Craniofacial microsomia (CFM) is characterized by a heterogeneous underdevelopment of the facial structures arising from the first and second branchial arches, but extracraniofacial malformations such as vertebral anomalies also occur. This systematic review provides an overview of the literature on the types and prevalence of vertebral anomalies found in patients with CFM. A systematic search was conducted. Data on the number of patients, patient characteristics, types and prevalence of vertebral anomalies, and other associations between CFM and vertebral anomalies were extracted from the articles identified. Thirty-one articles were included. Seventeen articles described both the prevalence and types of vertebral anomalies in CFM, five articles described solely the types of vertebral anomalies in CFM, and nine articles reported solely the prevalence of vertebral anomalies in CFM. The vertebral anomalies most often reported in CFM are hemivertebrae, block vertebrae, scoliosis/kyphoscoliosis, and spina bifida. These anomalies are mostly present in the cervical and thoracic spine and ribs. The reported prevalence of vertebral anomalies in CFM varies from 8% to 79%. To diagnose vertebral anomalies early in patients with CFM, further research should focus on determining which patients with CFM are at risk of vertebral anomalies.
Craniofacial microsomia (CFM) is a heterogeneous disorder, causing a wide variety of facial malformations ranging in severity . After cleft lip and palate, CFM is the most common congenital craniofacial disorder, with an incidence of 1:3000 to 1:5000 live-births . The craniofacial anomalies found in CFM are believed to be related to the first and second branchial arches . In CFM, the mandible, zygoma, external and middle ear, facial musculature, facial nerve, and soft tissues can be affected. Although ear deformities are part of CFM, isolated microtia is generally not regarded as CFM . However, it is still discussed whether isolated microtia might be a minor form of CFM .
CFM is primarily known for its craniofacial malformations, but extracranial manifestations, such as vertebral, renal, heart, central nervous system, lung, and gastrointestinal defects may also occur . Goldenhar reported what he believed to be a specific variant of CFM; these patients have the clinical features of CFM in combination with epibulbar dermoids and vertebral anomalies . However, Vento and colleagues documented no association between these anomalies and refuted the existence of this variant . More recently Tuin et al. attempted to differentiate Goldenhar syndrome from CFM and concluded that the term Goldenhar syndrome was inconsequential . The most frequently seen vertebral anomalies in patients with CFM are hemivertebrae, fusion of the vertebrae, scoliosis, accessory vertebrae, occipitalization of the atlas, and spina bifida .
Several terms are used for CFM, such as oculo-auriculo-vertebral spectrum, hemifacial microsomia, lateral facial dysplasia, and first and second branchial arch syndrome. Presumably, these conditions are part of the CFM spectrum . In this article, the deformity is referred to as craniofacial microsomia (CFM), as this is currently the term most often used in the literature.
The exact origin of CFM is unknown. The most widely accepted theory is that CFM is the result of a disturbance in the embryological development of the first and second branchial arches during the first 6 weeks of gestation . During these first 6 weeks of embryological development, both the skull and spine are formed . Therefore, a common pathogenic mechanism is likely to be the basis of both craniofacial and vertebral malformations in patients with CFM.
Although the precise link between the facial and vertebral malformations has not been clarified, the deficiency presumably occurs during vertebral somite formation, resulting in incorrect formation of the vertebrae and the skull . This may lead to congenital scoliosis or instability of the cervical spine . Instability of the cervical spine may also be the result of abnormal development of the ligamentous structures and could cause compression of the spinal cord during movement . The clinical presentation of vertebral instability is largely variable and may or may not be associated with signs or symptoms . Symptoms of cervical spine instability include neck pain, torticollis, and limited neck movement, and neurological symptoms may occur if there is compression of the spinal column or vertebral artery . The cerebellum and cranial nerves can be involved, which may lead to a wide range of neurological symptoms, including ataxia, coordination disturbances, and diplopia . Basilar impression, which is associated with cervicovertebral anomalies, can cause similar symptoms . Excessive cervical spine manipulation, which may be induced by sports activities, may result in spinal cord impingement in patients with unrecognized cervical instability . Besides the possible neurological effects, fusion or underdevelopment of the vertebrae could also result in fractures of the ankylosed segments or in progressive scoliosis . It is important to keep these, often asymptomatic, vertebral anomalies in mind when performing surgery, as cervical spine instability can put these patients at risk of spinal cord injury during intubation or surgical manipulation .
Since vertebral anomalies occur in CFM patients and may cause serious complications, it is important that clinicians are aware of the possible anomalies and their consequences. The aim of this systematic review was to study the available literature on vertebral anomalies and their respective prevalence rates in patients with CFM.
This study was guided by the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) . A systematic search of the literature was performed to identify papers focusing on CFM and its synonyms combined with synonyms for spinal and central nervous system anomalies. The search was conducted in Embase, Ovid MEDLINE, Cochrane Central, Web of Science, PubMed (articles not yet indexed in MEDLINE), and Google Scholar (most relevant articles) from inception until 21 June 2016. Results were limited to human studies written in English. No date limits were applied. Conference abstracts, letters, notes, and editorials were excluded. See the Supplementary Material online for the full search strategy.
The studies were selected independently by two researchers (R.W.R. and C.J.J.M.C.). Titles and abstracts were screened for relevance based on the inclusion and exclusion criteria. Studies concerning CFM in relation to vertebral anomalies were further reviewed. Those in which prevalence and/or the types of vertebral anomalies in CFM were mentioned were included. The articles had to report original studies. Case reports were excluded. Although there is still debate on whether isolated microtia is a form of CFM, this was considered to be a different entity for the purpose of this review. Therefore, studies describing solely patients with isolated microtia were not included. However, data concerning the CFM patients were extracted from papers describing both patients with microtia and patients with CFM.
A table with predetermined characteristics was constructed prior to the full-text review of the articles. All papers were graded on quality of evidence using the Oxford Centre for Evidence-Based Medicine (CEBM) criteria. The following information was extracted when available: the number of patients, inclusion criteria applied in the studies, prevalence of vertebral anomalies in CFM, types of vertebral anomalies, and other correlations between CFM and vertebral anomalies.
In total, 6034 articles were identified after the initial search and after including articles found through reference list searching. After removing duplicate articles, 3646 articles remained; these were examined based on title and abstract. A total 3467 articles were excluded at this stage as a result of not meeting the inclusion criteria. The full texts of the remaining 179 articles were reviewed. Finally, 31 articles were identified for inclusion in the review. Twenty-six articles described the prevalence of vertebral anomalies and 22 articles described the types of vertebral anomalies in their investigated population ( Fig. 1 ).
The characteristics of the studies included are described in Table 1 . Several studies included patients diagnosed with isolated microtia . These patients were extracted from the studies and not included in this literature review for further analysis. Patients with incomplete data were excluded from the analysis. Radiographs or computed tomography scans were used to evaluate the vertebral anomalies. Most studies were retrospective , although some prospective studies and case series were found . The number of patients studied ranged from six to 259 per study .
|Year||Author||CEBM level of evidence||Study type||Total number of patients||Patients included in this study||Aim of the study||Inclusion criteria of the study|
|2015||Al Kaissi et al.||4||Case series||6||6||To elucidate the underlying spine pathology in Goldenhar patients||Goldenhar syndrome: microtia with facial asymmetry, ear anomalies, skin tags, epibulbar dermoids, and extracranial malformations|
|2005||Anderson and David||3||Retrospective study||15||7||To clarify the nature and extent of spinal anomalies in Goldenhar patients||Goldenhar syndrome, spinal radiographs and chest radiographs|
|1998||D’Antonio et al.||3||Retrospective study||41||41||To describe the occurrence and magnitude of pharyngeal and laryngeal anomalies in OAVS patients||OAVS|
|1988||Avon and Shively||3||Retrospective study||23||21||To report orthopaedic findings in Goldenhar syndrome patients||Goldenhar syndrome or hemifacial microsomia|
|2014||Barisic et al.||3||Retrospective study||259||259||To provide population-based information on OAVS patients||Microtia and at least one major anomaly of the OAV spectrum (HFM, epibulbar dermoids, vertebral malformations)|
|2015||Beleza-Meireles et al.||3||Retrospective study||51||51||To provide an assessment of the OAVS phenotype and re-evaluation of the minimum diagnostic criteria||The presence of HFM of facial asymmetry together with microtia or milder ear malformations|
|1995||Cohen et al.||3||Cross-sectional study||24||18||To examine the neurodevelopmental profile of children with OAVS||Diagnosis of OAVS: malformation of the aural, oral, and mandibular structures|
|2007||Engiz et al.||3||Prospective study||31||31||To describe the phenotypic features and laboratory findings of patients with OAVS or Goldenhar||Diagnosis of OAVS: variety of craniofacial, auricular, and vertebral anomalies|
|2000||Ewart-Toland et al.||3||Retrospective study||14||14||To describe individuals born to diabetic mothers having OAVS features||Children of diabetic mothers with hemifacial microsomia|
|1978||Feingold and Baum||4||Case series||16||16||To present 16 patients with Goldenhar syndrome||Minimum 2 out of 3 Goldenhar syndrome criteria: eye abnormality associated with ear, mandibular, or vertebral anomalies|
|1985||Figueroa and Friede||3||Retrospective study||204||156||To investigate the cervicovertebral malformations in CFM||Hemifacial microsomia, Goldenhar syndrome, and OAVS|
|1996||Gibson et al.||3||Prospective study||35||35||To report the vertebral anomalies in Goldenhar patients||At least one of the basic criteria for Goldenhar syndrome|
|1994||Gosain et al.||3||Retrospective study||18||18||To establish the type and prevalence of cervicovertebral anomalies in Goldenhar syndrome||Goldenhar syndrome: microtia, mandibular hypoplasia, and epibulbar dermoids|
|2002||Healey et al.||3||Retrospective study||8||8||To study the vertebral involvement of the cervical spine in children with proven Goldenhar syndrome||Minimum 2 out of 3 Goldenhar syndrome criteria plus other strong associations with the syndrome|
|1995||Horgan et al.||3||Retrospective study||181||121||To document the frequency of extracraniofacial anomalies in HFM; determine associated anomalies; analyze possible correlations between extracraniofacial and craniofacial abnormalities||Hemifacial microsomia|
|2007||Johansson et al.||3||Prospective study||20||20||To analyze the relationships between OAVS and autism spectrum disorder, and identify CNS and chromosomal abnormalities||Malformation in 2 of the 4 areas: orocraniofacial, ocular, auricular, and vertebral|
|1989||Kaye et al.||3||Retrospective study||297||129||To identify and look for patterns in the associated anomalies in microtia patients||Patients with malformations of the cervical base/spine in patients with microtia and mandibular hypoplasia|
|2015||Manara et al.||3||Prospective study||29||29||To investigate the cranial nerve abnormalities in OAVS||Hemifacial microsomia and microtia|
|1992||Morrison et al.||3||Prospective study||25||24||To document the precise cardiovascular status of each patient to determine the prevalence of cardiac disease in OAVS||Microtia plus one of mandibular hypoplasia, skeletal anomalies, ocular abnormalities, and palate abnormalities|
|2016||Pegler et al.||3||Retrospective study||41||41||To describe the most prominent clinical features of a cohort of patients with oculo-auriculo-vertebral (OAV) dysplasia in Brazil||OAVS: involvement of minimum 2 of the 4 domains (face, eyes, ears, vertebrae)|
|1987||Rollnick et al.||4||Case series||294||202||To describe the phenotypic characteristics of individuals affected with OAVS and variants||Hemifacial microsomia, Goldenhar syndrome, OAVS|
|2010||Rooryck et al.||3||Retrospective study||95||93||To identify new genomic loci that are potentially involved in OAVS||Isolated microtia or hemifacial microsomia together with microtia|
|2010||Rosa et al.||3||Retrospective study||34||17||To describe the CNS abnormalities in a sample of OAVS patients||Malformation in minimum 2 of the 4 areas: orocraniofacial, ocular, auricular, vertebral|
|1982||Sherk et al.||3||Retrospective study||26||26||To report patients with specific facial abnormalities and document accompanying spinal anomalies||Hemifacial microsomia and Goldenhar syndrome|
|1977||Shokeir||3||Prospective study||24||24||To delineate the natural history of Goldenhar syndrome with regard to the possible therapeutic implications||Goldenhar syndrome: ocular manifestations, auricular involvement, facial abnormalities, skeletal dysplasia|
|2007||Strömland et al.||3||Prospective study||18||13||To survey the systemic and functional defects in a group of OAVS patients||Malformation in minimum 2 of the 4 areas: orocraniofacial, ocular, auricular, and vertebral malformations|
|2005||Tasse et al.||3||Prospective study||53||44||To investigate patients with OAVS and develop a new classification and scoring system||Microtia with or without HFM|
|2006||Touliatou et al.||4||Retrospective study||17||14||To describe the phenotypic data and evaluation of a group of 17 Goldenhar patients||Craniofacial anomalies and microtia as minimum|
|2006||Tsirikos et al.||3||Retrospective study||14||14||To determine the prevalence, type, and treatment of congenital spine deformities in Goldenhar syndrome||Hemifacial microsomia|
|2015||Tuin et al.||3||Retrospective study||255||138||To evaluate the use of the term Goldenhar syndrome||Clinical diagnosis of CFM or Goldenhar syndrome|
|1991||Vento et al.||3||Retrospective study||154||154||To create a new classification system to organize the dysmorphic manifestations in a logical, concise, and comprehensive manner||HFM and/or microtia|
Prevalence of vertebral anomalies in CFM
Details of the numbers of patients and level of spinal examination in articles on the prevalence of vertebral anomalies in CFM are reported in Table 2 . The reported prevalence of vertebral anomalies in CFM varied from 8% to 79% .
|Author||Total number of patients||Number of isolated microtia patients in study||Included patients||Number affected patients||Spinal examination|
|Full spine||Only cervical spine||Not specified|
|D’Antonio et al.||41||NA||41||20||X|
|Avon and Shively||23||NA||21||14||X|
|Barisic et al.||259||NA||259||63||X|
|Beleza-Meireles et al.||51||NA||51||10||X|
|Cohen et al.||24||NA||18||9||X|
|Engiz et al.||31||NA||31||22||X|
|Ewart-Toland et al.||14||NA||14||11||X|
|Feingold and Baum||16||NA||16||10||X|
|Figueroa and Friede||204||48||156||43||X|
|Gibson et al.||35||NA||35||21||X|
|Gosain et al.||18||NA||18||11||X|
|Horgan et al.||181||NA||121||57||X|
|Johansson et al.||20||NA||20||10||X|
|Kaye et al.||297||60||129||10||X|
|Manara et al.||29||NA||29||16||X|
|Morrison et al.||25||NA||24||15||X|
|Pegler et al.||41||NA||41||27||X|
|Rollnick et al.||294||92||202||59||X|
|Rooryck et al.||95||NA||93||33||X|
|Rosa et al.||34||NA||17||6||X|
|Sherk et al.||26||NA||26||13||X|
|Strömland et al.||18||NA||13||10||X|
|Tasse et al.||53||9||44||10||X|
|Touliatou et al.||17||3||14||3||X|
|Tuin et al.||255||NA||138||47||X|
|Vento et al.||154||NA||154||29||X|