DiagnosisClinical DiagnosisThe 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 featuresJoint 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 kneesScoliosisRadiographic findings. Skeletal radiographs establish the diagnosis in clinically suspected individuals (see Figure 1). Typical findings include the following:FigureFigure 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 brachydactylyDouble-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 TestingGene. 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, RecessiveView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency Test AvailabilitySLC26A2 Targeted mutation analysisPanel of three common mutations ^{1~90% 2ClinicalSequence analysisPrivate and common mutations~100%1. p.Arg279Trp, c.-26+2T>C, p.Cys653Ser2. Detects both mutant alleles in 90% of casesInterpretation 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) DisordersThree 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 HistoryIn 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 CorrelationsGenotype-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.Arg178*, the fourth most common mutation in SLC26A2, 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].

Differential DiagnosisRecessive 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 the genes 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]. This appears to be the mildest form of MED identified to date; however, this form of MED is associated with a high degree of intrafamilial variability [Makitie et al 2004, Zankl et al 2007, Unger et al 2008].

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with recessive multiple epiphyseal dysplasia (EDM4/rMED), the following evaluations are recommended:Height measurementRadiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral)Treatment of ManifestationsSymptomatic 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.SurveillanceRadiographic surveillance by an orthopedist is appropriate.Agents/Circumstances to AvoidSports involving joint overload are to be avoided.Evaluation of Relatives at RiskPresymptomatic testing of at-risk relatives is not indicated because no preventive measures or therapeutic interventions to reduce morbidity are availableSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC26A25q32Sulfate transporterFinnish Disease DatabaseSLC26A2Data 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) View in own window 226900EPIPHYSEAL DYSPLASIA, MULTIPLE, 4; EDM4 606718SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 2; SLC26A2Molecular Genetic PathogenesisMutations 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 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 SLC26A2 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 & Superti-Furga 2001].Pathologic allelic variants. Four pathologic alleles of SLC26A2 appear to be recurrent: p.Arg279Trp, p.Arg178*, 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 persons of northern European heritage. 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.[195T>A]+[-26+2T>C] p.[Gly678Val]+[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).Table 2. Selected SLC26A2 Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference SequencesNormalc.1474C>Tp.Arg492TrpNM_000112​.3
NP_000103​.2c.2065A>Tp.Thr689SerPathologicc.-26+2T>C
(IVS1+2T>C)--c.229A>Cp.Asn77Hisc.532C>Tp.Arg178*c.710G>Tp.Gly237Valc.767T>Cp.Phe256Serc.776G>Tp.Gly259Valc.835C>Tp.Arg279Trpc.844G>Tp.Gly282Cysc.1018_1020del
(1045_1047delGTT)p.Val341delc.1178G>Ap.Gly393Aspc.195T>Ap.Cys653Serc.2033G>Tp.Gly678Valc.2144C>Tp.Ala715ValSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal 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.Arg278* mutation was shown to abolish sulfate transporter activity in a Xenopus oocyte model [Karniski 2001].