Paediatric Liver Service, King's College Hospital, London, United Kingdom.
Department of Immunology, Camelia Bothnar Laboratories, Great Ormond Street Hospital, London, United Kingdom; Department of Rheumatology and Clinical Immunology, Semmelweis University, Budapest, Hungary.
J Pediatr. 2022 Nov;250:67-74.e1. doi: 10.1016/j.jpeds.2022.07.006. Epub 2022 Jul 11.
To investigate the prevalence of hemophagocytic lymphohistiocytosis (HLH) syndrome in pediatric acute liver failure (PALF) of infancy and assess the diagnostic role of rapid immunologic tests, genotype/phenotype correlations, and clinical outcomes.
We retrospectively analyzed 78 children with PALF aged <24 months referred over almost 2 decades. The studied patients with a phenotype of HLH syndrome had a comprehensive immunologic workup, including additional genetic analysis for primary immunologic causes.
Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The most common form of primary HLH was familial hemophagocytic lymphohistiocytosis (FHL)-2, diagnosed in 6 children, 4 of whom had a c.50delT (p.Leu17ArgfsTer34) mutation in the PRF1 gene. Three patients with primary HLH received genetic diagnoses of FHL-3, Griscelli syndrome, and LRBA (lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing) protein deficiency. Overall mortality in the series was 52.6% (10 of 19), and mortality in children with a documented biallelic pathogenic HLH mutation (ie, primary HLH) was 66.6% (6 of 9). Two children underwent liver transplantation, and 4 children underwent emergency hematopoietic stem cell transplantation; all but 1 child survived medium term.
Primary HLH can be diagnosed retrospectively in approximately one-third of infants with indeterminate PALF (iPALF) who meet the clinical criteria for HLH, often leading to their death. The most common HLH type in iPALF is FHL-2, caused by biallelic mutations in PRF-1. The clinical relevance of observed heterozygous mutations and variants of uncertain significance requires further investigation. Prompt hematopoietic stem cell transplantation could be life-saving in infants who survive the liver injury.
研究噬血细胞性淋巴组织细胞增生症（HLH）综合征在婴儿期急性肝衰竭（PALF）中的发生率，并评估快速免疫检测、基因型/表型相关性和临床结局的诊断作用。
我们回顾性分析了近 20 年来转诊的 78 例年龄<24 个月的婴儿 PALF 患者。具有 HLH 表型的研究患者进行了全面的免疫检查，包括对原发性免疫病因的额外基因分析。
78 例患儿中有 30 例表现为 HLH 表型并接受了基因评估，其中 19 例（63.3%）发现阳性结果，包括 9 例（30%）存在双等位基因原发性 HLH 突变和 10 例（33.3%）存在杂合突变和/或多态性。最常见的原发性 HLH 形式是家族性噬血细胞性淋巴组织细胞增生症（FHL）-2，在 6 例患儿中诊断，其中 4 例在 PRF1 基因中存在 c.50delT（p.Leu17ArgfsTer34）突变。3 例原发性 HLH 患儿的基因诊断为 FHL-3、Griscelli 综合征和 LRBA（脂多糖反应性囊泡运输、沙滩和锚定蛋白）蛋白缺乏症。本系列的总体死亡率为 52.6%（19 例中的 10 例），有明确双等位基因致病性 HLH 突变（即原发性 HLH）的患儿死亡率为 66.6%（9 例中的 6 例）。2 例患儿接受了肝移植，4 例患儿接受了紧急造血干细胞移植；除 1 例外，所有患儿均存活至中期。
大约三分之一符合 HLH 临床标准的不明原因 PALF（iPALF）婴儿可回溯性诊断为原发性 HLH，这往往导致其死亡。iPALF 中最常见的 HLH 类型是 FHL-2，由 PRF-1 的双等位基因突变引起。观察到的杂合突变和意义不明的变异的临床相关性需要进一步研究。在幸存肝损伤的婴儿中，紧急造血干细胞移植可能具有救生作用。
