key: cord-0862842-58q4emnc authors: Cheng, Ying; Xia, Zhi; Huang, Chengjiao; Xu, Hui title: Case report: A novel cause of acute liver failure in children: A combination of human herpesvirus‐6 infection and homozygous mutation in NBAS gene date: 2022-03-29 journal: J Clin Lab Anal DOI: 10.1002/jcla.24343 sha: 996e0921653036ecbc7ba53c7af72c491b90ef2f doc_id: 862842 cord_uid: 58q4emnc Etiologies of acute liver failure in children can be multiple factors including virus infection, drug‐induced damage, and different pathogens. Next‐generation sequencing (NGS) is an emerging method for pan‐pathogen screening. Here we reported a case of acute liver failure in a 15‐month‐old male, using NGS and gene sequencing to determine the cause of acute liver failure may be caused by pathogens, drug‐induction and pathogenic variant gene. On the first day of admission (Day 1), a physical examination revealed the following: the boy's temperature was 37°C; respiratory rate was 35 beats per minute; heart rate was 165 beats per minute; blood pressure was 90/52 mmHg; his peripheral capillary oxygen saturation (SpO 2 ) was 88%; and the boy was confused, delirium, and had poor mental response. Several red rashes can be seen on the face, hands, and feet. Pharyngeal hyperemia, no herpes. His abdomen was soft, splenomegaly was not palpated, but hepatomegaly 3 cm below costal margins was palpated. His kerning sign, brudzinkski sign, and babinski sign were all negative. High incidence of HFMD occurs in Wu Han during annual May. The boy had persistent hyperthermia, combined with gastrointestinal and neurological symptoms, hand and foot rashes. The signs suggested that it might be a severe HFMD. If it was based on previous diagnosis and treatment experience, the boy's condition would deteriorate progressively in the next time. The pediatricians had been prepared well for tracheal intubation for respiratory support at any time to deal with neurogenic pulmonary edema and circulatory failure, which are caused by severe HFMD-induced brainstem encephalitis. The laboratory results reported as critical values: aspartate aminotransferase 7642.4 U/L (normal range =15-60); alanine aminotransferase 7179.9 U/L (normal range =13-45) ( Table 1) ; lactate dehydrogenase 11550.7 U/L (normal range =120-300); the coagulation function also reported a critical value: prothrombin time measurement (PT) 114.7s (normal range =9. 4-12.5 ). Blood ammonia (AMM)138.9 μmol/L (normal range =10-47); lactic acid 2.5 mmol/l (normal range =0.5-1.7). At this time, the focus seemed to have suddenly shifted from severe HFMD to various diseases that might cause acute liver failure. Further examination showed that pathogens such as SARS-CoV-2, CA16, EV71, hepatitis A, B and C, MP, TP, CMV, EBV, flu virus, and TB, were all negative. The chest computed tomography (CT)scan showed that the boy had pneumonia and fatty liver. The boy's mother denied the family history of liver disease and recent history of unclean eating. After the illness, he was only given "ibuprofen suspension drops" orally for defervescence and "amoxicillin" for antibiotic treatment at home. Because the boy was still unconscious, treatment was performed with plasma exchange, which was performed on the Day 1 and Day 3, 2 h each time. On Day 5, the temperature dropped to normal. His mind was clear and his mental state improved significantly. Rashes subsided. To understand the molecular genetic basis of the family diseases, we performed whole exome sequencing and confirmatory Sanger sequencing of the proband, the proband' s father and mother. 2 G>A were as follows: 5′-TAAAATAATGGGTCAAGGGCAGGA-3′ (sense) and 5′-GGAATGAATTCCTGGGATGTGGTA-3′ (antisense). The sequencing process was performed by Chigene (Beijing) Translational Medical Research Center Co. Ltd. Quality control. Raw data were processed by fastp for adapters removing and low-quality reads filtering. Variants calling. The paired-end reads were performed using Burrows-Wheeler Aligner (BWA) to the Ensemble GRCh37/hg19 reference genome. Base quality score recalibration together with SNP and short indel calling was conducted using GATK. According to the sequence depth and variant quality, SNPs and indels were screened, and high quality and reliable variants were obtained. Variants annotation and pathogenicity prediction. infection is usually acquired very early in life, between 6 months and 2 years of age, following the loss of protective maternal antibodies, 13 which is consistent with this case. We use mNGS method to detect HHV6-B. In addition, the monocytes continued to increase at the peak of the disease. Blood smear heteromorphic lymphocyte were 12% in the second day after admission. T-cell, B-cell, and NK-cell all decreased. However, the patient had been in good health. Therefore, the possibility of secondary immune deficiency caused by virus infection was considered. In view of the specific role of the protein encoded by HHV-6, they act as analogs of cellular chemokines and are believed to promote viral growth, viral dissemination, and/or escape from the immune response. 14 It was reported that a woman with normal immunity suffered from liver failure due to infection with HHV-6. 15 In the case, the boy had no special disease history or had no immunosuppressive agents. If HHV-6B infection was the cause of the disease, was there any incentive? The patient's mother was a nurse. In order to prevent the abuse of drugs to the boy with fever, only ibuprofen suspension drops and amoxicillin were taken. It was REPORTED THAT AMOXICILLIN IS CAPable of directly stimulating HHV-6 replication, which induces ALF [12] . 16 ALT and AST activities were significantly increased. 6 Mutations in NBAS are delineated as a previously unknown cause of acute liver failure with onset in childhood triggered by febrile infections. 20 The exact mechanism of liver failure in NBAS deficiency is unclear and the physiologic function of NBAS remains to be further investigated. 19 The diagnosis of diseases caused by mutations in NBAS gene is complicated and mainly depends on the clinical manifestations and genetic testing. In summary, we believe that the boy's acute liver failure was induced by oral amoxicillin and homozygous mutation in NBAS gene after HHV-6B infection. c. 3596 G>A (p. Cys1199Tyr) homozygous variation was different from the compound heterozygous of heterozygous point and other mutations reported in the literatures. Therefore, children with unexplained fever and liver failure should be inquired about the medical history carefully, especially the history of medication, and conduct NGS and gene sequencing. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. YC conceived the idea and wrote the initial draft of the manuscript. HX and YC critically reviewed and revised the overall content of the manuscript. All the authors were involved in the care of the patient. All authors read and approved the final manuscript. Written informed consent was obtained from the parents of this patient. A copy of the written consent is available for review by request. All data generated and/or analyzed during this study are included in this published article. Hui Xu https://orcid.org/0000-0001-7647-7268 Identification of the neuroblastomaamplified gene product as a component of the syntaxin 18 complex implicated in Golgi-to-endoplasmic reticulum retrograde transport Identification and functional characterization of mutations in LPL gene causing severe hypertriglyceridaemia and acute pancreatitis Whole exome sequencing identified a homozygous novel variant in CEP290 gene causes Meckel syndrome Whole exome sequencing identified a novel heterozygous mutation in HMBS gene in a Chinese patient with acute intermittent porphyria with rare type of mild anemia Targeted next-generation sequencing reveals two novel mutations of NBAS in a patient with infantile liver failure syndrome-2 Novel NBAS mutations and feverrelated recurrent acute liver failure in Chinese children: a retrospective study Acute liver failure in neonates, infants and children Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United kingdom Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group The continuing challenge of "indeterminate" acute liver failure in children Analysis of etiology and biochemical markers of acute liver failure in children Research advances in liver failure of unknown etiology Clinical impact of primary infection with roseoloviruses Laboratory and clinical aspects of human herpesvirus 6 infections Fulminant hepatic failure attributed to infection with Human Herpesvirus 6 (HHV-6) in an immunocompetent woman: a case report and review of the literature Amoxicillin-induced flare in patients with DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): report of seven cases and demonstration of a direct effect of amoxicillin on Human Herpesvirus 6 replication in vitro Neuroblastoma Amplified Sequence (NBAS) mutation in recurrent acute liver failure: confirmatory report in a sibship with very early onset, osteoporosis and developmental delay Foveal hypoplasia in short stature with optic atrophy and Pelger-Huët anomaly syndrome with Neuroblastoma-Amplified Sequence (NBAS) gene mutation Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts Biallelic mutations in NBAS cause recurrent acute liver failure with onset in infancy Case report: A novel cause of acute liver failure in children: A combination of human herpesvirus-6 infection and homozygous mutation in NBAS gene