ORIGINAL PAPER

T. Bieganski á B. Dawydzik á K. Kozlowski

Spondylo-epimetaphyseal dysplasia: a new X-linkedvariant with mental retardation

Received: 4 November 1998 /Accepted in revised form: 11 March 1999

Abstract A new X-linked variant of spondylo-epimetaphyseal dysplasia with distinctivephenotype and severe mental retardation in three boys of one family is reported. Thechildren were normal at birth. After several months of normal development progressivephysical disability and slow mental deterioration were observed. Extensive biochemicaltests were normal.

Conclusion These patients represent a new form of X-linked spondylo-epimetaphysealdysplasia.

Key words Spondylo-epimetaphyseal dysplasia á Mental retardation á X-linkedinheritance

Abbreviations DMC Dyggve-Melchior-Clausen á SED Spondylo-epiphyseal dysplasia áSEMD Spondylo-epimetaphyseal dysplasia

Introduction

Spondylo-epimetaphyseal dysplasias (SEMD) are aheterogenous group of generalised bone diseases.Although some SEMD such as metatropic dysplasia,diastrophic dysplasia, pseudo-achondroplasia, spondy-lo-epimetaphyseal dysplasia with joint laxity andkyphoscoliosis, and Dyggve-Melchior-Clausen (DMC)disease are well de®ned, relatively common bone disor-ders [2, 14], many are rare and defy exact classi®cation.

We report on a new form of X-linked SEMD. Threemales were a�ected. We examined two boys and receivedclinical history and photographs of one. The mainclinical features were short stature, abnormal face,skeletal deformities and progressive mental retardation.Radiologically there were epimetaphyseal changes andspine involvement. Brachydactyly was present in thehands and feet.

Case reports

Case 1

The proband was the ®rst child of healthy, young, non-cons-anguinous parents. At the time of his birth his father was 19 and hismother 20 years old. He was born at term after an uncomplicatedpregnancy and delivery. Apgar score was 9 after 1 min. Birthweight was 3050 g, birth length 51 cm, head circumference 34 cm.No abnormality was detected at physical examination. His devel-opment during the ®rst 6 months of life was normal. At 7 monthsthe parents noted coarsening of the facial features and a rickets-likechest deformity. He sat up at 8 months and walked with help at 12months. Slow mental development and progressive skeletal defor-mities were observed in the following years.

At the age of 4 years 9 months his height was 86 cm ()4.85SD);his weight was 14 kg ()2SD). He could walk only with assistance.Facial abnormalities included low frontal hairline, slightly hypo-plastic midface, hypertelorism, depressed nasal bridge, broad nasaltip, prominent eyebrows and low set ears. The palate was high. Theneck was short. Chest deformity consisted of prominent sternum

Eur J Pediatr (1999) 158: 809±814 Ó Springer-Verlag 1999

T. BieganskiDepartment of Radiology, Centrum Zdrowia Matki Polki,Lodz, Poland

B. DawydzikDepartment of Metabolic Disorders,Centrum Zdrowia Matki Polki, Lodz, Poland

K. Kozlowski (&)1

Department of Radiology,Royal Alexandra Hospital for Children, Sydney, Australia

Present address:1New Children's Hospital, Westmead,NSW 2145, Australia

and ¯aring inferior ribs. There was exaggerated thoracic kyphosis.The hands and feet were large and broad (Fig. 1A) Physical ex-amination of the chest and abdomen were normal. Laboratoryinvestigations included routine blood and urine examinations, liverand renal function tests, serum calcium, phosphorus and alkalinephosphatase, urinary glycosaminoglycons, chromatography ofaminoacids and oligosaccharides, all of which were normal. Thekaryotype was 46, XY. Hearing tests were normal. Ophthalmo-

logical examination disclosed unco-ordinated eye movements and¯at, pale optic discs. IQ (Brunet-Lezine) at 3 years was 71. Mag-netic resonance examination at 5 years revealed a small corpuscallosum, markedly delayed myelination and wide subarachnoidspaces. Skeletal survey documented an ill-de®ned SEMD. X-raystaken between 2 and 4 years showed the following (Fig. 1B±G). Inthe spine there was uneven shape of the vertebral bodies. Thecervical vertebral bodies were ¯attened and rectangular in shape.

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The odontoid was hypoplastic. The thoracic vertebrae were moreround and the lumbar vertebrae were relatively high but of di�er-ent, hexagonal shape. There was no widening of the interpediculardistances of the lumbar spine. The iliac wings were ¯ared but thecraniocaudal dimensions of the iliac bones were short due tohypoplasia of the iliac bodies. The acetabulae were well formed.The femoral necks were hypoplastic, short, and in a mild coxa varaposition. Femoral ossi®cation centres were absent at the age of 4years. The long bones showed widened metaphyses with increasedtransradiancy and abnormal trabecular pattern. The metaphyses ofthe short tubular bones were cupped. The bone age was markedlyretarded. The distal femoral and proximal tibial epiphyses weresmall and ¯attened. The distal tibial metaphyses were ¯ared andshowed a peg-like central prominence. The humeral and the distalforearm ossi®cation centres were absent. There was only one carpalossi®cation centre in the hand and four tarsal ossi®cation centres inthe foot. The ribs were thin and cupped anteriorly. The craniumwas relatively large in relation to the face and excessive Wormianbones were present in the lambdoid suture. There was hypoplasiaof the mid-facial bones. The family history revealed that twocousins, sons of grandmother sisters were similarly a�ected (cases 2and 3) (Fig. 1H).

Case 2

The son of a great aunt of case 1 was born after a normal preg-nancy and delivery. Birth weight was 3350 g, length 52 cm. At thetime of his birth his father was 35 and his mother 32 years old. Hisdevelopment was normal in the ®rst 6 months. During the second 6months, coarsening of the facial features was noted. Slow mentaldevelopment, short stature and progressive skeletal deformitieswere noted in the following years. He has been extensively inves-tigated at the Child Health Centre in Warsaw at the age of 5 years.His height was 85 cm ()5.3SD) and weight 13 kg ()3.5SD). All thebiochemical tests with exception of slightly increased serum alka-line phosphatase (220 units/l; normal 180 units/l) were normal. Thepsychological examination showed delayed mental development.Ophthalmological examination disclosed pale optic discs. CTshowed minor enlargement of the lateral ventricles, prominentsubarachnoid spaces and cortical/subcortical cerebral atrophy. Theskeletal abnormalities were reported as SEMD consistent withpseudo-achondroplasia. A common pathogenesis for the neuro-logical and bony abnormalities was suggested. After discharge fromthe hospital his physical and mental retardation steadily pro-gressed. At the age of 16 years he was bedridden. His musclestonicity was increased and there were joint contractures. His eyemovements were unco-ordinated and his speech dysarthric. Simple,partial left-sided epileptic ®ts without loss of consciousness oc-curred sporadically. His height was 95 cm ()11SD) and weight22 kg ()4.6SD) (Fig. 2A). Limited skeletal survey was performedat the age of 15 years (Fig. 2B, C). There was platyspondyly and

champagne glass deformity of the pelvis with a highly abnormaltrabecular pattern in the acetabular region. The acetabulae wereshallow and in an oblique position. The capital femoral epiphyseswere cone shaped. The femoral necks were short and the meta-physes were elongated medially. The femoral shafts were osteo-penic. The hands were osteopenic with highly abnormal trabecularpattern. Epiphyses of the phalanges were already fused with themetaphyses. Severe epimetaphyseal changes were present in themetacarpals and distal forearms where the epiphyseal fusion wasnot yet complete, (Fig. 2B, C).

Case 3

The son of another great aunt of case 1 was born after normal termpregnancy. The birth weight was 3600 g, and the length 52 cm. Atthe time of his birth his father was 27 and his mother 26 years old.In the 1st year of life his development was normal. In his 2nd year,abnormal face, slow psychomotor development, short stature andprogressive skeletal deformities were noted (Fig. 1C). He diedundiagnosed at the age of 18 years.

Results

These three a�ected boys have similar histories andsimilar appearances (Figs. 1A, 2A, 3). The boys wereborn after normal pregnancy and delivery. Their devel-opment was normal in the ®rst 6±12 months of life. Atthat time coarse facial features, progressive delay inphysical and mental development, short stature andskeletal deformities were noted. The biochemical inves-tigations were normal. The skeletal survey revealed adistinctive, severe SEMD. Abnormal CT/MR ®ndingsare also characteristic of the disease.

Discussion

The spectrum and natural history of the anomaliessuggests a ``new'' SEMD/mental retardation syndrome.The subclassi®cation of SEMD is important in order togive proper genetic counselling. The exact diagnosis ofSEMD often cannot be made when a child presents earlyin life with no family history. The disorders whichshould be considered in the di�erential diagnosis are theSEMD/mental retardation syndromes. All of them havedi�erent phenotype, di�erent clinical history and dif-ferent radiographic appearances. DMC syndrome [14] isan autosomal recessive disorder. Newborns with DMCsyndrome are small. Relative microcephaly and pro-gnathism are frequent ®ndings. Diagnostic radiographic®ndings are uniform platyspondyly with notching of thevertebral end plate and lace-like appearance of the iliaccrests. The epiphyses are relatively little a�ected andbone age is within normal limits. Males, reported byYunis et al. [15] as X-linked DMC syndrome, represent aSEMD (J.W. Spranger, unpublished observation). Thesepatients were normal at birth, had normal faces andnormal mental development. The X-linked SEMD ineight a�ected males described by Camera et al. [4] issimilarly not detectable at birth. The patients have

Fig. 1A±H Case 1. A Phenotypic appearance at 4.5 years. Height86 cm. Weight 14 kg. Short trunk. Deformed chest. Short, broadhands and feet. Hypertelorism. Depressed nasal bridge. Broad nose.Prominent eyebrows. B, C 1.5 years old. B Lumbar spine. Hexagonalappearance of the lumbar vertebral bodies. C Left hand. Osteopenia.Abnormal, coarse trabecular pattern. The metacarpals and phalangesare short with cupped metaphyses and thin cortex. Clawing deformityof the ®ngers. Only one, small carpal ossi®cation centre is present.D, E2.5 years old. D Knees. Wide, smooth metaphyses with abnormaltrabecular pattern. Bird-head like shape of the proximal end of thetibial shaft. Small, oval shaped knee epiphyses. E Ankles. Wide,smooth metaphyses with central peg like prominence. Abnormaltrabecular pattern. F, G 4 years old. F Pelvis. Short, ¯aring iliac wings.Short, rounded proximally femoral necks are in varus position.G Lefthand. Small epiphyses appear in the cupped metaphyses. Abnormaltrabecular pattern at the end of the shafts. No progress in carpal boneage. Still only one ossi®cation centre is present. H Family tree

b

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normal faces, normal intelligence and the bony abnor-malities are localised predominantly in the spine andmetaphyses with epiphyses being relatively little a�ected.The lethal skeletal dysplasia with progressive centralnervous system degeneration of Khosravi et al. [8] is anautosomal recessive disorder. The clinical course ischaracterised by poor growth, seizures and progressive

central nervous system degeneration leading to death inthe ®rst few month of life. Wafer thin platyspondyly andulnar hypoplasia are distinctive radiographic features.Autosomal recessive spondylo-epiphyseal dysplasia(SED) tarda with mental retardation has been describedby Kohn et al. [9]. The three sisters reported had normalfaces and no gross phenotypic abnormalities. The spinal

Fig. 2A±C Case 2. 16 years old. A Distinctive facial appearance.Hypertelorism. Depressed nasal base. Broad nose. Prominenteyebrows. B Pelvis. Small iliac bones. Highly abnormal trabecularpattern in the region of hip joints, sacro-iliac joints and proximalfemora. Platyspondyly. Short sacrum. C Right hand. Osteopenia withhighly abnormal trabecular pattern in all the bones of the hand. Thincortex of the tubular bones. The hypoplastic/dysplastic carpal bonesare irregular in outline. Cupped distal radial epiphysis. Wide,deformed distal radial and to a lesser degree distal ulnar metaphyses

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and epiphyseal involvement was uniform and moder-ately severe. The epiphyseal dysplasia/mental retarda-tion syndromes are characterised by distinctivephenotype and grossly normal spine and metaphyses[3, 11].

There are many single or familial cases reportedunder the general title of mental retardation and skeletaldysplasias [1, 5, 6, 13]. The phenotype and clinicalcourse of those patients are di�erent from that of ourpatients. The mental retardation is characterised bydistinctive faces with variable pattern of anomalies dif-ferent from that in the three boys in this report. Thebony abnormalities in those patients were minor andnot those of a SEMD. Those cases cannot enter the listof reasonable di�erentials with our patients. Because ofminor skeletal involvement and multiple associated softtissues abnormalities they belong rather to the group ofmultiple congenital abnormalities/mental retardationsyndromes than bone dysplasia/mental retardationsyndromes. We believe that naming the mild, multifocalbut not generalised bony changes as bone dysplasia orSEMD is not correct. Minor-moderate uncharacteristicbony abnormalities are a constant feature in multiplecongenital abnormalities/mental retardation syndromes[10, 12].

Association of severe mental retardation with severebone dysplasia is rare. Psychomotor retardation is afeature of DMC syndrome, tricho-rhino-phalangealsyndrome II [14] and has been reported in Kenny-Caf-fey syndrome [7]. Severe mental retardation is fre-quently associated with chromosomal abnormalitiesand is a constant feature of some metabolic disorderssuch as X-linked mucopolysaccharidosis type II

(Hunter syndrome). The latter is characterised by pro-gressive mental retardation and generalised bone dis-ease, shows a di�erent phenotype, positive urinescreening for mucopolysaccharides and distinctive ra-diographic appearances designated as dysostosis multi-plex.

Most bone dysplasias are inherited as an autosomaldominant or autosomal recessive trait. X-linked bonedysplasias are rare. X-linked inheritance is most likely inour family. SED tarda is inherited in an X-linked fash-ion but mental retardation and facial coarsening are notassociated with the skeletal dysplasia in SED tarda. Acontiguous gene syndrome could be considered but thepattern of bone dysplasia in SED tarda is completelydi�erent from that in the present cases.

Acknowledgement The authors thank Prof David Sillence forreviewing the manuscript.

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Fig. 3 Case 3. Phenotypic appearance at 17 years. Similar facialappearance to cases 1 and 2. Flexure deformity in the large joints

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