Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss.

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.

The sequence and antiapoptotic functional domains of the human cytomegalovirus UL37 exon 1 immediate early protein are conserved in multiple primary strains.

The human cytomegalovirus UL37 exon 1 gene encodes the immediate early protein pUL37x1 that has antiapoptotic and regulatory activities. Deletion mutagenesis analysis of the open reading frame of UL37x1 identified two domains that are necessary and sufficient for its antiapoptotic activity. These domains are confined within the segments between amino acids 5 to 34, and 118 to 147, respectively. The first domain provides the targeting of the protein to mitochondria. Direct PCR sequencing of UL37 exon 1 amplified from 26 primary strains of human cytomegalovirus demonstrated that the promoter, polyadenylation signal, and the two segments of pUL37x1 required for its antiapoptotic function were invariant in all sequenced strains and identical to those in AD169 pUL37x1. In total, UL37 exon 1 varies between 0.0 and 1.6% at the nucleotide level from strain AD169. Only 11 amino acids were found to vary in one or more viral strains, and these variations occurred only in the domains of pUL37x1 dispensable for its antiapoptotic function. We infer from this remarkable conservation of pUL37x1 in primary strains that this protein and, probably, its antiapoptotic function are required for productive replication of human cytomegalovirus in humans.

DFNA25, a novel locus for dominant nonsyndromic hereditary hearing impairment, maps to 12q21-24.

Using linkage analysis, we identified a novel dominant locus, DFNA25, for delayed-onset, progressive, high-frequency, nonsyndromic sensorineural hearing loss in a large, multigenerational United States family of Czech descent. On the basis of recombinations in affected individuals, we determined that DFNA25 is located in a 20-cM region of chromosome 12q21-24 between D12S327 (centromeric) and D12S84 (telomeric), with a maximum two-point LOD score of 6.82, at recombination fraction.041, for D12S1030. Candidate genes in this region include ATP2A2, ATP2B1, UBE3B, and VR-OAC. DFNA25 may be the human ortholog of bronx waltzer (bv).

Outcome of newborn hearing screening by ABR compared with four different DPOAE pass criteria.

The purpose of this study is to compare the effectiveness and utility of distortion product otoacoustic emission (DPOAE) and auditory brain stem response (ABR) testing as screening methodologies suitable for universal application at a large birthing hospital. Five hundred sixty-nine neonates (1184 ears) without risk indicators for hearing loss underwent DPOAE and ABR screening before hospital discharge at birth. All ears (100%) passed the ABR screening. DPOAE results were categorized on the basis of the number of frequencies at which emissions were obtained as well as presence versus absence of a replicated response at each test frequency. Pass and refer rates varied widely, on the basis of whether the presence of DPOAE response at 2000 Hz or replication were required. With the most stringent criteria, only 64.44% of ears passed, whereas with the least stringent criteria 88.94% passed. Given that 100% of ears passed according to the gold standard of the ABR screening, these results indicate false-positive rates ranging from 11% to 35% by DPOAE screening. This discrepancy in pass and refer rates when various criteria are applied indicates the need for standardization and further comparison of appropriate pass criteria for newborn hearing screening programs.

A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus.

Non-syndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 reported gene localisations. We have identified a large Dutch family with autosomal dominant non-syndromic sensorineural hearing impairment. In most patients, the onset of hearing impairment is in the first or second decade of life, with a slow decline in the following decades, which stops short of profound deafness. The hearing loss is bilateral, symmetrical, and only affects low and mid frequencies up to 2000 Hz. In view of the phenotypic similarities of this family with an American family that has been linked to chromosome 4p16.3 (DFNA6), we investigated linkage to the DFNA6 region. Lod score calculations confirmed linkage to this region with two point lod scores above 6. However, as haplotype analysis indicated that the genetic defect in this family is located in a 5.6 cM candidate region that does not overlap the DFNA6 region, the new locus has been named DFNA14.

Pediatric myofibromatosis of the head and neck.

OBJECTIVES: To examine the clinical and pathological features of pediatric myofibroma of the head and neck and to discuss the challenges in diagnosis and treatment. DESIGN: A retrospective search of pathology department and clinical records to identify patients with myofibroma and a retrospective review of English-language medical publications. SETTING: Academic medical center. PATIENTS: Thirteen pediatric patients (aged from birth to 8 years old) diagnosed as having myofibroma of the head and neck. RESULTS: Nine of 13 patients were cured with conservative surgical excision. Four patients (31%) had recurrence, requiring multiple surgical procedures. One third showed spontaneous regression clinically or by histological examination. The clinical course did not parallel the histological appearance, as high cellularity and mitotic figures were commonplace among the specimens. A misdiagnosis of malignancy was not unusual in this series, as 3 patients had an initial diagnosis of fibrosarcoma, which on review was revised to myofibroma. CONCLUSIONS: Myofibromatosis is a distinct disorder among the great number of fibrous proliferations occurring in infants and children, with a particular predilection for the head and neck region. These lesions should be clearly distinguished from conventional adult-type fibromatoses (desmoid tumors), which are more aggressive. Most patients have solitary lesions that respond well to conservative surgical excision, whereas a few of these lesions behave more aggressively, requiring several surgical procedures for the management of recurrent or persistent tumor. Many of these lesions show spontaneous regression, suggesting that lesions not affecting vital functions, resulting in growth anomalies, or demonstrating rapid aggressive growth may be managed conservatively.

Laryngotracheal stenosis in children.

The diagnosis of laryngotracheal stenosis should be suspected in children with stridor, feeding difficulties, or atypical croup. Only half of the children with congenital laryngotracheal stenosis require tracheotomy, and many of these children can be decannulated following uncomplicated surgical therapy. In contrast, tracheotomy-dependent patients with acquired laryngotracheal stenosis require more extensive surgical intervention, which should be carried out as early as possible to provide the best opportunity for developing normal oral communication.

PCR detection of human cytomegalovirus DNA in clinical specimens using novel UL37 exon 3 and US3 primers.

The sensitivity and specificity of novel UL37 exon 3 (UL37x3) and US3 immediate-early (IE) gene PCR primers to detect human cytomegalovirus (HCMV) DNA in clinical specimens are comparable to those of HCMV DNA polymerase (UL54) primers. The use of these IE primers increases the diagnostic performance of HCMV PCR.

Otologic manifestations of Wolf-Hirschhorn syndrome.

OBJECTIVE: To determine if haploinsufficiency for chromosome 4p16.3 in Wolf-Hirschhorn syndrome (WHS) is associated with cochlear hearing loss. DESIGN: Case series. SETTING: Tertiary care center. PATIENTS: Six patients with WHS were identified through a database and charts were retrospectively reviewed. MAIN OUTCOME MEASURES: Presence of sensorineural hearing loss as assessed by brainstem auditory evoked response. RESULTS: One of the 6 patients had sensorineural hearing loss. Three of the 6 patients had chronic otitis media with effusion and underwent bilateral tympanostomy tube placement; 2 of these 3 had cleft lip and palate, and 1 had a bifid uvula. One of the 6 patients had spontaneous nystagmus. Five of the 6 patients had preauricular and/or auricular abnormalities. CONCLUSIONS: More than 25 genes for nonsyndromic hereditary hearing impairment have been mapped. One of these genes, DFNA6, was identified through linkage analysis of a family with dominant, progressive, low-frequency sensorineural hearing loss. DFNA6 maps to chromosome 4p16.3, a region that is partially deleted in patients with WHS. In our series, we identified the second patient with WHS in the literature with bilateral sensorineural hearing loss. The incidence and type of otologic findings are consistent with those reported in the literature. Analysis of patients with chromosomal rearrangements represents one strategy toward identifying candidate genes for genetic hearing impairment.

Assessment and management of laryngotracheal stenosis.

Laryngotracheal stenosis should be suspected in children with recurrent, prolonged, or atypical croup; a history of endotracheal intubation; or a history of stridor, feeding difficulties, and failure to thrive. Tracheotomy-dependent patients with acquired laryngotracheal stenosis are candidates for surgical intervention to provide the child with the earliest opportunity to develop normal oral communication.

Human papillomavirus types important in progression of inverted papilloma.

Recent evidence suggests that human papillomavirus may play a role in the pathogenesis of inverted papilloma, a benign but locally aggressive neoplasm with a high recurrence rate and an association with squamous cell carcinoma. Histologic features of inverted papilloma have not been useful in discriminating lesions at high risk for malignant transformation. We studied archival pathology specimens from 39 patients with inverted papilloma treated at the University of Michigan between 1980 and 1994 using polymerase chain reaction techniques and human papillomavirus L1 and E6 consensus primers. Previously we reported that 63% of these specimens tested positive for human papillomavirus sequences and that presence of human papillomavirus predicted recurrence of inverted papilloma. We used type-specific primer pairs and polymerase chain reaction techniques as well as hybridization with type-specific oligonucleotide probes to determine human papillomavirus type. A significant correlation was observed between the severity of the lesion (dysplasia or carcinoma) and high risk human papillomavirus type (p < 0.01). All 12 benign inverted papilloma specimens that contained human papillomavirus tested positive for human papillomavirus 6 or 11. Of seven inverted papilloma specimens that exhibited dysplasia, five were human papillomavirus positive, three contained human papillomavirus 6, one contained human papillomavirus 11, and one contained human papillomavirus 18. In each of the three specimens that contained inverted papilloma in association with squamous cell carcinoma, the inverted papilloma portion of the specimen tested positive for a single human papillomavirus type: human papillomavirus 6, 11, or 16.(ABSTRACT TRUNCATED AT 250 WORDS)

A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3.

Mapping genes for nonsyndromic hereditary hearing impairment may lead to identification of genes that are essential for the development and preservation of hearing. We studied a family with autosomal dominant, progressive, low frequency sensorineural hearing loss. Linkage analysis employing microsatellite polymorphic markers revealed a fully linked marker (D4S126) at 4p16.3, a gene-rich region containing IT15, the gene for Huntington's disease (HD). For D4S126, the logarithm-of-odds (lod) score was 3.64 at theta = 0, and the overall maximum lod score was 5.05 at theta = 0.05 for D4S412. Analysis of recombinant individuals maps the disease gene to a 1.7 million base pair (Mb) region between D4S412 and D4S432. Genes for two types of mutant mice with abnormal cochleovestibular function, tilted (tlt) and Bronx waltzer (bv), have been mapped to the syntenic region of human 4p16.3 on mouse chromosome 5. Further studies with the goals of cloning a gene for autosomal nonsyndromic hearing impairment and identifying the murine homologue may explain the role of this gene in the development and function of the cochlea.

Presence of human papillomavirus predicts recurrence of inverted papilloma.

Recent evidence suggests that human papillomavirus may play a role in the pathogenesis of inverted papilloma, a benign but locally aggressive neoplasm with a high recurrence rate and an association with squamous cell carcinoma. Histologic features of inverted papilloma have not been useful in discriminating lesions at high risk for recurrence. We studied archival pathology specimens from 32 patients with inverted papilloma treated at the University of Michigan between 1980 and 1994 with polymerase chain reaction techniques and human papillomavirus E6 and L1 consensus primers. Twenty (63%) specimens tested positive for human papillomavirus. The clinical status of the remaining 25 patients was reviewed after seven patients with recent diagnosis or who were lost to follow-up were excluded. A significant association was identified between the presence of human papillomavirus DNA in inverted papilloma and recurrence after surgical excision. Thirteen of 15 patients whose tumors tested positive for HPV recurred, whereas none of the 10 patients whose tumors were human papillomavirus negative recurred (p < 0.00002). This strongly suggests that the presence of human papillomavirus predicts recurrence of inverted papilloma.

Deafness induced cell size changes in rostral AVCN of the guinea pig.

The right cochleae of 250-350 g guinea pigs were lesioned by topical administration of neomycin in the middle ear cavity. Eight weeks after the lesion, the cochleae and cochlear nuclei were analyzed. Cochlear hair cell loss was assessed, and cell areas of spherical bushy cells in the rostral anteroventral cochlear nucleus (AVCN) were compared between the lesioned and normal hearing sides for each animal. In five animals with both inner and outer hair cell loss in the lesioned cochlea, the average area of neuronal somata in the rostral AVCN in the lesioned side was 22% smaller than the average area of these cells in the normal hearing side. In two animals with outer hair cell loss but inner hair cells remaining, there was no difference in cell size between the lesioned and non-lesioned AVCN. These results provide evidence that there is significant shrinkage in AVCN cell size in the mature mammal after hearing loss associated with inner hair cell loss.