Discussion
We identified an adolescent with Dravet syndrome who developed B-cell
lineage ALL. In addition, there are at least two other cases of ALL in
children with Dravet syndrome (personal communication, Veronica Hood,
PhD). One with Dravet syndrome due to SCN1A variant was diagnosed
with B cell ALL at age 7 years, having been on multiple anti-epileptics
including valproate. The incidence of Dravet syndrome among live births
is estimated at 1/15,000. According to the National Cancer institute,
the incidence rate of ALL in those below the age 19 in US is 1 per
1,000.
Dravet syndrome commonly appears during the first year of life usually
related to fever or vaccination. The first seizure typically is
generalized clonic then the child develops multiple seizure types
(convulsive seizures, myoclonic seizures, atypical absence seizures,
focal seizures, or rarely, tonic seizures).1 Patients
often develop psychomotor delay, behavioral disturbances, and cognitive
impairment. Autistic features usually persist into
adulthood.6
Eighty percent of patients with Dravet syndrome harbor a heterozygous
SCNA1 gene mutation,1 resulting in its
loss-of-function. SCN1A encodes the alpha subunit of a sodium
channel NaV1.1. In disease-associated SCN1A variants,
interneurons can no longer inhibit the electrical
activity.7 Loss-of-function mutations
of SCN1A cause functional impairments in the GABAergic neurons
and lead to a loss of appropriate inhibition in neuronal networks and a
predisposition to seizures. Over 650 missense and nonsense SCN1A
mutations have been described in these patients; some are de
novo .8
Although rarely reported, non-central nervous system cancers could
present in the context of seizure and/or autism disorders (AD). One case
reported ALL in a nine-year-old girl with isodicentric chromosome 15
syndrome, which is associated with early central hypotonia,
developmental delay, cognitive dysfunction, autism spectrum disorders,
and seizures.9 A retrospective cohort study of 8000
Taiwanese children and adolescents showed that cancer occurred more
frequently in pediatric patients with AD. The standardized incidence
ratio’s estimate is 1.94 (95% CI 1.18-2.99). During the observation
period, 20 patients with AD developed cancers. Five patients had
leukemia, two of them (one with intellectual disability, the second one
seizures) had ALL.10 Multiple copy number variants
identified in autism patients are found with individuals with cancer,
suggesting a link with chromosomal abnormalities and
carcinogenesis.11 According to a cohort study done on
patients with AD, there was an increased risk of developing cancer by
midlife.12 Other studies have not suggested an
increased association.13,14 The prevalence of autism
in a North Carolina population found that out of 702 cancer patients,
seven (1%, 95% CI of 0.4% - 2.04%) were labeled as AD in their
medical records. The diagnosis of AD was made prior to cancer
presentation in five of the seven of the patients; in the other two,
obvious behavioral issues at cancer presentation led to an evaluation
which suggested AD.13
While we cannot at this time conclude that patients with Dravet syndrome
are at increased risk for developing acute leukemia, it is tempting to
speculate that associated metabolic disturbances could produce
intracellular stress.15 Seizures can induce
endoplasmic reticulum stress, and mouse models suggest that this results
in the expression and distribution of Mdm2 and down-regulation of
Tp53.16 A complex host-environment interaction would
include long-term use of anti-seizure drugs. For instance, hematologic
side effects of valproate are well known17 and can be
associated with transient neoplasia.18 Occurrence of
cancer in children, a rare event, with non-hematologic monogenic
disorders, a rare event, should be considered as a candidate
predisposition syndrome. Hence, the number of pediatric and adult
patients with cancer predisposition syndromes may be even greater by
expanding the list of candidate genes not classically associated with
hematologic malignancies.
Conflict of Interests : The authors declare no conflict of
interests.
Acknowledgements : This work was supported in part by Rally
Foundation for Childhood Cancer, V Foundation for Cancer Research,
Alex’s Lemonade Stand Foundation (A-Award), and NIH/NCI K22 CA251649-01
to CH, VeloSano (HM), and Hyundai Hope Scholar Award to SJC.