This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schoemaker, M. J. Search for Related Content PubMed PubMed Citation Articles by Schoemaker, M. J. Related Collections Cardiovascular Endocrinology Female Endocrinology

Mortality in Women with Turner Syndrome in Great Britain: A National Cohort Study

Section of Epidemiology (M.J.S., A.J.S., C.D.H.), Institute of Cancer Research, Sutton SM2 5NG, United Kingdom; Cell and Molecular Genetics Section (A.F.W.), Medical Research Council Human Genetics Unit, Edinburgh EH4 2XU, United Kingdom; and Wessex Regional Genetics Laboratory (P.A.J.), Salisbury District Hospital, Salisbury SP2 8BJ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Minouk Schoemaker, Section of Epidemiology, Sir Richard Doll Building, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom. E-mail: minouk{at}icr.ac.uk.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Turner syndrome is characterized by complete or partial X chromosome monosomy. It is associated with substantial morbidity, but mortality risks and causes of death are not well described.

Objectives: Our objective was to investigate mortality and causes of death in women with Turner syndrome.

Design and Setting: We constructed a cohort of women diagnosed with Turner syndrome at almost all cytogenetic centers in Great Britain and followed them for mortality.

Patients: A total of 3439 women diagnosed between 1959–2002 were followed to the end of 2006.

Outcome Measures: Standardized mortality ratios (SMRs) and absolute excess risks were evaluated.

Results: In total, 296 deaths occurred. Mortality was significantly raised overall [SMR = 3.0; 95% confidence interval (CI) = 2.7–3.4] and was raised for nearly all major causes of death. Circulatory disease accounted for 41% of excess mortality, with greatest SMRs for aortic aneurysm (SMR = 23.6; 95% CI = 13.8–37.8) and aortic valve disease (SMR = 17.9; 95% CI = 4.9–46.0), but SMRs were also raised for other circulatory conditions. Other major contributors to raised mortality included congenital cardiac anomalies, diabetes, epilepsy, liver disease, noninfectious enteritis and colitis, renal and ureteric disease, and pneumonia. Absolute excess risks of death were considerably greater at older than younger ages.

Conclusions: Mortality in women with Turner syndrome is 3-fold higher than in the general population, is raised for almost all major causes of death, and is raised at all ages, with the greatest excess mortality in older adulthood. These risks need consideration in follow-up and counseling of patients and add to reasons for continued follow-up and preventive measures in adult, not just pediatric, care.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Turner (Ullrich-Turner) syndrome is the most common diagnosed sex chromosome abnormality in women. It affects one in 2000 live-born girls (1) and is characterized by complete or partial X chromosome monosomy. The most consistently reported clinical features are short stature, premature ovarian failure, and lymphedema. Congenital abnormalities include webbing of the neck and cardiovascular and genitourinary anomalies (2, 3). Girls diagnosed with Turner syndrome receive intensive medical follow-up in childhood, often with treatment with GH and estrogen replacement therapy, but until recently, adult patients were not monitored closely (4, 5).

Information on mortality and causes of death in women with Turner syndrome is limited but is important to know for counseling of parents and patients and for appropriate screening and follow-up of patients. Only two studies have assessed mortality risks in such women. One included 156 patients in Scotland (6), which was later extended to 285 patients in Scotland and England (7); these patients are included in the current study. The other study included 781 women in Denmark (1); although informative, there were too few deaths to investigate causes of death in detail.

We collected data from almost all cytogenetics centers in Great Britain on patients diagnosed with Turner syndrome during 1959–2002 to construct a national cohort study and investigate mortality and causes of death in women with this condition, based on much larger numbers. We have recently reported on cancer incidence risks in this cohort (8).

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Information on patients cytogenetically diagnosed with Turner syndrome was retrospectively collected from 27 of all 29 regional cytogenetic centers in Great Britain (i.e. England, Wales, and Scotland), the exceptions being two small centers. Turner syndrome was defined as a karyotype with a 45,X cell line (i.e. complete absence of a X chromosome) or a structurally abnormal or absent short arm of the X chromosome. Only records regarding postnatal examinations were retrieved, and these were collected as far back in time as records had been maintained at the cytogenetic centers (in most centers from the 1960s or 1970s). The cytogenetic records generally listed, apart from cytogenetic details, the patient’s name, sex, and date of birth or age at diagnosis, but the completeness of this information varied by center and calendar year. Permission for this study was obtained from appropriate ethics committees and personal information advisory groups.

Information on name, date of birth, and other identifying details, where available, for women identified from the cytogenetic centers was sent to the National Health Service Central Register (NHSCR) for England and Wales and the NHSCR for Scotland. These registers hold information on deaths, emigrations, and other exits from the NHS for all residents who are registered with a general practitioner and are effectively population registers of these countries. Subjects who could be uniquely identified on the NHSCR registers (flagged) based on the identifying information supplied were followed up for death and other loss to follow-up such as through emigration. The underlying cause of death, from death certificates, was coded to the revision of the International Classification of Diseases (ICD) in use at the time of death (9), and was subsequently bridge-coded to the ninth revision of the ICD (10) to give the categories shown in Results. Patients were excluded if they were known to have been cytogenetically examined as a consequence of a cancer diagnosis or if their karyotype included a cell line with an autosomal trisomy (e.g. 45,X/47,XX,+21), because this is itself associated with substantial morbidity.

Statistical methods

For each cohort member, we calculated person-years at risk of death by 5-yr age group, calendar year, and country (England and Wales vs. Scotland). Follow-up started at the date of cytogenetic diagnosis and ended on December 31, 2006, 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 the certified cause of death is often inaccurate, and national mortality rates are not available by 5-yr age group. Expected cause-specific mortality in the cohort was calculated by multiplying the age-, calendar year-, and country-specific person-years at risk in the cohort by the corresponding national mortality rates for females. Standardized mortality ratios (SMRs) were then derived as the ratio of observed to expected deaths, and their 95% confidence intervals (CIs) calculated using Fisher’s exact method (11). We calculated absolute excess risks (AERs) by subtracting the expected from the observed numbers of deaths, dividing by person-years at risk, and multiplying by 100,000. We estimated cumulative risk of death based on competing risks analysis (12), a method that calculates risks conditional on surviving to each specific age. The statistical software package Stata 9.0 was used for all analyses (Stata Corp., College Station, TX). All significance tests were two sided.

SMRs for overall and cause-specific mortality were calculated for the entire cohort, by age of Turner diagnosis, Turner karyotypic subtype (45,X; 46,X,i(Xq) or 45,X/46,X,i(Xq); 45,X/46,XX; other 45,X mosaic), and by attained age at diagnosis, time since Turner diagnosis, and calendar period of follow-up. To investigate the possibility that mortality might have been biased because some women were cytogenetically tested as a consequence of a prior illness, analyses were repeated after excluding from follow-up the first 12 and 36 months after cytogenetic diagnosis, because effects of such bias, if present, would be expected to wear off over time.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
We identified 4909 women cytogenetically diagnosed with Turner syndrome. Of these, 1287 could not be flagged on the NHSCR because insufficient identifying information was available, in particular on date of birth (n = 712) or full name (n = 223), or because the full name plus date of birth were too common, such that an exact match could not be found on the NHSCR (n = 352), and another 47 could not be followed up for other reasons. An additional 127 women were excluded because of unknown year of cytogenetic diagnosis, three because they were karyotyped as a result of a cancer diagnosis and six because their karyotype included a cell line with an autosomal trisomy. The remaining 3439 women (70%) were included in the cohort.

Patients were more likely to be excluded from the study for the above reasons if they were diagnosed with Turner syndrome during the early calendar years (e.g. of those with known year of cytogenetic diagnosis, 39.5% of women diagnosed before 1980 vs. 14.8% between 1990 and 2002 were excluded) or if they were diagnosed under age 5 (of those with known age at diagnosis, 32.5% under age 5 vs. 10.4% age 5 yr and over were excluded).

Of 3439 cohort members, 1869 (54%) had a mosaic karyotype, 1246 (36%) had 45,X monosomy, 186 (5.4%) had 46,X,i(Xq), and 132 (3.8%) were of other nonmosaic karyotypes (Table 1). The median age at diagnosis was 14.5 yr overall, ranging from 12.4 for women with 45,X monosomy to 23.8 yr for those with a 45,X/46,XX karyotype. The proportion of women with a nonmosaic 45,X karyotype decreased with calendar period of diagnosis, from 45% among those diagnosed before 1980 to 32% among those diagnosed during 1990–2002.

All-cause mortality was 3-fold raised compared with that in the general population (SMR = 3.0; 95% CI = 2.7–3.4). Cause-specific mortality was significantly raised for endocrine disease; diseases of the nervous, circulatory, respiratory, digestive, genitourinary, and musculoskeletal systems; congenital anomalies; and accidents and violence (Table 2). Absolute excess mortality risk corresponded to 307.9 excess deaths per 100,000 population per annum, with circulatory disease being the largest contributor (AER = 126.3, 41%), and respiratory disease being the next largest (AER = 40.5, 13%).

The raised mortality from respiratory disease was mainly due to pneumonia (SMR = 5.5; 95% CI = 3.5–8.3). The raised mortality from endocrine and allied diseases was due to diabetes mellitus, for which risk was over 11-fold raised (SMR = 11.3; 95% CI = 5.8–19.7); the type of diabetes was not specified on the death certificates. The nervous system deaths included six from epilepsy (SMR = 9.0; 95% CI = 3.3–19.7), with the remainder being from heterogeneous causes. Three of the epilepsy death certificates stated ‘status epilepticus’; the other three stated unspecified type of epilepsy or seizures. The deaths from digestive system disease included seven from liver disease (SMR = 3.3; 95% CI = 1.3–6.7) (four nonalcoholic or unspecified cirrhosis, one alcoholic fatty liver, one portal hypertension, and one unspecified) and one from cholangitis. Additionally, this category included two deaths from iodiopathic proctocolitis and one from Crohn’s disease (SMR = 5.9; 95% CI = 1.2–17.1 for noninfectious enteritis and colitis). The deaths from genitourinary disease were largely due to renal and ureteric disease (SMR = 7.1; 95% CI = 2.3–16.5) and unspecified urinary tract infection. Deaths from musculoskeletal diseases were heterogeneous. Specific causes of death from accidents and violence included poisoning (n = 5), road traffic accident (n = 4), compression of the neck, strangulation or hanging (n = 3), inhalation of vomitus or choking (n = 3), and complications of a medical procedure (n = 2). Suicide was noted on death certificates for three patients.

Although mortality from cancer overall was not raised (Table 2), analyses by cancer site showed borderline significantly reduced mortality from breast cancer (SMR = 0.3; 95% CI = 0.1–1.0; three deaths) and raised mortality from brain and nervous system tumors (SMR = 3.2; 95% CI = 1.0–7.4; five deaths) (not in table).

The relative risk of death (SMR) was greater at young than at older ages but remained significantly and substantially raised at ages over 45 (Table 3) and indeed even at ages over 65 yr (SMR = 2.4; 95% CI = 2.0–3.0; not in table). AERs, however, were considerably greater at older ages, notably, at ages 45–84 yr, mortality was raised with 1158.9 excess deaths per 100,000 population annually (i.e. 11.6 excess deaths per 1000), more than seven times greater than the AER at ages 0–14 or 15–44 yr. SMRs decreased with age and time since diagnosis of Turner syndrome (not in table).

We repeated the main analyses after excluding from follow-up deaths and person-time during the first 12 or 36 months after cytogenetic diagnosis. This showed all-cause SMRs that were only marginally lower than those in the main analyses (SMR = 2.9; 95% CI = 2.5–3.2 and SMR = 2.8; 95% CI = 2.5–3.2, after excluding the first 12 or 36 months, respectively; not in table), with no material changes in cause-specific SMRs, except for slight decreases in SMRs for cardiovascular congenital anomalies, aortic valve disease, and heart disease overall, due to the exclusion of 11, 2, and 7 deaths occurring within 36 months of diagnosis of Turner syndrome, respectively.

The cumulative risk of death from any cause in the cohort was 6.1% by age 15 yr, 12.4% by age 45, and 86.2% by age 85 (Fig. 1). For circulatory disease deaths, these risks were 0.2, 1.8, and 34.2% and for aortic aneurysm deaths 0, 0.8, and 2.7% by ages 15, 45, and 85 yr, respectively.

View larger version (15K): [in this window] [in a new window]   FIG. 1. Cumulative risk of death from all causes and from circulatory disease observed in the cohort of patients with Turner syndrome and risk expected based on general population rates for females.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

The all-cause SMR in our study is similar to that reported by the only other independent cohort study, of 781 patients with Turner syndrome identified from the Danish Central Cytogenetic Register (SMR = 2.86; 95% CI = 2.18–3.55) (1). The Danish study observed significantly raised mortality from endocrine and coronary heart disease, congenital anomalies, and other causes encompassing accidents, suicides, and unknown causes of death, and there were nonsignificantly raised risks for several other broad disease categories, but numbers of deaths were too small to investigate causes of death in more detail or to investigate cause-specific risks by karyotype or attained age.

Mortality from noncongenital circulatory disease and from cardiovascular congenital anomalies accounted for 41 and 8%, respectively, of absolute excess mortality risk in our study. Congenital cardiovascular abnormalities are common in women with Turner syndrome; the most well-known, bicuspid aortic valves and coarctation of the aorta, have been reported to be present in 12–30 and 7–18% of patients, respectively, but it is clear that the spectrum of cardiovascular abnormalities is considerably broader (13, 14). Aortic root dilatation is common (15), and aortic dissection has been reported to occur with increased frequency (15, 16). Women with Turner syndrome are also at increased risk of atherosclerosis, exacerbated by an increased prevalence of hypertension, insulin resistance, hyperlipidemia, obesity, and estrogen deficiency (4, 17). Our study shows that the cumulative risk of death from aortic aneurysm is high: 0.8% by age 45 and 2.7% by age 85 yr. It is also clear that such deaths may occur at strikingly young ages, as shown in a recent study of 5220 women with Turner syndrome monitored while on treatment with recombinant human GH, in which four deaths from aortic aneurysm and one from aortic dissection occurred in patients aged 14–16 yr (18). In our cohort, which was on average considerably older, we observed 12 deaths from aortic aneurysm in patients aged 15–44 yr (including seven under age 30), amounting to a more than 200-fold increased risk compared with the general population.

Raised mortality from endocrine causes was due to diabetes mellitus. In our study, the death certificates did not specify the type of diabetes, but both type I and type II diabetes have been reported to be more common in Turner syndrome (19). The particularly high mortality from diabetes in women with an i(Xq) lineage might perhaps be due to type I diabetes because an i(Xq) karyotype is thought to predispose to autoimmune disease (4).

Raised mortality from liver disease might be expected because Turner syndrome has been associated with raised levels of liver enzymes (20, 21, 22) as well as architectural liver changes such as cirrhosis, nodular regenerative hyperplasia, and focal nodular hyperplasia (23). Our finding is compatible with past observations of raised morbidity from liver cirrhosis in Turner syndrome (19), which does not appear to be alcohol related.

Mortality from renal disease was 7-fold raised. Congenital malformations of the urinary system are thought to be present in 30–40% of patients with Turner syndrome (24), giving rise to increased propensity to urinary tract infections (13) and potentially also to renal dysfunction.

The significant raised mortality from epilepsy in our study is unexpected because epilepsy does not appear to be an established clinical feature associated with this syndrome (3, 4, 5, 13). Structural and metabolic brain abnormalities have been described, however (25). We previously reported increased mortality from epilepsy in men with 47,XXY (Klinefelter syndrome) (26) and 47,XYY (27) karyotypes, highlighting a potential role of the sex chromosomes in epileptic disorders.

Deaths from accidents and violence were of a heterogeneous nature. Although patients with Turner syndrome show normal behavioral function, they may have lower self-esteem and higher anxiety levels than 46,XX females and might be at risk of psychological problems (28), potentially relevant to the observation that several deaths in the cohort were by suicide.

Respiratory disease accounted for 14% of absolute excess mortality, with raised mortality from pneumonia. This finding must be interpreted with caution because pneumonia is a diagnosis that is often entered on death certificates as the underlying cause when it may actually have been the terminal event in deaths due to other causes (29). Our data suggest that risk of death from respiratory disease other than pneumonia is not raised.

Although mortality from cancer overall was close to that expected in the general population, mortality was reduced for breast cancer, consistent with the lack of breast development and low estrogen levels associated with Turner syndrome (3), and raised for nervous system tumors. These findings are similar to our previous findings on cancer incidence risks in this cohort (8). Unfortunately, it was not practical to gain data on medical treatments such as estrogen replacement and GH treatment for this large cohort, so that we cannot determine to what extent (if any) the cancer or other results have been affected by such treatments.

Phenotypical severity of Turner syndrome is thought to be associated with karyotype, with the most severe phenotype in women with 45,X monosomy and the least severe in those mosaic for a normal cell line (3, 30). Our finding that women with 45,X were diagnosed with Turner syndrome on average at a much younger age and had greater mortality than women with 45,X/46,XX, is compatible with this. SMRs were greatest in women who were diagnosed in childhood, a likely consequence of greater phenotypical severity in women diagnosed at young ages.

Our study shows that mortality risks in women with Turner syndrome remain raised throughout life. Although the relative risk of death (SMR) (i.e. the ratio of deaths in the study population compared with the number expected from rates in the general population) was greater at childhood than at adult ages, the AER of mortality (i.e. the number of extra deaths per 100,000 population per annum, compared with rates in the general population) was considerably greater at older than younger ages. The AER is probably the more relevant measure from a clinical perspective, because it indicates the extra risk of death patients encounter. These findings, especially because some of the deaths are potentially preventable, emphasize the importance of medical follow-up of adult women with Turner syndrome (4, 5, 13).

The decrease in all-cause SMRs in more recent calendar periods observed in our study, as well as in the Danish study (1), could be due to changes in composition of the cohort over time, in particular in terms of a decreasing proportion of 45,X monosomy and increasing age of the cohort or due to a real decrease in mortality as a result of improved medical care of patients with Turner syndrome.

The possibility that bias has affected our results needs consideration. Patients were ascertained from historical records kept at cytogenetic centers. We could include only women in the cohort who had been diagnosed with Turner syndrome during the years that the cytogenetic centers had retained their records and for whom sufficient information was available for flagging at the NHSCR. There is no plausible reason, however, why these restrictions would relate to risk of death, because the absence of identifying information was a function of recording systems before follow-up occurred, and availability of records was based on year of karyotyping, not on diagnosis or follow-up. An exception is that one reason for lack of name information is if individuals were diagnosed very soon after birth before the infant was named. Because diagnosis in infancy is more likely with severe phenotypes (30, 31), the study may to a small extent have omitted individuals with such severe phenotypes. This would have led to underestimation of mortality in the neonatal period, because there is a strong association between neck webbing, a well-recognized clinical feature of Turner syndrome, and congenital cardiovascular defects (32). Such partial omission of girls with severe phenotypical features might have contributed to the relative low proportion of women with 45,X monosomy in our study (36%) compared with the Danish study (45%) (1), because girls with a severe phenotype are more likely to be of 45,X karyotype (3, 30). However, we also observed that the overall proportion of patients with nonmosaic 45,X declined in recent years, because diagnostic methods have improved in the detection of minor mosaicism, and thus the difference in proportions between the two studies could be due to our cohort having been diagnosed later, on average, than the Danish cohort.

We estimate that for the birth years for which we have the largest annual numbers of Turner cases (years of birth 1960–1989), our study included just over 50% of the number of patients expected based on a newborn prevalence of one in 2000 births (1) and the annual number of female births in Great Britain. Although some of this disparity might be due to unavailability of historical records at cytogenetic centers and legal abortions of prenatally diagnosed cases, it is also known that a substantial proportion of women with Turner syndrome remain undetected (1). Such undetected cases are likely to have fewer phenotypic features of Turner syndrome than do other cases (33). Our study is of diagnosed cases, and from a clinical perspective, it is the mortality of diagnosed cases that is of relevance rather than of cases that are never diagnosed. There is potential for bias in our results, however, if referral for cytogenetic testing for Turner syndrome was triggered by the clinical diagnosis of, or care for, another illness, with the consequence that mortality from this other condition could be artifactually raised in the cohort. Such bias would be expected to be greatest in the early years after diagnosis of Turner syndrome and diminish with time. Therefore, if it occurred, SMRs would be less elevated with exclusion of the early years of follow-up. We found some evidence for this related to congenital cardiovascular anomalies and heart disease including aortic valve disease, but not for other diseases. Some bias related to these diseases is highly likely because they are likely to result in cytogenetic testing, but they were responsible for only a small proportion of all deaths, and the analyses showed that the effect of this was small and did not explain the raised risks observed in the cohort.

Our study shows that mortality in women with Turner syndrome is three times higher than in the general population and that mortality is greatly raised from almost all major causes and at all ages, with much the greatest rate of excess mortality in older adulthood. The observed risks need to be considered when following up and counseling patients with Turner syndrome and adds to the reasons for continued follow-up and preventive measures in adult, not just pediatric, care.

	Acknowledgments

 
We thank the Medical Research Council for funding; D. Allen, F. Barber, A. Butlin, C. Maguire, P. Murnaghan, M. Pelerin, and M. Swanwick for data collection; E. Boyd, D. Couzin, J. Delhanty, P. Ellis, M. Faed, J. Fennell, A. Kessling, A. McDermott, A. Parkin, A. Potter, and D. Ravine for access to data; N. Mudie and A. Hart for help in coding; H. Nguyen and A. Butlin for data entry; Z. Qiao and J. Hemming for computer programming; M. Collinson, N. Dennis, M. Jones, and D. Alexandrou for advice; the NHSCRs and cancer registries of England, Wales, and Scotland for follow-up data; and M. Snigorska for secretarial assistance.

The United Kingdom Clinical Cytogenetics Group comprises the named authors above plus Paul J. Batstone (Inverness Genetics Laboratory, Raigmore Hospital, Inverness), Thomas Spencer (NE London Regional Cytogenetics Laboratory, Great Ormond Street Hospital, London), Teresa Davies (South West Regional Cytogenetics Centre, Southmead Hospital, Bristol), Valerie Davison (West Midlands Regional Genetics Laboratory, Birmingham Women’s Hospital, Birmingham), Zoe Docherty (SE Thames Regional Genetics Service, Guy’s Hospital, London), David P. Duckett (Leicestershire Cytogenetics Centre, Leicester Royal Infirmary, Leicester), Margaret Fitchett (Oxford Regional Genetics Service, The Churchill Hospital, Oxford), Alison Fordyce (Human Genetics Unit, Western General Hospital, Edinburgh), Lorraine Gaunt (Department of Medical Genetics, St. Mary’s Hospital, Manchester), Elizabeth Grace (SE Scotland Regional Genetics Centre, Western General Hospital, Edinburgh), Peter Howard (Regional Cytogenetics Laboratory, Liverpool Women’s NHS Foundation Trust, Liverpool), Gordon W. Lowther (West of Scotland Regional Genetics Service, Yorkhill NHS Trust, Glasgow), Carol Chu (Duncan Guthrie Institute of Medical Genetics, Yorkhill Hospital, Glasgow), Christine Maliszewska (E Scotland Human Genetic Laboratories, Ninewells Hospital and Medical School, Dundee), Edna L. Maltby (North Trent Clinical Genetics Service, Sheffield Children’s Hospital, Sheffield), Kevin P. Ocraft (Nottingham Regional Clinical Cytogenetics Service, City Hospital, Nottingham), Selwyn Roberts (Institute of Medical Genetics, University Hospital of Wales, Cardiff), Kim K. Smith (East Anglia Regional Genetics Service, Addenbrookes Hospital, Cambridge), Gordon S. Stephen (N Scotland Clinical Genetics Service, Aberdeen Royal Infirmary, Aberdeen), John W. Taylor (SW Thames Regional Genetics Service, St. George’s Hospital, London), Catherine S. Waters (NW Thames Regional Genetics Service, Northwick Park and St. Marks NHS Trust, Middlesex), Jeffery Williams (Yorkshire Regional Genetics Service, St. James’s University Hospital, Leeds), John Wolstenholme (Northern Region Genetics Service, Institute of Human Genetics, Newcastle), and Sheila Youings (Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury).

	Footnotes

 
Disclosure Statement: The authors have nothing to disclose.

First Published Online September 23, 2008

Abbreviations: AER, Absolute excess risk; CI, confidence interval; NHSCR, National Health Service Central Register; SMR, standardized mortality ratio.

Received May 15, 2008.

Accepted September 16, 2008.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH 2006 Prevalence, incidence, diagnostic delay, and mortality in Turner syndrome. J Clin Endocrinol Metab 91:3897–3902[Abstract/Free Full Text]
2. Sybert VP 1998 Cardiovascular malformations and complications in Turner syndrome. Pediatrics 101:E11
3. Sybert VP, McCauley E 2004 Turner’s syndrome. N Engl J Med 351:1227–1238[Free Full Text]
4. Elsheikh M, Dunger DB, Conway GS, Wass JA 2002 Turner’s syndrome in adulthood. Endocr Rev 23:120–140[Abstract/Free Full Text]
5. Conway GS 2002 The impact and management of Turner’s syndrome in adult life. Best Pract Res Clin Endocrinol Metab 16:243–261[CrossRef][Medline]
6. Price WH, Clayton JF, Collyer S, De Mey R, Wilson J 1986 Mortality ratios, life expectancy, and causes of death in patients with Turner’s syndrome. J Epidemiol Community Health 40:97–102[Abstract/Free Full Text]
7. Swerdlow AJ, Hermon C, Jacobs PA, Alberman E, Beral V, Daker M, Fordyce A, Youings S 2001 Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study. Ann Hum Genet 65:177–188[CrossRef][Medline]
8. Schoemaker MJ, Swerdlow AJ, Higgins CD, Wright AF, Jacobs PA 2008 Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol 9:239–246[CrossRef][Medline]
9. Swerdlow AJ, Dos Santos Silva I, Doll R 2002 Cancer incidence and mortality in England and Wales: trends and risk factors. Oxford, UK: Oxford University Press; 157–162
10. World Health Organization 1977 International statistical classification of diseases and related health problems, 9th revision. Geneva: World Health Organization
11. Breslow NE, Day NE 1987 Statistical methods in cancer research. Volume II. The design and analysis of cohort studies. IARC Scientific Publication No. 82. Lyon, France: International Agency for Research on Cancer
12. Satagopan JM, Ben Porat L, Berwick M, Robson M, Kutler D, Auerbach AD 2004 A note on competing risks in survival data analysis. Br J Cancer 91:1229–1235[CrossRef][Medline]
13. Bondy CA 2007 Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 92:10–25[Abstract/Free Full Text]
14. Bondy CA 2008 Congenital cardiovascular disease in Turner syndrome. Congenit Heart Dis 3:2–15[Medline]
15. Matura LA, Ho VB, Rosing DR, Bondy CA 2007 Aortic dilatation and dissection in Turner syndrome. Circulation 116:1663–1670[Abstract/Free Full Text]
16. Gravholt CH, Landin-Wilhelmsen K, Stochholm K, Hjerrild BE, Ledet T, Djurhuus CB, Sylven L, Baandrup U, Kristensen BO, Christiansen JS 2006 Clinical and epidemiological description of aortic dissection in Turner’s syndrome. Cardiol Young 16:430–436[CrossRef][Medline]
17. Gravholt CH 2004 Epidemiological, endocrine and metabolic features in Turner syndrome. Eur J Endocrinol 151:657–687[Abstract]
18. Bolar K, Hoffman AR, Maneatis T, Lippe B 2008 Long-term safety of recombinant human growth hormone in turner syndrome. J Clin Endocrinol Metab 93:344–351[Abstract/Free Full Text]
19. Gravholt CH, Juul S, Naeraa RW, Hansen J 1998 Morbidity in Turner syndrome. J Clin Epidemiol 51:147–158[CrossRef][Medline]
20. Larizza D, Locatelli M, Vitali L, Vigano C, Calcaterra V, Tinelli C, Sommaruga MG, Bozzini A, Campani R, Severi F 2000 Serum liver enzymes in Turner syndrome. Eur J Pediatr 159:143–148[CrossRef][Medline]
21. Albareda MM, Gallego A, Enriquez J, Rodriguez JL, Webb SM 1999 Biochemical liver abnormalities in Turner’s syndrome. Eur J Gastroenterol Hepatol 11:1037–1039[Medline]
22. Salerno M, Di Maio S, Gasparini N, Rizzo M, Ferri P, Vajro P 1999 Liver abnormalities in Turner syndrome. Eur J Pediatr 158:618–623[CrossRef][Medline]
23. Roulot D, Degott C, Chazouilleres O, Oberti F, Cales P, Carbonell N, Benferhat S, Bresson-Hadni S, Valla D 2004 Vascular involvement of the liver in Turner’s syndrome. Hepatology 39:239–247[CrossRef][Medline]
24. Bilge I, Kayserili H, Emre S, Nayir A, Sirin A, Tukel T, Bas F, Kilic G, Basaran S, Gunoz H, Apak M 2000 Frequency of renal malformations in Turner syndrome: analysis of 82 Turkish children. Pediatr Nephrol 14:1111–1114[CrossRef][Medline]
25. Cutter WJ, Daly EM, Robertson DM, Chitnis XA, van Amelsvoort TA, Simmons A, Ng VW, Williams BS, Shaw P, Conway GS, Skuse DH, Collier DA, Craig M, Murphy DG 2006 Influence of X chromosome and hormones on human brain development: a magnetic resonance imaging and proton magnetic resonance spectroscopy study of Turner syndrome. Biol Psychiatry 59:273–283[CrossRef][Medline]
26. Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA 2005 Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab 90:6516–6522[Abstract/Free Full Text]
27. Higgins CD, Swerdlow AJ, Schoemaker MJ, Wright AF, Jacobs PA 2007 Mortality and cancer incidence in males with Y polysomy in Britain: a cohort study. Hum Genet 121:691–696[CrossRef][Medline]
28. Kilic BG, Ergur AT, Ocal G 2005 Depression, levels of anxiety and self-concept in girls with Turner’s syndrome. J Pediatr Endocrinol Metab 18:1111–1117[Medline]
29. Ashley J, Devis T 1992 Death certification from the point of view of the epidemiologist. Popul Trends 67:22–28
30. El Mansoury M, Barrenas ML, Bryman I, Hanson C, Larsson C, Wilhelmsen L, Landin-Wilhelmsen K 2007 Chromosomal mosaicism mitigates stigmata and cardiovascular risk factors in Turner syndrome. Clin Endocrinol (Oxf) 66:744–751[CrossRef][Medline]
31. Massa G, Verlinde F, De Schepper J, Thomas M, Bourguignon JP, Craen M, de Zegher F, Francois I, Du CM, Maes M, Heinrichs C 2005 Trends in age at diagnosis of Turner syndrome. Arch Dis Child 90:267–268[Abstract/Free Full Text]
32. Loscalzo ML, Van PL, Ho VB, Bakalov VK, Rosing DR, Malone CA, Dietz HC, Bondy CA 2005 Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome. Pediatrics 115:732–735[Abstract/Free Full Text]
33. Gunther DF, Eugster E, Zagar AJ, Bryant CG, Davenport ML, Quigley CA 2004 Ascertainment bias in Turner syndrome: new insights from girls who were diagnosed incidentally in prenatal life. Pediatrics 114:640–644[Abstract/Free Full Text]

This article has been cited by other articles:

				G. S. Conway Adult Care of Pediatric Conditions: Lessons from Turner's Syndrome J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3185 - 3187. [Full Text] [PDF]

				M. Devernay, E. Ecosse, J. Coste, and J.-C. Carel Determinants of Medical Care for Young Women with Turner Syndrome J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3408 - 3413. [Abstract] [Full Text] [PDF]

				V. K. Bakalov, C. Cheng, J. Zhou, and C. A. Bondy X-Chromosome Gene Dosage and the Risk of Diabetes in Turner Syndrome J. Clin. Endocrinol. Metab., September 1, 2009; 94(9): 3289 - 3296. [Abstract] [Full Text] [PDF]

				F. J. Broekmans, M. R. Soules, and B. C. Fauser Ovarian Aging: Mechanisms and Clinical Consequences Endocr. Rev., August 1, 2009; 30(5): 465 - 493. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schoemaker, M. J. Search for Related Content PubMed PubMed Citation Articles by Schoemaker, M. J. Related Collections Cardiovascular Endocrinology Female Endocrinology