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.