Author information

¹Paediatric Gastroenterology and Digestive Endoscopy Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

²Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

³Department of Laboratory Medicine, Division of Anatomic Pathology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Abstract

Wilson's disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, resulting in copper accumulation. Symptoms rarely appear before the age of 5, almost never before 3. The phenotypic variability of WD suggests the presence of modifying factors, making early diagnosis challenging. We present a case of symptomatic WD in a toddler, emphasizing the importance of considering WD in differential diagnoses and exploring genetic modifiers influencing disease onset. Clinical and laboratory assessments, including liver biopsy, were performed on a 4.2-year-old boy presenting with hypertransaminasemia and mild hepatomegaly. Histological evaluation revealed chronic hepatitis with fibrosis and severe steatosis, indicating long-standing active disease. Genetic analysis identified a missense variant and a 15-nucleotide deletion in the 5' UTR promoter region of the ATP7B gene, confirming the WD diagnosis. Additionally, homozygosity for the HFE H63D variant was detected, with transferrin saturations at the upper limit of normal. The patient's clinical management included a trial of D-penicillamine, discontinued due to side effects, followed by successful zinc acetate therapy. This case underscores the consideration of WD in the differential diagnosis of toddlers. The Ferenci-Leipzig score remains a valid diagnostic tool for WD even in the presence of a single ATP7B variant, although extended genetic analysis should still be considered. Normal ceruloplasmin levels do not rule out WD. Environmental, epigenetic, and genetic factors appear to influence the WD phenotype; HFE variants may act as modifiers given the link between iron and copper homeostasis, possibly explaining the early symptomatic onset in our patient.