Erea-Noel Garabedian

SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations

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 (Pendreds syndrome), as well as in congenital isolated deafness (DFNB4). While the prevalence of SLC26A4 mutations in Pendreds 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.

Severe laryngomalacia: surgical indications and results in 115 patients.

Between 1987 and 1993, 115 children were operated on for severe forms of laryngomalacia in two pediatric ear, nose, and throat (ENT) departments. The criteria used to determine the severity of the illness were selected following short hospitalization periods during which the children received both pediatric and ENT checkups. Based on clinical manifestations and/or the results of pH monitoring gastroesophageal reflux was found to be present in 68% of the children in the study. Detailed analysis and endoscopy were used to differentiate the symptoms that were related to laryngomalacia from those that were caused by other conditions, including mixed‐breathing, swallowing, and sucking difficulties.

The Biology and Management of Subglottic Hemangioma: Past, Present, Future†

Objectives/Hypothesis: Objectives were 1) to review the presentation, natural history, and management of subglottic hemangioma; 2) to assess the affect of five variables (age, gender, degree of subglottic narrowing, location and extent of subglottic hemangioma, and lack or presence of other hemangioma) and the outcome of six different treatment modalities (conservative monitoring, corticosteroid, laser surgery, tracheotomy, laryngotracheoplasty, and interferon) in the management of subglottic hemangioma; and 3) to present specific guidelines to help determine the best possible treatment modality at the time of initial presentation.

Fourth branchial pouch anomalies: A study of six cases and review of the literature

A retrospective study in the ENT departments of the Timone Childrens Hospital in Marseille and the Armand Trousseau Hospital in Paris and a review of the literature was performed in order to update knowledge about fourth branchial pouch anomalies. Over the 12-year period studied, a total of six children were treated: three boys and three girls. The lesions were located on the left side in all cases and infection was the most common manifestation. Clinical presentation ranged from suppurative thyroiditis in most cases to stridor in a few newborns. The most useful diagnostic examinations are CT-scan of the neck and endoscopy of the pyriform sinus. The authors emphasize the need for complete surgical resection including the cyst and fistulous tract down to the pyriform sinus.

Myringoplasty in Children: Predictive Factors of Outcome

Objectives: To assess the results of myringoplasty in children and to determine which factors independently influence the postoperative results. Study Design: Retrospective study of the anatomic and functional results of 231 consecutive myringoplasties performed in 188 children between 1988 and 1992. Multivariate analysis of poor prognostic factors by cross‐sectional comparison 1 year after surgery. Methods: Myringoplasties were performed via an endaural approach with a fascia temporalis underlay graft. Results: In 216 of 231 ears (93.5%) the tympanic membrane was closed. A good anatomic outcome was considered to have been achieved in 188 ears (81.6%), although in 18 ears (7.8%) seromucous otitis media occurred, in 8 ears (3.5%) a progressive retraction pocket was encountered, and in 2 ears significant lateralization was present. One hundred thirty‐nine (67.5%) of the 206 ears tested in the postoperative period had a postoperative air‐bone gap of 10 dB or less. On average, mean bone conduction remained unaltered. The age of the patient and the size and the location of the perforation did not affect the outcome. Three prognostic factors for an abnormal postoperative tympanic membrane were found, with 95% confidence intervals: inflammatory changes in the middle ear mucosa (P < .05), contralateral tympanic perforation (P < .05), and contralateral cholesteatoma (P < .01). Conclusions: Myringoplasty with underlay grafting of the fascia temporalis in children gives good anatomic and functional results. Inflammatory changes within the middle ear mucosa, contralateral tympanic perforation, and contralateral cholesteatoma independently influence the risk of an abnormal postoperative tympanic membrane. The presence of one of these factors preoperatively should lead to the consideration of alternative, more durable graft material, such as autologous cartilage.

Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip

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.

Cochlear implantation in children with internal ear malformations.

Objective: To evaluate surgical aspects and results of cochlear implantation in inner ear malformations. Study Design: Retrospective cohort study. Setting: Ear, nose, and throat department of a tertiary referral hospital. Patients: Out of 260 implanted children, 18 (6.9%) had inner ear malformations: complex cochleovestibular malformation (n = 11), common cavity (n = 1), and enlarged vestibular aqueduct (EVA) (n = 6). Deafness was progressive in 12 cases (G1) and congenital in 6 cases (G2). Genetics lead to diagnosis in 12 of 13 cases: PSD mutation (n = 11), Waardenburg syndrome (n = 1), negative (1). Mean age at implant was 7.8 years. Mean follow-up period was 48 months. Main Outcome Measures: Medical and surgical outcomes were reported. Closed (CSW) and open (OSW) set word perception and level of speech production were evaluated each year. The results were compared pre- and postoperatively and between the two groups. Results: Gusher at surgery was observed in 50% of cases, with a persistent leak in one case. No facial injury or infectious complications were observed. At 12 months, 83% of the population had achieved more than 75% recognition in CSW, versus 16% before implant (p = 0.001). After 2 years, 64% of patients had more than 50% recognition in OSW. Good oral language was seen in 76% at 2 years and 100% at 3 years, versus 55% before implant (respectively, p > 0.05 and p = 0.03). At 1 year after implant, 83% of the G1 and 20% of the G2 achieved more than 50% recognition in OSW (p = 0.02). After 24 months, 83% of G1 and 40% of G2 had more than 50% in OSW (p > 0.05). Before implant, 75% in G1 and 0% in G2 had good oral language (p = 0.01). At 1 year, 83% in G1 and 16% in G2 had good oral language (p = 0.02). At 2 years, 100% in G1 and 20% in G2 had good oral language (p = 0.02). One child in G1 had no improvement after implantation. Conclusions: No major complication was seen. Perceptive and linguistic results were variable and depended on the type of the deafness. In progressive deafness, the perceptive and linguistic result are expected to be good. In congenital deafness, the results are more variable.

Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

Mutations in GJB2 are the most common cause of congenital nonsyndromic hearing loss. The controversial allele variant M34T has been hypothesized to cause autosomal dominant or recessive nonsyndromic hearing impairment and some in vitro data has been consistent with this hypothesis. In this report, we present the clinical and genotypic study of 11 families (seven familial forms of nonsyndromic sensorineural hearing loss (NSSNHL) and four sporadic cases) in which the M34T GJB2 variant has been identified. The M34T mutation did not segregate with the deafness in six of the seven familial forms of NSSNH. Eight persons with normal audiogram presented a heterozygous M34T variation and five normal hearing individuals were composite heterozygous for M34T and another GJB2 mutation. Four normal hearing individuals with a documented audiogram were M34T/35delG and one was M34T/(GJB6-D13S1830)del. Screening a French control population of 116 subjects we have found an M34T allele frequency of 1.72%. This percentage was not significatively different from the prevalence of the M34T allele in the deaf population, which was 2.12%. All these data suggest that the M34T variant is not clinically significant in human and is a frequent polymorphism in France.

Two large French pedigrees with non syndromic sensorineural deafness and the mitochondrial DNA T7511C mutation: evidence for a modulatory factor

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.

Surgical removal of subglottic hemangiomas in children.

Objective: To examine the indications and the results of surgical excision of severe subglottic hemangiomas.