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Sudden hearing loss in a family with GJB2 related progressive deafness
International Journal of Pediatric Otorhinolaryngology (2008) 72, 1735—1740
www.elsevier.com/locate/ijporl
CASE REPORT
Sudden hearing loss in a family with GJB2 related progressive deafness Haris Kokotas a,*, Maria Theodosiou b, George Korres b, Maria Grigoriadou a, Elisabeth Ferekidou b, Aglaia Giannoulia-Karantana c, Michael B. Petersen a, Stavros Korres b a
Department of Genetics, Institute of Child Health, ‘Aghia Sophia’ Children’s Hospital, Thivon & Levadias, 115 27 Athens, Greece b Department of Otorhinolaryngology — Head and Neck Surgery, Athens University, Hippokration Hospital, Athens, Greece c Department of Pediatrics, Athens University Medical School, Athens, Greece Received 13 May 2008; received in revised form 7 August 2008; accepted 9 August 2008 Available online 21 September 2008
KEYWORDS GJB2; 35delG; Sudden episodes; Progressive hearing loss; HL; Deafness
Summary Mutations of GJB2, the gene encoding connexin 26, have been associated with prelingual, sensorineural hearing loss of mild to profound severity. One specific mutation, the 35delG, has accounted for the majority of mutations detected in the GJB2 gene in Caucasian populations. Recent studies have described progression of hearing loss in a proportion of cases with GJB2 deafness. We report an unusual family with four 35delG homozygous members, in which the parents were deaf-mute whilst both children had a postlingual progressive hearing loss. Furthermore, the son suffered from sudden hearing loss. # 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Approximately one in 1000 children suffers from severe to profound hearing loss (HL) at birth or during early childhood (prelingual deafness) [1]. Around fifty percent of prelingual deafness has been related to genetic causes. Among genetic non-syndromic deafness, autosomal recessive inheritance predominates, accounting for about 80% of the cases [2], and up to date about 50 of the genes have been * Corresponding author. Tel.: +30 210 7467789; fax: +30 210 7700111. E-mail address: [email protected] (H. Kokotas).
identified. The autosomal recessive forms of deafness are usually the most severe and are almost exclusively due to cochlear defects (sensorineural deafness), in contrast to syndromic forms of deafness, which in most cases are conductive (external and/or middle ear developmental defects) or mixed [3]. Mutations in the GJB2 gene represent a major cause of prelingual, non-syndromic, recessive deafness, as they are responsible for up to 40% of such cases in many populations [4—9]. Around 90 GJB2 mutations have so far been reported to be associated with recessive, non-syndromic HL [10]. One specific mutation, 35delG, consists of a deletion of guanine (G) in a sequence of six Gs leading to
0165-5876/$ — see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2008.08.006
1736 a frameshift and truncation of connexin 26, the GJB2 gap junction protein [4]. Previous studies have reported a high prevalence of the 35delG mutation in Caucasians [3—5,11], with Greece demonstrating a carrier frequency of 3.5% [12]. As much as one third of prelingual deafness in the Greek population results from the 35delG mutation [13]. The GJB2 related HL is usually stable, but progression has been described in a proportion of cases. We present a Greek GJB2 deafness family of four members, the parents being deaf-mute while the offspring presented mild progressive postlingual HL with the boy suffering sudden HL. All individuals were tested homozygous for the common 35delG mutation.
2. Case report A Greek family of four individuals, all presenting HL of different severity, was referred to our Departments for clinical and molecular evaluation.
3. Clinical and genetic evaluation The boy, aged 23 years, showing postlingual progressive HL with an age of onset at 8 years, was hospitalized in the Department of Otorhinolaryngology — Head and Neck Surgery, Hippokration Hospital, University of Athens, for investigation of tinnitus and right sided sudden sensorineural HL. Pure tone audiometry showed profound (>90 db) and severe (70—90 db) HL on the right and left side, respectively (Fig. 1). Laboratory work included a complete blood cell count, determination of ESR, serum clotting and lipid studies, determination of blood glucose level, FTA-ABS test, thyroid function test, ANA, anti-ds DNA, AMA, ASMA, APCA, C3c, C4, Ra test, Asto, CRP, IgM/IgG CMV, IgM/IgG EpsteinBarr, and IgM/IgG toxo. High doses of i.v. steroids (prednisolone 25 mg daily, progressively diminished
H. Kokotas et al. within a period of 12 days), antiviral (acyclovir 800 mg, 5 tbl per day for 5 days) and i.v. vasodilators (amp. 50 mg buflomedil hydrochloride, 2 amp daily for a period of 7 days) were given but the hearing level on the right side deteriorated further. MRI scan of the internal auditory meati and clinical examination did not reveal any abnormality. Intratympanic infusion of steroids (dexamethasone 4 mg, 3 times in a period of 6 days) was performed at the end of treatment but the hearing level remained unchanged. Until the age of 8 years his hearing and speech were normally developed. Since then a progressive HL was reported and a hearing aid was applied on his right ear. For the last 10 years his hearing levels had been stable between 60 db at low frequencies and 75 db at mid and high frequencies on the right side (Figs. 2 and 3). After the sudden impairment on his right ear, hearing levels were detected only at 250 kHz (80 db) and 500 kHz (90 db) (Fig. 1). His sister, aged 21, presented with postlingual progressive mild to profound sensorineural HL with an onset at 2 years of age. Her audiograms showed a progressive HL at all frequencies and she is now concerned to be deaf (Figs. 4 and 5). However, she showed excellent abilities of oral communication. The mother, 49 years old, was reported being born deaf, but the father, aged 50 years, had a postlingual deafness with an onset around 5 years of age. Although hearing aid was applied on his left ear, he showed no ability of proper oral communication. The father had one deaf-mute brother while the mother had one male and one female deaf-mute sibling and one normal brother without hearing impairment. None of the patients had any of the following risk factors for acquired hearing deficit: (1) history of infections during pregnancy, (2) use of ototoxic medication (aminoglycosides, antibiotics, etc.), (3) bacterial meningitis, (4) need of neonatal mechanical ventilation, (5) history of head trauma associated with skull fracture or loss of consciousness, (6) signs
Fig. 1 Audiogram of the male subject at age 23 years immediately after the sudden sensorineural hearing loss (SSNHL) episode on his right ear (left panel).
Sudden hearing loss in a family with GJB2 related progressive deafness
1737
Fig. 2 Audiogram of the male subject at age 13 years. Hearing levels were better on his right ear (left panel) compared to his left ear (right panel).
Fig. 3 years.
Audiogram of the male subject, 6 months before the SSNHL episode. Hearing levels were almost stable for 10
of neurodegenerative disorders. None of the family members had undergone cochlear implantation. At this point, it should be acknowledged that generally, in the era before infant screening, early, prelingual progression commonly went undetected. Thus, there is a chance that both parents had a progressive HL.
Fig. 4
4. Molecular analysis Genomic DNA was isolated from EDTA-anticoagulated blood samples by a salting out procedure [14]. The GJB2 35delG mutation was detected by allele-specific polymerase chain reaction (PCR) amplification of genomic DNA by co-amplification
Audiogram of the female subject at age 15 years showing severe to profound hearing loss.
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Fig. 5
Audiogram of the female subject at age 21 years presenting profound hearing loss on both ears.
of the GJB2 gene with a segment of the X-Y homologous gene amelogenin as internal reaction control, as previously described [6,13]. All four members of the family were found homozygous for the GJB2 35delG mutation.
5. Discussion Mutations of GJB2 are the most common single cause of HL in many populations, and a broad spectrum of GJB2 mutations has been identified. In Caucasians, homozygosity of the most frequent GJB2 35delG mutation usually causes severe to profound, prelingual, non-progressive, neurosensory HL. We present an interesting family of individuals homozygous for the 35delG mutation in which the parents were deaf-mute but the offspring presented with postlingual progressive HL. Sudden sensorineural HL is defined as a 30 db drop of thresholds occurring in at least three contiguous frequencies in less than three days [15]. Our case meets these criteria. Variation in HL from mild to profound even in 35delG homozygotes within the same family, was reported by Murgia et al. [16] in a study of 53 unrelated subjects with congenital sensorineural hearing impairment, but no evidence of progression was found. Mild-moderate to profound HL, even within families with homozygotes for the 35delG, was also reported by Cohn et al. [17]. However, progression of HL was reported in 10 of the 30 subjects with GJB2 deafness. Episodes of sudden HL and the type of deafness (pre- or postlingual) were not reported. In a genotype—phenotype correlation study of 277 GJB2 deafness subjects, Cryns et al. [18] found that 35delG homozygotes have significantly more severe HL compared with 35delG/non-35delG compound heterozygotes indicating that the GJB2 genotype has a major impact on the degree of HL. In their study of 1531 persons from 16 countries with autosomal recessive, mild to profound HL, Snoeckx
et al. [19] suggested that the degree of HL associated with biallelic truncating mutations (56 patients) is significantly more severe than the HL associated with biallelic non-truncating mutations (30 patients). In an early study, Denoyelle et al. [20] reported progression of HL in five out of 16 children with GJB2 biallelic defects. They suggested that progression of HL is possible in young adulthood, in contrast to our case with possible progression of HL in childhood. In a meta-analysis of seven studies with non-overlapping data sets and similar ascertainment criteria, Gopalarao et al. [21] concluded that 19% of subjects with GJB2 deafness have progressive HL. Pagarkar et al. [22] reported a sibling pair with 35delG homozygosity, who passed hearing tests in early infancy and later developed sensorineural progressive HL. Sibling 1 presented postlingual HL with sufficient ability of speech, while sibling 2 showed postlingual HL with limited speech development, the latter having a cochlear implant. Both parents had normal hearing (genetic testing not indicated). In contrast to that, both sibs of our case had postlingual HL with proper oral communication abilities. The parents were deaf-mute but none of the family members had a cochlear implant. Janecke et al. [23] reported recurrent sudden sensorineural HL only in two and progression of HL in one out of 15 patients tested, all being compound heterozygous for GJB2 mutations. A number of genetic disorders exhibit inter- and intra-familial variability. Understanding the factors that control the expression of disease genes should provide insight into the fundamental disease processes and will have implications for counseling patients. Different mechanisms can account for this variability, including environmental factors, genotype—phenotype correlations and imprinting [24]. There is now increasing evidence that the manifestations of many genetic disorders are influenced by modifier genes distinct from the disease
Sudden hearing loss in a family with GJB2 related progressive deafness locus. Modifier genes are defined as background genes which interact with the disease mutation. The effect can be enhancing or suppressive and leads to a quantitative or qualitative difference in any aspect of the disease phenotype including the severity, the penetrance, the age of onset and the progression of the disease. The presumed influence of modifier genes of connexin 26 could involve one major modifier gene or be the effect of an interaction between several modifiers that possibly have an impact on the hair cells regarding attrition or gradual loss of endocochlear potential.
6. Conclusion The HL in GJB2 deafness is usually non-progressive, at least up to young adulthood. Profound hearing deficit due to mutations of the GJB2 gene might not always be congenital. In some individuals hearing capacities could be better, with normal hearing or mild-moderate deficit, in the first months of life. A rapidly progressive HL could occur during the preverbal age and the HL would remain essentially stable from that moment. An early window of time before establishment of the final profound defect has been assumed [25]. Our case suggests that other factors modify the phenotypic effects of GJB2 mutations and that it may be incorrect to assume that congenital HL due to the 35delG mutation is stable. Mapping and identifying any modifier genes of GJB2 in affected families may be useful in studying connexin 26 gap junctions and predictive of the clinical course of HL. An important element for genetic counseling is that the severity of HL due to GJB2 mutations is variable and cannot be predicted even within families. A considerable proportion of cases has a progressive HL, which might even include sudden episodes of HL.
Acknowledgment This study was supported by a grant from Oticon Fonden, Denmark (MBP).
References [1] N.E. Morton, Genetic epidemiology of hearing impairment, Ann. N.Y. Acad. Sci. 630 (1991) 16—31. [2] L. Zelante, P. Gasparini, X. Estivill, S. Melchionda, L. D’Agruma, N. Govea, et al., Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans, Hum. Mol. Genet. 6 (1997) 1605—1609.
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[3] C. Petit, Genes responsible for human hereditary deafness: symphony of a thousand, Nat. Genet. 14 (1996) 385—391. [4] F. Denoyelle, D. Weil, M.A. Maw, S.A. Wilcox, N.J. Lench, D.R. Allen-Powell, et al., Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene, Hum. Mol. Genet. 6 (1997) 2173—2177. [5] P.M. Kelley, D.J. Harris, B.C. Comer, J.W. Askew, T. Fowler, S.D. Smith, et al., Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss, Am. J. Hum. Mutat. 11 (1998) 387—394. [6] D.A. Scott, M.L. Kraft, R. Carmi, A. Ramesh, K. Elbedour, Y. Yairi, et al., Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss, Hum. Mut. 11 (1998) 387—394. [7] R. Rabionet, P. Gasparini, X. Estivill, Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins, Hum. Mut. 16 (2000) 190—202. [8] D.P. Kelsell, W.L. Di, M.J. Houseman, Connexin mutations in skin disease and hearing loss, Am. J. Hum. Genet. 68 (2001) 559—568. [9] A. Kenneson, K. Van Naarden Braun, C. Boyle, GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGe review, Genet. Med. 4 (2002) 258—274. [10] Ballana et al., The Connexin-Deafness Homepage, http:// davinci.crg.es/deafness/. [11] X. Estivill, P. Fortina, S. Surrey, R. Rabionet, S. Melchionda, L. D’Agruma, et al., Connexin-26 mutations in sporadic and inherited sensorineural deafness, Lancet 351 (1998) 394— 398. [12] T. Antoniadi, R. Rabionet, C. Kroupis, G.A. Aperis, J. Economides, J. Petmezakis, et al., High prevalence in the Greek population of the 35delG mutation in the connexin 26 gene causing prelingual deafness, Clin. Genet. 55 (1999) 381— 382. [13] A. Pampanos, J. Economides, V. Iliadou, P. Neou, P. Leotsakos, N. Voyiatzis, et al., Prevalence of GJB2 mutations in prelingual deafness in the Greek population, Int. J. Pediatr. Otorhinolaryngol. 65 (2002) 101—108. [14] S.A. Miller, D.D. Dykes, H.F. Polesky, A simple salting out procedure for extracting DNA from human nucleated cells, Nucleic Acids Res. 16 (1988) 1215. [15] W.R. Wilson, F.M. Byl, N. Laird, The efficacy of steroids in the treatment of idiopathic sudden hearing loss A double-blind clinical study., Arch. Otolaryngol. 106 (1980) 772—776. [16] A. Murgia, E. Orzan, R. Polli, M. Martella, C. Vinanzi, E. Leonardi, et al., Cx26 deafness: mutation analysis and clinical variability, J. Med. Genet. 36 (1999) 829—832. [17] E.S. Cohn, P.M. Kelley, T.W. Fowler, M.P. Gorga, D.M. Lefkowitz, H.J. Kuehn, et al., Clinical studies of familieswith hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1), Pediatrics 103 (1999) 546—550. [18] K. Cryns, E. Orzan, A. Murgia, P.L. Huygen, F. Moreno, I. del Castillo, et al., A genotype-phenotype correlation for GJB2 (connexin 26) deafness, J. Med. Genet. 41 (2004) 147—154. [19] R.L. Snoeckx, P.L. Huygen, D. Feldmann, S. Marlin, F. Denoyelle, J. Waligora, et al., GJB2 mutations and degree of hearing loss: a multicenter study, Am. J. Hum. Genet. 77 (2005) 945—957. [20] F. Denoyelle, S. Marlin, D. Weil, L. Moatti, P. Chauvin, E.N. Garabe ´dian, et al., Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexion-26 gene defect: implications for genetic counselling, Lancet 353 (1999) 1298—1303. [21] D. Gopalarao, W.J. Kimberling, W. Jesteadt, P.M. Kelley, K.L. Beauchaine, E.S. Cohn, Is hearing loss due to mutations in the Connexin 26 gene progressive? Int. J. Audiol. 47 (2008) 11—20.
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[22] W. Pagarkar, M. Bitner-Glindzicz, J. Knight, T. Sirimanna, Late postnatal onset of hearing loss due to GJB2 mutations, Int. J. Pediatr. Otorhinolaryngol. 70 (2006) 1119— 1124. [23] A.R. Janecke, A. Hirst-Stadlmann, B. Gu ¨nther, B. Utermann, T. Mu ¨ller, J. Lo ¨ffler, et al., Progressive hearing loss, and recurrect sudden sensorineural hearing loss associated with GJB2 mutations–—phenotypic spectrum and frequencies
of GJB2 mutations in Austria, Hum. Genet. 111 (2002) 145— 153. [24] R.S. Houlston, I.P.M. Tomlinson, Modifier genes in humans: strategies for identification, Eur. J. Hum. Genet. 6 (1998) 80—88. [25] E. Orzan, A. Murgia, Connexin 26 deafness is not always congenital, Int. J. Pediatr. Otorhinolaryngol. 71 (2007) 501—507.
Available online at www.sciencedirect.com
www.elsevier.com/locate/ijporl
CASE REPORT
Sudden hearing loss in a family with GJB2 related progressive deafness Haris Kokotas a,*, Maria Theodosiou b, George Korres b, Maria Grigoriadou a, Elisabeth Ferekidou b, Aglaia Giannoulia-Karantana c, Michael B. Petersen a, Stavros Korres b a
Department of Genetics, Institute of Child Health, ‘Aghia Sophia’ Children’s Hospital, Thivon & Levadias, 115 27 Athens, Greece b Department of Otorhinolaryngology — Head and Neck Surgery, Athens University, Hippokration Hospital, Athens, Greece c Department of Pediatrics, Athens University Medical School, Athens, Greece Received 13 May 2008; received in revised form 7 August 2008; accepted 9 August 2008 Available online 21 September 2008
KEYWORDS GJB2; 35delG; Sudden episodes; Progressive hearing loss; HL; Deafness
Summary Mutations of GJB2, the gene encoding connexin 26, have been associated with prelingual, sensorineural hearing loss of mild to profound severity. One specific mutation, the 35delG, has accounted for the majority of mutations detected in the GJB2 gene in Caucasian populations. Recent studies have described progression of hearing loss in a proportion of cases with GJB2 deafness. We report an unusual family with four 35delG homozygous members, in which the parents were deaf-mute whilst both children had a postlingual progressive hearing loss. Furthermore, the son suffered from sudden hearing loss. # 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Approximately one in 1000 children suffers from severe to profound hearing loss (HL) at birth or during early childhood (prelingual deafness) [1]. Around fifty percent of prelingual deafness has been related to genetic causes. Among genetic non-syndromic deafness, autosomal recessive inheritance predominates, accounting for about 80% of the cases [2], and up to date about 50 of the genes have been * Corresponding author. Tel.: +30 210 7467789; fax: +30 210 7700111. E-mail address: [email protected] (H. Kokotas).
identified. The autosomal recessive forms of deafness are usually the most severe and are almost exclusively due to cochlear defects (sensorineural deafness), in contrast to syndromic forms of deafness, which in most cases are conductive (external and/or middle ear developmental defects) or mixed [3]. Mutations in the GJB2 gene represent a major cause of prelingual, non-syndromic, recessive deafness, as they are responsible for up to 40% of such cases in many populations [4—9]. Around 90 GJB2 mutations have so far been reported to be associated with recessive, non-syndromic HL [10]. One specific mutation, 35delG, consists of a deletion of guanine (G) in a sequence of six Gs leading to
0165-5876/$ — see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2008.08.006
1736 a frameshift and truncation of connexin 26, the GJB2 gap junction protein [4]. Previous studies have reported a high prevalence of the 35delG mutation in Caucasians [3—5,11], with Greece demonstrating a carrier frequency of 3.5% [12]. As much as one third of prelingual deafness in the Greek population results from the 35delG mutation [13]. The GJB2 related HL is usually stable, but progression has been described in a proportion of cases. We present a Greek GJB2 deafness family of four members, the parents being deaf-mute while the offspring presented mild progressive postlingual HL with the boy suffering sudden HL. All individuals were tested homozygous for the common 35delG mutation.
2. Case report A Greek family of four individuals, all presenting HL of different severity, was referred to our Departments for clinical and molecular evaluation.
3. Clinical and genetic evaluation The boy, aged 23 years, showing postlingual progressive HL with an age of onset at 8 years, was hospitalized in the Department of Otorhinolaryngology — Head and Neck Surgery, Hippokration Hospital, University of Athens, for investigation of tinnitus and right sided sudden sensorineural HL. Pure tone audiometry showed profound (>90 db) and severe (70—90 db) HL on the right and left side, respectively (Fig. 1). Laboratory work included a complete blood cell count, determination of ESR, serum clotting and lipid studies, determination of blood glucose level, FTA-ABS test, thyroid function test, ANA, anti-ds DNA, AMA, ASMA, APCA, C3c, C4, Ra test, Asto, CRP, IgM/IgG CMV, IgM/IgG EpsteinBarr, and IgM/IgG toxo. High doses of i.v. steroids (prednisolone 25 mg daily, progressively diminished
H. Kokotas et al. within a period of 12 days), antiviral (acyclovir 800 mg, 5 tbl per day for 5 days) and i.v. vasodilators (amp. 50 mg buflomedil hydrochloride, 2 amp daily for a period of 7 days) were given but the hearing level on the right side deteriorated further. MRI scan of the internal auditory meati and clinical examination did not reveal any abnormality. Intratympanic infusion of steroids (dexamethasone 4 mg, 3 times in a period of 6 days) was performed at the end of treatment but the hearing level remained unchanged. Until the age of 8 years his hearing and speech were normally developed. Since then a progressive HL was reported and a hearing aid was applied on his right ear. For the last 10 years his hearing levels had been stable between 60 db at low frequencies and 75 db at mid and high frequencies on the right side (Figs. 2 and 3). After the sudden impairment on his right ear, hearing levels were detected only at 250 kHz (80 db) and 500 kHz (90 db) (Fig. 1). His sister, aged 21, presented with postlingual progressive mild to profound sensorineural HL with an onset at 2 years of age. Her audiograms showed a progressive HL at all frequencies and she is now concerned to be deaf (Figs. 4 and 5). However, she showed excellent abilities of oral communication. The mother, 49 years old, was reported being born deaf, but the father, aged 50 years, had a postlingual deafness with an onset around 5 years of age. Although hearing aid was applied on his left ear, he showed no ability of proper oral communication. The father had one deaf-mute brother while the mother had one male and one female deaf-mute sibling and one normal brother without hearing impairment. None of the patients had any of the following risk factors for acquired hearing deficit: (1) history of infections during pregnancy, (2) use of ototoxic medication (aminoglycosides, antibiotics, etc.), (3) bacterial meningitis, (4) need of neonatal mechanical ventilation, (5) history of head trauma associated with skull fracture or loss of consciousness, (6) signs
Fig. 1 Audiogram of the male subject at age 23 years immediately after the sudden sensorineural hearing loss (SSNHL) episode on his right ear (left panel).
Sudden hearing loss in a family with GJB2 related progressive deafness
1737
Fig. 2 Audiogram of the male subject at age 13 years. Hearing levels were better on his right ear (left panel) compared to his left ear (right panel).
Fig. 3 years.
Audiogram of the male subject, 6 months before the SSNHL episode. Hearing levels were almost stable for 10
of neurodegenerative disorders. None of the family members had undergone cochlear implantation. At this point, it should be acknowledged that generally, in the era before infant screening, early, prelingual progression commonly went undetected. Thus, there is a chance that both parents had a progressive HL.
Fig. 4
4. Molecular analysis Genomic DNA was isolated from EDTA-anticoagulated blood samples by a salting out procedure [14]. The GJB2 35delG mutation was detected by allele-specific polymerase chain reaction (PCR) amplification of genomic DNA by co-amplification
Audiogram of the female subject at age 15 years showing severe to profound hearing loss.
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Fig. 5
Audiogram of the female subject at age 21 years presenting profound hearing loss on both ears.
of the GJB2 gene with a segment of the X-Y homologous gene amelogenin as internal reaction control, as previously described [6,13]. All four members of the family were found homozygous for the GJB2 35delG mutation.
5. Discussion Mutations of GJB2 are the most common single cause of HL in many populations, and a broad spectrum of GJB2 mutations has been identified. In Caucasians, homozygosity of the most frequent GJB2 35delG mutation usually causes severe to profound, prelingual, non-progressive, neurosensory HL. We present an interesting family of individuals homozygous for the 35delG mutation in which the parents were deaf-mute but the offspring presented with postlingual progressive HL. Sudden sensorineural HL is defined as a 30 db drop of thresholds occurring in at least three contiguous frequencies in less than three days [15]. Our case meets these criteria. Variation in HL from mild to profound even in 35delG homozygotes within the same family, was reported by Murgia et al. [16] in a study of 53 unrelated subjects with congenital sensorineural hearing impairment, but no evidence of progression was found. Mild-moderate to profound HL, even within families with homozygotes for the 35delG, was also reported by Cohn et al. [17]. However, progression of HL was reported in 10 of the 30 subjects with GJB2 deafness. Episodes of sudden HL and the type of deafness (pre- or postlingual) were not reported. In a genotype—phenotype correlation study of 277 GJB2 deafness subjects, Cryns et al. [18] found that 35delG homozygotes have significantly more severe HL compared with 35delG/non-35delG compound heterozygotes indicating that the GJB2 genotype has a major impact on the degree of HL. In their study of 1531 persons from 16 countries with autosomal recessive, mild to profound HL, Snoeckx
et al. [19] suggested that the degree of HL associated with biallelic truncating mutations (56 patients) is significantly more severe than the HL associated with biallelic non-truncating mutations (30 patients). In an early study, Denoyelle et al. [20] reported progression of HL in five out of 16 children with GJB2 biallelic defects. They suggested that progression of HL is possible in young adulthood, in contrast to our case with possible progression of HL in childhood. In a meta-analysis of seven studies with non-overlapping data sets and similar ascertainment criteria, Gopalarao et al. [21] concluded that 19% of subjects with GJB2 deafness have progressive HL. Pagarkar et al. [22] reported a sibling pair with 35delG homozygosity, who passed hearing tests in early infancy and later developed sensorineural progressive HL. Sibling 1 presented postlingual HL with sufficient ability of speech, while sibling 2 showed postlingual HL with limited speech development, the latter having a cochlear implant. Both parents had normal hearing (genetic testing not indicated). In contrast to that, both sibs of our case had postlingual HL with proper oral communication abilities. The parents were deaf-mute but none of the family members had a cochlear implant. Janecke et al. [23] reported recurrent sudden sensorineural HL only in two and progression of HL in one out of 15 patients tested, all being compound heterozygous for GJB2 mutations. A number of genetic disorders exhibit inter- and intra-familial variability. Understanding the factors that control the expression of disease genes should provide insight into the fundamental disease processes and will have implications for counseling patients. Different mechanisms can account for this variability, including environmental factors, genotype—phenotype correlations and imprinting [24]. There is now increasing evidence that the manifestations of many genetic disorders are influenced by modifier genes distinct from the disease
Sudden hearing loss in a family with GJB2 related progressive deafness locus. Modifier genes are defined as background genes which interact with the disease mutation. The effect can be enhancing or suppressive and leads to a quantitative or qualitative difference in any aspect of the disease phenotype including the severity, the penetrance, the age of onset and the progression of the disease. The presumed influence of modifier genes of connexin 26 could involve one major modifier gene or be the effect of an interaction between several modifiers that possibly have an impact on the hair cells regarding attrition or gradual loss of endocochlear potential.
6. Conclusion The HL in GJB2 deafness is usually non-progressive, at least up to young adulthood. Profound hearing deficit due to mutations of the GJB2 gene might not always be congenital. In some individuals hearing capacities could be better, with normal hearing or mild-moderate deficit, in the first months of life. A rapidly progressive HL could occur during the preverbal age and the HL would remain essentially stable from that moment. An early window of time before establishment of the final profound defect has been assumed [25]. Our case suggests that other factors modify the phenotypic effects of GJB2 mutations and that it may be incorrect to assume that congenital HL due to the 35delG mutation is stable. Mapping and identifying any modifier genes of GJB2 in affected families may be useful in studying connexin 26 gap junctions and predictive of the clinical course of HL. An important element for genetic counseling is that the severity of HL due to GJB2 mutations is variable and cannot be predicted even within families. A considerable proportion of cases has a progressive HL, which might even include sudden episodes of HL.
Acknowledgment This study was supported by a grant from Oticon Fonden, Denmark (MBP).
References [1] N.E. Morton, Genetic epidemiology of hearing impairment, Ann. N.Y. Acad. Sci. 630 (1991) 16—31. [2] L. Zelante, P. Gasparini, X. Estivill, S. Melchionda, L. D’Agruma, N. Govea, et al., Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans, Hum. Mol. Genet. 6 (1997) 1605—1609.
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