Publications by authors named "Els M R De Leenheer"

27 Publications

  • Page 1 of 1

Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis.

Genet Med 2019 05 5;21(5):1199-1208. Epub 2018 Oct 5.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis.

Methods: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls.

Results: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060).

Conclusion: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-018-0300-5DOI Listing
May 2019

Cephalometrics in Stickler syndrome: Objectification of the typical facial appearance.

J Craniomaxillofac Surg 2016 Jul 15;44(7):848-53. Epub 2016 Apr 15.

Department of Orthodontics, Ghent University/Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.

Introduction: Stickler syndrome is a connective tissue disorder characterized by orofacial, ocular, skeletal and auditory symptoms. The orofacial phenotype mainly consists of midfacial hypoplasia, micrognathia and cleft palate. Large phenotypic variability is evident though. Few studies have tried to substantiate the typical facial appearance in Stickler syndrome patients.

Methods: Molecularly confirmed Stickler patients were invited to undergo cephalometric analysis based on a lateral radiograph in standardized conditions. Angular and linear measurements were performed according to Steiner's and Sassouni's analysis and compared with age- and gender-matched reference values.

Results: Thirteen patients aged 10-62y were included, twelve of whom had type 1 Stickler syndrome (COL2A1 mutation) and one type 2 Stickler syndrome (COL11A1 mutation). The position of maxilla and mandible relative to the cranial base was not significantly different from the reference population (S-N-A: p = 0.73, S-N-B: p = 0.43). The mandibular plane and y-axis showed an elevated angle with the cranial base in most patients, although not significant for the total group (S-N to Go-Me: p = 0.20, S-N to S-Gn: p = 0.18). Dental analysis was normal, except for a higher overjet value (p = 0.006) and a higher angle between occlusal plane and Frankfort plane (p = 0.022).

Conclusion: Cephalometric analysis was not able to thoroughly prove the abnormal facial appearance in Stickler syndrome. The majority of patients had normal dentofacial proportions. The most frequently observed anomaly in our series is a rather short and posteriorly rotated mandible, but clinical variability is high.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcms.2016.04.010DOI Listing
July 2016

Auditory phenotype in Stickler syndrome: results of audiometric analysis in 20 patients.

Eur Arch Otorhinolaryngol 2016 Oct 19;273(10):3025-34. Epub 2016 Jan 19.

Department of Otorhinolaryngology, Ghent University Hospital, Ghent University, De Pintelaan 185 (1P1), 9000, Ghent, Belgium.

Hearing loss in Stickler syndrome has received little attention due to the often more disabling ocular, orofacial and skeletal manifestations. Estimates suggest a global prevalence of sensorineural hearing loss (SNHL) ranging from 50 % to about 100 % though, depending on the underlying Stickler genotype. By performing extensive audiometric analysis in Stickler patients, we aimed to further elucidate the auditory phenotype. Twenty molecularly confirmed Stickler patients (age 10-62 year), of whom sixteen with type 1 Stickler syndrome (COL2A1 mutation) and four with type 2 Stickler syndrome (COL11A1 mutation) underwent an otological questionnaire, clinical examination, pure tone and speech audiometry, tympanometry and otoacoustic emission testing. Cross-sectional and longitudinal regression analysis of the audiograms was performed to assess progression. In type 1 Stickler syndrome, 75 % demonstrated hearing loss, predominantly in the high frequencies. No significant progression beyond presbyacusis was observed. All type 2 Stickler patients exhibited mild-to-moderate low- and mid-frequency SNHL and moderate-to-severe high-frequency SNHL. In both types, hearing loss was observed in childhood. Otoacoustic emissions were only detectable in 7/40 ears and had very low amplitudes, even in frequency bands with normal hearing on pure tone audiometry. Type 1 Stickler syndrome is characterized by a mild high-frequency SNHL, emerging in childhood and non-progressive. Absent otoacoustic emissions are a frequent finding. Patients with type 2 Stickler syndrome exhibit early-onset moderate SNHL affecting all frequencies with a sloping audiogram. Taking into account the visual impairment in many patients, we recommend regular auditory follow-up in patients with Stickler syndrome, especially in childhood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00405-016-3896-6DOI Listing
October 2016

Etiological approach in patients with unidentified hearing loss.

Int J Pediatr Otorhinolaryngol 2015 Feb 16;79(2):216-22. Epub 2014 Dec 16.

Department of Otorhinolaryngology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:

Objectives: Etiological diagnosis of hearing impairment is of great importance to ensure early and adequate management. Even after thorough history taking, clinical and audiometric evaluation, the cause of hearing loss remains unclear in a majority of patients. Further examinations can imply imaging, ophthalmologic investigations, laboratory tests, electrocardiography and genetic testing. Lately, the latter has taken an increasingly prominent place within this diagnostic work-up. However, clear guidelines about optimal implementation and sequence of these tests are required.

Methods: Records of patients who visited the consultation for otogenetics at Ghent University Hospital (Belgium) during the period 2006-2012 were retrospectively reviewed. In order to optimize the etiological-diagnostic work-up of unidentified hearing loss, application patterns and results of various diagnostic tests, audiometric and etiological data of each patient were collected and analyzed.

Results: Data of 191 patients were analyzed. In 81.2% of the patients, a cause of hearing loss could be determined or suspected. In total, 65.4% had a (presumably) genetic etiology, with connexin 26 (GJB2) mutations as the leading cause. Inquiry of risk factors, associated with congenital hearing loss, and pedigree analysis were found to have the highest diagnostic gain (61.3% and 41.8%). Connexin 26 gene mutations were only present in bilateral hearing impairment, whereas CT abnormalities were related to unilateral (P=0.003), profound (P<0.001) hearing loss. An enlarged vestibular aqueduct was present in 42.9% of all CT abnormalities. Ophthalmologic anomalies were detected in 35.7% of the studied patients.

Conclusions: A sequential approach for the etiological diagnosis of unidentified hearing loss could determine or suggest a cause in more than 80% of patients. The approach may vary based on the presenting phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijporl.2014.12.012DOI Listing
February 2015

Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing.

Mol Genet Metab 2014 Nov 8;113(3):230-5. Epub 2014 Sep 8.

Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. Electronic address:

Introduction: Stickler syndrome is caused by mutations in genes encoding type II and type XI collagens. About 85% of the pathogenic variants is found in COL2A1 (Stickler type 1), whereas a minority of mutations has been reported in COL11A1 (Stickler type 2) and COL11A2 (Stickler type 3). Beside the typical skeletal and orofacial manifestations, ocular anomalies are predominantly present in type 1 and type 2, while hearing loss is more pronounced in type 2 and type 3.

Methods: We performed COL11A1 mutation analysis for 40 type 2 Stickler patients and COL11A2 mutation analysis for five type 3 Stickler patients, previously all COL2A1 mutation-negative, using targeted next-generation sequencing (NGS) whereas whole-exome sequencing (WES) was performed in parallel for two patients. Three patients were analyzed for both genes due to unclear ocular findings.

Results: In total 14 COL11A1 and two COL11A2 mutations could be identified, seven of which are novel. Splice site alterations are the most frequent mutation type, followed by glycine substitutions. In addition, six variants of unknown significance (VUS) have been found. Identical mutations and variants were identified with both NGS techniques.

Conclusion: We expand the mutation spectrum of COL11A1 and COL11A2 in Stickler syndrome patients and show that targeted NGS is an efficient and cost-effective molecular tool in the genetic diagnosis of Stickler syndrome, whereas the more standardized WES might be an alternative approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2014.09.001DOI Listing
November 2014

Temporal bone imaging in osteogenesis imperfecta patients with hearing loss.

Laryngoscope 2013 Aug 12;123(8):1988-95. Epub 2013 Feb 12.

Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium.

Objectives/hypothesis: Osteogenesis imperfecta (OI) is an autosomal-dominant connective-tissue disorder, predominantly characterized by bone fragility. Conductive hearing loss develops in half of the OI patients and often progresses to mixed loss. Findings of computed tomography (CT) and magnetic resonance (MR) imaging of the temporal bone in the largest series of OI patients to date are presented and correlated with the audiograms.

Study Design: Retrospective case series.

Methods: CT images and audiograms of 17 hearing-impaired OI patients, aged 9 to 67 years, were analyzed retrospectively. In four patients, MR imaging was performed as well. Imaging abnormalities were correlated with type and severity of hearing loss deduced from the audiograms.

Results: CT revealed fenestral hypodense foci in the fissula ante fenestram (25 of 33 ears), oval window (23 of 33 ears), and round window (20 of 33 ears). Retrofenestral hypodensities were observed, affecting the cochlear turns (16 of 33 ears), facial nerve canal (10 of 33 ears), or semicircular canals (6 of 33 ears), or appearing like the fourth turn of the cochlea (11 of 33 ears). The site of hypodensities corresponded to the type of hearing loss in 72.2% of the OI ears. The air-bone gap and bone-conduction thresholds showed significant positive associations with the number of affected fenestral (P < .05) and retrofenestral structures (P < .01), respectively. Gadolinium-enhanced MR images demonstrated active lesions in three patients with mixed hearing loss or deafness.

Conclusions: The site of hypodensities on temporal bone CT images in OI corresponds to presence and type of hearing loss determined by audiometry. The more severe the hearing loss, the more affected temporal bone structures in OI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lary.23963DOI Listing
August 2013

Hearing impairment in Stickler syndrome: a systematic review.

Orphanet J Rare Dis 2012 Oct 30;7:84. Epub 2012 Oct 30.

Department of Otorhinolaryngology, 1P1, Ghent University / Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium.

Background: Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory defects. It is caused by mutations in different collagen genes, namely COL2A1, COL11A1 and COL11A2 (autosomal dominant inheritance), and COL9A1 and COL9A2 (autosomal recessive inheritance). The auditory phenotype in Stickler syndrome is inconsistently reported. Therefore we performed a systematic review of the literature to give an up-to-date overview of hearing loss in Stickler syndrome, and correlated it with the genotype.

Methods: English-language literature was reviewed through searches of PubMed and Web of Science, in order to find relevant articles describing auditory features in Stickler patients, along with genotype. Prevalences of hearing loss are calculated and correlated with the different affected genes and type of mutation.

Results: 313 patients (102 families) individually described in 46 articles were included. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Hearing impairment was predominantly sensorineural (67.8%). Conductive (14.1%) and mixed (18.1%) hearing loss was primarily found in young patients or patients with a palatal defect. Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).

Conclusions: Hearing impairment in patients with Stickler syndrome is common. Sensorineural hearing loss predominates, but also conductive hearing loss, especially in children and patients with a palatal defect, may occur. The distinct disease-causing collagen genes are associated with a different prevalence of hearing impairment, but still large phenotypic variation exists. Regular auditory follow-up is strongly advised, particularly because many Stickler patients are visually impaired.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1750-1172-7-84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3551705PMC
October 2012

Stapes surgery in osteogenesis imperfecta: retrospective analysis of 34 operated ears.

Audiol Neurootol 2012 7;17(3):198-206. Epub 2012 Mar 7.

Department of Otorhinolaryngology, Ghent University Hospital, Belgium. Freya.Swinnen @ UGent.be

Intraoperative findings of stapes surgery in 34 ears from 22 patients with genetically confirmed osteogenesis imperfecta (OI) are reported, as well as the audiometric results after the longest postoperative follow-up published to date. Twenty-nine out of 34 ears underwent primary stapes surgery and 5 ears revision surgery. Postoperative audiometric follow-up ranged from 6 months to 37 years. Stapes footplates were fixed in all ears. Additionally, footplates were thickened or fragile, stapes crura atrophic or fractured, and middle ear mucosae thickened or hypervascularized. Short-term postoperative audiometry revealed improved hearing and reduced air-bone gaps in 28/29 primary operated ears and in all revision cases. In the 22 ears with long-term postoperative follow-up (mean duration: 16 years), hearing gain was still significant at the latest audiometric evaluation. Independently of the patients being diagnosed with OI type I or IV and independently of the underlying OI genotype, beneficial results are obtained in the majority of OI patients undergoing primary or revision stapes surgery for reduction of conductive hearing loss components caused by stapes footplate fixation. Despite the progressive course of the concomitant sensorineural component, hearing gain remains beneficial over several decades.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000336211DOI Listing
August 2012

Association between bone mineral density and hearing loss in osteogenesis imperfecta.

Laryngoscope 2012 Feb 17;122(2):401-8. Epub 2012 Jan 17.

Department of Otorhinolaryngology, Unit for Osteoporosis, Ghent University Hospital, Ghent, Belgium.

Objectives/hypothesis: Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, predominantly characterized by bone fragility. In half of the patients, progressive hearing loss develops, which is associated with abnormal bony changes involving the middle ear ossicles and stapes footplate. In the present study, we investigated whether the development of hearing loss in OI may be related to the overall aberrant bone quality.

Study Design: Observational study.

Methods: Following audiologic evaluation, 56 adult OI patients were classified as presenting normal hearing or conductive/mixed or pure sensorineural hearing loss. Areal bone mineral density (BMD) (aBMD) was measured using lumbar spine (LS) and whole body (WB) dual X-ray absorptiometry. By means of peripheral computed tomography, volumetric BMD (vBMD) and morphometric bone parameters were determined at distal and proximal radius, providing separate results for trabecular and cortical bone. The obtained bone parameters were compared between normal-hearing OI patients and those with either conductive/mixed or pure sensorineural hearing loss.

Results: Z scores demonstrated decreased LS aBMD, WB aBMD, and trabecular vBMD in OI adults compared to the healthy population. Patients with conductive/mixed hearing loss had lower trabecular vBMD compared to those with normal hearing or pure sensorineural loss at both whole-group and between-relatives comparisons.

Conclusions: It is hypothesized that OI patients with lower BMD might be more susceptible to accumulating microfractures, which may interfere with the bone remodeling inhibition pathways in the temporal bone and, therefore, contribute to stapes footplate fixation and a conductive hearing loss component.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lary.22408DOI Listing
February 2012

Osteogenesis Imperfecta: the audiological phenotype lacks correlation with the genotype.

Orphanet J Rare Dis 2011 Dec 29;6:88. Epub 2011 Dec 29.

Department of Otorhinolaryngology, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.

Background: Osteogenesis Imperfecta (OI) is a heritable connective tissue disorder mainly caused by mutations in the genes COL1A1 and COL1A2 and is associated with hearing loss in approximately half of the cases. The hearing impairment usually starts between the second and fourth decade of life as a conductive hearing loss, frequently evolving to mixed hearing loss thereafter. A minority of patients develop pure sensorineural hearing loss. The interindividual variability in the audiological characteristics of the hearing loss is unexplained.

Methods: With the purpose of evaluating inter- and intrafamilial variability, hearing was thorougly examined in 184 OI patients (type I: 154; type III: 4; type IV: 26), aged 3-89 years, with a mutation in either COL1A1 or COL1A2 and originating from 89 different families. Due to the adult onset of hearing loss in OI, correlations between the presence and/or characteristics of the hearing loss and the underlying mutation were investigated in a subsample of 114 OI patients from 64 different families who were older than 40 years of age or had developed hearing loss before the age of 40.

Results: Hearing loss was diagnosed in 48.4% of the total sample of OI ears with increasing prevalence in the older age groups. The predominant type was a mixed hearing loss (27.5%). A minority presented a pure conductive (8.4%) or pure sensorineural (12.5%) loss. In the subsample of 114 OI subjects, no association was found between the nature of the mutation in COL1A1 or COL1A2 genes and the occurrence, type or severity of hearing loss. Relatives originating from the same family differed in audiological features, which may partially be attributed to their dissimilar age.

Conclusions: Our study confirms that hearing loss in OI shows a strong intrafamilial variability. Additional modifications in other genes are assumed to be responsible for the expression of hearing loss in OI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1750-1172-6-88DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267664PMC
December 2011

Audiologic phenotype of osteogenesis imperfecta: use in clinical differentiation.

Otol Neurotol 2012 Feb;33(2):115-22

Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium.

Objectives: To describe the audiologic phenotype in osteogenesis imperfecta (OI).

Study Design: Observational study.

Setting: Tertiary referral center.

Patients: One hundred eighty-two patients with genetically confirmed OI, aged 3 to 89 years.

Intervention: Diagnostic hearing evaluation through otoadmittance and acoustic stapedius reflex measurements, pure tone, and speech audiometry.

Main Outcome Measure(s): Prevalence, type, severity, symmetry, and audiometric configuration of the hearing loss in OI. Progression of hearing thresholds was determined by constructing age-related typical audiograms.

Results: Approximately 52.2% of all OI patients demonstrated hearing loss unilaterally (7.7%) or bilaterally (44.5%). Pure conductive, mixed, and pure sensorineural hearing losses were observed in 8.5%, 37.8%, and 11.6% of OI ears, respectively. Multiple linear regression revealed that thresholds progressed by 0.5 dB/yr at 0.25 kHz to 0.8 dB/yr at 0.8 kHz in the ears with conductive or mixed hearing loss. Pure sensorineural hearing loss progressed by less than 0.1 dB/yr at 0.25 kHz to 1.2 dB/yr at 8.0 kHz. Audiometric configuration was predominantly flat (70.5%) in the ears with conductive/mixed loss and sloping (50.0%) in those with pure sensorineural loss.

Conclusion: Patients with OI are at risk for hearing loss. The hearing loss in OI may initiate at a young age and is progressive. However, the rate of progression, as well as the hearing loss severity, onset, and configuration depend on the type of hearing loss, which may be conductive/mixed or pure sensorineural. For both types, age-related threshold audiograms are constructed and may help the clinician to estimate the course of the hearing loss in patients with OI. In addition, they may be valuable to distinguish between hearing loss associated with OI and other similar forms of hearing loss, such as in otosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MAO.0b013e31823e28e9DOI Listing
February 2012

Audiometric, surgical, and genetic findings in 15 ears of patients with osteogenesis imperfecta.

Laryngoscope 2009 Jun;119(6):1171-9

ENT Department, FC Donders Institute for Neurosciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. Freya.Swinnen@UGent

Objectives/hypothesis: To provide data on the outcome of stapes surgery in patients with osteogenesis imperfecta (OI). The audiometric results of 15 ears (12 patients), in which a stapes operation was performed, are presented and compared with results from literature.

Study Design: Retrospective study.

Methods: In 12 patients with genetically confirmed OI, intraoperative findings and audiometric evaluations were recorded.

Results: In all patients the genetic mutation was located in the COL1A1 gene. Surgical findings in OI may be particular like mobile, atrophic stapes crura combined with a fixation of the stapes footplate, which may be thickened, and a hypervascularized or thickened middle-ear mucosa. Outcome for hearing in 13 primary surgered ears was good because at short-term follow-up the air-bone gap was reduced in all cases. These results were maintained in the long-term, with exception of one ear, in which progression of the sensorineural component occurred shortly after the operation. Although initial success was noted in two ears with revision surgery, in the long term this was only maintained in one of them.

Conclusions: In general, stapes surgery is successful in resolving the conductive hearing loss in OI patients, even in the long term. Hearing loss in OI is mostly of the mixed type, and the sensorineural component is reported to be progressive. Stapedotomy, by improving the hearing level, may facilitate the rehabilitation with a hearing aid. Because the identified mutation could be located in the COL1A1 gene in all patients, conductive hearing loss in OI caused by stapes fixation is possibly linked to a mutation in this gene. Laryngoscope, 2009.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lary.20155DOI Listing
June 2009

Speech outcome regarding overall intelligibility, articulation, resonance and voice in Flemish children a year after pharyngeal flap surgery. A pilot study.

Folia Phoniatr Logop 2008 12;60(5):223-32. Epub 2008 Aug 12.

Department of Otorhinolaryngology, Head and Neck Surgery and Speech and Language Pathology, Craniofacial Team, University Hospital Gent, Gent, Belgium.

Objective: The main purpose of this study is to determine the treatment effectiveness of pharyngeal flap surgery by measuring speech outcome 1 year after surgery. The authors hypothesized that flap surgery is an effective technique for velopharyngeal inadequacy resulting in improved intelligibility, decreased hypernasality and nasalance scores and normal voice characteristics.

Patients And Methods: Objective (Nasometer, Dysphonia Severity Index) as well as subjective (perceptual evaluations) assessment techniques were performed in 7 subjects. Speech evaluations were performed 1 year after flap surgery and comparison was made between the speech results of the preoperative condition (1 week before surgery) and the first postoperative condition (6 weeks after surgery).

Results: After pharyngeal flap surgery there was improved though still slightly impaired intelligibility, with normal nasality, normal nasalance values for standard Flemish speech and normal voice characteristics. The normal nasality and nasalance values were not present in the preoperative condition. Persistence of the incorrect production of the thrill sound /r/ and the fricatives /s/ and /sch/ were observed.

Conclusion: It is likely that the slightly impaired speech intelligibility is determined by the presence of persistent articulation disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000151242DOI Listing
February 2009

The phenotype of the first otosclerosis family linked to OTSC5.

Otol Neurotol 2006 Apr;27(3):308-15

Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, and Department of Radiology, Rijnstate Hospital, Arnhem, The Netherlands.

Objective: To report the audiometric and radiologic findings in the first otosclerosis family linked to OTSC5.

Study Design: A clinical investigation of a family linked to OTSC5, including analyses of audiometric data and of high-resolution computed tomography (CT) images of the temporal bones from genetically affected family members.

Setting: Tertiary referral center.

Patients: Family members from a four-generation pedigree with otosclerosis segregating as an autosomal dominant trait.

Main Outcome Measure(s): Pre-surgery pure tone audiometric data. Classification of otosclerotic foci on high-resolution spiral CT images of the temporal bones of genetically affected individuals.

Results: Audiometric data showed a considerable degree of phenotypic variability. Cross-sectional regression analysis did not disclose any clear age dependence of threshold-related data. Systematic differences between mean parameter values relating to the thresholds in the best or the worst ear were found. High-resolution CT images revealed a fenestral otosclerotic focus in seven of nine (78%) clinically affected individuals and cochlear foci in one of these seven patients.

Conclusion: The phenotype of OTSC5 seems to be variable. Additional long-term audiometric data are needed to construct age-related typical audiograms, which may also facilitate the comparison between phenotypes of the different otosclerosis loci. The detection rate of otospongiotic foci in our study group is similar or lower compared with previous reports on CT data in consecutive otosclerosis patients who had stapes replacing surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00129492-200604000-00004DOI Listing
April 2006

Audiometric, vestibular, and genetic aspects of a DFNA9 family with a G88E COCH mutation.

Otol Neurotol 2005 Sep;26(5):926-33

Otorhinolaryngology, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands.

Objectives: To perform genetic analysis and to analyze cochleovestibular impairment features in a newly identified Dutch family with nonsyndromic autosomal dominant hearing impairment (DFNA9).

Study Design: Genetic analysis was performed using microsatellite markers and single nucleotide polymorphisms. Audiometric data were collected and analyzed longitudinally. Results were compared with those obtained in previously identified P51S COCH mutation carriers (n = 74). Special attention was also given to a comparison of age-related features such as progressive hearing loss and vestibular impairment.

Setting: Tertiary referral center.

Patients: G88E COCH mutation carriers from a Dutch family.

Main Outcome Measures: The study of clinical features of a DFNA9 family carrying a G88E COCH mutation and to compare this to the symptoms of those carrying a P51S/COCH mutation.

Results: Pure-tone thresholds, phoneme recognition scores, and vestibular responses of the G88E mutation carriers were essentially similar to those previously established in the P51S mutation carriers. Hearing started to deteriorate in G88E mutation carriers from age 46 to 49 years and onward, whereas deterioration of vestibular function started from approximately age 46 years. In the P51S mutation carriers, vestibular impairment started earlier, at approximately age 34 years. However, the difference in age of onset with the G88E mutation carriers was not significant. Remarkably, the proportion of patients who developed complete vestibular areflexia within the age range of 40 to 56 years was significantly lower for the G88E mutation carriers than for the P51S mutation carriers.

Conclusion: Apart from a significantly lower frequency of vestibular areflexia between the ages of 40 and 56 years, there are no phenotypic differences between carriers of the G88E and P51S mutations in the COCH gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.mao.0000185062.12458.87DOI Listing
September 2005

Audiological characteristics of some affected members of a Dutch DFNA13/COL11A2 family.

Ann Otol Rhinol Laryngol 2004 Nov;113(11):922-9

Department of Otorhinolaryngology, University Medical Center Nijmegen, Nijmegen, The Netherlands.

Members of a Dutch DFNA13/COL11A2 family were evaluated with pure tone audiometry, stapedial reflexes, otoacoustic emissions, loudness scaling, difference limen for frequency, gap detection, and speech perception in quiet and noise. The tone audiometry showed a predominant loss for the low and middle frequencies, with only a few otoacoustic emissions at thresholds better than 25 dB hearing level. The stapedial reflexes appeared elevated, and loudness growth curves were shifted parallel to those for normal-hearing subjects, indicating a shift of the dynamic range toward higher presentation levels. The data for the difference limen for frequency, gap detection, and speech perception in noise fell within the (near-)normal range. Despite elevated thresholds, all suprathreshold functions showed fairly normal properties, suggesting an attenuation of signal energy in the cochlea with limited degradation of the cochlea's signal analyzing capabilities. The effect of DFNA13/COL11A2 may thus be characterized as a cochlear conductive loss.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/000348940411301112DOI Listing
November 2004

Stickler syndrome type I and Stapes ankylosis.

Int J Pediatr Otorhinolaryngol 2004 Dec;68(12):1573-80

Department of Otorhinolaryngology Head and Neck Surgery, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

Objective: To report a successful stapedectomy for stapedial fixation in a patient with Stickler syndrome type I (COL2A1).

Setting: University Hospital Department for Otology, Pathology, Ophthalmology and Clinical Genetics.

Study Design: A clinical and genetic evaluation of a mother and daughter focusing mainly on the otological, ophthalmological, histological and genetical aspects.

Intervention: A stapedectomy was performed successfully.

Results: Hearing impairment improved after stapedectomy. Postoperatively a shift in high-frequency threshold wa seen related to the stapedectomy. A new mutation in COL2A1 gene was dectected.

Conclusion: Stapedial fixation can be the cause of hearing impairment in Stickler syndrome type I (COL2A1). The hearing impairment can be improved by stapes surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijporl.2004.07.015DOI Listing
December 2004

A Dutch family with hearing loss linked to the DFNA20/26 locus: longitudinal analysis of hearing impairment.

Arch Otolaryngol Head Neck Surg 2004 Mar;130(3):281-8

Department of Otorhinolaryngology, University Medical Center Nijmegen, Nijmegen, The Netherlands.

Objectives: To perform linkage analysis and to outline hearing loss characteristics in a family exhibiting a nonsyndromic, autosomal dominant type of progressive sensorineural hearing loss.

Design: Genetic analysis was performed using microsatellite markers. Audiometric data were collected and analyzed longitudinally. Sigmoidal dose-response curves enabled us to perform nonlinear regression analysis per frequency and on phoneme recognition scores. Speech recognition scores were compared with those of DFNA2, DFNA5, DFNA9, and presbyacusis subjects.

Subjects: Affected family members of a Dutch family (W99-060).

Results: We revealed linkage of hearing loss to the DFNA20/26 locus (maximum logarithm of odds score, 3.1 at theta=0.04) and reduced the critical region from 12 to 9.5 centimorgans. Patients younger than 15 years already showed gently downsloping audiograms. At ages 15 to 20 and 25 to 40 years, hearing loss was profound at 8 kHz and 1 to 4 kHz, respectively. The 0.25- to 0.5-kHz thresholds showed more gradual progression by about 1.5 to 2 dB/y. From about age 40 years onward, hearing was residual. Hearing impairment took a more severe course than in a known DFNA20 family. Score recognition in DFNA20/26 subjects was better than in DFNA9 subjects at any pure-tone average (1-4 kHz) threshold. Compared with subjects having DFNA2 and DFNA5, speech recognition in those with DFNA20/26 scored better at threshold levels below 85 dB hearing level, but worse at levels above 90 dB. Compared with presbyacusis subjects, those with DFNA20/26 scored better in speech recognition at levels below 100 dB and worse at levels above 100 dB.

Conclusions: Autosomal dominant hearing loss is linked to the DFNA20/26 locus in this Dutch family. The critical region is reduced from 12 to 9.5 centimorgans. Phenotypically, patients are more severely affected than those of a known DFNA20 family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archotol.130.3.281DOI Listing
March 2004

A novel mutation identified in the DFNA5 gene in a Dutch family: a clinical and genetic evaluation.

Audiol Neurootol 2004 Jan-Feb;9(1):34-46

Department of Otorhinolaryngology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.

A novel DFNA5 mutation was found in a Dutch family, of which 37 members were examined. A nucleotide substitution was identified in the splice acceptor site of intron 7, leading to skipping of exon 8 in part of the transcripts. The mutation was found in 18 individuals. Sensorineural hearing impairment was non-syndromic and symmetric. In early life, presumably congenitally, hearing impairment amounted to 30 dB in the high frequencies. Progression was most pronounced at 1 kHz (1.8 dB/year). Speech recognition was relatively good with a phoneme score of about 50% at the age of 70. Onset age was 37 years, and recognition deteriorated by 1.3% per year. The recognition score deteriorated by 1.0% per decibel threshold increase from a mean pure-tone average (PTA at 1, 2 and 4 kHz) of 63 dB onwards. Vestibular function was generally normal. The second mutation identified in the DFNA5 gene results in hearing impairment, similar to that in the original DFNA5 family in terms of pure-tone thresholds, but with more favourable speech recognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000074185DOI Listing
February 2004

Congenital conductive hearing loss in dyschondrosteosis.

Ann Otol Rhinol Laryngol 2003 Feb;112(2):153-8

Department of Otorhinolaryngology, University Medical Center St Radboud, Nijmegen, The Netherlands.

Conductive hearing loss was detected in a boy with a previous diagnosis of dyschondrosteosis. Dyschondrosteosis is a rare inherited condition characterized by mesomelic dwarfism and Madelung's deformity. The syndrome can be caused by mutations in the SHOX gene, and in that case, the pattern of inheritance is pseudoautosomal dominant. Indeed, SHOX mutation analysis in our patient revealed a deletion. The combination of dyschondrosteosis and conductive hearing loss has been reported in 2 previous cases. In our patient, exploratory tympanotomy revealed ankylosis of the stapes and a malformed incus. A substantial gain in hearing threshold was obtained by a stapedectomy in combination with a malleovestibulopexy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/000348940311200208DOI Listing
February 2003

The phenotype of DFNA13/COL11A2.

Adv Otorhinolaryngol 2002 ;61:85-91

Department of Otorhinolaryngology, University Medical Centre Nijmegen, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000066804DOI Listing
February 2003

DFNA10/EYA4--the clinical picture.

Adv Otorhinolaryngol 2002 ;61:73-8

Department of Otorhinolaryngology, University Medical Centre Nijmegen, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000066807DOI Listing
February 2003

Clinical features of DFNA5.

Adv Otorhinolaryngol 2002 ;61:53-9

Department of Otorhinolaryngology, University Medical Centre Nijmegen, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000066800DOI Listing
February 2003

DFNA2/KCNQ4 and its manifestations.

Adv Otorhinolaryngol 2002 ;61:41-6

Department of Otorhinolaryngology, University Medical Centre Nijmegen, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000066802DOI Listing
February 2003

Further delineation of the DFNA5 phenotype: results of speech recognition tests.

Ann Otol Rhinol Laryngol 2002 Jul;111(7 Pt 1):639-41

Speech recognition scores were analyzed in 34 carriers of a DFNA5 mutation. Cross-sectional linear regression analysis (last visit, maximum recognition score in %Correct on age or PTA1,2,4 kHz) established onset age (score 90%) at 16 years and onset PTA1,2,4 kHz level (score 90%) at 41 dB hearing level. The deterioration rate was 0.7%/y in the plot of maximum score against age, whereas the deterioration gradient was 0.4%/dB in the plot of maximum score against PTA1,2,4 kHz. Given the previously demonstrated rapid progression of hearing impairment, speech recognition was relatively good: at age 70, the score was still >50%.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/000348940211100712DOI Listing
July 2002

A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment.

Hum Mutat 2002 Jul;20(1):15-9

Department of Medical Genetics, University of Antwerp-UIA, Antwerp, Belgium.

Several different mutations in the KCNQ4 K+ channel gene are responsible for autosomal dominant nonsyndromic hearing impairment (DFNA2). Here we describe two additional families originating from Europe and Japan with a KCNQ4 missense mutation (W276S) that was previously found in one European family. We compared the disease-associated haplotype of the three W276S-bearing families using closely linked microsatellite markers and intragenic single nucleotide polymorphisms. Differences between the haplotypes were found, excluding a single founder mutation for the families. Therefore, the W276S mutation has occurred three times independently, and most likely represents a hot spot for mutation in the KCNQ4 gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.10096DOI Listing
July 2002

Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family.

Ann Otol Rhinol Laryngol 2002 Mar;111(3 Pt 1):267-74

Department of Otorhinolaryngology, University Medical Center St Radboud Nijmegen, The Netherlands.

We analyzed hearing thresholds, speech recognition scores, and vestibular responses in 32 affected persons in a large family with DFNA2/KCNQ4-related hearing impairment caused by a W276S missense mutation. Linear regression analysis of individual longitudinal data revealed significant threshold progression (1 dB/y) and offset (at age zero). The mean offset thresholds were 5, 21, 40, 39, 31, and 51 dB hearing level (HL) at 0.25, 0.5, 1, 2, 4, and 8 kHz, respectively. Cross-sectional analysis of last-visit thresholds against age produced less-steep slopes and higher offset thresholds. Nonlinear regression analysis of last-visit phoneme recognition scores against age in 25 cases showed that speech recognition did not deteriorate before the third decade. A hyperactive vestibuloocular reflex was found in 3 of 11 cases: 2 persons were especially susceptible to motion sickness. Persons with this KCNQ4 mutation showed congenital, progressive high-frequency impairment without substantial loss of speech recognition during the first decades of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/000348940211100312DOI Listing
March 2002