CHD7 mutational analysis and clinical considerations for auditory rehabilitation in deaf patients with CHARGE syndrome

Abstract

Background: Otologic manifestations are one of the most consistent findings of CHARGE syndrome found in more than 90%. Since genetic analysis of the CHD7 gene has rarely been performed in previous reports dealing with ear abnormalities, the genotypic spectrum of CHD7 mutations was analyzed in deaf patients with CHARGE syndrome, and the clinical considerations concerning auditory rehabilitation were investigated.

Methods: Nine Korean patients with CHARGE syndrome showing profound hearing loss and semicircular canal aplasia were included. All 38 exons of CHD7 were analyzed by direct sequencing. For splice site variations, in silico and exon-trapping analyses were performed to verify the pathogenicity of nucleotide variations. Clinical features and the outcome of auditory rehabilitation were also analyzed.

Results: Eight of 9 patients revealed alterations of the CHD7 gene including 3 frameshift, 2 nonsense, 2 splice site, and 1 missense mutations. Five of 9 patients were clinically diagnosed as atypical CHARGE syndrome but demonstrated various mutations of the CHD7 gene. One familial case showed intra-familial variability. Radiologic findings suggesting cochleovestibular nerve deficiency were identified in most of the patients. Of the 8 patients who underwent cochlear implantation, 5 patients demonstrated favorable outcome. Larger diameter of the cochleovestibular nerve on imaging and absence of severe mental retardation were factors related to better outcome after cochlear implantation rather than the type of CHD7 mutations. Auditory brainstem implantation was performed in two patients who did not benefit from cochlear implantation.

Conclusions: Genetic analysis of the CHD7 gene should be performed in cases with semicircular canal aplasia even when other typical features of CHARGE syndrome are absent. For auditory rehabilitation in CHARGE syndrome, cochlear implantation should be strongly recommended in selected cases with favorable prognostic factors. Auditory brainstem implantation may be a viable option in patients with CHARGE syndrome who have failed to benefit from cochlear implantation.

Figure 1. Pedigree and clinical findings of familial case of CHARGE syndrome (Patient 1).

(A) Pedigree shows that only two siblings are affected by deafness either bilaterally (Patient 1; proband marked by black arrow) or unilaterally (sister of Patient 1 marked by asterisk). (B) The sister of Patient 1 demonstrated unilateral deafness on pure tone audiometry. (C) Temporal bone CT of the sister of Patient 1 with unilateral deafness showed slightly dilated but present semicircular canals (white arrowhead) with mild cochlear abnormality and normal sized internal auditory canal on the affected side. (D) Temporal bone CT of Patient 1 with bilateral congenital deafness demonstrated complete absence of all semicircular canals (black arrow).

Figure 2. Computed tomography findings of inner ear anomalies typically seen in patients with CHARGE syndrome.

(A) Cochlear hypoplasia is shown by a black arrow (Patient 1). (B) Bony cochlear nerve canal is obliterated (black arrowhead) and complete aplasia of the semicircular canals is seen (white arrowhead). The incus is dysmorphic and slightly rotated state (asterisk). Ankylosis between the incus and malleus (white arrow) and between the ossicles and epitympanic bone (black arrows) is shown (Patient 4). (C) Bony obliteration of the round window is seen (small white arrow) (Patient 6). (D) Oval window atresia is seen on the coronal image (large white arrow) (Patient 2).

Figure 3. The parasagittal images of temporal MRI in patients with CHARGE syndrome.

(A–B) The cochleovestibular nerve (arrowheads) is larger in diameter than the facial nerve (arrows) at the cerebellopontine angle (A) and within the internal auditory canal (B) in Patient 1. (C–D) The cochleovestibular nerve (arrowheads) is smaller in diameter than the facial nerve (arrows) at the cerebellopontine angle (C) and within the internal auditory canal (D) in Patient 4.

Figure 4. The improvement of auditory performance after cochlear implantation (CI) and auditory brainstem implantation (ABI) in patients with typical or atypical CHARGE syndrome.