Introduction

Women with Turner syndrome (TS) harbor one intact X chromosome, with a complete or partial lack of the second X chromosome, yielding a 45,X karyotype or a mosaic form [1]. The absence of one X chromosome has detrimental impact on the development of comorbidities across many organs; hence women with TS may suffer from a wide range of diseases [2]. The most distinct features are hypergonadotropic hypogonadism with infertility, obesity, decreased height, and increased occurrence of diabetes, cardiovascular conditions, liver disease, and anemia [3,4,5,6].

It is also established that women with TS are affected by visual and hearing impairment. Most children with TS are born with normal hearing, but up to 50% develop a mid-frequency sensorineural hearing loss later in puberty and adolescents [7,8,9]. Girls with TS are more prone to acquire ear infections such as otitis media compared with their peers [7, 10, 11].

A diverse range of eye disorders have been detected, with impaired vision and strabismus being the most frequent, but unlike hearing loss, vision impairment does not seem related to karyotype [12]. Skin conditions such as lymphedema, nevi, and concave nails have been reported along with premature skin aging [2, 13, 14].

Investigating women with TS, a particular cognitive pattern is found with a normal full-scale IQ, but with shortfalls in visuospatial reasoning, executive function, and social cognition [15]. However, very few reports on the occurrence of nervous system disorders have been published. A population-based study from 2008 found an increased risk of amyotrophic lateral sclerosis among TS women [14], perhaps linked to the increased occurrence of autoimmune disorders [16]. However, most of our knowledge concerning these conditions are based on case reports and observational studies with limited number of cases, most of them reporting occurrence of epilepsy [17, 18]. No population-based studies have ever investigated the prevalence and risk of ear nose throat conditions nor disorders of the nervous system. Thus, we undertook an epidemiological investigation in all diagnoses and medical prescriptions related to the eye, ear, nose, skin, and nervous system in women with TS in comparison with background females.

Subjects and methods

We identified 1,156 individuals diagnosed postnatally with TS from 1960 to 2014 using the Danish Cytogenetic Central Registry (Table 1). This registry contains information on all karyotypes performed in Denmark since 1960, including the date of diagnosis. We have previously presented endocrine, cardiovascular, gastrointestinal, and cancer data from this population [3, 4, 19]. Statistics Denmark randomly identified 100 age-matched background females per TS individual from the background population (n = 115,577) and linked them with data from the following registries.

Table 1 Karyotype distribution and age at diagnosis.
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From the National Patient Registry [20], we retrieved date and type of hospital discharge diagnoses (primary and secondary), death, and emigration dates from 1977 to 2014. Similarly, we retrieved date and type of hospital outpatient diagnoses from 1995 to 2014. We included all discharge diagnoses, but only the first diagnosis from a sequence of identical outpatient diagnoses. Prior to 1994, diagnoses were classified according to the International Classification of Diseases, eighth revision (ICD-8), and from 1994 according to the tenth revision (ICD-10).

From the Danish Medication Statistics Registry, we retrieved information on medical prescriptions, date of dispatch, and Anatomical Therapeutic Chemical Classification (ATC) code, prescribed from both the primary and secondary sector since 1995 [21]. The Danish Medication Statistics Registry does not contain information on medicine administered during admission to hospital or over-the-counter drugs. We have no clinical data, such as alcohol, tobacco use, weight etc. Neither information on drug dose or duration.

End of the study was December 31, 2014.

ICD and ATC codes

ICD-8, ICD-10, and ATC codes are presented in Tables 2 and 3. We defined hormone replacement treatment (HRT) as the following ATC groups: hormonal anticonception (G03A), oestrogen (G03C), and oestrogen and progesterone combined (G03F). We excluded local oestrogen therapy and anticonception only consisting of progesterone (ATC code G03AC and G03DA), and emergency contraceptives (levonorgestrel).

Table 2 Risk of eye, ear, nose, skin or nervous system disorders in Turner syndrome females.
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Table 3 Prescription medication.
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Statistics

Discharge and outpatient diagnoses were analyzed by mixed-effects negative binomial regression, yielding incidence rate ratios (IRRs) as a measure of association. Each stratum of a TS woman and her matched controls constituted a cluster. We allowed for this clustering by using a random-effects model. Analyses were performed both from birth to the date of TS diagnosis, and from TS diagnosis until death, end of the study, or emigration, whichever came first. Time to first medical prescription was analyzed using stratified Cox regression with each TS woman and her matched controls constituting one stratum. Time at risk started at birth, with delayed entry at 1 January 1995 or date of diagnosis, whichever came last. Time at risk ended at the date of dispatch, death, end of study, or emigration, whichever came first.

Using logistic regression we examined a subcohort of TS women and control females with metabolic syndrome (type 2 diabetes, hypertension, ischemic heart disease, and hyperlipidaemia, alone or in combination) and examined the risk of hearing loss. Analyses were age adjusted.

The effect of hormone replacement therapy

Since the endogenous oestrogen production varies across TS karyotypes, we performed analyses regarding the effect of HRT on three subgroups of women with TS only. A subgroup of 329 45,X women, a subgroup of 584 mosaic TS women, and these two subgroups combined (n = 913). In all subgroups, the women were at some point during the study period between age 18 and 60 years, thus supposed to receive HRT according to international recommendations [1]. We used Cox regression to evaluate the effect of HRT on hospital contacts with disorders related to the eye, ear, skin, and nervous system. Before the first date of HRT prescription, a woman was categorized non-treated, and after this prescription date, HRT treated, regardless of the number of HRT prescriptions. Hence, analyses were split on the first HRT prescription date. Time at risk was from 1 January 1995, from the 18-years birthday, or from the date of TS diagnosis, whichever came last. Time at risk ended at date of hospital contact with a given diagnosis, death, end of study, or emigration, whichever came first. Analyses were adjusted for year of birth.

All analyses were performed using Stata software, version 15.1. P values < 0.05 were considered statistically significant. We made no formal adjustment for multiple testing, but we took the multiple testing into consideration in the interpretation of results.

The Danish Data Protection Authority approved the project with the registration number 2013-41-2017. Data were accessed through a secure link to Statistics Denmark, and civil registration numbers were anonymized.

Results

Our cohort consists of 422 women with 45,X (37%) and 734 women with other karyotypes, yielding a total of 1,156 Turner syndrome women (Table 1 and Supplementary Table 1). Overall the risk of admission with a diagnosis related to the eye, ear, nose, skin, or nervous system was increased in Turner syndrome women compared with background females (IRR 5.7 (95% CI 5.0–6.6) (Fig. 1).

Fig. 1: The risk of admission with eye, ear, nose, skin or nervous system related diagnosis in Turner syndrome females and background females.
figure 1

The grey line is the proportion of background females with a diagnosis at a given age. The black line is the proportion of women with Turner syndrome with a eye, ear, nose, skin or nervous system diagnosis at a given age.

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Eye, ear, and nose

In total, 19% (225/1,156) of the TS cohort were admitted with an eye diagnosis, and at the age of 30 years, 8% percent (88/1156) had at least one registration (compared with 3% in background females). Admission with almost all diagnoses related to the eye was more frequent among women with TS, including disorders of conjunctivae, sclera, cornea, choroid, and retina, glaucoma, cataract, strabismus, refraction, and accommodation (Table 2). When subdivided into karyotype groups, 45,X women (IRR 5.1 (3.7–7.1)) and TS women harboring an isochromosome (IRR 5.4 (2.8–10.2)) experience the highest risk of eye disorders (Supplementary Table 2). The increased risk of eye disorders is supported by the highly increased number of eye medications prescribed among women with TS. Especially anti-glaucoma medication was prescribed more frequently, along with mydriatics, antiinflammatory, and antibiotic eye medication (Table 3).

The same applied to disorders of the ear, since 38% of the TS cohort (445/1,156) compared with 4% of background females) had a diagnosis in this chapter, and 22% of the TS cohort had an ear diagnosis before the age of 30 years. Particularly, the risk of admission with otitis media, tympanic membrane perforation, cholesteatoma, and hearing loss was increased in women with TS compared with background females (Table 2). Interestingly, all karyotype groups were affected by ear disorders, especially otitis media, and hearing loss (Supplementary Table 2).

We examined the association between the presence of metabolic syndrome and concomitant hearing loss, and found an increased odds ratio of 6.4 (95% CI 4.5–9.1) of having both hearing loss and metabolic syndrome in TS women compared with controls.

The risk of cholesteatoma was highly increased in the group of TS with 45,X karyotypes, or mosaic karyotype with isochromosome material.

The risk of admission due to rhinitis, nasal polyps, and other nasal disorders such as septum deviation was not different among women with TS and background females, with the exception of sinusitis (Table 2). When the analysis was performed on only the 45,X group, however, the risk of rhinitis, sinusitis, and nasal polyps was increased compared with controls (supplementary table 2).

Skin

We report an increased risk of developing dermatitis and eczema, along with psoriasis. Atopic dermatitis and seborrheic dermatitis were among the most frequent diagnoses given, but also allergic contact dermatitis was common (Table 2). Interestingly, increased use of anti-psoriatic medication along with corticosteroids supports this finding (Table 3). When subdividing women with TS into karyotype groups, the risk of psoriasis was only increased in the group of TS women with isochromosome material (IRR 37.7 (2.8–509.5)), and the same applied for dermatitis and eczema (IRR 6.7 (1.9–23.7)) (Supplementary table 2). We also detected a higher prescription rate of fungicides, not reflected in our data concerning hospital admissions (Table 3). Furthermore, ingrown nails were common in TS. The risk of skin infections, lichen ruber, urticaria, erythema multiforme, and hirsuitism were equivalent to background females.

Nervous system

Overall, the risk of admission with a nervous system disorders was increased in TS women compared with background females. However, in both TS and background females the prevalence of a nervous system diagnosis was around 12% (TS; n:140/1156, background females; n:13,374/115,577). Especiallly the risk of epilepsy and systemic atrophies affecting the central nervous system were increased in Turner syndrome women compared with controls (Table 2). When stratifying on age, we found that the risk of admission with epilepsy was increased six-fold in TS children (<18 years old) (IRR 6.0 (95% CI 1.7–20.6)), but more than ten-fold in adults (IRR 10.6 (95% CI 3.3–33.8)). Six TS women were diagnosed with systemic atrophies affecting the central nervous system, of which two suffered from amyotrophic lateral sclerosis, three from unspecified ataxia, and one from muscle dystonia (Table 2). Interestingly, when subdividing our analysis into karyotype groups, women with 45,X had a decreased risk of migraine and headaches (IRR 0.3 (0.07–0.97)), and of neuropathy (IRR 0.4 (0.2–0.9)) (supplementary table 2). The decreased risk of migraine was supported by prescription data validating a lower use of migraine medication (HR 0.4 (0.3–0.6)) (Table 3).

Hormone replacement therapy

We report no effect of HRT on nervous system, eye, skin, or most disorders of the ear in the combined cohort (Fig. 2), nor when dividing them into subgroups of 45,X and other karyotypes. Data pointed toward an increased risk of hearing loss in those receiving HRT (Fig. 2), however, no increased risk of hearing loss in relation to HRT was seen in the 45,X subgroup.

Fig. 2: The effect of HRT on eye, ear, nose, skin, or nervous system disorders in the total cohort.
figure 2

The x-axis is a log scale. A hazard ratio below one suggests a decreased risk of hospital contact with the given diagnosis in HRT treated 45,X women compared with non-treated 45,X women, and vice versa.

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Discussion

The risk of admission to hospital with disorders related to eye, ear, nose, skin, and nervous system was increased in women with TS compared to background females and across all karyotype groups. Thus, we confirm findings from a wide range of case reports describing cases of women with TS suffering from strabismus, myopia, retinal detachment, cataract, and glaucoma [22,23,24]. A review pooling several case-series (n = 274), reported that amblyopia and strabismus were prevalent in one third of all TS patients, while almost half of these women suffered from reduced accommodation and convergence insufficiency [25]. In the same review, 1% of TS women were diagnosed with glaucoma, which is equivalent to our findings, however, we also report a three times increased risk of hospital contact with glaucoma compared with background females, predominantly carried by the group of 45,X women. The increased risk of almost all eye disorders supports the theory of a disrupted or altered early embryonal eye development in TS women.

The genetic background of eye disorders remains unsolved; however, two candidate genes (USP9X, LRP5) have been proposed to be involved in the pathogenesis [22]. USP9X, located on the X chromosome, escapes X chromosome inactivation, and has been found to be involved in eye, ovary and neural development [26,27,28,29], however a direct causal link cannot be established.

All diagnoses related to the organ of hearing are more prevalent in women with TS, across all karyotype groups. Our findings confirm the clinical picture of previous smaller studies demonstrating an increased prevalence of otitis media, conductive and sensorineural hearing loss, tympanic abnormalities, and dysfunction of the Eustachian tube, along with cholesteatoma [8,9,10,11, 30,31,32,33]. Intriguingly, the highest risk of both otitis media, cholesteatoma, and hearing loss are found in the group of 45,X and in the karyotype group “45,X/46,iso(X) and equivalents”, which correlates well with previous findings that especially lack the p-arm is detrimental for the TS phenotype [34]. Barrenäs et al. proposed that all auricular malformations, development of cholesteatoma, and hearing loss could be due to growth disturbances, caused by haploinsufficiency of the X chromosomal gene SHOX [10].

Interestingly, we found a strong association between the presence of metabolic syndrome and hearing loss in TS women, supporting recent research demonstrating the same [35]. This is of special interest since all aspects of the metabolic syndrome are potentially preventable and influenced by lifestyle in TS women and thus the prevention of these metabolic conditions could perhaps influence the development of hearing loss. This is of course speculative, but nevertheless, it would be interesting to establish interventional trials to study this.

To our knowledge, the increased risk of sinusitis has not been reported previously, however, known predisposing factors to sinusitis are allergies/atopic dermatitis and poor drainage conditions [36]. We speculate that the altered skeletal growth in TS women might also contribute to constricted drainage. Furthermore, our data show that TS women are at increased risk of atopic dermatitis which in itself increases the risk of sinusitis. In addition to increased risk of atopic dermatitis and eczema, we report an increased risk of psoriasis. Multiple case reports have linked Turner syndrome with different psoriatic manifestations [37,38,39,40,41,42], although two epidemiological studies were not able to document a correlation [2, 14]. We speculate that this might be due to small study populations, since we, in this larger cohort, report a significantly elevated risk of psoriasis. Psoriasis is an immune-mediated skin disease, consisting of both an autoimmune and autoinflammatory component [43, 44], fitting with the generalized picture of an altered immune response and a universal higher risk of developing autoimmune disease in Turner syndrome women, such as thyroid disorders, type 1 diabetes, celiac disease and inflammatory bowel disease [14, 45].

Epilepsy was strongly associated with Turner syndrome compared with control women. This supports prior case reports [17, 18]. As previously mentioned, USP9X, a gene differentially methylated in 45,X women, has also been linked with a higher prevalence of seizures [29, 46], and could be a candidate gene of interest in Turner syndrome.

Besides epilepsy, the risk of admission with systemic atrophies affecting the central nervous system was increased in TS women. Two TS women were diagnosed with ALS, the remaining two suffered from cerebellar ataxia. With a limited number of cases it might be a coincidence rather than a correlation, however, an epidemiological study from the United Kingdom reported a significant association between amyotrophic lateral sclerosis (ALS) and prior diagnosis of asthma, celiac disease, younger-onset diabetes, multiple sclerosis, myasthenia gravis, and myxedema [16], indicating that the increased frequency of autoimmune disorders in TS might itself predispose to ALS.

Interestingly, it seems that 45,X women have a decreased risk of being admitted with migraine, and headaches, for which we have no good explanation. However, we do believe this is a valid finding since prescription data, primarily being prescribed in the primary sector by general practitioners, also show a significant reduction in prescribed migraine medication.

Our results suggest an association between hearing loss and HRT treatment in TS, for which we have no explanation and it may be non-causal. It has previously been proposed that estrogen deficiency might cause the hearing deficit in TS women and that HRT has a positive impact on early debut of high-frequency hearing loss [9, 47]. Since the majority of HRT treated TS women are followed by an endocrinologist, this group of Turner syndrome women are probably more likely to be referred to ENT specialists and receive a hearing loss diagnosis, compared with the non-treated group of TS women. We also speculate, that since sensorineural hearing loss advances with age, and since a TS women can act as both HRT non-treated (early life) and later HRT treated, the increased risk might reflect an increased age. Median age in the HRT non-treated group was 30 years old (range 28–31 years) compared with 41 years old (range 40–42) in the HRT treated group of TS women. However, further scrutiny of the effect of oestrogens on the inner ear is warranted.

Strengths and limitations

The major strengths of this study are the nationwide design including all diagnosed and karyotype verified TS women in Denmark since 1960. All are age-matched with 100 control women per TS case and followed for 20 years, which suggests that the results likely can be extrapolated to TS cohorts in other countries. We combined hospital admissions with pharmaceutical data, in order to detect not only diseases diagnosed at the hospitals, but also diseases treated by general practitioners without admittance to the hospital. Lastly, we use negative binomial regression, which in contrast to Cox regression, not only compares “time to first event”, but also accounts for the total number of admissions with a specific diagnosis, providing a more nuanced picture of the general morbidity burden in women with TS.

A limitation to this study is that we do not know the indications for prescribing specific drugs. For instance, corticosteroids can be used to treat a wide range of skin diseases. Furthermore, we do not have data on “over-the counter drugs”. We are not able to account for admission type or length of admission, and the registries lack detailed information on comorbidities such as obesity, smoking, and alcohol consumption.

Conclusion

This population-based national study on 1,156 women with TS and 115,577 age-matched background females, demonstrates an increased risk of disorders related to the eye, ear, nose, skin, and nervous system. We must stress, that ophthalmologist should be aware of especially glaucoma, cataract, and visual disturbances in TS women. Furthermore, ear- nose- and throat specialists must exert vigilance towards symptoms of sinusitis, otitis media and cholesteatoma, and tympanic membrane perforation when treating TS women. Neurologists should be attentive to the association between TS and epilepsy and perhaps also ALS.

The primary caretaker (often the endocrinologist) must of course also exert extra vigilance towards symptoms of all these diagnoses when treating other aspects of TS individuals in order to make an appropriate referral. Furthermore, we emphasize the importance of treating all aspects of metabolic syndrome in Turner syndrome, since it might affect the increased prevalence of hearing loss.