It is now well known that certain clinical genetic syndromes recognized in childhood are associated with an increased risk of cancer development. For example, in the Gorlin syndrome (also known as Nevoid Basal Cell Carcinoma Syndrome), which may affect ~1 in 40,000 individuals, a mutation in the PTCH gene leads to a number of unusual features including multiple jaw cysts, a very large head circumference, and prominent foreheads in addition to skeletal (bifid ribs and wedge-shaped vertebrae) and other anomalies. Although the causative mutation in PTCH leads to these morphological abnormalities, it also leads to a substantial increase in cancer risk, primarily for skin basal cell carcinomas and medulloblastoma.
Although a number of studies have tried more broadly to assess the association between various birth defects (major malformations and minor anomalies) and cancer, these have been plagued by limitations including the reliance on chart reports of the morphological abnormalities.
A new study, reported in the January 2 issue of JAMA, provides an intriguing new look at this issue.
The authors personally examined a total of 1073 childhood cancer patients and 1007 controls individuals (all patients and controls were of northern European descent) without cancer with an eye toward cataloging "morphological abnormalities" (both major birth defects and minor anomalies) in a standardized fashion.
Interestingly, they found that both major birth defects and minor anomalies were significantly more common in the pediatric cancer group as compared to controls. For example, per 1000 individuals, 268 major abnormalities were found in cancer patients vs. 155 in controls; likewise, there were 1252 minor anomalies per 1000 individuals in cancer patients vs. 898 per 1000 controls. This was statistically significant and is consistent with the notion that at least a subset of pediatric cancers are associated with genetic defects that might also predispose to combinations of birth defects and/or minor congenital anomalies.
In 42 patients, there was an already established clinical genetic syndrome. Even after these patients were removed from the analysis, there was still a significantly higher number of major abnormalities and minor anomalies in the cancer patients as compared to controls.
After excluding the 42 patients with preexisting diagnoses, the authors sought to assess which congenital anomalies seem to be particularly associated with pediatric cancer. For example, they showed that blepharophimosis (a static reduction in the distance between the upper/lower eyelid resulting in a narrowed slit-like appearance), a minor anomaly, was about 11-times more likely to be found in pediatric cancer patients as compared to controls. Some of the other abnormalities that were statistically associated with pediatric cancer were asymmetric lower limbs and broad feet (appearing disproportionately wide for length and for which the measured width is >95th percentile for age).
The authors then went on to make some initial attempts to identify patterns of morphological abnormalities to classify them into putative new syndromes.
Overall, this study is very intriguing, but has some methodological limitations that will require validation of the result in an independent group of patients and controls. Nevertheless, this is a very plausible result supported by the existence of a number of known genetic syndromes in which certain birth defects cluster with certain types of cancer.
This study provides a foundation on which future efforts to identify new tumor predisposition syndromes will be based. Ultimately, this should allow improved efforts to screen for and/or prevent some childhood cancers.
