American Journal of Medical Genetics 44513-517 (1992)
Phenotypic Evidence for a Common Pathogenesis in X-Linked Deafness Pedigrees and in Xq13-q21 Deletion Related Deafness W. Reardon, S. Roberts, P.D. Phelps, N.S. Thomas, L. Beck, R. Issac, and H.E. Hughes Institute of Medical Genetics W . R . , S.R., N.S.T., H a . ) , Department of Ophthalmlogy (L.B.), Welsh Hearing Institute (R.I.), University Hospital of Wales, Heath Park, Cardiff, UX. and Department of Radiology, The Institute of Laryngology and Otology (PDPJ, 3301332 Grays Inn Rd., London, U.K.
A structural cochlear abnormality has been observed by high resolution CT scanning in some families where X-linked deafness is seg regating. We now present evidence that the same abnormality is present in a deaf patient who has a deletion within Xq21. This observa- tion provides phenotypic evidence that the ge- notypic basis of deafness is the same in both patient groups. It is also likely that the peri- lymphatic fluid gusher abnormality may be common to both. O 1992 Wiiey-Lisa, inc.
KEY WORDS: deafness, CT scanning, X-linked
INTRODUCTION Non syndromic X-linked deafness has been classified
1. Congenital sensorineural deafness (McKusick No 30450).
2. Progressive sensorineural deafness (McKusick No 30470).
3. High tone sensorineural deafness (McKusick No 30460).
4. Mixed conductive and sensorineural deafness asso- ciated with perilymphatic gusher at stapes surgery (McKusick No 30440). In this condition stapedial sur- gery, aimed at improving hearing by correcting the con- ductive element of the deafness leads to a profuse flow of fluid from the perilymphatic space of the cochlea, the so called perilymphatic gusher.
The noncongenital forms, types 2 and 3, are readily distinguishable from the others by their postlingual
into 4 different types (McKusick, 1988):
Received for publication July 31,1991; revision received May 19, 1992.
Address reprint requests to Dr. W. Reardon, Department of Paediatric Genetics, Institute of Child Health, 30 Guilford St., London WC1 NlEH, U.K.
O 1992 Wiley-Liss, Inc.
onset. However, they account for only a minority of ped- igrees reported [Mohr and Majeroy, 1960; Livan 1961; Pelletier and Tanguay 19751. In the vast majority of pedigrees with nonsyndromic X-linked deafness, the deafness is of prelingual onset. Traditionally, these fam- ilies have been separated into types 1 and 4 on the basis of audiogram changes. Considerable doubt now sur- rounds the validity of this separation as there is evi- dence that the audiogram may be an unreliable delinea- tor of different forms of prelingual X-linked deafness [Reardon et al., 1991; Reardon et al., 1992; Glasscock, 19731. Moreover, linkage data on pedigrees with audi- ologically different forms of prelingual nonsyndromic X-linked deafness suggest a possible common locus [Reardon et al., 19911.
In parallel with these developments, work has been progressing on the molecular investigation of deaf pa- tients with cytogenetically detectable X chromosome deletions. This form of inquiry stems from a report docu- menting 3 male patients, 2 brothers and a maternal uncle with deafness and choroideremia, an X-linked retina1 degenerative condition [Ayazi, 19811. Subse- quent molecular analysis showed a deletion in the Xq21 region and cytogenetic evaluation suggested a possible abnormality of Xq21 [Nussbaum et al., 1987; Merry et al., 19891. Other reports of male patients with cho- roideremia and a variety of clinical features, frequently including deafness, highlighted the association between deafness and deletions of variable size in the Xq13-q21 region [Tabor et al., 1983; Rosenberg et al., 1986; Nussbaum et al., 1987; Hodgson et al., 19871. Molecular characterisation of these deletions has been invaluable in the cloning of the choroideremia gene and also sug- gests that the deafness gene in these patients is cen- tromeric to the choroideremia gene [Schwartz et al., 1988; Merry et al., 1989; Cremers et al., 1989, 19901. Most of these patients with deletions had sensorineural deafness [Cremers et al., 19891 and in one a perilympha- tic gusher was observed at stapes surgery [Merry et al., 19891.
Linkage studies, performed in 2 separate cyto- genetically normal pedigrees with X-linked deafness and surgically confirmed gusher, but with no other
514 Reardon et al.
clinical manifestations, independently mapped the gene for this condition to probes in the Xq13-q21 region with lod scores of 6.32 [Wallis et al., 19881 and 3.07 [Brunner et al., 19881. Brunner et al. [19881 have speculated that the gene for mixed deafness and perilymphatic gusher may be identical to the gene involved in deaf patients with Xq13-q21 deletions. However, the only supporting evidence for this to date is the observation of peri- lymphatic gusher in the patient with Xq13-q21 dele- tion related deafness [Merry et al., 19891.
More recently a multipedigree linkage study of fami- lies with X-linked deafness as the sole clinical feature, and in whom cytogenetic studies have been normal, has confirmed linkage to Xq13-q21 probes [Reardon et al., 19911. This study has demonstrated a readily identifia- ble cochlear abnormality by high resolution CT scan- ning in some affected patients [Phelps et al., 19913. This radiological abnormality is likely to hold the key to the anatomical basis of the perilymphatic gusher some- times seen in X-linked deafness and has been discussed in detail elsewhere [Phelps et al., 19911. In brief, it appears that the CT scan is detecting a fistulous connec- tion between the cerebrospinal fluid space and the peri- lymphatic space of the cochlea and this fistula gives rise to the gush of clear cerebrospinal fluid observed sur- gically. Moreover, the multipedigree study into X-linked deafness showed that this radiological abnormality is independent of audiogram type, as it is observed in fami- lies with both mixed deafness and sensorineural deaf- ness [Reardon et al., 1991, 19921.
Scanning abnormalities of the cochlea have not been reported previously in deaf patients with Xq deletions, although these would not be unexpected in view of the observation of gusher in one such patient [Merry et al., 19891. The purpose of this report is to provide radiologi- cal evidence that, in a patient with a cytogenetically visible Xq21 deletion, the anatomical basis of deafness is identical to that seen in cytogenetically normal patients from families in whom X-linked deafness is the sole clinical feature. In so doing, we present phenotypic evi- dence that the genetic basis of deafness is the same in both patient groups.
CLINICAL REPORT The pedigree is shown in Figure 1. The propositus
WJ, age 9 years, was referred with his first cousins IV3 ard IV5, al1 with a diagnosis of sensorineural deafness. Delivery was at 40 weeks gestation and he had a normal birth weight (3.2 kg). Prune belly syndrome was noted and thought to be related to bladder dilation and ureteric reflux, secondary to urethral folds. He was hy- potonic and early motor development was delayed with walking attained at 2 years. Clinical examination showed no dysmorphic features. He now walks indepen- dently, has poor social skills and attends a special school for children with deafness and psychomotor delay. He has a severe bilateral sensorineural deafness, of the order of 90 dB observed across most frequencies, and a disturbance of retinal pigment on ophthalmoscopy. This is characterised by a granular depigmented appearance with normal optic discs. Visual acuity is normal.
Patient IV, was born by forceps delivery of the after-
I I 1
3 7 4 & 5
/ Fig. 1. Family pedigree.
coming head following a breech presentation at term. Birth weight was 2.16 kg. Early motor milestones were delayed and he walked at 18 months. On examination, at age 9 years, he has no dysmorphic features and is a hyperactive child. He attends the same special educa- tional needs school as IV,. The deafness is bilateral, sensorineural, and of moderate to severe degree. He has similar ophthalmic pigmentary disturbances to the propositus.
Patient IV5 is now 15 months old. Birth weight was 3.26 kg at term and delivery was normal. Bilateral sensorineural deafness was detected early and motor milestones have been slow, sitting at 9 months and not walking at 15 months. Retina] examination does not show pigmentary abnormalities a t present.
As seen from Figure 1, the maternal granduncle (11,) has some features in common with our patients. This man, to whom access was not granted, is said to have profound intellectual impairment and severe deafness. His ophthalmic status is unknown.
Although unavailable for electrodiagnostic testing of the retinae, female patients 112, 1112, and 111, are clini- cally normal and have normal hearing. Ophthal- moscopic examination in 111, and 1115 showed normal visual acuity and optic discs. Despite some granularity of the fundi in 1112, no frank pigmentary disturbance was seen. III, has normal fundi. 112 was not examined oph- thalmoscopically or audiologically but claims to have normal hearing and vision. She had 7 first or early second trimester miscarriages.
CYTOGENETIC STUDIES Chromosome investigations had previously been un-
dertaken on patient IV, when it was considered that he might have fragile X syndrome and no abnormality was detected at that time. In view of the recent recognition of the association between deafness, retinal pigmentary disturbances, and Xq21 deletions these investigations were repeated. On this occasion chromosomes suitable for high resolution G band analysis were obtained from lymphocyte cultures using deoxycytidine release of a thymidine block [Wheater and Roberts, 19871 and GTG banded using a modi