[Clinical features and genetic analysis of four cases of pediatric acute liver failure caused by NBAS gene variants].

Abstract

Objective: To analyze the clinical and genetic features of pediatric acute liver failure (PALF) caused by neuroblastoma-amplified sequence (NBAS) gene variants and to investigate the correlation between clinical phenotypes and genotypes. Methods: A retrospective analysis was conducted on the clinical data and genetic test results of 4 pediatric patients with NBAS gene variants presenting primarily with PALF, who were admitted to the Department of Gastroenterology at the Children's Hospital of Zhejiang University School of Medicine from August 2015 to June 2023. A literature review was performed using the keywords "NBAS", "neuroblastoma amplified sequence", "SOPH", "short stature with optic nerve atrophy and Pelger-Huët anomaly", "liver failure", and "neuroblastoma amplified sequence" in both Chinese and English, searching the CNKI, Wanfang Data Knowledge Service Platform, and PubMed databases for articles published from January 2015 to May 2024. The clinical features and genetic characteristics of domestic patients were summarized. Results: The age of first onset of PALF in the 4 patients ranged from 8 months to 3 years and 7 months. All patients developed PALF within 1-2 d after the onset of fever, with symptoms including vomiting, seizures, lethargy, or altered consciousness, accompanied by a sharp increase in transaminases, elevated bilirubin and blood ammonia, hyperlactatemia, and hepatomegaly. After antipyretic therapy, fluid supplementation, and other symptomatic supportive treatments, the PALF gradually improved in all patients, with 3 patients also exhibiting extrahepatic symptoms. Long-term follow-up showed that active temperature control and symptomatic management could reduce the recurrence of PALF. Genetic testing identified 8 NBAS gene variants sites, all confirmed as compound heterozygous mutations through family verification, including 4 missense mutations, 1 nonsense mutation, and 3 frameshift mutations. A literature review included 51 cases of domestic NBAS gene mutations, revealing that 98.0% (50/51) of patients had liver involvement, with 35 cases presenting as PALF. A total of 61 variant sites were identified, with c.3596G>A (45.1%, 23/51) being the most common hotspot mutation. Conclusions: NBAS gene mutations leading to PALF have distinct clinical and genetic characteristics, with a correlation between genotype and clinical phenotype. The c.3596G>A mutation is a hotspot variant in domestic patients and is strongly associated with the liver failure phenotype.