Clinical guidelines for the management of craniofacial fibrous dysplasia.

Fibrous dysplasia (FD) is a non-malignant condition caused by post-zygotic, activating mutations of the GNAS gene that results in inhibition of the differentiation and proliferation of bone-forming stromal cells and leads to the replacement of normal bone and marrow by fibrous tissue and woven bone. The phenotype is variable and may be isolated to a single skeletal site or multiple sites and sometimes is associated with extraskeletal manifestations in the skin and/or endocrine organs (McCune-Albright syndrome). The clinical behavior and progression of FD may also vary, thereby making the management of this condition difficult with few established clinical guidelines. This paper provides a clinically-focused comprehensive description of craniofacial FD, its natural progression, the components of the diagnostic evaluation and the multi-disciplinary management, and considerations for future research.

α-Synuclein deficiency and efferent nerve degeneration in the mouse cochlea: a possible cause of early-onset presbycusis.

OBJECTIVES/HYPOTHESIS: Efferent nerves under the outer hair cells (OHCs) play a role in the protection of these cells from loud stimuli. Previously, we showed that cochlear α-synuclein expression is localized to efferent auditory synapses at the base of the OHCs. To prove our hypothesis that α-synuclein deficiency and efferent auditory deficit might be a cause of hearing loss, we compared the morphology of efferent nerve endings and α-synuclein expression within the cochleae of two mouse models of presbycusis. STUDY DESIGN: Comparative animal study of presbycusis. METHODS: The C57BL/6J(C57) mouse strain, a well-known model of early-onset hearing loss, and the CBA mouse strain, a model of relatively late-onset hearing loss, were examined. Auditory brainstem responses and distortion product otoacoustic emissions were recorded, and cochlear morphology with efferent nerve ending was compared. Western blotting was used to examine α-synuclein expression in the cochlea. RESULTS: Compared with CBA mice, C57 mice showed earlier onset high-frequency hearing loss and decreased function in OHCs, especially within high-frequency regions. C57 mice demonstrated more severe pathologic changes within the cochlea, particularly within the basal turn, than CBA mice of the same age. Weaker α-synuclein and synaptophysin expression in the efferent nerve endings and cochlear homogenates in C57 mice was observed. CONCLUSIONS: Our results support the hypothesis that efferent nerve degeneration, possibly due to differential α-synuclein expression, is a potential cause of early-onset presbycusis. Further studies at the cellular level are necessary to verify our results.

Localization of synucleins in the mammalian cochlea.

Synucleins are widely expressed synaptic proteins within the central nervous system that have been implicated in such neurodegenerative disorders as Parkinson's disease. In this study, an initial characterization of all three synucleins, alpha-, beta-, and gamma-synuclein, within the cochlea was undertaken. Reverse transcriptase-polymerase chain reaction (PCR) demonstrated all three synuclein mRNA species within microdissected cochlear tissue. Quantitative PCR suggests that beta-synuclein is the most abundantly expressed form, followed by gamma- and then alpha-synuclein. Western blot analysis similarly demonstrates all three synuclein proteins within microdissected cochlear tissue. Immunofluorescence localizes the three synucleins predominantly to the efferent neuronal system at the efferent outer hair cell synapse, with some additional localization within the efferent tunnel-crossing fibers (alpha- and gamma-synuclein), spiral ganglion (beta-synuclein), inner spiral bundle (gamma-synuclein), and stria vascularis (alpha- > beta-synuclein). Developmentally, gamma-synuclein can be seen in the region of the outer hair cells by E19, while alpha- and beta-synuclein do not clearly appear there until approximately P10. Additional studies in a null-mutant gamma-synuclein mouse show no histological changes in the organ of Corti with normal hair cell and spiral ganglion cell counts, and normal ABR and DPOAE thresholds in wild-type vs mutant littermates. Together, these results localize synucleins to the efferent cholinergic neuronal auditory system, pointing to a role in normal auditory function, and raising the potential implications for their role in auditory neurodegenerative disorders. However, gamma-synuclein alone is not required for the development and maintenance of normal hearing through P21. Whether overlapping roles of the other synucleins help compensate for the loss of gamma-synuclein remains to be determined.

Chondrosarcomas of the skull base and temporal bone.

OBJECTIVE: To evaluate the clinical presentation and outcomes of treatment for patients with chondrosarcomas involving the skull base and temporal bone. STUDY DESIGN: Retrospective review. SETTING: Tertiary medical centre. PATIENTS: Cases of histologically confirmed chondrosarcoma involving the skull base and temporal bones. INTERVENTION: Surgery. MAIN OUTCOME MEASURES: Demographic features of presenting patients; presenting symptoms and signs; surgical approach employed; use of post-operative radiation therapy; histological grade of tumour; and interval of post-operative follow up. RESULTS: Twelve patients were identified with chondrosarcomas involving the skull base, with post-operative follow up ranging from three to 33 years. The average age at presentation was 42 years. The most common presenting symptoms were diplopia, decreased visual acuity and headaches. Five of the 12 patients required multiple surgical procedures. CONCLUSIONS: Patients with chondrosarcoma involving the skull base and temporal bone may present in a variety of ways. Surgical resection, even subtotal, in combination with radiation therapy, can often provide good tumour control over many years for these rare tumours.

Cochlear implantation in patients with osteogenesis imperfecta.

OBJECTIVE: Hearing loss has been shown to occur in 42% to 58% of patients with osteogenesis imperfecta (OI), with deafness arising in 25% to 60% of the patients. Implantation in patients with OI is relatively rare, with only 4 prior single case reports published in the English-language literature. The goal of this study was to evaluate the feasibility and functional outcome of cochlear implantation in 2 patients with OI tarda type I with profound sensorineural hearing loss. STUDY DESIGN: Case series. SETTING: The implantations were performed in a tertiary academic referral center (Johns Hopkins University). RESULTS: Though promontory vascularity was encountered, full insertion of a normal cochlear implant array could be achieved in both cases. One-year postimplant scores demonstrated 20 to 40 dB hearing thresholds, Consonant-Nucleus-Consonant Test word scores of 54% and 70%, Consonant-Nucleus-Consonant Test phoneme scores of 75% and 83%, Hearing in Noise Test scores of 76% and 99%, and Central Institute of the Deaf Sentence Score sentence scores of 99% and 100%, for patients 1 and 2, respectively. CONCLUSIONS: Cochlear implantation in patients with OI is not only technically possible but the results are similar to implant outcomes for patients with sensorineural hearing loss from a variety of other causes. EBM RATING: C.

Benign positional vertigo after cochlear implantation.

OBJECTIVE: To identify patients who underwent cochlear implantation (CI) and who subsequently developed benign positional vertigo (BPV) after the procedure and to identify any contributing factors. STUDY DESIGN AND SETTING: Academic tertiary referral center. Cochlear implant recipients' medical records were retrospectively reviewed to identify patients with both vertigo and, more specifically, BPV. Preoperative, intraoperative, and postoperative factors were studied vis-a-vis the development of BPV. RESULTS: BPV was newly diagnosed in 12 patients after CI. The etiology of hearing loss included presbycusis (16.6%), autoimmune inner ear disease (16.6%), congenital hearing loss (41.6%), Meniere's disease (8.3%), prematurity (8.3%), and idiopathic factors (8.3%). The onset of BPV varied after the procedure (mean +/- SD, 292 +/- 309 days). BPV symptoms did not affect implant performance. All patients were treated for BPV by Epley's maneuver and vestibular exercises. Symptoms disappeared in 11 patients and persisted in 1. CONCLUSIONS: BPV is an uncommon development after CI, although it occurs more frequently than in the general population. Two theories are proposed: the introduction of bone dust into the labyrinth and the dislodging of otoconia during surgery. The diagnosis, treatment, and prognosis of BPV after CI do not differ from those for non-CI-associated BPV. SIGNIFICANCE: Dizziness after CI usually develops as a result of vestibular hypofunction. BPV, which is a hyperfunctioning form of vestibular dysfunction, should be recognized as a possible sequelae of CI.

Chromosome location and characterization of the human nicotinic acetylcholine receptor subunit alpha (alpha) 9 (CHRNA9) gene.

The human nicotinic acetylcholine receptor (nAChR) subunit alpha9 gene (CHRNA9) codes for a component of the AChR in hair cells of the inner ear. While no direct evidence presently links this gene to known hearing disorders, it may underlie individual susceptibility to acoustic inner ear injury, and is associated with the autoimmune skin disorder Pemphigus vulgaris. Future studies will depend upon a thorough characterization of the nAChR alpha9 gene. CHRNA9 was localized to chromosome 4p15.1-->p14 by FISH analysis. Radiation hybrid mapping further localized the gene between markers D4S405 and D4S496 (Stanford G3 panel), and between markers WI-3875 and D4S1231 (Genebridge 4 panel), representing a distance of approximately 3.1 cR. The D4S405 marker has been linked to a non-syndromic form of hereditary hearing loss, DFNB-25. The gene contains five exons, separated by four introns. Exons 1-5 are 78, 145, 154, 532 and 877 bases, respectively. Introns 1-4 are 294, 1239, 11517, and 4571 bases, respectively. The intron-exon splice junction sites correlate identically with those of the rat alpha9 gene and are nearly identical to those of the human alpha10 gene. Sequence promoter analysis reveals a number of potential regulatory elements, including several in common with the nAChR alpha10 gene, whose expressed protein is assumed to combine with alpha9 in the inner ear.

Fibrous dysplasia involving the skull base and temporal bone.

OBJECTIVE: To gain a broader appreciation of the clinical presentation, operative treatment, and outcome of patients with fibrous dysplasia involving the skull base. DESIGN: Retrospective review of a clinical case series. SETTING: A single tertiary academic medical center. PATIENTS: Twenty-one patients with histopathologically confirmed fibrous dysplasia involving the skull base cared for over a 15-year-period (1983-1998). MAIN OUTCOME MEASURES: Clinical and radiographic location of the fibrous dysplasia lesions within the skull base, clinical presentation, surgical intervention, and clinical outcome were tabulated for each patient. RESULTS: The ethmoids were most commonly involved (71%), followed by the sphenoid (43%), frontal (33%), maxilla (29%), temporal (24%), parietal (14%), and occipital (5%) bones. The most common presenting features included atypical facial pain and headache, complaints referable to the sinuses, proptosis and diplopia, hearing loss, and facial numbness. Surgical treatment, guided by clinical presentation, ranged from simple biopsy with conservative follow-up to craniofacial resection. CONCLUSIONS: Fibrous dysplasia can present in myriad ways within the skull base. Modern imaging modalities and histopathologic analysis have made diagnosis relatively straightforward. Surgery, particularly in such a challenging region as the skull base, should be reserved for patients with functional impairment or a cosmetic deformity. Because of the benign nature of the condition, the surgery itself should be relatively conservative, with the primary goal being preservation of existing function.

Assessment of denaturing high-performance liquid chromatography (DHPLC) in screening for mutations in connexin 26 (GJB2).

Mutations in the gene GJB2 encoding connexin 26 (Cx26), a gap junction protein, have been shown to be responsible for a majority of recessive nonsyndromic hereditary hearing impairment in children. Over 60 different mutations in Cx26 have been reported. To obviate the need for direct sequencing of each specimen, a variety of screening techniques have been used to detect mutations in Cx26. However, each of these methods has significant shortcomings including expense, time consumption, and limited sensitivity. Denaturing high-performance liquid chromatography (DHPLC) has been recently introduced as a rapid and highly sensitive method of detecting sequence alterations. We have assessed the efficacy of DHPLC as a screening assay for detecting mutation in Cx26 coding region in 154 patients with hereditary hearing impairment. The GJB2 coding exon was amplified in one or two fragments, analyzed by DHPLC, and sequenced. Sequence analysis identified sequence variations in 34 patients concordant with abnormal DHPLC results. Three novel Cx26 mutations were identified: a single base pair substitution 511G>A, a 4 bp insertion 504insAACG, and a 3 bp deletion 358delAGG in three unrelated patients. In 120 patients with normal Cx26 sequence, DHPLC was normal. These results yield sensitivity and specificity of 100% for DHPLC-based detection of Cx26 mutations, and demonstrate that DHPLC is a highly sensitive and specific method of screening for sequence variations in Cx26 that is time and labor efficient. Further, our experience suggests that DHPLC screening alone followed by DNA sequencing only when DHPLC is abnormal may be adequate for identification of all sequence alterations in Cx26.

Hearing rehabilitation using the BAHA bone-anchored hearing aid: results in 40 patients.

OBJECTIVE: This study evaluates the U.S. experience with the first 40 patients who have undergone audiologic rehabilitation using the BAHA bone-anchored hearing aid. STUDY DESIGN: This study is a multicenter, nonblinded, retrospective case series. SETTING: Twelve tertiary referral medical centers in the United States. PATIENTS: Eligibility for BAHA implantation included patients with a hearing loss and an inability to tolerate a conventional hearing aid, with bone-conduction pure tone average levels at 60 dB or less at 0.5, 1, 2, and 4 kHz. INTERVENTION: Patients who met audiologic and clinical criteria were implanted with the Bone-Anchored Hearing Aid (BAHA, Entific Corp., Gothenburg, Sweden). MAIN OUTCOME MEASURES: Preoperative air- and bone-conduction thresholds and air-bone gap; postoperative BAHA-aided thresholds; hearing improvement as a result of implantation; implantation complications; and patient satisfaction. RESULTS: The most common indications for implantation included chronic otitis media or draining ears (18 patients) and external auditory canal stenosis or aural atresia (7 patients). Overall, each patient had an average improvement of 32+/-19 dB with the use of the BAHA. Closure of the air-bone gap to within 10 dB of the preoperative bone-conduction thresholds (postoperative BAHA-aided threshold vs. preoperative bone-conduction threshold) occurred in 32 patients (80%), whereas closure to within 5 dB occurred in 24 patients (60%). Twelve patients (30%) demonstrated 'overclosure' of the preoperative bone-conduction threshold of the better hearing ear. Complications were limited to local infection and inflammation at the implant site in three patients, and failure to osseointegrate in one patient. Patient response to the implant was uniformly satisfactory. Only one patient reported dissatisfaction with the device. CONCLUSIONS: The BAHA bone-anchored hearing aid provides a reliable and predictable adjunct for auditory rehabilitation in appropriately selected patients, offering a means of dramatically improving hearing thresholds in patients with conductive or mixed hearing loss who are otherwise unable to benefit from traditional hearing aids.

Molecular cloning and mapping of the human nicotinic acetylcholine receptor alpha10 (CHRNA10).

We report the isolation and initial characterization of a new member of the human nicotinic acetylcholine receptor (nAChR) subunit family, alpha10 (CHRNA10), from both inner-ear neuroepithelium and lymphoid tissue. The cDNA is 1959 nucleotides in length, with a coding region predicting a protein of 451 amino acids that is 90% identical to rat alpha10. The alpha10 gene was localized to chromosome 11p15.5. Human alpha10 was detected in human inner-ear tissue, tonsil, immortalized B-cells, cultured T-cells and peripheral blood lymphocytes using reverse transcriptase-polymerase chain reaction, Northern blot hybridization, and immunohistochemistry. We also detected the expression of the human nAChR alpha9 (CHRNA9) mRNA in these same tissues using RT-PCR and Northern blot hybridization.

Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.

The KvLQT1 gene encodes a voltage-gated potassium channel. Mutations in KvLQT1 underlie the dominantly transmitted Ward-Romano long QT syndrome, which causes cardiac arrhythmia, and the recessively transmitted Jervell and Lange-Nielsen syndrome, which causes both cardiac arrhythmia and congenital deafness. KvLQT1 is also disrupted by balanced germline chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome (BWS), which causes prenatal overgrowth and cancer. Because of the diverse human disorders and organ systems affected by this gene, we developed an animal model by inactivating the murine Kvlqt1. No electrocardiographic abnormalities were observed. However, homozygous mice exhibited complete deafness, as well as circular movement and repetitive falling, suggesting imbalance. Histochemical study revealed severe anatomic disruption of the cochlear and vestibular end organs, suggesting that Kvlqt1 is essential for normal development of the inner ear. Surprisingly, homozygous mice also displayed threefold enlargement by weight of the stomach resulting from mucous neck cell hyperplasia. Finally, there were no features of BWS, suggesting that Kvlqt1 is not responsible for BWS.

Hemangioblastoma of the internal acoustic canal in a patient with von Hippel-Lindau disease: a case report and review of the literature.

We report a case of von Hippel-Lindau disease in a 55-year-old woman who presented with an intracanalicular hemangioblastoma and discuss the otologic manifestations of this disease. A review of the literature revealed no previous reports of this entity originating in the internal acoustic canal.

Vestibular hair cells of the chick express the nicotinic acetylcholine receptor subunit alpha 9.

The efferent cholinergic pathways to the vestibular periphery have yet to be fully characterized. While the nicotinic acetylcholine receptor subunit (nAChR) alpha 9 is now regarded as the principle receptor for efferent cholinergic signaling to the organ of Corti, there is still uncertainty over how the more complex efferent effects of the labyrinth are produced. Recent experimental work has demonstrated that the nAChR alpha 9 is present in the vestibular end-organs of the rat and mouse, suggesting that alpha 9 may be one of the mediators of efferent cholinergic signaling in the vestibular periphery as well. In this experiment, we sought to determine whether alpha 9 was also present in the vestibular end-organs of the chick. A homologue of alpha 9 has been cloned recently from the chick cochlea. Using reverse transcription polymerase chain reaction (RT-PCR), individual vestibular end-organ preparations, including posterior ampulla, combined horizontal and superior ampulla, saccule, utricle, and the vestibular ganglion were screened for alpha 9 messenger RNA expression. In each end-organ and the vestibular ganglion, a cDNA of the expected size was obtained by RT-PCR and was confirmed to be alpha 9 by sequence analysis. Further, alpha 9 mRNA was identified by RT-PCR from individually isolated type I and type II vestibular hair cells (single-cell RT-PCR). Lastly, insitu hybridization using digoxigenin-labeled alpha 9 riboprobes confirmed the presence of alpha 9 in type I and type II hair cells throughout the vestibular periphery. These results demonstrate the expression of alpha 9 in the vestibular end-organs of the chick, and lend further support for the role of alpha 9 as a mediator of efferent cholinergic signaling in vestibular hair cells.

Doxycycline sclerosis of benign lymphoepithelial cysts in patients infected with HIV.

Benign lymphoepithelial cysts (BLCs) are a widely recognized cause of parotid gland swelling in HIV-infected patients. Although they are neither invasive nor associated with malignant degeneration, BLCs can become large and disfiguring. Multiple modalities have been used to control these cysts, but no ideal treatment has been identified. The current study examines the efficacy of doxycycline as a BLC sclerosant in eight patients, and nine BLCs (bilateral BLC in one patient). Follow-up ranged from 12 to 17 months in all cases. Doxycycline sclerosis controlled further cyst growth in 100% of cases with no serious complications. The BLCs became negligible or unnoticeable in two patients, and in six patients (seven BLCs) the cyst became fibrosed and showed no evidence of further growth over the follow-up period. Although further studies are needed to determine the long-term efficacy of this treatment modality, doxycycline sclerosis appears to offer a simple, safe, cost-effective, office-based therapeutic option for the treatment of BLCs in patients infected with HIV.

Contemporary presentation and management of a spectrum of mastoid abscesses.

BACKGROUND: The incidence of complications resulting from suppurative otitis media has significantly decreased since the introduction of antibiotics. At the start of the 20th century 50% of all cases of otitis media developed a coalescent mastoiditis. By 1959, the incidence had fallen to 0.4%. Recent studies suggest a current incidence of only 0.24%. Additionally, during the time of Friedrich Bezold (1824-1908), 20% of patients with mastoiditis developed subperiosteal abscess. Interestingly, this has incidence increased; today nearly 50% of patients diagnosed with coalescent mastoiditis have subperiosteal abscess. OBJECTIVE: To review the contemporary presentation, diagnosis, and management of a spectrum of mastoid abscesses. DESIGN: Retrospective case series. SETTING: Hospitals associated with the Department of Otolaryngology/Head and Neck Surgery at the University of California, San Francisco. PATIENTS: Three patients with mastoid abscesses are reported. One patient displayed "classic" Bezold's abscess, with pus escaping the mastoid near the incisura digastrica and tracking along the digastric and sternocleidomastoid muscles into the neck. The second and third patients exhibited temporoparietal swelling secondary to mastoid abscess eroding the root of the zygomatic process, a complication noted by Bezold in 1908 as occurring "in only very rare cases." RESULTS AND CONCLUSIONS: Since only one third of patients show pathologic tympanic membrane changes, and since complaints of otalgia, fever, and tenderness are inconstant, subperiosteal mastoid abscess is frequently a delayed diagnosis. The clinical presentation, pathogenesis, and routes of abscess spread are presented with photographic and radiographic illustration. Medical and surgical management is reviewed, and methods for accurate diagnosis are emphasized.