Acute liver failure with hemolytic anemia in children with Wilson's disease: Genotype-phenotype correlations?

BACKGROUND Wilson’s disease(WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure(ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant(HSD17 B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD.AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia.METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations(ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, ATP7 B variants, and the HSD17 B13:TA(rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations.RESULTS We analyzed the data of 51 patients with WD, 26 females(50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children(15.67%), all adolescent girls. The KayserFleisher ring was present in 9 children(17.65%). The most frequent variants of the ATP7 B gene were p.His1069 Gln(c.3207 A>G) in 38.24% of all alleles, p.Gly1341 Asp(c.4021 G>A) in 26.47%, p.Trp939 Cys(c.2817 G>T) in 9.80%, and p.Lys844 Ter(c.2530 A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939 Cys(c.2817 G>T) and p.Lys844 Ter(c.2530 A>T) variants were more frequent than in other less severe forms, in which p.His1069 Gln(c.3207 A>G) was more frequent. p.Gly1341 Asp(c.4021 G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17 B13 genotype was evaluated. The overall HSD17 B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease(26.92%) than those with ALF and hemolytic anemia(14.28%).CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069 Gln(c.3207 A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.