Dataset Information

HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

ABSTRACT: Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.

SUBMITTER: Brown KK

PROVIDER: S-EPMC3883620 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

Brown Kerry K KK Viana Lucas M LM Helwig Cecilia C CC Artunduaga Maria A MA Quintanilla-Dieck Lourdes L Jarrin Patricia P Osorno Gabriel G McDonough Barbara B DePalma Steven R SR Eavey Roland D RD Seidman Jonathan G JG Seidman Christine E CE

Human mutation 20130711 10

Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss ...[more]

PMID: 23775976

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Project description:ObjectivesTo evaluate the long-term outcomes of three different types of bone conduction hearing implants (BCHI)-BAHA, Ponto, and Bonebridge-in Mandarin-speaking patients with bilateral microtia-atresia.MethodsThis cohort study enrolled 59 patients affected by bilateral microtia-atresia, with an upper bone conduction threshold limit of 30 dB HL at frequencies of 0.5 to 4 kHz. All subjects underwent unilateral BCHI surgery, including 26 (18 males, 8 females, of mean age 8.7 ± 1.9 yr) implanted with BAHA devices; 10 (7 males, 3 females, of mean age 11.7 ± 2.8 yr) implanted with Ponto devices; and 23 (14 males, 9 females, of mean age 9.0 ± 1.8 yr) implanted with Bonebridge devices. The main outcome measures included long-term audiological benefits, patient satisfaction, and complications. Each subject acted as his or her own control.ResultsTwo years after BCHI surgery, the mean hearing thresholds in the BAHA, Ponto, and Bonebridge groups had improved to 22.6 ± 1.6 dB HL, 21.6 ± 1.2 dB HL, and 22.5 ± 1.5 dB HL, respectively. The mean percentages of subjects in these three groups recognizing speech at 65 dB SPL under quiet conditions were 97.7 ± 4.2%, 96.3 ± 1.1%, and 94.4 ± 9.4%, respectively, whereas the mean percentages recognizing speech under noise conditions (signal:noise ratio +5) were 87.0 ± 1.8%, 89.3 ± 9.3%, and 85.3 ± 4.7%, respectively. Questionnaires revealed patients' benefits and satisfaction with this surgery. Three (11.5%) of 26 patients in the BAHA group and 1 (10%) of 10 in the Ponto group experienced skin irritation, but all recovered after local treatment. Five (19.2%) patients in the BAHA group and two (20%) in the Ponto experienced abutment extrusion about 6 months postoperatively, with all achieving good results after revision surgery to replace the abutment. One (3.8%) patient in the BAHA group experienced local chronic inflammation and underwent surgery to replace the BAHA with a Bonebridge implant. One (4.3%) patient in the Bonebridge group developed a local infection 3 months postoperatively and underwent implant removal.ConclusionsAll three BCHIs were well tolerated after long-term follow-up, and all improved audiometric thresholds and the intelligibility of speech in the presence of both quiet and noise. These implants should be considered valid and safe options for the functional rehabilitation of patients with bilateral microtia-atresia.

Project description:ObjectivesThis study aims to characterize lateralization of sounds and localization of sounds in children with bilateral conductive hearing loss (BCHL) when listening with either one or two percutaneous bone conduction devices (BCDs).DesignSound lateralization was measured with the minimum audible angle test in which children were asked to indicate from which of the two visible speakers the sound originated. Sound localization was measured with a test in which stimuli were presented from speakers that were not visible to the children. In the sound localization test, 150 ms broadband noise bursts were presented, and sound level was roved over a 20-dB range. Because speakers were not visible the localization response was not affected by any visual cue. The sound localization test provides a clear distinction between lateralization and localization of sounds. Ten children with congenital BCHL and one child with acquired BCHL participated.ResultsBoth lateralization and sound localization were better with bilateral BCDs compared with the unilaterally aided conditions. In the bilateral BCD condition, lateralization was close to normal in nearly all the children. The localization test demonstrated lateralization rather than sound localization behavior when listening with bilateral BCDs. Furthermore, in the unilateral aided condition, stimuli presented at different sound levels were mainly perceived at the same location.ConclusionsThis study demonstrates that, in contrast to listening with two BCDs, children demonstrated difficulties in lateralization of sounds and in sound localization when listening with just one BCD (i.e., one BCD turned off). Because both lateralization and sound localization behavior were tested, it could be demonstrated that these children are more able to lateralize than localize sounds when listening with bilateral BCDs. The present study provides insight in (sub-optimal) sound localization capabilities of children with congenital BCHL in the unilateral-aided and bilateral-aided condition. Despite the sub-optimal results on sound localization, this study underlines the merits of bilateral application of BCDs in such children.

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HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

Publications

HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

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