Mutations in the Wolfram Syndrome Type 1 Gene (WFS1) Define a Clinical Entity of Dominant Low-Frequency Sensorineural Hearing Loss

ORIGINAL ARTICLE Mutations in the Wolfram Syndrome Type 1 Gene (WFS1) Define a Clinical Entity of Dominant Low-Frequency Sensorineural Hearing Loss

Marci M. Lesperance, MD; James W. Hall III, PhD; Theresa B. San Agustin, MD; Suzanne M. Leal, PhD

Objective: To describe low-frequency sensorineural patients, few of whom use hearing aids. Speech percep- hearing loss (LFSNHL) inherited as a dominant trait in tion becomes affected in later decades when patients de- 3 families and in 1 sporadic case. velop high-frequency loss. Even children with a strong family history of dominant LFSNHL were not monitored Design: Longitudinal clinical study from 1968 to 2001. routinely. Penetrance appears complete in that all individuals with a genetic mutation developed hearing loss. Setting: Tertiary care hospital; field studies conducted by molecular genetic research laboratory. Conclusions: Dominant LFSNHL is most commonly caused by mutations in the Wolfram syndrome type 1 Participants: Dominant LFSNHL families. gene (WFS1). Mutations in WFS1 also cause a rare recessive syndromic form of hearing loss known as Wol- Interventions: Questionnaires, serial audiograms, and fram syndrome or DIDMOAD (diabetes insipidus, dia- interviews, correlated with molecular genetic data. betes mellitus, optic atrophy, and deafness). Routine newborn hearing screening methods will not typically Outcome Measures: Symptoms, age of onset, serial au- identify hearing loss affecting frequencies below 2000 Hz; diometric data, and hearing aid use. thus, children at risk must be specifically monitored. Ge- netic counseling and genetic testing may be useful in the Results: Low-frequency sensorineural hearing loss is typi- management of patients with this type of hearing loss. cally diagnosed in the first decade and slowly progresses over decades; LFSNHL is often asymptomatic in young Arch Otolaryngol Head Neck Surg. 2003;129:411-420

OW-FREQUENCY sensorineu- Mutations in the DIAPH1 gene cause ral hearing loss (LFSNHL) is LFSNHL linked to DFNA1, which is ex- an unusual type of hearing tremely rare (reported in only 1 family From the Division of Pediatric impairment in which fre- worldwide). Otolaryngology, Department of quencies below 2000 Hz are Otolaryngology–Head and predominantlyL affected. The European For commentary Neck Surgery, University of Working Group on Genetics of Hearing Michigan, Ann Arbor Impairment has defined such loss as low- see page 405 (Dr Lesperance); Department of to mid-frequency hearing impairment with Communicative Disorders, a difference of at least 15 dB between the College of Health Professions, In contrast, DFNA6/14 hearing impair- University of Florida, poorer lower-frequency and the better ment appears to be composed of a large pro- Gainesville (Dr Hall); National higher-frequency thresholds and an air- portion of hereditary LFSNHL. We have 1 Institute on Disability and bone gap of less than 15 dB. There are at shown that mutations in the Wolfram syn- Rehabilitation Research, least 5 types of LFSNHL: (1) acute low- drome type 1 gene (WFS1) underlie DFNA6/ Washington, DC (Dr San tone SNHL2; (2) DFNA1 hearing impair- 14, identifying 5 heterozygous missense mu- Agustin); and Laboratory of ment3,4; (3) DFNA6/14 hearing impair- tations in WFS1 in 5 dominant LFSNHL Statistical Genetics, Rockefeller ment; (4) LFSNHL associated with families and 1 sporadic case.6 One muta- University, New York, NY Meniere disease5; and (5) sporadic iso- tion, A716T, was found in 2 unrelated fami- (Dr Leal). Dr Leal is now with lated LFNSHL. While both DFNA1 and lies in our study and also in a third family the Department of Molecular 7 and Human Genetics, Baylor DFNA6/14 are genetic loci linked to non- from Newfoundland. The purpose of this College of Medicine, Houston, syndromic, autosomal dominant LFSNHL, article is to describe the clinical phenotype Tex. The authors have no DFNA1 deafness is distinguished by rapid of dominant LFSNHL caused by genetic mu- relevant financial interest in progression that results in profound bi- tations in WFS1 in 4 families (families 59, this article. lateral deafness by the fourth decade of life. 35, 19, and 21).

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 METHODS tion thresholds obtained in the right ear at age 29 years were considered vibrotactile. A second subject was re- The family pedigrees have been previously described.6,8,9 Fami- ported to have had a cochlear implant, but the genetic lies 59, 35, and 19 have autosomal dominant inheritance, status of this subject is presently unknown. whereas the proband of family 21 has sporadic unilateral low- The proband of family 21 was a 5-year-old girl di- frequency hearing loss. The institutional review boards of the agnosed with sporadic unilateral LFSNHL through a rou- respective institutions (University of Michigan, Rockefeller Uni- tine school screening (Figure 3, person 21-A). She had versity, Vanderbilt University, and the National Institute on Deaf- no risk factors for hearing loss, and the family had sus- ness and Other Communication Disorders) approved the study, and informed consent was obtained from each participating sub- pected hearing loss for at least 2 years. ject. Information regarding the history of the hearing loss and assessing risk indicators for acquired hearing loss was ob- AGE OF ONSET tained through a questionnaire or by personal interviews. Au- diometric data were obtained by testing at tertiary care centers A pure-tone hearing loss at 250 and 500 Hz was usually and at private audiology offices as well as field testing at sub- evident by age 10 years (Figure 6). A small number of jects’ homes. Prior audiograms were obtained when available, individuals could not recall when they first became aware including 10 dating from 1968 for family 59. of hearing loss and/or had the diagnosis made later in life The test battery included pure-tone audiometry with high- through participation in our study. One individual had frequency ipsilateral masking (GSI-16 clinical audiometer [Grason- documented normal hearing at age 6 years with a fol- Stadler Inc, Madison, Wis] and external masker),10 word recog- nition performance, aural immittance measurement (GSI-33 middle low-up audiogram at age 22 years documenting LFSNHL ear analyzer; Grason-Stadler Inc), and distortion product oto- (Figure 4, person 59-N). In addition, audiologic data ob- acoustic emissions (Virtual 330; Virtual Corporation, Portland tained for 10 children at risk, age 10 years or younger, Ore). For field testing, pure-tone thresholds were obtained using revealed only 1 child with LFSNHL (data not shown). a Beltone 120 audiometer with ER3-A earphones and EAR link foam ear tips (Beltone Electronic Corp, Chicago, Ill). Tasco T250 USE OF AMPLIFICATION earmuffs (The American Safety Company, Brownwood, Tex) were positioned during air conduction testing. Age of onset was de- Most of the affected family members were not successful termined by the age at which hearing loss was first documented hearing aid users. Of the affected members in family 59, 5 or by the patient’s recollection, whichever date was earlier. (24%) of 21 had hearing aids and even fewer were regular users. Of the affected members in families 35 and 19, 5 (50%) RESULTS of 10 and 3 (50%) of 6 wore hearing aids, respectively.

AUDIOMETRIC ASPECTS ASSOCIATED SYMPTOMS Comparison of audiograms within and across families re- On questioning, nearly all subjects with low-frequency vealed progression of hearing loss with increasing age and hearing loss reported tinnitus. However, none found it variability in the pattern of hearing loss among affected disabling, and there were no periods of exacerbations or members within family 59 (Figure 1), family 35 Meniere-like episodes. None reported vestibular com- (Figure 2), and families 19 and 21 (Figure 3). Serial plaints. Based on a comprehensive medical examination audiometric data are presented for selected individuals in 1968 as well as a health questionnaire in 1993, no other in family 59 (Figure 4A-B) and family 35 (Figure 5). clinical features were found to segregate with the hear- Overall, the natural history of hearing loss in families 59, ing loss in family 59.8 Review of family questionnaires 35, and 19 was similar, although variable within fami- in families 19, 35, and 21 was also consistent with non- lies. Several members of family 35 have better hearing at syndromic hearing loss. low (250- and 500-Hz) compared with middle (1000- and 2000-Hz) frequencies. MOLECULAR GENETICS The hereditary hearing loss developed in the first and second decades of life as a symmetric bilateral SNHL The hearing loss was completely penetrant in an age- affecting frequencies below 2000 Hz, with excellent speech dependent fashion, since all subjects with a confirmed discrimination. With advancing age, hearing loss for au- WFS1 deafness–causing mutation generally developed hear- diometric frequencies of 250 through 2000 Hz wors- ing loss by age 20 years, and there were no affected chil- ened in a low- to high-frequency sequence with thresh- dren without an affected parent. However, presymptom- olds on average exceeding a 50-dB hearing loss by age atic genetic testing was not performed on children with 50 years. In the fifth and sixth decades, the hearing loss normal hearing. In family 59, a 27-year-old woman became flatter with hearing loss developing at high fre- (Figure 7, person 59-O) with minimal LFSNHL lacked quencies (4000 Hz) with relative preservation at mid- the L829P mutation in WFS1 common to the affected mem- frequencies, creating a “peaked” audiogram. Loss of dis- bers of the family and was considered a phenocopy. tortion product otoacoustic emissions implicated outer hair cells either directly or indirectly. COMMENT Only 2 subjects had profound hearing loss, both in family 59. A 61-year-old woman (Figure 4, person 59-J) Low-frequency sensorineural hearing loss was formerly had lifelong right profound loss with the more typical called bass perceptive deafness, although some doubted low-frequency loss pattern in the left ear. Bone conduc- whether isolated LFSNHL even existed.11 Because inad-

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Hearing Threshold, dB 70 Left Ear Right Ear 80 Left Masked 90 Right Masked 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

59-C: F (Age, 24 y) 59-D: M (Age, 31 y) –10 0 10 20 30 40 50 60

Hearing Threshold, dB 70 80 90 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

59-E: F (Age, 56 y) 59-F: M (Age, 59 y) –10 0 10 20 30 40 50 60

Hearing Threshold, dB 70 80 90 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000 Frequency, Hz Frequency, Hz

Figure 1. Representative audiograms of affected individuals from family 59 showing pure-tone audiometry results for air conduction bilaterally.

equate methods for masking made it difficult to obtain an infrequent cause of deafness,” since 3 such families true bone conduction levels, a rising audiometric con- from their patient population were ascertained.15 How- figuration was often assumed to herald a conductive hear- ever, most other studies agree that LFSNHL is rare,12,16 ing loss.11-13 These authors also noted that patients with with an incidence of only 0.6% in Denmark.17 Heredi- isolated LFSNHL had excellent speech discrimination, tary LFSNHL has been described in affected relative which tends to delay diagnosis. pairs13,18 and in other large families with autosomal domi- Family 59 was the subject of the first description of nant inheritance.19,20 dominant LFSNHL, reported as kindred I by the Vander- Overall, hearing loss is one of the most genetically bilt Hereditary Deafness Study Group.8 At that time, 15 heterogeneous disorders described, with over 40 ge- family members were identified as affected, with 4 chil- netic loci identified for dominant deafness alone.21 The dren considered “borderline” affected. The hearing loss audiometric pattern may vary even among members of was interpreted as cochlear in nature based on Bekesy a family with the same genetic mutation.22 Modifier genes23 audiometry and short increment sensitivity index scores. or environmental factors may modulate the effect of the In 1969, Konigsmark14 published a seminal article de- primary genetic mutation.24 In general, the responsible scribing 8 major types of hereditary hearing loss. He sug- gene cannot be predicted from the audiogram; for ex- gested that dominant low-frequency hearing loss “is not ample, congenital profound deafness may be caused by

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Hearing Threshold, dB 70 80 Left Ear 90 Right Ear 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

35-C: F (Age, 53 y) 35-D: M (Age, 56 y) –10 0 10 20 30 40 50 60

Hearing Threshold, dB 70 80 90 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000 Frequency, Hz Frequency, Hz

Figure 2. Representative audiograms of affected individuals from family 35 showing pure-tone audiometry results for air conduction bilaterally.

mutations in any of several genes, the most common being bers, beginning in childhood and progressing slowly over GJB2 or Connexin 26 (CX26). In contrast, autosomal time. With increasing age, affected family members de- dominant LFSNHL appears highly predictive of a WFS1 veloped high-frequency SNHL (HFSNHL) with relative mutation.6,25 preservation of hearing in the mid-frequencies. The like- Other causes of LFSNHL include retrocochlear le- lihood of hearing aid use depended on the person’s age sions and cochlear otosclerosis.26 Acquired LFSNHL has and probably also on socioeconomic status. A similar been reported as a rare complication of spinal anesthe- “double-notch audiogram” has been reported in rare pa- sia, with loss of perilymph hypothesized to cause a rela- tients with noise exposure.32 The HFSNHL in the older tive increase in endolymphatic pressure analogous to hy- affected members in our study could be caused by the drops.27 WFS1 mutations do not appear to be a major cause WFS1 mutation or may be merely superimposed on the of sporadic LFSNHL (unpublished data, 2001).25 Fur- LFSNHL secondary to noise or presbycusis. Because pres- ther genetic studies may help elucidate whether spo- bycusis and noise-induced hearing loss usually do not radic LFSNHL without vertigo is a variant of Meniere dis- segregate in families as autosomal dominant traits and ease or a separate clinical entity. WFS1 mutations cause HFSNHL in patients with Wol- The WFS1 gene was first identified as the cause of fram syndrome, we hypothesize that the HFSNHL is part Wolfram syndrome, also known as DIDMOAD (diabe- of the WFS1 phenotype. Genetic analysis of the WFS1 tes insipidus, diabetes mellitus, optic atrophy, and gene in additional patients with LFSNHL as well as other deafness).28,29 Wolfram syndrome is a rare autosomal re- types of hearing loss such as presbycusis will be neces- cessive syndrome with the minimal diagnostic criteria of sary to further define genotype-phenotype correlations. juvenile-onset diabetes mellitus and optic atrophy. The The molecular mechanisms explaining the differ- hearing loss associated with Wolfram syndrome is most ent phenotypes caused by WFS1 mutations are cur- commonly delayed onset and progressive, and surpris- rently unknown. WFS1 encodes a unique protein, wol- ingly, is usually described as affecting the high frequen- framin, that has no homology to any known protein. The cies.30,31 Patients with Wolfram syndrome generally lack WFS1 gene is expressed in the endoplasmic reticulum any functional wolframin protein, while the deafness- of cells, and therefore a role in protein sorting, protein associated WFS1 mutations are heterozygous missense trafficking, or calcium homeostasis has been hypoth- mutations that affect only 1 copy of the gene and typi- esized.33 There are currently no animal models of hu- cally change only 1 amino acid. man low-frequency hearing loss, since few nonhuman In the 3 dominant families in our study, the natural mammals have useful hearing below 2000 Hz. Further- history of the hearing loss varied among family mem- more, experiments attempting to create such a model

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Hearing Threshold, dB 70 80 Left Ear 90 Right Ear 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

19-B: M (Age, 53 y) 19-C: F (Age, 58 y) –10 0 10 20 30 40 50 60

Hearing Threshold, dB 70 80 90 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

19-D: F (Age, 59 y) 19-E: F (Age, 77 y) –10 0 10 20 30 40 50 60

Hearing Threshold, dB 70 80 90 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000 Frequency, Hz

19-F: F (Age, 79 y) –10 0 10 20 30 40 50 60

Hearing Threshold, dB 70 80 90 100 250 500 750 1000 1500 2000 3000 4000 6000 8000 Frequency, Hz

Figure 3. Audiograms of affected individuals from families 19 (19A-F) and 21 (21-A) showing pure-tone audiometry results for air conduction bilaterally.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 A 59-G Right 59-G Left –10 0 10 20 30 40 50 Thresholds 60 Thresholds At Age 9 y 70 At Age 9 and 10 y At Age 10 y 80 At Age 12 y At Age 12 y Hearing Threshold, dB At Age 15 y At Age 15 y 90 At Age 40 y At Age 40 y 100 At Age 43 y At Age 43 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

59-H Right 59-H Left –10 0 10 20 30 40 50 60 70 80 Thresholds Thresholds Hearing Threshold, dB At Age 20 y At Age 20 y 90 At Age 24 y At Age 24 y 100 At Age 46 y At Age 46 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

59-I Right 59-I Left –10 0 10 20 30 40 50

60 Thresholds Thresholds 70 At Age 18 y At Age 18 y 80 At Age 33 y At Age 33 y Hearing Threshold, dB At Age 44 y At Age 44 y 90 At Age 48 y At Age 48 y 100 At Age 52 y At Age 52 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

59-J Right 59-J Left –10 0 10 Thresholds At Age 29 y 20 At Age 54 y 30 At Age 59 y 40 At Age 62 y 50 60 70 Thresholds 80 At Age 29 y Hearing Threshold, dB At Age 54 y 90 At Age 59 y 100 At Age 62 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000 Frequency, Hz Frequency, Hz

Figure 4. A, Audiograms (divided into right and left ear) of patients 59-G to 59-J with low-frequency hearing loss from family 59 demonstrating progression of hearing loss over decades. All curves represent air conduction thresholds, with the exception of person 59-J, right ear, curve for age 29 years, which represents bone conduction thresholds (considered vibrotactile).

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 B 59-K Right 59-K Left –10 0 10 20 30 40 50 60 70 80 Thresholds Thresholds Hearing Threshold, dB At Age 17 y At Age 17 y 90 At Age 21 y At Age 21 y 100 At Age 24 y At Age 24 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

59-L Right 59-L Left –10 0 10 20 30 40 50 60 70 Thresholds Thresholds 80 At Age 6 y At Age 6 y Hearing Threshold, dB At Age 12 y At Age 12 y 90 At Age 15 y At Age 15 y 100 At Age 17 y At Age 17 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

59-M Right 59-M Left –10 0 10 20 30 40 50

60 Thresholds Thresholds 70 At Age 4 y At Age 4 y 80 At Age 5 y At Age 5 y Hearing Threshold, dB At Age 7 y At Age 7 y 90 At Age 35 y At Age 35 y 100 At Age 38 y At Age 38 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

59-N Right 59-N Left –10 0 10 20 30 40 50 60 70 80 Thresholds Thresholds Hearing Threshold, dB At Age 6 y At Age 6 y 90 At Age 32 y At Age 32 y 100 At Age 37 y At Age 37 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000 Frequency, Hz Frequency, Hz

Figure 4. B, Audiograms (divided into right and left ear) of patients 59-K to 59-N with low-frequency hearing loss from family 59 demonstrating progression of hearing loss over decades. All curves represent air conduction thresholds.

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 35-E Right 35-E Left –10 0 10 20 30 40 50 60 70 80 Thresholds Thresholds Hearing Threshold, dB 90 At Age 11 y At Age 11 y At Age 12 y At Age 12 y 100 At Age 13 y At Age 13 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

35-F Right 35-F Left –10 0 10 20 30 40 50 60 70 Thresholds Thresholds 80 At Age 24 y At Age 24 y Hearing Threshold, dB 90 At Age 30 y At Age 30 y At Age 35 y At Age 35 y 100 At Age 39 y At Age 39 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

35-G Right 35-G Left –10 0 10 20 30 40 50 60 70 80 Thresholds Thresholds Hearing Threshold, dB 90 At Age 30 y At Age 36 y At Age 30 y At Age 36 y At Age 32 y At Age 37 y At Age 32 y At Age 37 y 100 At Age 34 y At Age 39 y At Age 34 y At Age 39 y 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000

35-H Right 35-H Left –10 0 Thresholds Thresholds 10 At Age 51 y At Age 51 y 20 At Age 58 y At Age 58 y 30 At Age 66 y At Age 66 y 40 50 60 70 80 Hearing Threshold, dB 90 100 110 120 250 500 750 1000 1500 2000 3000 4000 6000 8000 250 500 750 1000 1500 2000 3000 4000 6000 8000 Frequency, Hz Frequency, Hz

Figure 5. Audiograms (divided into right and left ear) of selected patients with low-frequency hearing loss from family 35 demonstrating progression of hearing loss over decades. All curves represent air conduction thresholds.

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5 40 50 4 60 3 No. of Family Members Hearing Threshold, dB 70 2 80 Left Ear 1 90 Right Ear 0 100 0-10 11-20 21-30 31-40 41-50 51-60 >60 250 500 750 1000 1500 2000 3000 4000 6000 8000 Age of Onset, y Frequency, Hz

Figure 6. Age of onset of hearing loss in families 59, 35, and 19. Bars Figure 7. Audiogram of an individual from family 59 with an atypical pattern indicate number of individuals noting onset of hearing loss in each decade of hearing loss that is not caused by WFS1 mutation (phenocopy). of life. answer the question, but to date, almost none of the af- found that animals with apical cochlear lesions are still fected family members or their physicians sought new- able to respond to low-frequency stimuli.34 This phe- born hearing screening for children at risk. nomenon results from the response of the basal cochlea Routine methods of newborn hearing screening, to the harmonics of low-frequency tones, thus masking whether by distortion product otoacoustic emissions or at frequencies higher than the stimulus frequency is nec- auditory brainstem response, will not typically assess fre- essary.35,36 Transgenic mice may be helpful in the future quencies lower than 2000 Hz. A family history should to elucidate the role of WFS1 in the pathophysiology of be obtained in patients with LFSNHL to allow audio- LFSNHL. logic monitoring for children at risk. For such children, The final question is whether patients with WFS1 visual reinforcement audiometry at age 6 months, or pref- mutations have normal hearing at birth or congenital erably, auditory brainstem response prior to 6 months, LFSNHL that is not detected until years later. Determin- is advised. Because the sound energy of a click stimulus ing the exact age of onset is hampered by the lack of au- is concentrated at 2000 to 4000 Hz,37 the physician should diologic data at early ages, the relative lack of symptoms specifically request 500- and 1000-Hz tone bursts to rule with isolated LFSNHL, and the tendency for people to out LFSNHL. An awareness of the hereditary nature of delay getting a hearing test even when hearing loss is sus- LFSNHL among clinicians will facilitate identification of pected. Often, 10 years or more elapsed between the time families who might benefit from genetic counseling or that hearing loss was suspected and when it was for- perhaps genetic testing. mally diagnosed by audiometry. In our study, several In summary, we describe a sporadic case and 3 fami- members had not noted hearing loss until they had a rou- lies with autosomal dominant nonsyndromic progres- tine hearing test at school, at work, or through partici- sive low-frequency cochlear SNHL, all found to have mu- pation in our study. Indeed, participation in our study tations in the WFS1 gene. In the future, molecular genetic increased awareness in the families that their hearing loss studies may be increasingly useful to allow clinicians to was hereditary. One patient (Figure 1, person 59-C) at- distinguish between similar clinical entities. tributed her hearing loss to noise exposure, since she first noticed it after attending a rock concert at age 13 years. Accepted for publication August 30, 2002. Most likely, she experienced a temporary threshold shift This work was supported by grants DC00161 (Dr Les- in the high frequencies, which in combination with he- perance) and DC03594 (Dr Leal) from the National Insti- reditary LFSNHL left her severely disabled for a period, tutes of Health, Bethesda, Md; Professional Service Con- whereas others experiencing a temporary threshold shift tract 92-DC-0234 from the National Institute on Deafness still had useful hearing in the low frequencies. and Other Communication Disorders, Bethesda (Dr Hall); In family 59, the incidence of LFSNHL in children the Starr Center for Human Genetics, New York, NY (Dr with an affected parent was far lower than 50% as would Leal), and the American Hearing Research Foundation, Chi- be expected with a fully penetrant dominant trait. As- cago, Ill (Dr Leal). certainment bias may explain why all children tested were This study was presented at the 17th Annual Meeting found to have normal hearing, if parents who suspect hear- of the American Society of Pediatric Otolaryngology, Boca ing loss in their child were reluctant to participate. Al- Raton, Fla, May 13, 2002. ternatively, it is possible that only 1 in 10 children in- We thank the families for their participation; Laura herited the dominant trait by chance alone. However, Miller and Angelique Boerst, MA, CCC-A, for assistance with considering the case of person 59-N, with documented preparation of the manuscript; and Pamella McMillan, MA, normal hearing prior to developing LFSNHL, we favor CCC-A, Susan Barker, MA, CCC-A, David Brown, MD, and the explanation that WFS1 hearing loss develops later in Theresa Kim, BA, for assistance with data collection. children born with normal hearing. Evaluating children Corresponding author and reprints: Marci M. Lesper- for hearing loss at an early age will be the only way to ance, MD, Division of Pediatric Otolaryngology, De-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 partment of Otolaryngology–Head and Neck Surgery, F6905 19. Parving A, Johnsen NJ, Holm-Jensen S. Dominantly inherited low-frequency hear- Mott, Box 0241, 1500 E Medical Center Dr, Ann Arbor, MI ing loss. Audiology. 1978;17:165-172. 20. Kunst H, Marres H, Huygen P, Van Camp G, Joosten F, Cremers C. Autosomal 48109-0241 (e-mail: [email protected]). dominant non-syndromal low-frequency sensorineural hearing impairment linked to chromosome 4p16 (DFNA14): statistical analysis of hearing threshold in re- REFERENCES lation to age and evaluation of vestibulo-ocular functions. Audiology. 1999;38: 165-173. 21. Smith RJH, Van Camp G, eds. Hereditary Hearing Loss Homepage. Available at: 1. European Work Group on Genetics of Hearing Impairment. Infoletter 2. Vol 2. http://www.uia.ac.be/dnalab/hhh/. Accessed 2002. 1996. 22. Van Camp G, Willems PJ, Smith RJ. Nonsyndromic hearing impairment: unpar- 2. Imamura S, Nozawa I, Imamura M, Murakami Y. Clinical observations on acute alleled heterogeneity. Am J Hum Genet. 1997;60:758-764. low-tone sensorineural hearing loss: survey and analysis of 137 patients. Ann 23. Riazuddin S, Castelein CM, Ahmed ZM, et al. Dominant modifier DFNM1 sup- Otol Rhinol Laryngol. 1997;106:746-750. presses recessive deafness DFNB26. Nat Genet. 2000;26:431-434. 3. Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King MC. Nonsyndromic 24. Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNA mu- deafness DFNA1 associated with mutation of a human homolog of the Dro- tation associated with both antibiotic-induced and non-syndromic deafness. Nat sophila gene diaphanous. Science. 1997;278:1315-1318. Genet. 1993;4:289-294. 4. Lalwani AK, Jackler RK, Sweetow RW, et al. Further characterization of the DFNA1 25. Cryns K, Pfister M, Pennings RJE, et al. Mutations in the WFS1 gene that cause audiovestibular phenotype. Arch Otolaryngol Head Neck Surg. 1998;124:699-702. low-frequency sensorineural hearing loss are small non-inactivating mutations. 5. Van de Heyning PH, Wuyts FL, Claes J, Koekelkoren E, Van Laer C, Valcke H. Hum Genet. 2002;110:389-394. Definition, classification and reporting of Meniere’s disease and its symptoms. 26. Carhart R. Atypical audiometric configurations associated with otosclerosis. Ann Acta Otolaryngol Suppl. 1997;526:5-9. Otol. 1962;71:744-758. 6. Bespalova IN, Van Camp G, Bom SJH, et al. Mutations in the Wolfram syndrome 27. Walsted A, Salomon G, Olsen KS. Low-frequency hearing loss after spinal an- 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. esthesia. Perilymphatic hypotonia? Scand Audiol. 1991;20:211-215. Hum Mol Genet. 2001;10:2501-2508. 28. Strom TM, Hortnagel K, Hofmann S, et al. Diabetes insipidus, diabetes mellitus, 7. Young TL, Ives E, Lynch E, et al. Nonsyndromic progressive hearing loss DFNA38 optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene is caused by heterozygous missense mutation in the Wolfram syndrome gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet. 1998; WFS1. Hum Mol Genet. 2001;10:2509-2514. 7:2021-2028. 8. Vanderbilt Hereditary Deafness Study Group. Dominantly inherited low- 29. Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a transmembrane pro- frequency hearing loss. Arch Otolaryngol. 1968;88:242-250. tein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram 9. Lesperance MM, Hall JW III, Bess FH, et al. A gene for autosomal dominant non- syndrome). Nat Genet. 1998;20:143-148. syndromic hereditary hearing impairment maps to 4p16.3. Hum Mol Genet. 1995; 30. Higashi K. Otologic findings of DIDMOAD syndrome. Am J Otol. 1991;12:57-60. 4:1967-1972. 31. Cremers CW, Wijdeveld PG, Pinckers AJ. Juvenile diabetes mellitus, optic atro- 10. Humes LE, Tharpe AM, Bratt GW. Validity of hearing thresholds obtained from phy, hearing loss, diabetes insipidus, atonia of the urinary tract and bladder, and the rising portion of the audiogram in sensorineural hearing loss. J Speech Hear other abnormalities (Wolfram syndrome): a review of 88 cases from the litera- Res. 1984;27:206-211. ture with personal observations on 3 new patients. Acta Paediatr Scand Suppl. 11. Gravendeel DW, Plomp R. Perceptive bass deafness. Acta Otolaryngol. 1960; 1977;264:1-16. 64:548-560. 32. Chung DY. Meanings of a double-notch audiogram. Scand Audiol. 1980;9:29- 12. Ross M, Matkin ND. The rising audiometric configuration. J Speech Hear Dis- 32. ord. 1967;32:377-382. 33. Takeda K, Inoue H, Tanizawa Y, et al. WFS1 (Wolfram syndrome 1) gene prod- 13. Parving A, Bak-Pedersen K. Clinical findings and diagnostic problems in senso- uct: predominant subcellular localization to endoplasmic reticulum in cultured rineural low frequency hearing loss. Acta Otolaryngol. 1978;85:184-190. cells and neuronal expression in rat brain. Hum Mol Genet. 2001;10:477-484. 14. Konigsmark BW. Hereditary deafness in man. N Engl J Med. 1969;281:827-832. 34. Prosen CA, Moody DB, Stebbins WC, et al. Apical hair cells and hearing. Hear 15. Konigsmark BW, Mengel M, Berlin CI. Familial low frequency hearing loss. La- Res. 1990;44:179-193. ryngoscope. 1971;81:759-771. 35. Turner C, Burns EM, Nelson DA. Pure tone pitch perception and low-frequency 16. Lundborg T. Nerve deafness for low tones. Acta Otolaryngol. 1955;45:215-225. hearing loss. J Acoust Soc Am. 1983;73:966-975. 17. Parving A, Sakihara Y, Christensen B. Inherited sensorineural low-frequency hear- 36. Prosen CA, Moody DB. Low-frequency detection and discrimination following ing impairment: some aspects of phenotype and epidemiology. Audiology. 2000; apical hair cell destruction. Hear Res. 1991;57:142-152. 39:50-60. 37. Gorga MP, Worthington DW, Reiland JK, Beauchaine KA, Goldgar DE. Some com- 18. Iinuma T, Shitara T, Hoshino T, Kirikae I. Sensorineural hearing loss for low tones. parisons between auditory brain stem response thresholds, latencies, and the Arch Otolaryngol. 1967;86:110-116. pure-tone audiogram. Ear Hear. 1985;6:105-112.

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