Introduction

The association of oculoauriculovertebral spectrum (OAVS) and radial defects have been reported since 19291, 2, 3, 4, 5, 6, 7, 8, 9 and, the early literature on the issue used to quote radial anomalies as a clinical feature belonging to the OAVS; however, some authors have considered it as a unique association, representing a ‘new’ condition within the spectrum (OMIM 141400).7, 10 Taking into account the clinical manifestation of the OAVS with radial defects, and the OAVS without limb involvement, there are no differences concerning craniofacial and extracraniofacial anomalies when both are compared. To date, about 32 cases on OAVS and radial defects have been reported, and in 26 instances, the data were informative.3, 5, 6, 7, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 Here, we describe 14 Brazilian patients with clinical signs of OAVS associated with several radial defects (Figures 1a–d, 2a–d, 3a–d, 4a–d, 5a–d, 6a–d, 7a–d, 8a–d, 9a–d, 10a–d, 11a–d, 12a–d, 13a–d and 14a–d). Hearing evaluation through audiometry and brainstem evoked response, and radiological evaluation through temporal bone CT scan, were performed in all patients. The relationship among clinical, audiological, and radiological findings is discussed.

Figure 1
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(a–d) – Clinical aspects of the face and upper limbs of patient 1.

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Figure 2
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(a–d) – Clinical aspects of the face and upper limbs of patient 2.

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Figure 3
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(a–d) – Clinical aspects of the face and upper limbs of patient 3.

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Figure 4
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(a–d) – Clinical aspects of the face and upper limbs of patient 4.

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Figure 5
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(a–d) – Clinical aspects of the face and upper limbs of patient 5.

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Figure 6
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(a–d) – Clinical aspects of the face and upper limbs of patient 6.

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Figure 7
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(a–d) – Clinical aspects of the face and upper limbs of patient 7.

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Figure 8
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(a–d) – Clinical aspects of the face and upper limbs of patient 8.

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Figure 9
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(a–d) – Clinical aspects of the face and upper limbs of patient 9.

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Figure 10
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(a–d) – Clinical aspects of the face and upper limbs of patient 10.

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Figure 11
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(a–d) – Clinical aspects of the face and upper limbs of patient 11.

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Figure 12
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(a–d) – Clinical aspects of the face and upper limbs of patient 12.

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Figure 13
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(a–d) – Clinical aspects of the face and upper limbs of patient 13.

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Figure 14
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(a–d) – Clinical aspects of the face and upper limbs of patient 14.

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Materials and methods

We selected a sample of 24 cases from the Clinical Genetic Service with the Hospital de Reabilitação de Anomalias Craniofaciais of the University from São Paulo – Bauru-SP, Brazil. Ten cases were excluded due to interruption of treatment, social problems, or premature death. The remaining concerns the present sample that involves 14 patients (Figures 1a–d, 2a–d, 3a–d, 4a–d, 5a–d, 6a–d, 7a–d, 8a–d, 9a–d, 10a–d, 11a–d, 12a–d, 13a–d and 14a–d). Minimal criteria for propositi to be included in the casuistic were the presence of asymmetrical external ear malformation and radial defects. The protocol for evaluation of the patients included: identification data; prenatal, perinatal, and family history. Clinical evaluation included: general examination with particular concern to the classification of the external ear defect and the facial type of cleft. Complementary evaluation included: skull, facial, and upper limbs X-rays; temporal bone CT scan; and hematological and G-banded chromosome studies. Audiological evaluation included puretone audiometry, speech audiometry, tympanometry, stapedius reflex measurement, and brainstem evoked response. In some ears, it was not possible to perform the tympanometry and stapedius reflex measurement owing to malformation. Malformations of the external ear were graded according to modified system from Meurman;27 atypical facial clefts were classified according to Tessier system;28 and hearing loss type was classified according to Katz.29 The clinical aspects of our patients (14 cases) and of those described in the literature (26 patients) were compared.

Results

From the total of the sample, eight patients were male and six female (sex-ratio 1:1); mean age was 11.1 years (range, 1–25 years); mean maternal age was 24.1 years; and mean paternal age was 28.7 years. There was no history of exposure neither to known teratogenic agents nor maternal diseases. All cases were isolated with negative family history for related features. No parental consanguinity was observed. Hematological and cytogenetic studies were normal in all patients.

From the informative reviewed cases, the sex ratio was 1:1; mean age was 5.5 years (range, 1 month to 25 years); mean maternal age was 30.3 years; and mean paternal age was 37.2 years. Maternal diabetes or gestational diabetes was present in four cases; cocaine exposure was reported in one case. Twenty-four out of twenty-six reported cases were isolated; familial recurrence was described once and, parental consanguinity was reported in one instance.

Clinical findings

The main clinical findings of our cases and those previously reported in the literature are listed in Table 1.

Table 1 Main clinical features reported in our patients compared with the previously described cases
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Radial defects

Varied defects involving the radial developmental field occurred in all patients studied.

The most common anomalies observed were hypoplasia of the thumb and hypoplasia and/or agenesis of the radio. The radial defects observed with less frequency were thumb agenesis, preaxial polydactyly, and triphalangeal thumb.

Taking into account the literature cases, agenesis of the thumb and hypoplasia and/or agenesis of the ratio were most common, whereas trifalangeal thumb, preaxial polydactyly, and thumb hypoplasia were rarely observed.

Laterality

In relation to facial anomalies, unilateral facial involvement was observed in eight out of 14 patients (57.1%): right-sided in five instances (62.5%) and left-sided in three (37.5%). Bilateral facial involvement was present in six out of 14 patients (42.8%).

Considering the radial defects, the unilateral radial involvement was observed in eight out of 14 cases: right-sided involvement in five instances (61.5%) and left-sided in three (37.5%). Bilateral involvement was present in six cases (42.8%).

From the eight patients with unilateral facial involvement, five (62.5%) had ipsilateral upper limbs defects; one (12.5%) had contralateral upper limb defects; and two (25%) had bilateral upper limbs involvement. From the six patients with bilateral facial involvement, four (66.7%) had also bilateral involvement of the upper limbs and two (33.3%), had unilateral upper limbs defects.

From the informative reviewed cases, unilateral facial involvement was described in 20 of 24 cases: right-sided in 12 instances and left-sided in eight. Bilateral involvement was present in four patients. In relation to radial defects, unilateral involvement was observed in 23 out of 26 cases: right-sided involvement in 12 instances and left-sided in 11. Bilateral involvement was present in three cases. From the 20 patients with specific unilateral facial involvement, 14 had ipsilateral upper limbs defects; three had bilateral upper limbs involvement; and five had contralateral upper limb defects. All patients with bilateral facial involvement had unilateral upper limbs involvement.

Ears structural involvement and hearing loss

In relation to external ear anomalies, 20 out of 28 ears presented microtia. Type I was the most common and it was observed in 10 (50%) out of 20 ears. Type II microtia was observed in two (10%) out of 20 ears, and type III microtia was observed in eight (40%) out of 20 ears. Middle ear malformations were detected in four (20%) out of 20 ears with microtia; inner ear malformations were detected in four (20%); and middle and inner ear malformations were detected in 11 (55%). Structural middle and/or inner abnormalities were absent in one ear with microtia. From the 10 ears with type I microtia, two (20%) had middle ear malformation; three (30%) had inner ear malformation; four (40%) had both, middle and inner malformation; and one (10%) had no malformation of middle and/or inner ear. From the two ears type II with microtia, one (50%) had middle ear malformation; and one (50%) had inner ear malformation. From the eight ears with type III microtia, one (12.5%) had middle ear malformation and seven (87.5%) had middle and inner ear malformation.

Taking into account, the external ear anomalies of the literature sample, 30 out of 50 ears presented microtia. Type I was the most common and it was reported in 16 (53.3%) out of 30 ears. Type II microtia was reported in two (6.7%) out of 30 ears, and type III microtia was observed in six (20%) out of 30 ears. Anotia was reported in two (6.7%) out of 30 ears and, the type was not specified in four (13.3%) out of 30 ears. Evaluation of middle and/or inner ear was performed in five out of 30 ears with microtia (four with type I and one with type II). Structural middle ear malformations were described in one (20%) out of five ears; structural inner ear malformations were reported in three (60%); and structural middle and inner ear malformations were detected in one (20%). From the four ears with type I microtia, one had middle ear malformation and three had inner ear malformation. Structural middle and inner ear malformation was observed in one ear with type II microtia.

In relation to hearing loss, 27 out of 28 ears showed hearing loss. All ears with microtia (20 ears) had hearing loss: four (20%) presented conductive hearing loss; six (30%) presented mixed hearing loss; eight (40%) presented sensorioneural hearing loss. It was not possible to conclude the type of hearing loss in two (10%) out of 20 ears with microtia. From the eight ears without microtia, normal hearing was present in one ear; conductive hearing loss in three; mixed hearing loss in two; and sensorioneural hearing loss in two. Taking into account, the type of microtia and the type of hearing loss, from 10 ears with type I microtia, four (40%) had conductive hearing loss; two (20%) had mixed hearing loss; and four (40%) had sensorioneural hearing loss. The two ears with type II microtia had sensorineural hearing loss. From eight ears with type III microtia, four (50%) had mixed hearing loss; two (25%) had sensorioneural hearing loss; and in two (25%), the type of hearing loss was not conclusive.

From the reviewed cases of the literature, only 14 ears had audiological evaluation. Conductive hearing loss was present in three out of 14 ears and mixed hearing loss in one ear. The hearing loss type was no conclusive in eight out of 14 ears and, the hearing was normal in two ears.

Discussion

OAVS, or Goldenhar syndrome, is a well-recognized condition characterized by variable degree of uni- or bilateral involvement of craniofacial structures involving first and second branchial arches, ocular anomalies and vertebral defect. Clinically, it ranges from isolated microtia with or without mandibular hypoplasia, to a more complex phenotype with skeletal, cardiac, renal, pulmonary, and central system manifestations.2, 5 The pathogenetic mechanisms involved have been a matter of controversy and theories2, 30, 31 but so far, no definitive causal agent could be found. It has been postulated that the Goldenhar syndrome represents a defect of blastogenesis32 that could be attributed to interferences in cephalic neural crest cell migration,33 however, in some cases of OAVS with multi systemic malformations, the involvement of several developmental fields do not sustain a localized damage.

The OAVS with radial defects characterizes a subset within the OAVS mainly involving uni- or bilaterally the first branchial arches and limb primordium. The main signs include external, middle, and inner ear malformations; facial asymmetry, orofacial clefts, mandible hypoplasia, and radial defect, which is a ‘sine qua non’ anomaly for clinical diagnosis. Inner ear involvement was frequently observed in OAVS with radial defects (78.6% of cases and, 80% of cases of literature sample). This type of anomaly has been reported once in patients with the Goldenhar syndrome with a low frequency (36% of cases).34 The high frequency of inner ear involvement in patients with OAVS and radial anomalies could suggest that this is a common clinical sign of this subset.

The inner ear anomalies have been reported in patients with microtia but without correlation with the degree of microtia.35 In the patients here reported, type I and type III microtia were most common, corresponding to 50 and 40%, respectively, and in both, a high incidence of inner ear malformation associated, or not with middle ear malformation, was noted – 70 and 87.5%, respectively, showing that the severity of the external ear malformation was not predictive of inner structural anomalies. These data suggest that type I and type III microtia, in OAVS, could be related to inner ear involvement. It has to be stressed that in patients with bilateral ear involvement, the association of type I and type III microtia was most common. In the literature, type I microtia was most frequent (53.3%) and, such as in our sample, a high incidence of inner ear malformation was reported, too.3, 6, 7, 8, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24 Rollnick and Kaye36 found that, type II microtia was most frequent (42%) in familial cases with hemifacial microssomia and in variants without radial anomalies, but the inner ear evaluation was not performed. In our sample, sensorioneural hearing loss was most common in type I microtia (40%) and in type II microtia (100%) showing that the type of microtia had no predictive value for the type of hearing loss. These data suggest that the sensorioneural hearing loss is a sign related to the OAVS with radial anomalies. In the previously reported cases with this condition, in 14 patients that were submitted to audiological evaluation, hearing loss was detected in 12.

The low weight and short stature in patients show that these clinical findings are a part of the phenotypic spectrum of OAVS with radial defects. Tasse et al,37 in a sample of 53 patients with OAVS, found that anomalies of extremities, such as, thumb hypoplasia, were significantly associated with the short stature.

Systemic anomalies represented by cardiovascular and pulmonary defects and, anal anomalies, in our sample, were also observed in OAVS, however, the real incidence of these anomalies is not well known.2, 4, 5, 20 In relation to OAVS with radial defects, the presence of some systemic anomalies did not exceed that observed in previously reported cases with OAVS except, the cardiovascular defect that was detected in 33.3% of the patients here studied and in 92.8% of the cases in the literature.3, 6, 7, 8, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24 These data support the hypothesis that cardiovascular defects are a frequent clinical sign of OAVS with radial defect. The presence of imperforate anus, stresses the importance of differential diagnosis with the Townes–Brocks syndrome (TBS). A family, considered for a long time as an interesting example of OAVS, has been presently regarded as an example of TBS, after a baby was born with imperforate anus. Both the baby and his grandmother had radial anomalies.38 Two studies have, so far, reported a nonsense mutation in SALL1 in one patient with features of both TBS and hemifacial microsomia.39, 40 The molecular analysis may be helpful in establishing a correct diagnosis for some cases, taking into account that mutation in the SALL1 gene causes TBS.41 Other important report concerns an unusual family in which affected individuals showed an extremely variable phenotype, consistent with the Okihiro syndrome, or hemifacial microsomia, or the isolated Duane anomaly.42 These studies indicate that not only SALL1 testing might be considered in some cases but SALL4 analysis is indicated as well. Other conditions with ear and/or radial involvement, such as, the Nager syndrome (OMIM 154400), Holt–Oram syndrome (OMIM 142 900), radial–renal syndrome (OMIM 179 280), facioauriculoradial dysplasia (OMIM 171 480), Fanconi anemia (OMIM 257 650), and VACTERL (OMIM 192 350) association should be considered for differential diagnosis.10

Conclusion

In conclusion, we postulate that the patients presented with radial defects, inner ear malformation and sensorioneural hearing loss associated with anomalies of first and second branchial arches may characterize a new subset within OAVS, however, molecular analysis of SALL1 and SALL4 should be performed for exclusion of TBS and Okihiro syndrome. This study showed that this subset (OAVS with radial defect) had unknown etiology and sex ratio of 1M:1F. Clinical findings such as low weight postnatal and short stature are part of the phenotypic spectrum of OAVS with radial defects. Concerning systemic anomalies, cardiac defects are the most frequent.

In relation to facial involvement, this subset presents, frequently, unilateral facial involvement, with the right-sided involvement in most cases, and the ipsilateral radial defect is usually observed. The high occurrence of structural inner ear malformation and sensorioneural hearing loss, observed in these patients, show that these findings are particular clinical signs of the OAVS with radial defects. Taking into account that some few cases with OAVS and radial defects were reported in mothers with a history of diabetes21, 23 and that pregnant women with pre-existing or gestational diabetes have a higher risk of giving birth to a child with malformations,43 special attention should be paid to maternal glicemia. Our study suggests that we are dealing with a new condition within the OAVS, however, molecular analysis of SALL1 and SALL4, to exclude TBS and Okihiro syndrome is essential to clarify this point.