Deafness, X-Linked 2

A number sign (#) is used with this entry because X-linked deafness-2 (DFNX2), also known as conductive deafness with stapes fixation (DFN3), is caused by mutation in the POU3F4 gene (300039) on chromosome Xq21. The disorder can also be caused by deletions, inversions, and duplications upstream of the gene in a putative regulatory element region.

Description

DFNX2, also known as DFN3, is an X-linked recessive disorder characterized by progressive conductive and sensorineural hearing loss and a pathognomonic temporal bone deformity that includes dilatation of the inner auditory canal and a fistulous connection between the internal auditory canal and the cochlear basal turn, resulting in a perilymphatic fluid 'gusher' during stapes surgery (summary by de Kok et al., 1995 and Song et al., 2010).

See also choroideremia, deafness, and mental retardation (303110), a contiguous gene deletion syndrome involving the POU3F4 and CHM (300390) genes on Xq21; isolated choroideremia (303100) is caused by mutation in the CHM gene.

Clinical Features

Shine and Watson (1967) described a Hawaiian-Chinese family with 9 males in 2 generations affected with conductive hearing loss and vestibular disturbance. At operation, the footplate of the stapes was found to be fixed. When it was mobilized, profuse drainage of perilymph and cerebrospinal fluid occurred, indicating abnormal patency of the cochlear aqueduct. Nance et al. (1970, 1971) observed a similar family of European extraction, indicating that this is a bona fide syndrome; in this family, hearing loss was of mixed type. The existence of this syndrome had been suggested by Olson and Lehman (1968).

Cremers and Huygen (1983) suggested that stapes surgery should not be performed because of the unavoidable complication of a stapes gusher. They reported a pedigree with 9 obligate and 10 possible female carriers of the disorder. Affected males show severe progressive mixed hearing loss and lack or strong reduction of vestibular responses; 4 of the 9 obligate heterozygotes showed similar but much milder audiologic abnormalities and no vestibular abnormalities.

Phelps et al. (1991) studied 7 pedigrees in which deafness was inherited as an X-linked trait. CT scan showed a distinctive inner ear deformity characterized by a wide bulbous internal auditory meatus and a deficient or absent bone between the lateral end of the meatus and the basal turn of the cochlea. Phelps et al. (1991) concluded that this results in a communication between the subarachnoid space in the internal auditory meatus and the perilymph in the cochlea, leading to perilymphatic hydrops and a 'gusher' if the stapes is disturbed. Some of the obligate female carriers seemed to have a milder form of the same anomaly associated with slight hearing loss.

In their summary of the features of DFN3, de Kok et al. (1995) pointed out that this mixed type of deafness is characterized by both conductive hearing loss resulting from stapes fixation and progressive sensorineural deafness, and that sometimes a profound sensorineural deafness masks the conductive element. Computerized tomography shows abnormal dilatation of the internal acoustic canal, as well as an abnormally wide communication between the internal acoustic canal and the inner ear compartment. As a result, there is an increased perilymphatic pressure that is thought to underlie the observed 'gusher' during the opening of the stapes footplate.

From the study of 2 families in which the occurrence of DFN3 was well established by the demonstration of specific mutations in the POU3F4 gene (300039), Bitner-Glindzicz et al. (1995) concluded that DFN3 should be characterized, not by mixed conductive and sensorineural deafness associated with perilymphatic gusher at stapes surgery, but by profound sensorineural deafness with or without a conductive component associated with a unique developmental abnormality of the ear. Profound sensorineural deafness is, they concluded, the sine qua non of this disorder.

Song et al. (2010) reported a 9-year-old Korean boy who was first diagnosed with hearing loss at age 6 years. Initial audiogram showed a mixed type of moderately severe hearing loss on the right side and severe hearing loss on the left side, which did not progress over 3 years. He had good language development after speech therapy. High-resolution CT scan showed a wide fistulous connection between the basal cochlear turn and the inner auditory canal, consistent with DFN3. There was no family history of a similar disorder. Genetic analysis identified a 1- to 1.5-Mb deletion located about 90 kb upstream of the POU3F4 gene, and no mutation within the coding exon of the POU3F4 gene. The deletion was not found in his mother or sister, suggesting a sporadic occurrence. Song et al. (2010) noted that the lack of mutation in the coding sequence made the detection of carrier females difficult; the authors used multiplex ligation-dependent probe analysis for molecular analysis.

Clinical Management

Lee et al. (2009) reported successful treatment of 3 Korean boys, including 2 brothers, with DFN3 using cochlear implants. Pure tone audiometry (PTA) in the 2 brothers improved from 87.5 to 97.5 dB before implantation to 26.3 to 31.3 dB after implantation. Speech performance also improved significantly. The third boy, who also had mental retardation, showed improved PTA from no response to 36.3 dB. All 3 patients had truncating mutations in the POU3F4 gene.

Mapping

In a large Dutch kindred, Brunner et al. (1988) found tight linkage (maximum lod = 3.07 at theta = 0.00) with PGK (311800), which is located at Xq13. Brunner et al. (1988) pointed out that deafness is one of the predominant clinical features in males with deletions of Xq21 (Ayazi, 1981; Nussbaum et al., 1987; Rosenberg et al., 1987). Ballo et al. (1988) and Wallis et al. (1988) showed tight linkage to DXYS1 (lod = 6.32 at theta = 0.0), thus placing DFN3 at Xq13-q21.1.

Merry et al. (1989) studied 2 patients with X-chromosome deletions who had both choroideremia and deafness with stapes fixation. In both cases, 2 members of the family were affected: 2 first cousins in 1 kindred, and 2 brothers in the second. The smaller of the deletions, which was not detectable cytogenetically, was estimated to represent 3.3% of the X chromosome by dual laser flow cytometry. Assuming that the X chromosome represents about 6% of the human haploid genome, which has about 3 billion basepairs, then the 2 loci should be within 6 megabases of each other.

Reardon et al. (1991) reported a family with nonsyndromic X-linked deafness which was not linked to markers in the Xq13-q21 region; in 6 other families they confirmed the location for X-linked deafness to that region, with maximum lod = 15 at theta = 0.0, using the probe PXG7 (DXS72). As a further suggestion of heterogeneity, they pointed to the fact that the phenotype of the deafness in individuals with a deletion in the Xq13-q21 region is variable. They also pointed out that their unlinked family lacked the findings in the temporal bone on CT scan described by Phelps et al. (1991) as typical of the gusher-deafness syndrome. Using probe pHU16, which defines the anonymous DNA site DXS26, Bach et al. (1992) found microdeletion in 2 of 13 unrelated male probands with this disorder. One of the deletions also encompassed locus DXS169, indicating that it extends farther toward the centromere.

Robinson et al. (1992), like Reardon et al. (1991), found close linkage between X-linked deafness and DXS159 in Xq12, with a lod score of 3.155 at zero recombination. An affected male showed gross dilatation of the internal auditory meatus bilaterally with very poor separation from the basal cochlear turns, as described by Phelps et al. (1991).

In a study of several overlapping deletions involving different parts of Xq21 with DNA probes, Bach et al. (1992) assigned the DFN3 locus and a locus for nonspecific X-linked mental retardation(see 303110) to an interval that encompasses the locus DXS232 and that is flanked by DXS26 and DXS121.

Huber et al. (1994) found that the microsatellite marker DXS995 mapped to all previously described deletions that had been found in association with X-linked mixed deafness with or without choroideremia and mental retardation. Employing this marker and also DXS26, they identified 2 partially overlapping YAC clones that were used to construct a complete 850-kb cosmid contig. Cosmids from this contig were tested by Southern blot analysis on DNA from 16 unrelated males with X-linked deafness. Two novel microdeletions were detected in patients with the characteristic DFN3 phenotype. Both deletions were contained completely within 1 of the known DFN3 deletions, but 1 of them did not overlap with 2 previously described deletions in patients with contiguous gene syndromes consisting of DFN3, choroideremia, and mental retardation. Assuming that only a single gene is involved, this suggested that the DFN3 gene spans a chromosomal region of at least 400 kb.

Hildebrand et al. (2007) reported a family with X-linked sensorineural deafness and nonsyndromic mental retardation associated with an approximate 200-kb microdeletion upstream of the POU3F4 gene, predicted to affect a regulatory region controlling POU3F4 expression. The microdeletion was believed to cause deafness, consistent with DFNX2, but not likely to have caused mental retardation. Hildebrand et al. (2007) noted that several candidate XLMR genes are located within the deleted region and may have contributed to mental retardation. Affected individuals lacked other prominent clinical features, such as visual impairment, aggressive behavior, or skeletal anomalies.

Molecular Genetics

De Kok et al. (1995) used the candidate gene approach to demonstrate that the defect in DFN3 resides in a transcription factor with a POU domain known as brain-4 (POU3F4; 300039). In 4 patients with X-linked mixed deafness, de Kok et al. (1995) demonstrated 2 missense mutations and 2 nonsense mutations, and in a fifth patient, classified as sensorineural deafness, a nonsense mutation was found (300039.0001-300039.0005). In addition, de Kok et al. (1995) found that 3 Xq21 microdeletions and 1 duplication that had been identified previously (Huber et al., 1994) in patients with DFN3 did not encompass the POU3F4 gene. In all 4 instances, the rearrangement was located proximal and 5-prime to POU3F4, with physical distances varying between 15 and 400 kb. In none of these patients, nor in 2 others with either a perilymphatic gusher during stapes surgery or a temporal bone defect, were point mutations detected within the POU3F4 gene. De Kok et al. (1995) concluded that these cases may be caused by mutations that affect 5-prime noncoding or regulatory sequences. Alternatively, these aberrations may affect the gross chromosomal structure and thus affect expression of POU3F4. A less likely explanation might be the presence of other genes in Xq21.1 that can cause DFN3.

From observations of DFN3 in association with a complex duplication/paracentric inversion, de Kok et al. (1995) concluded that there is a regulatory element located at least 400 kb upstream of the POU3F4 gene and that this was disconnected from the POU3F4 gene by the inversion.

Nomenclature

Petersen et al. (2008) proposed the designation DFNX2 for this disorder.

Animal Model

Minowa et al. (1999) created Brn4 (Pou3f4)-deficient mice. They had profound deafness. No gross morphologic changes were observed in the conductive ossicles or cochlea, although there was a dramatic reduction in endocochlear potential. Electron microscopy revealed severe ultrastructural alterations in cochlear spiral ligament fibrocytes. These findings suggested that these fibrocytes, which are mesenchymal in origin and for which a role in potassium ion homeostasis has been postulated, may play a critical role in auditory function.