Oculo-auriculo-vertebral Spectrum Patients Research Articles

Using three-dimensional geometric morphometry for facial analysis in patients with the oculo-auriculo-vertebral spectrum.

To utilize three-dimensional (3D) geometric morphometry for visualization of the level of facial asymmetry in patients with the oculo-auriculo-vertebral spectrum (OAVS). Three-dimensional facial scans of 25 Czech patients with OAVS were processed. The patients were divided into subgroups according to Pruzansky classification. For 13 of them, second 3D facial scans were obtained. The 3D facial scans were processed using geometric morphometry. Soft tissue facial asymmetry in the sagittal plane and its changes in two time spots were visualized using colour-coded maps with a thermometre-like scale. Individual facial asymmetry was visualized in all patients as well as the mean facial asymmetry for every Pruzansky subgroup. The mean colour-coded maps of type I and type IIA subgroups showed no differences in facial asymmetry, more pronounced asymmetry in the middle and the lower facial third was found between type IIA and type IIB (maximum 1.5 mm) and between type IIB and type III (maximum 2 mm). The degree of intensity facial asymmetry in affected middle and lower facial thirds did not change distinctly during the two time spots in all subgroups. The 3D geometric morphometry in OAVS patients could be a useful tool for objective facial asymmetry assessment in patients with OAVS. The calculated colour-coded maps are illustrative and useful for clinical evaluation.

The Enigmatic Etiology of Oculo-Auriculo-Vertebral Spectrum (OAVS): An Exploratory Gene Variant Interaction Approach in Candidate Genes.

The clinical diagnosis of oculo-auriculo-vertebral spectrum (OAVS) is established when microtia is present in association with hemifacial hypoplasia (HH) and/or ocular, vertebral, and/or renal malformations. Genetic and non-genetic factors have been associated with microtia/OAVS. Although the etiology remains unknown in most patients, some cases may have an autosomal dominant, autosomal recessive, or multifactorial inheritance. Among the possible genetic factors, gene-gene interactions may play important roles in the etiology of complex diseases, but the literature lacks related reports in OAVS patients. Therefore, we performed a gene-variant interaction analysis within five microtia/OAVS candidate genes (HOXA2, TCOF1, SALL1, EYA1 and TBX1) in 49 unrelated OAVS Mexican patients (25 familial and 24 sporadic cases). A statistically significant intergenic interaction (p-value < 0.001) was identified between variants p.(Pro1099Arg) TCOF1 (rs1136103) and p.(Leu858=) SALL1 (rs1965024). This intergenic interaction may suggest that the products of these genes could participate in pathways related to craniofacial alterations, such as the retinoic acid (RA) pathway. The absence of clearly pathogenic variants in any of the analyzed genes does not support a monogenic etiology for microtia/OAVS involving these genes in our patients. Our findings could suggest that in addition to high-throughput genomic approaches, future gene-gene interaction analyses could contribute to improving our understanding of the etiology of microtia/OAVS.

Proposed clinical approach and imaging studies in families with oculo-auriculo-vertebral spectrum to assess variable expressivity.

A diagnosis of oculo-auriculo-vertebral spectrum (OAVS) is established when microtia is present in association with hemifacial hypoplasia (HH) and/or ocular, vertebral, and/or renal malformations. There is no consensus on which imaging studies should be used to rule out variable expressivity and distinguish "sporadic" from "familial" patients. This observational and descriptive study was performed in a Mexican population of 51 patients (32 males, 19 females, 0-18 years old) with microtia/OAVS, and their available parents. A clinical history, genealogy, and physical examination were obtained from all included patients, as were a computed tomography (CT) scan of the ear, audiological evaluation, orthopantomography, complete spine radiography, and renal ultrasound. The same approach was completed in their available parents (51 mothers and 40 fathers), excluding the CT scan and audiological evaluation. By genealogy, 53% of patients were classified as "sporadic"; of the "familial" patients, at least 79.1% had suggestion of a multifactorial inheritance. In the available parents, orthopantomography, complete spine X-ray, and renal ultrasound identified the following OAVS-related manifestations: HH (16.2%, n=14/86), vertebral alterations (10.9%, n=10/91), and renal anomalies (2.2%, n=2/90). Our evaluation of the parents allowed three patients to be reclassified from "sporadic" to "familial" (5.8%, n=3/51). Our proposed clinical and imaging approach allowed the identification of variable expressivity that more clearly distinguished between "sporadic" and "familial" OAVS patients, which is of utmost importance in providing proper genetic counseling to these families.

Genome-Wide DNA Methylation Analysis of a Cohort of 41 Patients Affected by Oculo-Auriculo-Vertebral Spectrum (OAVS)

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, and ZYG11B gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.

Oculo-auriculo-vertebral spectrum associated to progressive external ophthalmoplegia. Biological, laboratory, electrophysiological and clinical aspects

The authors discuss about the relationships between oculoauriculo- vertebral spectrum (OAVS), a malformative condition affecting eyes, ears and vertebral structures mainly derived from neural crests, and autosomal dominant progressive external ophthalmoplegia (adPEO) – an electron transport chain disorder characterized by palpebral ptosis and muscular symptoms – on the basis of laboratory data and clinical signs in a case belonging to a family in which symptoms of both diseases occur. Hemifacial microsomia and ears abnormalities were the main neural crest cells (NCC) derived signs for OAVS diagnosis. Palpebral ptosis and the associated hyperlactacidemia with high Lactate to Pyruvate ratio were main signs for the suspicion of adPEO, but the diagnosis was proposed by clinical, biochemical, electrophysiological and genetic methods because the biopsy not always is diagnostic, as in our case. The association of two groups of symptoms (malformed, NCCrelated, and myopatic-electron transport related) in the same subject as observed in our case and partially in the family, may be ascribed to nuclear abnormalities and mitochondrial electron transport disorder, respectively, as well as to a possible common etiopathogenetic mechanism. In some cases of OAVS, the malformations may be consequent to oxidative phosphorilation disease (OXPHOS) derangement, as previously demonstrated; the extensive determination of lactacidemia may be important to address the research on OAVS patients in the mitochondrial/OXPHOS genetic domain, with advantage in the knowledge of OAVS pathogenesis.

Anomalous Extratemporal Facial Nerve in Oculoauriculovertebral Spectrum

Facial nerve dysfunction is common in oculoauriculovertebral spectrum (OAVS). However, the course of the nerve has rarely been described. A 23-year-old woman with OAVS underwent excision of microtic ear remnants in preparation for an osseointegrated prosthesis and suffered iatrogenic transection of the facial nerve-the pes anserinus was within the subcutaneous tissue 15 mm posterior and 15 mm cephalad to the external acoustic meatus. The patient underwent primary nerve repair and regained nearly complete preoperative function. When considering reconstruction for OAVS patients, clinicians should have a high index of suspicion for anomalous facial nerve anatomy.

Salivary glands abnormalities in oculo-auriculo-vertebral spectrum.

Feeding and swallowing impairment are present in up to 80% of oculo-auriculo-vertebral spectrum (OAVS) patients. Salivary gland abnormalities have been reported in OAVS patients but their rate, features, and relationship with phenotype severity have yet to be defined. Parotid and submandibular salivary gland hypo/aplasia was evaluated on head MRI of 25 OAVS patients (16 with severe phenotype, Goldenhar syndrome) and 11 controls. All controls disclosed normal salivary glands. Abnormal parotid glands were found exclusively ipsilateral to facial microsomia in 21/25 OAVS patients (84%, aplasia in six patients) and showed no association with phenotype severity (14/16 patients with Goldenhar phenotype vs 7/9 patients with milder phenotype, p=0.6). Submandibular salivary gland hypoplasia was detected in six OAVS patients, all with concomitant ipsilateral severe involvement of the parotid gland (p<0.001). Submandibular salivary gland hypoplasia was associated to Goldenhar phenotype (p<0.05). Parotid gland abnormalities were associated with ipsilateral fifth (p<0.001) and seventh cranial nerve (p=0.001) abnormalities. No association was found between parotid gland anomaly and ipsilateral internal carotid artery, inner ear, brain, eye, or spine abnormalities (p>0.6). Salivary gland abnormalities are strikingly common in OAVS. Their detection might help the management of OAVS-associated swallowing and feeding impairment.

Oculo-auriculo-vertebral spectrum: going beyond the first and second pharyngeal arch involvement

Intracranial vascular, bone, and brain abnormalities might be observed in oculo-auriculo-vertebral spectrum (OAVS) patients even though these structures do not derive embryologically from the first and second pharyngeal arches. This neuroimaging study investigated their type, frequency and phenotype correlations among OAVS patients. Thirty-five OAVS patients (mean-age 4.8±6.0years; age range 0.3-30, 14 females) underwent head CT (all patients) and brain MRI (32 patients); 19 patients had a more severe phenotype (Goldenhar syndrome). Internal carotid artery hypoplasia/agenesia and abnormal course, brain abnormalities, internal acoustic canal stenosis/aplasia, cochlear-vestibular malformations, facial nerve bony canal anomalies, and oval window atresia were recorded. Nine of 35 (26%) OAVS patients showed internal carotid artery anomalies; 18/32 (56%) had protean brain MRI abnormalities, ranging from tegmental cap anomaly to mild ventriculomegaly, which were associated with Goldenhar syndrome (p<0.001) and concomitant cranial nerve abnormalities (p=0.004); 11/35 (31%) disclosed cochlear-vestibular abnormalities including Michel deformity, common cavity, cochlear hypoplasia, and incomplete partition type-1 that were associated with Goldenhar syndrome (p=0.01) and ipsilateral VIII cranial nerve abnormalities (p<0.001); 16/35 (46%, 23 sides) presented facial nerve bony canal abnormalities that were associated with Goldenhar syndrome (p<0.001) and ipsilateral VII cranial nerve (p<0.001) and cochlear-vestibular (p<0.001) abnormalities; and 23/31 (74%, 31 sides) showed oval window atresia, always with concomitant ossicular chain dysplasia. Intracranial vascular, bone, and brain abnormalities in OAVS patients are strikingly common and heterogeneous. As their detection might impact significantly on clinical and surgical management of affected patients, accurate neuroimaging investigations should be included in the diagnostic work-up of OAVS.

Facial asymmetry quantitative evaluation in oculoauriculovertebral spectrum.

Facial asymmetries in oculoauriculovertebral spectrum (OAVS) patients might require surgical corrections that are mostly based on qualitative approach and surgeon's experience. The present study aimed to develop a quantitative 3D CT imaging-based procedure suitable for maxillo-facial surgery planning in OAVS patients. Thirteen OAVS patients (mean age 3.5 ± 4.0 years; range 0.2-14.2, 6 females) and 13 controls (mean age 7.1 ± 5.3 years; range 0.6-15.7, 5 females) who underwent head CT examination were retrospectively enrolled. Eight bilateral anatomical facial landmarks were defined on 3D CT images (porion, orbitale, most anterior point of frontozygomatic suture, most superior point of temporozygomatic suture, most posterior-lateral point of the maxilla, gonion, condylion, mental foramen) and distance from orthogonal planes (in millimeters) was used to evaluate the asymmetry on each axis and to calculate a global asymmetry index of each anatomical landmark. Mean asymmetry values and relative confidence intervals were obtained from the control group. OAVS patients showed 2.5 ± 1.8 landmarks above the confidence interval while considering the global asymmetry values; 12 patients (92%) showed at least one pathologically asymmetric landmark. Considering each axis, the mean number of pathologically asymmetric landmarks increased to 5.5 ± 2.6 (p = 0.002) and all patients presented at least one significant landmark asymmetry. Modern CT-based 3D reconstructions allow accurate assessment of facial bone asymmetries in patients affected by OAVS. The evaluation as a global score and in different orthogonal axes provides precise quantitative data suitable for maxillo-facial surgical planning. CT-based 3D reconstruction might allow a quantitative approach for planning and following-up maxillo-facial surgery in OAVS patients.

Congenital heart defects in patients with oculo‐auriculo‐vertebral spectrum (Goldenhar syndrome)

The oculo-auriculo-vertebral spectrum (OAVS) is a non-random association of microtia, hemifacial microsomia with mandibular hypoplasia, ocular epibulbar dermoid, and cervical vertebral malformations. Congenital heart defects (CHDs) have been reported in 5-58% of the patients. We analyze the frequency and anatomic features of CHD in a series of 87 patients with OAVS examined between January 1990 and February 2007 with normal chromosomes, ranging in age between 0.1 and 16.8 years. A twin pregnancy occurred in eight cases (dizygotic in six cases and monozygotic in two). CHDs were diagnosed in 28/87 (32%) patients, and classified into categories of postulated developmental mechanisms including 9 (32%) atrial and ventricular septal defects, 11 (39%) conotruncal defects, 4 (14%) targeted growth defects, two (7%) with situs and looping defects, one (4%) with a left-sided obstructive lesion and one (4%) with patent ductus arteriosus. As noted in other series, the most common individual CHDs were ventricular septal defect (six patients) and tetralogy of Fallot (TOF) (classic or with pulmonary atresia) (six patients). Comparing the frequencies of CHDs groups observed in the OAVS patients with the findings of the Emilia-Romagna Registry which ascertained CHDs prevalence in the general population, conotruncal defects, targeted growth defects, and heterotaxia were significantly associated with OAVS.