Mutations in the RINT1 gene represent a rare genetic cause of recurrent fever-associated acute liver failure (ALF) accompanied by skeletal abnormalities in infants and children. We report the case of a 9-month-old infant presenting with multisystem involvement, primarily characterized by recurrent fever-associated ALF and cranial dysmorphism, due to compound heterozygous mutations in the RINT1 gene. The patient exhibited abnormal liver function tests and coagulation dysfunction following febrile episodes. Over a period of more than one year, the patient initially experienced two episodes of acute liver injury, followed by two episodes of ALF, with progressively worsening clinical manifestations. Whole-exome sequencing (WES) identified compound heterozygous variants in the RINT1 gene (exons 12-14 deletion; intron 11, c.1672-1G > T, p.?), consistent with a diagnosis of infantile liver failure syndrome-3 (ILFS3). Between episodes, liver function failed to return fully to baseline and was accompanied by growth retardation, delayed psychomotor development, cranial dysmorphism, and beak-like deformities of vertebral bodies. This case highlights the critical role of RINT1 mutations in the pathogenesis of recurrent fever-associated ALF and emphasizes the importance of recognizing associated skeletal developmental abnormalities, including cranial dysmorphism. Early genetic diagnosis and prompt antipyretic intervention may mitigate liver injury and improve long-term outcomes. By documenting cranial dysmorphism in this context, we aim to expand the recognized phenotypic spectrum of ILFS3 and improve clinical awareness among pediatricians and geneticists.

Infant liver failure syndrome type 2 (ILFS2), a rare autosomal recessive disorder manifesting as recurrent acute liver failure (ALF) triggered by febrile illness, is associated with neuroblastoma amplified sequence (NBAS) mutations. This study employs molecular dynamics simulation (MDS) to investigate how missense variants in the Sec39 domain influence protein conformation and thermostability. We identified novel compound heterozygous variants in the NBAS gene, c.2231 T > C (p.Leu744Pro) and c.2266C > T (p.Arg756Cys), in two Chinese siblings diagnosed with ILFS2. According to ACMG guideline, both variants were initially classified as variants of uncertain significance. To elucidate the potential functional impact, MDS was performed to compare structural dynamics between wild-type (WT) and mutant (MUT) NBASs at physiological temperature (37°C) and under thermal stress (42°C). The results revealed distinct thermal responses. WT demonstrated robust thermotolerance, with comparable trajectory patterns and curve parameters across two temperatures. In contrast, specific variants induced localized conformational perturbations and secondary structural reorganization. Notably, while MUT exhibited kinetic profiles similar to WT at 37°C, it showed pronounced fluctuations in flexible regions under thermal stress, with disrupted hydrogen-bonding networks and significant conformational changes, indicating compromised thermostability. The diagnosis of ILFS2 primarily relies on clinical presentation and genetic confirmation. Although the exact pathogenesis remains unclear, our findings suggest that temperature-sensitive structural destabilization induced by missense mutations within the Sec39 domain of NBAS probably underlies the fever-associated ALF. This provides critical guidance for subsequent protein structural elucidation and mechanism research, and regions exhibiting significantly reduced thermostability represent promising therapeutic targets.

Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1-deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro-active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.