oculo-auriculo-vertebral spectrum: a review of the literature and genetic update
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Oculo-auriculo-vertebral spectrum: a review of theliterature and genetic updateAna Beleza-Meireles,1,2,3 Jill Clayton-Smith,3,4 Jorge M Saraiva,1 May Tassabehji3,4
1Servio de Gentica,Departamento Peditrico,Centro Hospitalar eUniversitrio de Coimbra,Coimbra, Portugal2Center for Human Genetics,Cliniques Universitaires St Luc,Universit Catholique deLouvain, Brussels, Belgium3Faculty of Medical andHuman Sciences, ManchesterCentre for Genomic Medicine,Institute of HumanDevelopment, University ofManchester, Manchester, UK4Central Manchester UniversityHospitals NHS FoundationTrust as part of ManchesterAcademic Health ScienceCentre (MAHSC), Manchester,UK
Correspondence toDr May Tassabehji, Faculty ofMedical and Human Sciences,Manchester Centre forGenomic Medicine, Institute ofHuman Development,University of Manchester,Manchester M13 0JH, UK;email@example.com
Received 28 May 2014Revised 14 July 2014Accepted 15 July 2014
To cite: Beleza-Meireles A,Clayton-Smith J, Saraiva JM,et al. J Med Genet PublishedOnline First: [please includeDay Month Year]doi:10.1136/jmedgenet-2014-102476
ABSTRACTOculo-auriculo-vertebral spectrum (OAVS, OMIM164 210) is a developmental disorder primarily involvingstructures derived from the first and second pharyngealarches during embryogenesis. The phenotype is clinicallyheterogeneous and is typically characterised by abnormaldevelopment of the ear, mandible anomalies and defectsof the vertebral column. OAVS may occur as a multiplecongenital abnormality, and associated findings includeanomalies of the eye, brain, heart, kidneys and otherorgans and systems. Both genetic and environmentalfactors are thought to contribute to this craniofacialcondition, however, the mechanisms are still poorlyunderstood. Here, we present a review of the literatureon OAVS, discussing what is known about the aetiology,candidate loci, possible mechanisms and the range ofclinical features that characterise this condition. We alsocomment on some important aspects of recurrence riskcounselling to aid clinical management.
OVERVIEW OF OCULO-AURICULO-VERTEBRALSPECTRUMOculo-auriculo-vertebral spectrum (OAVS) is a dis-order of craniofacial morphogenesis,1 2 with areported prevalence of up to 1/3500 births.36 Itincludes a group of malformations primarily involv-ing structures derived from the first and secondpharyngeal arches, in particular the ear, mouth andmandible.728 OAVS is aetiologically and pathogen-etically heterogeneous. As a result of this, manyterms have been used to designate this complexspectrum of anomalies, such as hemifacial microso-mia, first and second pharyngeal arch anomalies,facio-auriculo-vertebral syndrome and Goldenharsyndrome. The term OAVS has its origin from thedesignation oculoauriculovertebral dysplasia, sug-gested by Cohen et al (1989),2 who noted thatthere was a significant overlap between the differ-ent entities described above and suggested that theyrepresent a phenotypic continuum.Generally, the OAVS phenotype can range from
mild to severe. Craniofacial abnormalities includeasymmetric ear anomalies (preauricular tags andpits, ear dysplasia, anotia, microtia) with orwithout hearing loss (conductive and/or sensori-neural); hemifacial microsomia resulting in facialasymmetry; orofacial clefts; ocular defects (epibul-bar dermoids, microphthalmia, coloboma of uppereyelid); and vertebral abnormalities. Facial abnor-malities are limited to one side in many, but not allcases. The majority of patients have some degree offacial asymmetry.13 When bilateral involvement ispresent, most of them demonstrate asymmetricinvolvement4 18 with more severe expression onone side.1 The right side appears to be more
frequently involved.18 Other features such ascardiac, genitourinary and cerebral malformationshave also been reported.7 Since not all patientswith OAVS present with all the common features,microtia is accepted as the minimum criterion fordiagnosis, but microtia, facial asymmetry and epi-bulbar dermoids/lipodermoids are consideredtypical phenotypes.OAVS usually occurs sporadically. However, seg-
regation analysis has suggested genetic transmissionin some cases.29 Reports of familial cases followingautosomal dominant3033 or autosomal recessiveinheritance,4 34 35 as well as evidence for geneticlinkage in two families,36 37 and the presence ofOAVS features in patients with various chromo-somal aberrations and genomic imbalances,3567 allsuggest that OAVS has a genetic basis in some cases.Environmental causes have also been suggested,such as maternal diabetes during pregnancy, gesta-tional or pre-existing vasoactive drugs, smokingand twinning, indicating that a multifactorial aeti-ology (environmental and genetic) also contributesto some cases of OAVS.6885
The OAVS clinical phenotypeThe spectrum of phenotypic features in OAVS isvariable, ranging from subtle facial asymmetry witha small skin tag in front of an otherwise normal-appearing ear, to a complex phenotype comprisingmultiple congenital abnormalities (see figure 1 andtable 1 for summary of phenotypes and their preva-lence in 158 published cases710). Due to the vari-able expressivity, there is no consensus regardingthe minimum diagnostic criteria for OAVS. Tasseet al7 suggested either isolated microtia or hemifa-cial microsomia together with mild ear malforma-tions, such as preauricular tags and hillocks,(suggested to be variants of microtia) as minimaldiagnostic criteria. From our clinical experience ofthe condition and evidence from the literature, wesuggest that the presence of isolated hemifacialmicrosomia associated with a family history ofOAVS should also be considered to be diagnostic.Nearly all patients with OAVS have some degree
of hemifacial microsomia, resulting from maxillaryand/or mandibular hypoplasia (see summary ofphenotypes in table 1). External ear abnormalitiesare also very common and include microtia, anotia,aural atresia, preauricular tags or hillocks and pre-auricular pits. Most affected individuals have somedegree of hearing loss, therefore, all patients withOAVS need to have an audiological evaluation.Facial clefts, or cleft lip and/or palate may beobserved, but these are not common features; butmacrostomia is frequently seen. The craniofacialinvolvement is most commonly unilateral; but it
Beleza-Meireles A, et al. J Med Genet 2014;0:111. doi:10.1136/jmedgenet-2014-102476 1
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can also be bilateral, usually asymmetrical. Facial palsy, asym-metric palatal elevation, impairment of extraocular movementsand trigeminal anaesthesia have been described in OAVS.
A variety of ocular abnormalities may also be observed,although less frequently than the name of the condition wouldsuggest. Epibulbar dermoids is the most common ocular find-ings. Microphthalmia or other severe eye malformations mayalso be present but are rare. Spine deformities, impaired mobil-ity of the spine, restricted neck movements and torticollisshould raise the suspicion of vertebral anomalies in patientswith OAVS. Moreover, congenital heart defects (tetralogy ofFallot, septal defects, transposition of the great vessels, aorticarch anomalies, situs inversus, dextrocardia) are not uncommonin patients with OAVS,710 and screening for structural cardiacanomalies should be part of the clinical evaluation of thesepatients.
Limb (particularly radial anomalies), renal (unilateral kidneyagenesis, double ureter, renal ectopia, hydronephrosis, hydrour-eter) and central nervous system (developmental delay, micro-cephaly, encephalocele, hydrocephaly, hypoplasia of the corpuscallosum, ArnoldChiari malformation, holoprosencephaly)anomalies have also been observed in patients with OAVS.1 2 725
The aetiology of OAVSAlthough knowledge of the genetic basis of human disease andits effect on embryonic development has greatly expanded inrecent years, the causes of OAVS are still largely unknown, andthe involvement of both genetic and environmental factors have
been suggested.1 9 OAVS involves primarily the derivatives ofthe first and second pharyngeal arches, so it has been proposedthat the aetiology and mechanisms of OAVS are related to thedevelopment of these structures. The pharyngeal arches, whichstart to develop in the 4th week of embryonic development, arecomposed of mesenchymal cells and give rise to various facialstructures, including skeletal, muscular and neural elements,through a complex but poorly characterised signallingnetwork.2628 The morphogenesis of the pharyngeal arch deri-vatives depends on continuous and reciprocal tissuetissue inter-actions. One of the key features of craniofacial development isthe formation of cranial neural crest cells, which migrate ventro-laterally as they populate the craniofacial regions. Disturbancesin the specification, migration, proliferation, survival and ultim-ate fate determination of the cranial neural crest cells have beenproposed as a possible mechanism for OAVS.2628 The pheno-typic characteristics of OAVS and severity of the defects prob-ably depend on how the expression and activation of certaindevelopmental genes and proteins have been disrupted duringfacial development.
Microtia is a common phenotype in OAVS, which may ariseas a consequence of neural crest cell defects and/or vascular dis-ruption. This clinical feature can occur as an isolated defect orin association with other anomalies, such as Treacher Collins(TCOF13 mutations) and Branchio-oto-renal (EYA1, SIX1,SIX5) syndromes.86 87 Although the role of these genes in exter-nal ear development is not clearly