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, 124 (19), 3900-3908

Klinefelter Syndrome in Males With Germ Cell Tumors: A Report From the Children's Oncology Group


Klinefelter Syndrome in Males With Germ Cell Tumors: A Report From the Children's Oncology Group

Lindsay A Williams et al. Cancer.


Background: Males with Klinefelter syndrome (KS) (47,XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. To date, there are no reports characterizing the prevalence of KS among male GCT cases.

Methods: The authors used array genotyping data from a Children's Oncology Group epidemiology study to estimate the prevalence of KS in males with GCTs (433 males aged birth-19 years). Using Fisher's exact tests, the authors examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and several birth characteristics between cases of KS-GCT and GCT cases without chromosomal abnormalities. Using publicly available data, the authors estimated the 1-year risk, risk ratio, and corresponding 95% confidence interval of GCTs among KS cases.

Results: Based on analysis of array genotyping data, 3% of male GCT cases (13 cases) had KS. The additional X chromosome was of maternal origin in 7 of the 13 cases. Of these 13 KS cases, 5 of 9 KS-GCT cases with parental questionnaire data (56%) reported a diagnosis of KS. No significant differences were observed with regard to patient or birth characteristics between KS-GCT and non-KS-GCT cases. KS-GCT cases were significantly more likely to be diagnosed with mediastinal tumors than non-KS-GCT cases (P<.01). The authors estimated the risk of developing a GCT among males with KS to be 0.00025, or 1 per 4000 males (risk ratio, 18.8; 95% confidence interval, 11.7-30.0).

Conclusions: Compared with males without chromosomal abnormalities, males with KS are more likely to be diagnosed with a mediastinal GCT. The presence of KS should be considered in males with a diagnosis of mediastinal GCT. In the current study, the authors report that approximately one-third of males with mediastinal germ cell tumors have Klinefelter syndrome, and therefore screening of these individuals for the syndrome may be warranted. Males with Klinefelter syndrome are 19 times as likely as males without Klinefelter syndrome to develop germ cell tumors.

Keywords: Klinefelter syndrome; epidemiology; germ cell tumors; histology; mediastinal tumors.

Conflict of interest statement

Conflicts of Interest

A. Lindsay Frazier has acted as a paid consultant for Decibel Therapeutics for work performed outside of the submitted study. The remaining authors made no disclosures.


Figure 1.
Figure 1.
An image generated by the SexPlot module (Genvisis) displaying individuals with an extra X chromosome. KS cases have median intensities matching females for the X chromosome (x-axis) and males for the Y chromosome (y-axis). The individual with Triple X syndrome was a mother of a normal karyotype GCT case.
Figure 2.
Figure 2.
B allele frequencies plots (x-axis: X chromosome marker position; y-axis: estimated proportion of B alleles). Normal males and females have two gene copies at pseudoautosomal regions (PARs), whereas individuals with Klinefelter syndrome have three (BAF: 0.0, 0.33, 0.66 and 1.0). Gray dots indicate markers that failed QC and were excluded.

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