Mortality in Patients with Klinefelter Syndrome in Britain: A Cohort Study

Photo Credit: Martin Adams

47XXY also known as Klinefelter’s Syndrome is a numerical chromosome variation, characterised by the presence of one or more extra X chromosomes. It occurs in about 1.5 per 1000 of the male population. The clinical syndrome was initially described in 1942, and the chromosome constitution was discovered in 1959. Characteristically, the patients have hypogonadism and elevated gonadotropin levels, and various other hormonal and physical abnormalities occur. There has been limited information about long-term mortality risks, however, because of the lack of large cohort (follow-up) studies. The only such published studies have been a cohort of 466 men from a Scottish register, later extended to two other centres with a total of 695 men, and a cohort of 781 men from Denmark. To enable more detailed analyses, based on much larger numbers, we assembled a cohort of cases of Klinefelter syndrome diagnosed in Britain for as long as records are held by the cytogenetics centres in the country and followed up the cohort for mortality, for periods of up to 40 years.

For each person in the cohort, we computed person-years of follow-up by 5-yr age group, calendar year, and country (England and Wales vs. Scotland), beginning from the date of cytogenetic diagnosis and ending at June 30, 2003, or the 85th birthday, date of death, or other loss to follow-up, whichever was earliest. Follow-up was censored at age 85 because at older ages than this, national (i.e. expected) mortality rates are not available by 5-yr age group, and the certified cause of death is often inaccurate. We calculated expected cause-specific mortality in the cohort by multiplying the age-, calendar years, and country-specific person-years at risk in the cohort by the corresponding national mortality rates for men. Standardized mortality ratios (SMRs) were then calculated as the ratio of observed to expected deaths, and 95% confidence intervals (CIs) for the SMRs were calculated assuming a Poisson distribution (8). Tests for trend and for the difference between SMRs were conducted as described by Breslow and Day (8). Significance tests were two-sided. Absolute excess risks were calculated by subtracting the expected from the observed numbers of deaths and dividing by person-years at risk.

We subdivided the subjects for analysis by the number of sex chromosomes, whether mosaicism was present, and if so, the constitution of the non-Klinefelter component. Where information was available for mosaics on the numbers of cells diagnosed with each mosaic component, we designated the subject as mosaic only if more than one cell had been counted with each component. We did not have direct information for the study subjects on whether mosaicism was congenital or acquired, but as a rough proxy for this [because the prevalence of acquired mosaicism rises with age (9)], we conducted separate analyses for mosaics diagnosed before age 45 yr and those diagnosed at older ages.

To assess, as far as possible, whether bias might account for certain of the results, we conducted several subanalyses of risks in subdivisions by birth year, risks omitting follow-up and deaths in the early years after cytogenetic diagnosis, and risks omitting cohort members recorded by the Medical Research Council Human Genetics Unit.

Results and further reading