Clinical Insights into Bilateral Cochlear Implantation for a Child with Dominant Deafness-Onychodystrophy Syndrome

Abstract

Background:

Dominant deafness-onychodystrophy (DDOD) syndrome is a rare genetic disorder characterized by sensorineural hearing loss and the absence or hypoplasia of nails, associated with defects in the ATP6V1B2 gene. This gene defect significantly affects hearing function, leading to congenital severe-to-profound hearing loss.

Purpose:

We present the comprehensive cochlear implant (CI) outcome of a 5-year-old child with DDOD syndrome who received bilateral sequential CIs at the ages of 1  and 4 years.

Research Design:

Case study.

Data Collection and Analysis:

Retrospective chart review of aural-communication and language performance.

Results:

After the follow-up following the first CI, there was improvement in auditory, language, and cognitive abilities. At 41 months after the first CI, the child received the second CI. Although his language ability still lagged behind, his auditory and communication performance continued to improve after bilateral CI surgery. He obtained 95 percent on the Parents’ Evaluation of Aural/Oral Performance of Children scale at the last follow-up.

Conclusions:

Children with DDOD syndrome (ATP6V1B2 c.1516C > T) receiving bilateral CIs can enhance aural and communication skills.

INTRODUCTION

Dominant deafness-onychodystrophy (DDOD) syndrome (OMIM 124480), a rare genetic disorder characterized by congenital sensorineural hearing loss and the absence or hypoplasia of nails, was first recognized by Feinmesser and Zelig (1961). The prevalence of DDOD syndrome is less than 4–6 in 10,000 (Human Disease Genes, 2023). Its underlying pathogenesis remains unclear. DDOD syndrome is reported to be related to ATP6V1B2 gene mutation (Yuan et al, 2014; Menendez et al, 2017; Zhao et al, 2019; Zádori et al, 2020; Li et al, 2021; Human Disease Genes, 2023). Pathogenic variants of ATP6V1B2 are also associated with Zimmermann–Laband (ZL) syndrome (OMIM 616455) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome (OMIM 220500) (Yuan et al, 2014; Menendez et al, 2017; Zhao et al, 2019; Zádori et al, 2020; Li et al, 2021; Gao et al, 2022). Previous studies suggest that the ATP6V1B2 (c.1516C > T) mutation is possibly associated with DDOD syndrome (Yuan et al, 2014; Menendez et al, 2017; Zhao et al, 2019; Li et al, 2021; Gao et al, 2022; Human Disease Genes, 2023; Rousseau et al, 2023) or DOORS syndrome (Zádori et al, 2020; Gao et al, 2022; Rousseau et al, 2023), and the ATP6V1B2 (c.1454G > C) mutation is possibly associated with ZL syndrome (Menendez et al, 2017; Zhao et al, 2019; Gao et al, 2022). The pattern of inheritance differs among these syndromes, with autosomal dominant inheritance observed in DDOD syndrome (Vind-Kezunovic and Torring, 2013; Yuan et al, 2014; Menendez et al, 2017; Zhao et al, 2019; Zádori et al, 2020; Li et al, 2021; Gao et al, 2022) and ZL syndrome (Menendez et al, 2017; Gao et al, 2022) and autosomal recessive inheritance in DOORS syndrome (Zádori et al, 2020; Gao et al, 2022). Moreover, de novo mutations in DDOD syndrome have been reported in several studies (Vind-Kezunovic and Torring, 2013; Yuan et al, 2014; Menendez et al, 2017; Li et al, 2021; Gao et al, 2022).

Hearing loss in ATP6V1B2 defects is congenital and severe-to-profound, resulting from apoptosis of spiral ganglion neurons (Qiu et al, 2021), and cochlear implantation (CI) is an option to improve hearing for affected individuals (Gao et al, 2022). The hearing outcomes of cochlear implantation may be varied for such postsynaptic lesions. Some patients with DDOD syndrome have chosen to receive CI, but comprehensive reports of CI outcomes are lacking (Vind-Kezunovic and Torring, 2013; Yuan et al, 2014; Zhao et al, 2019; Li et al, 2021). Here, we present the comprehensive CI outcome of a child with DDOD syndrome who received bilateral sequential CIs.

CASE REPORT

The study was approved by the hospital institutional review board (no.: 24MMHIS051e). The requirement for obtaining informed consent was waived.

The patient was a 5-year-old boy with congenital hearing loss and the absence of nails. He was born full-term with a weight of 3,120 grams. The newborn hearing screen with automated auditory brainstem response showed bilateral refer at birth. The acoustic reflex threshold test showed an absent response on the contralateral side in both ears, auditory brainstem response showed no response at 95 dB nHL, and behavioral observation audiometry showed minimal response levels of 90–95 dB HL in the right ear and 95–110 dB HL in the left ear; the infant was diagnosed with severe-to-profound hearing loss at 5 months of age (Figure 1A). Physical examination revealed facial anomalies including hypertelorism, small palpebral fissures, internal strabismus, flat and wide-based nose tip, bulbous nose, bilateral low-set ears, and prominent and long philtrum. Furthermore, we observed the absence of all fingernails and toenails on both hands and feet and brachydactyly (Figure 1B and 1C). Computed tomography and magnetic resonance imaging confirmed that both the cochlea and cochlear nerve were of typical size. Electroencephalogram examination of the brain was unremarkable. Genetic testing of the child, performed using Sanger sequencing, identified a heterozygous mutation in the ATP6V1B2 gene (c.1516C > T), confirming the diagnosis of DDOD syndrome (Figure 2A). Neither of his parents carried the same mutation in the ATP6V1B2 gene (c.1516C > T) (Figure 2B and 2C), confirming a de novo mutation (Figure 2D).

Figure 1.

The phenotype of the patient shows bilateral profound hearing loss at 500 hertz (Hz), 1 kHz, 2 kHz, and 4 kHz (A) and absence of all fingernails (B) and toenails (C) with brachydactyly.

Figure 2.

The Sanger sequencing analysis report of the patient (A) and his parents (B and C) and the pedigree (D).

The child underwent cochlear implantation at the age of 1 year and 1 month on the right side, using CI24RE (Nucleus 6). We used the Mandarin Chinese Parents’ Evaluation of Aural/Oral Performance of Children (PEACH) rating scale (Pan, 2016), which is suitable for individuals of all ages with mild-to-profound hearing loss, to assess the auditory and oral performance in daily life after CI. The PEACH rating scale comprises 13 questions across five categories and is rated by parents. The test scores were summed up and divided by the overall score to calculate the percentage. The patient obtained scores of 7 percent, 25 percent, 61 percent, and 82 percent at preoperative, post-CI 6-month follow-up, 12-month follow-up, and 24-month follow-up, respectively, using bimodal fitting (CI on the right, hearing aid on the left) (Figure 3). After the first CI, he diligently participated in aural rehabilitation to train auditory skills (e.g., detection, discrimination, identification, and comprehension). The Revised Preschoolers Language Assessment (RPLA) was used to evaluate language development (Lin et al, 2008), with bimodal hearing revealing scores of 17, 24, and 41 for language comprehension, oral expression, and overall language development, respectively. These scores indicate risk of language delay (below 1.5 standard deviation [SD] of the mean score at the actual age norm) (Lin et al, 2008) at the age of 4 years and 3 months (first CI at 38 months). He showed improvement in auditory, language, and cognitive abilities after the first CI. After 41 months after the first CI, he underwent a second CI on the left side at the age of 4 years and 7 months, using CI512 (Nucleus 7). He obtained a PEACH score of 86 percent at the second CI preoperatively (CI on the right, hearing aid on the left). At the last follow-up, he obtained a score of 95 percent on the PEACH scale (first CI at 48 months, second CI at 6 months). All PEACH rating scale results are shown in Figure 3. The RPLA showed scores of 20, 23, and 43 for language comprehension, oral expression, and overall language development, still indicating a risk of language delay (below 1.5 SD of the mean score at the actual age norm) (Lin et al, 2008) at the age of 4 years and 9 months (first CI at 43 months, second CI at 2 months). In addition, we used the Mandarin Functioning after Pediatric Cochlear Implantation (FAPCI-M) (Fan and Teng, 2020) instrument to comprehensively evaluate communicative performance after bilateral CIs. The FAPCI-M scale, rated by parents, consists of 23 questions across five categories, with test scores summed and percentile rank calculated. At the last follow-up (first CI at 48 months, second CI at 6 months), the patient achieved a score of 92, with a percentile rank of 60 in FAPCI-M (Fan and Teng, 2020). His Categories of Auditory Performance (CAP) scores were 6 (understand conversation without lip-reading) in both the right and left CI, and his Speech Intelligibility Ratings (SIR) score was 3 (connected speech is intelligible to a listener who concentrates and lip-reads within a known context). Now, he receives intensive aural rehabilitation, attends a deaf school and uses total communication (oral communication in adjuvant with sign language).

Figure 3.

The PEACH (Parents’ Evaluation of Aural/Oral Performance of Children) rating scale results. The black line indicates the bimodal condition with cochlear implant (CI) on the right and hearing aid on the left; the gray line indicates the bilateral CIs condition.

DISCUSSION

Diagnosing DDOD syndrome can be challenging due to overlapping clinical features with other related disorders, such as ZL syndrome and DOORS syndrome. Molecular testing is essential for accurate diagnosis and distinguishing these syndromes (Gao et al, 2022). DDOD syndrome results from a mutation in the ATP6V1B2 or TBC1D24 gene (Yuan et al, 2014; Menendez et al, 2017; Zhao et al, 2019; Li et al, 2021; Gao et al, 2022), whereas ZL syndrome can be caused by mutations in either the ATP6V1B2, KCNH1, or KCNN3 gene (Menendez et al, 2017; Gao et al, 2022), and DOORS syndrome is linked to a mutation in the ATP6V1B2 or TBC1D24 gene (Yuan et al, 2014; Menendez et al, 2017; Zádori et al, 2020; Li et al, 2021; Gao et al, 2022). Additionally, findings associated with ZL syndrome include deafness, onychodystrophy, intellectual disability, seizures, gingival enlargement, hypertrichosis, joint hyperextensibility, and hepatosplenomegaly (Menendez et al, 2017; Zhao et al, 2019; Gao et al, 2022), and DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures (Menendez et al, 2017; Zádori et al, 2020; Li et al, 2021; Gao et al, 2022). However, not all individuals with the ATP6V1B2 mutation exhibit intellectual disability and seizures (Vind-Kezunovic and Torring, 2013). In our patient, deafness and facial anomalies were present, along with ATP6V1B2 gene defects (c.1516C > T), and nails were absent. Therefore, we diagnosed him with DDOD syndrome.

ATP6V1B2 defects (c.1516C > T) may lead to dysfunction of V-ATPases and impaired lysosome acidification, potentially resulting in apoptosis in the spiral ganglia, whereas no excessive apoptosis occurs in the organ of Corti (Qiu et al, 2021). Consequently, this affects hearing function, resulting in congenital and severe to profound hearing loss (Yuan et al, 2014; Zhao et al, 2019; Qiu et al, 2021). CI has been used to treat hearing loss in DDOD syndrome patients (Gao et al, 2022); however, unsatisfactory CI outcomes have been observed due to pathological lesions in the spiral ganglia (Qiu et al, 2021). In our patient, aural, language, and communication performance continues to improve after bilateral CIs. The score of 92 on the FAPCI-M scale was higher than the mean score of 74.1 in Fan and Teng’s study (Qiu et al, 2021). However, our patient still remains at risk for language delay. The aural rehabilitation program should be focused on enhancing speech and developing language skills for this child. Zhao et al (2019) described a similar case of a patient with DDOD with unilateral CI for 7 years who had unsatisfactory language rehabilitation outcomes (Zhao et al, 2019). Li et al (2021) also documented a case of a patient with DDOD with unilateral CI. Her CAP and SIR scores were 4 and 3, respectively. Additionally, she exhibited difficulty in speech and language expression and showed poor memory (Li et al, 2021). Zhao et al (2019) and Qiu et al (2021) used zebrafish and mice to verify that ATP6V1B2 defects (c.1516C > T) may cause central nervous system issues and concluded that these unsatisfactory CI outcomes may be associated with learning and memory problems (Zhao et al, 2019; Qiu et al, 2021). Regrettably, we did not conduct speech recognition tests due to the patient’s young age. Furthermore, intelligence and memory assessments were not performed. Further clarification of speech recognition, intelligence, and memory in patients with DDOD syndrome may be warranted.

CONCLUSIONS

This case study of DDOD syndrome (ATP6V1B2 c.1516C > T) highlights the potential for enhancing aural and communication skills, although the patient’s language performance may still be limited. Continued aural rehabilitation is crucial for further improvement in his speech and language.

Abbreviations:

CAP

Categories of Auditory Performance

CI

cochlear implantation

DDOD

dominant deafness-onychodystrophy

DOORS

deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures

FAPCI-M

Mandarin Functioning after Pediatric Cochlear Implantation

PEACH

Parents’ Evaluation of Aural/Oral Performance of Children

RPLA

Revised Preschoolers Language Assessment

SD

standard deviation

SIR

Speech Intelligibility Ratings

ZL

Zimmermann–Laband