Mechanisms involved in hearing disorders of thyroid ontogeny: a literature review.

Endocochlear, retrocochlear and/or central origin hearing damage may be related to the absence of appropriate levels of thyroid hormone during morphogenesis and/or auditory system development. Hearing disorders related to the thyroid are not well studied, despite speculation on the pathophysiological mechanisms. The objective of this review was to characterize the main pathophysiological mechanisms of congenital hypothyroidism and to evaluate the relationship with central and peripheral hearing disorders. We conducted a literature review using the databases MedLine, LILACS, Cochrane Library, SciELO, Institute for Scientific Information (ISI), Embase, and Science Direct between July and September on 2016. We identified the studies that address hearing disorder mechanisms on the congenital hypothyroidism. Congenital hypothyroidism may have clinical and subclinical manifestations that affect the auditory system and may be a potential risk factor for hearing impairment. Hearing impairment can severely impact quality-of-life, which emphasizes the importance of monitoring and evaluating hearing during the clinical routine of these patients.

Mechanisms involved in hearing disorders of thyroid ontogeny: a literature review

ABSTRACT Endocochlear, retrocochlear and/or central origin hearing damage may be related to the absence of appropriate levels of thyroid hormone during morphogenesis and/or auditory system development. Hearing disorders related to the thyroid are not well studied, despite speculation on the pathophysiological mechanisms. The objective of this review was to characterize the main pathophysiological mechanisms of congenital hypothyroidism and to evaluate the relationship with central and peripheral hearing disorders. We conducted a literature review using the databases MedLine, LILACS, Cochrane Library, SciELO, Institute for Scientific Information (ISI), Embase, and Science Direct between July and September on 2016. We identified the studies that address hearing disorder mechanisms on the congenital hypothyroidism. Congenital hypothyroidism may have clinical and subclinical manifestations that affect the auditory system and may be a potential risk factor for hearing impairment. Hearing impairment can severely impact quality-of-life, which emphasizes the importance of monitoring and evaluating hearing during the clinical routine of these patients.

[Mutation analysis and prenatal diagnosis for 12 families affected with hereditary hearing loss and enlarged vestibular aqueduct].

OBJECTIVE: To carry out mutation analysis and prenatal diagnosis for 12 families affected with hearing loss and enlarged vestibular aqueduct from southern Zhejiang province. METHODS: Clinical data and peripheral venous blood samples of 38 members from the 12 families were obtained. Mutations of 4 genes, namely SLC26A4, GJB2, c.538C to T and c.547G to A of GJB3, m.1555A to G and m.1494C to T of 12S rRNA, were detected by PCR and Sanger sequencing. Maternal contamination was excluded by application of STR detection during prenatal diagnosis. RESULTS: Among the probands from the 12 families, 11 were found to be compound heterozygotes or homozygotes and 25 were heterozygotes. All of the families were detected with IVS7-2A to G mutations, and 4 had a second heterozygous mutation (c.2168A to G of the SLC26A4 gene). Four rare pathogenic mutations, namely IVS5-1G to A, c.946G to T, c.1607A to G and c.2167C to G, were detected in another four families. In addition, the partner of proband from pedigree 3 was identified with compound heterozygous mutations of c.235delC and c.299-300delAT, and proband of pedigree 5 has carried a mutation of c.109G to A in GJB2. For SLC26A4 gene, prenatal diagnostic testing has revealed heterozygous mutations in 6 fetuses and compound heterozygous mutations in 2 fetuses. CONCLUSION: IVS7-2A to G and c.2168A to G of the SLC26A4 gene were the most common mutations in southern Zhejiang. Such mutations can be found in most families affected with hearing loss and enlarged vestibular aqueduct, which may facilitate genetic counseling and prenatal diagnosis for such families.

Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing.

UNLABELLED: The stria vascularis is a nonsensory structure that is essential for auditory hair cell function by maintaining potassium concentration of the scala media. During mouse embryonic development, a subpopulation of neural crest cell-derived melanocytes migrates and incorporates into a subregion of the cochlear epithelium, forming the intermediate cell layer of the stria vascularis. The relation of this developmental process to stria vascularis function is currently unknown. In characterizing the molecular differentiation of developing peripheral auditory structures, we discovered that hepatocyte growth factor (Hgf) is expressed in the future stria vascularis of the cochlear epithelium. Its receptor tyrosine kinase, c-Met, is expressed in the cochlear epithelium and melanocyte-derived intermediate cells in the stria vascularis. Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling. In addition, inactivation of either the ligand or receptor developmentally resulted in a profound hearing loss at young adult stages. These results suggest a novel connection between HGF signaling and deafness via melanocyte deficiencies. SIGNIFICANCE STATEMENT: We found the roles of hepatocyte growth factor (HGF) signaling in stria vascularis development for the first time and that lack of HGF signaling in the inner ear leads to profound hearing loss in the mouse. Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and DFNB97. Our findings reveal an additional example of context-dependent c-MET signaling diversity, required here for proper cellular invasion developmentally that is essential for specific aspects of auditory-related organogenesis.

Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates.

The stereotyped arrangement of cochlear sensory and supporting cells is critical for auditory function. Our previous studies showed that Muenke syndrome model mice (Fgfr3P244R/+) have hearing loss associated with a supporting cell fate transformation of two Deiters' cells to two pillar cells. We investigated the developmental origins of this transformation and found that two prospective Deiters' cells switch to an outer pillar cell-like fate sequentially between embryonic day 17.5 (E17.5) and postnatal day 3 (P3). Unexpectedly, the Fgfr3P244R/+ hearing loss and supporting cell fate transformation are not rescued by genetically reducing fibroblast growth factor 8 (FGF8), the FGF receptor 3c (FGFR3c) ligand required for pillar cell differentiation. Rather, reducing FGF10, which normally activates FGFR2b or FGFR1b, is sufficient for rescue of cochlear form and function. Accordingly, we found that the P244R mutation changes the specificity of FGFR3b and FGFR3c such that both acquire responsiveness to FGF10. Moreover, Fgf10 heterozygosity does not block the Fgfr3P244R/+ supporting cell fate transformation but instead allows a gradual reversion of fate-switched cells toward the normal phenotype between P5 and at least P14. This study indicates that Deiters' and pillar cells can reversibly switch fates in an FGF-dependent manner over a prolonged period of time. This property might be exploited for the regulation of sensory cell regeneration from support cells.

Risk of cytomegalovirus-associated sequelae in relation to time of infection and findings on prenatal imaging.

OBJECTIVE: To determine the outcome of pregnancies with documented fetal cytomegalovirus (CMV) infection with and without abnormal findings on ultrasound examination and magnetic resonance imaging (MRI). METHODS: In this prospective cohort study of pregnant women with documented fetal CMV infection, vertical CMV transmission occurred during the first and second trimesters following primary maternal infection. Patients underwent serial prenatal ultrasound scans and fetal MRI. All neonates underwent ocular fundus examination, ultrasound brain scan and hearing evaluation, and were then followed periodically by a pediatrician. RESULTS: Primary CMV infection occurred during the first and second trimesters of pregnancy in 71 and 74 patients, respectively. Seven patients (4.8%) decided to terminate pregnancy because of prenatal findings and one neonate died because of CMV complications. Patients with first-trimester infection had infants with significantly more associated sequelae (either auditory damage or neurodevelopmental disabilities) than did patients with second-trimester infection (19.7% vs 5.6%, respectively; P = 0.01). Abnormal prenatal findings on ultrasound examination were associated with increased risk of sequelae. When both ultrasound and MRI findings were normal, the rate of sequelae was decreased to 15.6% for first-trimester infections and to 2.0% for second-trimester infections, partial hearing loss being the sequela in most cases. In the presence of abnormal ultrasound and/or MRI findings the risk was 25% and 16%, respectively, and in most cases the sequelae were deafness and neurodevelopmental delay. The rate of intrauterine growth restriction (IUGR) in the study group was 11.7% and was not affected by the time of onset of maternal infection. Isolated IUGR was not associated with increased risk of sequelae. CONCLUSION: The risk of sequelae is higher following first-than second-trimester CMV infection. However, the risk of severe sequelae is significantly reduced in the presence of normal prenatal ultrasound and MRI findings.

Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28.

Congenital and progressive hearing impairment is a common distressing disease. The progressive dominant hearing loss DFNA28 in human is associated with a frameshift mutation of Grainyhead-like 2 (GRHL2) but its etiology and mechanism remain unknown. Here we report a zebrafish grhl2b(T086) mutant line in which grhl2b expression is interrupted by an insertion of a Tol2 transposon element. The mutants exhibit enlarged otocysts, smaller or eliminated otoliths, malformed semicircular canals, insensitiveness to sound stimulation and imbalanced swimming motion. Since grainyhead-like family members can regulate epithelial adhesion, we examined the expression of some genes encoding junction proteins in mutants. We show that the expression of claudin b (cldnb) and epcam is abolished or dramatically reduced and apical junctional complexes are abnormal in otic epithelial cells of mutant embryos. Co-injection of cldnb and epcam mRNA could largely rescue the mutant phenotype. Injection of human wild-type GRHL2 mRNA but not the mutant GRHL2 mRNA derived from DFNA28 patients into grhl2b(T086) mutant embryos could rescue the inner-ear defects. Furthermore, we demonstrate that Grhl2b directly binds to the enhancers and promotes the expression of cldnb and epcam. Thus, this work reveals an evolutionarily conserved function of Grhl2 in otic development and provides a fish model for further studying mechanisms of Grhl2-related hearing loss.

Infant neurodevelopment following fetal growth restriction: relationship with antepartum surveillance parameters.

OBJECTIVES: To evaluate the relationship between fetal Doppler parameters, biophysical profile score (BPP) and neurodevelopmental delay at 2 years of corrected age in infants who had been growth-restricted in utero. METHODS: This was a prospective observational study including 113 pregnancies complicated by intrauterine growth restriction (IUGR) (abdominal circumference<5th percentile and elevated umbilical artery (UA) pulsatility index). The relationships of UA, middle cerebral artery and ductus venosus (DV) Doppler features, BPP, birth acidemia (artery pH<7.0+/or base deficit>12), gestational age at delivery, birth weight and neonatal morbidity (i.e. bronchopulmonary dysplasia, >Grade 2 intraventricular hemorrhage, or necrotizing enterocolitis) with a 2-year neurodevelopmental delay were evaluated. Best Beginnings Developmental Screen, Bayley Scale of Infant Development II (BSID) and Clinical Adaptive/Clinical Linguistic Auditory Milestone Stage were used. BSID<70, cerebral palsy, abnormal tone, hearing loss and/or blindness defined neurodevelopmental delay. RESULTS: Seventy-two of the 113 pregnancies completed assessment; there were 10 stillbirths, 19 neonatal deaths, three infant deaths and nine pregnancies with no follow-up. Twenty fetuses (27.8%) had UA reversed end-diastolic velocity (REDV), 34 (47.2%) abnormal DV Doppler features and 31 (43.1%) an abnormal BPP. Median gestational age at delivery and birth weight were 30.4 weeks and 933 g, respectively. Twelve infants had acidemia and 28 neonatal morbidity. There were 38 (52.8%) infants with neurodevelopmental delay, including 37 (51.4%) with abnormal tone, 20 (27.8%) with speech delay, 23 (31.9%) with an abnormal neurological examination, eight (11.1%) with a hearing deficit and six (8.3%) with cerebral palsy. Gestational age at delivery was associated with cerebral palsy (r2=0.52, P<0.0001; 92% sensitivity and 83% specificity for delivery at <27 weeks). UA-REDV was associated with global delay (r2=0.31, P=0.006) and birth weight with neurodevelopmental delay (r2=0.54, P<0.0001; 82% sensitivity and 64% specificity for BW<922 g). CONCLUSIONS: Although UA-REDV is an independent contributor to poor neurodevelopment in IUGR no such effect could be demonstrated for abnormal venous Doppler findings or BPP. Gestational age and birth weight remain the predominant factors for poor neurodevelopment in growth-restricted infants.

The role of Six1 in mammalian auditory system development.

The homeobox Six genes, homologues to Drosophila sine oculis (so) gene, are expressed in multiple organs during mammalian development. However, their roles during auditory system development have not been studied. We report that Six1 is required for mouse auditory system development. During inner ear development, Six1 expression was first detected in the ventral region of the otic pit and later is restricted to the middle and ventral otic vesicle within which, respectively, the vestibular and auditory epithelia form. By contrast, Six1 expression is excluded from the dorsal otic vesicle within which the semicircular canals form. Six1 is also expressed in the vestibuloacoustic ganglion. At E15.5, Six1 is expressed in all sensory epithelia of the inner ear. Using recently generated Six1 mutant mice, we found that all Six1(+/-) mice showed some degree of hearing loss because of a failure of sound transmission in the middle ear. By contrast, Six1(-/-) mice displayed malformations of the auditory system involving the outer, middle and inner ears. The inner ear development in Six1(-/-) embryos arrested at the otic vesicle stage and all components of the inner ear failed to form due to increased cell death and reduced cell proliferation in the otic epithelium. Because we previously reported that Six1 expression in the otic vesicle is Eya1 dependent, we first clarified that Eya1 expression was unaffected in Six1(-/-) otic vesicle, further demonstrating that the Drosophila Eya-Six regulatory cassette is evolutionarily conserved during mammalian inner ear development. We also analyzed several other otic markers and found that the expression of Pax2 and Pax8 was unaffected in Six1(-/-) otic vesicle. By contrast, Six1 is required for the activation of Fgf3 expression and the maintenance of Fgf10 and Bmp4 expression in the otic vesicle. Furthermore, loss of Six1 function alters the expression pattern of Nkx5.1 and Gata3, indicating that Six1 is required for regional specification of the otic vesicle. Finally, our data suggest that the interaction between Eya1 and Six1 is crucial for the morphogenesis of the cochlea and the posterior ampulla during inner ear development. These analyses establish a role for Six1 in early growth and patterning of the otic vesicle.