Multiple epiphyseal dysplasia is a type of short-limbed dwarfism characterized by impaired enchondral ossification affecting multiple epiphyses and premature degenerative joint disease.
GENETICS/BASIC DEFECTS
1. Inheritance: genetically heterogeneous a. Autosomal dominant
i. Multiple epiphyseal dysplasia type I (EDM1) ii. Multiple epiphyseal dysplasia type II (EDM2) iii. Multiple epiphyseal dysplasia type III (EDM3)
iv. Multiple epiphyseal dysplasia type V (EDM5) v. Multiple epiphyseal dysplasia type VI (EDM6) b. Autosomal recessive: multiple epiphyseal dysplasia
type IV (EDM4) 2. Causes:
a. EDM1: mutations in the gene (COMP) encoding car- tilage oligomeric matrix protein (COMP) on the cen- tromeric region of 19p (19p13.1-p12), same locus as (allelic to) pseudoachondroplasia (the disease that shares some clinical features with multiple epiphyseal dysplasia)
b. EDM2: mutations in the type IX collagen, alpha-1 polypeptide gene (COL9A1) on 6q13
c. EDM3: mutations in the type IX collagen, alpha-2 polypeptide gene (COL9A2) on 1p33-p32.3
d. EDM4: mutations in the diastrophic dysplasia sul- phate transporter gene (DTDST) on 5q32-q33.1 e. EDM5: mutations in the gene (MATN3) encoding
matrilin-3 on 2p24-p23
f. EDM6: mutations in the type IX collagen, alpha-3 polypeptide gene (COL9A3) on 20q13.3
3. Mutations in extracellular matrix proteins, COMP, types II and IX collagens, and matrilin-3
a. Produce a spectrum of mild to severe chondrodys- plasias characterized by epiphyseal and vertebral abnormalities
b. Disrupt protein processing and excessive accumula- tion of some of these proteins in the rER that appears to compromise cellular function
4. Genotype–phenotype correlations a. Patients with COMP mutations
i. Significant involvement at the capital femoral epiphyses
ii. Irregular acetabuli
b. Patients with type IX collagen defects i. More severe involvement of the knees ii. Relative sparing of the hips
c. Patients with MATN3 mutations
i. Abnormalities similar to those in patients with COL9A2 mutations: more severe hip abnormalities ii. More intra/interfamilial variability
CLINICAL FEATURES
1. Broad historical classification
a. Ribbing: milder form with flat epiphyses and minimal involvement of the hands and feet
b. Fairbank: more severe form with late appearing epi- physes and greater involvement of the hands and feet 2. Onset: usually in childhood
a. Waddling gait b. Easy fatigue
c. Joint pain after exercise
d. Limp, pain, and stiffness in hip, knee, and ankle joints 3. Mild to moderate short stature with normal body proportion 4. Mild short-limb dwarfism
5. Stubby hands and feet
6. Osteoarthritis: severe osteoarthritis of the hip develops in early childhood
7. Limited joint motions 8. Hip pain
9. Proximal muscle weakness with mild variability in mus- cle fiber size in EDM3
10. Association with diabetes mellitus in early infancy (Wolcott-Rallison syndrome)
11. Prognosis
a. Normal life expectancy
b. Joint deformities resulting from abnormal epiphyseal ossification frequently leading to early degenerative arthroses
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Radiographic abnormalities may be present before the onset of physical symptoms
b. Predominantly epiphyseal involvement
i. Initial stage: delayed appearance of epiphyseal ossification
ii. Later stage in the appearance of epiphysis a) Usually small ossification centers
b) Sometimes fragmented ossification centers with irregular contours
c) Adjacent metaphyseal borders may be slightly abnormal
iii. Adulthood
a) Flattened and dysplastic articular surfaces b) Presence of early features of osteoarthrosis iv. Characteristic epiphyseal involvement
a) Epiphyses of the hips and knees: most affected b) Ivory epiphyses in the hands
c) Schmorl nodes in the spine d) Double-layered patella c. Vertebrae
i. Ovoid vertebral bodies
ii. Mildly irregular vertebral endplates 697
d. Limbs
i. Late ossifying epiphyses
ii. Small, irregular, fragmented, and in some cases flattened epiphyses
iii. Osteoarthritis iv. Short femoral neck
v. Markedly dysplastic capital femoral epiphyses vi. Often initially diagnosed as Legg-Perthes dis-
ease (avascular necrosis of femoral head) vii. Genu varum or valgum
viii. Short metacarpals and phalanges with irregular epiphyses
ix. Small, irregular carpal and tarsal bones x. Normal metaphyses
e. Irregular acetabuli f. Patella
i. Doubled-layered
ii. Dislocation or subluxation
g. Absence of severe spinal involvement and minimal metaphyseal defects allows differentiating multiple epiphyseal dysplasia from other disorders with simi- lar clinical features such as spondyloepimetaphyseal dysplasia and spondyloepiphyseal dysplasia
2. Histology: chondrocytic inclusion (ultrastructurally, a dilated rER containing accumulated material)
3. Mutation analyses: available on clinical basis a. Mutations in the COMP gene
b. Mutations in the COL9A1 gene c. Mutations in the COL9A2 gene d. Mutations in the COL9A3 gene e. Mutations in the MATN3 gene
f. Mutations in the DTDST gene
GENETIC COUNSELING
1. Recurrence risk
a. Autosomal dominant inheritance i. Patient’s sib
a) 50% if one of the parent is affected b) Not increased if parents are normal ii. Patient’s offspring: 50%
b. Autosomal recessive inheritance i. Patient’s sib: 25%
ii. Patient’s offspring: not increased unless the spouse is also carrying the gene
2. Prenatal diagnosis for pregnancies at risk for COMP and other mutations is possible if the disease-causing allele of an affected family member has been identified
a. Amniocentesis b. CVS
3. Management
a. Initial aims of management i. Control pain
a) Can be difficult
b) Combination of analgesics and physiotherapy including hydrotherapy
ii. Limit joint destruction and the development of osteoarthritis
b. Weight control
c. Avoid exercise that causes repetitive strain on affect- ed joints
d. Realignment osteotomy and/or acetabular osteotomy to slow the progression of symptoms
e. Total joint arthroplasty in some cases
f. Psychosocial support to address issues of short stature, disability, and employment
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Fig. 1. A boy with multiple epiphyseal dysplasia showing short stature and epiphyseal dysplasia in the wrists, hips, and knee joints.
Fig. 2. A girl and an adult female with multiple epiphyseal dysplasia showing mild short stature with normal body proportion.
Fig. 3. Radiograph of the pelvis of a 12-year-old boy with multiple epiphyseal dysplasia showing poorly developed acetabular fossae and flat, fragmented femoral heads.
Fig. 4. Radiographs of another patient with multiple epiphyseal dys- plasia showing poorly formed acetabular fossae, poorly ossified femoral heads, and flattened epiphyses of the knees and ankles.
