Clinical research
Oculo-auriculo-vertebral spectrum: Clinical and molecular analysis of 51 patients

https://doi.org/10.1016/j.ejmg.2015.07.003Get rights and content

Abstract

Introduction

Oculo-auriculo-vertebral spectrum (OAVS OMIM 164210) is a craniofacial developmental disorder affecting the development of the structures derived from the 1st and the 2nd branchial arches during embryogenesis, with consequential maxillary, mandibular, and ear abnormalities. The phenotype in OAVS is variable and associated clinical features can involve the cardiac, renal, skeletal, and central nervous systems. Its aetiology is still poorly understood.

Methods

We have evaluated the clinical phenotypes of 51 previously unpublished patients with OAVS and their parents, and performed comparative genomic hybridization microarray studies to identify potential causative loci.

Results

Of all 51 patients, 16 (31%) had a family history of OAVS. Most had no relevant pre-natal history and only 5 (10%) cases had a history of environmental exposures that have previously been described as risk factors for OAVS. In 28 (55%) cases, the malformations were unilateral. When the involvement was bilateral, it was asymmetric. Ear abnormalities were present in 47 (92%) patients (unilateral in 24; and bilateral in 23). Hearing loss was common (85%), mostly conductive, but also sensorineural, or a combination of both. Hemifacial microsomia was present in 46 (90%) patients (17 also presented facial nerve palsy). Ocular anomalies were present in 15 (29%) patients. Vertebral anomalies were confirmed in 10 (20%) cases; 50% of those had additional heart, brain and/or other organ abnormalities. Brain abnormalities were present in 5 (10%) patients; developmental delay was more common among these patients. Limb abnormalities were found in 6 (12%) patients, and urogenital anomalies in 5 (10%). Array-CGH analysis identified 22q11 dosage anomalies in 10 out of 22 index cases screened.

Discussion

In this study we carried out in-depth phenotyping of OAVS in a large, multicentre cohort. Clinical characteristics are in line with those reported previously, however, we observed a higher incidence of hemifacial microsomia and lower incidence of ocular anomalies. Furthermore our data suggests that OAVS patients with vertebral anomalies or congenital heart defects have a higher frequency of additional brain, limb or other malformations.

We had a higher rate of familial cases in our cohort in comparison with previous reports, possibly because these cases were referred preferentially to our genetic clinic where family members underwent examination. We propose that familial OAVS cases show phenotypic variability, hence, affected relatives might have been misclassified in previous reports. Moreover, in view of its phenotypic variability, OAVS is potentially a spectrum of conditions, which overlap with other conditions, such as mandibulofacial dysostosis.

Array CGH in our cohort identified recurrent dosage anomalies on 22q11, which may contribute to, or increase the risk of OAVS. We hypothesize that although the 22q11 locus may harbour gene(s) or regulatory elements that play a role in the regulation of craniofacial symmetry and 1st and 2nd branchial arch development, OAVS is a heterogeneous condition and many cases have a multifactorial aetiology or are caused by mutations in as yet unidentified gene(s).

Introduction

Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is a phenotypically, and aetiologically heterogeneous disorder of craniofacial morphogenesis (Hennekam et al., 2010, Beleza-Meireles et al., 2014, Barisic et al., 2014, Mastroiacovo et al., 1995, Cousley and Calvert, 1997, Heike et al., 2009) with a reported prevalence in Europe of 3.8 per 100,000 births; this incidence has based from data from EUROCAT, a large network of population-based congenital anomaly registries in Europe (Barisic et al., 2014). The term OAVS, suggested by Gorlin and colleagues (Beleza-Meireles et al., 2014), encompasses different overlapping diagnoses such as hemifacial microsomia, 1st and 2nd branchial arches syndrome, otomandibular dysostosis, facioauriculovertebral syndrome and Goldenhar syndrome, all representing a phenotypic continuum of the same entity.

OAVS includes a group of malformations primarily involving the structures derived from the 1st and 2nd branchial arches and the intervening first pharyngeal pouch and branchial cleft, in particular the ear, mouth, mandible, eye and cervical spine. The craniofacial anomalies are generally asymmetrical (unilateral or bilateral). OAVS can range from mild to severe and includes hemifacial microsomia, bilateral or unilateral ear anomalies (preauricular tags and pits, ear dysplasia, anotia, microtia), hearing loss (conductive and/or sensorineural), ocular defects (epibulbar dermoids, microphthalmia, coloboma of upper eyelid), orofacial clefts and vertebral abnormalities. According to a recent report (Barisic et al., 2014), there is a high rate of associated anomalies of other organs/systems (up to 69.5%), most commonly congenital heart defects (in about in 27.8% of patients), but also renal and cerebral malformations (Barisic et al., 2014, Tasse et al., 2005, Rooryck et al., 2010a, Figueroa and Pruzansky, 1982, Melnick, 1980, Rollnick et al., 1987). Most patients with OAVS do not usually present with all the common features, hence there has been no universal agreement upon minimal diagnostic criteria for OAVS, but an ear anomaly has been suggested by some authors as the mildest form (Tasse et al., 2005, Rooryck et al., 2010a, Figueroa and Pruzansky, 1982).

OAVS usually occurs sporadically, however, segregation analysis has suggested genetic transmission in some familial cases (Kaye et al., 1992). Moreover, clinical studies have shown that, following careful history and clinical examination of the relatives of probands with OAVS, up to 45% of “unaffected” relatives do have minor OAVS manifestations (Rollnick and Kaye, 1983). Reports of familial cases following Mendelian inheritance (Mastroiacovo et al., 1995, Tasse et al., 2007, Vendramini-Pittoli and Kokitsu-Nakata, 2009, Tsai and Tsai, 1993, Goodin et al., 2009), as well as evidence for genetic linkage in two families (Huang et al., 2010a, Kelberman et al., 2001), and the presence of OAVS features in patients with various chromosomal aberrations and genomic imbalances (Callier et al., 2008, Huang et al., 2010b, Ala-Mello et al., 2008, Rooryck et al., 2009, Abdelmoity et al., 2011, Ballesta-Martínez et al., 2013, Brun et al., 2012, Verloes et al., 1991, Herman et al., 1988, Xu et al., 2008, Digilio et al., 2009a, Tan et al., 2011, Quintero-Rivera and Martinez-Agosto, 2013, Torti et al., 2013, Rao et al., 2005, Garavelli et al., 1999, Poonawalla et al., 1980, Rooryck et al., 2010b, Wilson and Barr, 1983), all suggest that some cases of OAVS have a genetic basis. Environmental causes have also been suggested, particularly twinning, assisted reproductive techniques and maternal pre-pregnancy diabetes (Hennekam et al., 2010, Barisic et al., 2014).

To advance studies into OAVS we have carried out a detailed clinical evaluation of 51 previously unreported patients with OAVS and also collated data on published cases. We provide a comprehensive assessment of the OAVS phenotype and revaluation of the minimal diagnostic criteria for clinical diagnosis and counselling purposes. Comparative genomic hybridization array screening (aCGH) of DNA samples was performed to identify recurrent copy number variations (CNVs) and identify candidate genes for mutation screening in our OAVS population.

Section snippets

Patients

Fifty-one patients were re-examined after a search for all cases of OAVS, Goldenhar syndrome and Hemifacial Microsomia in our clinical archives in Manchester and in Coimbra Clinical Genetics Centres. Details of family and medical histories were collected on all patients. Each patient from the cohort underwent a detailed physical examination by the clinical authors. Clinical data was entered into a comprehensive OAVS phenotype database designed in house.

As the minimal inclusion criteria for

Clinical characterisation of 51 OAVS patients

We included 51 patients, 23 (45%) female and 28 (55%) male, with a diagnosis of OAVS in this study (see Table 1 for a summary of the clinical features). Sixteen cases from seven different families (31% of all cases) had a confirmed family history of OAVS compatible with an autosomal dominant (14) or recessive (2) mode of inheritance. The remaining individuals (69%) were unrelated sporadic cases. Fig. 1 shows some of the characteristic craniofacial features seen in our OAVS patients. All these

Clinical characterisation of OAVS

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. Due to the variable expressivity, it has been difficult to reach a general consensus regarding the minimum diagnostic criteria for OAVS. In view of this phenotypic variability, OAVS might be a spectrum of conditions, which overlap with other conditions such as

Acknowledgements

We thank the families for their participation in the study. We thank The Newlife Foundation (13-14/14) and The Rosetrees Trust for funding this study. We also thank The Manchester NIHR Biomedical Research Centre and the Manchester Academic Health Sciences Centre for funding part of this study, and the UK Cleft Cooperative funded by the Healing Foundation which supports craniofacial research within the University of Manchester.

References (55)

  • C. Rooryck et al.

    2.3 Mb terminal deletion in 12p13.33 associated with oculoauriculovertebral spectrum and evaluation of WNT5B as a candidate gene

    Eur. J. Med. Genet.

    (2009)
  • C. Rooryck et al.

    Characterization of a de novo balanced translocation t(9;18)(p23;q12.2) in a patient with oculoauriculovertebral spectrum

    Eur. J. Med. Genet.

    (2010)
  • C. Tasse et al.

    Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification

    Eur. J. Med. Genet.

    (2005)
  • D.P. van Nunen et al.

    Microtia in the Netherlands: clinical characteristics and associated anomalies

    Int. J. Pediatr. Otorhinolaryngol.

    (2014)
  • S. Ala-Mello et al.

    Further evidence for a relationship between the 5p15 chromosome region and the oculoauriculovertebral anomaly

    Am. J. Med. Genet. A

    (2008)
  • M.J. Ballesta-Martínez et al.

    Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication

    Am. J. Med. Genet. A

    (2013)
  • I. Barisic et al.

    Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe

    Eur. J. Hum. Genet.

    (2014)
  • A. Beleza-Meireles et al.

    Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update

    J. Med. Genet.

    (2014)
  • P. Callier et al.

    Array-CGH in a series of 30 patients with mental retardation, dysmorphic features, and congenital malformations detected an interstitial 1p22.2-p31.1 deletion in a patient with features overlapping the Goldenhar syndrome

    Am. J. Med. Genet. A

    (2008)
  • J.M. Cline et al.

    Characterization of facial paresis in hemifacial microsomia

    Otolaryngol. Head. Neck Surg.

    (2014)
  • M.C. Digilio et al.

    Three patients with oculo-auriculo-vertebral spectrum and microdeletion 22q11.2

    Am. J. Med. Genet. A

    (2009)
  • M.C.1 Digilio et al.

    Three patients with oculo-auriculo-vertebral spectrum and microdeletion 22q11.2

    Am. J. Med. Genet. A

    (2009)
  • L. Edelmann et al.

    A common molecular basis for rearrangement disorders on chromosome 22q11

    Hum. Mol. Genet.

    (1999)
  • L. Garavelli et al.

    Oculo-auriculo-vertebral spectrum in Klinefelter syndrome

    Genet. Couns.

    (1999)
  • K. Goodin et al.

    Familial transmission of oculoauriculovertebral spectrum (Goldenhar syndrome) is not due to mutations in either EYA1 or SALL1

    Am. J. Med. Genet. A

    (2009)
  • C.L. Heike et al.

    Craniofacial microsomia overview

  • R.C.M. Hennekam et al.
    (2010)
  • Cited by (77)

    • Hearing impairment and ear anomalies in craniofacial microsomia: a systematic review

      2022, International Journal of Oral and Maxillofacial Surgery
      Citation Excerpt :

      In addition, Bisdas et al.13 described additional inner ear malformations including common cavity in one patient and an enlarged internal auditory canal in two patients. Hearing loss was reported in 29–100% of patients in 40 records (Table 3)12,14–18,20,21,23–30,32,33,35,40,42–46,48,49,51–55,59,60,66,68–70,72,73. The type of hearing loss was specified in 21 records12,15,20,21,23,26–28,30,32,33,43–46,48,51,52,54,55,73: conductive hearing loss (CHL) was described in 11.1–97% of patients, sensorineural hearing loss (SNHL) in 1–40%, and mixed hearing loss (MHL) in 4.5–44.4%.

    • Genetics of craniofacial malformations

      2021, Seminars in Fetal and Neonatal Medicine
      Citation Excerpt :

      As some clinical reports of familial cases with Mendelian inheritance patterns have been published, suggesting autosomal recessive and autosomal dominant inheritance, there seems to be a genetic basis of OAVS at least in those patients. In addition, many different chromosomal aberrations have been described in combination with OAVS, but their significance remains unclear [18,20]. There are also some recent reports of mutations in candidate genes (MYT1, AMIGO2, ZYG11B, ZIC3, EYA3) identified in a few OAVS patients [21–25].

    • A child with cat-eye syndrome and oculo-auriculo-vertebral spectrum phenotype: A discussion around molecular cytogenetic findings

      2021, European Journal of Medical Genetics
      Citation Excerpt :

      NEDD4 plays an important function in neuronal development and is responsible for the dendritic formation in neurons, forming a signaling complex. USP18 has already been described in patients clinically diagnosed with OAVS presenting a duplication overlapping in the critical region of CES (Torti et al., 2013) and Dup22q11 (Beleza-Meireles et al., 2015). The important role in cell ubiquitination may be the key to understanding how this gene would be involved in the occurrence of malformations, especially in the cranial neural crest.

    View all citing articles on Scopus
    View full text