Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Rome, ItalyItaly
Department of Otorhinolayngology, Audiology and Ophtalmology, Sapienza University of Rome, Rome, ItalyItaly
Also available as PDF (figures and tables appear in the PDF).
Introduction: Turner’s Syndrome (TS) is associated with hearing disorders in about 20 to 50% of affected individuals. The most common hearing disorders include congenital auricular mal-formations, recurrent otitis media and sensorineural hearing loss, although altered vestibular function and tinnitus have also been reported. Objectives: The aim of this paper is to provide an up-to-date overview of the principal findings and research perspectives about the association between TS and hearing disorders. Review: Middle ear disorders, found in a range between 21 and 91% of subjects, are a consequence of morphological cranio-facial alterations resulting in middle ear ventilation dysfunction. Sensorineural hearing loss follows 2 main audiological profiles: a bilateral symmetrical mid-frequency dip and a high frequency down-sloping curve. Although the pathophysiologic basis of sensorineural hearing loss in TS patients are still unclear, several hypothesis have been made so far and are reviewed in this paper. Conclusion: Literature confirms that hearing disorders, although not the most relevant clinical problem in these patients, have a high incidence in patients with TS and should therefore undergo early evaluation and monitoring over time.
Keywords: Turner’s Syndrome (TS); Hearing disorders; Hearing loss; Tinnitus
Turner’s Syndrome (TS), a common chromosomal condition with an estimated incidence of 1 per 2,000 women,1 is associated with hearing disorders in about 20 to 40% of affected individuals. TS, also known as 45,X, is caused by a complete or partial deletion of one of X chromosomes; affected subjects are characterized by short stature, typical dysmorphic features, cardiac abnormalities, gonadal dysgenesis, congenital lymphoedema, renal malformations, obesity, diabetes and other minor somatic anomalies described by the Turner’s Syndrome Association.2 Intelligence is usually within normal range, minor problems with non-verbal, social and psychomotor skills may be present.3
The most common hearing disorders found in patients with TS include congenital auricular malformations, recurrent otitis media and sensorineural hearing loss.4 Current studies available in the literature report an incidence of hearing loss in about 50% of patients with TS: 60% for sensorineural hearing loss, 25% for conductive hearing loss, and 15% for mixed 4-7
Conductive hearing loss may be a consequence of lymphatic hypoplasia, common in dimension, and causing inadequate ventilation of the middle ear. The most common alterations include cylindrical shape of the tympanic ostium of the tube, hypotonia of tensor veli palatini muscle and mastoid hypocellularity. This results in chronic ventilation dysfunction often followed by chronic otitis media sometimes associated to cholesteatoma.9
Sensorineural hearing loss (SNHL) in TS represents a relatively recent finding and seems to be independent from middle ear diseases; several hypothesis about the pathophysiologic basis have been made so far, but still remain unclear. The most common sensorineural audiological finding in TS patients consists in a bilateral symmetrical mid-frequency dip, mainly at 2 kHz, probably correlated to karyotype.10 In some patients, high frequency down-sloping SNHL can also be present. SNHL in TS patients can have an early onset, starting during the first decade of life or, most commonly, during the second and third decades, with a tendency to worsen over time. Studies have attributed the mid-frequency dip to cell cycle delay that is more evident in the middle turn of the cochlea where hair cells have the highest concentration per millimeter length of the organ of Corti. The early onset of the high-frequency hearing loss may instead be a consequence of a faster apoptotic process of hair cells in the basal turn. Estrogen deficiency could play an important role in
Acute otitis media Common Recurrent acute otitis media Common Otitis media with effusion Uncommon Cholesteatoma Rare Retraction pocket Common Perforation of the tympanic membrane Uncommon
Bilateral high frequencies hearing loss Common Bilateral mid frequencies hearing loss Common Profound hearing loss (>85 dBHL) Very Rare
Tinnitus Case Report Asymptomatic vestibular dysfunction Case Report
Table 1. Audiological findings reported in patients with Turner’s Syndrome with re- lated frequency.
these processes through its action on estrogen receptors in the 10,13 inner ear. It is also important to mention that different alterations of auditory brainstem responses (ABR) have been reported in TS, revealing possibly impaired cochlear nerve function to the level of brainstem.
Although several papers have been published about the association between Turner’s Syndrome and hearing disorders, some aspects, especially for patients with sensorineural hearing loss, are still debated and certainly need more clinical and basic research studies.14 The purpose of this review paper is to provide an up-to-date overview of the principal findings and research perspectives about such association.
Several studies have focused on the hearing function in patients with TS. From a literature research, 26 studies that focused on 11,12 hearing disorders in patients with TS have been found (Table 2). Studies have been published between 1988 and 2015, with an average of 0.89/year (Figure 1). The most relevant are reported in the following paragraph.
In 2003, Hultcrantz10 performed audiometric and karyotype exams in 325 women with TS, finding otitis media in 61% and SNHL in 80% of the individuals studied, most of them having the 45XO or 45XO/46Xi(Xq) karyotype. In 2005, Dhooge23 published a prospective study with a questionnaire and audiologic evaluation in 41 patients with TS (median age: 24 years), finding pure sensorineural hearing loss in one-third of the patients (38.8%) and pure conductive losses in one-fifth (21.3%). The remaining 60.1% had normal hearing. One year later, Morimoto24 studied 33 TS patients with age ranging between 8 and 40 years; 20 subjects showed high-frequency SNHL (60.1%) with a statistically significant correlation between hearing loss, age and body height (p<.001). Also, age-dependent hearing loss was more apparent in patients with monosomic 45,X kariotype than in those with the mosaic type. This was confirmed in a later study published in 2013 by Oliveira30 who reported a large prevalence of high frequency hearing loss in TS patients; those with a 45,X karyotype and isochromosomes with loss of the p-arm of the X chromosome had a greater risk of developing hearing loss than patients with mosaicism. Furthermore, the authors described a linear association between hearing loss and age in these patients. In 2008, Gawron25 studied 51 TS patients (median age: 14.3 years), reporting recurrent acute otitis media in 19.6% of subjects, conductive hearing loss in 11.7%, mixed hearing loss
Leheupet al 60 1988 Watkin et al 24 1989 Sculerati et al 22 1990 Hultcrantz et al 44 1994 Sculerati et al 24 1996 Hultcrantz et al 40 1997 Benazzo et al 62 1997 Stenberg et al 56 1998 Barrenas et al 115 1999 Barrenas et al 119 2000 Gungo R et al 38 2000 Serra et al 21 2003 Hultcrantz 325 2003 Beckam et al 113 2004 Ostberg et al 138 2004 Dhooge et al 41 2005 Morimoto et al 33 2006 Gawron et al 51 2008 Bergamaschi et al 153 2008 Parkin et al 23 2008 Hederstierna et al 69 2009 Verver et al 60 2011 Oliveira et al 52 2013 Ros et al 31 2014 Verver et al 65 2014 Bakhshaee et al 24 2015
Table 2. Previous studies reporting audiological findings in patients with Turner’s Syn- drome (literature review).
in 5.9% and a moderate sensorineural hearing loss in 18.6%. The authors also reported altered ABR in 52% of the patients revealing a possible retrocochlear involvement. In the same year, 23 26 a large study by Bergamaschi and colleagues26 was performed in 173 TS patients (median age: 12 years). Conductive hearing loss was found in 38.7% of patients: persistent secretory otitis media in 55.2%, chronic otitis media in 10.4%, pars flaccida retraction pocket in 19.4%, chronic otitis media with cholesteatoma in 15% of the subjects. Sensorineural hearing loss occurred in 15.6% of the subjects, mostly bilateral (93%) for both high (42%) and mid (58%) frequencies. In a different paper, Parkin and Walker27 focused on 23 children with TS (median age: 10.4 years), finding middle ear disease in 91% of subjects and SNHL in 9%. In 2009, Hederstierna28 conducted a longitudinal study of hearing decline in women with Turner syndrome, confirming that young and middle-aged women with TS have a progressive type of hearing impairment, deteriorating rapidly in adult age. The group of Verver of the Radboud University Nijmegen Medical Centre, Netherlands, published 2 studies on hearing function and TS. In the first, the authors studied a group of 60 children with TS and correlated their findings to karyotype, supporting the hypothesis that hearing can be affected by loss of the p-arm of the X-chromosome.29 In the second paper, published in 2014, the authors studied 65 TS patients finding a higher prevalence of
hearing disorders in patients with monosomy 45,X or isochromosome 46,X,i(Xq), thus confirming the results of their previous study.32 In the same year, Ros compared 31 adult patients with TS to 15 women with other congenital hypogonadims and 41 healthy age-matched women. Their findings confirmed that more than a half of TS females presented HL; SNHL was the most frequent pattern among middle-aged women with TS and old age, karyotype and recurrent otitis were predisposing factors to induce HL.31
In conclusion, literature confirms that hearing disorders, although not the most relevant clinical problem in these patients, have a high incidence in individuals with TS. They can be both conductive due to morphological alterations common to other conditions with similar cranio-facial alterations, and sensorineural with a chronic worsening trend over time. Also, sensorineural hearing loss may not be clinically noticeable in most cases, especially at its onset and during the first decades of life. Therefore, it is always recommended investigating the hearing function in TS patients with subjective and objective techniques including audiometry, otoacoustic emissions and auditory brainstem responses; both early hearing evaluation and monitoring over time are necessary. Because patients with TS can present with different manifestations affecting multiple systems, the otolaryngologist should be aware of TS and its association with hearing disorders. Further studies are required to better understand the pathophysiologic basis of SNHL in patients with TS, while an increased clinical attention to conductive hearing loss in the recent years has contributed to a substantial decrease in chronicization of hearing loss and its consequences.
The authors declare that they have no conflicts of interest.