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  • 2Multiple epiphyseal dysplasia: clinical

    Andrea Superti-Furga*

    Key words: multiple epiphyseal dysplasia; COMP; COL9A1; COL9A2; COL9A3; MATN3; DTDST;

    * Corresponding author. Centre for Paediatrics and Adolescent Medicine, Freiburg University Hospital,

    1521-6942/$ - see front matter 2007 Published by Elsevier Ltd.

    Best Practice & Research Clinical RheumatologyVol. 22, No. 1, pp. 1932, 2008

    doi:10.1016/j.berh.2007.11.009available online at http://www.sciencedirect.comMathildenstr. 1, D-79106 Freiburg, Germany, Tel.: 49 761 270 4305; Fax: 49 761 270 4454.E-mail address: asuperti@uniklinik-freiburg.de (A. Superti-Furga).bone age; delayed epiphyseal ossification.Director and Chair

    Department of Paediatrics, University of Freiburg, Freiburg, Germany

    Multiple epiphyseal dysplasia is one of the more common skeletal dysplasias but it can still bedifficult to diagnose. The presenting signs are often rheumatological (joint pain) or neurological(myopathy) in nature, and the cardinal feature of skeletal dysplasia (short stature) may not bepresent. A radiographic skeletal survey is necessary to delineate the pattern of generalized de-layed epiphyseal ossification and changes in epiphyseal contour. Once the diagnosis of multipleepiphyseal dysplasia has been established, careful examination of the radiographs can help todetermine which genes should be analysed. Mutations in at least six different genes can causemultiple epiphyseal dysplasia, and it can be either dominant or recessive. Molecular diagnosisis important for accurate prognosis and genetic counselling.and radiographic features, differential

    diagnosis and molecular basis

    Sheila UngerStaff Geneticist and ESDN Coordinator

    Department of Paediatrics and Institute of Human Genetics, University of Freiburg, Freiburg, Germany

    Luisa BonafeHead

    Division of Molecular Paediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

  • Multiple epiphyseal dysplasia (MED) is a mild form of skeletal dysplasia. Genetically, it isfairly heterogeneous with mutations in COMP, DTDST (SLC26A2), MATN3, COL9A1,

    examination and a radiographic skeletal survey should be performed to rule out MED.

    20 S. Unger et alAs the mildest phenotype of skeletal dysplasia, MED affects the epiphyses of tubularbones, including metacarpals, metatarsals and phalanges; the metaphyses and vertebralbodies are only affected slightly or not at all. The effect on the epiphyses manifests on ra-diographs as a maturational delay. The pattern of delay and the changes in shape are helpfulin distinguishing the different genetic forms of MED. The type of MED needs to be deter-mined before providing the patient and their family with precise genetic counselling.

    Table 1 gives an overview of the distinctive features of the various forms of MED. Inthe following sections, some of the features that are useful in the differential diagnosisbetween the various forms of MED will be presented. The MED forms are discussed inorder of decreasing incidence.COL9A2 and COL9A3 capable of producing the clinical picture of MED. While full-blown, severe phenotypic expressions of mutations in genes such as COMP, DTDST(SLC26A2) and MATN3 produce quite distinct phenotypes, less severe mutationstend to blend into the relatively mild phenotype of MED. Nonetheless, the distinctgenetic forms of MED can usually be distinguished by virtue of subtle clinical andradiographic signs and by their mode of inheritance. Clinically, the disease manifestswith joint disease and sometimes with reduced growth. Radiographically, there isboth a delay in ossification (maturation) of epiphyses and changes in their shape.Originally, MED was subdivided into Fairbanks and Ribbing forms but this has notproved useful.

    COMMON CLINICAL FEATURES

    As a rule, the MED phenotype is not recognizable at birth or during the first 12 yearsof life. A newborn destined to develop MED shows normal length and normal bodyproportions. One exception to this rule is the presence of club foot at birth insome cases, with recessive MED caused by mutations in DTDST.1

    A common presenting sign is joint pain affecting the hip and knee joints, occur-ring, at least initially, after physical exercise. During childhood, progressive deviationfrom the normal growth curve can occur, resulting in mild to moderate short stat-ure (around or slightly below the third percentile) by the age of 56 years. However,there are many examples of adults with MED of normal stature.2 Muscular hypotoniais frequent in young children with MED caused by COMP mutations (sometimes evenfrank myopathy).3 Thus, a typical history would be that of a child who was clinicallynormal at birth, but with some delay in motor development, and who starts to com-plain about joint pain after a long walk, after a ball game or after physical exercise.Paediatric examination may reveal a deviation of the growth curve. At that time, a di-agnosis of MED in the child may be supported by a family history of similar symp-toms in one of his parents or older siblings, or of a history of chronic joint disease,sometimes leading to total hip arthroplasty at a relatively early age, in one of his par-ents or grandparents.

    Changes in the femoral heads occurring in school-age children with MED may re-semble those seen in idiopathic necrosis of the femoral head (Legg-Calve-Perthes dis-ease). While the majority of cases of Perthes disease are limited to one side and arerarely (as far as is known) the expression of a generalized skeletal anomaly, in caseswhere Perthes disease is familial, bilateral or associated with short stature, a clinical

  • Table 1. Overview of the different forms of multiple epiphyseal dysplasia (MED) and their distinctive features.

    EDM1

    (COMP-MED)

    EDM4

    (rMED)

    EDM5

    (MATN3-MED)

    EDM2 EDM3 EDM6

    MIM

    number

    132400 226900 607078 600204 600969 (see 120210)

    Gene COMP DTDST (SCL26A2) MATN3 COL9A2 COL9A3 COL9A1

    Inheritance AD AR AD AD AD AD

    Relative

    frequency

    Rare (but may beunder reported)

    Rare (but may

    be under

    reported)

    Very rare (one

    single family

    reported)

    Distinctive

    clinical

    features

    Muscular hypotonia, pseudo-

    myopathy, joint laxity, mild

    genu vara

    Club feet at birth, genu valga

    rather than genu vara; joint

    contractures, mild to moderate

    brachydactyly

    Distinctive

    radiographic

    features

    Hand Carpal bones more delayed

    than phalangeal epiphyses;

    ragged carpal bones, small,

    rounded phalangeal epiphyses

    Phalangeal epiphyses delayed,

    but maturation of carpal bones

    normal or advanced; flat

    epiphyses or phalanges and

    radius; snow cap sign of

    metacarpals

    Unspecific changes

    at the hands

    Proximal

    femur

    Proximal femoral epiphyses

    round and small

    Proximal femoral epiphyses

    are small and flat

    Proximal femoral

    epiphyses are small

    but not as rounded

    as in COMP-MED

    Knee Small epiphyses with lateral

    thinning, additional ossification

    centres with glacier crevice

    sign before puberty

    Double-layered patella Small epiphyses

    with harlequin hat

    appearance;

    metaphyseal

    striations

    Knee epiphyses

    more affected than

    proximal femoral

    epiphyses

    Knee epiphyses

    more affected

    than proximal

    femoral epiphyses

    Multip

    leep

    iphyseal

    dysp

    lasia21

  • FREQUENCY OF MED

    approximately one in 20 000 for MED. This figure is almost certainly an underestima-

    and radiographic evaluation is needed in making a diagnosis of MED, in case other

    22 S. Unger et aladult-onset and spurious phenotypes are included.5,6 However, it is clear that someMED cases, even familial ones, are caused by genes other than those known todate. Gene mapping and mutation analysis will certainly reveal other MED genes,although they are not likely to be very common.

    COMP-MED (EDM1) (MIM 132400)

    This is the most common form of MED. It is dominantly inherited and while several de-novo mutations have been reported, a family history can be elicited in more than half ofcases. As in other MED forms, the newborn is clinically healthy and measurements arenormal. Motor development in the first months is normal but onset of walking can bedelayed or progress can be slower than average. This may be caused by laxity of largejoints (knees and hips), muscular hypotonia, and (rarely) mild myopathy with mildly ele-vated creatine kinase and/or evidence of myopathy on muscle biopsy. Joint pain is com-mon. It is not rare for children to present to neuropaediatric clinics for hypotonia ordelayed or uncoordinated walking. Growth retardation may be observed after 2 yearsof age, and a slight disproportion with mild shortening of the arms and legs with a normaltrunk can occur. During the clinical course, muscular hypotonia becomes less prominentin late childhood but joint laxity persists, leading to premature osteoarthritis of the hipsand knees. Joint replacement at the hip joints may be required in the third decade or later.

    Radiographic changes of COMP-MED

    In COMP-MED, there is a delay in appearance of the carpal bones. During ossification,their contour is not smooth but irregular, sometimes jagged. The phalanges may betion, as making the diagnosis of MED in an index case often reveals a significant numberof affected relatives who had not been diagnosed previously.

    More is known about the relative incidence of the various types of MED. It is cer-tain that MED caused by the COMP (cartilage oligomeric matrix protein) gene (EDM1;COMP-MED) is the most common f