INTRODUCTION
The etiology of pediatric cancer is largely unknown 1.
Recent studies of large cohorts of pediatric cancer have shown that
approximately 10% of the patients carry germline pathogenic variants in
a broad spectrum of cancer susceptibility genes 2–5.
The evidence of the link between pediatric cancer and congenital
anomalies is robust 6–8, however, the etiology of
most of these associations remains underexplored.
Hepatoblastoma (HB) is the most common malignant tumor of liver in the
pediatric population 9, although it is considered an
ultrarare disease, accounting for only 1% of pediatric tumors10,11. In Brazil, collected data on hepatoblastomas
are concordant with the worldwide prevalence 12–14.
Increased risk for hepatoblastoma development has been reported in
association with specific congenital syndromes, including
Beckwith-Wiedemann 15,16, familial adenomatous
polyposis (FAP) 17, and trisomy of chromosome 1818. Non-genetic factors known to be associated with
hepatoblastoma risk are mainly related to very low birth weight
(<1500 g), including preterm birth (<33 weeks),
small size for gestational age, and multiple birth pregnancies9,19. To date, there is a single report of a patient
with hepatoblastoma and Hirschsprung disease 20, which
is a rare congenital anomaly resulting from the absence of enteric
neurons at the end of the bowel, affecting about 1-5 in 10,000 newborns21,22. Related symptoms arise because there is no
propulsive motility in the aganglionic bowel as a consequence of
defective neural crest cell development, causing severe chronic
constipation, abdominal distension, vomiting, and growth failure22,23. Hirschsprung disease is a multigenic disorder
with variable penetrance and severity, characterized by extensive
genetic heterogeneity. Predisposing mutations have been recognized in
several genes, including RET, GDNF, GFRA1, NRTN, EDNRB, EDN3,
ZEB2, PHOX2B, SOX10, SHH, ECE1, DHCR7, L1CAM, KIF1BP, BBS1-BBS11 andRMRP 22,24. Some conditions, such as chromosome
21 trisomy, increase the risk for Hirschsprung disease25. The sibling recurrence rate varies according to
both the length of the aganglionic bowel and to the sex of the first
affected sibling 26,27 in a pattern of multifactorial
inheritance with different liability threshold for sex.
In the course of genomic studies in a cohort of Brazilian individuals
with childhood cancer, we ascertained one additional syndromic patient
presenting Hirschsprung disease and hepatoblastoma, besides the first
case reported by Pinto et al. (2016) 20. In this
report, we performed a germline exome analysis of these two patients in
whom the association of Hirschsprung disease and hepatoblastomas was
documented, and of one parent of each patient. We also investigated the
spectrum of somatic mutations in one of the tumors.