Oculo-Auriculo-Vertebral Spectrum (Goldenhar syndrome)

Oculo-auriculo-vertebral spectrum (OAVS) is a rare developmental disorder characterized by congenital abnormalities of the mouth, ears, eyes, and vertebrae. This term includes different overlapping diagnoses such as hemifacial microsomia (HFM), Goldenhar syndrome (GS) and OAV disorder, and may represent a phenotypic continuum of the same disorder with varying degrees of severity (1,2). The clinical phenotype is highly heterogeneous and most frequently presents with hemifacial microsomia (one side of the face is smaller or underdeveloped or has parts that are missing), asymmetric ear anomalies (microtia, preauricular tags and pits), epibulbar dermoids, orofacial clefts, and vertebral malformations. Additional anomalies of the heart, kidneys and central nervous system may also be present. Life span is normal and Intellectual disability is rare (3,4).

ICD-10: Q87.0
ICD-11

OAVS has an estimated prevalence that ranges from 1 in 3,500 live births up to 1 in 45,000 live births. This wide range is due to the fact that there are no minimum diagnostic criteria for OAVS. Male infants are more commonly affected (5). 
HFM is the second most common facial congenital defect behind cleft lip and palate, affecting 1 in 3,500 to 4,000 live births.

The pathogenesis of OAVS is related to the abnormal development of structures derived from the first and second branchial arches, including eyes, mouth (lips, tongue, and palate), ear, maxilla, and mandible. The proposed mechanisms include abnormal formation, migration, proliferation, and survival of the neural crest cells, as well as disruption of embryonic blood flow during development due to hemorrhage or ischemia. Different phenotypes may be explained by distinct mechanisms (3,6).

The etiology of OAVS is still unknown. Most cases are expected to be multifactorial (1,7). It usually occurs sporadically, however, there are reports of family cases with a 2 to 3% risk of OAVS in first-degree relatives of an affected individual (6).

Certain environmental factors have been suggested to increase the risk of OAVS, particularly prenatal exposure to vasoactive medications and other drugs (eg. retinoic acid, thalidomide, mycophenolate mofetil), smoking, maternal diabetes, twin pregnancy, and assisted reproductive techniques (3).

A genetic contribution has been demonstrated in a small proportion of patients. Some chromosomal abnormalities and copy number variants (CNVs) are strongly correlated with the OAVS phenotype (6): aneuploidies involving chromosomes 3, 5, 9, 18, 22, and X; mosaicism of trisomy 7, 9 and 22; partial trisomy 22q; 5p15.33-pter deletion (del), 12p13.33 del, 12q13.33 del,  14q31.1q31.3 del, 14q22.3 duplication (dup), 22q11.2 del (8), have all been reported in patients with OAVS. There are also few reports of familial cases following autosomal dominant (AD) and recessive inheritance (AR). Many candidate genes have been proposed (SF3B2, AMIGO2, ZYG11B, ZIC3, VWA1, OTX2, EYA3), and particularly the MYT1 gene (myelin transcription factor 1; 20q13.33) has been implicated in a recurrent form of OAVS with AD inheritance (1,2,7,8,9). More recently, the contribution of epigenetics is being studied since it could explain the association of OAVS with assisted reproductive techniques and twinning (3,10).

The phenotype of OAVS is heterogeneous (8). The classical triad consists of oculo-auricular anomalies, vertebral defects and mandibular hypoplasia with facial asymmetry. The spectrum ranges from mild facial asymmetry to a severe form with facial abnormalities and multisystem involvement. Although there is no universal agreement, isolated microtia or HFM, together with mild ear malformations (e.g., preauricular tags and pits) have been suggested as minimal diagnostic criteria (8). Other authors also include epibulbar dermoids.

Craniofacial involvement is usually unilateral, but in some cases, it can be bilateral with asymmetric severity (6,11): 
1) Ear: preauricular appendage, pit or fistula, microtia, anotia, ear asymmetry, atresia of the external auditory canal, with or without hearing loss;   
2) Hemifacial microsomia: facial asymmetry with one side of the face smaller, underdeveloped, or with missing  parts; 
3) Ocular: epibulbar dermoids, upper eyelid coloboma, strabismus, anophthalmia, microphthalmia, eye asymmetry, and exophthalmos;  
4) Cleft lip and palate, particularly lateral oral cleft.

Other anomalies are present in more than 60 % of the cases and may include: vertebral anomalies (40 to 60 %): fused or absent vertebrae, hemivertebrae, and scoliosis; congenital heart defects (15 to 45 %): tetralogy of Fallot septal defects, transposition of the great vessels, aortic arch anomalies, situs inversus, and dextrocardia; central nervous system anomalies (5 to 15 %): microcephaly, encephalocele, hydrocephalus, corpus callosum hypoplasia, Arnold-Chiari malformation, holoprosencephaly; gastrointestinal anomalies (10 %): tracheoesophageal fistula, rectal atresia, and esophageal atresia; genitourinary anomalies (5 to 6 %): unilateral kidney agenesis, double ureter, renal ectopia, hydronephrosis, hydroureter (2,6).

HFM and GS are considered variable expressions of the same disorder termed the OAVS, with GS showing HFM with epibulbar dermoid and vertebral anomalies.
 

OAVS  usually occurs sporadically, but there are some familial cases reported with both AD and AR inheritance. First-degree relatives should be evaluated for minimal clinical manifestations. In cases with no family history and normal genetic tests, recurrence risk in the next pregnancy is estimated to be 2 to 3% (6). 

Prenatal diagnosis of OAV spectrum is unusual. The ultrasound findings that should raise suspicion of OAV spectrum are facial asymmetry, micrognathia, and ear abnormalities (microtia, preauricular tags). Hemifacial involvement is usually unilateral (60-90%) and more common on the right side of the face. Ocular defects are a common finding, ranging from microphthalmia to epibulbar dermoids. Orofacial clefts are rare.

The coexistence of extrafacial anomalies, such as vertebral, radial, cardiac and genitourinary defects, may help to reach the diagnosis, as it will increase the likelihood of prenatal detection and referral to a specialized fetal medicine unit. Unusual findings reported prenatally in confirmed cases include ambiguous genitalia, club feet, cystic eyes, and wormian bones. OAVS with radial defects (OMIM 141400) and oculo-auriculo-fronto-nasal syndrome (OMIM %601452) are considered two separate entities among OAVS.

The evaluation of facial asymmetry, lateral clefts, and ear anomalies can be greatly facilitated by 3D ultrasound.

Magnetic resonance imaging can be useful in the complementary assessment of suspected facial, brain, or spinal anomalies, as well as in the evaluation of ocular defects such as colobomas.

There is considerable overlap between different craniofacial syndromes. The main differential diagnosis when assessing a fetus with  multiple defects in the face are:

●   Treacher-Collins syndrome: bilateral and symmetrical hypoplasia of the zygomatic bones and mandible, down-slanted palpebral fissures, coloboma of the lower eyelid, malformations of the ears with conductive hearing loss. Genes: POLR1B (AD), POLR1D (AD), TCOF1 (AD), POLR1C (AR), POLR1D (AR)
●   Auriculo-condylar syndrome: "question mark" ears, variable abnormalities of the mandible, possible asymmetry of the face. Genes: GNAI3 (AD), EDN1 (AD), PLCB4 (AD)
●   Branchio-oto-renal syndrome: abnormal ears, branchial fistulae, renal malformations. Genes: EYA1 (AD), SIX1 (AD), SIX5 (AD)
●   Miller syndrome: micrognathia, cleft lip and palate, postaxial dysplasia of the limbs, coloboma of the eyelids, supernumerary nipples. Genes: DHODH (AR)
●  Nager syndrome: down-slanted palpebral fissures, midface retrusion, micrognathia, specific limb defects. Genes: SF3B4 (AD)
●  CHARGE syndrome: Coloboma, heart defects, choanal atresia, restricted growth, genital anomalies, ear anomalies. Facial palsy. Genes: CHD7 (AD)
●  Townes-Brocks syndrome: dysplastic ears, abnormal thumb and imperforate anus. Genes: SALL1 (AD)
●  VACTERL association: Vertebral, Anal atresia, Cardiac anomalies, Tracheoesophageal fistula with Esophageal atresia, Renal and Limb abnormalities. Genes: unknown.
●  Cat eye syndrome: coloboma of the iris, anal atresia with fistula, downslanting palpebral fissures, preauricular tags/pits, heart and renal malformations. Genes: unknown
●  Oculo-auriculo-fronto-nasal syndrome: microtia/skin tags, epibulbar dermoids, cleft lip/palate, mandibular hypoplasia, notched/bifid nasal tip, encephalocele. Genes: unknown

OAV spectrum is a rare birth defect with unknown etiology. Although molecular diagnosis is not currently available for all cases, prenatal suspicion is certainly possible. Both the reliability of sonographic diagnosis and perinatal prognosis are based on the systemic abnormalities and deformities detected prenatally. However, due to the considerable phenotypic overlap between this and other craniofacial syndromes, in addition to the inherent heterogeneity of OAV, it may not be possible to identify most fetuses with mild forms of the disease prenatally.

The finding of multiple structural defects of the face, spine, and other organs warrants genetic counseling to discuss with parents the possibility of extended prenatal genetic testing, including CMA (chromosome microarray) and whole-genome sequencing, which can be performed prenataly or deferred to the postnatal period.
OAVS should be considered and mentioned to parents when a fetal scan shows obvious facial asymmetry and ear abnormalities with or without accompanying ocular and spinal findings.

Parents should be counseled by a multidisciplinary team that includes a maternal-fetal medicine specialist, geneticist, neonatologist, oral surgeon, and pediatric ophthalmologist 

In the case of severe micrognathia, a focused MRI study of the mouth and upper airway could help the perinatal team assess the need for an EXIT-to-airway procedure. 

Patients with HFM and GS usually have nasal airway obstruction and a significantly narrowed oropharyngeal airway. The most common symptoms observed in these patients include tachypnea, stridor, cyanosis, retractions, and episodic upper airway obstruction with apnea. Airway problems first appear in infants and usually worsen as children grow older. All airway obstructions and facial malformations can complicate intubation, compromise the airway, increase work breathing, cause severe obstructive sleep apnea, and even lead to respiratory distress. Because of the potentially increased mortality and morbidity in this patient population, tracheostomy is still the method of choice for airway control.

Severe maxillomandibular hypoplasia may require surgical distraction, bone grafts, and osteotomies. Other common surgical procedures include the repair of oral clefts and congenital heart defects, removal of epibulbar dermoids, and occipitocervical fusion in cases of spinal instability 

To ameliorate the risk of negative psychosocial effects, early treatment with multistage reconstruction seems to be the preferred option in individuals with severe facial deformities.

Hearing loss does not correlate with the extent of abnormalities of the external ear. Treatment (cochlear implants, hearing prostheses) should be initiated as soon as possible to allow healthy speech development.

In summary, the management of patients with OAVS is a complex process that is influenced by the clinical manifestation and the age of the patient. Some newborns need urgent surgical intervention within the first hours of life due to life-threatening organ abnormalities or airway obstruction. All abnormalities must be corrected through a comprehensive, multistage therapeutic approach involving a number of different specialists. It is therefore critical to understand the needs of the patient and family, discuss realistic expectations, and create a workable, individualized treatment plan.

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