Rare Causes of Recurrent Acute Liver Failure In Children: Infantile Liver Failure Syndromes

Introduction

Recurrent acute liver failure (RALF) is a rare clinical entity characterized by recurrent episodes of acute liver failure and complete recovery of symptoms and laboratory findings within the episodes. Causes include autoimmune disease, which may flare and subside; intermittent exposure to toxins, as with ingestions; and metabolic disorders affecting the mitochondrial respiratory chain, the long-chain fatty acid oxidation pathway or the carnitine cycle, dihydrolipoamide dehydrogenase (E3) deficiency, Wolcott-Rallison syndrome and citrullinemia (Haack TB et al., Am J Hum Genet 2015; 97: 163–9. Bindi V et al., Arch Argent Pediatr 2017; 115: 39–42). However, approximately 50% of the patients cannot be diagnosed despite detailed laboratory investigations. It is likely that monogenic disorders could explain at least some of these undiagnosed cases.

With the introduction of new diagnostic tools (whole-exome sequencing) into healthcare, many monogenic disorders were able to diagnose faster in the early life, and able to prevent the disease-related long-term complications with specific or supportive treatments. With the defining the novel diseases, it seems that novel tools will be increasingly implemented in the diagnostic approach of pediatric RALF. Apart from metabolic and mitochondrial diseases, mutations responsible genes in the cytosolic and mitochondrial pathways such as LARS (infantile liver failure syndrome type 1), NBAS (infantile liver failure syndrome type 2), TRMU (transient infantile liver failure syndrome), IARS (growth retardation, intellectual developmental disorder, hypotonia and hepatopathy), MARS (interstitial lung disease and liver disease), RINT1 and SCYL1 were shown to be associated with RALF (Jiang B et al., Front Pediatr 2021; 8: 607005. Haack TB et al., Am J Hum Genet 2015; 97: 163–9. Staufner C et al., Genet Med 2020; 22: 610–621. Fuchs SA et al., Genet Med 2019; 21: 319–330. Cousin MA et al., Am J Hum Genet 2019; 105: 108–121. Chavany J et al., Arch Pediatr 2020; 27: 155–159).

In this report, we report three interesting patients in two families with RALF finally diagnosed monogenic disorder, infantile liver failure syndromes (ILFS) (LARS and NBAS) based on clinical, laboratory and genetic findings. They have novel variants and some different features compared to previous reported cases. We want to emphasize the clinical variability in presentation of monogenic diseases in order to early clinical suspicious and perform genetic analysis for the diagnosis.

Publication History

Article published online:
27 February 2023