Spectrum of Temporal Bone Abnormalities in Patients with Waardenburg Syndrome and SOX10 Mutations

Discussion

Abnormalities of the labyrinth have previously been reported in WS. In a review of the literature combined with their own data, Oysu et al⁹ found abnormalities in 6 of 36 cases in radiologic studies (polytomography and CT examinations). SCC abnormalities were the most frequent finding, with hypoplastic cochleae also observed. None of these studies were conducted in conjunction with molecular analysis, however, and most did not account for WS types. We and others recently reported isolated cases of inner ear abnormalities in patients with SOX10 mutations. In this article, we report a series of imaging results associated with molecular analysis (SOX10 mutations) in WS. In addition to confirming SCC defects and cochlear abnormalities, this series allows further conclusions to be drawn regarding this genetic subtype of WS.

Even though there is an inclusion bias in that only patients with reported abnormalities of the temporal bone were included, this study allowed analysis of the different patterns and their relative prevalence. Cochlear and vestibular morphologic abnormalities were similar in frequency to each other (Table 1: cochlear abnormalities 93%, vestibular abnormalities 100%). Although all SCCs showed a comparable frequency of abnormalities, the agenesis pattern had a more specific distribution. Posterior SCC agenesis was seen with the highest frequency and was followed by agenesis of the superior SCC and lateral SCC, respectively.

Generally, posterior and superior SCC abnormalities are rare, and lateral SCC abnormalities are frequent, possibly due to the later formation of the lateral SCC during embryogenesis.²² The frequency of posterior and superior SCC agenesis found in patients with SOX10 mutations does not follow the hypothesis of Jackler et al,²³ which stipulates that radiographically detectable malformations correlate with arrested inner ear organogenesis at different stages. Agenesis of posterior and superior SCCs being rare findings, they may be more evocative of a SOX10 mutation than agenesis of the lateral SCC.

Total absence of the SCCs is found in coloboma, heart malformation, choanal atresia, growth retardation, genital hypoplasia, and ear abnormalities (CHARGE) syndrome, often with a hypoplastic vestibule and variable cochlear deformities, including abnormal partitioning; moreover, cochlear nerve canal atresia with cochlear nerve aplasia is common.^10,24 While absence of all the SCCs is more common, absence of only 1 or 2 has also been described in CHARGE.²⁵ Nevertheless, abnormalities of the middle ear structures, such as ossicular malformations, facial canal malposition, and oval window aplasia, are usually associated,²⁴ and the clinical spectrum in CHARGE is different from that in WS. Total or partial absence of SCCs has also been described in Noonan and Alagille syndromes. Noonan syndrome shows a dysmorphic external ear and may also present with middle ear abnormalities.²⁶ Histopathologic²⁷ and CT²⁸ studies of Alagille syndrome have shown partial agenesis of the posterior SCC, a hypoplastic superior SSC, and a normal lateral SCC.

We found inner ear abnormalities in patients with both WS2 and WS4, which, in some cases, also presented neurologic symptoms (eg, PCWH). This finding correlates with the hypothesis of Oysu et al⁹ that inner ear malformations are often present in WS2 but not in WS1, because 15% of WS2 cases (and no WS1 cases) are caused by SOX10 mutations.² The malformations we describe in this article have not been associated with other WS genes and may represent pathognomonic features of SOX10 molecular defects. However, within SOX10-linked WS, we did not find a correlation between the type of WS (WS2, WS4, or PCWH) and the type or severity of the inner ear malformations observed.

SOX10 is a regulator of neural crest development.²⁹ It is particular among WS genes for its early expression in inner ear development: in the otic placode and the otic vesicle, then in the developing epitheliums of the cochlea and vestibule before being restricted to supporting cells of the neurosensory epithelium. SOX10 has been shown to promote the survival of cochlear progenitors during otocyst formation and the establishment of the organ of Corti.³⁰ It is also expressed persistently in the cochleovestibular ganglia and plays a role in glial development.^{30⇓⇓⇓–34}

In Sox10 homozygous mutant mice, the differentiation and cellular organization of the organ of Corti and the vestibule appear normal. However, the cochlear duct is shortened.³⁰ In humans, where SOX10 mutations are heterozygous, vestibular abnormalities are much more apparent than those in mice. Other differences have been observed across species: In Sox10 mutant zebrafish, the otic vesicle is smaller or distended, semicircular canals have a delayed development and are thinner than normal, and the sensory epithelia are incorrectly patterned.³⁵ These expression and functional studies, in combination with our findings, suggest that cochleosaccular degeneration is not the only mechanism leading to SNHL in patients carrying SOX10 mutations.

It is tempting to correlate the high frequency of vestibular malformations to vestibular dysfunction. The prevalence of vestibular dysfunction in WS is not well-established but may be high.³⁶ Results of vestibular function tests were only available for 6 of our patients. The most severe imaging pattern (agenesis of all canals) was associated with complete loss of vestibular function. However, in the case of ≥1 hypoplastic canal, the vestibular function was not constantly impaired; this finding could signify that some hypoplastic canals contain functional sensory epithelium.

The large majority of our patients were implant candidates, so assessment of the cochlear nerve was mandatory. Two patients, both with a PCWH phenotype, had bilateral cochlear nerve agenesis and CNC atresia. In addition, 1 patient with WS4 had a unilateral cochlear nerve agenesis with a patent CNC on CT, and 1 patient with PCWH had a unilaterally thin cochlear nerve compared with the contralateral nerve on the oblique sagittal plane perpendicular to the internal auditory canal.

Previous articles have described in detail white matter abnormalities associated with SOX10 mutations in patients with neurologic impairments (for examples see Pingault et al,² Inoue et al,¹³ Barnett et al,¹⁷ and Inoue et al³⁷). The presence of such defects in this cohort was correlated to the PCWH phenotype, with the notable exceptions of patients D1 and I. A more surprising finding was the very high percentage of agenesis or hypoplasia of olfactory bulbs and lacrimal and parotid glands, which existed in 79%–88% of these patients with temporal bone abnormalities (Table 2). Olfactory bulb agenesis is also commonly found in CHARGE syndrome. The high percentages found here are likely to contribute to anosmia and possibly, in parallel to the previously suspected dysautonomia,³⁸ to alacrima and asialia, which have been reported in a limited number of patients with PCWH.^11,33,39 Of note, these imaging findings were not limited to patients with neurologic impairments in the cohort presented here.