide chain or affect amino acids that are located in transmembrane domains or are conserved in man, mouse, and rat. Individuals homozygous for the "Finnish" mutation c.-26+2T>C have reduced levels of mRNA with intact coding sequence. Thus, the mutation presumably interferes with splicing and/or further mRNA processing and transport [Hastbacka et al 1996, Hastbacka et al 1999].

The p.Arg178Ter mutation was shown to abolish sulfate transporter activity in a Xenopus oocyte model [Karniski 2001].

References

Literature Cited

  1. Ballhausen D, Bonafe L, Terhal P, Unger SL, Bellus G, Classen M, Hamel BC, Spranger J, Zabel B, Cohn DH, Cole WG, Hecht JT, Superti-Furga A. Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W. J Med Genet. 2003;40:65–71. [PMC free article: PMC1735262] [PubMed: 12525546]
  2. Bonafé L, Hästbacka J, de la Chapelle A, Campos-Xavier AB, Chiesa C, Forlino A, Superti-Furga A, Rossi A. A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia. J Med Genet. 2008;45:827–31. [PubMed: 18708426]
  3. Cai G, Nakayama M, Hiraki Y, Ozono K. Mutational analysis of the DTDST gene in a fetus with achondrogenesis type 1B. Am J Med Genet. 1998;78:58–60. [PubMed: 9637425]
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  5. Corsi A, Riminucci M, Fisher LW, Bianco P. Achondrogenesis type IB: agenesis of cartilage interterritorial matrix as the link between gene defect and pathological skeletal phenotype. Arch Pathol Lab Med. 2001;125:1375–8. [PubMed: 11570921]
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Chapter Notes

Revision History

  • 23 January 2014 (me) Comprehensive update posted live
  • 18 March 2010 (me) Comprehensive update posted live
  • 27 December 2006 (me) Comprehensive update posted to live Web site
  • 20 July 2004 (me) Comprehensive update posted to live Web site
  • 29 August 2002 (me) Review posted to live Web site
  • 25 February 2002 (db) Original submission
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