Background: Men with Klinefelter syndrome have one or more extra X chromosomes and have endocrine abnormalities. Case reports have led to suggestions that men with Klinefelter syndrome have elevated risks of several cancers, but published cohort studies have been relatively small. We conducted a nationwide cohort study to examine these risks. Methods: We followed a cohort of 3518 men who had been cytogenetically diagnosed with Klinefelter syndrome in Britain from 1959 through 2002 and compared their cancer incidence and mortality with that of men in the national population. All statistical tests were two-sided. Results: The standardized mortality ratio (SMR) for all cancers was 1.2 (95% confidence interval [CI] = 1.0 to 1.4). Compared with the general population, men with Klinefelter syndrome had higher mortality from lung cancer (SMR = 1.5, 95% CI = 1.0 to 2.0), breast cancer (SMR = 57.8, 95% CI = 18.8 to 135.0), and non-Hodgkin lymphoma (SMR = 3.5, 95% CI = 1.6 to 6.6) and lower mortality from prostate cancer (SMR = 0, 95% CI = 0 to 0.7). The standardized mortality ratios were particularly high for breast cancer among men with 47,XXY mosaicism (SMR = 222.8, 95% CI = 45.9 to 651.0) and for non-Hodgkin lymphoma among men with a 48,XXYY constitution (SMR = 36.7, 95% CI = 4.4 to 132.5). The cancer incidence data corroborated these associations. Conclusions: These results support a hormonal etiology for breast cancer in men and for prostate cancer and suggest that men with Klinefelter syndrome may be at substantially elevated risks for non-Hodgkin lymphoma, breast cancer, and, perhaps, lung cancer.

Klinefelter syndrome was first described in 1942 (1), and in 1959, it was discovered that men with Klinefelter syndrome have an excess number of X chromosomes (2). Hypogonadism is characteristic of this syndrome, as are various hormonal, physical, and developmental abnormalities (3). Information about the long-term cancer risks among men with Klinefelter syndrome is limited, however, reflecting the lack of large cohort studies. The largest studies to date have been a Danish cohort study of 696 men with Klinefelter syndrome, among whom 39 neoplasms were diagnosed (4), and a British cohort study of 646 men with Klinefelter syndrome, among whom 37 cancer deaths were recorded (5). Although the findings of these two studies were not mutually consistent, when they are considered together with the other literature concerning men with Klinefelter syndrome, primarily case reports, there is substantial evidence that such men have increased risks of breast cancer (68) and midline teratoma (4,9,10), and less well-supported suggestions of increased risks of several other malignancies (4,1114), compared with men in the general population.

To obtain systematic data on cancer incidence and mortality from a larger number of men with Klinefelter syndrome than was included in the previous cohort studies, we gathered information from almost all of the cytogenetics laboratories in Britain about all cases of Klinefelter syndrome diagnosed as far back as records are held, i.e., cases from a population of more than 50 million people over a period of up to 44 years. Here, we report cancer incidence and cancer mortality risks in a follow-up of this cohort.

Article: //jnci.oxfordjournals.org/content/97/16/1204.full