56MedGenet 1998;35:566-572

A distinct form of spondyloepimetaphysealdysplasia with multiple dislocations

Christine M Hall, Nursel H ElSioglu, Donald G Shaw

Department ofRadiology, GreatOrmond StreetHospital for ChildrenNHS Trust, LondonWCIN 3JH, UKC M HallN H ElSioglu*D G Shaw

Correspondence to:Dr Hall.

*Present address:Department of Genetics,Cerrahpasa Medical School,Istanbul, Turkey.

Received 1 September 1997Revised version accepted forpublication31 December 1997

AbstractThree unrelated patients with identicalradiological features are presented. Hypo-tonia was noted at birth and one patientwas diagnosed as having congenital fibretype disproportion in the neonatal period.Later muscle biopsies, however, wereentirely normal. All patients, now in theirteens and twenties, are of normal inteli-gence, show striking epiphyseal and meta-physeal changes of the long bones, andhave joint laxity and multiple dislocationsof large joints, which are particularlyincapacitating at the knees. These threecases represent a sporadic, previouslyunreported skeletal dysplasia withspondyloepimetaphyseal distribution andmultiple large joint dislocations.(JMed Genet 1998;35:566-572)

Keywords: spondyloepimetaphyseal dysplasia; joint dis-locations

The term "spondyloepimetaphyseal dysplasia"(SEMD) embraces a large group of disorders

which are characterised by involvement of theepiphyses, metaphyses, and vertebral bodiesand are distinguished on the basis of clinicaland radiological features.'A review of 450 undiagnosed cases on the

Skeletal Dysplasia Registry of the Departmentof Radiology, Great Ormond Street Hospitalfor Children NHS Trust identified three unre-lated children with virtually identical clinicaland radiological features. We believe theyrepresent a unique form of SEMD.

Case reportsCASE 1

This female infant presented at birth with adislocated hip which was treated conserva-tively. Subsequently joint laxity was pro-nounced and her knees became unstable. Shewas noted to be very short at the age of 6 yearsbut no measurements were recorded. Her skinappeared to be velvety and floppy over the backof the hands although elasticity was normal.There was no excessive bruising and healingwas normal. The sclerae, teeth, and hair werenormal. Her mother had similar skin changesresulting in premature ageing of her face with

Figure 1 Spine of case I aged 7years. (A) Dorsal scoliosis. (B) Narrow interpedicular distances, low set L5. (C) "Pear shaped" lower dorsal vertebralbodies. Lumbar posterior vertebral body scalloping.

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Spondyloepimetaphyseal dysplasia with multiple dislocations

Figure 2 Hips of case 1. (A) Aged 2 years. Right hipdislocated wzith a dysplastic acetabulunm. Femoral capitalepiphyses absent. Femoral necks attenuated. (B) Aged 7years. Small flattened capital femoral epiphyses.Fragmentation onX right.

loose cheeks, but joints were normal. This sug-gested a dominantly inherited connective tissuedisorder and Ehlers-Danlos syndrome wassuggested. Skeletal radiographs of the child,

A

however, showed features of a skeletal dysplasiawith strikingly severe epiphyseal and metaphy-seal changes. She developed a scoliosis. By 8years of age she had striking joint laxity and herknees were so unstable that rigid callipers wererequired for standing and walking.

Radiolographic findingsSpine. At the age of 7 years, there was a doublecurve scoliosis in the thoracic region (fig 1A).There was progressive caudal narrowing of theinterpedicular distances, L5 was low setbetween the iliac wings, and there was minorspinal dysraphism of Si (fig 1B). The lumbarvertebral bodies had mild vertebral end plateirregularity with posterior scalloping (fig 1C).

Hips. At the age of 2 years, the right acetabu-lum was sloping and irregular and the right hipdislocated. The femoral necks were narrow andtapered with no ossification of the capital femo-ral epiphyses. The femoral metaphyses showedirregular ossification and the diaphyses were dis-proportionately wide with some cortical thick-ening. The ischia were tapered (fig 2A). At theage of 3 years, small, flattened, and irregularlyossified capital femoral epiphyses were present.The femoral necks remained slender andelongated. The right acetabulum was betterdeveloped with no dislocation. By the age of 7years, fragmentation of the right capital femoralepiphysis most probably represented superim-posed changes of ischaemic necrosis secondary

B

Figure 3 (A, B) Knees of case 1 aged 8years. Epiphyses small,flattened, and irregular. Metaphysealflaring andirregularity. Right knee is dislocated. Absent patellae.

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Figure 4 Upper limbs of case 1 aged 7years. (A) Radial head dislocated. Humeral epiphysessmall,flattened, and irregular. (B) Metacarpals gracile. Phalanges long and slender withbroad, squared distal ends. Tufts prominlent. Carpal bones small with delayed retardationl.Overall small carpus. Epiphyses of the radius and phalanges small, irregular,flattened, anddense. Short distal ulna.

to treatment of the hip dislocation The iliacwings appeared normal (fig 2B).

Lower limbs. At the age of 8 years, theepiphyses at the knee and ankle joints wereextremely small and flattened with irregularossification. The metaphyses were moderatelyflared with irregular ossification and some lon-gitudinal streaky sclerosis. The patellae wereunossified. All joints where frank dislocationwas not present showed significant subluxa-tion. There was dislocation at the right knee(fig 3A, B). The tarsal centres were small andirregular.

Upper limbs. At the age of 7 years, the proxi-mal humeral epiphyses and the epiphysesaround the elbow joints were small andflattened. There was dislocation of the radialhead (fig 4A) and the distal end of the ulna wasshort. The overall size of the carpus wasextremely small and the individual carpal cen-tres were small. The metacarpals were slenderand undermodelled. The middle and proximalphalanges were slender with slightly expandedand squared distal ends. The distal phalangealtufts were prominent. There were multiplesmall ivory epiphyses of the phalanges andmetacarpals. Phalangeal and metacarpal epi-physes corresponded to a standard of no morethan 1 year 6 months at a chronological age of7 years (fig 4B).

CASE 2

This female patient presented in the newbornperiod with dislocated hips and hypotonia andsubsequently developed limitation of jointmovements. Initial muscle biopsies suggested atype I fibre disproportion myopathy but thiswas not confirmed. She had proportionate

short stature, below the 3th centile, measuring77 cm at 4 years 5 months and 85 cm at 5 years6 months. She had mild midface hypoplasia.There was no relevant family history. The hipdislocations did not respond to conservativetreatment in abduction harness and bilateralupper femoral osteotomies and a right acetabu-loplasty were performed.

Radiographic findingsSpine. At the age of 6 years there was a verymild double curve thoracic scoliosis. L5 waslow set between the iliac wings and theinterpedicular distances failed to widen in thenormal manner. There was spinal dysraphismof SI and S2. There was posterior scallopingand end plate irregularity of the vertebral bod-ies in the lumbar region. In the thoracic regionthe vertebral bodies had a "pear shaped" con-figuration with some posterior constriction (fig5). In addition, the thorax was broad and theupper humeral epiphyses were small andflattened. The skull showed quite pronouncedconvolutional markings but normal sutures atthe age of 6 years.

Pelvis. At the age of 3 years, both hips weredislocated. There was delayed ossification ofboth capital femoral epiphyses. The femoralnecks were long, slender, and tapering withirregular metaphyses. The acetabula were

Figure 5 Spine of case 2 aged 6 years. Dorsal vertebralbodies "pear shaped". Posterior scalloping of the lunmbarvertebral bodies.

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Spondyloepimetaphyseal dysplasia with multiple dislocations

Figure 6 Hips of case 2 aged 3 years. Bilateral dislocationof the hips and slenderfemoral necks. Femoral capitalepiphyses are only just visible. Medial ends of ischiatapered; shallow acetabula. Narrow lower lumbarinterpedicular distances and spinal dysraphism.

shallow, sloping, and irregular (fig 6). Follow-ing treatment, by the age of 9 years, theposition was improved but the capital femoralepiphyses remained small and flattened.Lower limbs. At the age of 61/2 years, there was

a genu valgum deformity. The metaphyseswere flared with irregular ossification and somemarginal streaky sclerosis. The epiphyses wereextremely small and flattened with deficientossification laterally. Small marginal spurs werepresent. The patellae were unossified (fig 7A).Similar metaphyseal and epiphyseal changeswere present at the ankles (fig 7B).

Hands. At the age of 41/2 years, the metacar-pals were gracile and undermodelled. The dis-tal ends of the middle phalanges were relativelywide and flattened.The size of the carpus wassmall with only two small carpal centresossified. Bone maturation was severely re-tarded. Phalangeal epiphyseal bone maturationcorresponded to about 1 year of age at this time(fig 8).

CASE 3

This male patient presented at birth withmarked joint laxity and was thought to have aform of Ehlers-Danlos syndrome although hedid not have the classical skin changes. He was

Figure 8 Hand of case 2 aged 4%/ years. Metacarpalsslender. Small carpus and carpal bones. Epiphyses smallandflattened. Distal ends ofproximal and middlephalanges broad and squared. Delayed maturation.

short but measurements were not available.The family history was unremarkable.

Radiographic findingsSpine. At the age of4 years, there was a very mildtriple curve scoliosis. L5 was low set between theiliac wings and there was spinal dysraphism ofS 1 and S2. There was progressive caudalnarrowing of the interpedicular distances (fig9A). There was a very mild thoracolumbarkyphosis with adjacent disc space narrowingand vertebral end plate irregularity. There wasmild anterior and posterior scalloping of the

Figure 7 (A, B) Lower limbs of case 2 aged 6½12years. Epiphyses small,flattened, and irregular. Metaphysealflaring andstreaky sclerosis and irregularity with spurformation. Genu valgum. Absent patellae.

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I.

Figure 9 Spine of case 3 aged 4 years. (A) Narrow interpedicular distances. Scoliosis. Spinal dysraphism. (B) Mildkyphosis. Irregular end plates. Pear shaped thoracic vertebral bodies. Posterior and anterior vertebral body scalloping.

vertebral bodies in the lumbar region and someposterior constriction in the thoracic region(fig 9B).

Figure 10 Hips of case 3 aged 10years. Right coxa vara. Small,flattened capitalfemoralepiphyses. Mild protrusio acetabulae.

Pelvis. At the age of 4 months, the acetabulawere noted to be shallow with bilateral disloca-tion of the hips. At the age of 3 years, the femo-ral necks were slender and there was a rightcoxa vara deformity. The capital femoralepiphyses were small but well located within theacetabula. Subsequently, by the age of 10 years,there was a coarse trabecular pattern through-out and some protrusio acetabulae (fig 10).Lower limbs. At the age of 3 years there were

very mild bowing deformities of the diaphysesof the long bones of the lower limb. The meta-physes were flared and irregular with somestreaky sclerosis extending towards the diaphy-ses. The epiphyses were extremely small,flattened, and irregular with some fragmenta-tion. There was no patellar ossification (figlIA). By the age of 10 years, the metaphyseswere irregular and sclerotic with flattened,irregular, fragmented epiphyses. There wasquite marked subluxation and genu valgumdeformity on the right. The patella was smalland dislocated laterally (fig 11B, C).

Hands. By 10 years of age, there was markeddelay in bone maturation. The metacarpalswere slender and the phalanges long withsquared distal ends of the proximal and middlephalanges. The tufts of the terminal phalanges

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Spondyloepimetaphyseal dysplasia with multiple dislocations

Figure 11 Lower limbs of case 3. (A) Aged 3 years. Narrow femoral necks. Flared and irregular metaphyses with streaky sclerosis. Smallflattenedirregular epiphyses. Absent patellae. (B, C) Aged 10 years. Right genu valgum with subluxation and dislocated patella. Flattened irregullar small epiphyses.Metaphyses flared and irregular with streaky sclerosis.

Figure 12 Left hand of case 3 aged 10. Delayedmaturation. Slender metacarpals. Squared distal middlephalanges. Small, irregular epiphyses and carpals. Smallcarpus. Short distal ulna. Pronminent distal phalangeal tufts.Irregular, cupped nmetaphyses.

were prominent. The epiphyses and the carpalcentres were small, irregular, sclerotic, andfragmented. The overall size of the carpus wassmall. All the metaphyses showed irregularitywith some cupping. The ulna was short distally(fig 12).

DiscussionThese cases were isolated, in families withunrelated parents, and no relevant family

history has been elicited. Chromosome analysiswas not undertaken. They all presented ininfancy with hip dislocation and joint laxity anddeveloped progressive deformity particularlyinvolving the knees, spine, and hips. Clinically,the facies were normal in two of the three caseswith no evidence of ocular or auditoryabnormalities. There was no cleft palate and noother significant clinical abnormality. The fea-tures of these three children of normalintelligence with short stature included jointlaxity with dislocations initially at the hip jointsand subsequently the knees with weightbearing. Dislocation of the radial head waspresent in case 1. The epiphyses were small,flattened, irregular, and fragmentated. Themetaphyses showed widening, irregularity, andstreaky sclerosis. The dorsal vertebral bodiesshowed some posterior decrease in height butappeared more rounded anteriorly and therewas scalloping of the posterior aspects of thelumbar vertebral bodies with vertebral endplate irregularity and narrow interpediculardistances. Scolioses developed. The handchanges were particularly characteristic. Themetacarpals were gracile, the phalanges longand slender with some squared ends, and thetufts were prominent. The carpal bones wereindividually small, irregular, and flattened andthe overall size of the carpus was reduced.There was gross delay in the appearance of thephalangeal epiphyses. There was absent (se-verely delayed) ossification of the patellae in allthree cases.Two cases with virtually identical findings

have been published previously. One wasreported as a case of sponastrime dysplasia byCamera et af- and the other by Langer et al in apaper describing five new cases of sponastrimedysplasia and differentiating this disorder fromboth the case of Camera et a12 and one of their

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Table 1 Clinical and radiologicalfindings of our three cases and the two previouslypublished cases

Case Case Case Camera LangerFeatures 1 2 3 et a12 et al'

ClinicalfindingsFamily history - - - -Gender F F M M FMidface hypoplasia - + - + +Short stature + + + + +Joint laxity + + + + ?Dislocations + + + ? ?Genu valgum + + + + +Radiographic findingsMild scoliosis + + + + ?Narrow lumbar IP distances + + + + ?Sacral spinal dysraphism + + + + ?Lumbar posterior scalloping + + + + ?Vertebral end plate irregularity + + + + ?Hip subluxation/dislocation + + + -Slender femoral necks + + + + +Small irregular epiphyses + + + + +Metaphyseal irregularity, sclerosis, striations + + + + +Delayed bone maturation + + + + +Delayed patellar ossification + + + + +Gracile metacarpals + + + + +Small carpus + + + + +Small carpal bones + + + + +Squared distal ends of middle phalanges + + + + +

own. Langer et af also stated that they had seensix cases with this particular type of SEMD.The salient clinical and radiological findings ofour cases and the two previously reported areshown in table 1.

Confusion with sponastrime dysplasia arisesbecause of the short stature and sclerotic longi-tudinal striations seen at the metaphyses of theknees in both conditions. However, our casesshow striking epiphyseal changes, specific handfindings, and joint laxity with dislocations. Inaddition, the spinal changes are quite distinctwith narrow interpedicular distances andposterior scalloping.

Other conditions from the large heterogene-ous group of SEMDs require differentiation.Taybi and Lachman' have classified the SEMDsand identified common and rare forms. Ourcases are classified as rare with the designation"SEMD with large joint dislocations". Theother form with joint laxity and dislocations is"SEMD with joint laxity (SEMD-JL)". This isclassified as one of the more commonly des-cribed forms and was first reported by Beightonand Kozlowski in 19804 and later expanded in1983,5 1984,6 and 1994.7 These have mainly,but not exclusively, been reported from theSouth African Afrikaans population with mostfamilies being of Dutch or German descent andinheritance is autosomal recessive. The kypho-scoliosis is present at birth and progresses tosevere deformity, sometimes with cardiorespira-tory compromise, during early childhood,

unlike the mild kyphoscolioses identified in ourcases. Additional features include talipes, cleftpalate, congenital heart disease, and specificfacial dysmorphism. The typical radiologicalfindings in the spine and hands in our patientsare not seen in SEMD-JL.Other conditions with spondyloepimetaphy-

seal changes include SEMD type Strudwick,spondyloepiphyseal dysplasia congenita,and Stickler syndrome, all identified as result-ing from type 2 collagen mutations. Inaddition, otospondylometaepiphyseal dyspla-sia (OSMED) and some Stickler-like disor-ders have been identified as type 11 collagendisorders. These conditions all have dysmor-phic features similar to three of the five cases ofSEMD with multiple dislocations with mid-face hypoplasia.

Families with overlapping features of pseu-doachondroplasia and multiple epiphyseal dys-plasia are caused by COMP mutations andsome of these, together with some families withthe severe form of multiple epiphyseal dyspla-sia (type Fairbank), have type 9 collagen muta-tions.

Given the increasing evidence of allelicdisorders in the skeletal dysplasias it will beinteresting to see whether SEMD with multipledislocations is caused by specific mutations intype 2 or 11 collagen genes or COMP or in asimilar gene.We have described a new form of SEMD in

three unrelated sporadic cases and identifiedtwo additional published cases. The term"SEMD with multiple dislocations" is used todifferentiate this condition from the well delin-eated autosomal recessive disorder of SEMD-JL. Further reports will help towards a betterunderstanding of the nosology of this disorder.

The authors express their thank to Drs Helen M Carty, StevenChapman, and Robert F Mueller for referral of the patients.

1 Taybi H, Lachman RS, eds. Radiology of syndronmes, mnetabolicdisorders, atnd skeletal dysplasias. 4th ed. St Louis: Mosby,1996:916-23.

2 Camera G, Camera A, Pozzolo S, Costa P. Sponastrimedysplasia: report on a male patient. Pediatr Radiol 1994;24:322-4.

3 Langer LO Jr, Beals RK, Scott CI Jr. Sponastrime dysplasia:diagnostic criteria based on five new and six previouslypublished cases. Pediatr Radiol 1997;27:409- 14.

4 Beighton P, Kozlowski K. Spondylo-epi-metaphyseal dys-plasia with joint laxity and severe, progressive kyphoscolio-sis. Skeletal Radiol 1980;5:205-12.

5 Beighton P, Gericke G, Kozlowski K, Grobler L. Spondylo-epimetaphyseal dysplasia with joint laxity and severe,progressive kyphoscoliosis. S Afr MedJ7 1983;64:772-5.

6 Beighton P, Kozlowski K, Gericke G, Wallis G, Grobler L.The manifestations and natural history of spondylo-epi-metaphyseal dysplasia with joint laxity. Clin Genet 1984;26:308-17.

7 Beighton P. Spondyloepimetaphyseal dysplasia with jointlaxity (SEMDJL). _

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