Boyarchuk Oksana, Volokha Alla, Yarema Nataliia, Dyvoniak Olga, Tomashivska Tetyana, Shymanska Ivanna, Makukh Halyna, Walter Jolan E
Department of Children's Diseases and Pediatric Surgery, I.Horbachevsky Ternopil National Medical University, Ternopil, Ukraine.
Department of Pediatrics N1, Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine.
Front Immunol. 2025 May 19;16:1602107. doi: 10.3389/fimmu.2025.1602107. eCollection 2025.
INTRODUCTION: X-linked lymphoproliferative disease type 1 (XLP1) is an inborn error of immunity (IEI) caused by pathogenic variants in the gene, leading to severe immune dysregulation, often triggered by Epstein-Barr virus (EBV) infection. Hemophagocytic lymphohistiocytosis (HLH) is one of the most severe manifestations of XLP1 with high mortality. OBJECTIVE: Present a clinical case of fatal HLH associated with a novel variant, highlighting the variability of clinical presentation and the potential role of co-infections. METHODS: We analyzed clinical and laboratory data of three brothers who died from HLH in early age. Genetic evaluation was performed using a 576-gene panel for IEI (Veritas, Spain, supported by the Jeffrey Modell Foundation). Alive siblings and parents were tested in Scientific Medical Genetic Center LeoGENE, Ukraine. RESULTS: A 1-year-old boy was admitted with a persistent 4-day fever and clinical signs of hepatosplenomegaly, anemia, neutropenia, hypertransaminasemia, and hypoproteinemia. Immunophenotyping revealed decreased CD4, increased CD8 T cells, reduced NK cell counts, and elevated immunoglobulin levels. This patient demonstrated high EBV viremia and positive serological markers for SARS-CoV-2. Despite intensive treatment, HLH progressed rapidly, leading to fatality within 35 days. Genetic testing identified a novel, likely pathogenic hemizygous variant, c.175delC (p.Thr59Glnfs*22), not previously reported in affected individuals or the gnomAD database. Family history shows that two older male siblings died at 11 months and 1 year 9 months from a rapidly developed disease presented by fever, hepatosplenomegaly, dermatitis, enterocolitis, anemia, thrombocytopenia, and hypertransaminasemia. The second affected sibling tested positive for EBV serology. The family also included a healthy sister and brother, both with positive EBV serology (IgG) but no detectable viremia. Carrier testing confirmed that the mother and sister are heterozygous carriers, while two male siblings (one of them was born 1 month ago) are unaffected. CONCLUSION: We identified a novel variant associated with fatal HLH in XLP1. Our findings highlight the importance of early genetic diagnosis before EBV exposure to improve patient outcomes. The potential role of co-infections, including SARS-CoV-2, in triggering HLH in XLP1 remains an area for further investigation.
引言：1型X连锁淋巴细胞增殖性疾病（XLP1）是一种由该基因的致病变异引起的遗传性免疫缺陷病（IEI），导致严重的免疫失调，常由爱泼斯坦-巴尔病毒（EBV）感染引发。噬血细胞性淋巴组织细胞增生症（HLH）是XLP1最严重的表现之一，死亡率很高。 目的：介绍一例与一种新的变异相关的致命性HLH临床病例，强调临床表现的变异性以及合并感染的潜在作用。 方法：我们分析了三名早年死于HLH的兄弟的临床和实验室数据。使用针对IEI的576基因panel（由杰弗里·莫德尔基金会支持的西班牙Veritas公司提供）进行基因评估。在世的兄弟姐妹和父母在乌克兰的科学医学遗传中心LeoGENE进行检测。 结果：一名1岁男孩因持续4天发热以及肝脾肿大、贫血、中性粒细胞减少、转氨酶升高和低蛋白血症等临床症状入院。免疫表型分析显示CD4减少、CD8 T细胞增加、NK细胞计数减少以及免疫球蛋白水平升高。该患者显示出高EBV病毒血症以及SARS-CoV-2血清学标志物阳性。尽管进行了强化治疗，HLH仍迅速进展，导致在35天内死亡。基因检测发现了一种新的、可能致病的半合子变异，c.175delC（p.Thr59Glnfs*22），此前在受影响个体或gnomAD数据库中均未报道。家族史显示，两名年长的男性兄弟姐妹分别在11个月和1岁9个月时死于一种迅速发展的疾病，表现为发热、肝脾肿大、皮炎、小肠结肠炎、贫血、血小板减少和转氨酶升高。第二名受影响的兄弟姐妹EBV血清学检测呈阳性。该家族还包括一个健康的姐姐和哥哥，两人EBV血清学（IgG）均为阳性，但未检测到病毒血症。携带者检测证实母亲和姐姐是杂合子携带者，而两名男性兄弟姐妹（其中一名1个月前出生）未受影响。 结论：我们在XLP1中鉴定出一种与致命性HLH相关的新变异。我们的研究结果强调了在EBV暴露前进行早期基因诊断以改善患者预后的重要性。包括SARS-CoV-2在内的合并感染在触发XLP1中的HLH方面的潜在作用仍是一个需要进一步研究的领域。
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