Otolaryngologists, Pediatric Specialist, Surgical Specialist
22 years of experience

Accepting new patients
Northeast Ann Arbor
Va Ann Arbor Healthcare System
2215 Fuller Rd
Ann Arbor, MI 48105
734-769-7100
Locations and availability (5)

Education ?

Medical School Score Rankings
University of Michigan Medical School (1988)
  • Currently 4 of 4 apples
Top 25%

Awards & Distinctions ?

Associations
American Academy of Otolaryngology: Head and Neck Surgery
American Board of Otolaryngology

Affiliations ?

Dr. Lesperance is affiliated with 4 hospitals.

Hospital Affilations

Score

Rankings

  • University of Michigan Hospitals & Health Centers
    Otolaryngology
    1500 E Medical Center Dr, Ann Arbor, MI 48109
    • Currently 4 of 4 crosses
    Top 25%
  • University of Michigan Health System
  • Ann Arbor Veterans Affairs Medical Center
    2215 Fuller Rd, Ann Arbor, MI 48105
  • C.S. Mott Children's Hospital
    1500 E Medical Center Dr, Ann Arbor, MI 48109
  • Publications & Research

    Dr. Lesperance has contributed to 42 publications.
    Title Development of Canal Cholesteatoma in a Patient with Prenatal Isotretinoin Exposure.
    Date December 2010
    Journal International Journal of Pediatric Otorhinolaryngology
    Excerpt

    To describe the clinical and radiologic findings in a case of isotretinoin embryopathy-like syndrome and discuss management of hearing loss, congenital external auditory canal (EAC) stenosis, and EAC cholesteatoma.

    Title Increased Activity of Diaphanous Homolog 3 (diaph3)/diaphanous Causes Hearing Defects in Humans with Auditory Neuropathy and in Drosophila.
    Date September 2010
    Journal Proceedings of the National Academy of Sciences of the United States of America
    Excerpt

    Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function. We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24. Genotyping of additional family members narrowed the interval to an 11-Mb, 3.28-cM gene-poor region containing only four genes, including DIAPH3. DNA sequencing of DIAPH3 revealed a c.-172G>A, g. 48G>A mutation in a highly conserved region of the 5' UTR. The c.-172G>A mutation occurs within a GC box sequence element and was not found in 379 controls. Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2- to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals. Likewise, a significant increase (approximately 1.5-fold) in DIAPH3 protein was found by quantitative immunoblotting of lysates from lymphoblastoid cell lines derived from affected individuals in comparison with controls. In addition, the c.-172G>A mutation is sufficient to drive overexpression of a luciferase reporter. Finally, the expression of a constitutively active form of diaphanous protein in the auditory organ of Drosophila melanogaster recapitulates the phenotype of impaired response to sound. To date, only two genes, the otoferlin gene OTOF and the pejvakin gene PJVK, are known to underlie nonsyndromic auditory neuropathy. Genetic testing for DIAPH3 may be useful for individuals with recessive as well as dominant inheritance of nonsyndromic auditory neuropathy.

    Title A Novel Chromosome 19p13.12 Deletion in a Child with Multiple Congenital Anomalies.
    Date April 2009
    Journal American Journal of Medical Genetics. Part A
    Excerpt

    We describe a patient with multiple congenital anomalies including deafness, lacrimal duct stenosis, strabismus, bilateral cervical sinuses, congenital cardiac defects, hypoplasia of the corpus callosum, and hypoplasia of the cerebellar vermis. Mutation analysis of EYA1, SIX1, and SIX5, genes that underlie otofaciocervical and/or branchio-oto-renal syndrome, was negative. Pathologic diagnosis of the excised cervical sinus tracts was revised on re-examination to heterotopic salivary gland tissue. Using high resolution chromosomal microarray analysis, we identified a novel 2.52 Mb deletion at 19p13.12, which was confirmed by fluorescent in situ hybridization and demonstrated to be a de novo mutation by testing of the parents. Overall, deletions of chromosome 19p13 are rare.

    Title Impairment of Slc17a8 Encoding Vesicular Glutamate Transporter-3, Vglut3, Underlies Nonsyndromic Deafness Dfna25 and Inner Hair Cell Dysfunction in Null Mice.
    Date August 2008
    Journal American Journal of Human Genetics
    Excerpt

    Autosomal-dominant sensorineural hearing loss is genetically heterogeneous, with a phenotype closely resembling presbycusis, the most common sensory defect associated with aging in humans. We have identified SLC17A8, which encodes the vesicular glutamate transporter-3 (VGLUT3), as the gene responsible for DFNA25, an autosomal-dominant form of progressive, high-frequency nonsyndromic deafness. In two unrelated families, a heterozygous missense mutation, c.632C-->T (p.A211V), was found to segregate with DFNA25 deafness and was not present in 267 controls. Linkage-disequilibrium analysis suggested that the families have a distant common ancestor. The A211 residue is conserved in VGLUT3 across species and in all human VGLUT subtypes (VGLUT1-3), suggesting an important functional role. In the cochlea, VGLUT3 accumulates glutamate in the synaptic vesicles of the sensory inner hair cells (IHCs) before releasing it onto receptors of auditory-nerve terminals. Null mice with a targeted deletion of Slc17a8 exon 2 lacked auditory-nerve responses to acoustic stimuli, although auditory brainstem responses could be elicited by electrical stimuli, and robust otoacoustic emissions were recorded. Ca(2+)-triggered synaptic-vesicle turnover was normal in IHCs of Slc17a8 null mice when probed by membrane capacitance measurements at 2 weeks of age. Later, the number of afferent synapses, spiral ganglion neurons, and lateral efferent endings below sensory IHCs declined. Ribbon synapses remaining by 3 months of age had a normal ultrastructural appearance. We conclude that deafness in Slc17a8-deficient mice is due to a specific defect of vesicular glutamate uptake and release and that VGLUT3 is essential for auditory coding at the IHC synapse.

    Title The Relationship Between Acute Mastoiditis and Antibiotic Use for Acute Otitis Media in Children--invited Commentary.
    Date March 2008
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Airway Obstruction Caused by Pten Hamartoma (bannayan-riley-ruvalcaba) Syndrome.
    Date December 2007
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Proboscis Lateralis: Case Report and Review.
    Date October 2007
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title A Pediatric Otolaryngologist Learns to Diagnose Acute Otitis Media.
    Date September 2007
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Tracheotomy in Very Low Birth Weight Neonates: Indications and Outcomes.
    Date June 2006
    Journal The Laryngoscope
    Excerpt

    OBJECTIVE/HYPOTHESIS: To review incidence of, indications for, and outcomes of tracheotomy in very low birth weight (VLBW) infants. STUDY DESIGN: Retrospective review in tertiary care hospital. METHODS: Eighteen VLBW (<1,500 g) infants with bronchopulmonary dysplasia undergoing tracheotomy in the neonatal intensive care unit between October 1997 and June 2002 were studied. Controls consisted of 36 VLBW infants undergoing intubation without tracheotomy, two per study infant, matched by gestational age and weight. Outcome measures included duration and number of intubation events, time to decannulation, complications, comorbidities, length of stay, and speech, language, and swallowing measures. RESULTS: Infants undergoing tracheotomy had an average duration of intubation of 128.8 days with a median number of 11.5 intubation events, both significantly greater than those of controls. Percentage of those with laryngotracheal stenosis was 44% of study infants had laryngotracheal stenosis compared to 1.6% in all intubated VLBW infants. The tracheotomy group had a significantly higher incidence of gastroesophageal reflux, pulmonary hypertension, and gastrostomy tube placement. The overall tracheotomy-related complication rate was 38.9%. Three were lost to follow-up, and five deaths occurred, two possibly tracheotomy-related. Six of ten were decannulated by an average time of 3.8 years, two of six after laryngotracheal reconstruction. Four of ten remained cannulated for a variety of reasons. Disorders of speech, language, and swallowing were common. CONCLUSIONS: When considering tracheotomy in VLBW infants, the total number of intubation events should be monitored as well as the total duration of intubation. The relatively high incidence of laryngotracheal stenosis argues for earlier endoscopy and possibly earlier tracheotomy in infants with developing stenoses.

    Title Hairy Polyp of the Pharynx Obscured on Physical Examination by Endotracheal Tube, but Diagnosed on Brain Imaging.
    Date February 2006
    Journal Pediatric Radiology
    Excerpt

    We report a case of hairy polyp of the pharynx diagnosed on brain MRI in order to stress the need to examine carefully all tissues included on an imaging study, even those outside the clinically stated region of interest, and to remind practitioners to consider unusual as well as common etiologies for neonatal respiratory distress. Our case is unique in that thorough examination of a brain MRI, ordered in the evaluation of presumed central apnea, led to the correct diagnosis.

    Title Haplotype and Linkage Disequilibrium Analysis of the Crmp1 and Evc Genes.
    Date May 2005
    Journal International Journal of Molecular Medicine
    Excerpt

    In this report, we present the haplotype and linkage disequilibrium (LD) pattern in the Collapsin Response Mediator Protein 1 (CRMP1) and Ellis-van Creveld syndrome (EVC) gene region. We genotyped eight different single nucleotide polymorphisms (SNPs) in the CRMP1 and EVC genes in 90 control individuals of diverse ethnicity. The minor allele frequencies ranged from 3.3-49.4%, with most having a frequency >25%. A total of 37 haplotypes were derived from these eight polymorphisms, with only one haplotype having a frequency >10%. Pairwise LD analysis showed a weak but significant LD between markers located about 243 kb apart in this region. The LD was significant between markers spaced about 208 kb apart in EVC, whereas no LD was found between a pair of markers located about 5 kb apart in CRMP1. However, in general, LD correlated with the distance between loci. The CRMP1 and EVC genes are located near WFS1, the Wolfram syndrome type 1 gene, in which mutations also cause low frequency sensorineural hearing loss (LFSNHL). The haplotypes obtained from these polymorphisms will be useful to track the segregation of phenotypes in families with Ellis-van Creveld syndrome, Weyers acrodental dysostosis, LFSNHL and Wolfram syndrome type 1.

    Title A Gene Responsible for Autosomal Dominant Auditory Neuropathy (auna1) Maps to 13q14-21.
    Date April 2005
    Journal Journal of Medical Genetics
    Title A Dominantly Inherited Progressive Deafness Affecting Distal Auditory Nerve and Hair Cells.
    Date March 2005
    Journal Journal of the Association for Research in Otolaryngology : Jaro
    Excerpt

    We have studied 72 members belonging to a large kindred with a hearing disorder inherited in an autosomal dominant pattern. We used audiological, physiological, and psychoacoustic measures to characterize the hearing disorders. The initial phenotypic features of the hearing loss are of an auditory neuropathy (AN) with abnormal auditory nerve and brainstem responses (ABRs) and normal outer hair cell functions [otoacoustic emissions (OAEs) and cochlear microphonics (CMs)]. Psychoacoustic studies revealed profound abnormalities of auditory temporal processes (gap detection, amplitude modulation detection, speech discrimination) and frequency processes (difference limens) beyond that seen in hearing impairment accompanying cochlear sensory disorders. The hearing loss progresses over 10-20 years to also involve outer hair cells, producing a profound sensorineural hearing loss with absent ABRs and OAEs. Affected family members do not have evidence of other cranial or peripheral neuropathies. There was a marked improvement of auditory functions in three affected family members studied after cochlear implantation with return of electrically evoked auditory brainstem responses (EABRs), auditory temporal processes, and speech recognition. These findings are compatible with a distal auditory nerve disorder affecting one or all of the components in the auditory periphery including terminal auditory nerve dendrites, inner hair cells, and the synapses between inner hair cells and auditory nerve. There is relative sparing of auditory ganglion cells and their axons.

    Title Mutational Spectrum of the Wfs1 Gene in Wolfram Syndrome, Nonsyndromic Hearing Impairment, Diabetes Mellitus, and Psychiatric Disease.
    Date April 2004
    Journal Human Mutation
    Excerpt

    WFS1 is a novel gene and encodes an 890 amino-acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition, several WFS1 sequence variants have been shown to be significantly associated with diabetes mellitus and this gene has also been implicated in psychiatric diseases. Wolfram syndrome is highly variable in its clinical manifestations, which include diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Wolfram syndrome mutations are spread over the entire coding region, and are typically inactivating, suggesting that a loss of function causes the disease phenotype. In contrast, only non-inactivating mutations have been found in DFNA6/14 families, and these mutations are mainly located in the C-terminal protein domain. In this paper, we provide an overview of the currently known disease-causing and benign allele variants of WFS1 and propose a potential genotype-phenotype correlation for Wolfram syndrome and LFSNHI.

    Title Phenotypic Characterization of Hereditary Hearing Impairment Linked to Dfna25.
    Date October 2003
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVES: To clinically characterize a family with nonsyndromic sensorineural hearing loss linked to the DFNA25 gene and to assess whether mitochondrial mutations influence the penetrance of the phenotype. DESIGN: Longitudinal clinical and basic science molecular genetic study. SETTING: Academic medical center and molecular genetic research laboratory. PARTICIPANTS: Members of a family with dominant high-frequency sensorineural hearing loss. INTERVENTIONS: Questionnaires, serial audiograms, and interviews correlated with molecular genetic data. MAIN OUTCOME MEASURES: Symptoms, age at onset, serial audiometric data, and the presence or absence of 4 deafness-associated mitochondrial mutations. RESULTS: Affected individuals typically manifest a high-frequency, slowly progressive sensorineural hearing loss in the postlingual period. The mode of inheritance is autosomal dominant with age-dependent penetrance. Male affected members tended to report an earlier onset of hearing loss than female members. In those inheriting the DFNA25-associated haplotype from an affected mother, hearing loss invariably developed by the second decade of life, whereas those inheriting the DFNA25 haplotype from an affected father often maintained hearing levels comparable to those of age-matched control subjects, even into the seventh decade of life. None of 4 deafness-associated mitochondrial mutations screened (1555A>G, 7445A>G, Cins7472, and 7511T>C) were found to segregate in the family. CONCLUSIONS: It is difficult to differentiate delayed-onset high-frequency sensorineural hearing loss inherited as a simple mendelian trait like DFNA25-associated hearing loss from that due to noise exposure or presbycusis, disorders that may also have a genetic component. An awareness of the clinical presentation of such hearing loss may help clinicians identify hearing loss attributable to genetic causes and improve care for these patients.

    Title A Pcr-rflp Assay for the A716t Mutation in the Wfs1 Gene, a Common Cause of Low-frequency Sensorineural Hearing Loss.
    Date May 2003
    Journal Genetic Testing
    Excerpt

    Nonsyndromic low-frequency sensorineural hearing loss (LFSNHL) is an unusual type of hearing loss that affects frequencies at 2,000 Hz and below. Recently, we reported five different heterozygous missense mutations in the Wolfram syndrome gene, WFS1, found to be responsible for LFSNHL in six families. One of the five mutations, A716T, may be a common cause of LFSNHL, as it has been reported in three families to date (Bespalova et al., 2001; Young et al., 2001). We have developed a PCR-based restriction fragment-length polymorphism (RFLP) assay to detect the A716T mutation in a simple, specific test. This method was evaluated with DNA samples from a family in which the A716T mutation was segregating with LFSNHL. This simple assay successfully detected the presence of the A716T mutation in all of the individuals predicted to be affected, based on audiologic results. Therefore, this assay can be routinely used for initial screening of the A716T mutation in patients with LFSNHL, before screening the entire coding region of the WFS1 gene.

    Title Mutations in the Wolfram Syndrome Type 1 Gene (wfs1) Define a Clinical Entity of Dominant Low-frequency Sensorineural Hearing Loss.
    Date May 2003
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    OBJECTIVE: To describe low-frequency sensorineural hearing loss (LFSNHL) inherited as a dominant trait in 3 families and in 1 sporadic case. DESIGN: Longitudinal clinical study from 1968 to 2001. SETTING: Tertiary care hospital; field studies conducted by molecular genetic research laboratory. PARTICIPANTS: Dominant LFSNHL families. INTERVENTIONS: Questionnaires, serial audiograms, and interviews, correlated with molecular genetic data. OUTCOME MEASURES: Symptoms, age of onset, serial audiometric data, and hearing aid use. RESULTS: Low-frequency sensorineural hearing loss is typically diagnosed in the first decade and slowly progresses over decades; LFSNHL is often asymptomatic in young patients, few of whom use hearing aids. Speech perception becomes affected in later decades when patients develop high-frequency loss. Even children with a strong family history of dominant LFSNHL were not monitored routinely. Penetrance appears complete in that all individuals with a genetic mutation developed hearing loss. CONCLUSIONS: Dominant LFSNHL is most commonly caused by mutations in the Wolfram syndrome type 1 gene (WFS1). Mutations in WFS1 also cause a rare recessive syndromic form of hearing loss known as Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Routine newborn hearing screening methods will not typically identify hearing loss affecting frequencies below 2000 Hz; thus, children at risk must be specifically monitored. Genetic counseling and genetic testing may be useful in the management of patients with this type of hearing loss.

    Title Efficiency of the Operating Room Vs the Short Procedure Room: Squeezing the Balloon.
    Date May 2003
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Characterization of a Stapes Ankylosis Family with a Nog Mutation.
    Date April 2003
    Journal Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology
    Excerpt

    OBJECTIVE: To characterize the otologic phenotype in a family with autosomal dominant stapes ankylosis, hyperopia, and skeletal abnormalities caused by a mutation in the noggin gene (NOG). STUDY DESIGN: Case series. SETTING: Academic tertiary care center. PATIENTS: Eight affected and 3 unaffected family members. MAIN OUTCOME MEASURES: History, physical and radiologic examination, and surgical outcomes. RESULTS: Although affected members were initially presumed to have typical nonsyndromic otosclerosis, the clinical data were most consistent with an autosomal dominant congenital stapes ankylosis syndrome. Eight of eight affected family members had bilateral low-frequency conductive hearing loss. Six of eight underwent fenestration procedures and/or stapedectomies. All members with initial postoperative closure of the air-bone gap returned to their baseline conductive loss within 2 years. Two affected family members had documented maximal conductive hearing loss by age 4, and two members without previous otologic surgery have not experienced sensorineural hearing loss. High-resolution temporal bone computed tomography showed stapes ankylosis and indistinction of the incudomalleal junction bilaterally and bony regrowth over the stapedotomy for those with stapedectomies. Detailed physical and radiologic examination identified multiple other skeletal abnormalities. CONCLUSIONS: Although this phenotype may present as classic otosclerosis to the otolaryngologist, detailed investigation revealed a congenital stapes ankylosis syndrome. Because is essential in regulating normal bone development and maturation, mutations in this gene may be associated with excessive bony overgrowth and refixation of the stapes footplate after initial successful surgery. Patients with hereditary conductive hearing loss should be assessed to rule out subtle features of a skeletal syndrome.

    Title Autosomal Dominant Stapes Ankylosis with Broad Thumbs and Toes, Hyperopia, and Skeletal Anomalies is Caused by Heterozygous Nonsense and Frameshift Mutations in Nog, the Gene Encoding Noggin.
    Date October 2002
    Journal American Journal of Human Genetics
    Excerpt

    Although fixation of the stapes is usually progressive and secondary to otosclerosis, it may present congenitally, with other skeletal manifestations, as an autosomal dominant syndrome-such as proximal symphalangism (SYM1) or multiple-synostoses syndrome (SYNS1), both of which are caused by mutations in NOG, the gene encoding noggin. We describe a family that was ascertained to have nonsyndromic otosclerosis but was subsequently found to have a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and great toes, and other minor skeletal anomalies but lacked symphalangism. A heterozygous nonsense NOG mutation-c.328C-->T (Q110X), predicted to truncate the latter half of the protein-was identified, and a heterozygous insertion in NOG-c.252-253insC, in which the frameshift is predicted to result in 96 novel amino acids before premature truncation-was identified in a previously described second family with a similar phenotype. In contrast to most NOG mutations that have been reported in kindreds with SYM1 and SYNS1, the mutations observed in these families with stapes ankylosis without symphalangism are predicted to disrupt the cysteine-rich C-terminal domain. These clinical and molecular findings suggest that (1) a broader range of conductive hearing-loss phenotypes are associated with NOG mutations than had previously been recognized, (2) patients with sporadic or familial nonsyndromic otosclerosis should be evaluated for mild features of this syndrome, and (3) NOG alterations should be considered in conductive hearing loss with subtle clinical and skeletal features, even in the absence of symphalangism.

    Title Evidence in Support of a Different Model of Universal Newborn Hearing Loss Identification.
    Date April 2002
    Journal American Journal of Audiology
    Title Mutations in the Wolfram Syndrome 1 Gene (wfs1) Are a Common Cause of Low Frequency Sensorineural Hearing Loss.
    Date February 2002
    Journal Human Molecular Genetics
    Excerpt

    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.

    Title The Carboxyl Terminus of the Human Cytomegalovirus Ul37 Immediate-early Glycoprotein is Conserved in Primary Strains and is Important for Transactivation.
    Date August 2001
    Journal The Journal of General Virology
    Excerpt

    The human cytomegalovirus (HCMV) UL37 exon 3 (UL37x3) open reading frame (ORF) encodes the carboxyl termini of two immediate-early glycoproteins (gpUL37 and gpUL37(M)). UL37x3 homologous sequences are not required for mouse cytomegalovirus (MCMV) growth in vitro; yet, they are important for MCMV growth and pathogenesis in vivo. Similarly, UL37x3 sequences are dispensable for HCMV growth in culture, but their requirement for HCMV growth in vivo is not known. To determine this requirement, we directly sequenced the complete UL37x3 gene in multiple HCMV primary strains. A total of 63 of the 310 amino acids in the UL37x3 ORF differ non-conservatively in one or more HCMV primary strains. The HCMV UL37x3 genetic diversity is non-random: the N-glycosylation (46/186 aa) and basic (9/15 aa) domains have the highest proportion of non-conservative variant amino acids. Nonetheless, most (15/17 signals) of the N-glycosylation signals are retained in all HCMV primary strains. Moreover, new N-glycosylation signals are encoded by 5/20 primary strains. In sharp contrast, the UL37x3 transmembrane (TM) ORF completely lacks diversity in all 20 HCMV sequenced primary strains, and only 1 of 28 cytosolic tail residues differs non-conservatively. To test the functional significance of the conserved carboxyl terminus, gpUL37 mutants lacking the TM and/or cytosolic tail were tested for transactivating activity. The gpUL37 carboxyl-terminal mutants are partially defective in hsp70 promoter transactivation even though they trafficked similarly to the wild-type protein into the endoplasmic reticulum and to mitochondria. From these results, we conclude that N-glycosylated gpUL37, particularly its TM and cytosolic domains, is important for HCMV growth in humans.

    Title Substituting a Telephone Call for Pediatric Adenotonsillectomy Postoperative Visits.
    Date April 2001
    Journal Archives of Otolaryngology--head & Neck Surgery
    Title Outcome of Newborn Hearing Screening by Abr Compared with Four Different Dpoae Pass Criteria.
    Date March 2001
    Journal American Journal of Audiology
    Excerpt

    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.

    Title The Sequence and Antiapoptotic Functional Domains of the Human Cytomegalovirus Ul37 Exon 1 Immediate Early Protein Are Conserved in Multiple Primary Strains.
    Date February 2001
    Journal Virology
    Excerpt

    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.

    Title Dfna25, a Novel Locus for Dominant Nonsyndromic Hereditary Hearing Impairment, Maps to 12q21-24.
    Date February 2001
    Journal American Journal of Human Genetics
    Excerpt

    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).

    Title Characterization of Autosomal Dominant Non-syndromic Hearing Loss Loci: Dfna 4, 6, 10 and 13.
    Date October 2000
    Journal Advances in Oto-rhino-laryngology
    Title Interpretation of Linkage Data for a Huntington-like Disorder Mapping to 4p15.3.
    Date August 2000
    Journal American Journal of Human Genetics
    Title No Association Between Dfna6 and Pro250arg Mutation in Fgfr3.
    Date November 1999
    Journal American Journal of Medical Genetics
    Title A Gene for Autosomal Dominant Hearing Impairment (dfna14) Maps to a Region on Chromosome 4p16.3 That Does Not Overlap the Dfna6 Locus.
    Date August 1999
    Journal Journal of Medical Genetics
    Excerpt

    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.

    Title Pediatric Myofibromatosis of the Head and Neck.
    Date February 1999
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    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.

    Title Laryngotracheal Stenosis in Children.
    Date July 1998
    Journal European Archives of Oto-rhino-laryngology : Official Journal of the European Federation of Oto-rhino-laryngological Societies (eufos) : Affiliated with the German Society for Oto-rhino-laryngology - Head and Neck Surgery
    Excerpt

    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.

    Title Pcr Detection of Human Cytomegalovirus Dna in Clinical Specimens Using Novel Ul37 Exon 3 and Us3 Primers.
    Date May 1998
    Journal Clinical and Diagnostic Laboratory Immunology
    Excerpt

    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.

    Title Otologic Manifestations of Wolf-hirschhorn Syndrome.
    Date March 1998
    Journal Archives of Otolaryngology--head & Neck Surgery
    Excerpt

    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.

    Title Assessment and Management of Laryngotracheal Stenosis.
    Date January 1997
    Journal Pediatric Clinics of North America
    Excerpt

    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.

    Title A Gene for Autosomal Dominant Nonsyndromic Hereditary Hearing Impairment Maps to 4p16.3.
    Date April 1996
    Journal Human Molecular Genetics
    Excerpt

    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.

    Title Deafness Induced Cell Size Changes in Rostral Avcn of the Guinea Pig.
    Date March 1996
    Journal Hearing Research
    Excerpt

    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.

    Title Squamous Cell Carcinoma Arising in Inverted Papilloma.
    Date February 1996
    Journal The Laryngoscope
    Excerpt

    A retrospective review of all cases of inverted papilloma at the University of Michigan from 1975 to 1992 revealed 51 cases of inverted papilloma. Of these, 14 (27%) had an associated squamous cell carcinoma (SCC). Eight (16%) were metachronous and 6 (11%) were synchronous. At a mean follow-up of 53 months, the disease-free survival of patients with carcinoma limited to the nasal cavity and paranasal sinuses was 57% (4/7) compared to 14% (1/7) of those patients presenting with disease extending beyond the nasal cavity and paranasal sinuses. The data also support the lateral rhinotomy approach with medial maxillectomy and ethmoidectomy as a minimum procedure followed by postoperative radiation therapy. The mean interval between the diagnosis of inverted papilloma and development of SCC was 63 months (range, 6 months to 13 years). Therefore, long-term follow-up with clinical examination and computed tomography (CT) scan is indicated for all patients with inverted papilloma.

    Title Human Papillomavirus Types Important in Progression of Inverted Papilloma.
    Date December 1995
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    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)

    Title Presence of Human Papillomavirus Predicts Recurrence of Inverted Papilloma.
    Date August 1995
    Journal Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-head and Neck Surgery
    Excerpt

    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.

    Title Commentary on "occupational Noise, Smoking and a High Body Mass Index Are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: a European Population-based Multicentre Study" by Fransen Et Al., J. Assoc. Res. Otolaryngol. Doi 10.1007/s10162-008-0123-1.
    Date
    Journal Journal of the Association for Research in Otolaryngology : Jaro

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