Recurrent acute liver failure in infancy - a novel SCYL1 mutation: A case report

Recurrent acute liver failure (ALF) in children is rare and diagnostically challenging. Despite rigorous investigations, a significant proportion of patients remain without a definitive diagnosis. Recently across the literature, biallelic pathogenic variants in the SCYL1 gene had been identified to cause a hepatocerebellar syndrome characterized by low gamma-glutamyl transferase (GGT) cholestasis, episodic ALF, and progressive neurodegeneration, collectively termed cholestasis, ALF, and neurodegeneration (CALFAN) syndrome (or spinocerebellar ataxia, autosomal recessive type 21). A high index of suspicion is paramount to recognizing this entity early, given that its presentation overlaps with more prevalent conditions, and delayed diagnosis carries significant morbidity and mortality risk.

We report a 19-month-old girl of Middle Eastern ethnicity, presenting with recurrent episodes of febrile illness, ALF, and low-GGT cholestasis initially misattributed to viral hepatitis. Clinical evaluation revealed subtle neurological abnormalities, including tremors and fine motor delay. The highlight of her presentation was pancytopenia, which expanded the known phenotypic spectrum. Extensive metabolic, infectious, and autoimmune investigations were inconclusive. Whole exome sequencing identified a homozygous likely pathogenic SCYL1 variant (c.1420C>T; p.Arg474*), consistent with CALFAN syndrome/spinocerebellar ataxia, autosomal recessive type 21. Liver biopsy showed degenerative and early fibrotic changes. Liver function partially improved with corticosteroids and supportive care but did not normalize; a third episode of liver failure occurred at 22 months in the setting of a febrile urinary tract infection.

SCYL1-related disease should be considered in children with unexplained recurrent ALF, particularly when low-GGT cholestasis and neurological features co-exist. Early genetic evaluation using whole exome sequencing is essential for establishing the diagnosis. Steroid therapy was transiently associated with partial biochemical improvement, although its mechanism in a genetic disorder remains uncertain. This case further demonstrates that pancytopenia may be part of the CALFAN phenotypic spectrum.