Risk of solid tumors and hematological malignancy in persons with Turner and klinefelter syndromes: a national cohort study
Abstract
The risk of solid and hematological malignancy in patients with Turner syndrome, characterized by X chromosome monosomy in women, and Klinefelter syndrome, characterized with two and more X chromosomes in men, is not well established, but such evidence may have etiological implications on cancer development. We identified a total of 1,409 women with Turner syndrome and 1,085 men with Klinefelter syndrome from the Swedish Hospital Discharge and Outpatient Register. These individuals were further linked to the Swedish Cancer Register to examine the standardized incidence ratios (SIRs) of cancer using the general population without Turner and Klinefelter syndromes as reference. The overall risk of cancer was 1.34 for women with Turner syndrome; it was increased only for solid tumors. For a specific type of tumor, the risk of melanoma and central nervous system tumor was significantly increased. For persons with Klinefelter syndrome, the risk of solid tumors was decreased (SIR = 0.66), whereas the risk of hematological malignancy was increased (SIR = 2.72). Non-Hodgkin lymphoma and leukemia showed an increased SIR of 3.02 and 3.62, respectively. Our study supported the hypothesis that X chromosome plays an important role in the etiology of solid tumors. The underlying mechanisms for the increased incidence of non-Hodgkin lymphoma and leukemia in persons with Klinefelter syndrome need to be investigated further.
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Large cohort studies disagree on whether there is an increased risk for melanoma in TS.
“Large cohort studies disagree on whether there is an increased risk for melanoma.332,682”
From Clinical practice guidelines for the care of girls and women with Turner syndrome. (2024) · cites this paper as [682]
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Update on Physical, Psychological, and Quality of Life Management in Klinefelter Syndrome
Mehmet, B., Dwyer, A. A., Jayasena, C. N., Gillard, S., & Llahana, S. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf261 · Cited by 12 · see citing works
Gender Differences in Urothelial Bladder Cancer: Effects of Natural Killer Lymphocyte Immunity
Lutz, C. T., Livas, L. I., Presnell, S. R., Sexton, M., & Wang, P. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10215163 · Cited by 13 · see citing works
“Similarly, solid tumor incidence is decreased in Klinefelter syndrome patients, who carry at least 2 X chromosomes and 1 Y chromosome, have small testicle size, and reduced testosterone [213].”
BackgroundKlinefelter syndrome or testicular dysgenesis: Genetics, endocrinology, and neuropsychology
Skakkebaek, A. H., Wallentin, M., & Gravholt, C. H. (2021) · Handbook of clinical neurology · doi:10.1016/b978-0-12-820683-6.00032-4 · Cited by 13 · see citing works
Dhabhai, B., Sharma, A., Maciaczyk, J., & Dakal, T. C. (2021) · Cancer Investigation · doi:10.1080/07357907.2021.1981364 · Cited by 11 · see citing works
“Similarly, an increased risk of solid tumors has been discussed in Turner syndrome, whereas the risk appeared to be lower in individuals with Klinefelter syndrome (20).”
BackgroundOncologic manifestations of Klinefelter syndrome
Rojas, A. P., Vo, D. V., Mwangi, L., Rehman, S., & Peiris, A. N. (2020) · HORMONES · doi:10.1007/s42000-020-00241-7 · Cited by 11 · see citing works
Moretti, N. R., da Silva, A. B. N., Guimarães, G. V., Bezerra, I. D. P., Taumaturgo, J. A. C., Alves, N. G. S., Kelly, F. A., & de Moraes, F. C. A. (2024) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2024.104558 · Cited by 10 · see citing works
Neoplasia in Turner syndrome: a retrospective cohort study in a tertiary referral centre in Belgium
Dejonckheere, C. S., Moyson, C., de Zegher, F., Antonio, L., Buggenhout, G. V., & Decallonne, B. (2020) · Acta Clinica Belgica · doi:10.1080/17843286.2020.1805237 · Cited by 11 · see citing works
“naevi TS women exhibit, as previously noted [13,14].”
ResultWorse survival after breast cancer in women with anorexia nervosa
Bens, A., Papadopoulos, F. C., Pukkala, ., Ekbom, A., Gissler, M., & Mellemkjær, L. (2017) · Breast Cancer Research and Treatment · doi:10.1007/s10549-017-4618-5 · Cited by 10 · see citing works
Immunology, Immunotherapy, and Translating Basic Science into the Clinic for Bladder Cancer
Ingersoll, M. A., Li, X., Inman, B. A., Greiner, J. W., Black, P. C., & Adam, R. M. (2018) · Bladder Cancer · doi:10.3233/blc-180175 · Cited by 10 · see citing works
“The overall risk of solid tumors, including BCa, in Turner patients is significantly higher compared to the general population [9, 10].”
BackgroundSexual dimorphism in bladder cancer: a review of etiology, biology, diagnosis, and outcomes
Zhu, S., & Zhao, H. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1326627 · Cited by 9 · see citing works
Breast Cancer and Major Deviations of Genetic and Gender-related Structures and Function
Bennink, H. J. T. C., Egberts, J. F. M., Mol, J. A., Roes, K. C. B., & van Diest, P. J. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa404 · Cited by 9 · see citing works
Genomic instability in individuals with sex determination defects and germ cell cancer
Krivega, M., Zimmer, J., Slezko, A., Frank‐Herrmann, P., Rehnitz, J., Hohenfellner, M., Bettendorf, M., Luzarowski, M., & Strowitzki, T. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01470-6 · Cited by 9 · see citing works
Gender and sex interactions are intrinsic components of cancer phenotypes
Rubin, J. B. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-025-00829-4 · Cited by 8 · see citing works
“The decrease in cancer incidence across individuals with the karyotypes XY to XXY (Klinefelter syndrome) to XO (Turner syndrome) to XX genotypes, suggests that, overall, Y chromosomes are associated with higher and X chromosomes with lower cancer incidence 64 .”
Papillary thyroid carcinoma in a patient with Turner syndrome treated with human growth hormone
Bautembach-Minkowska, J., Birkholz-Walerzak, D., Kędzia, A. W., & Myśliwiec, M. (2018) · Pediatric Endocrinology Diabetes and Metabolism · doi:10.5114/pedm.2018.80997 · Cited by 7 · see citing works
Kjeldsen, E. (2022) · Cancers · doi:10.3390/cancers14092316 · Cited by 7 · see citing works
“Female Turner syndrome patients have an increased risk of gonadoblastoma and brain tumors [18], while men with Y polysomy have rates of cancer incidence equivalent to the general population [19].”
BackgroundAversa, T., SANCTIS, L. D., Faienza, M. F., Gambineri, A., Balducci, A., D'Aprile, R., Somma, C. D., Giavoli, C., Grossi, A., Meriggiola, M. C., et al. (2024) · Journal of Endocrinological Investigation · doi:10.1007/s40618-024-02315-4 · Cited by 6 · see citing works
Klinefelter syndrome and 47, XYY syndrome in children with B cell acute lymphoblastic leukaemia
Rau, R. E., Carroll, A. J., Heerema, N. A., Arland, L., Carroll, W. L., Winick, N. J., Raetz, E. A., Loh, M. L., Yang, W., Relling, M. V., et al. (2016) · British Journal of Haematology · doi:10.1111/bjh.14258 · Cited by 6 · see citing works
Papanikolaou, M., Chohan, T., & Millington, G. W. M. (2019) · Clinical and Experimental Dermatology · doi:10.1111/ced.14153 · Cited by 5 · see citing works
Gawrychowska, A., Iżycka‐Świeszewska, E., Lipska-Ziętkiewicz, B. S., Kuleszo, D., Bautembach-Minkowska, J., Łosin, M., & Stefanowicz, J. (2020) · Diagnostics · doi:10.3390/diagnostics10121067 · Cited by 6 · see citing works
“Another cohort study reported that women with TS had an increased risk of melanoma and central nervous system tumors, mainly meningiomas [20].”
BackgroundChromosome-wide gene dosage rebalance may benefit tumor progression
Zhang, H., Yang, X., Feng, X., Xu, H., Yang, Q., Zou, L., Yan, M.-R., Liu, D., Su, X., & Jiao, B. (2018) · Zeitschrift für Induktive Abstammungs- und Vererbungslehre · doi:10.1007/s00438-018-1429-2 · Cited by 5 · see citing works
“Human X chromosome aneuploidy including Turner syndrome (Lee and Conway 2014) characterized by X chromosome monosomy in women has been extensively reported to be associated with various cancer risk (Hasle et al. 1996; Scott et al. 2006; Ganmore et al. 2009; Ji et al. 2016).”
BackgroundOutcomes in hospitalisations of women with Turner syndrome compared to women without Turner syndrome
Singh, I., Duca, L. M., Kao, D. P., Chatfield, K. C., & Khanna, A. D. (2021) · Cardiology in the Young · doi:10.1017/s1047951121000858 · Cited by 5 · see citing works
Qi, X., Wang, Q., Yu, M., Kong, Y., Shi, F., & Wang, S. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1024244 · Cited by 5 · see citing works
Nonneoplastic Diseases of the Testis
Nistal, M., Paniagua, R., & González‐Peramato, P. (2020) · Elsevier eBooks · doi:10.1016/b978-0-323-54941-7.00012-8 · Cited by 5 · see citing works
Ding, F., Xu, J., Xiong, J., Li, Q., Cheng, Z., & Deng, L. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1552300 · Cited by 5 · see citing works
Type 1 Diabetes Mellitus and Klinefelter Syndrome
Sakurai, T., Iizuka, K., Kato, T., & Takeda, J. (2018) · Internal Medicine · doi:10.2169/internalmedicine.1051-18 · Cited by 4 · see citing works
“There is no universal guideline regarding the follow-up of KS patients; however, we will continue to counsel this patient with respect to the increased incidence of malignancies, such as breast and hematological cancers (20, 21), bone fracture, and cardiovascular diseases (22), and continue to control his glycemic lev…”
Yiğin, A. K., Alay, M. T., Uğurlu, S., & Seven, M. (2023) · American Journal of Men s Health · doi:10.1177/15579883231165173 · Cited by 4 · see citing works
“5-fold increase in hematological malignancy, leukemia, and lymphoma risk in KS patients (Ji et al., 2016).”
BackgroundInfluentialCanCHD Study of Hematopoietic Cancers in Children With and Without Genetic Syndromes
Hasan, M. S., Ganni, E., Liu, A., Guo, L., Mackie, A. S., Kaufman, J. S., & Marelli, A. J. (2023) · Journal of the American Heart Association · doi:10.1161/jaha.122.026604 · Cited by 4 · see citing works
“In 28–32 Nevertheless, research on evaluating the role of genetic syndromes on hematopoietic cancer (HC) risk in pediatric patients with CHD has remained sparse, with conflicting findings.”
Tumour occurrence in women with Turner syndrome: A narrative review and single‐centre case series
Diddhenipothage, S. A. D. M., Goindoo, R., Bragg, F., Orchard, E., Shears, D. J., Calanchini, M., & Turner, H. E. (2023) · Clinical Endocrinology · doi:10.1111/cen.14910 · Cited by 4 · see citing works
“In contrast to the discordant results discussed for the different tumours above, all recently reported large population studies consistently observed reduced occurrence of breast cancers in women with TS compared to the background female population.(2,10,11) Additionally, the UK(11) and Swedish(2) cohorts observed low…”
BackgroundResultHong, Y. H., Kim, D. G., Lee, J. H., Jung, M. J., & Choi, C. Y. (2020) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2020.2019.0223 · Cited by 4 · see citing works
“Some large retrospective observational studies [8-10] have undertaken a comparison of cytogenetic and cancer registries recording data.”
BackgroundLauhan, C. R., Schiff, D. E., & Gloude, N. J. (2020) · Pediatric Blood & Cancer · doi:10.1002/pbc.28528 · Cited by 4 · see citing works
Alvarez, G. V., Liao, K.-P. E., Wehner, M. R., & Rogge, M. N. (2024) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2024.09.055 · Cited by 3 · see citing works
Cai, F., Xu, S., Li, Y., He, Q., Su, Q., Chen, H., Liu, W., Chen, J., Wang, Q., Assaraf, Y. G., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1554829 · Cited by 3 · see citing works
Medulloblastoma and secondary acute myeloid leukemia in a patient with Turner syndrome
Davidow, K. A., & Walter, A. W. (2018) · Pediatric Blood & Cancer · doi:10.1002/pbc.27576 · Cited by 3 · see citing works
Global burden and health inequalities of sex chromosomal DSDs (1990–2021): a GBD 2021 analysis
Su, X., Chen, F., Shi, Z., Tao, Y., Han, X., & Li, X. (2025) · International Urology and Nephrology · doi:10.1007/s11255-025-04677-x · Cited by 2 · see citing works
“Additionally, it is associated with an increased risk of numerous conditions, such as metabolic syndrome, cardiovascular and cerebrovascular diseases, bone metabolism disorders, autoimmune diseases, hematological malignancy, congenital anomalies, and mental health issues [5–11].”
Lost but not least: Y chromosome loss as a driver of cancer
Corchete, L. A., & Rheinbay, E. (2025) · Trends in cancer · doi:10.1016/j.trecan.2025.11.009 · Cited by 3 · see citing works
Krzyścin, M., Soszka-Przepiera, E., Zając, K., Brodowska, A., Przepiera, A., Pietrzyk, D., Bumbuliene, Z., & Sowińska-Przepiera, E. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15031088 · Cited by 2 · see citing works
“Population statistics vary geographically, with studies from Europe, the US, and Poland providing prevalence estimates between 17 and 35 per 100,000 girls and women [12,13].”
Genetic Disorders with Predisposition to Paediatric Haematopoietic Malignancies—A Review
Filipiuk, A., Kozakiewicz, A., Kośmider, K., Lejman, M., & Zawitkowska, J. (2022) · Cancers · doi:10.3390/cancers14153569 · Cited by 3 · see citing works
“Leukaemias and NHL were mainly diagnosed [84].”
Scarfì, F., Magnaterra, E., Santini, S., & Taviti, F. (2023) · Dermatology Reports · doi:10.4081/dr.2023.9812 · Cited by 2 · see citing works
Telomere Dysfunction in Pediatric Patients with Differences/Disorders of Sexual Development
Younoussa, H., Gadji, M., Soumboundou, M., Colicchio, B., Said, A. G., Ndoye, N. A., Junker, S., Plesch, A., Heidingsfelder, L., Diagne, N. R., et al. (2024) · Biomedicines · doi:10.3390/biomedicines12030565 · Cited by 2 · see citing works
“DSD patients exhibit a very high risk of gonadal cancers [18], hypogonadism [19,20], lung and breast cancers [21,22], as well as various fertility complications and hormonal insufficiency [23].”
BackgroundAli, I., Moore, T., Kashyap, A., Starling, C. T., Thomas, J. A. L., Truong, V. T. T., Prakash, S. K., & Rogge, M. N. (2024) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2024.06.034 · Cited by 2 · see citing works
Stanton, A. R., Aydin, S. C., Skelly, D. A., McGarr, T., Stavish, D., Leonhard, K., Taapken, S. M., Ludwig, T. E., McIntire, E. M., Pankratz, M. T., et al. (2026) · Stem Cell Reports · doi:10.1016/j.stemcr.2026.102933 · Cited by 2 · see citing works
Rossini, B., Skrypets, T., Minoia, C., Quinto, A. M., Zaccaria, G. M., Ferrari, C., Maggialetti, N., Mastrorosa, A., Gatti, P., Casiello, M., et al. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11070644 · Cited by 2 · see citing works
“The loss of chromosome X in TS could favor the onset of PRL as it contains nearly 10% of all microRNAs with the function implicated in controlling immunity and cancer [10].”
BackgroundInfluentialOncological diseases in Klinefelter Syndrome: an overview
Amer, M., VACCALLUZZO, L., Vena, W., Mazziotti, G., Morenghi, E., & Pizzocaro, A. (2021) · Minerva Endocrinology · doi:10.23736/s2724-6507.21.03440-0 · Cited by 2 · see citing works
Turner Syndrome, Atypical Naevi and Multiple Melanoma: Coincidence or Causality?
Clabbers, J. M. K., van Doorn, R., & Kukutsch, N. A. (2023) · Acta Dermato Venereologica · doi:10.2340/actadv.v103.5586 · Cited by 2 · see citing works
“In 2016, a Swedish national cohort study was published, showing data from a cancer registry of, in total, 1,409 women with Turner syndrome (10).”
BackgroundPrenatal Diagnosis of Sex Chromosome Abnormalities
Milunsky, J. M. (2021) · Wiley eBooks · doi:10.1002/9781119676980.ch12 · Cited by 2 · see citing works
Epidemiology of an Underdiagnosed Syndrome
Zavattaro, M., Marinelli, L., Motta, G., & Lanfranco, F. (2020) · Trends in andrology and sexual medicine · doi:10.1007/978-3-030-51410-5_2 · Cited by 1 · see citing works
Shen, Y., Song, C., Du, Y., Wang, L., Li, X., Shi, Y., Ye, D., Dong, S., & Liu, H. (2025) · Medicine · doi:10.1097/md.0000000000044519 · Cited by 1 · see citing works
“[46] The median age at TS diagnosis reported in previous studies ranges from 9.4 to 15 years, [7,47–49] generally younger than for KS, probably due to earlier clinical presentation.”
InfluentialBalle, C. M., Kassentoft, C. G., van Heusden, J. I., Knudsen, M., Raaby, L., & Gravholt, C. H. (2023) · Sexual Development · doi:10.1159/000536236 · Cited by 1 · see citing works
Turner syndrome: fertility, familial clustering, and cancer risk
Allen‐Brady, K., Verrilli, L. E., Austin, B., Letourneau, J. M., Johnstone, E. B., & Welt, C. K. (2024) · Human Reproduction · doi:10.1093/humrep/deae266 · Cited by 1 · see citing works
Biochemical and Clinical Features of Insulinoma in a Patient with Turner Syndrome
Schneider, D., Zare, M., Behnia, F., Matesan, M. C., & Tylee, T. S. (2019) · Case Reports in Endocrinology · doi:10.1155/2019/6809479 · Cited by 1 · see citing works
Woman with Turner syndrome and her child with acute leukemia (a case report)
Kitsera, N., Дорош, О. І., & Makukh, H. (2020) · Experimental Oncology · doi:10.32471/exp-oncology.2312-8852.vol-42-no-4.15275 · Cited by 1 · see citing works
Increased Colorectal Cancer Rate in Turner Syndrome: A Case Control Study
Gorrepati, V. S., Ba, D. M., Liu, G., Levenick, J. M., & McGarrity, T. J. (2022) · Advanced Biomedicine · doi:10.54730/abm.2022.040208 · Cited by 1 · see citing works
Intercellular competition and levels of development: The plasticity of inevitability
Eckhardt, R. B., Weller, A. S., & Henneberg, M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1719479115 · Cited by 1 · see citing works
Genomic instability in patients with sex determination defects and germ cell cancerPreprint
Krivega, M., Zimmer, J., Slezko, A., Frank‐Herrmann, P., Rehnitz, J., Hohenfellner, M., Bettendorf, M., Luzarowski, M., & Strowitzki, T. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.08.495249 · Cited by 1 · see citing works
Carriel, J., Leone, A. M., Borreguero-Martínez, E., Ruiz‐Artacho, P., Tornero-Romero, F., & Manuel, E. C. (2019) · Revista médica de Chile · doi:10.4067/s0034-98872019000400518
Description of Turner Syndrome
Roberts, A. J. C., & Fechner, P. Y. (2020) · Springer eBooks · doi:10.1007/978-3-030-34150-3_1
47,XXY (KLINEFELTER SYNDROME) AND RELATED X AND Y CHROMOSOMAL CONDITIONS
Samango‐Sprouse, C. A., Graham, J. M., Counts, D., & Visootsak, J. (2020) · doi:10.1002/9781119432692.ch35
Gender Disparities in Bladder Cancer
Zhang, Y., Theodorescu, D., & Li, X. (2021) · IntechOpen eBooks · doi:10.5772/intechopen.98225
Turner Syndrome and Craniopharyngioma
Korula, S., Beryl, S., Kamath, V., Mathew, S. S., & Joseph, V. (2021) · The Indian Journal of Pediatrics · doi:10.1007/s12098-021-03990-4
Sherwood, J. S. (2020) · Springer eBooks · doi:10.1007/978-3-030-52215-5_48
Gravholt, C. H. (2022) · doi:10.1093/med/9780198870197.003.0485
- Authors
- Ji, J., Zöller, B., Sundquist, J., & Sundquist, K.
- Affiliations
- Lund University (SE)
- Corresponding author
- Ji, Jianguang
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2016-04-19
- Volume
- 139
- Issue
- 4
- Pages
- 754-758
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2335787821
- Cited by
- 116
- References
- 47
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 17 · 2023: 11 · 2022: 11 · 2021: 11 · 2020: 21 · 2019: 8 · 2018: 10 · 2017: 3 · 2016: 1
- FWCI
- 5.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Swedish Research Council (K2012-70X-15428-08-3)
- Region Skåne
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Epidemiology › Multiple and Secondary Primary Cancers
- Keywords
- Turner syndrome, Klinefelter syndrome, solid tumors, hematologic malignancies, cancer risk, X chromosome, non-Hodgkin lymphoma, leukemia, melanoma, central nervous system tumors, sex chromosome aneuploidy
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Klinefelter Syndrome, Male, Middle Aged, Neoplasms, Population Surveillance, Registries, Risk, Sweden, Turner Syndrome, Cohort Studies, Hematologic Neoplasms, Young Adult
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