Population Prevalence, Cancer Risk, and Mortality Risk of Turner Syndrome in South Korean Women Based on National Health Insurance Service Data

Turner syndrome (TS), first introduced in 1938 by Henry Turner,1 is defined as a phenotypic female condition with one or more typical clinical features and partial or complete absence of a second X chromosome in karyotyping.2, 3 Although exact rates differ among studies, approximately half of individuals with TS have complete monosomy of the X chromosome. Common physical features of newborn patients with TS are webbing of the neck, protruding ears, and lymphedema of the hands and feet.4 Among children with TS, valve diseases, such as mitral regurgitation, bicuspid aortic valve, and aortic coarctation, and renal anomalies, such as hydronephrosis and horseshoe kidney, are often reported.5, 6 In adolescents and adults, short stature, amenorrhea, and a lack of secondary sex characteristics are generally common.7 TS is the most common sexual development disorder with primary amenorrhea.8

Since the first diagnosis of TS, epidemiology of this genetic disorder has been thoroughly investigated across various nations and ethnic groups, although there is a lack of nationwide studies in Africa, Asia, and South America. Most studies on the epidemiology of TS in Asian countries are old. A Japanese study in 1993 reported an incidence of 1 in 476 live-born females,9 and a Singapore study in 2009 reported an incidence of 1 in 1176 live-born females.10 The Singapore study was based on data from 1999 to 2004. A multicenter, but not nationwide, Korean study in 1999 reported 10 TS cases in 11000 samples of amniotic fluid, in which the incidence among live-born females could not be estimated.11 Although there are ethnic and racial differences, the prevalence of TS is estimated to be approximately 1 in 2500 live-born females.12 With the recent increase in incidence of TS in female live births, a prevalence of 1 in 1700 live-born females was suggested in a Danish study based on nationwide cytogenetic registry.13

Patients with TS face several medical problems throughout their lives. The life expectancy of women with TS is shorter than that of normal women as a result of complications from heart disease and diabetes.14 Significant increased risks for certain types of cancer, such as nervous system cancer, gastrointestinal cancer, and melanoma, have been reported in patients with TS,15 and a possible risk of gonadoblastoma was suggested in mosaic TS with Y chromosome.16 Regarding these issues, epidemiologic data of TS-associated cancer and mortality has been lacking in South Korea.

Since 1989, South Korea has maintained a universal compulsory National Health Insurance Service (NHIS) that offers health care services to nearly 100% of the Korean population.17 This system not only covers insurance of the population but also maintains records of individual health information. The data of rare and intractable diseases, such as TS, are managed separately in the Rare Disease Registry (RDR) program, initiated by the NHIS in 2004 to support patients suffering from these diseases.18 Using from the program, TS prevalence and incidence and TS-associated mortality and cancer morbidity in South Korea were estimated in this study.

The prevalence of TS per 100000 persons in South Korea increased from 5.24 in 2007 to 7.84 in 2017. At the same time, the IRs of TS per 100000 populations were 0.65 and 0.48, respectively. Prevalence distribution of TS across 10-year interval age groups in 2017 showed a peak prevalence in teenage years, and it started to decrease after 20s. As for cancers, there was high risk of having thyroid cancer in patients with TS. Mortality was significantly high in patients with TS after the age of 40.

The epidemiology of TS has been thoroughly investigated in Europe and America. In Denmark, TS population prevalence was 59 per 100000 newborn females in 2014.13 In Sweden, TS population prevalence was 30 per 100000 females as estimated crudely by a study investigating TS-associated cancer risk.29 Among the British population, a crude prevalence estimate of 17 patients with TS per 100000 females was reported based on a population-based study of cancer incidence.30 In another British study reported in 2017, single nucleotide polymorphism array data from the UK Biobank were analyzed. The corresponding TS prevalence was 88 per 100000 females, the highest prevalence among TS epidemiology studies.31 45,X/46,XX mosaicism presumably accounted for this result, and the statistical reliability of the data was limited due to lack of “healthy volunteers.” In the United States, the National Organization of Rare Disease estimated that more than 70000 women and girls have TS, approximately 21 cases per 100000 females.32 As far as we know, there have been no recent studies on the national prevalence of TS in Asia. A study of prevalence of TS in several regions of China was recently conducted in 2018, and various prevalences ranging from 25 to 210 per 100000 females were reported.33 Overall, the prevalence of TS in South Korea was considerably lower than that of Europe and the United States. While it is difficult to explain this discrepancy with one clear reason, one presumable reason may be the absence of a national screening system for TS. This may lead to lower participation of parents in screening suspected children.

Although the prevalence of TS in South Korea was comparatively lower than that in other studies on TS prevalence, the prevalence trend with age coincides with epidemiologic studies conducted in Europe and the United States. A Danish national cohort study published in 2019 reported that the median age for diagnosis of TS was 15.1 (range: 0.0–85.4) and that the prevalence of TS was highest in teenagers.13 A study conducted at a single center in the United Kingdom reported that half of patients with TS were diagnosed after the age of 5 years.34 Delayed diagnosis of TS with an average age of 12.8 years was observed in a study in the United States.35 Delayed diagnosis of TS in South Korea was evident in our study. As seen in the incidence trend of patients with TS in 2017, 43 patients were newly diagnosed before 10 years, and 46 patients were newly diagnosed as teenagers. Nearly 30% (36 patients) of the total number were diagnosed after an age of 20 years. Furthermore, although not included in Table 2, the same data for years 2015 and 2016 were 37% and 25%, respectively. The falling prevalence trend for TS in those 30 years or older can possibly be explained by relatively fewer cases of newly diagnosed TS after an age of 30 years. Although the annual prevalence of TS is increasing, most newly diagnosed cases of TS are younger than 30, and this implies that many patients with TS over 30 years live undiagnosed. The prevalence was less than 1 per 100000 persons (0.38) in those 50 years and over, probably owing to short life expectancy of patients with TS. TS has a life expectancy that is reduced by up to 13 years and shows a three-fold increase in overall mortality.13, 14 In this study, the HR for mortality in patients with TS was 3.42, consistent with ratios in the aforementioned studies. Since this study was based on data from the NHIS, the detailed causes of death in patients with TS are absent, which should be clarified to find major cause of increased mortality. We presume possible causes for the increased mortality, as discussed earlier, would be heart diseases, and a study in Korea suggested the possibility of impaired vascular function of aorta in teenage TS.36 The TS-associated mortality HR in those 40 years and over was 6.51, more than double that of patients under 20 (3.07). This discrepancy supplements the explanation for the dramatic fall in TS prevalence in those 40 years and over, with a remarkable decrease in those 50 years and over. Accordingly, medical management of TS needs to be focused on decreasing the MR, especially in those 20 years and older. Modes of surveillance to manage patients with TS should be envisioned with succeeding comprehensive medical care for their co-morbidities.

Regarding TS comorbidity, this study showed an increased risk of cancer occurrence in patients with TS, compared to the control group (Table 3). Among different types of cancer, risk of thyroid cancer occurrence was notably high in this study, suggesting a positive correlation between thyroid cancer and TS. Many previous studies have discussed TS-associated cancer risk, and the issue of whether TS increases risk of cancer is still controversial. A British national cohort study of 4909 women with TS reported an insignificant association between cancer risk and TS, inconsistent with the results reported in this study.30 The British study reported an increased risk of specific tumors, such as brain or urogenital tumors, but only one case of thyroid cancer was reported among 73 malignancy cases in TS. An Italian study that surveyed the prevalence of different types of neoplasia in TS reported an increased risk of skin neoplasm/cancer, CNS tumor, while thyroid cancer occurred in only one of 87 women with TS.37 Consistently, two other European studies reported correlation of TS with skin neoplasm and brain tumor.38, 39 The main reason for the notably high incidence of thyroid cancer among individuals with TS in South Korea would be the high incidence of thyroid cancer among all Korean women, regardless of having TS. With readily available thyroid screening, the incidence of thyroid cancer in Korean women in 2010 was 111.3 per 100000 persons, 10-fold higher than the average global IR.40 To our knowledge, there is no other Asian study that has reported IRs for cancer in TS. Future studies of this may provide some clues on racial differences in TS. In addition, another possible explanation for the increased thyroid cancer risk observed in this study may be the predisposition of patients with TS to autoimmune diseases of the thyroid. Haploinsufficiency of X chromosome in TS may be confer susceptibility to autoimmune diseases.41 Although the exact mechanism remains unclear, autoimmunity involving the thyroid gland has been suggested as a cause of thyroid cancer in previous studies.42, 43, 44 Most of the thyroid cancer cases in this study were diagnosed after 20 years, which coincides with the age distribution of thyroid cancer in the general population of South Korea. There is also a concern for ovarian gonadoblastoma in TS with Y chromosome, either overt or cryptic. A Korean study conducted in 2017 revealed that 12.9% (16/124) of patients with TS had Y chromosomes on karyotyping or Y chromosome material on polymerase chain reaction, and 18.8% (3/16) of them were diagnosed with gonadoblastoma.45 Since this study was based on registry data under certain diagnostic codes, the exact proportion of patients with TS with Y chromosome material was not found. Therefore, the study could not provide data on the risk of gonadoblastoma in patients with TS.

This study investigated the epidemiology of TS from 2007 to 2017 based on the NHIS and the RDR, national registries that reflect nearly 100% of the entire female population in South Korea. A long period of follow-up with a maximum of 10 years was covered in this research, and this may be representative of national status. In addition, to the best of our knowledge, this study is the largest study of TS epidemiology conducted in Asia. Other large-scaled Asian studies on TS epidemiology are necessary to elucidate definite epidemiological properties among Asians. Further studies might suggest ethnic differences in TS that were previously obscure. In conclusion, this study presents the national prevalence of TS for Korea and a substantially increased risk of TS-associated thyroid cancer and mortality, the reason for which should be clarified through further studies.