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Congenital malformations
Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update
  1. Ana Beleza-Meireles1,2,3,
  2. Jill Clayton-Smith3,4,
  3. Jorge M Saraiva1,
  4. May Tassabehji3,4
  1. 1Serviço de Genética, Departamento Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
  2. 2Center for Human Genetics, Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium
  3. 3Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester, UK
  4. 4Central Manchester University Hospitals NHS Foundation Trust as part of Manchester Academic Health Science Centre (MAHSC), Manchester, UK
  1. Correspondence to Dr May Tassabehji, Faculty of Medical and Human Sciences, Manchester Centre for Genomic Medicine, Institute of Human Development, University of Manchester, Manchester M13 0JH, UK; m.tassabehji{at}manchester.ac.uk

Abstract

Oculo-auriculo-vertebral spectrum (OAVS, OMIM 164 210) is a developmental disorder primarily involving structures derived from the first and second pharyngeal arches during embryogenesis. The phenotype is clinically heterogeneous and is typically characterised by abnormal development of the ear, mandible anomalies and defects of the vertebral column. OAVS may occur as a multiple congenital abnormality, and associated findings include anomalies of the eye, brain, heart, kidneys and other organs and systems. Both genetic and environmental factors are thought to contribute to this craniofacial condition, however, the mechanisms are still poorly understood. Here, we present a review of the literature on OAVS, discussing what is known about the aetiology, candidate loci, possible mechanisms and the range of clinical features that characterise this condition. We also comment on some important aspects of recurrence risk counselling to aid clinical management.

  • Molecular genetics
  • Microarray
  • Genetics
  • Developmental
  • Clinical genetics

https://doi.org/10.1136/jmedgenet-2014-102476

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    Overview of oculo-auriculo-vertebral spectrum

    Oculo-auriculo-vertebral spectrum (OAVS) is a disorder of craniofacial morphogenesis,1 ,2 with a reported prevalence of up to 1/3500 births.3–6 It includes a group of malformations primarily involving structures derived from the first and second pharyngeal arches, in particular the ear, mouth and mandible.7–28 OAVS is aetiologically and pathogenetically heterogeneous. As a result of this, many terms have been used to designate this complex spectrum of anomalies, such as hemifacial microsomia, first and second pharyngeal arch anomalies, facio-auriculo-vertebral syndrome and Goldenhar syndrome. The term OAVS has its origin from the designation ‘oculoauriculovertebral dysplasia’, suggested by Cohen et al (1989),2 who noted that there was a significant overlap between the different entities described above and suggested that they represent a phenotypic continuum.

    Generally, the OAVS phenotype can range from mild to severe. Craniofacial abnormalities include asymmetric ear anomalies (preauricular tags and pits, ear dysplasia, anotia, microtia) with or without hearing loss (conductive and/or sensorineural); hemifacial microsomia resulting in facial asymmetry; orofacial clefts; ocular defects (epibulbar dermoids, microphthalmia, coloboma of upper eyelid); and vertebral abnormalities. Facial abnormalities are limited to one side in many, but not all cases. The majority of patients have some degree of facial asymmetry.13 When bilateral involvement is present, most of them demonstrate asymmetric involvement4 ,18 with more severe expression on one side.1 The right side appears to be more frequently involved.18 Other features such as cardiac, genitourinary and cerebral malformations have also been reported.7 Since not all patients with OAVS present with all the common features, microtia is accepted as the minimum criterion for diagnosis, but microtia, facial asymmetry and epibulbar dermoids/lipodermoids are considered ‘typical’ phenotypes.

    OAVS usually occurs sporadically. However, segregation analysis has suggested genetic transmission in some cases.29 Reports of familial cases following autosomal dominant30–33 or autosomal recessive inheritance,4 ,34 ,35 as well as evidence for genetic linkage in two families,36 ,37 and the presence of OAVS features in patients with various chromosomal aberrations and genomic imbalances,35–67 all suggest that OAVS has a genetic basis in some cases. Environmental causes have also been suggested, such as maternal diabetes during pregnancy, gestational or pre-existing vasoactive drugs, smoking and twinning, indicating that a multifactorial aetiology (environmental and genetic) also contributes to some cases of OAVS.68–85

    The OAVS clinical phenotype

    The spectrum of phenotypic features in OAVS is variable, ranging from subtle facial asymmetry with a small skin tag in front of an otherwise normal-appearing ear, to a complex phenotype comprising multiple congenital abnormalities (see figure 1 and table 1 for summary of phenotypes and their prevalence in 158 published cases7–10). Due to the variable expressivity, there is no consensus regarding the minimum diagnostic criteria for OAVS. Tasse et al7 suggested either isolated microtia or hemifacial microsomia together with mild ear malformations, such as preauricular tags and hillocks, (suggested to be variants of microtia) as minimal diagnostic criteria. From our clinical experience of the condition and evidence from the literature, we suggest that the presence of isolated hemifacial microsomia associated with a family history of OAVS should also be considered to be diagnostic.

    View this table:
    Table 1

    Comparison of the prevalence of phenotypes from 158 published cases (7–10). (A) Summary of phenotype prevalence rates from 19 reports published between 1983 and 1996 as described by Cousley & Calvert, 1997,8 and adapted by Heike & Hing, 2009.9 (B) Clinical evaluation of 53 patients7; (C) Analysis of a cohort of 86 patients10

    Figure 1
    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.

    Nearly all patients with OAVS have some degree of hemifacial microsomia, resulting from maxillary and/or mandibular hypoplasia (see summary of phenotypes in table 1). External ear abnormalities are also very common and include microtia, anotia, aural atresia, preauricular tags or hillocks and preauricular pits. Most affected individuals have some degree of hearing loss, therefore, all patients with OAVS need to have an audiological evaluation. Facial clefts, or cleft lip and/or palate may be observed, but these are not common features; but macrostomia is frequently seen. The craniofacial involvement is most commonly unilateral; but it can also be bilateral, usually asymmetrical. Facial palsy, asymmetric palatal elevation, impairment of extraocular movements and 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 would suggest. Epibulbar dermoids is the most common ocular findings. Microphthalmia or other severe eye malformations may also be present but are rare. Spine deformities, impaired mobility of the spine, restricted neck movements and torticollis should raise the suspicion of vertebral anomalies in patients with OAVS. Moreover, congenital heart defects (tetralogy of Fallot, septal defects, transposition of the great vessels, aortic arch anomalies, situs inversus, dextrocardia) are not uncommon in patients with OAVS,7–10 and screening for structural cardiac anomalies should be part of the clinical evaluation of these patients.

    Limb (particularly radial anomalies), renal (unilateral kidney agenesis, double ureter, renal ectopia, hydronephrosis, hydroureter) and central nervous system (developmental delay, microcephaly, encephalocele, hydrocephaly, hypoplasia of the corpus callosum, Arnold–Chiari malformation, holoprosencephaly) anomalies have also been observed in patients with OAVS.1 ,2 ,7–25

    The aetiology of OAVS

    Although knowledge of the genetic basis of human disease and its effect on embryonic development has greatly expanded in recent years, the causes of OAVS are still largely unknown, and the involvement of both genetic and environmental factors have been suggested.1 ,9 OAVS involves primarily the derivatives of the first and second pharyngeal arches, so it has been proposed that the aetiology and mechanisms of OAVS are related to the development of these structures. The pharyngeal arches, which start to develop in the 4th week of embryonic development, are composed of mesenchymal cells and give rise to various facial structures, including skeletal, muscular and neural elements, through a complex but poorly characterised signalling network.26–28 The morphogenesis of the pharyngeal arch derivatives depends on continuous and reciprocal tissue–tissue interactions. One of the key features of craniofacial development is the formation of cranial neural crest cells, which migrate ventrolaterally as they populate the craniofacial regions. Disturbances in the specification, migration, proliferation, survival and ultimate fate determination of the cranial neural crest cells have been proposed as a possible mechanism for OAVS.26–28 The phenotypic characteristics of OAVS and severity of the defects probably depend on how the expression and activation of certain developmental genes and proteins have been disrupted during facial development.

    Microtia is a common phenotype in OAVS, which may arise as a consequence of neural crest cell defects and/or vascular disruption. This clinical feature can occur as an isolated defect or in association with other anomalies, such as Treacher Collins (TCOF1–3 mutations) and Branchio-oto-renal (EYA1, SIX1, SIX5) syndromes.86 ,87 Although the role of these genes in external ear development is not clearly defined, it does show that single gene defects can cause this phenotype by interfering in the genetic pathways necessary for normal development of mesenchymal tissues during fetal development.

    Most OAVS cases are sporadic with no relevant family history. However, a genetic predisposition has been proposed based on growing evidence from the literature.29–34 Segregation analysis performed in 311 members of the families of 74 probands with OAVS provided evidence for an autosomal dominant mode of inheritance with reduced penetrance.29 Interestingly, a positive family history has been documented in only 2% of patients with OAVS,30–34 however, from our clinical experience of the condition, we believe that this number is an underestimate, and it is noteworthy that a recent report by Rooryck et al10 identified 12% of familial cases in a cohort of 95 patients. An additional clinical study by Rollnick et al19 has presented pedigree data on 97 cases, 44 of whom had a family history of the same or similar anomaly, even if it was only minor OAVS manifestations (minor external ear anomalies or preauricular tag, which might have been removed, being the most common). The authors have reported that first-degree relatives were most often affected (35/433, 8%). Of 176 sibs cited, 11 (6%) were considered affected. In view of the family segregation of these anomalies, the authors suggest a multifactorial determination. Furthermore, the authors observe a broad phenotypic spectrum within families, an aspect that has also been reported by others,17 ,18 and have proposed that familial inheritance is more frequent than originally reported.19 The evidence, so far, does not suggest that the familial OAVS phenotype is different from the sporadic OAVS cases.

    Additional evidence for a genetic basis for OAVS comes from the identification of chromosomal anomalies in patients with phenotypic characteristics of this spectrum (summarised in table 2). Some of these abnormalities are recurrent. The 5p15 deletion has been observed in several patients with OAVS features;39–41 the region was further narrowed down to 5p15.33-pter by Ala-Mello, et al.42 Deletions of the 12p13.33 region, involving the WNT5B gene, were observed in some but not all patients with OAVS features.44 ,45 Partially overlapping microduplications on 14q23.1 were identified in two families with autosomal dominant OAVS;46 ,47 one of these families included two first-degree relatives with clinical features of OAVS and Branchio-oto-renal syndrome; hence, the region 14q23.1 might harbour candidate genes for OAVS and additional first and second pharyngeal arch developmental disorders. Anomalies in 22q have been frequently documented in patients with OAVS, particularly the 22qter deletion,51 22q11.2 deletions,52–54 the 22q11.1-q11.21 (Cat-eye) region,56 ,57 and a partial 22 trisomy (47,XX,+der(22)t(11;22)(q23;q11)), which duplicates the 22q11 region.66 Chromosomal mosaicism for trisomy 2266 has also been described, making this region a good candidate for some cases of OAVS.

    View this table:
    Table 2

    Published chromosomal anomalies in patients with phenotypic characteristics of OAVS

    Other candidate single gene loci for OAVS have also been suggested. Kelberman et al,36 reported linkage to a region of approximately 10.7 cM on chromosome 14q32 (D14S987 and D14S65) containing the GSC (GOOSECOID) gene in an OAVS family with apparent autosomal dominant inheritance. Additionally, Gimelli et al,48 reported an interstitial 14q31.1q31.3 deletion, a region adjacent to GSC, transmitted from a mother to her daughter, both with features of hemifacial microsomia. Although GSC could be regarded as a candidate gene, no mutation has been found in OAVS cases with normal karyotypes. However, GSC is now known to be mutated in a syndrome of short stature, auditory-canal atresia, mandibular hypoplasia and skeletal abnormalities (SAMS syndrome).88 This is a rare autosomal-recessive developmental disorder with a unique skeletal phenotype which, in our view, represents a different entity, clinically distinct from OAVS.

    In another family with five OAVS patients, potential linkage was suggested at 15q26.2-q26.3.37 Moreover, 12 genomic rearrangements (4 deletions and 8 duplications) ranging from 2.7 kb to 2.3 Mb, were found by Rooryck et al,10 by high-density oligonucleotide array comparative genomic hybridization (aCGH) analysis (see table 3). These included a de novo 12q13.33 deletion, which has previously been associated with OAVS44 ,45; a 2q11 deletion, which was present in a proband and his affected maternal aunt; and trisomy X in a girl OAVS. Table 2 summarises the putative chromosomal loci for OAVS based on the abnormalities described in this review. In spite of growing evidence for high heritability, the molecular basis of OAVS is still elusive and, although Mendelian inheritance is more likely in familial cases of OAVS, sporadic cases may have polygenic or multifactorial causes.

    View this table:
    Table 3

    aCGH CNV loci reported in patients with OAVS

    There is no doubt that environmental factors, such as maternal diabetes during pregnancy, thalidomide, vasoactive drugs, smoking and multiple pregnancy may also play a part in causation of this condition. One of the most favoured hypotheses is that of vascular disruption of insufficiency in utero.68–71 In fact, disruption of embryonic blood flow during development, maternal vasoactive medication use, diabetes and twinning are predisposing factors to a number of structural congenital anomalies.72 ,73 Moreover, a great number of case reports on concordant and discordant twins with OAVS suggest that there might be an association between reproductive abnormalities, twinning and OAVS.74–76 An excess of affected infants born after assisted reproductive techniques and frequent twinning among naturally conceived patients with OAVS has been reported.75 ,76 Furthermore, the high frequency of sporadic cases and the notable occurrence of discordant monozygotic twins defy simple Mendelian inheritance.77–83 It is worthwhile pointing out that some of these reports, in which an environmental exposure was considered causative, do not all mention whether or not the relatives were carefully evaluated in order to exclude the effect of genetic background.

    Epigenetic mechanisms may be one of the ways to explain how genes and the environment interact to impair cranial neural crest cell development and cause this spectrum of craniofacial disorders. Both assisted reproduction and monozygotic twinning may predispose to epigenetic modification. Studies with model organisms reveal how the identity and patterning of vertebrate-specific portions of the skull are epigenetically regulated and how epigenetic dysregulation in cranial neural crest cells induces severe skull vault defects.84 Epigenetic factors have been suggested as a possible pathogenic mechanism leading to histone acetylation-dependent imbalance of allelic expression of the BAPX1 gene, a member of the NKX family of homeobox-containing proteins, which play a role in skeletal development and patterning of the middle ear, in five patients with OAVS.85

    Heterogeneity encompassing genetic, epigenetic and non-genetic factors appears to be the most likely explanation for OAVS. A multifactorial and complex aetiology is a possible model to explain the occurrence of this birth defect. In support of this hypothesis, an increased recurrence risk was observed in families with an affected OAVS relative.17–20 The recurrence risk in first-degree relatives of affected individuals is estimated to be 2%–3% (as we have discussed, this is probably an underestimate). It has been proposed that the presence of rare and common genetic variation, of variable penetrance and effect, combined with environmental factors, may affect specific tissue interactions that occur between the cranial neural crest cells and the endoderm, mesoderm and ectoderm, and the way they connect during their migration in establishing the foundations of craniofacial morphogenesis, hence affecting the risk to OAVS.

    Differential diagnoses of OAVS

    Some patients with OAVS have clinical findings that overlap with other syndromes involving structures derived from the first and second pharyngeal arches. We highlight five syndromes with known causative genes in table 4: Treacher Collins syndrome,86 Townes–Brocks syndrome,89 CHARGE syndrome,90 Branchio-oto-renal spectrum disorders,91 and the phenotypic spectrum associated with mutations in EFTUD2.92 ,93 Our view is that these conditions are distinctive and recognisable phenotypic entities. The presence of anal anomalies, for instance, points strongly towards Townes–Brock syndrome; the shape of the ear and semicircular canal abnormality in CHARGE syndrome are very characteristic, and individuals with EFTUD2 mutations have microcephaly and may also have associated oesophageal atresia. However, if features are sufficiently suggestive, molecular testing of the genes that cause these syndromes might be considered in some OAVS cases.

    View this table:
    Table 4

    Differential diagnoses of OAVS

    Recommendations for genetic counselling

    The diagnosis of OAVS is frequently based only on clinical phenotyping, since no specific genetic tests are available and chromosome abnormalities have been identified in only a few cases. The lack of consensus regarding the minimum clinical diagnostic criteria for OAVS and the uncertainties regarding its aetiology cause difficulties in genetic counselling. An empiric sibling recurrence risk of 2%–3% is given in the case of a proband with OAVS, with normal chromosomes and no family history. However, one must be aware of occasional autosomal dominant or autosomal recessive inheritance observed in some cases. Before counselling these families, parents and siblings must be observed and the family history ascertainment must be thorough. The identification of subtle clinical manifestations of OAVS in relatives is important for recurrence risk counselling. A three-generation family history profile specifically enquiring about other relatives with facial asymmetry, ear tags, ear pits, hearing loss, vertebral malformations, eye abnormalities, cardiac or urogenital malformations and/or abnormalities of the extremities is essential.

    If an individual with OAVS is found to have an inherited or de novo chromosome abnormality, genetic counselling for that condition is advised, although because of phenotypic heterogeneity, one cannot accurately predict the severity of OAVS should it occur in another child with the same chromosomal disorder. To illustrate this, we can take into account the phenotypic variability in genomic disorders such as those on 22q11 (Cat-eye syndrome, der(22) syndrome and velocardiofacial syndrome/DiGeorge syndrome), where chromosomal rearrangements lead to abnormal gene dosage, resulting in phenotypes including intellectual disability and congenital malformations.94–99 Therefore, although no specific genetic test is currently available, aCGH screening should be considered in patients with OAVS when recurrence risk counselling is sought, particularly in those with multiple anomalies and/or developmental delay.

    Prenatal diagnosis of sporadic cases has been seldom reported and when achieved, has typically been in those with severe malformations, but with the advent of more detailed 3D scans, milder cases may be detectable (reviewed in Ref 9). Fetal ultrasound examination to detect microtia, preauricular tags and/or asymmetric mandibular hypoplasia is possible. However, since the genetic causes of OAVS have not been identified, prenatal diagnosis using genetic testing is not yet possible.

    Understanding the molecular basis of these malformations will contribute to the identification of critical genes for craniofacial development and the identification of causative gene(s) will provide tools for diagnosis and genetic counselling of this complex disorder.

    Acknowledgments

    We thank The Rosetrees Trust for the funding part of this study. We would also like to acknowledge the Department of Medical Genetics at the Paediatric Hospital in Coimbra, Portugal and the patients who consented to having their pictures published in this paper.

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    Footnotes

    • Contributors MT and AB-M researched and wrote the manuscript. JC-S edited and contributed to the manuscript.

    • Patient consent Obtained.

    • Competing interests None.

    • Ethics approval Ethical Review Board at Department of Medical Genetics, Coimbra University Hospital Centre (Centro Hospitalar e Universitário de Coimbra).

    • Provenance and peer review Not commissioned; externally peer reviewed.