Associations between birth defects and childhood and adolescent germ cell tumors according to sex, histologic subtype, and site

Abstract

BackgroundStudies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics.MethodsBirth defect–GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population‐based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and by genetic and chromosomal syndromes and nonsyndromic defects. Stratification was by sex, tumor histology (yolk sac tumor, teratoma, germinoma, and mixed/other), and location (gonadal, extragonadal, and intracranial).ResultsBirth defects and syndromic defects were more common among GCT cases than controls (6.9% vs. 4.0% and 2.7% vs. 0.2%, respectively; both p < .001). In multivariable models, GCT risk was increased among children with birth defects (OR, 1.7; 95% CI, 1.3–2.4) and syndromic defects (OR, 10.4; 95% CI, 4.9–22.1). When stratified by tumor characteristics, birth defects were associated with yolk sac tumors (OR, 2.7; 95% CI, 1.3–5.0) and mixed/other histologies (OR, 2.1; 95% CI, 1.2–3.5) and both gonadal tumors (OR, 1.7; 95% CI, 1.0–2.7) and extragonadal tumors (OR, 3.8; 95% CI, 2.1–6.5). Nonsyndromic defects specifically were not associated with GCTs. In sex‐stratified analyses, associations were observed among males but not females.ConclusionsThese data suggest that males with syndromic birth defects are at an increased risk of pediatric GCTs, whereas males with nonsyndromic defects and females are not at an increased risk.Plain Language Summary We investigated whether birth defects (such as congenital heart disease or Down syndrome) are linked to childhood germ cell tumors (GCTs), cancers that mainly develop in the ovaries or testes. We studied different types of birth defects (defects that were caused by chromosome changes such as Down syndrome or Klinefelter syndrome and defects that were not) and different types of GCTs. Only chromosome changes such as Down syndrome or Klinefelter syndrome were linked to GCTs. Our study suggests that most children with birth defects are not at an increased risk of GCTs because most birth defects are not caused by chromosome changes.

Non-syndromic and Syndromic Defects in Children with Extracranial Germ Cell Tumors (eGCT): Data of 2,610 Children Registered with the German MAKEI 96/MAHO 98 Registry Compared to the General Population

“…In the literature few papers used a control group describing potential associations of syndromes and later emergence of eGCTs [39][40][41][42][43]. Whereas some previous papers only reported associations between tumor and syndrome in cases [44][45][46][47], a recent paper with a control group allowing for individual case control analysis with adjustment confirmed a strong statistical association for Klinefelter with comparison to controls, but not for Turner and Down syndrome [19]. Our data confirmed the latter.…”

“…For non-syndromic defects we failed to identify an increased risk for eGCTs in accordance with Schraw et al [19]. A subgroup analysis linking tumor site and congenital anomaly did not yield significant results either.…”

“…In accordance with Schraw et al [19] we distinguished effects of syndromes and isolated nonsyndromic defects. In cases with an associated syndrome, we could not distinguish those potential additional non-syndromic defects because of the aggregated data structure regarding controls.…”

“…Regarding our data the estimate for Klinefelter syndrome was likely, however, to reflect diagnostic bias. Unlike in other registers [19] no systematic screening for Klinefelter was performed in our MAKEI/MAHO patients. Similarly, no systematic screening for Turner syndrome was performed in eGCT cases in MAKEI/MAHO.…”

“…Such associations should only be discussed in case of a possible causative pathways. Regarding the congenital anomalies the Mainz registry, like EUROCAT aims to provide essential epidemiological information on the birth prevalence of congenital malformations and anomalies in Europe [18,19]. The strength of the Mainz registry, however, is a complete case ascertainment and a structured clinical assessment and ultrasound screening for the entire cohort.…”