Audiological profile of the prevalent genetic form of childhood ...

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Abstract. The present study describes the audiological profile of genetic hearing loss resulting from GJB2 mutations in northern Greece, as this represents the ...
Eur Arch Otorhinolaryngol (2004) 261 : 259–261 DOI 10.1007/s00405-003-0679-7

O TO L O G Y

V. Iliadou · N. Eleftheriades · A. S. Metaxas · A. Skevas · T. Kiratzidis · A. Pampanos · N. Voyiatzis · M. Grigoriadou · M. B. Petersen · T. Iliades

Audiological profile of the prevalent genetic form of childhood sensorineural hearing loss due to GJB2 mutations in northern Greece Received: 5 August 2003 / Accepted: 5 August 2003 / Published online: 30 September 2003 © Springer-Verlag 2003

Abstract The present study describes the audiological profile of genetic hearing loss resulting from GJB2 mutations in northern Greece, as this represents the most frequent single cause of childhood sensorineural hearing loss. The 35delG mutation in homozygosity was detected in 27 of 107 patients (25.2%). The audiological profile is that of a profound or severe sensorineural hearing loss, with a sloping or flat configuration of the audiogram, mostly symmetrical, non-progressive and affecting more the higher frequencies. This profile underlines the importance of early identification and genetic family counseling leading to the future possibility of prevention of deafness. Keywords Congenital sensorineural hearing loss · Connexin 26 · GJB2 mutation · Audiological profile · Prevention

Introduction Congenital sensorineural hearing loss (SHL) affects communication through lack of normal development of verbal

skills and inadequate language acquisition. Children having this condition are considered handicapped when early intervention is not implemented. At least 50% of congenital SHL in developed countries is estimated to be of genetic origin, and two-thirds of them are non-syndromic, with the hearing loss being the only pathological condition. About 80% of the non-syndromic genetic forms of congenital SHL show an autosomal recessive mode of inheritance [1, 2]. Although there is a great genetic heterogenity of congenital SHL, one gene (GJB2 encoding connexin 26) is responsible for a high proportion of cases [3, 4, 5]. In the Greek population, the 35delG frameshift mutation in the GJB2 gene has a carrier frequency of 3.5% or 1 in 28 normal hearing people [6]. The present study is dealing with the audiological profile of GJB2 SHL in northern Greece, as this represents the most prevalent form of childhood SHL. The audiological profile can provide us the clinical phenotype of GJB2 SHL and thereby contribute to the investigation of this common form of congenital SHL.

Subjects and methods V. Iliadou · N. Eleftheriades · A. S. Metaxas · N. Voyiatzis · T. Iliades Department of Otorhinolaryngology, Aristotle University of Thessaloniki, Thessaloniki, Greece A. Pampanos · M. Grigoriadou · M. B. Petersen Department of Pediatrics, Aristotle University of Thessaloniki, Thessaloniki, Greece A. Pampanos · M. Grigoriadou · M. B. Petersen Institute of Child Health, Athens, Greece A. Skevas Department of Otorhinolaryngology, University of Ioannina, Ioannina, Greece T. Kiratzidis Veria Medical Center of Hearing, Veria, Greece V. Iliadou (✉) Filellinon 6 Panorama, 55236 Thessaloniki, Greece Tel.: +3023-10345893, Fax: +302310240776, e-mail: [email protected]

Subjects A total of 107 children were recruited from the Audiological Department of the Aristotelian University of Thessaloniki, Greece. All children included in this study had congenital non-syndromic SHL. Informed consent was obtained from all participants and from parents of patients younger than 18 years old. Method A detailed history was taken for each subject followed by a thorough clinical evaluation and audiological assessment. Clinical evaluation included micro-otoscopy. Audiological assessment involved pure tone audiometry for frequencies of 250 Hz, 500 Hz, 1,000 Hz, 2,000 Hz, 4,000 Hz and 8,000 Hz for each ear. The degree of hearing loss was evaluated by the average of the pure tone thresholds of the better hearing ear at 0.5, 1, 2 and 4 kHz. Hearing loss was characterized as mild, moderate, severe or profound when the average of pure tone thresholds were 20–39, 40–69, 70–89 and >90 dB HL, respectively. Hearing loss was further characterized as flat or slop-

260 ing, symmetrical or asymmetrical and progressive or non-progressive. A flat hearing loss was defined as a difference of pure tone thresholds between 500 and 4,000 Hz of less than 15 dB HL. Symmetry of hearing loss was evaluated by the degree and configuration of hearing loss in both ears of each subject. Asymmetrical hearing loss was defined as one in which the degree and/or configuration of the loss is different for each ear. Progressive HL was defined as an elevation of pure tone thresholds greater than 15 dB in at least two frequencies or greater than 10 dB for an average of four frequencies. The presence of the GJB2 35delG mutation was detected by allele-specific polymerase chain reaction (PCR) amplification of genomic DNA [6].

Results Of the 107 subjects with congenital non-syndromic SHL evaluated in this study 27 (25.2%) presented the 35delG mutation in homozygosity. The first parameter that was analyzed was the severity of hearing loss. Of the 27 children, only 4 (14.8%) presented severe HL with the remaining 23 (85.2%) presenting profound HL. Regarding audiogram configuration, 26 ears (48.1%) presented a flat audiogram with a difference of pure tone thresholds between 500 and 4,000 Hz of less than 15 dB HL. Twentyeight ears presented a sloping audiogram with a difference of pure tone thresholds between 500 and 4,000 Hz of more than 15 dB HL. Symmetry of hearing loss was evaluated by the degree and configuration of hearing loss in both ears of each subject. Only four children (14.8%) presented an asymmetrical hearing loss, with the remaining 23 (85.2%) having symmetrical hearing loss. Only in the frequency area of 250 to 2,000 Hz did all 54 ears tested had measurable audiometric thresholds. This number decreased at 4,000 and 8,000 Hz to 46 and 30 ears, respectively, as shown in Fig. 1. This could be considered as an indication that GJB2 deafness mostly affects higher frequencies and thus the base of the cochlea. If only measurable thresholds are considered, then the average audio-

Fig. 2 Mean measurable audiometric thresholds ±1 SD for each frequency

metric configuration would represent a notch at around 2,000 Hz as shown in Fig. 2. This indicates that the average pure tone threshold at 8,000 Hz in ears with residual hearing at this frequency is slightly better than the average pure tone threshold at 2,000 Hz, although with a greater standard deviation (18.1 compared to 14 dB HL). Pure tone audiometry was performed in each subject annually since the initial diagnosis in order to monitor for progression of HL. Progressive HL was defined as an elevation of pure tone thresholds greater than 15 dB in at least two frequencies or greater than 10 dB for an average of four frequencies. No progression regarding the HL was recorded in any patient. This could be an indication that homozygosity for the 35delG mutation causes permanent, non-progressive SHL.

Discussion

Fig. 1 Number of ears with measurable audiometric thresholds for each frequency

Homozygosity for the 35delG mutation in the GJB2 gene was detected in this study in 25.2% of the subjects originating from northern Greece. In a larger study in the Greek population the percentage was 30.0% [7]. The prevalence of 35delG homozygosity as a cause of congenital SHL ranges from 2.0% in a U.S. study [8] to 32.4% in a study in Italy and Spain [5]. The high frequency of GJB2 HL requires a description of the phenotype of this common childhood SHL. This description is essential both for prognostic information in deaf children with a compatible phenotype and for genetic counseling. Profound HL was present in 85.2% in the present study and severe HL in 14.8%. An unexpectedly wide range of severity of HL from mild-moderate to severe-profound has been reported in the literature.[9, 10]. The present study, however, is dealing only with 35delG homozygous subjects. Studies have shown a great diversity even in 35delG

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homozygous subjects, while other researchers come to the conclusion that individuals with severe or profound HL are more likely to have two identifiable mutations in the GJB2 gene than patients with mild or moderate HL [11]. The present study reveals that the vast majority of homozygous patients in the northern Greek population has a profound HL. Audiogram configuration was assessed as being sloping in 51.9% and flat in 48.1%. Sloping and flat audiograms are the most frequent configurations in recent studies when dealing with the 35delG mutation in the homozygous state [12]. Non-progressive hearing loss was demonstrated in all cases in the present study as has already been shown in other studies with 35delG homozygous patients [11, 12]. Symmetrical hearing loss was found in the vast majority (85.2%) of the present sample. The literature shows that symmetrical HL is the most common type found in 35delG homozygosity, and this finding is not different when compared with other mutations of the GJB2 gene. [5, 13, 14, 15]. The fact that only in the frequency spectrum of 250 to 2,000 Hz did all 54 ears tested have measurable audiometric thresholds further supports the sloping configuration of the audiogram as being the most prevalent one. In summary, the results of the present study are in agreement with other studies showing that the GJB2 35delG mutation is a major cause of congenital non-syndromic SHL in Caucasians. The audiological profile is that of a profound or severe HL with a sloping or flat configuration, mostly symmetrical, non-progressive and affecting more the higher frequencies. This suggests the importance of early identification. The presence of the above audiological profile should imply molecular testing for the existence of GJB2 mutations and appropriate genetic counseling leading to future possible prevention of profound hearing loss.

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