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About one woman in 1,000 has an extra X chromosome, but such women have no recognised characteristic somatic features and little is known about their long-term health and cancer risks. We conducted a cohort study of mortality and cancer incidence in 542 women diagnosed with X polysomy at 25 cytogenetic centres in Britain since 1959. Fifty-nine deaths occurred during follow-up to mid-2004. Mortality was significantly raised (standardised mortality ratio (SMR) = 2.5 (95% confidence interval (CI) 1.9–3.2)), with excess deaths due particularly to cardiovascular disease (SMR = 2.5 (95% CI 1.5–3.8)) and respiratory disease (SMR = 4.0 (95% CI 1.7–7.9)). Risks of cancer incidence and cancer mortality overall were not raised, but there was significantly raised mortality from non-Hodgkin’s lymphoma (NHL) (SMR = 10.4 (95% CI 1.3–37.6); based on 2 cases). The data indicate that mortality in women diagnosed with X polysomy is considerably raised. The raised risk of NHL is seen also in males with more than one X chromosome, and hence although unexpected and based on small numbers, it might indicate the action of a gene on the X chromosome, possibly in the pseudoautosomal region, that escapes X-inactivation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The incidence of skewed X-inactivation in normal women is controversial, with up to 10-fold differences being reported by different authors. In order to clarify this issue, we have conducted a survey of the X-inactivation patterns in 270 informative females from various age groups, using the androgen receptor gene/polymerase chain reaction assay. Results obtained by using DNA extracted from blood samples show that the incidence of severe skewing (defined here as ratios ≥90:10) is relatively common and increases with age (P<0.05), occurring in 7% of women under 25 years of age, and 16% of women over 60. In order to study tissue-specific patterns of X-inactivation, samples of both buccal and urinary epithelia were also obtained from 88 of the females studied. Although there was a significant association of the X-inactivation ratios between each tissue in most individuals, wide variations were apparent in some cases, making accurate extrapolations between tissues impossible. The degree of correlation between each tissue also fell markedly with age. Our data are consistent with the hypothesis that the major factors in the aetiology of skewed X-inactivation are secondary selection processes. [ABSTRACT FROM AUTHOR]

Abstract: Integrity of the long arm of the X chromosome is important for maintaining female fertility and several critical regions for normal ovarian function have been proposed. In order to understand further the importance of specific areas of the X chromosome, we describe a series of 20 previously unreported patients missing part of Xq in whom detailed phenotypic information has been gathered as well as precise chromosome mapping using array Comparative Genomic Hybridization. Features often associated with Turner syndrome were not common in our study and excluding puberty, menarche and menstruation, the phenotypes observed were present in only a minority of women and were not specific to the X chromosome. The most frequently occurring phenotypic features in our patients were abnormalities of menstruation and fertility. Larger terminal deletions were associated with a higher incidence of primary ovarian failure, occurring at a younger age; however patients with similar or even identical deletions had discordant menstrual phenotypes, making accurate genetic counselling difficult. Nevertheless, large deletions are likely to be associated with complete skewing of X inactivation so that the resulting phenotypes are relatively benign given the amount of genetic material missing, even in cases with unbalanced X;autosome translocations. Some degree of ovarian dysfunction is highly likely, especially for terminal deletions extending proximal to Xq27. In conjunction with patient data from the literature, our study suggests that loss of Xq26–Xq28 has the most significant effect on ovarian function. [Copyright &y& Elsevier]

Summary: Background: Turner syndrome, one of the most common cytogenetic abnormalities, is characterised by complete or partial X-chromosome monosomy. Cancer risks in women with Turner syndrome have not been clearly established. We aimed to compare the risk of cancer in women with this syndrome with that of the general population. Methods: We formed a national cohort of 3425 women who were cytogenetically diagnosed with Turner syndrome in Great Britain between 1959 and 2002. Identifying information for these patients was sent to the National Health Service Central Register (NHSCR) for England and Wales and to the NHSCR for Scotland. Individuals who were identified on this register were followed-up for cancer incidence. Standardised incidence ratios (SIRs) and 95% CIs were calculated on the basis of the number of cancers observed compared with that expected based on national incidence rates. Cumulative risk estimates were obtained by use of the Kaplan-Meier method. Findings: A total of 58 299 person-years were accrued during the study, with a mean of 17·0 years (SD 8·6) follow-up per patient. 73 malignancies other than non-melanoma skin cancer occurred (SIR 0·9 [95% CI 0·7–1·2]). Risks were significantly increased for tumours of the CNS (n=13; 4·3 [2·3–7·4]), especially for meningioma (n=7; 12·0 [4·8–24·8]) and childhood brain tumours (n=3; 10·3 [2·1–30·1]), and for cancers of the bladder and urethra (n=5; 4·0 [1·3–9·2]) and eye (n=2; 10·5 [1·3–37·9]), compared with the general population. However, the risk of breast cancer was significantly decreased (n=10; 0·3 [0·2–0·6]). The SIR for cutaneous melanoma was 2·2 (95% CI 1·0–4·4; n=8), and one of the ocular cancers was a melanoma. The risk of corpus uteri cancer was significantly increased at ages 15–44 years (n=3; 8·0 [1·6–23·2]). During follow-up, five women, all with a Y-chromosome lineage, developed gonadoblastoma of the ovary, corresponding to a cumulative risk of 7·9% (95% CI 3·1–19·0) by age 25 years in this group. Interpretation: This study shows that, in addition to having an increased risk of gonadoblastoma, women with Turner syndrome seem to be at increased risk for meningioma and childhood brain tumours, and possibly bladder cancer, melanoma, and corpus uteri cancer, but are at a decreased risk for breast cancer. Reasons for these risks might relate to genetic and hormonal factors or to the effects of hormonal treatments given to women with Turner syndrome. [Copyright &y& Elsevier]