Ear and hearing in relation to genotype and growth in Turner syndrome

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Abstract

Hearing loss, auricular anomalies and middle ear infections are common findings in many genetic disorders, but the mechanisms have remained unknown. We studied ear and hearing problems in Turner’s syndrome (TS) in relation to the degree of X chromosome loss (i.e. degree of mosaicism) and growth. One hundred and nineteen girls and women with TS were studied regarding audiometry, fluorescent in situ hybridisation, serum concentration of insulin-like growth factor-1 (IGF-1) and body height. It was found that sensorineural hearing loss and occurrence of auricular anomalies were significantly increased the greater the proportion of 45,X cells in a particular individual (P<0.05 and P<0.001, respectively). Middle ear infections and sensorineural hearing loss were negatively correlated with IGF-1 (P<0.05 and P<0.001, respectively). Hearing correlated positively with height (P<0.01) and IGF-1 independently of age (P<0.05). Height correlated positively with IGF-1 (P<0.001). Auricular malformations, middle ear infections and hearing impairment in TS were interpreted as due to growth disturbances during development. A new hypothesis on the pathophysiology of external, middle and inner ear disorders due to a delayed cell cycle caused by chromosomal aberrations per se and not only to the specific X chromosome deletion is presented.

Introduction

Turner syndrome (TS) is caused by a total or partial deletion of either X chromosome and occurs in one out of 2000–3000 liveborn girls (Gravholt et al., 1996). Genetically, the karyotypes in TS are divided into three main categories: (1) monosomy 45,X, having one X chromosome only in all cells, (2) those having 46 chromosomes in all cells but with a part of the sex chromosome deleted (46,XXdel or 46,XYdel) and (3) those having a mosaicism of cells with a varying number of sex chromosomes, as some cells may have a normal set of 46 chromosomes while others are monosomic 45,X. A reduced receptor sensitivity to growth hormone is one important mechanism in TS, the main characteristics of which are short stature, failure to enter puberty and an accelerated rate of atresia of ovarian follicles causing gonadal insufficiency and infertility. Auricular malformations, otitis media and sensorineural hearing loss are common (Watkin, 1989). It has repeatedly been suggested that the ear and hearing disorders in TS are due to the lack of genes on the X chromosome. It was recently verified that TS females with monosomy 45,X exhibited more severe hearing loss and a higher occurrence of auricular anomalies and recurrent otitis media than TS cases with mosaicism and structural deletions (Barrenäs et al., 1999). Interestingly, both recurrent acute and/or secretory otitis media (the major ear and hearing problem among children) and presbycusis (the major hearing problem among the elderly) occur more frequently in men (46,XY) than in women (46,XX) (Stenström and Ingvarsson, 1994, Jönsson et al., 1998).

The main objective of this study was to correlate ear and hearing dysfunctions in TS with the degree of mosaicism of 45,X cells. It has recently been suggested that all TS subjects are mosaicism cases (Fernandez et al., 1996, Leonova and Hanson, 1999). Since short stature is a main clinical finding in TS, an additional aim was to investigate the association between growth and hearing. The aim was also to present a hypothesis explaining why short stature and ear and hearing problems are often combined in chromosomal disorders.

Section snippets

Subjects

This study comprises 119 girls and women with TS from western Sweden (age range: 4–73 years), who participated in a national multidisciplinary research programme, aimed at establishing an optimum treatment and overall care recommendations for individuals with TS in Sweden. The subjects were recruited from the Turner Syndrome Society by an advertisement in the society’s newsletter and by referral from the hospitals. The subjects were examined by different specialists. The occurrence of auricular

Results

Descriptive audiologic data regarding ear problems, hearing function and chromosomal aberration according to degree of mosaicism (severe or moderate/slight) are presented in Table 1. The degree of mosaicism varied between 2 and 100% (median=96%). Among the severe cases (proportion of 45,X cells≥96%), auricular anomalies (such as low-set auricles, narrowing of the external auditory canal, cupped auricles and abnormally protruding ears), occurred somewhat more frequently and hearing loss was

Discussion

This study showed that ear and hearing disorders in TS were related to genotype, serum concentrations of IGF-1 and height. The more severe the sensorineural hearing loss or the higher the prevalence of auricular anomalies, the higher the proportion of 45,X cells, i.e. the more severe the degree of mosaicism. Furthermore, with increasing age the proportion of 45,X cells in the buccal mucosa declined. Moreover, both middle ear infections and sensorineural hearing loss were related to low IGF-1

Acknowledgments

We thank Professors Lars Wilhelmsen, Kerstin Albertsson-Wikland, P.O. Jansson, Olle Isaksson, Inger Bryman and K.M. Holgers for fruitful discussions. The study was supported by grants from the Hjalmar Svensson Foundation and The Swedish Medical Research Council (11606).

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