Inner Ear Anomalies Are Frequent but Nonobligatory Features of the Branchio-oto-renal Syndrome

Objective  To summarize the syndromic features and evaluate the presence of inner ear anomalies in 35 patients with branchio-oto-renal (BOR) syndrome from 6 families.

Design  Retrospective evaluation of magnetic resonance imaging of the temporal bones and clinical features in patients with BOR syndrome.

Setting  Tertiary referral center.

Patients  The study population comprised 35 clinically affected patients with BOR syndrome from 6 families. Most of these families were followed for over 25 years.

Main Outcome Measures  Twenty-four patients underwent high-resolution, heavily T2-weighted 3-dimensional magnetic resonance imaging of the temporal bones for evaluation of inner ear anomalies. Special attention was paid to the endolymphatic duct and sac.

Results  A total of 7 enlarged endolymphatic ducts and sacs (3 bilaterally and 4 unilaterally) and 5 enlarged endolymphatic ducts only (2 bilaterally and 3 unilaterally) were observed. Eight hypoplastic cochleas and 6 hypoplastic labyrinths were seen bilaterally. Seven family members had normal inner ears.

Conclusion  These findings suggest that inner ear anomalies are frequent but nonobligatory features of BOR syndrome.

THE BRANCHIO-OTO-RENAL (BOR) syndrome is defined as an autosomal dominant inherited disorder characterized by the following 3 essential clinical features: (1) hearing loss with structural defects of the external (including earpits), middle, and/or inner ear; (2) second branchial arch defects; and (3) renal anomalies, ranging from mild hypoplasia to aplasia, which can lead to varying degrees of renal failure. Accompanying features such as lacrimal duct stenosis or a high-arched palate can also be present in these patients.^1-4 One gene underlying the BOR syndrome, EYA1 (chromosome 8q13.3), has been identified.^5-8 Recent linkage analysis provided evidence for a second gene on chromosome 1q31.⁹ This disorder has a high penetrance but variable clinical expression. The major clinical findings associated with BOR syndrome are branchial clefts, hearing loss, and renal failure.^1-4,10,11 The general prevalence of BOR syndrome is 1 in 40 000 people, and it occurs in 2% of profoundly deaf children.¹²

Radiological and histological investigations have demonstrated the presence of congenital inner ear anomalies in patients with BOR syndrome.^4,13 Enlarged vestibular aqueduct and cochlear hypoplasia have been identified and may be important findings in BOR syndrome.

The syndromic features of 35 patients with BOR syndrome from 6 families are described in the present article. Magnetic resonance imaging (MRI) of the temporal bones was performed in most of the patients to evaluate inner ear anomalies. Special attention was paid to a large endolymphatic duct and sac.

We investigated 6 families with BOR syndrome (families A-F) with 35 affected family members. The family members who participated in this study were seen at the outpatient clinic of the Department of Otorhinolaryngology, University Medical Center St Radboud, Nijmegen, the Netherlands. Most of these BOR syndrome families were followed for over 25 years.^{3,10,11,14-17} Renal function tests, intravenous pyelography, and/or ultrasonography of the kidneys have been performed to record any renal involvement in most patients.¹¹ Pedigrees were updated (Figure 1), and the results of the otorhinolaryngological examination were evaluated (Table 1).

Twenty-four patients underwent high-resolution, heavily T2-weighted 3-dimensional MRI of the temporal bones (Siemens Magnetom Vision, 1.5 T; Siemens, Erlangen, Germany). This MRI technique enables 3-dimensional reconstruction in any desirable plane to study abnormalities of the inner ear structures. Owing to the presence of endolymph, these structures have a high-signal intensity on T2-weighted images. Thin-section MRI technique enables us to visualize the often invisible endolymphatic duct and sac, especially if they are enlarged.¹⁹ The endolymphatic duct is considered to be dilated when its diameter, at the midpoint between the common crus and its external aperture, is 1.5 mm or more on thin-section images.²⁰ Linkage analysis and/or mutation analysis of the EYA1 gene was performed in all 6 families.

The pedigrees of the families A through F are shown in Figure 1, and relevant clinical information is presented in Table 1 for each affected family member separately. The number of affected individuals in each generation conformed to an autosomal dominant pattern of inheritance with close to 100% penetrance in almost each family, including the ones indicated as "affected by history," whose children were affected. The only possible exception was the second generation of family E (P = .04 in binomial distribution). Male-to-male transmission was documented in families A, C, and D.

Clinical features, present in about 32 cases (95%) of cases, were malformed auricles, preauricular sinus and/or pit, second branchial arch fistula, and hearing impairment. Renal malformation was fairly common (13 patients [37%]), whereas preauricular tags and lip pits (6 patients [17%]) were less common. The penetrance of these features did not differ significantly in any of the separate families from the average penetrance calculated for the combined families.

Most patients had had their second branchial arch fistulas surgically removed. Preauricular sinus and/or pits or tags had only been removed incidentally. Surgical intervention is often indicated because of recurrent infection of these anatomical variations. Aesthetic surgical correction of malformed auricles has been performed in a few cases (Table 1). Nine patients (38%) required middle ear surgery. Cremers et al^10,14,16 and Kemperman et al¹⁷ described the results and details of these interventions and, based on these data, discussed the impact of syndromic diagnosis, including BOR syndrome, on the outcome of reconstructive ear surgery.²¹

The MRI findings in the 6 BOR syndrome families are given in detail in Table 2, together with the findings of serial audiometry, and the relative frequency of anomalous MRI findings by structure are summarized below:

In 7 patients, a large endolymphatic duct and sac (3 bilaterally and 4 unilaterally) and in 5 others a large endolymphatic duct (2 bilaterally and 3 unilaterally) were observed. Nine hypoplastic cochleae and 6 bilateral hypoplastic labyrinths were present (Table 2). We did not find any congenital defects in 8 affected BOR syndrome patients (Figure 2, Figure 3, and Figure 4). In most cases the type of hearing loss was mixed. Long-term audiometric follow-up analysis (threshold data not shown) demonstrated that progressive, fluctuant sensorineural hearing loss is not uncommon in BOR syndrome (Table 2); we were unable to confirm this feature in all BOR syndrome patients.^17,22 Although a considerable proportion of cases exhibited anomalous findings, we were unable to find a clear relationship between these and any of the features of hearing impairment (progressive and/or fluctuant).

Linkage to the EYA1 locus was found in family A²² and family B; however, no mutations were detected by mutation analysis (S.K., unpublished data, 1999). In family C, a mutation (IVS-9 + G>C at −1) (S.K., unpublished data, 1999) was found, which probably results in aberrant splicing of the gene. Mutation analysis in family D showed the presence of a missense mutation (T-to-C transition at position 1360) in exon 13, resulting in a Ser454Pro substitution in the EYA1 protein.⁶ Family E has a delC at position 1592 of exon 15 causing a frameshift mutation.⁷ No mutation has been detected in family F yet.

Inner ear abnormalities can be regarded as common findings in patients with BOR syndrome. Recently, the presence of such abnormalities in combination with progressive hearing loss has been demonstrated in Pendred syndrome. In particular, the presence of an enlarged vestibular aqueduct was an almost obligatory finding in these patients.^23,24 The autosomal recessively inherited large vestibular aqueduct syndrome is a distinct clinical entity, although mutation analysis has shown that the large vestibular aqueduct syndrome and the Pendred syndrome both share mutations in the pendrin gene (PDS).²⁵

The present study shows that inner ear anomalies, such as cochlear hypoplasia and large endolymphatic duct and sac, are frequent features of BOR syndrome. This syndrome shares these features as well as progressive, fluctuant hearing loss with the Pendred syndrome. However, although such features were nonobligatory but frequently present in our BOR syndrome patients, they were not clearly correlated to one another. The latter result was obtained by testing on possible correlations of the pooled data of all families. This procedure is, obviously, not permitted if there is genetic heterogeneity between the present families. Unfortunately, we have insufficient information on form (MRI), impaired function (progressive and/or fluctuant hearing impairment), and linkage/mutation analysis to test for such a correlation in each family, even the largest ones, separately.

Because of the pathognomic presence of an enlarged vestibular aqueduct, computed tomographic scanning of the temporal bones can function as a diagnostic procedure in Pendred syndrome. We know from our experience that the branchiogenic origin of BOR syndrome can cause a wide range of anatomic malformations of the outer, middle, and inner ear structures. Indeed, many different forms of inner ear anomalies were present in our patients; however, none of them seems to be pathognomic for BOR syndrome. Nevertheless, MRI remains a useful additional tool that can visualize the neuronal tissues and the endolymphatic- and perilymphatic-filled structures, such as the cochlea and endolymphatic duct. It is clear that this technique refines our knowledge of the inner ear anatomy in general and specifically in BOR syndrome patients.

Until now many mutations in the EYA1 gene have been described,^5-7 and recent linkage analysis provided evidence of involvement of another gene underlying the BOR syndrome.⁹ No mutations are detected in the coding sequence of EYA1 in approximately 70% of families with the BOR phenotype. It would be interesting to perform further linkage analysis in such families. This would enable us to study the possible correlations between imaging findings, audiometrical follow-up results, and linkage results.

Accepted for publication March 4, 2002.

This study was financially supported by the Dutch Organization for Scientific Research, counsel for medical and health research (project No. 920-03-100). The BOR research work in the United States was supported by grant 1R01 DE14090-01 from the National Institute on Dental and Cranial-Facial Research, National Institutes of Health (Dr Kumar).

We would like to thank the family members who participated in this study.

Corresponding author and reprints: Martijn H. Kemperman, MD, Department of Otorhinolaryngology, University Medical Center St Radboud, PO Box 9101, 6500 HB Nijmegen, the Netherlands (e-mail: M.Kemperman@kno.azn.nl).