Discussion
Composite tumors in children are very rare and usually have no
definitive etiology. Many of them have been linked to TP53, a gene that
controls many cell cycle regulation pathways and thus is susceptible to
many germline mutations that have been identified. ACT in particular is
noted as closely related tumor to the TP53 gene
mutation.4 Very little evidence links NB to LFS.
Cases of LFS with multiple malignancies are numerous but are rarely
simultaneous.5 A handful of cases have reported
homozygous TP53 mutations with associated with ACT and NB, most of which
presented with unique presentations and TP53 gene
variations.6–9 One case did report a simultaneous ACT
and NB in an eight-month-old infant, but its germline p53 mutation was
not present in this patient.10 The variation in this
case is different from any previously cited in the literature. To
discern understanding links between ACT and NB in the context of TP53,
more cases are warranted.
The patient’s particular mutation, c.818G>A, pArg273His, is
one that has only been cited twice, both due to different malignant
etiologies. One case report indicated a child with LFS with two separate
germline mutations, c.818G>A and c.814G>A,
leading to three separate malignancies presenting as early as four
months.11–13 Although none of the three malignancies
were either ACT or NB, it is notable that the c.818G>A
mutation is present in both cases. The mutation c.818G>A is
within the DNA binding domain of TP53 and prevents wild-type
transcriptional activity. This can inactivate the second allele,
granting gain-of-function properties that show a more aggressive
phenotype than mutations resulting in loss of TP53
expression.14 This may explain the early onset of the
compound tumor in this patient and literature reveals a near decade
earlier mean age of onset of primary cancer in LFS due to TP53 gene
missense mutations compared to TP53 deletions15. The
other article indicated its pathogenicity, among many other mutations,
in cases of adult gastric type mucinous carcinoma.16It is noteworthy that c.818G>A, pArg273His has now been
seen in tumors in both pediatric and adult patients. Additional links
between the mutation and its various linked pathologies across the
lifespan are warranted but are out of the scope of this paper.
It is speculated that this germline mutation may be a factor in the
pathogenesis of this composite tumor and in composite adrenal
malignancies in general. Family cancer history also plays an important
clue for TP53 gene mutation screening due to LFS’s autosomal dominant
inheritance, such analysis maybe indicated for the first-degree
relatives of this patient, and close monitoring is warranted for
subsequent LFS-related tumors in the patient.
We report a composite NB and ACT in an infant associated with a
heterozygous TP53 c.818G>A, pArg273His mutation, the first
of its kind. The mutation is pathogenic and may predispose carriers to
malignancies across the lifespan.