Non-progressive Hearing Loss Research Articles

Sociodemographic factors influencing survival of infants with isolated, left-sided congenital diaphragmatic hernia: A systematic review

OTOG was identified as a nonsyndrmoic hearing loss gene in 2012 in two families with nonprogressive mild-to-moderate hearing loss. However, no further literature have this gene for nonsyndromic hearing loss. Furthermore, it is still unclear whether vestibular impairment is involved or not in patients with mutations in OTOG. This study presents a validated second report for homozygous causative mutations in OTOG of mild hearing loss. Whole exome sequencing (WES) was performed in a five-year-old male proband with mild hearing loss. The analysis of WES revealed a homozygous truncating mutation (c.330C > G; p.Tyr110*) in OTOG. The identified novel mutation, p.Tyr110*, leads to a null allele based on the fact that early truncated protein contains no functional domain of otogelin. While defects in otogelin previously reported to result in hearing loss and vestibular dysfunction, p.Tyr110* only caused nonsydromic and nonprogressive hearing loss without any vestibular impairment, indicating that vestibular phenotype would be variable. Given that mild hearing loss is not easy to be detected early, mutations of OTOG may be more prevalent than reported. Therefore, genetic evaluation for OTOG should be considered in children with mild hearing loss with/without vestibular dysfunction.

A novel early truncation mutation in OTOG causes prelingual mild hearing loss without vestibular dysfunction

OTOG was identified as a nonsyndrmoic hearing loss gene in 2012 in two families with nonprogressive mild-to-moderate hearing loss. However, no further literature have this gene for nonsyndromic hearing loss. Furthermore, it is still unclear whether vestibular impairment is involved or not in patients with mutations in OTOG. This study presents a validated second report for homozygous causative mutations in OTOG of mild hearing loss. Whole exome sequencing (WES) was performed in a five-year-old male proband with mild hearing loss. The analysis of WES revealed a homozygous truncating mutation (c.330C > G; p.Tyr110*) in OTOG. The identified novel mutation, p.Tyr110*, leads to a null allele based on the fact that early truncated protein contains no functional domain of otogelin. While defects in otogelin previously reported to result in hearing loss and vestibular dysfunction, p.Tyr110* only caused nonsydromic and nonprogressive hearing loss without any vestibular impairment, indicating that vestibular phenotype would be variable. Given that mild hearing loss is not easy to be detected early, mutations of OTOG may be more prevalent than reported. Therefore, genetic evaluation for OTOG should be considered in children with mild hearing loss with/without vestibular dysfunction.

Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene.

PDZD7 was identified in 2009 in a family with apparent nonsyndromic sensorineural hearing loss. However, subsequent clinical reports have associated PDZD7 with digenic Usher syndrome, the most common cause of deaf-blindness, or as a modifier of retinal disease. No further reports have validated this gene for nonsyndromic hearing loss, intuitively calling correct genotype-phenotype association into question. This report describes a validating second case for biallelic mutations in PDZD7 causing nonsyndromic mild to severe sensorineural hearing loss. It also provides detailed audiometric and ophthalmologic data excluding Usher syndrome in both the present proband (proband 1) and the first proband described in 2009 (proband 2). Proband 1 was sequenced using a custom-designed next generation sequencing panel consisting of 151 deafness genes. Bioinformatics analysis and filtering disclosed two PDZD7 sequence variants (c.1648C>T, p.Q550* and c.2107del, p.S703Vfs*20). Segregation testing followed in the family. For both probands, audiograms were collected and analyzed for progressive hearing loss and detailed ophthalmic evaluations were performed including electroretinography. Proband 1 demonstrated a prelingual, nonsyndromic, sensorineural hearing loss that progressed in the higher frequencies between 4 and 9 years old. PDZD7 segregation analysis confirmed biallelic inheritance (compound heterozygosity). Mutation analysis determined the c.1648C>T mutation as novel and reported the c.2107del deletion as rs397516633 with a calculated minor allele frequency of 0.000018. Clinical evaluation spanning well over a decade in proband 2 disclosed bilateral, nonprogressive hearing loss. Both probands showed healthy retinas, excluding Usher syndrome-like changes in the eye. PDZD7 is confirmed as a bona fide autosomal recessive nonsyndromic hearing loss gene. In both probands, there was no evidence of impaired vision or ophthalmic pathology. As the current understanding of PDZD7 mutations bridge Mendelian and complex phenotypes, the authors recommend careful variant interpretation, since PDZD7 is one of many genes associated with both Usher syndrome and autosomal recessive nonsyndromic hearing loss. Additional reports are required for understanding the complete phenotypic spectrum of this gene, including the possibility of high-frequency progression, as well as noise-induced hearing loss susceptibility in adult carriers. This report rules out all forms of Usher syndrome with an onset before 12 and 15 years old in probands 1 and 2, respectively. However, due to the young ages of the probands, this report is uninformative regarding older patients.

A Chromosome 17 Locus Engenders Frequency-Specific Non-Progressive Hearing Loss that Contributes to Age-Related Hearing Loss in Mice.

The 129S6/SvEvTac (129S6) inbred mouse is known for its resistance to noise-induced hearing loss (NIHL). However, less is understood of its unique age-related hearing loss (AHL) phenotype and its potential relationship with the resistance to NIHL. Here, we studied the physiological characteristics of hearing loss in 129S6 and asked if noise resistance (NR) and AHL are genetically linked to the same chromosomal region. We used auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to examine hearing sensitivity between 1 and 13 months of age of recombinant-inbred (congenic) mice with an NR phenotype. We identified a region of proximal chromosome (Chr) 17 (D17Mit143-D17Mit100) that contributes to a sensory, non-progressive hearing loss (NPHL) affecting exclusively the high-frequencies (>24 kHz) and maps to the nr1 locus on Chr 17. ABR experiments showed that 129S6 and CBA/CaJ F1 (CBACa) hybrid mice exhibit normal hearing, indicating that the hearing loss in 129S6 mice is inherited recessively. An allelic complementation test between the 129S6 and 101/H (101H) strains did not rescue hearing loss, suggesting genetic allelism between the nphl and phl1 loci of these strains, respectively. The hybrids had a milder hearing loss than either parental strain, which indicate a possible interaction with other genes in the mouse background or a digenic interaction between different genes that reside in the same genomic region. Our study defines a locus for nphl on Chr 17 affecting frequencies greater than 24 kHz.

Bilateral congenital absence of the stapes superstructure in two siblings.

Middle ear ossicle malformations are an uncommon event. Among them, the congenital absence of the stapes is a very rare condition that is seldom described in the literature. We report the cases of two women, aged 19 and 22 , who presented with a long history of conductive deafness. An exploratory tympanotomy was performed and the absence of the stapes superstructure and an abnormal position of the facial nerve could be observed. A bone anchored hearing aid (BAHA) was implanted in both patients with good results. It is believed that stapes agenesis is related to an abnormal development of the facial nerve, which by the 5th to 6th week of gestation would interpose between the otic capsule and the stapes blastema, preventing these structures from contacting. A long history of nonprogressive hearing loss from birth or early childhood is the key to reach a diagnosis. Several treatment options have been described. The authors opted for a hearing aid due to the high risk of facial nerve lesion, with good functional results.

Operative findings of conductive hearing loss with intact tympanic membrane and normal temporal bone computed tomography

Despite recent technological advances in diagnostic methods including imaging technology, it is often difficult to establish a preoperative diagnosis of conductive hearing loss (CHL) in patients with an intact tympanic membrane (TM). Especially, in patients with a normal temporal bone computed tomography (TBCT), preoperative diagnosis is more difficult. We investigated middle ear disorders encountered in patients with CHL involving an intact TM and normal TBCT. We also analyzed the surgical results with special reference to the pathology. We reviewed the medical records of 365 patients with intact TM, who underwent exploratory tympanotomy for CHL. Fifty nine patients (67 ears, eight bilateral surgeries) had a normal preoperative TBCT findings reported by neuro-radiologists. Demographic data, otologic history, TM findings, preoperative imaging findings, intraoperative findings, and pre- and postoperative audiologic data were obtained and analyzed. Exploration was performed most frequently in the second and fifth decades. The most common postoperative diagnosis was stapedial fixation with non-progressive hearing loss. The most commonly performed hearing-restoring procedure was stapedotomy with piston wire prosthesis insertion. Various types of hearing-restoring procedures during exploration resulted in effective hearing improvement, especially with better outcome in the ossicular chain fixation group. In patients with CHL who have intact TM and normal TBCT, we should consider an exploratory tympanotomy for exact diagnosis and hearing improvement. Information of the common operative findings from this study may help in preoperative counseling.

Audiometric characteristics of two Dutch families with non-ocular Stickler syndrome (COL11A2)

ObjectiveTo evaluate hearing impairment and cochlear function in non-ocular Stickler syndrome. Study designMultifamily study. Patients & methodsTen patients from two different families with non-ocular Stickler syndrome (Stickler syndrome type 3) were included. Six members of the first family and four members of the second family participated in this study. Otorhinolaryngologic examinations were performed. Pure-tone and speech audiograms were obtained. Longitudinal analysis was performed. Psychophysical measurements, including loudness scaling, gap detection, difference limen for frequency and speech perception in noise were administered to assess cochlear function at a deeper level. ResultsAffected individuals in the first family were carriers of a heterozygous splice donor mutation in the COL11A2 gene. Affected individuals in the second family were carriers of a novel heterozygous missense mutation in COL11A2. Both families showed bilateral, non-progressive hearing impairment with childhood onset. The severity of the hearing impairment exhibited inter- and intrafamilial variability and was mostly mild to moderate. The results of the psychophysical measurements were similar to those previously published for DFNA8/12 (TECTA) and DFNA13 (COL11A2) patients and thus consistent with an intra-cochlear conductive hearing impairment. This is in line with the theory that mutations in COL11A2 affect tectorial membrane function. ConclusionHearing impairment in non-ocular Stickler syndrome is characterized by non-progressive hearing loss, present since childhood, and mostly mild to moderate in severity. Psychophysical measurements in non-ocular Stickler patients were suggestive of intra-cochlear conductive hearing impairment.

Novel connexin 30 and connexin 26 mutational spectrum in patients with progressive sensorineural hearing loss

Mutations in the gap junction protein beta-2 gene ('GJB2') are known to be responsible for mild to profound congenital and late-onset hearing loss. This study aimed to investigate the molecular basis of progressive hearing loss compared with non-progressive hearing loss. Following clinical otorhinolaryngological evaluation, a genetic analysis was performed in a cohort of 72 patients with progressive sensorineural hearing loss. Pathological genotypes were established in 16 patients (22.2 per cent). Six different gap junction protein beta-2 gene mutations were detected in 15 patients, with the c.35delG mutation responsible for 56 per cent of the mutated alleles. A novel gap junction protein beta-6 gene ('GJB6') mutation (p.Met203Val) was observed in one patient with mild progressive hearing loss. Analyses of gap junction protein beta-2 and -6 genes revealed that similar pathological genotypes, occurring with similar frequencies, were responsible for progressive hearing loss, compared with reported genotypes for non-progressive hearing loss patients. Thus, genotype cannot be used to differentiate non-progressive from progressive hearing loss cases; in this study, patients both with and without an established pathological genotype had a similar clinical course.

Clinical comparison of hearing‐impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations

The aim of the study is to assess clinical characteristics of individuals with nonsyndromic sensorineural hearing loss (NSSNHL) with genetic mutations in GJB2 and/or GJB6. We describe and compare one group with biallelic mutations against a group of heterozygote mutation carriers. A total of 350 patients between the ages of 3 months and 80 years referred to a tertiary care outpatient otology practice for NSSNHL were screened for genetic mutations. Direct sequencing of GJB2 and polymerase chain reaction analysis of GJB6 was performed and clinical data from history and physical, audiologic testing and radiographic studies were reviewed. Thirty-two patients were found to have biallelic mutations (incidence of 9.1%). Twenty-five patients were found to have only one GJB2 mutation (incidence of 7.1%). Severe to profound hearing loss occurred in 85% of the homozygote group and 38% of the heterozygote group. Both groups similarly had a propensity toward bilateral, symmetric, nonprogressive hearing loss with rare inner ear malformations on radiologic imaging. These two patient populations have similar incidences in a cohort of patients evaluated for NSSNHL, which is higher than general population heterozygote carrier rates. Heterozygote mutation carriers had less hearing impairment, but most other factors demonstrated no differences. These results support the theory of an unidentified genetic factor contributing to hearing loss in some heterozygote carriers. Therefore, genetic counseling should consider the complexity of their genetic factors and the limitations of current screening.

Late postnatal onset of hearing loss due to GJB2 mutations

GJB2 mutations account for approximately 50% of recessive non-syndromic deafness, with 35delG being the most prevalent. Homozygous 35delG mutations cause pre-lingual, non-progressive hearing loss that is detected on newborn hearing screening programmes. We present a sibling pair with homozygous 35delG mutations, who passed hearing tests in early infancy and developed progressive sensorineural hearing loss, one requiring a cochlear implant. These cases illustrate that deafness due to such mutations may have a late onset and consequently be missed on neonatal screening programmes and they may present an argument to consider neonatal screening for GJB2 mutations in order to aid early intervention.

Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2)

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.

Prevalence of 2314delG mutation in Spanish patients with Usher syndrome type II (USH2)

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.

A novel locus for Usher syndrome type II, USH2B, maps to chromosome 3 at p23-24.2.

Usher type II syndrome is defined by the association of retinitis pigmentosa, appearing in the late second to early third decade of life, with congenital moderate to severe non-progressive hearing loss. This double sensory impairment is not accompanied by vestibular dysfunction. To date, only one Usher type II locus, USH2A, at chromosome band 1q41, has been defined. Here, we demonstrate by linkage analysis, that the gene responsible for Usher type II syndrome in a Tunisian consanguineous family maps to chromosome 3 at position p23-24.2, thus providing definitive evidence for the genetic heterogeneity of the syndrome. A maximum lod score of 4.3 was obtained with the polymorphic microsatellite markers corresponding to loci D3S1578, D3S3647 and D3S3658. This maps the gene underlying USH2B to a chromosomal region which overlaps the interval defined for the non-syndromic sensorineural recessive deafness DFNB6, raising the possibility that a single gene underlies both defects. However, the audiometric features in the patients affected by USH2B and DFNB6 are very different.