Hearing Loss in Stickler Syndrome: An Update.

Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory manifestations. Its main symptoms are high myopia, retinal detachment, joint hypermobility, early osteoarthritis, cleft palate, midfacial hypoplasia, micrognathia and hearing loss. Large phenotypical variability is apparent and partly explained by the underlying genetic heterogeneity, including collagen genes (COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, COL9A3) and non-collagen genes (BMP4, LRP2, LOXL3). The most frequent type of Stickler syndrome (COL2A1) is characterized by a rather mild high-frequency sensorineural hearing loss in about half of the patients. COL11A1- and COL11A2-related Stickler syndrome results in more frequent hearing loss, being moderate and involving all frequencies. Hearing loss in the rarer types of Stickler syndrome depends on the gene expression in the cochlea, with moderate to severe downsloping hearing loss for Stickler syndrome caused by biallelic type IX collagen gene mutations and none or mild hearing loss for the non-collagen genes. Inherent to the orofacial manifestations, middle ear problems and temporary conductive hearing loss, especially at young age, are also prevalent. Consequently, hearing loss should be actively sought for and adequately treated in Stickler syndrome patients given its high prevalence and the concomitant visual impairment in most patients.

Twelve years of neonatal hearing screening: audiological and etiological results.

PURPOSE: Most developed countries have implemented some form of universal newborn hearing screening program. Early identification and rehabilitation of congenital hearing loss is important in functional outcome, and the need to identify the cause of hearing impairment has become clear. We aimed to evaluate audiological and etiological outcomes in a large group of patients with failed neonatal hearing screening. METHODS: We performed a retrospective chart analysis of patients who were referred to our tertiary referral center after failing neonatal hearing screening during a 12-year period (2007-2019). Screening was based on automated auditory brainstem response (AABR) or a combined approach of AABR and auditory steady-state response (ASSR) with chirp stimulus. Extensive audiometric testing was performed to confirm and determine the type and degree of hearing loss. In case of permanent hearing loss, a standardized etiological protocol was followed to determine the cause. RESULTS: Of the 802 referred newborns, hearing loss was confirmed by diagnostic ABR in 78%. Main causes of hearing loss included otitis media with effusion (56%, higher in patients screened by AABR/ASSR compared to AABR), a genetic disorder (12%), congenital cytomegalovirus infection (cCMV, 5%) and atresia/stenosis of the external ear canal (5%). Of the patients with permanent hearing loss, 15% showed changes in hearing loss severity over time. CONCLUSION: In the majority of newborns referred after failing universal neonatal hearing screening, hearing loss could be confirmed. The leading cause was reversible hearing loss due to otitis media with effusion, but hearing loss proved permanent in about 35% of referred newborns, with genetics as predominant cause. Follow-up of congenital hearing loss patients is important as deterioration as well as improvement was observed over time.

Congenital Unilateral Hearing Loss: Characteristics and Etiological Analysis in 121 Patients.

OBJECTIVE: To describe the characteristics and etiological analysis in patients with congenital unilateral hearing loss. STUDY DESIGN: Retrospective cohort analysis. SETTING: Tertiary referral center. PATIENTS: Children with permanent congenital unilateral hearing loss born between 2007 and 2018. Patients were referred after universal newborn hearing screening or by a colleague to confirm the diagnosis and perform etiological examinations. MAIN OUTCOME MEASURES: Hearing loss type, severity, and evolution linked with the results of etiological testing. RESULTS: In the 121 included children, aural atresia is the leading cause of congenital unilateral hearing loss (32%), followed by structural anomalies (19%) and cCMV (13%), whereas 24% remained idiopathic after etiological work-up. Severity is mainly moderately severe (33% with 56-70 dB hearing loss, majority aural atresia) or profound (31% with > 90 dB hearing loss, predominantly cochlear nerve deficiency). Syndromic features were present in 26%. Although discussed with all parents, only 26% of the children regularly used hearing amplification. CONCLUSIONS: Congenital conductive unilateral hearing loss is mainly caused by aural atresia, which proportion in congenital unilateral hearing loss proved higher than previously reported. Cochlear nerve deficiency and cCMV are the predominant etiologies of congenital unilateral sensorineural hearing loss. Etiological work-up in affected patients is mandatory as it might impact the approach, and syndromic features should be actively searched for.

Otological manifestations in branchiootorenal spectrum disorder: A systematic review and meta-analysis.

Branchiootorenal spectrum disorder (BORSD) is a group of rare autosomal dominant entities characterized by branchiogenic malformations, hearing loss (HL) and renal anomalies. It comprises branchiootorenal syndrome and branchiootic syndrome, distinguished by the presence or absence of renal abnormalities. Pathogenic variants have been discovered in the following genes: EYA1, SIX5, SIX1 and SALL1. As the otological phenotype in BORSD is inconsistently reported, we performed a systematic review to provide an up-to-date overview, correlated with the genotype. Forty publications were included, describing 295 individual patients. HL was diagnosed in 95%, usually bilateral and mixed-type, and differed among the different genes involved. Mixed moderate-to-severe HL was the predominant finding in patients with EYA1 involvement, regardless of the presence of renal abnormalities. The sensorineural HL of profound severity was more prevalent in patients with SIX1 mutations. No significant differences among different mutation types or location within the genes could be observed. Structural otological manifestations, ranging from periauricular to inner ear anomalies, were common in both genes. Especially periauricular anomalies were more common and more severe in EYA1. In summary, otological differences among the different genes involved in BORSD are observed, so the molecular analysis is strongly advised.

Cephalometrics in Stickler syndrome: Objectification of the typical facial appearance.

INTRODUCTION: Stickler syndrome is a connective tissue disorder characterized by orofacial, ocular, skeletal and auditory symptoms. The orofacial phenotype mainly consists of midfacial hypoplasia, micrognathia and cleft palate. Large phenotypic variability is evident though. Few studies have tried to substantiate the typical facial appearance in Stickler syndrome patients. METHODS: Molecularly confirmed Stickler patients were invited to undergo cephalometric analysis based on a lateral radiograph in standardized conditions. Angular and linear measurements were performed according to Steiner's and Sassouni's analysis and compared with age- and gender-matched reference values. RESULTS: Thirteen patients aged 10-62y were included, twelve of whom had type 1 Stickler syndrome (COL2A1 mutation) and one type 2 Stickler syndrome (COL11A1 mutation). The position of maxilla and mandible relative to the cranial base was not significantly different from the reference population (S-N-A: p = 0.73, S-N-B: p = 0.43). The mandibular plane and y-axis showed an elevated angle with the cranial base in most patients, although not significant for the total group (S-N to Go-Me: p = 0.20, S-N to S-Gn: p = 0.18). Dental analysis was normal, except for a higher overjet value (p = 0.006) and a higher angle between occlusal plane and Frankfort plane (p = 0.022). CONCLUSION: Cephalometric analysis was not able to thoroughly prove the abnormal facial appearance in Stickler syndrome. The majority of patients had normal dentofacial proportions. The most frequently observed anomaly in our series is a rather short and posteriorly rotated mandible, but clinical variability is high.

Auditory phenotype in Stickler syndrome: results of audiometric analysis in 20 patients.

Hearing loss in Stickler syndrome has received little attention due to the often more disabling ocular, orofacial and skeletal manifestations. Estimates suggest a global prevalence of sensorineural hearing loss (SNHL) ranging from 50 % to about 100 % though, depending on the underlying Stickler genotype. By performing extensive audiometric analysis in Stickler patients, we aimed to further elucidate the auditory phenotype. Twenty molecularly confirmed Stickler patients (age 10-62 year), of whom sixteen with type 1 Stickler syndrome (COL2A1 mutation) and four with type 2 Stickler syndrome (COL11A1 mutation) underwent an otological questionnaire, clinical examination, pure tone and speech audiometry, tympanometry and otoacoustic emission testing. Cross-sectional and longitudinal regression analysis of the audiograms was performed to assess progression. In type 1 Stickler syndrome, 75 % demonstrated hearing loss, predominantly in the high frequencies. No significant progression beyond presbyacusis was observed. All type 2 Stickler patients exhibited mild-to-moderate low- and mid-frequency SNHL and moderate-to-severe high-frequency SNHL. In both types, hearing loss was observed in childhood. Otoacoustic emissions were only detectable in 7/40 ears and had very low amplitudes, even in frequency bands with normal hearing on pure tone audiometry. Type 1 Stickler syndrome is characterized by a mild high-frequency SNHL, emerging in childhood and non-progressive. Absent otoacoustic emissions are a frequent finding. Patients with type 2 Stickler syndrome exhibit early-onset moderate SNHL affecting all frequencies with a sloping audiogram. Taking into account the visual impairment in many patients, we recommend regular auditory follow-up in patients with Stickler syndrome, especially in childhood.

Etiological approach in patients with unidentified hearing loss.

OBJECTIVES: Etiological diagnosis of hearing impairment is of great importance to ensure early and adequate management. Even after thorough history taking, clinical and audiometric evaluation, the cause of hearing loss remains unclear in a majority of patients. Further examinations can imply imaging, ophthalmologic investigations, laboratory tests, electrocardiography and genetic testing. Lately, the latter has taken an increasingly prominent place within this diagnostic work-up. However, clear guidelines about optimal implementation and sequence of these tests are required. METHODS: Records of patients who visited the consultation for otogenetics at Ghent University Hospital (Belgium) during the period 2006-2012 were retrospectively reviewed. In order to optimize the etiological-diagnostic work-up of unidentified hearing loss, application patterns and results of various diagnostic tests, audiometric and etiological data of each patient were collected and analyzed. RESULTS: Data of 191 patients were analyzed. In 81.2% of the patients, a cause of hearing loss could be determined or suspected. In total, 65.4% had a (presumably) genetic etiology, with connexin 26 (GJB2) mutations as the leading cause. Inquiry of risk factors, associated with congenital hearing loss, and pedigree analysis were found to have the highest diagnostic gain (61.3% and 41.8%). Connexin 26 gene mutations were only present in bilateral hearing impairment, whereas CT abnormalities were related to unilateral (P=0.003), profound (P<0.001) hearing loss. An enlarged vestibular aqueduct was present in 42.9% of all CT abnormalities. Ophthalmologic anomalies were detected in 35.7% of the studied patients. CONCLUSIONS: A sequential approach for the etiological diagnosis of unidentified hearing loss could determine or suggest a cause in more than 80% of patients. The approach may vary based on the presenting phenotype.

Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing.

INTRODUCTION: Stickler syndrome is caused by mutations in genes encoding type II and type XI collagens. About 85% of the pathogenic variants is found in COL2A1 (Stickler type 1), whereas a minority of mutations has been reported in COL11A1 (Stickler type 2) and COL11A2 (Stickler type 3). Beside the typical skeletal and orofacial manifestations, ocular anomalies are predominantly present in type 1 and type 2, while hearing loss is more pronounced in type 2 and type 3. METHODS: We performed COL11A1 mutation analysis for 40 type 2 Stickler patients and COL11A2 mutation analysis for five type 3 Stickler patients, previously all COL2A1 mutation-negative, using targeted next-generation sequencing (NGS) whereas whole-exome sequencing (WES) was performed in parallel for two patients. Three patients were analyzed for both genes due to unclear ocular findings. RESULTS: In total 14 COL11A1 and two COL11A2 mutations could be identified, seven of which are novel. Splice site alterations are the most frequent mutation type, followed by glycine substitutions. In addition, six variants of unknown significance (VUS) have been found. Identical mutations and variants were identified with both NGS techniques. CONCLUSION: We expand the mutation spectrum of COL11A1 and COL11A2 in Stickler syndrome patients and show that targeted NGS is an efficient and cost-effective molecular tool in the genetic diagnosis of Stickler syndrome, whereas the more standardized WES might be an alternative approach.

Hearing impairment in Stickler syndrome: a systematic review.

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.