Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

Cisplatin-induced hearing loss: the need for a long-term evaluating system.

Cisplatin is an effective chemotherapeutic agent against pediatric cancers; however, ototoxicity is a concern. This study describes the frequency, severity, and clinical course of hearing loss in Japanese pediatric patients treated with cisplatin-based multimodal therapy. A total of 55 children who received cisplatin-based therapy from 1983 to 2012 underwent audiologic evaluations. Data were analyzed to determine the onset, time-to-progression, and severity of hearing loss. Thirty-five patients, 12 of 16 older patients (4 y or older), and 23 of 39 younger patients (under 4 y), including 7 of 8 patients treated with cisplatin, carboplatin, and radiotherapy, developed hearing loss. Ten of 18 patients who received a cumulative cisplatin dose of <360 mg/m developed hearing loss at a minimum dose of 200 mg/m. Median time to onset after the last cisplatin dose was 71 days; 6 patients developed hearing loss after ≥2 years. Four patients required hearing aids, 6 patients developed progressive hearing loss with time, and 4 patients exhibited persistent hearing failure at low frequencies. Risk factors for acquired hearing loss and its severity may be associated with a combination of factors such as cisplatin and carboplatin therapy, radiotherapy, age at diagnosis, and genetic background. Our results suggested that all pediatric patients treated with cisplatin would have their hearing evaluated regularly, irrespective of the cumulative cisplatin dose as a suggestion, and that further prospective studies regarding ototoxicity including genetic polymorphisms analysis were required.

GJB2-associated hearing loss undetected by hearing screening of newborns.

The hearing loss caused by GJB2 mutations is usually congenital in onset, moderate to profound in degree, and non-progressive. The objective of this study was to study genotype/phenotype correlations and to document 14 children with biallelic GJB2 mutations who passed newborn hearing screening (NHS). Genetic testing for GJB2 mutations by direct sequencing was performed on 924 individuals (810 families) with hearing loss, and 204 patients (175 families) were found to carry biallelic GJB2 mutations. NHS results were obtained through medical records. A total of 18 pathological mutations were identified, which were subclassified as eight inactivating and 10 non-inactivating mutations. p.I128M and p.H73Y were identified as novel missense GJB2 mutations. Of the 14 children with biallelic GJB2 mutations who passed NHS, eight were compound heterozygotes and 3 were homozygous for the c.235delC mutation in GJB2, and the other three combinations of non-c.235delC mutations identified were p.Y136X-p.G45E/p.V37I heterozygous, c.512ins4/p.R143W heterozygous, and p.V37I/p.R143W heterozygous. These 14 cases demonstrate that the current NHS does not identify all infants with biallelic GJB2 mutations. They suggest that the frequency of non-penetrance at birth is approximately 6.9% or higher in DFNB1 patients and provide further evidence that GJB2 hearing loss may not always be congenital in onset.

Etiology and one-year follow-up results of hearing loss identified by screening of newborn hearing in Japan.

OBJECTIVE: To evaluate the incidence of newborn hearing loss in a Japanese population and to elucidate etiological factors and one-year prognosis. STUDY DESIGN: Screening of newborn hearing. SETTING: Children's tertiary referral center. SUBJECTS AND METHODS: Between 1999 and 2008, 101,912 newborn infants were screened, with 693 infants (0.68%) referred. Etiology investigation included CT, detection of cytomegalovirus (CMV) DNA, and connexin 26 mutation. RESULTS: Abnormal results (auditory brainstem response [ABR] threshold > or = 35 normal hearing level [dB nHL] in either side) were observed in 312 infants (0.31%), and 133 subjects (0.13%) with ABR thresholds > or = 50 dB nHL on both sides were classified into the habilitation group. In this group, inner ear/internal auditory meatus anomalies were detected in 20 of 121 subjects (17%) tested, middle/external ear anomalies in 14 of 121 subjects (12%), CMV DNA in 13 of 77 subjects (17%), and connexin 26 mutation in 28 of 89 subjects (31%). In 68 subjects undergoing all three investigations (CT, CMV, and connexin 26), 41 (60%) had positive results in at least one test. With inclusion of otitis media with effusion and perinatal problems, this rate amounted to 78% (53 subjects). Of the 97 infants in the habilitation group successfully followed up to one year, 36 (37%) showed a threshold change of 20 dB or more in either ear: 11 (11%) progression and 25 (26%) improvement, and 15 infants (15%) were reclassified into a less severe classification. CONCLUSION: Considering that 26 percent of infants with bilateral moderate to severe hearing loss showed improvement in one year, habilitation protocols, especially very early cochlear implantation within one year of birth, should be reconsidered.

Surgical treatment for sleep apnea: changes in craniofacial and pharyngeal airway morphology in a child with achondroplasia.

Here, we report the case of a male child with achondroplasia who was diagnosed with obstructive sleep apnea and underwent adenoidectomy and tonsillectomy. By analyzing lateral cephalograms, we evaluated the craniofacial and pharyngeal airway morphology immediately before surgery (age, 5 years 6 months) and 1 year 2 months after surgery (age, 6 years 8 months). Adenoidectomy and tonsillectomy dilated the pharynx and improved the craniofacial and pharyngeal morphologies, apparently thus improving the sleep apnea.

Sleep disordered breathing in children with achondroplasia. Part 2. Relationship with craniofacial and airway morphology.

We evaluated the craniofacial and airway morphology in children with achondroplasia complicated by snoring and apnea during sleep (AP group) in comparison with children with snoring and apnea during sleep without chromosomal aberrations (adenoid group) and healthy children without sleep disordered breathing or malalignment (healthy group). Lateral cephalograms in 10 children each (four males and six females) in the three groups were analyzed. When the AP and healthy groups were compared, the AP group showed significantly lower values for facial depth, nasal floor length, point A, point pog, and saddle angle (p<0.01) and significantly higher values for mandibular plane angle and gonial angle (p<0.01) regarding craniofacial morphology and significantly lower values for D-AD1, D-AD2, and upper pharynx (p<0.01) regarding airway morphology. When the AP and adenoid groups were compared, the AP group showed significantly lower values for facial depth, nasal floor length, point A, point pog, and saddle angle (p<0.01) and significantly higher values for mandibular plane angle and gonial angle (p<0.01) regarding craniofacial morphology and significantly lower values for D-AD1, D-AD2, and upper pharynx (p<0.05) regarding airway morphology. Thus, the craniofacial/airway morphology in the AP group was characterized by upper airway stenosis, a retruded position of the chin, and an increased mandibular plane angle due to partial early ossification of cranial bones, and an increased lower facial height due to an increased mandibular angle, which may tend to induce sleep snoring and apnea.

Survey of the present status of sleep-disordered breathing in children with achondroplasia Part I. A questionnaire survey.

An achondroplasia is known to be the inherited disease causing a growth impairment of limb bones. Recently, as a symptom of achondroplasia, a sleep-disordered breathing has been reported. Considering the scientific evidence that the sleep-disordered breathing in children such as that due to tonsillar hypertrophy inhibits somatotropin secretion and causes growth retardation, sleep-disordered breathing in children with achondroplasia may aggravate growth/developmental retardation in addition to the bone growth impairment. However, the present status of the development of sleep-disordered breathing in children with achondroplasia has been unknown. Therefore, in order to clarify the present status of sleep-disordered breathing in children with achondroplasia (AP group), we carried out a questionnaire survey of the breathing state during sleep, growth/development history and the oral state at preschool age and school age in the AP group, and compared the results with previously reported data in healthy children (control group). 1. Among the questionnaire items, the incidences of snoring, apnea, mouth breathing, anterior cross bite, and open bite at preschool age were significantly higher in the AP group than in the control group (P < 0.01) At school age, the AP group showed significantly higher incidences of mouth breathing and cross/open bite (P < 0.01) and snoring and apnea (P < 0.05) than the control group. 2. Height and weight at birth and at the ages of 1.5 and 3 years, excluding birth weight, were significantly lower in the AP group than in the control group (P < 0.01). 3. The chronological age at the initiation of eruption of the deciduous or permanent teeth did not significantly differ between the two groups. Thus, the AP group showed higher incidences of sleep-disordered breathing and malocclusion than the control group, and development of sleep-disordered breathing at preschool age.

Temporal bone pathology in hydrocephalus: changes in the inner ear due to increased intracranial pressure.

Changes in the inner ear due to increased intracranial pressure have not yet been clearly defined. We present a postmortem temporal bone study of child with hydrocephalus. The temporal bone was from a 2-year-old female with IVth ventricle ependymoblastoma. In the basal turn of the cochlea, degeneration of the organ of Corti and the nerve ganglion was observed. In the top and middle turn, structures were intact. The utricle and saccule were well preserved. We propose that changes in the inner ear due to increased intracranial pressure begin in the base of the cochlea, and extend to the apex in decreasing degree.