1. Introduction
Turner Syndrome (TS) is one of the most common human chromosomal abnormalities and is a major cause of short stature and ovarian insufficiency in women, which is caused by partial or complete loss of the X chromosome. The most common karyotype of TS is 45, X, accounting for about 30 to 40% of all karyotypes, followed by mosaic patterns (45, X/46, XX), accounting for about 20–30%, and the rest are X chromosome abnormalities (1, 2). The incidence of TS in live born girls is about 1/2,000–1/2,500, and the incidence may vary in different countries and regions (3). In recent years, with the wide application of prenatal diagnosis technology, the age of diagnosis of TS has been advanced, but most TS patients are usually diagnosed in childhood or adolescence due to short stature or primary gonadal dysplasia, and the average age of diagnosis is 15 years old (3).
In addition to gonadal dysgenesis and short stature, with the increase of age, TS is often accompanied by a variety of complications, such as cardiovascular disease, autoimmune disease, metabolic disease, osteoporosis, and neurocognitive deficits (4). Hearing loss (HL) is one of the main medical problems for girls and women with TS and has a negative impact on the health and quality of life for these patients. A previous study demonstrated that only 48% of Swedish women aged 25 to 38 with TS had normal hearing, while 45% had mild HL and 7% had moderate or severe HL (5). On average, the hearing threshold of TS women is equivalent to the hearing threshold of women in the general population 20 years older than their actual age (5). The specific etiology of HL caused by TS has not been extensively studied, it may be the influence of estrogen, chromosome and gene abnormalities, or their combination (6, 7). Due to ovarian hypoplasia, TS patients have little or no endogenous estrogen production, and estrogen has a certain protective effect on hearing (8, 9). In addition, some genes on the short arm of the X chromosome may have a regulatory effect on hearing function, and their deletion may cause abnormal craniofacial development and auricle abnormalities, which may be related to the prolonged cell cycle caused by chromosomal abnormalities (7, 10). Some patients with TS may have abnormalities of the Eustachian tube and the skull base, repeated occurrence of otitis media, middle ear effusion, and cholesteatoma can lead to middle ear destruction and progressive HL (7, 11).
TS patients often also have endocrine abnormalities, metabolic disease and abnormal bone metabolism. Studies have shown that low bone mineral density (BMD), thyroid dysfunction and metabolic syndrome are risk factors for HL (12–17), and timely supplementation of thyroid hormone or lowering of blood lipids can improve hearing. However, it is not known if this association also exists in women with TS.
At present, the treatment of TS is mainly growth-promoting therapy, inducing and maintaining the development of secondary sexual characteristics, preventing and curing osteoporosis. Less attention has been paid to the ear health of TS patients, which delays optimal treatment time. Early diagnosis and proper management of associated hearing abnormalities are important to minimize the adverse effects on learning and social functions and improve quality of life. Here, we analyzed the incidence, types and risk factors of HL in TS patients in China, with an aim to improve the prevention and treatment of TS ear diseases and improve the quality of life of women living with TS.
4. Discussion
Due to complete or partial deletion of the X chromosome, patients with TS often have associated developmental abnormalities and malformations, and different cytogenetic changes can lead to clinical heterogeneity. In addition to gonadal dysgenesis and short stature, with the increase of age, TS women often encounter a variety of complications, such as cardiovascular disease, autoimmune disease, metabolic disease, osteoporosis, and neurocognitive deficits (4).
Hearing problems can occur at all ages in TS patients, and the incidence is higher than that of normal people (5, 20–22). The types of HL in TS patients included conductive hearing loss (CHL), sensorineural hearing loss (SNHL), and mixed hearing loss (MHL). The study found that the incidence of TS combined with HL varies greatly in different regions and populations. The occurrence of CHL is related to pharyngeal canal and craniofacial dysplasia (23). The incidence of CHL in TS patients is about 6–43%, and it is often secondary to chronic or recurrent otitis media (23–25), which is more common in childhood and adolescence, and continues to develop into adulthood (23). At present, the diagnostic criteria and definition of the intermediate frequency range of SNHL vary, and the incidence of SNHL varies greatly among different studies. Some scholars further distinguished mid-frequency hearing loss (MFHL) or high frequency hearing loss (HFHL) as distinct forms of HL. Chan et al. (26) stipulated that the intermediate frequency was between 1–2 k Hz, while Verver et al. (27) believed that the intermediate frequency was between 0.5–2 k Hz. Studies have found that the incidence of SNHL in women with TS is about 9–66%, often presenting as HFHL and/or MFHL. The pure tone audiometry shows a gradual descent and steep descent curve, which is similar to age-related HL, but the onset age is much younger and the progression rate is much faster (20). This progressive HL is more common in people with a history of recurrent ear infections in the early stage, and is usually associated with a defect in the outer helix hair cells in the middle and lower part of the cochlea, which is aggravated with age (28). MHL occurs in 3–13% of TS patients, and is more common in patients aged 30 years and above (10, 28). In this study, 46 TS patients aged 14–32 years were studied. The incidence of CHL was 2.2%, SNHL 17.4%, HFHL 13.0%, and MHL was not found, presenting with age-related HL. Compared with previous studies, the incidence of various types of HL in TS patients in this study was lower, which may be related to race, age composition ratio and small sample size. In addition, we did not compare HL levels with the normal population, however based on relevant reference ranges levels of HL were higher in our TS population.
Young and middle-aged women with TS often present with progressive HL, which intensifies rapidly in adulthood (20–22). HL is mainly composed of two causes: MFHL, which may be related to genetic factors; and age-related HFHL, which may be affected by estrogen deficiency (21). The incidence of HL in TS women was much higher than that in the general population. Regardless of initial age, hearing level, karyotype, or the presence or absence of MFHL, TS patients had a similar rate of de-cline as normal women aged 70–90 years, especially in the high-frequency region, with a decrease of 0.8–2.2 dB per year (21). High-frequency SNHL is common in TS patients (5, 29). Compared with chimeric TS patients, 45, X haplotype TS patients had a more significant age-dependent increase in high-frequency hearing threshold (29). Morimoto et al. (29) studied the hearing status of 33 female TS patients aged 8–40 years and found that more than 60% of TS patients suffered from high-frequency SNHL, and the incidence increased with age, and is usually associated with defect in the outer helix hair cells in the middle and lower part of the cochlea (30, 31). Animal experiments (32, 33) showed that “Turner mice” had ear and hearing problems similar to those of TS women, SNHL was usually accompanied by MFHL and early HFHL, and the loss of outer hair cells was obvious in the cochlear basal turn of Turner mice, and the expression of estrogen receptor in outer hair cells of the helical organ was weakened. These results suggest that estrogen and its receptor have protective effects on the development of cochlea. The results of our study also found that TS patients presented with age-related HL in middle and high frequency, and 45, X karyotypes were more common, indicating that HL was related to age and chromosome karyotype. Given the age related incidence of HL in TS patients we would recommend yearly follow up for these patients, in line with Chinese guidelines for people at high risk of HL.
Previous studies have observed that karyotype is related to the type and degree of HL in TS patients. It has been reported that those with a TS karyotype of 45, X are more likely to suffer from SNHL, compared to mosaicism or structural anomaly, patients with a monosomy 45, X or isochromosome (both have a total deletion of the short (p) arm of the X-chromosome) had more pronounced HL, which supports the hypothesis that hearing can be affected due to the loss of the X chromosome p arm, and the loss of different parts of the short arm of the X chromosome causes different phenotypes of HL (27, 33, 34). Barrenas et al. (35) found that the incidence of SNHL and auricular abnormalities increased significantly with the proportion of 45, X cells in TS individuals, suggesting that the disease was not only caused by specific X chromosome deletion, but also related to the cell cycle extension caused by chromosome aberration itself. Hearing is affected by dysfunctions of the outer, middle and inner ears caused by growth disorders during development. However, Bazilio et al. (28), Bois et al. (36) found that there was no statistically significant correlation between karyotype and the type or degree of HL. This study explored the relationship between chromosome karyotype and hearing in TS patients, and it was found that chromosome karyotype was unrelated to the type and degree of HL. Compared with other chromosome karyotypes (including chimeric type, abnormal chromosome structure type and body type with Y staining), hearing frequency of 45, X haplotypes increased at 1,000, 2,000, and 4,000 Hz. It suggests that the HL of TS may be related to the short arm deletion of X chromosome. In addition, our study found that audiology was normal in the 3 TS patients without deletion of SHOX gene, supporting the hypothesis that the absence of growth regulation genes, such as SHOX gene, may be associated with the occurrence of early HL, suggesting that karyotype or SHOX gene can be used as a predictor of hearing problems in TS.
Studies have shown that the incidence of HL with TS women is much higher than that in women of the same age, and age-related hearing impairment may be affected by estrogen deficiency (10, 21, 29). It has been observed that the incubation period of the auditory brainstem response (ABR) in women is shorter than that in men, but the incubation period and amplitude of postmenopausal women are the same as those of men of the same age (8). In addition, HL in women continues to decline after menopause, with hearing decline being more rapid after menopause than before (9). The difference of hearing level between males and females and the change of hearing level in perimenopausal women suggests a protective effect of estrogen on hearing. TS is a chromosome aberration caused by the deletion of all or part of the X chromosome. The main feature is ovarian hypoplasia, little or no endogenous estrogen production, often accompanied by ear and hearing problems. “Turner mice”, as a model of TS ear problems, showed otitis media and early HL, and the ABR of Turner mice showed progressive HL in high-frequency ranges, and was related to age (32, 33). Another study found that the hearing of female mice before menopause is better than that of male mice, but this advantage is weakened after menopause, which indicates that estrogen has certain effects on hearing (7, 37). However, in the current study there was no correlation between hearing loss and estrogen levels in TS patients. The reason for this is unclear but may relate to all patients receiving HRT. In addition, TS patients often display additional different non-sex chromosomal abnormalities that may affect hearing associated genes, although this association required further investigation.
TS patients often also present with endocrine abnormalities, metabolic diseases and abnormal bone metabolism. Approximately 30–50% of TS patients suffer from thyroiditis or hypothyroidism, 40–45% are positive for peroxidase antibodies, and have an increased risk for development of autoimmune diseases (38–40). Congenital and acquired hypothyroidism is a common cause of SNHL, mainly manifested by changes in audiological examinations such as brainstem auditory evoked potentials and hearing thresholds, these changes will occur after timely thyroid hormone replacement therapy (12). Animal models also found that reduced thyroid hormone secretion affects the development of the inner ear, leading to changes in the structure of the inner ear cochlea, which leads to SNHL (41–43). At present, there is no relevant research on the relationship between hearing level and thyroid function in patients with TS, and our data demonstrate no association between HL and thyroid function, further studies are needed to assess the relationship.
Metabolic syndrome is more common in TS, and it has been reported that about 50% of adolescents with TS have hypercholesterolemia (4, 44). Previous studies have shown that lipid profiles and obesity are risk factors for HL (13, 14, 45). Metabolic syndrome and its related factors are risk factors for HL. With an increase in the number of related factors, such as abdominal obesity, hypertension, increased fasting blood glucose, in-creased TG level and decreased HDL-C level, the risk of HL will increase, and the number of metabolic syndrome related factors is significantly correlated with hearing threshold (46–48). It has also been shown that patients with mosaic karyotypes are more likely to develop dyslipidemia than patients with other karyotypes, while patients with circular chromosomes are more likely to develop metabolic disorders (22). Alvarez-Nava et al. (49) found that metabolic syndrome was a risk factor for SNHL in adult patients with TS and that reducing the severity of metabolic syndrome may help reduce the progression of SNHL. Our study compared the blood lipid, insulin levels, and BMI of the TS between the normal hearing group and the hearing loss group, and found that TS with HL was not associated with insulin resistance, obesity, and dyslipidemia, may be related to lifestyle or drug treatment interventions, such as metformin, metabolic abnormalities, and further studies are needed to explain the potential pathological mechanism between metabolic abnormalities and SNHL.
The occurrence time of abnormal bone metabolism of TS is about 20–30 years earlier than that of normal women, and the risk of fracture is about 25% higher than that of normal people (50, 51). Previous studies have found that osteoporosis and low BMD can lead to HL, which may be associated with abnormal bone metabolism in the temporal bone, including loss of bone mass in the ossicular chain in the middle ear and osseous structures in the inner ear such as the bone labyrinth (15–17, 52). Yueniwati (53) found that BMD of cochlea, ossicles, femur or spine was negatively correlated with hearing threshold, indicating that abnormal bone metabolism may lead to HL. Current studies have found that decreased HL and BMD increase the risk of fracture in women with TS (54, 55), while no study has confirmed that decreased BMD in women with TS increases the risk of HL. Previous studies have found that HRT can effectively improve the BMD levels of the whole body, femoral neck and hip in TS patients (56). In this study, it was found that after HRT in TS patients, there was no statistical difference in BMD between the normal hearing group and the hearing loss group, suggesting that HRT can improve BMD of patients to a certain extent, but there was no significant improvement in hearing level of patients. Therefore, hearing abnormalities in TS patients cannot be explained only by insufficient estrogen level, and it may be necessary to expand the sample size and conduct grouping studies to explore the correlation between clinical phenomena of HL and related etiology in TS.