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Cochleovestibular dysfunctions are rare conditions misrecognized. A homozygous pathogenic variation c.1561C > T (p.Arg521*) in RIPOR2 (RHO family interacting cell polarization regulator 2) has been identified by WES in Tunisian siblings suffering from congenital bilateral profound hearing and vestibular dysfunctions. In contrast to the vestibular areflexia observed in our patients, deaf Ripor2 KO mouse model and our zebrafish model have normal vestibular function., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Introduction: Deletions or variants of the STRC gene coding for stereocilin cause congenital bilateral mild-to-moderate sensorineural hearing loss without vestibular disorder: DFNB16. Stereocilin is a protein present in vestibular kinocilia embedded in the otoconial membrane of the utricular macula. Benign paroxysmal positional vertigo (BPPV) is a rare form of vertigo in children. The present study reports recurrent positional vertigo in two DFNB16 siblings., Observation: Two patients, 10 and 15 years old, presented with recurrent disabling positional vertigo episodes, triggered by turning over in bed, with a falling sensation. The diagnosis of right posterior canal BPPV was confirmed on Dix-Hallpike maneuvers in one of the patients. Variations in the response of ocular vestibular-evoked myogenic potentials were observed. Probable BPPV was diagnosed in the second patient. Their other two siblings did not have hearing loss or vertigo., Conclusion: The absence of stereocilin due to homozygous deletions of the STRC gene in DFNB16 patients can cause vestibular dysfunction, including BPPV., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: Deletions of STRC gene (DFNB16) account for 12% of isolated congenital mild to moderate hearing loss (HL). In mice, the stereocilin protein, encoded by STRC , is present in the vestibular kinocilium embedded in the otoconial membrane of the utricular macula. Despite this, effects on vestibular function have not been widely investigated. The aim of this study was to investigate the prevalence of benign paroxysmal positional vertigo (BPPV) in a cohort of DFNB16 patients., Study Design: Observational descriptive epidemiological study., Setting: Single-center study, in a tertiary referral center., Patients: Older than 5 years, with a genetic diagnosis of HL related to biallelic STRC gene deletions, diagnosed between 2015 and 2021., Intervention: Patients or their parents were interviewed to determine whether they had experienced vertigo or episodes of BPPV., Main Outcome Measure: Criteria were at least five acute episodes of rotatory vertigo, each lasting less than 1 minute, episodes triggered by changes in specific head position, and an absence of neurological symptoms., Results: Sixty-four patients having mild (33%) to moderate (66%) HL were included. Median age was 15 years (range, 6-48 yr). Prevalence of BPPV was 39% (25 of 64). Median age of first onset was 13 years (range, 3-18 yr)., Conclusions: This study showed recurrent BPPV and early age of onset in patients with biallelic STRC gene deletions. BPPV may be associated with the HL phenotype in patients with STRC gene deletions. It is important to inform patients and families of this potential risk such that appropriate management can be proposed., Competing Interests: Conflicts of interest and source of funding: None., (Copyright © 2023, Otology & Neurotology, Inc.)

Heimler syndrome is a rare syndrome associating sensorineural hearing loss with retinal dystrophy and amelogenesis imperfecta due to PEX1 or PEX6 biallelic pathogenic variations. This syndrome is one of the less severe forms of peroxisome biogenesis disorders. In this chapter, we will review clinical, biological, and genetic knowledges about the Heimler syndrome.

The specific association of Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (LCA-like) with sensorineural hearing loss (SHL) is uncommon. Recently, we ascribed some of these distinctive associations to dominant and de novo mutations in the β-tubulin 4B isotype-encoding gene (TUBB4B), providing a link between a sensorineural disease and anomalies in microtubules behavior. Here, we report 12 sporadic cases with LCA/SHL or LCA-like/SHL and no TUBB4B mutation. Trio-based whole exome sequencing (WES) identified disease-causing mutations in 5/12 cases. Four out of five carried biallelic mutations in PEX1 (1/4) or PEX6 (3/4), involved in peroxisome biogenesis disorders from Zellweger syndrome characterized by severe neurologic and neurosensory dysfunctions, craniofacial abnormalities, and liver dysfunction to Heimler syndrome associating SHL, enamel hypoplasia of the secondary dentition, nail abnormalities, and occasional retinal disease. Upon reexamination, the index case carrying PEX1 mutations, a 4-year-old girl, presented additional symptoms consistent with Zellweger syndrome. Reexamination of individuals with PEX6 mutations (1/3 unavailable) revealed normal nails but enamel hypoplasia affecting one primary teeth in a 4-year-old girl and severe enamel hypoplasia of primary teeth hidden by dental prosthesis in a 50-year-old male, describing a novel PEX6-associated disease of the Zellweger/Heimler spectrum. Finally, hemizygosity for a CACNA1F mutation was identified in an 18-year-old male addressed for LCA/SHL, redirecting the retinal diagnosis to congenital stationary night blindness (CSNB2A). Consistent with the pure CSNB2A retinal involvement, SHL was ascribed to biallelic mutations in another gene, STRC, involved in nonprogressive DFNB16 deafness.

Objective: To highlight Noonan syndrome as a clinically recognizable cause of severe to profound sensorineural hearing impairment., Study Design: New clinical cases and review., Setting: Patients evaluated for etiological diagnosis by a medical geneticist in a reference center for hearing impairment., Patients: Five patients presenting with confirmed Noonan syndrome and profound sensorineural hearing impairment., Interventions: Diagnostic and review of the literature., Results: Five patients presented with profound sensorineural hearing impairment and molecularly confirmed Noonan syndrome. Sensorineural hearing impairment has been progressive for three patients. Cardiac echography identified pulmonary stenosis in two patients and was normal for the three other patients. Short stature was found in two patients. Mild intellectual disability was found in one patient. Inconspicuous clinical features as facial dysmorphism, cryptorchidism, or easy bruising were of peculiar interest to reach the diagnosis of Noonan syndrome., Conclusion: Profound sensorineural hearing impairment can be the main feature of Noonan syndrome. Associated features are highly variable; thus, detailed medical history and careful physical examination are mandatory to consider the diagnosis in case of a sensorineural hearing impairment.

Objective: Unilateral sensorineural hearing loss (USNHL) is known to impact on school performance and social skills during childhood, but the etiologies remain unclear. The aim of this study was to assess various etiologies and to study the clinical contexts in this population., Methods: The study is a retrospective review. Characteristics of hearing loss (HL), audiometric parameters, imaging, and genetic and medical contexts were analyzed., Results: Eighty children were included. USNHL was profound in 68%, could be progressive in 19%, and become bilateral in 7.5% of cases. Inner ear malformations were identified in 41% of cases; cochlear nerve deficiency (CND) was frequent (33%). Cytomegalovirus (CMV) infection and genetic syndromes were confirmed in 10 and 6% of cases, respectively., Conclusion: Long-term hearing follow-up remains useful in USNHL as it can become bilateral. Looking to etiology, MRI should be the gold standard, as CND is frequently observed and screening for CMV infection should be systematic. Genetic etiologies appear to be different compared to bilateral HL. Further genetic research in this domain is needed., (© 2017 S. Karger AG, Basel.)

Perrault syndrome (PS) is a rare autosomal recessive condition characterized by deafness and gonadic dysgenesis. Recently, mutations in five genes have been identified: C10orf2, CLPP, HARS2, HSD17B4, and LARS2. Probands included are presented with sensorineural deafness associated with gonadic dysgenesis. DNA was sequenced using next-generation sequencing (NGS) with a panel of 35 deafness genes including the five Perrault genes. Exonic variations known as pathogenic mutations or detected with <1% frequency in public databases were extracted and subjected to segregation analysis within each family. Both mutations and low coverage regions were analyzed by Sanger sequencing. Fourteen female index patients were included. The screening in four cases has been extended to four family members presenting with PS phenotype. For four unrelated patients (28.6%), causative mutations were identified: three homozygous mutations in C10orf2, CLPP, and HARS2, and one compound heterozygous mutation in LARS2. Three additional heterozygous mutations in LARS2 and HSD17B4 were found in three independent familial cases. All these missense mutations were verified by Sanger sequencing. Familial segregation analyses confirmed the molecular diagnosis in all cases carrying biallelic mutations. Because of NGS, molecular analysis confirmed the clinical diagnosis of PS in 28.6% of our cohort and four novel mutations were found in four Perrault genes. For the unsolved cases, exome sequencing should be performed to search for a sixth unknown PS gene., (© 2016 WILEY PERIODICALS, INC.)

Heterozygous COL2A1 variants cause a wide spectrum of skeletal dysplasia termed type II collagenopathies. We assessed the impact of this gene in our French series. A decision tree was applied to select 136 probands (71 Stickler cases, 21 Spondyloepiphyseal dysplasia congenita cases, 11 Kniest dysplasia cases, and 34 other dysplasia cases) before molecular diagnosis by Sanger sequencing. We identified 66 different variants among the 71 positive patients. Among those patients, 18 belonged to multiplex families and 53 were sporadic. Most variants (38/44, 86%) were located in the triple helical domain of the collagen chain and glycine substitutions were mainly observed in severe phenotypes, whereas arginine to cysteine changes were more often encountered in moderate phenotypes. This series of skeletal dysplasia is one of the largest reported so far, adding 44 novel variants (15%) to published data. We have confirmed that about half of our Stickler patients (46%) carried a COL2A1 variant, and that the molecular spectrum was different across the phenotypes. To further address the question of genotype-phenotype correlation, we plan to screen our patients for other candidate genes using a targeted next-generation sequencing approach.

CHARGE syndrome (MIM#214800) (Coloboma, Heart defect, Atresia of choanae, Retarded growth and development, Genital hypoplasia, Ear abnormalities/deafness) is caused by heterozygous mutation of CHD7 transmitted in an autosomal dominant manner. In this report, we describe a patient with bilateral hearing impairment, unusually-shaped ears, no intellectual disability and a patent ductus arteriosus. Further investigation showed abnormal semicircular canals and the presence of olfactory bulbs. He does not fulfill the Blake or the Verloes criteria for CHARGE. A de novo mutation at the donor splice site of intron 33 was identified (c.7164 + 1G > A). It is of importance to diagnose mildly affected patients for appropriate genetic counselling and to better understand the mild end of the phenotypic spectrum of CHARGE syndrome., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Objectives: To propose categories for the various types of residual hearing in children and to review the outcomes of cochlear implantation (CI) in children with these different hearing conditions., Methods: We identified 53 children with residual hearing who had received a cochlear implant. Five groups were arbitrarily defined based on auditory features: G1, characterized by low-frequency residual hearing (n=5); G2, characterized by severe sensorineural hearing loss (SNHL) and low speech discrimination (n=12); G3, characterized by asymmetric SNHL (n=9); G4, characterized by progressive SNHL (n=15); and G5, characterized by fluctuating SNHL (n=12). The main audiometric features and outcomes of the groups were analyzed., Results: The mean age at implantation was 10.15 years (range, 2.5-21 years). The mean preoperative score for the discrimination of open-set words was 48%; this score increased to 74% at 12 months and 81% at 24 months after the CI procedure (G1 to G5, respectively: 79/62/77%, 50/81/88%, 59/75/86%, 35/74/67%, and 39/69/80%). Children who were implanted after 10 years of age did not improve as much as those who were implanted at a younger age (open-set word list speech perception [OSW] score at 12 months: 62% vs 83%; P=.0009). Shorter delays before surgery were predictive of better performance (P=.003). Inner ear malformation and SLC26A4 mutations were not predictive of the outcome., Conclusions: CIs provide better results compared with hearing aids in children with residual hearing. Factors that may impact the benefits of CIs in patients with residual hearing are age, delay in performing the CI procedure, which ear is implanted, and initial underestimation of the patient's hearing difficulties., (© The Author(s) 2015.)

Objectives: Kallmann syndrome (KS) usually combines an anosmia and a hypogonadotrophic hypogonadism. Hearing impairment was described in a few cases of KS. Our objective is to describe an unusual presentation of KS in 2 cases and to explore the pattern of inheritance in this family., Patients: Two brothers presented with a sensorineural hearing impairment associated with cryptorchidism and abnormal movements., Results: Genome-wide array analysis identified a large deletion of KAL1 in both patients confirming the diagnosis of Kallmann syndrome. The absence of familial history has been explained by a somatic mosaicism identified in their mother., Conclusion: The description of a hearing defect in 2 brothers with Kallmann syndrome allows asserting that deafness is part of the clinical features of this disease and must lead the physician to monitor the hearing function of Kallmann patients.

Hearing loss is the most common sensory disability with an incidence of one over 1000 newborns. Hearing loss may be caused by environmental and genetic factors; inherited causes are assumed in two thirds of cases. There is a great clinical and genetic heterogenicity. All inheritance modes have been described. Mutations in the GJB2 gene, which encodes connexin 26, are mainly responsible for sensorineural deafness resulting in prelingual non syndromic autosomal recessive phenotypes DFNB1. The 35 delG mutation of this gene is very frequent (70% of the cases). Thus, 35 delG is, with the delta F508 mutation of the CFTR gene, the most frequent human pathogenic mutation known. Hearing loss might also be associated with other clinical features. Some of these syndromes, including hearing loss, have to be looked for systematically because of their frequency, of their possible clinical presentation as an isolated hearing loss and of the possibility of a medical treatment., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

In 2008, SLC29A3 has been implicated in a syndromic form of genodermatosis: H syndrome. The major features encountered in H syndrome are Hearing loss, Hyperglycaemia, Heart anomalies, Hypertrichosis, Hyperpigmentation, Hepatomegaly and Hypogonadism. More recently, SLC29A3 mutations have been described in families presenting syndromes associating generalized histiocytosis to systemic progressive features: severe camptodactyly, hearing loss, hypogonadism, hepatomegaly, heart defects and skin hyperpigmentation. We have identified a homozygous missense SLC29A3 mutation in a patient presenting with only a progressive sensorineural hearing impairment and a single cervical node (Rosai Dorfman). SLC29A3 mutations appear to be involved in a large phenotypic continuum which should prompt physicians to study this gene even in mild clinical presentations., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Mutations of the COCH gene inherited in an autosomal dominant mode are responsible for late-onset cochleovestibular impairment on both sides. Our objective is to report the youngest patient (3 years) associating a molecular variant of the COCH gene and a cochleovestibular impairment on both sides. The clinical sequence has started with a vestibular dysfunction in a two-year-old child: recurrent rotatory dizziness during 12 months. At the age of 3, a sensorineural hearing loss on both sides has occured associated with spontaneous variation during 6 months. The lack of mutation of the connexin 26, connexin 30 and pendrin genes has reorientated the genetic investigation. A molecular variant of the COCH gene was found in the vWFA2 domain. It was an in-frame deletion predicting the synthesis of an abnormal protein in which 21 aminoacid were missing. Others family members with mutation were asymptomatics. In this isolated case report, the study was in favor of a non pathogenic molecular variant of the COCH gene. For all that, mutations of the COCH gene could be searched in progressive cochleovestibular dysfunctions on both sides in children, even without family affect.

Transient deafness associated with an increase in core body temperature is a rare and puzzling disorder. Temperature-dependent deafness has been previously observed in patients suffering from auditory neuropathy. Auditory neuropathy is a clinical entity of sensorineural deafness characterized by absent auditory brainstem response and normal otoacoustic emissions. Mutations in OTOF, which encodes otoferlin, have been previously reported to cause DFNB9, a non-syndromic form of deafness characterized by severe to profound prelingual hearing impairment and auditory neuropathy. Here we report a novel mutation in OTOF gene in a large family affected by temperature-dependent auditory neuropathy. Three siblings aged 10, 9 and 7 years from a consanguineous family were found to be affected by severe or profound hearing impairment that was only present when they were febrile. The non-febrile patients had only mild if any hearing impairment. Electrophysiological tests revealed auditory neuropathy. Mapping with microsatellite markers revealed a compatible linkage in the DFNB9/OTOF region in the family, prompting us to run a molecular analysis of the 48 exons and of the OTOF intron-exon boundaries. This study revealed a novel mutation p.Glu1804del in exon 44 of OTOF. The mutation was found to be homozygous in the three patients and segregated with the hearing impairment within the family. The deletion affects an amino acid that is conserved in mammalian otoferlin sequences and located in the calcium-binding domain C2F of the protein., (Copyright 2010 Elsevier Inc. All rights reserved.)

To report on the outcomes of sequential bilateral cochlear implantation (CI) in children with inner ear malformation. The study design is a retrospective case study. The setting is a tertiary reference center. Two children presenting a profound bilateral congenital hearing loss with bilateral hypoplasia of the cochleovestibular nerves and hypoplasic external semicircular canal had a cochlear implant at respectively 16 months and 33 months. A second implant was proposed at respectively 17 and 20 months after the first implant. The main outcome measures are audiometry, perceptive results in closed and open set words (CSW and OSW) and oral production at follow-up. The first cochlear implant gave respectively mean thresholds at 60 dB and 70 dB. Bilateral CI showed mean threshold at respectively 40 dB and 55 dB. In case 1, perceptive assessment was 83% and 70% in respectively CSW and OSW with oral production and comprehension of sentences after 1 year follow-up. In case 2, the perceptive assessment showed no perceptive or linguistic evolution at 6 months follow-up. In cochleovestibular nerve hypoplasia, bilateral implantation could be discussed in cases of limited result after unilateral implant.

We report on two sporadic and two familial new cases with sensorineural hearing impairment and ovarian dysgenesis which are the cardinal signs of Perrault syndrome in females. Only one of them has a nervous system defect. We reviewed all the published cases of Perrault syndrome in order to define the clinical variability and to evaluate the frequency of the neurological anomalies in this clinical entity. Moreover we excluded GJB2, POLG, and FOXL2 as candidate genes in Perrault syndrome., ((c) 2008 Wiley-Liss, Inc.)

Mitochondrial DNA (mtDNA) mutations have been implicated in non-syndromic hearing loss either as primary or as predisposing factors. As only a part of the mitochondrial genome is usually explored in deafness, its prevalence is probably under-estimated. Among 1350 families with non-syndromic sensorineural hearing loss collected through a French collaborative network, we selected 29 large families with a clear maternal lineage and screened them for known mtDNA mutations in 12S rRNA, tRNASer(UCN) and tRNALeu(UUR) genes. When no mutation could be identified, a whole mitochondrial genome screening was performed, using a microarray resequencing chip: the MitoChip version 2.0 developed by Affymetrix Inc. Known mtDNA mutations was found in nine of the 29 families, which are described in the article: five with A1555G, two with the T7511C, one with 7472insC and one with A3243G mutation. In the remaining 20 families, the resequencing Mitochip detected 258 mitochondrial homoplasmic variants and 107 potentially heteroplasmic variants. Controls were made by direct sequencing on selected fragments and showed a high sensibility of the MitoChip but a low specificity, especially for heteroplasmic variations. An original analysis on the basis of species conservation, frequency and phylogenetic investigation was performed to select the more probably pathogenic variants. The entire genome analysis allowed us to identify five additional families with a putatively pathogenic mitochondrial variant: T669C, C1537T, G8078A, G12236A and G15077A. These results indicate that the new MitoChip platform is a rapid and valuable tool for identification of new mtDNA mutations in deafness.

Sensorineural hearing loss is the most frequent sensory deficit of childhood and is of genetic origin in up to 75% of cases. It has been shown that mutations of the SLC26A4 (PDS) gene were involved in syndromic deafness characterized by congenital sensorineural hearing impairment and goitre (Pendred's syndrome), as well as in congenital isolated deafness (DFNB4). While the prevalence of SLC26A4 mutations in Pendred's syndrome is clearly established, it remains to be studied in large cohorts of patients with nonsyndromic deafness and detailed clinical informations. In this report, 109 patients from 100 unrelated families, aged from 1 to 32 years (median age: 10 years), with nonsyndromic deafness and enlarged vestibular aqueduct, were genotyped for SLC26A4 using DHPLC molecular screening and sequencing. In all, 91 allelic variants were observed in 100 unrelated families, of which 19 have never been reported. The prevalence of SLC26A4 mutations was 40% (40/100), with biallelic mutation in 24% (24/100), while six families were homozygous. All patients included in this series had documented deafness, associated with EVA and without any evidence of syndromic disease. Among patients with SLC26A4 biallelic mutations, deafness was more severe, fluctuated more than in patients with no mutation. In conclusion, the incidence of SLC26A4 mutations is high in patients with isolated deafness and enlarged vestibular aqueduct and could represent up to 4% of nonsyndromic hearing impairment. SLC26A4 could be the second most frequent gene implicated in nonsyndromic deafness after GJB2, in this Caucasian population.

Objective: The purpose of the study is to present the results of cochlear implantation in case of deafness involving mutations in the OTOF gene. This form of deafness is characterized by the presence of transient evoked otoacoustic emissions (TEOAE). In cases of profound deafness with preserved TEOAE, two main etiologies should be considered: either an auditory neuropathy (a retrocochlear lesion) or an endocochlear lesion. It is essential to differentiate these two entities with regards to therapy and screening., Patients: We report two children who presented with profound prelingual deafness, confirmed by the absence of detectable responses to auditory evoked potentials (AEP), associated with the presence of bilateral TEOAE. Genetic testing revealed mutations in OTOF, confirming DFNB9 deafness. Both patients have been successfully implanted (with a follow-up of 18 and 36 months, respectively)., Main Outcome Measures: Clinical (oral production, closed and open-set words and sentences list, meaningful auditory integration scale), audiometric evaluation (TEOAE, AEP) before and after implantation, and neural response telemetry (NRT)., Results: Both patients present a good quality of clinical responses and electrophysiological tests after implantation, indicating satisfactory functioning of the auditory nerve. This confirms the endocochlear origin of DFNB9 and suggests that these mutations in OTOF lead to functional alteration of inner hair cells., Conclusion: In the absence of a context of neurological syndrome, the combination of absent AEP and positive TEOAE should lead to a genetic screening for mutations in OTOF, in order to undertake the appropriate management.

Aims: The purpose of the study was to define boundaries between endocochlear hearing loss and auditory neuropathy in children with congenital profound hearing loss and positive otoacoustic emissions., Patient: A child presented with bilateral profound hearing loss, which was confirmed by the absence of evoked auditory potentials at 110 dB and with conserved otoacoustic emissions. The lack of any relevant medical history, a normal neurologic pediatric examination, and the improvement obtained with powerful hearing aids suggested an endocochlear cause. Genetic testing identified mutations in OTOF, responsible for the DFNB9 recessive form of hearing loss., Results: In recent years, cases of children with hearing loss associated with positive otoacoustic emissions have been labeled as "auditory neuropathy." Classically, this form of hearing loss is refractory to the use of hearing aids and cochlear implants. Mutations in OTOF lead to inner hair cells dysfunction, whereas the outer hair cells are initially functionally preserved. As this form of endocochlear hearing loss can be detected at a molecular level, genetic testing can be proposed for cases of nonsyndromic auditory neuropathy, as those children could benefit from cochlear implantation., Conclusion: It is advisable to reserve the term "auditory neuropathy" for patients who present hearing loss and conserved otoacoustic emissions in the context of a neurologic syndrome or for children with suggestive perinatal history. In other cases, genetic testing for mutations in OTOF should be carried out.

Objective: To evaluate the symptoms leading to diagnosis and the quality of rehabilitation after cochlear implantation in Usher syndrome., Study Design: Retrospective cohort study., Setting: ENT department of a tertiary referral hospital., Patients: Among 210 patients given an implantation in the Ear, Nose, and Throat department, 185 were congenitally deaf and 13 had Usher syndrome (7.0%). Five had a family history of Usher, and eight were sporadic cases. Eleven cases were Usher type I, one was Usher type III, and one was not classified. The age at implantation ranged from 18 months to 44 years (mean, 6 years 1 month). The mean follow-up was 52 months (range, 9 months to 9 years)., Main Outcome Measures: All patients had audiophonological and clinical examination, computed tomography scan of the temporal bones, ophthalmologic examination with fundoscopy, and an electroretinogram. Cerebral magnetic resonance imaging and vestibular examination were performed in 9 of 13 and 10 of 13 cases, respectively. Logopedic outcome measured preimplant and postimplant closed- and open-set word recognition and oral expression at follow-up., Results: The most frequent initial sign of Usher syndrome was delayed walking, with a mean age of 20 months. Among the 172 other congenitally deaf children with implants, when deafness was not associated with other neurologic disorders, the mean age at walking was 14 months (p < 0.001). The fundoscopy was always abnormal after the age of 5 years, and the electroretinogram was abnormal in all cases. Vestibular function was abnormal in all but one case (nonclassified). The computed tomography scan and the magnetic resonance imaging were always normal. Logopedic results with cochlear implants showed good perception skills in all but one case. The best perceptive results were obtained in children implanted before the age of 9 years. Oral language had significantly progressed in 9 of 13 at follow-up. There was no relation between the visual acuity and the logopedic results., Conclusion: The earliest clinical sign associated with deafness evoking Usher syndrome is late walking. The electroretinogram is the only reliable examination to enable the diagnosis. When severe profound deafness is associated with late walking, the electroretinogram should be systematically proposed. Logopedic results are linked to precocity of implantation, and early Usher's diagnosis contributes to optimize speech therapy.

Hearing impairment is the most frequent sensory defect in children, with a genetic basis in about 50% of cases. Several point mutations and deletions in mitochondrial DNA (mtDNA) have been identified in non-syndromic sensorineural hearing loss (NSSNHL). Beside the frequent A1555G mutation, a number of mutations in tRNAs have been reported recently, but their incidence remains unknown. We identified the T7511C mutation in the tRNASer(UCN) gene in two French families with isolated deafness. Maternal transmission was obvious in both. The 15 patients with hearing impairment exhibited a variable disease phenotype in terms of onset, severity, and progression. T7511C was present in all the patients screened. Homoplasmic and heteroplasmic levels were observed and did not correlate with the severity of the disease. T7511C was also present in 12 hearing offspring of the oldest deaf mothers, confirming the existence of modulatory factors. Our data suggest that this mtDNA mutation should be screened for in all cases of familial NSSNHL compatible with maternal transmission.

Deafness is the most common sensory defect. The investigation of the cause of deafness is critical for genetic counselling, and sometimes for appropriate management of associated pathologies. About two thirds of cases of congenital deafness are genetic forms, and the proportion is probably similar concerning the forms of deafness that appears during childhood. Some of the genetic forms are syndromic and the associated signs are sometimes inapparent or may appear during childhood. Consequently, a systematic search for the most frequent syndromes is necessary in each deaf individual. In the majority of genetic cases, deafness is the sole defect (non-syndromic deafness) and the major mode of transmission is autosomal recessive. The DFNB1 form of deafness, due to connexin 26 gene mutations, underlies half of the cases of non syndromic congenital deafness cases. The hearing loss has a prelingual onset, and it is most frequently severe or profound. There is no associated pathologies or radiological anomalies of the inner ear, and the vestibular tests are normal. The possibility of offering molecular diagnosis of connexin 26 gene defects is profoundly modifying daily medical practice in the investigation of the cause of deafness.

Potassium channels regulate electrical signaling and the ionic composition of biological fluids. Mutations in the three known genes of the KCNQ branch of the K+ channel gene family underlie inherited cardiac arrhythmias (in some cases associated with deafness) and neonatal epilepsy. We have now cloned KCNQ4, a novel member of this branch. It maps to the DFNA2 locus for a form of nonsyndromic dominant deafness. In the cochlea, it is expressed in sensory outer hair cells. A mutation in this gene in a DFNA2 pedigree changes a residue in the KCNQ4 pore region. It abolishes the potassium currents of wild-type KCNQ4 on which it exerts a strong dominant-negative effect. Whereas mutations in KCNQ1 cause deafness by affecting endolymph secretion, the mechanism leading to KCNQ4-related hearing loss is intrinsic to outer hair cells.

Townes-Brocks syndrome (TBS) is an autosomal dominant developmental disorder characterized by anal and thumb malformations and by ear anomalies that can affect the three compartments and usually lead to hearing loss. The gene underlying TBS, SALL1, is a human homolog of the Drosophila spalt gene which encodes a transcription factor. A search for SALL1 mutations undertaken in 11 unrelated affected individuals (five familial and six sporadic cases) led to the detection of mutations in nine of them. One nonsense and six different novel frameshift mutations, all located in the second exon, were identified. Together with the previously reported mutations [Kohlhase et al., 1999], they establish that TBS results from haploinsufficiency. The finding of de novo mutations in the sporadic cases is consistent with the proposed complete penetrance of the disease. Moreover, the occurrence of the same 826C>T transition in a CG dimer, in three sporadic cases from the present series and three sporadic cases from the other series [Kohlhase et al., 1999] (i.e., six of the eight mutations identified in sporadic cases), reveals the existence of a mutation hotspot. Six different SALL1 polymorphisms were identified in the course of the present study, three of which are clustered in a particular region of the gene that encodes a stretch of serine residues. Finally, the chromosome 16 breakpoint of a t(5;16)(p15.3;q12.1) translocation carried by a TBS-affected individual was mapped at least 180 kb telomeric to SALL1, thus indicating that a position effect underlies the disease in this individual., (Copyright 1999 Wiley-Liss, Inc.)

Two previous case reports described two sibs affected with both sensorineural hearing loss and oligodontia. Here, we report a similar syndrome in a male patient with an, as yet, undescribed vestibular aqueduct enlargement on tomodensitometry. The analysis of the parent's audiograms is consistent with the suggested autosomal recessive mode of inheritance of this disorder.