Chong Ae Kim

Débora R. Bertola

Juliana F. Mazzu

Luiz A. N. Oliveira

Lílian Maria Albano

Clinics

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Omodysplasia: the first reported Brazilian case

Albano, Lílian Maria

Oliveira, Luiz A. N.

Bertola, Débora R.

Mazzu, Juliana F.

Kim, Chong Ae

Cadernos Espinosanos (E-Journal)

531CLINICS 2007;62(4):531-4LETTER TO THE EDITORSCentro de Estudos do Genoma Humano, Departamento de Genética eBiologia Evolutiva do Instituto de Biociências, Univesidade de São Paulo -São Paulo/SP, BrazilEmail: majoli@icr.hcnet.usp.brOMODYSPLASIA: THE FIRST REPORTED BRAZILIANCASELílian Maria Albano, Luiz A. N. Oliveira, Débora R. Bertola, Juliana F. Mazzu, Chong Ae KimINTRODUCTIONOmodysplasia, a heterogeneous osteochondrodysplasia,was first observed by Barrow and Fitzsimmons (1984), butbetter delineated and named by Maroteaux et al. (1989).It was only in 1991, with Borochowitz et al., that two formswere recognized: autosomal dominant and recessive.Recently, Elçioglu (2004) studied five cases of reces-sive Omodysplasia and made an excellent review of the lit-erature based on these patients and on 16 other previouslyreported cases, thus improving knowledge regarding thenatural course and variability of the disorder.Patients present the following typical clinical and radio-logical findings: a round and flat facies with a prominentforehead, frontal bossing, short nose with a depressed broadbridge, short columella, anteverted nostrils, long philtrumand small chin. A rhizomelic shortening and radial head dis-location that leads to a characteristic limited extension ofthe elbows are observed. They also present a short and broadchest, widely spaced nipples and, in males, criptorchidismis frequent. Mental retardation was reported in four patientsand delayed motor development occurred in a few cases.Skeletal findings are confined to the limbs with shortenedhumeri with hypoplastic condyles and axial rotation of theirshafts. At birth, radius and ulna are short and thick, butstraighten with age. Likewise, in newborns, the humerus isshorter than the radius, but with age it becomes longer. Theradial head is anteriorly and laterally dislocated, the ulna isabnormally placed resulting in a radioulnar diastasis. Femorashow bulky proximal ends and a distal hypoplasia, remain-ing relatively short with age, but the distal tapering decreasesdue to metaphyseal widening and decreasing outward rota-tion of the femoral shafts. The tibia and fibulae are moder-ately short and the epiphyseal ossification centers of thefemora and tibiae are strikingly flat.The facial features of omodysplasia overlap with achon-droplasia and Robinow syndrome and both these conditionsshould be considered in the differential diagnosis as wellas other ryzomelic dwarfisms. The skeletal survey is deci-sive for differential diagnosis, because the skeletal defectsare characteristic for each syndrome.In the autosomal dominant form of omodysplasia,which is much rarer than the recessive one, abnormalitiesare limited to the upper limbs, while in the recessive formthere is a generalized involvement of the limbs and severedwarfism. Both types share the facial features, the typicaldefect of the distal humerus and the complex deformity ofthe elbows.Fewer than 25 autosomal recessive cases have been sofar reported. We describe the first Brazilian case, a malepatient, born of consanguineous parents, affected by therecessive form of the syndrome.The genetic cause of omodysplasia has yet to be iden-tified. Omodysplasia shares several phenotypic character-istics with autosomal recessive Robinow syndrome includ-ing limb shortening, facial dysmorphisms and genital de-fects. Recessive Robinow syndrome is caused by mutationsin ROR2 (Afzal et al., 2000; van Bokhoven et al, 2000).Considering that both syndromes could affect similar struc-tures, we hypothesized that they could be caused by muta-tions in the same gene, and tested ROR2 as a candidate forautosomal recessive omodysplasia.CASE REPORTA 9 year-3 month-old boy with unremarkable familyhistory, complaining of pain in his shoulders, hip and legswas evaluated. He was born at term from healthy consan-guineous parents (1st degree), by vaginal delivery, after anuneventful pregnancy. Birth weight was 2,700g and hislength at birth is unknown. He presented short stature, fron-tal bossing, midfacial flattening, depressed nasal bridge,small nose and, shortened arms, limited extension of theelbows and knees, cryptorchidism, and a tiptoe gait. Neu-532CLINICS 2007;62(4):531-4Omodysplasia: the first reported brazilian caseAlbano LM et al.Fig. 1 – 9 year 3 month-old boy with short limbs, typical facies and limited extension of the elbows and knees.Fig. 2 – Skeletal survey showing the shortened humeri and femora, radial dislocation and radioulnar diastasis.romotor development was within normality.Mutational screening of ROR2 gene was performed bysingle strand conformation polymorphism (SSCP) analy-sis with previously described primers (Van Bohoven et al.,2000).A detailed skeletal survey was performed revealed short-ened humeri with abnormal sloping of the distal articularsurface, shallow olecranon fossae with partially subluxedradii and radioulnar diastasis; short femora with metaphy-seal widening and small laterally displaced patellae. Other533CLINICS 2007;62(4):531-4 Omodysplasia: the first reported brazilian caseAlbano LM et al.bones and growth structures were normal.Mutation analysis of ROR2 gene by SSCP, showed noaltered migration pattern, thus revealing no mutations inthese segments.DISCUSSIONThe patient described herein has the typical features ofthe autosomal recessive form of Omodysplasia: involve-ment of the upper and lower limbs and severe short stat-ure. Furthermore, our case is the product of a consanguin-eous couple.The features of all autosomal recessive reported cases1-13 were compared with our patient (Table 1). As in othercases of recessive omodysplasia, our patient does not havemetacarpal shortening, a feature of the dominant form.Our case adds to previous reports that the recessive formof omodysplasia is the most common type with male pre-ponderance, and shows no metacarpal shortening.In some instances, omodysplasia can be misdiagnosedas recessive Robinow syndrome. Thus, in Robinow syn-drome with a predominantly rhizomelic (and notmesomelic, which is typical of Robinow syndrome) limbshortening we can have some difficult. A detailed skeletalsurvey should then be performed for differential diagno-sis. In our patient, limb and genital involvement, resemblethose in Robinow syndrome, but the rhizomelic shorten-Table 1 – Main features of the reported autosomal recessivecases1-13Features All autosomal recessive Presentedreported cases caseSex 15M/7F MCharacteristic facies 22/22 +Limited extension of elbows/ knees 13/21 +Short humeri 20/22 +Short femora 21/22 +Dislocated elbows 22/22 +Motor delayed/mental retardation 06/22 –Short stature 14/14 +Cryptorchidism 12/15 +ing with humerus and radius anomalies are typical ofomodysplasia, thus allowing this diagnosis to be estab-lished.Our negative results in the ROR2 gene screening notonly reinforce the diagnosis of omodysplasia but also sug-gest that the two syndromes are not caused by mutationsin the same gene, in spite of their phenotypical similarity..Skeletal survey is an essential tool for the differentialdiagnosis of omodysplasia, since the skeletal features in thissyndrome differ from those in achondroplasia and Robinowsyndrome, as well as in other syndromes with ryzomelicdisproportion.14,15REFERENCES1. Barrow M, Fitzsimmons JS. A new syndrome: short limbs, abnormalfacial appearance, and congenital heart defect. Am J Med Genetv.18:p.431-433, 1984.2. Maroteaux P, Sauvegrain J, Chrispin A, Farriaux, JP. Omodysplasia.Am J Med Genet v.32: p.371-375, 1989.3. Borochowitz Z, Barak M, Hershkowitz S. Familial congenitalmicromelic dysplasia with dislocation of radius and distinct face: a newskeletal dysplasia syndrome. Am J Med Genet v.39:p. 91-96, 1991.4. Elçioglu NH, Gustavson KH, Wilkie AOM, Yuksel-Apak M.; SprangerJW. Recessive omodysplasia: five new cases and review of the literature.Pediat Radiol v.34: p.75-82, 2004.5. Al Gazali LI, Al-Asaad FA. Autosomal recessive omodysplasia. Clin.Dysmorph v.4: p.52-56, 1995.6. Baxova A, Maroteaux P, Barosova J, Netriova I. Parental consanguinityin two sibs with omodysplasia. Am J Med Genet v.49: p.263-265, 1994.534CLINICS 2007;62(4):531-4Omodysplasia: the first reported brazilian caseAlbano LM et al.7. Borochowitz Z, Sabo E, Misselevitch I, Boss JH. Autosomal-recessiveomodysplasia: prenatal diagnosis and histomorphometric assessmentof the physeal plates of the long bones. Am J Med Genet v.76: p.238-244, 1998.8. Gugliantini P, Kozlowski K., Cappa M, Orazzi C, Borreli P, Pagnotta G.Rhizomelic bone dysplasia with club-like femora: a distinctive, easilyrecognisable disease. Radiol Med (Torino) v.81:p.550-552, 1991.9. Kiss P, Kozlowski K, Zavodi E. Rhizomelic bone dysplasia with club-like femora (case report and confirmation of a syndrome). Aust Radiolv.35: p.266-267, 1991.10. Masel JP, Kozlowski K, Kiss P. Autosomal recessive omodysplasia:report of three additional cases. Pediatr Radiol v.28:p.608-611, 1998.11. Stoll C, Alembik Y, Dott B, Meyer MJ, Pennerath A, Petter MO, et al.Evaluation of prenatal diagnosis of congenital heart disease. PrenatDiagn v.18:p.801-807, 1998.12. Tan TY, McGillivray G, Kornman L, Fink AM, Superti-Furga A, BonafeL et al. Autosomal recessive omodysplasia: early prenatal diagnosisand a possible clue to the gene location. Am J Med Genet v.135A: p.324-327, 2005.13. Viljoen D, Goldblatt J, Wallis C, Beighton, P. Familial rhizomelicdysplasia: phenotypic variation or heterogeneity? Am J Med Genet v.26:p.941-947, 1987.14. Afzal AR, Rajab A, Fenske C, Oldridge M, Elanko N, Terne-Pereira Eet al. Recessive Robinow syndrome, allelic to dominant brachydactylytype B, is caused by mutation of ROR2. Nat Genet v.25:p.419-422,2000.15. Van Bokhoven H, Celli J, Kayserili H, Van Beusekom E, Balci S, BrusselW, et al. Mutation of the gene encoding the ROR2 tyrosine kinase causesautosomal recessive Robinow syndrome. Nat Genet v.25:p;423-426,2000.

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Omodysplasia: the first reported Brazilian case

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