American Journal of Medical Genetics 125A:61–66 (2004)
Clinical Report
Spondyloepimetaphyseal Dysplasia of Maroteaux(Pseudo-Morquio Type II Syndrome): Report of a NewPatient and Review of the Literature
Andre Megarbane,1* Pierre Maroteaux,2 Catherine Caillaud,3 and Martine Le Merrer2
1Unite de Genetique Medicale, Laboratoire de Biologie Moleculaire et Cytogenetique, Faculte de Medecine,Universite Saint-Joseph, Beirut, Lebanon2Service de Genetique Medicale, Hopital Necker-Enfants Malades, Paris, France3Service de Biochimie Genetique, Hopital Cochin, Paris, France
An 11-year-old girl was seen with shortstature, a head positioned in hyperexten-sion, mild arched palate, prominent joints,limited elbow movements, hyperextensiblewrists and fingers, brachydactyly, broadthorax, pectus carinatum, short trunk, agenu valgum, and flat feet. A radiographicskeletal survey revealed a generalized osteo-porosis, platyspondyly, thoracic kyphosco-liosis, small and square iliac wings, shortfemoral necks, dysplastic epiphyses, flaredmetaphyses and brachydactyly with variouscarpal, metacarpal, and finger malforma-tions. These features are very close to a veryrare entity: the spondyloepimetaphysealdysplasia (SEMD) of Maroteaux or ‘‘pseudo-Morquio’’ type II syndrome, whose specificradiological characteristics are found in thiscase. � 2003 Wiley-Liss, Inc.
KEY WORDS: spondyloepimetaphyseal;dysplasia; morquio disease;pseudo-Morquio type II;autosomal dominant
INTRODUCTION
Spondyloepimetaphyseal dysplasia syndromes(SEMD) are a heterogeneous group of disorders char-acterized by dysplasia of the epiphyses, metaphyses,
and vertebral bodies, with or without additional abnor-mal bone features. Here, we report on a rare SEMDentity in a young girl, the SEMD of Maroteaux (MIM184095). A relevant review of the literature is alsopresented.
CLINICAL REPORT
The proband is the only child of a healthy G1P1A0mother. Her parents are non-consanguineous. At thetime of birth, the mother’s age was 34 years andthe father’s 42. The parents are perfectly normal.Medical follow up during pregnancy was unremarkable.Delivery at term by cesarean section was normal, as wasthe amniotic fluid. Birth weight was 3,580 g (75thcentile), length 50 cm (>25th, <50th centile), and headcircumference (OFC) 35 cm (50th centile). At 4 months adorso-lumbar kyphoscoliosis was noted. A total bodyskeletal radiography was performed that confirmed thekyphoscoliosis and revealed in addition a generalizedplatyspondyly, small epiphyses, enlarged and flaredmetaphyses, and a delayed bone age (Fig. 1a,b).
At that time, the baby girl was treated conservativelyby a cast until age 1 year when the cast was replaced bya corset. Her developmental milestones were withinnormal limits. However, by age 1½ year, her growthchart started showing a marked delay. Her fontanelsclosed at age 2 years. At age 8 years, cervical spinalcompression and instability of the cervical spine at C1and C2 were noted for which she underwent spinalfusion (Fig. 2).
The girl was first seen at the age of 11 years for shortstature. She had normal intelligence. Height was 103 cm(<3rd centile), weight 23 kg (<3rd centile), OFC 53,8 cm(75th centile), and chest circumference 69 cm (75thcentile). On physical exam, there was a disproportio-nately short stature, a head positioned in hyperexten-sion with limited flexion, a mild arched palate,prominent joints, limited elbow movements, hyperex-tensible wrists and fingers, brachydactyly, a broad
*Correspondence to: Dr. Andre Megarbane, M.D., Ph.D., Unitede Genetique Medicale, Faculte de Medecine, Universite Saint-Joseph 42, rue de Grenelle, 75007 Paris, France.E-mail: [email protected]
Received 23 February 2003; Accepted 4 June 2003
DOI 10.1002/ajmg.a.20442
� 2003 Wiley-Liss, Inc.
Fig. 1. a: Pelvic and (b) right upper limb X-rays of the patient at 4 months. Note the generalized platyspondyly, small epiphyses, enlarged and flaredmetaphyses, and delayed bone age.
Fig. 2. Cervical X-ray of the patient at 8 years showing the abnormal positioning and deformity of the cervical spine.
62 Megarbane et al.
thorax, a pectus carinatum, a short trunk, a genuvalgum, and flat feet (Fig. 3).
There was no hyperextensible skin. The externalgenitalia exam showed nothing remarkable. Ophthal-
mologic, neurological, and heart examinations were allnormal. On physical measurements, the upper armlength was 21.5 cm (normal value for 4½ years), theforearm length 15 cm (normal value for 4½ years), thehand length 11 cm (normal value for 2½ years), the totallower limb length 58 cm (normal value for 5 years), andthe foot length 16.2 cm (normal value for 4 years).
A total body skeletal radiography was performedand revealed a generalized decreased bone density, flatand antero-posteriorly enlarged vertebral bodies withsclerosis of the endplates, a thoracic kyphoscoliosis, andsmall and square iliac wings. Femoral necks were shortwith flattened capital femoral epiphyses. The epiphysesof the knees were dysplastic, small, flattened, irregular,and fragmented. Flared metaphyses were noted as well.Carpal bones were dysplastic, and a supernumerarypiece of bone was present at the right extremity ofthe cubitus. There was evidence of brachydactylywith broadening of the metacarpal bases, pointed 3rdand 4th proximal metacarpals, cupped distal metacar-pal metaphyses with pointed epiphyses and widediaphyses of the short–long-bones of the hands(Fig. 4a,b).
Results of complete blood count, blood glucose, uri-nalysis, aminoacid studies of plasma and urine, urinarymucopolysaccarides screening, white blood cells enzymeassays screening including a-galactose 6 sulfatase andb-galactosidase, electrolytes, vitamin D, cortisol andgrowth hormone levels, as well as liver and thyroidfunction studies, were all normal. Chromosome studiesof lymphocytes with high resolution in G- and R-bandingwere normal (46,XX).
DISCUSSION
The patient reported herein presents a form of spon-dyloepimetaphyseal dysplasia (SEMD). No biochemicalabnormalities were found after an extensive work-up.Her clinical features are very close to a specific SEMD,referred to in the literature as SED of Maroteauxand ‘‘pseudo-Morquio’’ type II syndrome; the latter indistinction to the Dyggve-Melchior-Clausen syndromereferred also as a pseudo-Morquio. Beside our patient,we are aware of six other reported cases [Kochs, 1932(1st case); Matteini et al., 1981; Doman et al., 1990].Table I summarizes the clinical and radiographicfeatures of those previously reported patients and ofthe present case.
Short stature appears a few months after birth. Theadult maximum height usually remains around 125–145 cm, and the extremities are most particularlyaffected. There are no internal malformations. Theoldest patient reported was 51-years old showing mostlikely a normal life expectancy. From this small series,no characteristic facial features could be individualized,but a short neck is common and may be a true componentof the syndrome. Both hands and feet are short andstubby. Scoliosis appeared before the age of 1 year in 2cases (Table I) and seems to be frequent in thissyndrome. Arthrosis of the large joints is a commoncomplication. Of seven described patients, all were ofnormal intelligence.
Fig. 3. a, b: Photographies of the patient at 11 years. Note the shortstature, the head positioned in hyperextension, hyperextensible wrists andfingers, brachydactyly, broad thorax, pectus carinatum, short trunk, genuvalgum, and flat feet.
Spondyloepimetaphyseal Dysplasia of Maroteaux 63
Radiologically, early in childhood metaphyseal defor-mities are obvious with an irregular and flare aspect,and retarded ossification of the epiphyses. The vertebralbodies are flattened and irregular. Disk spaces seem tobe conserved. During growth, metaphyseal and epiphy-seal changes worsen, leading to arthrosis. Kneesdeformations are important with intra-articular boneformation. Vertebral bodies become large and flat withsclerosis of the endplates and reduction of the inter-vertebral spaces. Follow-up data on a patient seen byone of us (P.M.) and reported by Doman et al. [1984]confirmed this evolution of skeletal alterations in thedisorder (Fig. 5a,b).
Unlike previously described instances, this patienthad cervical spine instability and distal joint laxityshowing that this syndrome presents clinical or geneticheterogeneity.
SEMD of Maroteaux or ‘‘pseudo-Morquio’’ type II isdistinguished from the ‘‘real’’ Morquio syndrome of anytype (253000) by the clinical absence of clouding of thecornea, different bone modifications during growth, theabsence of any metabolic abnormality, and different
mode of inheritance. In Morquio disease, the deforma-tion of vertebral bodies worsens with time. The platy-spondyly in SEMD of Maroteaux is present since birth,but does not end in tongue-like deformity. Besidediffering configurations of iliac wings [Doman et al.,1984], the deformation of the femoral necks is alsodifferent: in Morquio disease there is a coxa valga withflattened epiphyses, while in SEMD of Maroteaux theupper femoral metaphyses are enlarged and short.Finally, inheritance in Morquio is autosomal recessive,which is different from the dominant inheritance of theSEMD of Maroteaux.
Few other chondrodysplasias need to be differentiatedfrom the SEMD of Maroteaux. Spondylometaphysealdysplasia type Kozlowski (MIM 184250) is characterizedby platyspondyly with irregularity of the endplates andmetaphyseal changes of the long bones. Nevertheless,onset is in infancy or childhood and the femoral necksare broad and short with progressive coxa vara. TheSEMD Irapa type [Arias et al., 1976] presents rhizomelicshortening of the limbs, enlarged joints with restrictedmobility and radiologically platyspondyly, epi-metaphy-
Fig. 4. X-rays of the patient at age 11 years. a: Note the platyspondyly, flat and large anteroposteriorly vertebral bodies with sclerosis of the end-plates,and thoracic kyphoscoliosis; (b) the small and square iliac wings, the short femoral necks with flattened epiphyses; (c) the dysplastic epiphyses of the kneesand flared metaphyses; and (d) the dysplastic carpal bones, the supernumerary piece of bone, broad metacarpal bases, pointed 3rd and 4th proximalmetacarpals, cupped distal metaphyses with pointed epiphyses and the wide diaphyses of the short–long-bones.
64 Megarbane et al.
Fig. 4. (Continued)
TABLE I. Review of Clinical Features Associated With SEMD of Maroteaux Syndrome
Present case Kochs [1932] Matteini et al. [1981]
Doman et al. [1984]
Total (M/F)Case 1 Case 2 Case 3 Case 4
Sex F F M F M F M 3/4Delivery at term þ þ þ þ þ þ þ 7/7Age of examination (years) 11 14½ 108=12 20 51 20 4½Post natal short stature þ þ þ þ þ þ þ 7/7Short neck þ ? þ, � ? þ ? � 3/4Atlanto-axial instability þ � � � � � � 1/7Broad thorax þ � � � � � � 1/7Short trunk þ ? þ þ þ þ þ 6/6Pectus carinatum þ þ � � � � � 2/7Short hands þ þ þ þ þ þ þ 7/7Genu valgum þ þ þ þ þ þ þ 7/7Flat feet þ � þ � � � � 2/7Limited movements large joints þ ? � þ þ þ þ 5/6Hyperextensible small joints þ � � � � � � 1/7Diffuse osteoporosis þ þ þ þ þ þ þ 7/7Platyspondyly with sclerosis of
the endplatesþ þ þ þ þ þ þ 7/7
Kyphoscoliosis þ � þ � � � � 2/7Abnormal pelvis þ þ þ þ þ þ þ 7/7Short femoral neck þ þ þ þ þ þ þ 7/7Dysplastic epiphyses þ þ þ þ þ þ þ 7/7Broad metacarpal bases þ þ þ þ þ þ þ 7/7Arthrosis þ þ ? þ þ þ þ 6/6
Spondyloepimetaphyseal Dysplasia of Maroteaux 65
seal dysplasia, osteopenia, and osteoarthritic changes.However, the costochondral junctions are wide withirregular calcification of the edges, the pelvis is hypo-plastic with acetabular dysplasia, and there is carpalhypoplasia and short broad metacarpals. Spondyloepi-physeal dysplasia tarda (MIM 313400) manifest in latechildhood by growth retardation, short trunk, sternalprotrusion, and back pain with secondary osteoarthritisin adulthood. Nevertheless, the vertebrae show a poster-ior hump of bone on their superior and inferior aspectswhen viewed laterally and extremities are normal.Furthermore, inheritance is X-linked. Brachyolmiasyndrome [Gardner and Beighton, 1994] is character-ized by generalized platyspondyly which involved cervi-cal, thoracic, and lumbar regions but epiphyses andmetaphyses of the long bones are rarely involved. Inpseudoachondroplasia (MIM 177170), short staturebecome apparent at 2–3 years, the limbs are short, thejoints lax, and arthritis develops later, but vertebralbodies are biconvex and platyspondyly can appears inadult life. Finally, the entity reported by Leonard andHughes [1994] in a 2-year-old girl with a severe form ofspondyloepimetaphyseal dysplasia and where platy-spondyly was present in the neonatal period is differ-
entiated from the SEMD of Maroteaux by the presence ofprenatal short stature and facial dysmorphism.
The etiology of the SEMD of Maroteaux is still un-known. The karyotype performed in our patient wasnormal. In order to better delineate this rare chondro-dysplasia, further report and the identification of theresponsible gene(s) will be interesting. Pooling suchpatients worldwide is the only chance to achieve thelatter work.
REFERENCES
Arias S, Mota M, Pinto-Cisternas J. 1976. L’osteochondrodysplasiespondylo-epiphyso-metaphysaire type Irapa. Nouveau nanisme avecrachis et metatarsiens courts. Nouv Presse Med 5:319–323.
Doman AN, Maroteaux P, Lyne ED. 1984. Spondyloepiphyseal dysplasia ofMaroteaux. J Bone Joint Surg A 72:1364–1369.
Gardner J, Beighton P. 1994. Brachyolmia: An autosomal dominant form.Am J Med Genet 49:308–312.
Kochs J. 1932. Beitrag zur Chondodystrophie und Chondromatose. ArchOrthop Unfall 31:419–433.
Leonard NJ, Hughes HE. 1994. An unknown spondyloepimetaphysealdysplasia with a positive sweat chloride test, sparse hair and mild facialdysmorphism. Clin Dysmorphol 3:309–317.
Matteini M, Cotrozzi G, Relli P, Valenza T. 1981. Sindrome pseudo-Morquiotipo II. Arch Putti 31:225–235.
Fig. 5. X-rays of (a) the spine and of (b) the pelvis in a patient aged 15 years showing identical osseous abnormalities.
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