Table 1. Clinical characteristics for the 3 patients in our cohort with LS and CRC.DiscussionWe describe a unique case series of 15-year-old patients who all presented with variable and
vague symptoms and were eventually diagnosed with colorectal cancer. To the best of our knowledge, ours is the only case series outlining pediatric patients with CRC with multiple gene mutations. It is important to understand the underlying factors that may predispose an individual to the development of CRC in childhood and adolescence, which in turn will facilitate earlier diagnosis as well as guide surveillance strategy and treatment.
One factor depends on which mismatch repair gene is mutated. Based on a recent meta-
analysis, the cumulative risk for CRC up to 70-years-old varied by mutation and sex: 43.9% in
male carriers and 37.3% in female carriers of MLH1 , 53.9% in male carriers and 38.6% in
female carriers of MSH2 , and 12% in male carriers and 12.3% in female carriers of MSH6 .5
Interestingly, all three of our patients were male and were carriers of the MLH1 and MSH2genes. Furthermore, amongst the MMR genes, there is variable penetrance with higher prevalence of PMS2 and MSH6variants in the general population but lower frequencies of colorectal cancer compared to MLH1 andMSH2 .5-8
Genetic anticipation is a phenomenon that may result in earlier age of CRC in successive
generations of families with Lynch syndrome. This may also contribute to the presentation of
CRC in childhood and adolescence as in patient 1 and 2’s cases. Current guidelines recommend screening for Lynch syndrome for at-risk patients at 20 to 25-years-old or 5 years before the youngest age a relative was diagnosed, but this case series among other reports highlight the need for earlier genetic testing. A recently published case series outlines 7 pediatric patients with various pediatric malignancies with subsequent diagnosis of LS.11It is important to acknowledge that Lynch syndrome can also occur in the setting of negative
family history as in Patient 3’s case. There is possibility of de novo mutation due to parental
gonadal mosaicism or a single prezygotic or early postzygotic mutation event.2,4 Hence, there
should be heightened clinical suspicion in the presence of concerning symptoms in the absence
of family history. The first step in the evaluation of all pediatric patients with colorectal cancer
should include microsatellite instability and immunohistochemistry staining of the tumor.
Multigene panel testing and genetic counseling should then be considered for all patients with
early-onset CRC given high likelihood and wide spectrum of mutations.11-12A polygenic etiology may be the cause of a virulent phenotype resulting in colorectal cancer
earlier in life such as adolescence as in all three of our patients’ cases. Outside of MMR genes, there are likely many unrecognized genetic or epigenetic factors that may influence the risk of developing malignancy in children and adolescents. A double-hit mutation in various cancer- predisposing genes can lead to early-onset colorectal cancer. In the other isolated cases reported in the literature, there were more than one detectable mutation.9-10,12-15Interestingly, our first patient carried a mutation within the APC gene at c.3920T>A (p.Ile1307Lys), which is found in 10 percent of people with Ashkenazi Jewish ancestry. This mutation has been identified as an increased risk allele that can slightly increase predisposition to colorectal cancer, but does
not cause the classic phenotype of familial adenomatous polyposis or attenuated familial
adenomatous polyposis seen for other mutations in the APCgene.16 There is lack of knowledge
on the effects of this APC risk allele when present in combination with another mutation such as
those in the MMR proteins as was the case with our first patient. In summary, this case series highlights the occurrence of LS and malignancy in the pediatric population. Although rare, patients can present in various domains of practice and awareness of
this clinical phenomenon is crucial especially given earlier intervention can reduce risk of CRC with Aspirin as chemoprevention and immunotherapy in tumors with high mutational burden.3 A firm understanding of the clinical presentation along with a thorough review of the patient’s family history, and appropriate germline work-up will help ensure early detection and guide colorectal cancer treatment.Conclusion
Pediatric colorectal cancer is a rare but transpirable occurrence and should raise suspicion for a hereditary cancer predisposition syndrome such as Lynch syndrome. The presence of multiple mutations may lead to a hypermutator phenotype resulting in a more aggressive clinical course
and earlier presentation in adolescence. Further genetic and molecular studies are needed to determine pathogenesis in patients with compound mutations which can interact synergistically
to potentiate disease progression. High index of suspicion and timely genetic testing can lead to
an earlier diagnosis and reduction in disease morbidity and mortality.