Gain-of-function STAT1 mutation and visceral leishmaniasis

ABSTRACT Gain-of-function mutations in the STAT1 gene have been initially associated with chronic mucocutaneous candidiasis. However, further research has shown that STAT1 GOF variants may increase susceptibility to infection by other intracellular pathogens. This report describes the first case of disseminated leishmaniasis associated with a STAT1 GOF mutation in a pediatric patient who did not have chronic mucocutaneous candidiasis. The patient was a four-year-old boy presenting with fever, severe asthenia, hepatosplenomegaly, pancytopenia, and liver failure. Bone marrow aspirate revealed hemophagocytosis and Leishmania parasites. Treatment consisted primarily of liposomal amphotericin B, as per the Hemophagocytic Lymphohistiocytosis 2004 protocol. After eight weeks of treatment, the patient did not improve and was submitted to diagnostic splenectomy. Activated macrophages and nodular spleen necrosis secondary to the visceral leishmaniasis were detected. Unfortunately, the patient died in the second week after splenectomy due to overwhelming systemic infection. DNA sequencing revealed a pathogenic (p. R274Q) GOF mutation in STAT1.

摘要：STAT1基因的功能获得性（gain-of-function, GOF）突变最初被认为与慢性皮肤黏膜念珠菌病（chronic mucocutaneous candidiasis）相关。后续研究表明，STAT1 GOF变异体可增加机体对其他胞内病原体感染的易感性。本病例报告首次描述1例无慢性皮肤黏膜念珠菌病病史的儿科患者，其播散性利什曼病（disseminated leishmaniasis）与STAT1 GOF突变相关。该患者为4岁男性，临床表现为发热、重度乏力、肝脾肿大、全血细胞减少症及肝功能衰竭。骨髓穿刺涂片可见噬血细胞现象（hemophagocytosis）与利什曼原虫。参照噬血细胞淋巴组织细胞增生症2004诊疗方案（Hemophagocytic Lymphohistiocytosis 2004 protocol），主要予以脂质体两性霉素B（liposomal amphotericin B）治疗。治疗8周后患者病情无改善，遂接受诊断性脾切除术。术中发现内脏利什曼病（visceral leishmaniasis）继发激活的巨噬细胞浸润及结节性脾脏坏死。不幸的是，患者于脾切除术后第2周因暴发性全身感染死亡。DNA测序检测显示，其携带致病性（p.R274Q）STAT1基因功能获得性突变。