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.