Osteogenesis imperfecta: the audiological phenotype lacks correlation with the genotype

Freya Kr Swinnen,Els Mr De Leenheer,Patrizia D'Eufemia,Ton Jtm Garretsen,Anne M De Paepe,Filomena V Gentile,Cor Wrj Cremers,Ingeborg Jm Dhooge,Paul J Coucke,Luca Sangiorgi,Fransiska Malfait,Mauro Celli,Sofie Symoens

doi:10.1186/1750-1172-6-88

Abstract

BackgroundOsteogenesis Imperfecta (OI) is a heritable connective tissue disorder mainly caused by mutations in the genes COL1A1 and COL1A2 and is associated with hearing loss in approximately half of the cases. The hearing impairment usually starts between the second and fourth decade of life as a conductive hearing loss, frequently evolving to mixed hearing loss thereafter. A minority of patients develop pure sensorineural hearing loss. The interindividual variability in the audiological characteristics of the hearing loss is unexplained.MethodsWith the purpose of evaluating inter- and intrafamilial variability, hearing was thorougly examined in 184 OI patients (type I: 154; type III: 4; type IV: 26), aged 3-89 years, with a mutation in either COL1A1 or COL1A2 and originating from 89 different families. Due to the adult onset of hearing loss in OI, correlations between the presence and/or characteristics of the hearing loss and the underlying mutation were investigated in a subsample of 114 OI patients from 64 different families who were older than 40 years of age or had developed hearing loss before the age of 40.ResultsHearing loss was diagnosed in 48.4% of the total sample of OI ears with increasing prevalence in the older age groups. The predominant type was a mixed hearing loss (27.5%). A minority presented a pure conductive (8.4%) or pure sensorineural (12.5%) loss. In the subsample of 114 OI subjects, no association was found between the nature of the mutation in COL1A1 or COL1A2 genes and the occurrence, type or severity of hearing loss. Relatives originating from the same family differed in audiological features, which may partially be attributed to their dissimilar age.ConclusionsOur study confirms that hearing loss in OI shows a strong intrafamilial variability. Additional modifications in other genes are assumed to be responsible for the expression of hearing loss in OI.

Highlights

Osteogenesis Imperfecta (OI) is a heritable connective tissue disorder mainly caused by mutations in the genes COL1A1 and COL1A2 and is associated with hearing loss in approximately half of the cases
Most authors agree that the majority of OI patients initially develop a conductive loss in the second to fourth decade of life which gradually progresses to a mixed hearing loss [13,14,15,16,17]
In this study among 184 Belgian, Dutch, and Italian OI patients, hearing loss presents in 53% of patients and the proportion of hearing-impaired patients rises with increasing age

Summary

Introduction

Osteogenesis Imperfecta (OI) is a heritable connective tissue disorder mainly caused by mutations in the genes COL1A1 and COL1A2 and is associated with hearing loss in approximately half of the cases. Glycine substitutions in the triple helical domain are the most common, but some splice site mutations leading to in-frame exon skips may induce structurally impaired type I collagen. This group of mutations has a negative dominant effect. The overall clinical outcome depends on the type of impairment of type I collagen synthesis (quantitative or qualitative), the mutated gene, the substituting amino acid, and the location of the mutation in the triple helical domain [2,3]. Genotype-phenotype correlation studies have not been straightforward and inter- and intrafamilial variability in clinical characteristics partially remain unresolved [4]

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