Natalie Loundon

Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity

Sensorineural hearing defect and goiter are common features of Pendreds syndrome. The clinical diagnosis of Pendreds syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re‐evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendreds syndrome had been made. Twenty‐seven families had at least one mutated allele. Twenty‐eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.

Medical and surgical complications in pediatric cochlear implantation.

OBJECTIVES To report complications of cochlear implantation (CI) in children and to analyze risk factors. DESIGN Retrospective study from January 1, 1990, through April 30, 2008, with a mean follow-up of 5.5 years (range, 1 month to 17 years). SETTING Tertiary academic center. PATIENTS Four hundred thirty-four patients younger than 16 years. Mean age at CI was 4.7 (range, 0.6-16.0) years. Forty-one children (9.4%) underwent CI when younger than 24 months. Forty-three (9.9%) had inner ear malformations. MAIN OUTCOME MEASURES Complications after CI, classified into early (0-8 days) or delayed (>8 days) and major or minor. Spontaneous failures of internal devices were excluded. Correlation to age at CI, local trauma, and inner ear malformations were analyzed using the chi(2) test. RESULTS Forty-three patients (9.9%) experienced complications. Delayed complications occurred in 28 patients (65.1%), with a mean delay of 2.2 (range, 0.1-8.4) years. Twenty-four patients (5.5%) had major complications, consisting of severe cutaneous infections (15 patients), magnet displacement (3), meningitis (2), cholesteatoma (2), cerebrospinal fluid leak (1), and electrode misplacement (1). Nineteen (4.4%) had minor complications, consisting of vertigo (9 patients), soft-tissue infection (5), persistent otitis media (4), and facial palsy (1). Complications led to reimplantation in 13 of the 43 patients (30.2%). Trauma to the mastoid area (14 patients) and inner ear malformations (51) were highly correlated with major delayed complications (P < .001) and early minor complications (P < .001), respectively. Young age at CI was not correlated with any type of complication. CONCLUSIONS Complications of CI in children are common, with trauma as a major factor. Inner ear malformations should prompt specific preventive management. Cochlear implantation in young children did not appear to be a risk factor in this study.

Evaluation of Cytomegalovirus (CMV) DNA Quantification in Dried Blood Spots: Retrospective Study of CMV Congenital Infection

ABSTRACT We compared two protocols for extracting DNA from dried blood spots for cytomegalovirus (CMV) DNA detection and quantification by real-time PCR. Both extraction methods were reliable for the retrospective diagnosis of CMV congenital infection. Quantification of CMV DNA was valuable after normalization of viral loads with albumin gene PCR amplification results.

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.

Usher syndrome and cochlear implantation.

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 Ushers diagnosis contributes to optimize speech therapy.

Temperature-sensitive auditory neuropathy associated with an otoferlin mutation: Deafening fever!

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.

Audiophonological results after cochlear implantation in 40 congenitally deaf patients: preliminary results

The aim of this study is to evaluate the prognostic factors of audiophonological results in cochlear implant in congenitally deaf patients. Between 1991 and 1996. 40 congenitally deaf children underwent cochlear implantation in our department, at an average age of 7 years (median: 5 years). The results of speech therapy were evaluated with a mean follow-up of 2 years and were classified according to four criteria: perception of sound, speech perception, speech production and the level of oral language. For each criterion, a score was established ranging from zero to four. These scores were weighted according to age such that the results before and after implantation only reflected the changes related to the implantation. The prognostic factors for good results were: a good level of oral communication before implantation, residual hearing, progressive deafness and implantation at a young age. On the other hand, poor prognostic factors were: the presence of behavioral disorders and poor communication skills prior to implantation. Overall, the major prognostic factor for a good outcome appeared to be the preoperative level of oral language, even if this was rudimentary.

Alu -mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4

Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15–35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.

Phenotype and genotype in females with POU3F4 mutations

X‐linked deafness is a rare cause of hereditary isolated hearing impairment estimated as at least 1% or 2% of the non‐syndromic hearing loss. To date, four loci for DFN have been identified and only one gene, POU3F4 responsible for DFN3, has been cloned. In males, DFN3 is characterized by a progressive deafness associated with perilymphatic gusher at stapes surgery and with a characteristic inner ear malformation. The phenotype of eight independent females carrying POU3F4 anomalies is defined, and a late‐onset hearing loss is found in three patients. Only one has an inner ear malformation. No genotype/phenotype correlation is identified.

Velopharyngoplasty for noncleft velopharyngeal insufficiency: results in relation to 22q11 microdeletion.

OBJECTIVE To evaluate the results of velopharyngoplasty for velopharyngeal insufficiency (VPI) in relation to 22q11 deletion or nonsyndromic VPI. DESIGN Retrospective study. SETTING Academic medical center. PATIENTS Eleven of 45 patients with 22q11 microdeletion (group 1) and 9 patients without 22q11 microdeletion (group 2) with noncleft VPI (hypoplastic velum or hypodynamic velopharynx and deep pharynx) underwent velopharyngoplasty (midline pharyngeal flap with superior pedicle). Exclusion criteria included cleft palate, submucous cleft palate, all syndromic cases, and all associated malformations (except those related to 22q11 microdeletion in patients with DiGeorge syndrome). MAIN OUTCOME MEASURES Speech assessment before surgery using the Borel-Maisonny scale and at 9 months and 24 months after surgery. Velopharyngeal insufficiency was classified as normal, inconsistent, mild, moderate, and severe. RESULTS Before surgery, in group 1, 3 patients had mild and 8 had severe VPI, and in group 2, 1 had mild and 8 had severe VPI. Postoperative outcomes at 9 months showed that in group 1, 2 patients had excellent results (normal and inconsistent) and 9 had mild VPI, while in group 2, 6 patients had excellent results and 3 had mild VPI (P = .03). Postoperative outcomes at 24 months showed that in group 1, 10 patients had excellent results and 1 had mild VPI, while in group 2, 8 patients had excellent results and 1 had mild VPI. CONCLUSIONS Surgical treatment of noncleft VPI by pharyngoplasty was efficient in 10 of the 11 patients (91%) in the 22q11 group and in 8 of the 9 patients (89%) in the nonsyndromic group. Postoperative remission took longer for patients with the 22q11 microdeletion than for the control group. However, long-term results following surgical treatment were equally good in the 2 groups.