SENSORINEURAL DEAFNESS, PROFOUND, WITH OR WITHOUT A CONDUCTIVE COMPONENT, ASSOCIATED WITH A UNIQUE DEVELOPMENTAL ABNORMALITY OF THE EAR
PERILYMPHATIC GUSHER-DEAFNESS SYNDROME
DEAFNESS, MIXED, WITH PERILYMPHATIC GUSHER
DEAFNESS 3, CONDUCTIVE, WITH STAPES FIXATION
DEAFNESS, CONDUCTIVE, WITH STAPES FIXATION
DFN3
DFNX2
Conductive deafness with stapes fixation
X-linked mixed conductive and neurosensory deafness
X-linked mixed conductive and neurosensory hearing loss
X-linked deafness type 2
X-linked mixed conductive and sensorineural deafness
X-linked mixed conductive and sensorineural hearing loss
nance deafness
X-linked stapes gusher syndrome
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 ... 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.
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, ... 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.
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) 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.