Case Report: Pediatric Recurrent Acute Liver Failure Caused by Neuroblastoma Amplified Sequence (NBAS) Gene Mutations

Abstract

Acute liver failure (ALF) in childhood is a rapidly progressive, potentially life-threatening condition that occurs in previously healthy children of all ages. However, the etiology of ~50% of cases with pediatric ALF remains unknown. We herein report a 4-year-old Chinese girl with recurrent ALF (RALF) due to a mutation in the neuroblastoma amplified sequence (NBAS) gene. The patient had suffered from multiple episodes of fever-related ALF since early childhood. She had also suffered from acute kidney injury, hypertension, mild pulmonary hypertension, pleural effusion, and hypothyroidism. A novel compound heterozygote mutation, c.3596G> A (p.C1199Y)/ex.9del (p.216-248del), in the NBAS gene was identified by whole-exome sequencing (WES). The missense mutation c.3596G> A (p. C1199Y) was inherited from her father, and ex.9del (p.216-248del) was inherited from her mother. The patient was managed with intensive treatments, such as renal replacement therapy (CRRT), intravenous antibiotics, and glucose infusion, and was discharged after full recovery. We identified a novel compound heterozygote mutation in the NBAS gene that caused fever-related RALF in a Chinese child, which further expands the mutational spectrum of NBAS.

A mysterious cause of recurrent acute liver dysfunction for over a decade

“…ILFS2 is characterized by unique clinical and laboratory characteristics. Features such as the Pelger-Huët anomaly, osteopenia, short stature, joint hypermobility, and vomiting during attacks were present in our patient as consistent with the cases reported in the literature [ 1 , 4 , 6–8 ] ( Supplementary Table 1 ). Liver biopsy usually shows non-specific findings in NBAS deficiency.…”

“…Pathogenic variants in the NBAS gene cause different clinical findings in patients, including SOPH syndrome (short stature, optic atrophy, and Pelger-Huët anomaly) and ILFS2 [ 1 , 4 , 6 ]. RALF is typically triggered by fever in patients with ILFS2 and ILFS3.…”

Origins of SOPH syndrome: A study of 93 Yakut patients with review of C‐terminal phenotype

“…But the exact mechanism of action is still not well understood. Recent experimental data suggest a role of NBAS in cell bulky cargo transporting machinery, such as autophagosomal secretion of collagen 19–27 . Collagen analysis in fibroblasts from NBAS patients revealed an accumulation of mature mCOL Iα2 and its precursor pro‐COL Iα1 inside the cell; it was then considered that this was due to another variant in the P4HB gene.…”

“…Recent experimental data suggest a role of NBAS in cell bulky cargo transporting machinery, such as autophagosomal secretion of collagen . [19][20][21][22][23][24][25][26][27] Collagen analysis in fibroblasts from NBAS patients revealed an accumulation of mature mCOL Iα2 and its precursor pro-COL Iα1 inside the cell; it was then considered that this was due to another variant in the P4HB gene. To test collagen secretion, Saos-2 cells were transfected in another study.…”

Distinct diagnostic trajectories in NBAS‐associated acute liver failure highlights the need for timely functional studies

“…26 There are no published management guidelines for NBAS-related RALF. Based on published case reports and series', NBAS-related acute liver failure is usually self-limiting and resolves with conservative and supportive management in most, 7,[27][28][29] but not all 30 individuals. Invasive investigations such as liver biopsy are generally not required.…”