Infantile ATP7B-Related End-Stage Liver Disease: An Exceptional Wilson Disease Phenotype From Consecutive Generations

Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism typically presenting after 3 years of age. We describe a girl presenting with neonatal cholestasis rapidly progressing to end-stage liver disease. She presented hepatosplenomegaly, neurological impairment, Coombs-negative hemolytic anemia, central hypothyroidism. A patient-parents whole exome sequencing identified a homozygous state for ATP7B mutations causing WD in the proband (p.Gln7fs/p.His1069Gln) and her mother (p.His1069Gln/p.His1069Gln), who was then confirmed to have cirrhotic WD. A causative role of copper toxicity due to ATP7B loss of function was indicated by the presence of extrahepatic features of WD, consistent tests of copper metabolism—including a 7-fold increase in liver copper—and similarity of patient’s liver gene expression profile and ultrastructure with that of WD models. This exceptionally early presentation could result from the combination of the ATP7B impairment and the intrauterine copper overload due to maternal undiagnosed WD.