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Oculo-Auriculo-Vertebral Spectrum: a Review of the Literature and Genetic Update Ana Beleza-Meireles,1,2,3 Jill Clayton-Smith,3,4 Jorge M Saraiva,1 May Tassabehji3,4

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Oculo-Auriculo-Vertebral Spectrum: a Review of the Literature and Genetic Update Ana Beleza-Meireles,1,2,3 Jill Clayton-Smith,3,4 Jorge M Saraiva,1 May Tassabehji3,4 View metadata, citation and similar papersDownloaded at core.ac.uk from jmg.bmj.com on August 13, 2014 - Published by group.bmj.com brought to you by CORE JMG Online First, published on August 12, 2014 as 10.1136/jmedgenet-2014-102476provided by Repositório Institucional dos Hospitais da Universidade de Coimbra Review Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update Ana Beleza-Meireles,1,2,3 Jill Clayton-Smith,3,4 Jorge M Saraiva,1 May Tassabehji3,4 1Serviço de Genética, ABSTRACT frequently involved.18 Other features such as Departamento Pediátrico, Oculo-auriculo-vertebral spectrum (OAVS, OMIM cardiac, genitourinary and cerebral malformations Centro Hospitalar e 7 Universitário de Coimbra, 164 210) is a developmental disorder primarily involving have also been reported. Since not all patients Coimbra, Portugal structures derived from the first and second pharyngeal with OAVS present with all the common features, 2Center for Human Genetics, arches during embryogenesis. The phenotype is clinically microtia is accepted as the minimum criterion for Cliniques Universitaires St Luc, heterogeneous and is typically characterised by abnormal diagnosis, but microtia, facial asymmetry and epi- Université Catholique de development of the ear, mandible anomalies and defects bulbar dermoids/lipodermoids are considered Louvain, Brussels, Belgium ‘ ’ 3Faculty of Medical and of the vertebral column. OAVS may occur as a multiple typical phenotypes. Human Sciences, Manchester congenital abnormality, and associated findings include OAVS usually occurs sporadically. However, seg- Centre for Genomic Medicine, anomalies of the eye, brain, heart, kidneys and other regation analysis has suggested genetic transmission Institute of Human organs and systems. Both genetic and environmental in some cases.29 Reports of familial cases following Development, University of – factors are thought to contribute to this craniofacial autosomal dominant30 33 or autosomal recessive Manchester, Manchester, UK 43435 4Central Manchester University condition, however, the mechanisms are still poorly inheritance, as well as evidence for genetic Hospitals NHS Foundation understood. Here, we present a review of the literature linkage in two families,36 37 and the presence of Trust as part of Manchester on OAVS, discussing what is known about the aetiology, OAVS features in patients with various chromo- – Academic Health Science candidate loci, possible mechanisms and the range of somal aberrations and genomic imbalances,35 67 all Centre (MAHSC), Manchester, UK clinical features that characterise this condition. We also suggest that OAVS has a genetic basis in some cases. comment on some important aspects of recurrence risk Environmental causes have also been suggested, Correspondence to counselling to aid clinical management. such as maternal diabetes during pregnancy, gesta- Dr May Tassabehji, Faculty of tional or pre-existing vasoactive drugs, smoking Medical and Human Sciences, Manchester Centre for and twinning, indicating that a multifactorial aeti- Genomic Medicine, Institute of ology (environmental and genetic) also contributes OVERVIEW OF OCULO-AURICULO-VERTEBRAL 68–85 Human Development, SPECTRUM to some cases of OAVS. University of Manchester, Manchester M13 0JH, UK; Oculo-auriculo-vertebral spectrum (OAVS) is a dis- 12 [email protected]. order of craniofacial morphogenesis, with a The OAVS clinical phenotype – uk reported prevalence of up to 1/3500 births.3 6 It The spectrum of phenotypic features in OAVS is includes a group of malformations primarily involv- variable, ranging from subtle facial asymmetry with Received 28 May 2014 fi Revised 14 July 2014 ing structures derived from the rst and second a small skin tag in front of an otherwise normal- Accepted 15 July 2014 pharyngeal arches, in particular the ear, mouth and appearing ear, to a complex phenotype comprising – mandible.7 28 OAVS is aetiologically and pathogen- multiple congenital abnormalities (see figure 1 and etically heterogeneous. As a result of this, many table 1 for summary of phenotypes and their preva- – terms have been used to designate this complex lence in 158 published cases7 10). Due to the vari- spectrum of anomalies, such as hemifacial microso- able expressivity, there is no consensus regarding mia, first and second pharyngeal arch anomalies, the minimum diagnostic criteria for OAVS. Tasse facio-auriculo-vertebral syndrome and Goldenhar et al7 suggested either isolated microtia or hemifa- syndrome. The term OAVS has its origin from the cial microsomia together with mild ear malforma- designation ‘oculoauriculovertebral dysplasia’, sug- tions, such as preauricular tags and hillocks, gested by Cohen et al (1989),2 who noted that (suggested to be variants of microtia) as minimal there was a significant overlap between the differ- diagnostic criteria. From our clinical experience of ent entities described above and suggested that they the condition and evidence from the literature, we represent a phenotypic continuum. suggest that the presence of isolated hemifacial Generally, the OAVS phenotype can range from microsomia associated with a family history of mild to severe. Craniofacial abnormalities include OAVS should also be considered to be diagnostic. asymmetric ear anomalies (preauricular tags and Nearly all patients with OAVS have some degree pits, ear dysplasia, anotia, microtia) with or of hemifacial microsomia, resulting from maxillary without hearing loss (conductive and/or sensori- and/or mandibular hypoplasia (see summary of neural); hemifacial microsomia resulting in facial phenotypes in table 1). External ear abnormalities asymmetry; orofacial clefts; ocular defects (epibul- are also very common and include microtia, anotia, bar dermoids, microphthalmia, coloboma of upper aural atresia, preauricular tags or hillocks and pre- eyelid); and vertebral abnormalities. Facial abnor- auricular pits. Most affected individuals have some To cite: Beleza-Meireles A, malities are limited to one side in many, but not all degree of hearing loss, therefore, all patients with Clayton-Smith J, Saraiva JM, cases. The majority of patients have some degree of OAVS need to have an audiological evaluation. et al. J Med Genet Published 13 Online First: [please include facial asymmetry. When bilateral involvement is Facial clefts, or cleft lip and/or palate may be Day Month Year] present, most of them demonstrate asymmetric observed, but these are not common features; but doi:10.1136/jmedgenet- involvement418with more severe expression on macrostomia is frequently seen. The craniofacial 2014-102476 one side.1 The right side appears to be more involvement is most commonly unilateral; but it Copyright Article author (orBeleza-Meireles their employer) A, et al. J Med2014. Genet Produced2014;0:1–11. doi:10.1136/jmedgenet-2014-102476by BMJ Publishing Group Ltd under licence. 1 Downloaded from jmg.bmj.com on August 13, 2014 - Published by group.bmj.com Review Figure 1 Characteristic craniofacial features of oculo-auriculo-vertebral spectrum (OAVS). (A–B) Two girls with OAVS, showing hemifacial microsomia and external ear defects. The first girl presents right hemifacial microsomia and right microtia, with agenesis of the external auditory meatus; she has no facial palsy, and her visual acuity is normal. The second girl has a left hemifacial microsomia and a displastic right ear with preauricular tags and displaced tragus; she has no facial palsy, and her visual acuity is normal. Neither had any additional malformations. (C–F) Different severities of microtia. The auricle is formed by a series of auricular hillocks that surround the 1st pharyngeal groove during the 6th week of gestation. At the initial stages, the auricle is formed at the base of the neck, but as the mandible develops, the auricles migrate to their normal anatomical position. Microtia occurs when the structures that form the auricle fail to develop normally. Several authors define four types of microtia according to the level of severity (type I, when the external ear is small, the auricle retains most of its normal structure, including the external auditory; type II, when the external ear is moderately anomalous, including hook-shaped, S-shaped or question mark-shaped auricle; type III, when the external is a rudimentary soft tissue structure with no cartilage and the auricle does not have a normal appearance; and type IV, characterised by anotia and absence of all external ear structures). Most cases of microtia may be difficult to define as the different forms of microtia-anotia follow a spectrum as opposed to tight groups as depicted in these photos. (G) normal ear. can also be bilateral, usually asymmetrical. Facial palsy, asym- been suggested.19OAVS involves primarily the derivatives of metric palatal elevation, impairment of extraocular movements the first and second pharyngeal arches, so it has been proposed and trigeminal anaesthesia have been described in OAVS. that the aetiology and mechanisms of OAVS are related to the A variety of ocular abnormalities may also be observed, development of these structures. The pharyngeal arches, which although less frequently than the name of the condition would start to develop in the 4th week of embryonic development, are suggest. Epibulbar dermoids is the most common ocular find- composed of mesenchymal cells and give rise to various facial ings. Microphthalmia or other severe eye malformations may structures, including skeletal, muscular and neural elements,
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