Multiple Epiphyseal Dysplasia, Recessive

Clinical 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 pathogenic variants 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 pathogenic 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.

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.

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 pathogenic variants are known to cause with EDM4/rMED.

Clinical testing.

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 [Mäkitie et al 2003].

Targeted analysis for the four most common SLC26A2 pathogenic variants 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 variants, and another 16% of cases carry one of the most common pathogenic variants in compound heterozygosity with another pathogenic allele).

Sequence analysis of SLC26A2 is indicated in probands with only one heterozygous SLC26A2 pathogenic variant and in probands who tested negative with targeted analysis for pathogenic variants 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 pathogenic variants in SLC26A2 are found more frequently in simplex cases than dominant pathogenic variants 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.

Multigene panel. Another strategy for molecular diagnosis of a proband suspected of having EDM4/rMED is use of a multigene panel (see Differential Diagnosis). For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants 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 pathogenic variants in the family.

Clinical Description

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 pathogenic variants predicting stop codons or structural pathogenic variants in transmembrane domains of the sulfate transporter are associated with ACG1B.
• Pathogenic variants 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].

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

Variant p.Arg178Ter is the second-most common pathogenic variant (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 pathogenic variant. It has also been found in some cases of more severe rMED and of ACG1B, making it one of two pathogenic variants identified in all four SLC26A2-related dysplasias.

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

c.-26+2T>C is sometimes referred to as the "Finnish" pathogenic variant 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 pathogenic variant (p.Arg279Trp, p.Cys653Ser).

Together with p.Arg178Ter, c.-26+2T>C is the only pathogenic variant 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].

Pathogenic variant p.Cys653Ser results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other pathogenic variants.

The same pathogenic variants 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 pathogenic variant. Indeed, missense variants 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 pathogenic variants 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 pathogenic variants 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].

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)
• Consultation with a clinical geneticist and/or genetic counselor

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 in the US and www.ClinicalTrialsRegister.eu in Europe 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.