背景:CBL综合征是一种由CasitasB系淋巴瘤(CBL)基因的杂合种系突变引起的RASY病。它的特点是临床表型异质性,包括发育迟缓,面部畸形,心血管畸形和癌症发展的风险增加,特别是幼年型粒单核细胞白血病(JMML)。尽管近年来临床表型已逐步定义,迄今为止,尚未很好地阐明免疫学表现。
方法:我们研究了遗传,免疫学,凝固,以及我们在诊断为JMML后观察到的CBL综合征家族的临床概况,具有纯合CBL突变,在其中一个成员。
结果:变异分析显示,在另外两个成员中同时出现CBL杂合突变(c.1141T>C)和SH2B3突变(c.1697G>A)。携带两种突变的患者表现出淋巴细胞增殖的ALPS样表型,血细胞减少,双阴性T细胞增多,Fas介导的淋巴细胞凋亡受损,改变PBMC中的细胞死亡和低TRECs表达。还进行了凝血检查,并显示在携带两种突变的患者中存在亚临床凝血改变。
结论:在报告的家庭中,我们描述了免疫失调,作为CBL突变与SH2B3共存的临床谱的一部分。
BACKGROUND: CBL syndrome is a RASopathy caused by heterozygous germline mutations of the Casitas B-lineage lymphoma (CBL) gene. It is characterized by heterogeneous clinical phenotype, including developmental delay, facial dysmorphisms, cardiovascular malformations and an increased risk of cancer development, particularly juvenile myelomonocytic leukemia (JMML). Although the clinical phenotype has been progressively defined in recent years, immunological manifestations have not been well elucidated to date.
METHODS: We studied the genetic, immunological, coagulative, and clinical profile of a family with CBL syndrome that came to our observation after the diagnosis of JMML, with homozygous CBL mutation, in one of the members.
RESULTS: Variant analysis revealed the co-occurrence of CBL heterozygous mutation (c.1141 T > C) and SH2B3 mutation (c.1697G > A) in two other members. Patients carrying both mutations showed an ALPS-like phenotype characterized by lymphoproliferation, cytopenia, increased double-negative T-cells, impaired Fas-mediated lymphocyte apoptosis, altered cell death in PBMC and low TRECs expression. A coagulative work-up was also performed and showed the presence of subclinical coagulative alterations in patients carrying both mutations.
CONCLUSIONS: In the reported family, we described immune dysregulation, as part of the clinical spectrum of CBL mutation with the co-occurrence of SH2B3.