Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study

Abstract

Background: Knowledge 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).

Methods: This 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.

Results: The 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).

Conclusions: The 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.

Keywords: Age at diagnosis; Double Y syndrome; Incidence; Klinefelter syndrome; Prevalence; Triple X syndrome; Turner syndrome.

Fig. 1

Absolute prevalence of Turner syndrome, Klinefelter syndrome, Triple X syndrome and Double Y syndrome in the Danish population. The observed number of a Turner syndrome (TS) and Triple X syndrome and b Klinefelter syndrome (KS) and Double Y syndrome (Double Y) being alive during 1970–2014 are illustrated by solid and dotted lines. Deceased or emigrated individuals were subtracted. Dashed lines indicate the expected number assuming a true prevalence of 1) 50 TS per 100,000 at birth; 2) 84 Triple X per 100,000 at birth; 3) 152 KS per 100,000 at birth; and 4) 98 Double Y per 100,000 at birth as well as a similar mortality as in the general population

Fig. 2

Incidence of Turner syndrome according to karyotype. Incidence of a all Turner syndrome (TS); b 45,X TS; and c TS with other karyotypes per million females during 1970–2014. Solid lines illustrate time trend in incidence during the 1970–2014. P-values indicate the significance level of time trend in incidence

Fig. 3

Incidence of Triple X syndrome, Klinefelter syndrome and Double Y syndrome. Incidence of a Triple X syndrome; b Klinefelter syndrome; and c Double Y syndrome per million females or males during 1970–2014. Solid lines illustrate time trend in incidence during the 1970–2014. P-values indicate the significance level of time trend in incidence

Fig. 4

Prevalence of sex chromosome abnormalities among newborns. a Prevalence of Turner syndrome (TS). Black bars indicates the prevalence of 45,X TS among all TS; b Triple X syndrome (Triple X); c Klinefelter syndrome (KS); and d Double Y syndrome (Double Y) during 1901–2014. Dashed lines indicate the expected prevalence and dotted lines indicate the observed maximum average prevalence of TS, Triple X, KS and Double Y per 100,000 newborn females or males

Fig. 5

Age at diagnosis among sex chromosome abnormalities. Violin plots of age at diagnosis among a Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y) and among b all Turner syndrome (TS), TS with a 45,X karyotype and TS with other karyotypes, diagnosed during 1970–2014. The small circle in the middle of the plot is median age, the dark rectangle depicts interquartile range, the thin dark lines depicts 95% confidence interval, and the density plot width equals frequency of age at diagnosis