Wilson’s disease (WD) is a rare autosomal recessive condition caused by genetic changes in the ATP7B gene, leading to copper excess that primarily affects the liver and later impacts other organs. Symptoms typically appear between ages 5 and 35, seldom before age 5. The condition’s phenotypic variability is likely influenced by clinical modifiers. The authors highlighted the importance of considering potential modifying genes in genetic diagnostics and analyses to better understand disease onset and progression.
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The WD case went through clinical, histological, and genetic analyses. Liver examination was performed with histological staining and immunohistochemistry. Genetic analysis included Whole-Exome Sequencing (WES) of 140 genes linked to hereditary liver diseases, as well as Whole-Genome Sequencing (WGS) analysis which provided further insights using the Geneyx Analysis platform for data interpretation.
Pedigree: half‐filled diagrams are carriers; filled‐in diagram is carrier of both variants in a compound heterozygosity form.
(a) Validation by Sanger sequencing of the missense variant c.2128G > A shows the variant allele (arrow) in heterozygous state in the proband, his mother and his maternal grandmother while, the father and the maternal grandfather show homozygosity for the reference allele. (b) Validation by Sanger sequencing of the deletion c.-436_-422delTGGCCGAGACCGCGG (highlighted by the black bar): the mother and the paternal grandfather show homozygosity for the reference allele and the correct reading frame; the proband, his father, the paternal uncle and paternal grandmother show heterozygosity for this variant that causes a reading frameshift (the sequence is shown in direction right to left).
The 4 years of age boy presented with head swelling, imaging abnormalities, and elevated liver enzymes, prompting further investigation. Initial tests excluded autoimmune hepatitis, but persistently elevated liver enzymes led to liver examination, revealing chronic hepatitis. High intrahepatic copper levels suggested WD. WES identified a heterozygous missense variant in the ATP7B gene (c.2128G>A, p.Gly710Ser) inherited from his mother. WGS later revealed a 15-nucleotide deletion in the ATP7B gene promoter region (c.-436_-422del), inherited from his father. This compound heterozygosity confirmed WD. Additionally, a homozygous HFE c.187C>G (p.His63Asp) mutation was detected.
(a) Liver biopsy showed a pattern of diffuse macrovesicular steatosis and expansion of portal spaces with mild mixed inflammatory infiltrates; (b) histochemical investigation by Masson’s Trichrome showed the presence of fibrosis even with porto-portal septa formation; (c) pearls Prussian blue histochemical staining showed no iron deposits, both in the hepatocytes and in the Kupfer cells.
In summary, the authors report a case of early-onset WD in a 4-year-old boy, highlighting the challenges in its timely diagnosis due to nonspecific symptoms that mimic other disorders. The patient’s genetic analysis revealed compound heterozygosity in ATP7B and a homozygous HFE mutation, which may have contributed to the early onset and liver impairment by affecting copper metabolism. This case emphasizes the need for comprehensive genetic testing and early intervention for better outcomes, even in young children.
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