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Hearing impairment in Stickler syndrome: a systematic review.

ABSTRACT: BACKGROUND: Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory defects. It is caused by mutations in different collagen genes, namely COL2A1, COL11A1 and COL11A2 (autosomal dominant inheritance), and COL9A1 and COL9A2 (autosomal recessive inheritance). The auditory phenotype in Stickler syndrome is inconsistently reported. Therefore we performed a systematic review of the literature to give an up-to-date overview of hearing loss in Stickler syndrome, and correlated it with the genotype. METHODS: English-language literature was reviewed through searches of PubMed and Web of Science, in order to find relevant articles describing auditory features in Stickler patients, along with genotype. Prevalences of hearing loss are calculated and correlated with the different affected genes and type of mutation. RESULTS: 313 patients (102 families) individually described in 46 articles were included. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Hearing impairment was predominantly sensorineural (67.8%). Conductive (14.1%) and mixed (18.1%) hearing loss was primarily found in young patients or patients with a palatal defect. Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%). CONCLUSIONS: Hearing impairment in patients with Stickler syndrome is common. Sensorineural hearing loss predominates, but also conductive hearing loss, especially in children and patients with a palatal defect, may occur. The distinct disease-causing collagen genes are associated with a different prevalence of hearing impairment, but still large phenotypic variation exists. Regular auditory follow-up is strongly advised, particularly because many Stickler patients are visually impaired.

SUBMITTER: Acke FR

PROVIDER: S-EPMC3551705 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Hearing impairment in Stickler syndrome: a systematic review.

Acke Frederic R E FR Dhooge Ingeborg J M IJ Malfait Fransiska F De Leenheer Els M R EM

Orphanet journal of rare diseases 20121030

<h4>Background</h4>Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory defects. It is caused by mutations in different collagen genes, namely COL2A1, COL11A1 and COL11A2 (autosomal dominant inheritance), and COL9A1 and COL9A2 (autosomal recessive inheritance). The auditory phenotype in Stickler syndrome is inconsistently reported. Therefore we performed a systematic review of the literature to give an up-to-date overview of hearing loss in ...[more]

PMID: 23110709

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Project description:Introduction: As the prevalence of age-related sensory impairment increases, more evidence emerges on the association between uni-sensory and cognitive impairment (CI) in older adults. However, the link between CI and concurrent hearing and vision impairment (referred to as dual sensory impairment/DSI) is not well-understood, and this combined effect may be additive or multiplicative. Moreover, the existing evidence on CI in older adults with DSI is scattered and limited. Through this systematic scoping review, we aim to map existing evidence on CI in older adults with DSI, and to summarize what is known about the prevalence, incidence and risk factors of CI, and tools used to screen or assess CI in older adults with DSI. Methods and Analysis: We will use the Joanna Briggs Institute framework to perform the review. Eleven databases [MEDLINE, CINAHL/EBSCO, EMBASE, Mednar, WorldWideScience, PsycEXTRA, OAIster, OpenGrey (SIGLE), Global Health, PsycINFO, and Web of Science] and clinical trial registries (ISRCTN Registry, WHO ICTRP, and ClinicalTrials.gov) will be searched. Study selection will be completed using Covidence, and data will be extracted using an a priori data extraction tool. To be included, studies had to be peer-reviewed, had older adults with DSI as the focal population, and are related to CI. Data will be presented using a narrative summary with emphasis on implications for future research and practice. Discussion: Reliable cognitive screening is of the utmost importance for prevention and treatment of CI within DSI population. The study findings will have significant implications for health services delivery and policy research. The summarized findings on the prevalence, incidence, associated risk factors, and CI screening and assessment tools will inform geriatric care. The review will also document knowledge gaps on CI in the DSI population and identify areas of interest for future studies. Ethics and Dissemination: The scoping study, being a review of existing documents, does not require ethics approval. The findings will be disseminated with relevant stakeholders using knowledge translation activities such as scientific presentations and publications. We intend to use the findings to conduct a Delphi study to evaluate which CI tools are suitable for older population with DSI.

Project description:Hearing impairment is a cardinal feature of Down syndrome (DS), but its clinical manifestations have been attributed to multiple factors. Murine models could provide mechanistic insights on various causes of hearing loss in DS. To investigate mechanisms of hearing loss in DS in the absence of the cadherin 23 mutation, we backcrossed our DS mice, Dp(16)1Yey, onto normal-hearing CBA/J mice and evaluated their auditory function. Body weights of wild type (WT) and DS mice were similar at 3-months of age, but at 9-months, WT weighed 30% more than DS mice. Distortion product otoacoustic emissions (DPOAE), a test of sensory outer hair cell (OHC) function negatively impacted by conductive hearing loss, were reduced in amplitude and sensitivity across all frequencies in DS mice. The middle ear space in DS mice appeared normal with no evidence of infection. MicroCT structural imaging of DS temporal bones revealed a smaller tympanic membrane diameter, oval window, and middle ear space and localized thickening of the bony otic capsule, but no gross abnormalities of the middle ear ossicles. Histological analysis of the cochlear and vestibular sensory epithelium revealed a normal density of cochlear and vestibular hair cells; however, the cochlear basal membrane was approximately 0.6 mm shorter in DS than WT mice so that the total number of hair cells was greater in WT than DS mice. In DS mice, the early and late peaks in the auditory brainstem response (ABR), reflecting neural responses from the cochlear auditory nerve followed by subsequent neural centers in the brainstem, were reduced in amplitude and ABR thresholds were elevated to a similar degree across all frequencies, consistent with a conductive hearing impairment. The latency of the peaks in the ABR waveform were longer in DS than WT mice when compared at the same intensity; however, the latency delays disappeared when the data were compared at the same intensity above thresholds to compensate for the conductive hearing loss. Future studies using wideband tympanometry and absorbance together with detailed histological analysis of the middle ear could illuminate the nature of the conductive hearing impairment in DS mice.

Project description:BackgroundType 2 Stickler syndrome is usually a dominant disorder resulting from pathogenic variants in COL11A1 encoding the alpha 1 chain of type XI collagen. Typical molecular changes result in either substitution of an obligate glycine within the Gly-Xaa-Yaa amino acid sequence repeat region of the molecule, mRNA missplicing or deletions/duplications that typically leaves the message in-frame. Clinical features include myopia, retinal detachment, craniofacial, joint, and hearing problems. Fibrochondrogenesis is also a COL11A1 related disorder, but here disease-associated variants are recessive and may be either null alleles or substitutions of glycine, and the condition is usually lethal in infancy.MethodsThe patient was assessed in the NHS England Stickler syndrome diagnostic service. DNA from the patient and family were analyzed with Next Generation Sequencing on a panel of genes known to cause Stickler Syndrome. The effect of sequence variants was assessed using minigene analysis. Allele-specific RT-PCR was performed.ResultsThis patient had clinical type 2 Stickler syndrome but with severe hearing loss and severe ocular features including retinal atrophy and retinal tears in childhood. We identified a de novo in frame deletion of COL11A1 (c.4109_4126del) consistent with dominantly inherited Stickler syndrome but also a second inherited variant (c.1245+2T>C), on the other allele, affecting normal splicing of COL11A1 exon 9.ConclusionExon 9 of COL11A1 is alternatively expressed and disease causing changes affecting only this exon modify the phenotype resulting from biallelic COL11A1 disease-associated variants and, instead of fibrochondrogenesis, produce a form of Stickler syndrome with severe hearing loss. Disease phenotypes from de novo pathogenic variants can be modified by inherited recessive variants on the other allele. This highlights the need for functional and family analysis to confirm the mode of inheritance in COL11A1-related disorders, particularly for those variants that may alter normal pre-mRNA splicing.

Project description:Mutations in connexins are the most common causes of hearing impairment (HI) in many populations. Our aim was to review the global burden of pathogenic and likely pathogenic (PLP) variants in connexin genes associated with HI. We conducted a systematic review of the literature based on targeted inclusion/exclusion criteria of publications from 1997 to 2020. The databases used were PubMed, Scopus, Africa-Wide Information, and Web of Science. The protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews, with the registration number "CRD42020169697". The data extracted were analyzed using Microsoft Excel and SPSS version 25 (IBM, Armonk, New York, United States). A total of 571 independent studies were retrieved and considered for data extraction with the majority of studies (47.8% (n = 289)) done in Asia. Targeted sequencing was found to be the most common technique used in investigating connexin gene mutations. We identified seven connexin genes that were associated with HI, and GJB2 (520/571 publications) was the most studied among the seven. Excluding PLP in GJB2, GJB6, and GJA1 the other connexin gene variants (thus GJB3, GJB4, GJC3, and GJC1 variants) had conflicting association with HI. Biallelic GJB2 PLP variants were the most common and widespread variants associated with non-syndromic hearing impairment (NSHI) in different global populations but absent in most African populations. The most common GJB2 alleles found to be predominant in specific populations include; p.Gly12ValfsTer2 in Europeans, North Africans, Brazilians, and Americans; p.V37I and p.L79Cfs in Asians; p.W24X in Indians; p.L56Rfs in Americans; and the founder mutation p.R143W in Africans from Ghana, or with putative Ghanaian ancestry. The present review suggests that only GJB2 and GJB3 are recognized and validated HI genes. The findings call for an extensive investigation of the other connexin genes in many populations to elucidate their contributions to HI, in order to improve gene-disease pair curations, globally.

Dataset Information

Hearing impairment in Stickler syndrome: a systematic review.

Publications

Hearing impairment in Stickler syndrome: a systematic review.

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