Best Practice & Research Clinical Rheumatology Vol. 22, No. 1, pp. 33–44, 2008 doi:10.1016/j.berh.2007.12.009 available online at http://www.sciencedirect.com
3 Spondylo-epi-metaphyseal dysplasia Vale´rie Cormier-Daire *
Professor of Genetics Department of Medical Genetics and INSERM U781, Universite´ Paris V, Hopital Necker Enfants Malades, Paris, France
The spondylo-epi-metaphyseal dysplasias (SEMD) are a heterogeneous group of disorders comprising more than 20 distinct entities with differing modes of inheritance, all defined by the combination of vertebral, epiphyseal and metaphyseal abnormalities. The presenting symptom of SEMD patients is usually disproportionate short stature. The diagnosis is either based on the specificity of the skeletal manifestations or on the presence of characteristic extraskeletal features which may appear during the course of the disease, highlighting the importance of follow-up of SEMD patients. The complications are variable but epiphyseal dysplasia is often a predominant feature, and the course of the disease is marked by premature osteoarthritis. A systematic survey of odontoid hypoplasia responsible for atlantoaxial instability with a risk of spinal cord is also required. Key words: heterogeneity; x rays; extraskeletal features; long-term follow-up; osteoarthritis; atlantoaxial instability.
GENERAL PRESENTATION OF THE SEMD GROUP The spondylo-epi-metaphyseal dysplasias (SEMD) are a heterogeneous group of disorders comprising more than 20 distinct entities with differing modes of inheritance, all defined by the combination of vertebral, epiphyseal and metaphyseal abnormalities. The metaphyseal involvement is variable, and several SEMD are mainly characterized by vertebral and epiphyseal involvement. The majority of these entities are rare, with less than 15 reported cases. Some of them have been described in a single family and are purely defined on clinical and radiological features, with the molecular basis still unknown.
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Clinical presentation The presenting symptom of SEMD patients is usually disproportionate short stature. The specific diagnosis is either based on the specificity of the skeletal manifestations or on the presence of characteristic extraskeletal features. These features are often a clue for the final diagnosis, but may appear in the course of the disease, highlighting the importance of follow-up of SEMD patients. Table 1 summarizes the discriminating clinical and skeletal features of the SEMD group. The complications are variable but epiphyseal dysplasia is often a predominant feature, and the course of the disease is marked by premature osteoarthritis. Radiological and biological investigations Apart from a complete skeletal survey (spine, hips, knees, hands) which often allows accurate diagnosis, the frequency of extraskeletal features illustrates the importance of a multi-organ survey and the necessity of careful follow-up. In addition, some of these disorders have a progressive course with the appearance, during the course of the disease, of some characteristic radiological features, e.g. in Morquio or DyggveMelchior-Clausen syndromes. Management Orthopaedic management is often required with particular attention to the spine, and a systematic survey of odontoid hypoplasia responsible for atlantoaxial instability with a risk of spinal compression is needed. Other complications include lumbar lordosis, scoliosis, thoracic kyphosis, subluxation of the hips, deformations of the knees and restricted joint motility. Epiphyseal dysplasias are often responsible for early osteoarthrosis. Depending on the specific diagnosis, management will include ophtalmological survey and immunological, renal, cardiac and endocrine follow-up. Molecular basis Several genes have been identified in the SEMD group (Table 1). It is difficult to define a common molecular pathway among all the SEMD group components. Indeed, these genes encode proteins involved in various functions, i.e. extracellular structural proteins (collagen type 2 (COL2A1), cartilage oligomeric matrix protein (COMP), matrillin 3 (MATN3), perlecan) and post-translational processing and transport (eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3), galactosamine6-sulphatase (GALNS) and beta-galactosidase (GLBI), 30 -phosphoadenosine 50 -phosphosulfate synthase (ATPSK2), dymeclin). The molecular basis of many of them are still unknown. THE MOST COMMON SEMDS Pseudoachondroplasia Pseudoachondroplasia is characterized by normal size at birth and normal growth curves until 2–4 years of age. Patients present with marked shortness of hands and feet, bowing
Table 1 SEMD type
Mode of inheritance
Pseudoachondroplasia Strudwick type Mucopolysaccharidosis IV, Morquio syndrome
Observed clinical features
Observed radiological features
AD AD AR
177170 184250 253000
19p13.1 12q13 16q24.3
COMP COL2A1 GALNS
Anterior tongue of vertebral bodies Flocculated dappled metaphyses Central beak protruding from the vertebral bodies, small and irregular carpal bones, pointed distal end of the middle and distal phalanges
Normal stature at birth Myopia, deafness Corneal clouding, cataract, sensorineural deafness, coarse facial features, valvular heart disease, excess keratane sulphate excretion Mental retardation
SEMD with joint laxity
Joint laxity, facial features, cleft or high palate Multiple dislocations
SEMD with multiple dislocations (Hall type)
156530/ 250600 258480
Facial features, þ/ mental retardation e
Missouri type17 Wolcott-Rallison syndrome18
Rhizomelic micromelia, large fontanelle, facial features e Diabetes, mental retardation
Lacy pelvis iliac crest, double vertebral humps Lacy pelvis iliac crest, double vertebral humps Biconvex vertebral bodies, delayed bone age Delayed epiphyseal ossification, irregular metaphyses with sclerotic striations, mild platyspondyly, abnormal hands Codfish vertebrae, metaphyseal striations Severe platyspondyly, dumbbellshaped bones Severe delay in skeletal maturation
e e (continued on next page)
Spondylo-epi-metaphyseal dysplasia 35
Mode of inheritance
Schimke (immunoosseous dysplasia)20
Pakistani type21 Omani type22 Dyssegmental dysplasia, Silverman-Handmaker type23
AR AR AR
603005 608637 224410
10q22 10q22.1 1p36.1
PAPSS2 CHST3 Perlecan
Dyssegmental dysplasia, Rolland-Desbuquois type24 Handigodu type25 Maroteaux type (pseudo Morquio type II)26 Irapa type (SEMDIT)27
Renal failure, hypothyroidism, T-cell immune deficiency, hyperpigmented macules Pakistani origin Oman origin Lethal, encephalocele or occipital defect, narrow chest Cleft palate
India origin e
Shohat type, also named Iraqi type28
Short limbehand type or short limbeabnormal calcification type29
Observed clinical features
SEMD, spondylo-epi-metaphyseal dysplasia; AD, autosomal dominant; AR, autosomal recessive.
Observed radiological features Wide metaphyses with lateral spurs, small and underossified ischia e
Delayed bone age Vertebral fusion in later stage Anisospondyly, small round dense ilia
Vertebrae clefting, dumbbell femurs e Champagne-glass configuration of pelvic inlet Capitate-hamate fusion, delayed bone age Delayed bone age, platyspondyly with central notches of vertebral end-plates Premature stippled calcification (epiphyses, trachea, bronchia, costochondral junctions), dumbbell-shaped bones
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Table 1 (continued)
Spondylo-epi-metaphyseal dysplasia 37
of long bones and hyperlordosis. Defective epiphyseal growth causes early osteoarthrosis, and metaphyseal lesions are responsible for limb deformations, often leading to surgery. Skeletal x rays reveal very small, fragmented and irregular epiphyses, anterior tonguing of vertebral bodies and metaphyseal abnormalities (Figure 1). Treatment is based on physiotherapy management of spinal deformation and orthopaedic surgery for limb deformation. The disorder has an autosomal-dominant mode of inheritance (estimated prevalence one in 30 000, often with new mutations). Mutations in the cartilage oligomeric matrix protein gene (COMP), located at 19p13.1, are responsible for this condition.1 Mutations in this gene have also been identified in Fairbanks type multiple epiphyseal dysplasia. COMP is a member of the thrombospondin gene family and is highly expressed in the extracellular matrix (ECM) of chondrocytes. Mutations observed in pseudoachondroplasia altered the type III calmodulin-like repeats, which possess a high affinity to bind collagen I, II and IX. This abnormality is responsible for accumulation of the abnormal COMP within the rough endoplasmic reticulum. Mucopolysaccharidosis IV Mucopolysaccharidosis IV, also named Morquio syndrome, is a lysosomal storage disease characterized by severe kyphoscoliosis, pectus carinatum, corneal opacifications, mild sensorineural deafness, mildly coarse facial features and (sometimes) valvular heart disease.2 In the classical form, bone x rays show spondyloepimetaphyseal dysplasia with a central beak protruding from the vertebral bodies, small and irregular carpal bones, and pointed distal ends of the middle and distal phalanges (Figure 2). The main complication is spinal cord compression by atlantoaxial dislocation, due to hypoplasia of the odontoid. The disorder has an autosomal-recessive mode of inheritance. Two genes are responsible for this condition: galactosamine-6-sulphatase (GALNS ), located at 16q24.3, responsible for Morquio type A3; and beta-galactosidase (GLBI ), located at 3p21.33, responsible for Morquio type B.4,5
Figure 1. Pseudoachondroplasia. Note the small epiphyses, the anterior tonguing of the vertebral bodies and the abnormal metaphyses.
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Figure 2. Morquio syndrome. Note the absence of femoral epiphyses, the abnormal metaphyses and the central beak protruding from the vertebral bodies.
Dyggve-Melchior-Clausen syndrome Dyggve-Melchior-Clausen syndrome (DMC) is a progressive autosomal-recessive SEMD associated with mental retardation.6 Clinical manifestations are short trunk dwarfism with a barrel-shaped chest, rhizomelic limb shortening, microcephaly, a coarse face and variable mental retardation. Radiological features include misaligned spine, markedly flattened vertebral bodies with a double-humped appearance, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small pelvis with lacy iliac crests (Figure 3). DMC is a progressive disorder and the first manifestations are usually recognized between 1 and 18 months of age. The double-humped appearance of the vertebral bodies and the very specific aspect of iliac crests become evident by 3–4 years of age. Orthopaedic complications include possible spinal cord compression due to atlantoaxial instability, lumbar lordosis, scoliosis, thoracic kyphosis, subluxation of the hips, deformations of the knees, and restricted joint mobility. Mental retardation is also a progressive feature and is quite variable in severity. DMC is allelic to Smith-McCort dysplasia which is distinct by the absence of mental retardation. Mutations in the dymeclin gene (DYM ), located at 18q21 and encoding a protein of unknown function, have been identified in both disorders.7,8 Strudwick type SEMD Strudwick type SEMD was identified initially as a variant form of SED congenita (SEDC). Both skeletal dysplasias are due to mutations in COL2A2, located at 12q13, and are inherited in an autosomal-dominant manner.9 Among the structural proteins, collagen type II is one of the most abundant, and mutations in COL2A2 have also been observed in a wide variety of chondrodysplasias, ranging from mild to perinatal lethal
Spondylo-epi-metaphyseal dysplasia 39
Figure 3. Dyggve-Melchior-Clausen syndrome. Note the double-humped appearance of the vertebral bodies, the lacy pelvis iliac crest, the metaphyseal irregularities and abnormal epiphyses.
disorders, i.e. Stickler syndrome, Kniest syndrome, SEDC, achondrogenesis type II and hypochondrogenesis. Myopia, deafness and cleft palate are certainly helpful for the diagnosis of Strudwick type SEMD. Mutations identified in Strudwick type SEMD are glycine substitutions leading to abnormal chains which are incorporated in the ECM, as observed in hypochondrogenesis and SEDC, but the precise correlation between clinical severity and the relative amount of abnormal type II procollagen, which is retained intracellularly rather than secreted and incorporated in the ECM, remains speculative. At birth, patients present with short limbs, short trunk and often with cleft palate. Myopia leading to retinal detachment may be observed in the course of the disease. Stature is significantly reduced and a waddling gait, genu valgum and lumbar lordosis develop. Hands and feet are normal. Orthopaedic complications include coxa vara, hip dislocation, kyphoscoliosis, cervical spine instability, genu valgum and premature osteoarthritis. Regular ophtalmological survey is needed to evaluate myopia and prevent retinal detachment. Skeletal x rays are characterized by generalized platyspondyly with mild posterior constriction and rounded anterior borders of vertebral bodies. There is marked delay in ossification of capital femoral epiphyses, and coxa vara deformity develops in early childhood. Flocculated dappled metaphyses, which defined Strudwick type as a distinct entity, are only present in the course of the disease after the age of 4 years. Hands and feet are spared. SEMD with joint laxity First described in South Africa, SEMD with joint laxity is characterized at birth by short stature, joint and ligamentous laxity with hip dislocation, and dislocation of the radial heads.10 Kyphoscoliosis is also present, as well as mobile talipes equinovarus. Other findings include hyperelastic soft skin, prominent eyes with blue sclerae, cleft palate and congenital cardiac anomalies.
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Skeletal x rays are characterized by severe kyphoscoliosis and platyspondyly with biconvex vertebral bodies. Epiphyseal ossification is delayed, and metaphyses are wide and irregular. Tubular bones of hands and feet are short. The inheritance is autosomal recessive and no gene has been identified to date. SEMD with multiple dislocations (Hall type) or leptodactylic type Clinical manifestations at birth include short stature, hypotonia, midface hypoplasia and (often) laryngeal stenosis.11 There is progressive joint laxity with hip dislocation, and genu valgum and mild scoliosis during childhood. Management is aimed at maintaining mobility and preventing dislocations. Skeletal x rays are characterized by generalized delay in epiphyseal ossification, hip and knee dislocations, irregular metaphyses with sclerotic striations (Figure 4), and mild platyspondyly with biconcave configuration of the vertebral bodies in the adulthood. Hand epiphyses are small and fragmented. Inheritance is autosomal dominant and no gene has been identified to date. The major differential diagnosis is sponastrime dysplasia which is transmitted in an autosomal-recessive manner (see Table 1). Metatropic dysplasia Metatropic dysplasia is a severe SEMD characterized at birth by a long trunk with short extremities and usually normal length.12 The chest is narrow and there is often a long tail-like appendage at the level of the coccyx. The proportions change during childhood with relative shortening of the trunk due to progressive kyphosis and relatively long extremities. Chest deformity and flexion contractures of major joints are associated findings. The adult height is up to 120 cm. Skeletal x rays at birth are characterized by marked playspondyly with flattening of all vertebral bodies, short tubular bones with broad concave metaphyses, and delayed ossification of epiphyses. The proximal end of the femur is club shaped. With time, the metaphyseal changes regress, but osteoarthritic changes develop as well as progressive kyphoscoliosis with decreasing flattening of vertebral bodies (Figure 5). Early management of kyphoscoliosis is needed (brace in hyperextension), and physiotherapy is required to prevent knee and hand arthropathy. Hypoplasia with C1/C2
Figure 4. Spondylo-epi-metaphyseal dysplasia with multiple dislocations. Note the abnormal epiphyses and the irregular metaphyses with sclerotic striations.
Spondylo-epi-metaphyseal dysplasia 41
Figure 5. Metatropic dysplasia. Note the club-shaped appearance of the proximal femoral end, the concave metaphyses and the flat vertebral bodies.
instability is a possible feature, and narrowing of the cervical and thoracic spinal canal may be present. Sensorineural hearing has been observed in a few cases. Autosomal-recessive and autosomal-dominant inheritance have been reported, with high variability in severity ranging from severe forms with early death due to neonatal respiratory infections to survivors.13 No gene has been identified to date. Opsismodysplasia Opsismodysplasia (opsismos in Greek means ‘late’) is characterized by micromelia, extremely short hands and feet, and respiratory distress often responsible for death in the first years of life.14 However, the outcome is quite variable and survivors present with short stature (<3 standard deviation (SD)) and severe orthopaedic complications dominated by scoliosis and lower limb deformities.15 Cognitive development is normal. Skeletal x rays are characterized at birth by severe platyspondyly, major delay in skeletal ossification and metaphyseal cupping. In survivors, x rays show persistence of an extremely delayed epiphyseal ossification with dysplastic carpal ossification, major shortness of the metacarpals, and metaphyseal irregularities in the knees (Figure 6). The inheritance is autosomal recessive and no gene has been identified to date. The other SEMD Table 1 summarizes the other SEMD with their main clinical and radiological features and genetic basis, including sponastrime dysplasia, Missouri type, Wolcott-Rallison syndrome,
42 V. Cormier-Daire
Figure 6. Opsismodyplasia. Note the major delay in epiphyseal ossification, the metaphyseal cupping and the severe platyspondyly.
Matrilin type, Schimke immuno-osseous dysplasia, Pakistani type, Omani type, dyssegmental dysplasia, Handigodu type, Maroteaux type, Irapa type, Shohat type and short limb– hand type.16–29 Some of these have been described in a single family and specific regions (Matrilin type, Pakistani type, Omani type etc.), and others are mainly defined by extraskeletal features (Wolcott-Rallison syndrome, Schimke immuno-osseous dysplasia). CONCLUSION The precise description of radiological and extraskeletal features is needed for the specific diagnosis of any SEMD. This diagnosis is required for appropriate genetic counselling and for the specific management of these rare entities. Management includes not only an orthopaedic survey with often premature osteoarthritis and a risk of medullar compression due to atlanto-axial instability, but also a multi-organ survey depending on the natural course of the disease.
Practice points diagnosis is based on the specificity of the skeletal manifestations or on the presence of characteristic extraskeletal features complications include premature osteoarthritis and atlantoaxial instability requiring a systematic survey of odontoid hypoplasia a multi-organ survey is often required depending on the specific diagnosis
Spondylo-epi-metaphyseal dysplasia 43
Research agenda heterogeneous group of disorders with various modes of inheritance no common molecular pathway beyond this group rare entities with the molecular basis for many still unknown
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