Cochlear implantation in children with congenital inner ear malformations.

OBJECTIVE/HYPOTHESIS: To assess the audiologic and surgical outcomes for pediatric cochlear implant patients with inner ear malformations. STUDY DESIGN: Retrospective review of 315 pediatric cochlear implant cases from 1994 to 2002. METHODS: Twenty-eight pediatric cochlear implant patients with known inner ear malformations determined on high-resolution computed tomography (HRCT) of the temporal bone were the subjects of review. Results of HRCT findings, intraoperative findings, postoperative complications, and objective measures of both closed- and open-set testing of speech perception were analyzed. RESULTS: Patients with the constellation of an incompletely partitioned (IP) cochlea, enlarged vestibular aqueduct (EVA), and a dilated vestibule (i.e., Mondini's malformation) as well as those with an isolated EVA or partial semicircular canal aplasia have relatively good levels of speech perception. Patients with total semicircular canal aplasia, isolated IP, cochlear hypoplasia, or common cavity demonstrated lower levels of performance. Poor performance may be related to associated developmental delays rather than labyrinthine anatomy alone. Complications of surgery were relatively limited. CONCLUSIONS: Cochlear implantation can be successfully performed in children with inner ear malformations. These children and their parents can expect significant auditory benefits from this intervention. The various types of inner ear malformations may have quite different prognoses for good auditory performance.

Molecular assay to detect metastatic head and neck squamous cell carcinoma.

BACKGROUND: The presence or absence of metastatic disease in cervical lymph nodes is the single most important determinant of therapy and prognosis for patients with head and neck squamous cell carcinoma (HNSCC). However, histologic examination fails to detect metastatic disease in a subset of neck dissection specimens. The accuracy of neck staging may be improved by the use of molecular techniques. Cytokeratins 5, 14, and 20 may be appropriate markers for HNSCC because they are expressed in HNSCC but not in lymphatic tissue. DESIGN: To test the sensitivity of detection of cytokeratin 5, 14, and 20 messenger RNA by quantitative reverse transcription polymerase chain reaction (RT-PCR), full-length coding DNA sequences were cloned and transcribed. The expression of cytokeratin 5, 14, and 20 messenger RNA was quantified in 4 HNSCC cell lines and 11 tumors. A cell culture lymph node model was created. RESULTS: As few as 32 molecules of cytokeratin 14 could be detected using quantitative RT-PCR. Cytokeratins 5 and 14 were easily detected in all 4 HNSCC cell lines and almost all tumors. Cytokeratin 20 was not a useful marker, as expression was absent or significantly reduced in cell lines and tumors. In the lymph node model, cytokeratin 14 quantitative RT-PCR was able to detect 1 cancer cell in a background of 10 million lymphatic cells. CONCLUSIONS: Quantitative RT-PCR detection of cytokeratin 5 or 14 is a sensitive new molecular technique that may be used for detection of cervical micrometastases in head and neck cancer.

Molecular genetic advances in semicircular canal abnormalities and sensorineural hearing loss: a report of 16 cases.

OBJECTIVES: The study goals were (1) to determine if the degree and pattern of semicircular canal dysmorphology and the presence or absence of a cochlea in patients with congenital sensorineural hearing loss predict audiologic outcome, severity, or the frequencies involved and (2) to review the recent advances in molecular genetics of the semicircular canals and correlate this information with audiologic and anatomic patterns seen in our series of patients. DESIGN AND SETTING: We conducted a retrospective study at a tertiary care center with a large otologic and cochlear implant service. PATIENTS AND METHODS: The study population consisted of 16 patients with congenital sensorineural hearing loss in 28 congenitally malformed inner ears consisting of semicircular canal dysplasia or aplasia, with or without cochlear malformation. History, physical examination, computed tomography scans, and serial audiograms were reviewed. Factors analyzed included other phenotypic dysmorphology characteristic of syndromes, audiometric configuration, severity and type of hearing loss, and the presence of associated inner ear anomalies other than the vestibular system. An extensive review of the literature regarding molecular genetic factors in semicircular canal anomalies, with or without cochlear abnormalities, was performed. RESULTS: Sixteen patients (31 ears) were identified with profound sensorineural hearing loss and semicircular canal abnormalities. Only 3 patients had known syndromes, although 4 patients had other congenital anomalies. Most radiographic detectable abnormalities were bilateral. Audiograms of the patients demonstrated pure tone averages between 90 and 100 dB in the affected ears with few exceptions. No correlation was found between type and severity of malformation of either the cochlea or semicircular canals with the severity of hearing loss. There was no stepwise progression of hearing loss increasing malformation severity. Seven of the 16 patients received cochlear implants. Of these 7, 3 patients had cochlear hypoplasia and 1 patient had a common cavity deformity. Audiologic follow-up on all 7 patients revealed improvement in both speech assessment threshold and pure tone average. Presence or absence of the cochlea was not a factor in outcome after cochlear implantation. CONCLUSION: We have assembled the largest series of patients with semicircular canal dysmorphology, with or without various cochlear abnormalities. Our study failed to correlate the type and severity of semicircular canal malformation with any specific audiologic outcome. The variation in hearing loss severity and pattern even in patients with similar bony radiographic findings must be explained by other non-radiologically detectable defects, likely abnormalities in membranous labyrinthine development. New molecular genetic discoveries have linked specific genes to the development of certain inner ear structures in mice studies. The independent development of the individual semicircular canals in relation to the cochlea and vestibule and the variability in hearing loss suggest a more complex embryologic process than merely an arrest in development as previously thought. As genetic studies are extended into humans, we will likely be able to stratify these patients by molecular defect and severity of hearing loss.

Nontraumatic atlantoaxial subluxation (Grisel syndrome): a rare complication of otolaryngological procedures.

OBJECTIVE: At the conclusion of the report, the readers should be able to recognize the rare complication of adenotonsillectomy of Grisel syndrome, discuss its pathogenesis, and provide early, effective treatment. STUDY DESIGN: Analysis of the clinical presentation, plain radiographs, computed tomography scans, and magnetic resonance imaging scans of a child with Grisel syndrome after adenotonsillectomy. METHODS: Retrospective study of the case record and a review of the literature regarding the pathogenesis, treatment modalities, outcome, and prognosis after early and delayed treatment of Grisel syndrome. RESULTS: Pathophysiology of atlantoaxial subluxation revolves around the periodontoid vascular plexus that drains the posterosuperior pharyngeal region. Infectious and inflammatory emboli cause synovial engorgement, weakening paraspinal ligaments. Radiological studies play an important role in diagnosis. Treatment consists of cervical immobilization, muscle relaxants, analgesics, and antibiotics. Full resolution is expected with early conservative management. Failure to recognize the syndrome can lead to catastrophic results. CONCLUSIONS: Recognition of Grisel syndrome in addition to other rare complications of adenotonsillectomy requires a high index of suspicion. Early intervention is the critical factor for a positive outcome. However, delayed diagnosis is common and can result in catastrophic consequences, including neurological deficits, cosmetic deformity and, in rare instances, paralysis and death in the short term.

Familial head and neck cancer: molecular analysis of a new clinical entity.

OBJECTIVE: The tumor suppressor gene p16 encodes a cyclin-dependent kinase inhibitor that normally inhibits cell proliferation by causing a G1 cell cycle arrest. The p16 gene is frequently mutated in a variety of somatic tumors, as well as in familial melanoma and familial pancreatic carcinoma. We identified a family with a high incidence of head and neck squamous cell carcinoma (HNSCC) and melanoma. Molecular analyses of the p16 gene locus in blood and tumor DNA from this family was performed to determine whether an association between germline p16 gene mutation and HNSCC exists. STUDY DESIGN: Molecular pedigree analyses. METHODS: Exon 2 of p16 was polymerase chain reaction amplified from blood, tumor, or nontumor DNA isolated from affected and unaffected members, then directly sequenced and compared with consensus p16 sequence. Cell cycle position of cells expressing wild-type or mutant p16 was determined by flow cytometry. RESULTS: Molecular analyses revealed a nonfunctional germline point mutation within exon 2 of the p16 gene that encodes a mutant p16 protein substituting proline at amino acid position 87 for the wild-type arginine (p16R87P). Relative to wild-type p16, p16R87P lost ability to cause a growth arrest following ectopic expression. The mutant (p16R87P) allele segregated with cancer predisposition in tested family members, and analyses of HNSCC tumor tissues demonstrated universal loss of wild-type allele. CONCLUSIONS: Significance of the mutant p16 (p16R87P) in HNSCC tumorigenesis is strongly suggested by its loss of cell cycle arrest activity and its retention in tumor tissue with simultaneous loss of the wild-type allele. Further, the germline p16 mutation segregated with cancer predisposition within the family. In aggregate, these data suggest that there is a direct causal relationship between the germline p16 mutation in this family and HNSCC tumorigenesis. Based on our observations, the spectrum of familial cancers associated with p16 mutations should include a new clinical entity, familial HNSCC.