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

Figure 1. Double patella
Reprinted with permission from the BMJ Publishing Group: Ballhausen et al [2003].

• 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 currently known to be associated with EDM4/rMED.

Clinical testing. In a series of 72 individuals with clinical and radiologic features compatible with recessive multiple epiphyseal dysplasia and no evidence of autosomal dominant inheritance, mutations in SLC26A2 were identified in approximately 70%.

The radiologic sign of double-layered patella in lateral knee radiograph is specific for rMED; mutations in SLC26A2 were found in all individuals with this sign [Superti-Furga et al 1999, Ballhausen et al 2003, Makitie et al 2003]:

• Targeted mutation analysis. Using a panel of the three most common SLC26A2 mutations associated with rMED, p.Arg279Trp, c.-26+2T>C ("Finnish"), and p.Cys653Ser [Ballhausen et al 2003], findings in individuals with EDM4/rMED included:

  • Homozygosity for the mutation p.Arg279Trp (60% of individuals)

  • Homozygosity for the mutation p.Cys653Ser (10% of individuals)

  • Heterozygosity for one of the three most common mutations (30% of individuals)

• Sequence analysis may detect rare "private" mutations in individuals in whom targeted mutation analysis detects none or only one of the common alleles.

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency	Test Availability
SLC26A2	Targeted mutation analysis	Panel of three common mutations 1	~90% 2	Clinical
	Sequence analysis	Private and common mutations	~100%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. p.Arg279Trp, c.-26+2T>C, p.Cys653Ser

2. Detects both mutant alleles in 90% of cases

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

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 of SLC26A2 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 cases and of both pathogenic mutations in approximately 90% of EDM4/rMED cases.

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-causing genes, as recessive mutations in SLC26A2 are found more frequently in simplex cases than dominant mutations in other MED-causing genes [Jakkula et al 2005].

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.

Genetically Related (Allelic) Disorders

Three other skeletal dysplasias (all with an autosomal recessive mode of inheritance) are associated with mutations in SLC26A2:

• Achondrogenesis Type 1B (ACG1B) is among the most severe skeletal disorders in humans. It is characterized by severe hypodysplasia of the spine, rib cage, and extremities, with a relatively preserved cranium. ACG1B is invariably lethal in the perinatal period [Superti-Furga et al 1996b].

• Atelosteogenesis 2 (AO2) is a neonatal-lethal chondrodysplasia with clinical and histologic characteristics that resemble those of diastrophic dysplasia [Hastbacka et al 1996].

• Diastrophic dysplasia (DTD) is characterized by short stature, joint contractures, cleft palate, and characteristic clinical signs such as the "hitchhiker" thumb and cystic swelling of external ears.

Natural History

In retrospect, approximately 50% of individuals with recessive multiple epiphyseal dysplasia (EDM4/rMED) have some 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].

The most frequent SLC26A2 mutation found outside Finland, p.Arg279Trp, is a mild mutation resulting in the EDM4/rMED phenotype when homozygous and mostly in the diastrophic dysplasia (DTD) phenotype when compounded.

Mutation p.Cys653Ser is the second most common mutation found in EDM4/rMED, with a frequency among SLC26A2 pathogenic alleles slightly higher than that of the c.-26+2T>C mutation in non-Finnish populations. It results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other mutations.

Mutation c.-26+2T>C is the third most common mutation, very frequent in Finland ("Finnish" mutation). 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).

Mutation p.Arg178X, the fourth most common mutation in the SLC26A2 gene, is associated with the severe phenotypes ACG1B and atelosteogenesis 2 (AO2).

The same mutations associated in some individuals who have 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 Disorders of Bone [Superti-Furga & Unger 2007]. 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 the COMP gene (~50% of cases). The remaining 20%-25% of cases are split between the genes 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 such as achondroplasia or osteogenesis imperfecta, it seems reasonable to estimate an overall prevalence of approximately 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 about 25% of all cases of MED.

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)

Treatment of Manifestations

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

Surveillance

Radiographic surveillance by an orthopedist is appropriate.

Agents/Circumstances to Avoid

Sports involving joint overload are to be avoided.

Testing 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.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 the SLC26A2 gene.

• Heterozygous carriers are asymptomatic and have normal stature.

• No evidence that carriers are at increased risk of developing degenerative joint disease has been presented.

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.

• To date, de novo mutations in the proband and germline mosaicism in the parents have not been reported.

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

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.Arg178X, 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 is also found to have 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. Both disease-causing alleles of an affected family member must be identified and carrier status confirmed in the parents before prenatal molecular genetic testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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

Requests for prenatal testing for mild conditions that (like EDM4/rMED) 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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Mutations in the SLC26A2 (DTDST) gene 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 only 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].

Normal allelic variants. The coding sequence of the SLC26A2 gene is organized in two exons separated by an intron of approximately 1.8 kb, it encodes a 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]. 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]. 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 polymorphism [Cai et al 1998, Rossi & Superti-Furga 2001].

There is evidence that p.Arg492Trp is a rare normal 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 was erroneously considered pathologic in previous reports [Rossi et al 2001].

Pathologic allelic variants. Four pathologic alleles of the SLC26A2 gene appear to be recurrent: p.Arg279Trp, p.Arg178X , c.-26+2T>C, and p.Cys653Ser. Together they represent approximately three-quarters of the pathologic mutations 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 the Caucasian population. When homozygous, it results in an EDM4/rMED phenotype; when heterozygous, the phenotype depends on the severity of the mutation of the second allele. If compounded with a truncated allele or an amino acid substitution in a transmembrane domain, it results in DTD. Apart from homozygous p.[Arg279Trp]+[Arg279Trp] or p.[Cys653Ser]+[Cys653Ser], compound heterozygosity for the following have been found in EDM4/rMED.

• c.[835C>T]+[-26+2T>C]

• p.[Arg279Trp]+[Gly237Val]

• p.[Arg279Trp]+[Gly259Val]

• p.[Arg279Trp]+[Asn77His]

• c.[ c.195T>A]+[-26+2T>C]

• p.[G678V]+[Arg279Trp]

• p.[Gly282Cys]+[Arg279Trp]

• p.[Ala715Val]+[Cys653Ser]

• p.[Gly259Val]+[Arg279Trp]

• p.[Gly393Asp]+[Arg279Trp]

• c.[767T>C]+[-26+2T>C]

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

Normal gene product. The diastrophic dysplasia sulfate transporter gene SLC26A2 encodes a transmembrane protein that 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.Arg278X mutation was shown to abolish sulfate transporter activity in a Xenopus oocyte model [Karniski 2001].

Literature Cited

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Revision History

• 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