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BackgroundKnowledge on the prevalence of sex chromosome abnormalities (SCAs) is limited, and delayed diagnosis or non-diagnosis of SCAs are a continuous concern. We aimed to investigate change over time in incidence, prevalence and age at diagnosis among Turner syndrome (TS), Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y).MethodsThis study is a nationwide cohort study in a public health care system. The Danish Cytogenetic Central Registry (DCCR) holds information on all karyotypes performed in Denmark since 1961. We identified all individuals in the DCCR with a relevant SCA during 1961–2014; TS: n = 1156; KS: n = 1235; Triple X: n = 197; and Double Y: n = 287. From Statistics Denmark, which holds an extensive collection of data on the Danish population, complete data concerning dates of death and migrations in and out of Denmark were retrieved for all individuals.ResultsThe prevalence among newborns was as follows: TS: 59 per 100,000 females; KS: 57 per 100,000 males; Triple X: 11 per 100,000 females; and Double Y: 18 per 100,000 males. Compared with the expected number among newborns, all TS, 38% of KS, 13% of Triple X, and 18% of Double Y did eventually receive a diagnosis. The incidence of TS with other karyotypes than 45,X (P < 0.0001), KS (P = 0.02), and Double Y (P = 0.03) increased during the study period whereas the incidence of 45,X TS decreased (P = 0.0006). The incidence of Triple X was stable (P = 0.22).ConclusionsThe prevalence of TS is higher than previously identified, and the karyotypic composition of the TS population is changing. Non-diagnosis is extensive among KS, Triple X and Double Y, whereas all TS seem to become diagnosed. The diagnostic activity has increased among TS with other karyotypes than 45,X as well as among KS and Double Y.

The first estimate on prevalence of 46,XY females is 6.4 per 100 000 live born females. The presentation of AIS and gonadal dysgenesis is distinctly different, with AIS being diagnosed during childhood and gonadal dysgenesis during pubertal years. The presenting phenotype is dependent on the cause of 46,XY DSD.

This study received support from Aarhus University and the Novo Nordisk Foundation. The authors have no competing interests that may be relevant to the study.

Turner syndrome is a condition in females missing the second sex chromosome (45,X) or parts thereof. It is considered a rare genetic condition and is associated with a wide range of clinical stigmata, such as short stature, ovarian dysgenesis, delayed puberty and infertility, congenital malformations, endocrine disorders, including a range of autoimmune conditions and type 2 diabetes and neurocognitive deficits. Morbidity and mortality is clearly increased compared with the general population and the average age at diagnosis is quite delayed. During recent years it has become clear that a multidisciplinary approach is necessary towards the patient with Turner syndrome. A number of clinical advances has been implemented, and these are reviewed. Our understanding of the genomic architecture of Turner syndrome is advancing rapidly, and these latest developments are reviewed and discussed. Several candidate genes, genomic pathways and mechanisms, including an altered transcriptome and epigenome are also presented.

Objective: Although the overall risk of cancer is not increased in Turner syndrome, the pattern of cancer occurrence differs from the general population. We aim to describe the cancer morbidity pattern in Turner syndrome and evaluate the effect of long-term hormone replacement therapy (HRT). Design: Nationwide epidemiological study. Methods: 1,156 females with Turner syndrome diagnosed during 1960-2014, were linked with data from the Danish National Patient Registry. Statistics Denmark randomly identified 115,578 female controls. Stratified Cox regression was used to analyze cancer morbidity, mortality and effect of HRT. Results: Overall risk of cancer was not elevated (Hazard ratio 1.04 (95%CI 0.80-1.36)). The risk of skin cancer and benign skin neoplasms was two-fold increased, while the risk of breast cancer was decreased (Hazard ratio 0.4 (0.2-0.9)). Turner syndrome (45,X) had a two- to five-fold increased risk of benign central nervous system tumors, colon and rectal cancers, benign skin neoplasms and skin cancer. Turner syndrome women with a 45,X/46,XX karyotype had increased risk of tongue cancer. HRT had no impact on the risk of any cancer investigated in this study. Conclusions: The lack of one X chromosome might play a role in skin neoplasms, central nervous system tumors, colon and rectal cancers. The risk of breast cancer is lower than in the general population. Long-term HRT during the premenopausal age range seem not to exert a cancerous effect in Turner syndrome. Increased vigilance concerning specific types of cancer in Tuner syndrome harboring a 45,X karyotype is needed.

The pathogenesis of Turner syndrome (TS) and the genotype–phenotype relationship has been thoroughly investigated during the last decade. It has become evident that the phenotype seen in TS does not only depend on simple gene dosage as a result of X chromosome monosomy. The origin of TS specific comorbidities such as infertility, cardiac malformations, bone dysgenesis, and autoimmune diseases may depend on a complex relationship between genes as well as transcriptional and epigenetic factors affecting gene expression across the genome. Furthermore, two individuals with TS with the exact same karyotype may exhibit completely different traits, suggesting that no conventional genotype–phenotype relationship exists. Here, we review the different genetic mechanisms behind differential gene expression, and highlight potential key‐genes essential to the comorbidities seen in TS and other X chromosome aneuploidy syndromes. KDM6A, important for germ cell development, has shown to be differentially expressed and methylated in Turner and Klinefelter syndrome across studies. Furthermore, TIMP1/TIMP3 genes seem to affect the prevalence of bicuspid aortic valve. KDM5C could play a role in the neurocognitive development of Turner and Klinefelter syndrome. However, further research is needed to elucidate the genetic mechanism behind the phenotypic variability and the different phenotypic traits seen in TS.

Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome