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.

Figure 1

PRISMA flow diagram, showing the overview of the search process. Schematic overview of the various steps involved in the search process, according to the PRISMA guidelines. We read 451 articles about Stickler syndrome, whose content, if relevant, could be included in the discussion. Data from 46 articles, meeting the inclusion criteria of the meta-analysis, are used to provide accurate prevalences about hearing loss in the results section of this article.

Figure 2

The prevalence and type of hearing loss in Stickler syndrome. The percentages of the 313 included Stickler patients without and with hearing loss are displayed. Of the hearing-impaired patients, a subdivision into conductive, mixed and sensorineural hearing loss is provided. The group of hearing-impaired patients in which the type was not mentioned (6.4% of the total population), was proportionally divided among the three hearing loss groups.

Figure 3

Prevalences of hearing phenotype in Stickler patients, divided into age groups. The percentages of hearing loss and its type for each age group can be derived from this diagram. The group of hearing-impaired patients in which the type was not mentioned (6.4%), was proportionally divided among the three hearing loss groups.

Figure 4

Hearing phenotype in distinct Stickler types. The percentages of hearing loss and its type for each type of Stickler syndrome (according to the affected gene) are shown in this figure. The group of hearing-impaired patients in which the type was not mentioned (6.4%), was proportionally divided among the three hearing loss groups.

Figure 5

Typical audiograms for Stickler syndrome in general, and for STL3 and STL4. A) ARTA for Stickler patients in general (without genetic subclassification), based on the detailed audiometric results in 44 patients [14]. Mean air conduction thresholds of both ears are shown. B) ARTA for type III Stickler syndrome, based on the detailed audiometric results in 18 STL3 patients (52 different measurements) [17,53]. Air conduction thresholds of the best ear are shown, unless in patients where an air-bone gap was present, in which bone conduction of the best ear is shown. C) Average audiogram for type IV Stickler syndrome, based on the detailed audiometric results in 7 STL4 patients (median age 15y) [8,41]. Air conduction thresholds of the best ear are shown.