Commentary on Diagnostic Problems in Hepatology Cases

Case 1

In their article, “Beneath The Copper—Pediatric Wilson's Disease Cirrhosis and Hepatocellular Carcinoma: A Case Report,” Rosencrantz et al report the youngest case of Wilson's disease with hepatocellular carcinoma (HCC) to date. Such early-onset severe disease suggests genetic contribution to this outcome. Appropriately, the authors review the molecular genetics of Wilson's disease. The authors discuss how most individuals affected with Wilson's disease are compound heterozygotes, meaning that they have two different mutations affecting the same gene, ATP7B, which cause the disease. The authors highlight that more than 780 mutations in ATP7B are reported worldwide in the Human Genome Mutation Database, of which 508 are believed to be disease causing. They discuss how individuals of European, East Asian, and Indian ancestry most commonly harbor the H1069Q (exon 14), R778L, and C271X mutations in ATP7B, respectively. They further note that mutations in other geographic and ethnic groups vary considerably, are uncommon, and are virtually unique to these groups. Because only common known mutations in ATP7B can be assayed, the diagnosis of Wilson's disease is often missed as most individuals with Wilson's disease are not homozygous for these mutations. With exome sequencing becoming more available and affordable, detecting changes in the coding regions of genes, including compound heterozygous mutations in ATP7B, to diagnose Wilson's disease will become routine. If this testing is done early enough (possibly at birth), diseases such as Wilson's could be diagnosed before the onset of symptoms and copper chelation instituted to delay or prevent the disease. Furthermore, these same tools can identify genetic changes in tumor versus normal tissue that promote tumor development which can be immediately targeted to facilitate personalized treatment of cancer (see Case 4).