Introduction
Pediatric Acute Liver Failure (PALF) presents a considerable threat to children with a high risk of mortality, despite its rarity. However, the exact cause remains unknown in about half of the cases, emphasizing the need for continued investigation and advancements in our understanding of the condition. Recurrent Acute Liver Failure (RALF) represents an even more uncommon phenomenon, defying diagnosis despite thorough examination. The advent of Whole Exome Sequencing offers hope in uncovering its elusive genetic origins, potentially shedding light on specific genetic disorders underlying this condition.
Aims & Methods
This study aimed to report spectrum of Recurrent Acute Liver Failure (RALF) cases and role of Whole Exome Sequencing (WES) in establishing a cause for RALF, during January 2023 – January 2024 in a tertiary care institute.
Results
We report 4 cases of Recurrent Acute Liver Failure (RALF). First case was a 5 year old 1st born female child of 3rd degree consanguineous marriage who presented with RALF during febrile episodes at 10 months, 18 months and 5 years. Child had low GGT (19 IU/L) cholestasis initially. Etiological workup for Wilson, infective, metabolic was normal. Provisionally, Fever Associated Infantile Liver Failure (ILFS) was thought. But, Upper GI endoscopy revealed esophageal varices confirming portal hypertension, and liver biopsy revealed- acute on chronic hepatitis with cirrhosis, confirming chronic liver disease, which was in contrast to complete liver function resolution seen in ILFS. Change in gait and expressive language ability was lost from 3 years of age. The child had rigidity, increased deep tendon reflexes, tremor and ataxia on examination. Genetic analysis revealed homozygous (autosomal recessive) likely pathogenic variant of SCYL1 gene mutation leading to Spinocerebellar Ataxia 21.
The second child also presented with RALF at 8 months, 1year and 1.5 years during febrile episodes, with low GGT Cholestasis. WES revealed pathogenic variant of SCYL1 gene mutation leading to Spinocerebellar Ataxia 21. Child died at 1.5years of age.
Third child is a 10 year old girl presented with multiple fever-related RALF since 9 years of age and was asymptomatic in between episodes. As the cause was indeterminate after extensive evaluation, WES was done which revealed novel compound heterozygote mutation in RINT1 gene in exon 8 and 12.
The fourth child is a sibling of third case who succumbed with the first acute liver failure following a febrile episode at 12 years of age.
Conclusion
Understanding the genetic basis of PALF is crucial for accurate diagnosis and management. Genetic testing, including targeted gene sequencing or whole-exome sequencing, can help identify these mutations and provide insights into the underlying causes of PALF in affected individuals. This information is essential for personalized treatment approaches and genetic counseling for families. In addition to metabolic and mitochondrial diseases, mutations in genes related to both cytosolic and mitochondrial pathways—such as NBAS, TRMU, IRAS, MARS, RINT1, and SCYL1—have been implicated in pediatric acute liver failure (PALF).
References
1. Lenz D, Schlieben LD, Shimura M, Bianzano A, Smirnov D, Kopajtich R, Berutti R, Adam R, Aldrian D, Baric I, Baumann U. Genetic landscape of pediatric acute liver failure of indeterminate origin. Hepatology. 2024 May 1;79(5):1075-87.
2. Çakır M, İssi F, Güven B, Yakici N, Karaguzel G, Selimoglu A. Rare Causes of Recurrent Acute Liver Failure In Children: Infantile Liver Failure Syndromes. Klinische Pädiatrie. 2023 Jul;235(04):245-9.
3. Youssef, Mariam et al. “CALFAN (Low γ-Glutamyl Transpeptidase (GGT) Cholestasis, Acute Liver Failure, and Neurodegeneration) Syndrome: A Case Report with 3-Year Follow-Up after Liver Transplantation in Early Adulthood.” Case reports in hepatology vol. 2023 3010131. 31 Jul. 2023, doi:10.1155/2023/3010131
