A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation
A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation
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DOI：
10.1182/blood-2011-04-347641
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发表时间：
2011-11-03
期刊：
影响因子：
20.3
通讯作者：
Rieux-Laucat, Frederic
中科院分区：
文献类型：
--
作者：
Neven, Benedicte;Magerus-Chatinet, Aude;Rieux-Laucat, Frederic
自身免疫性淋巴组织增生综合征（ALPS）是一种遗传性疾病，其特征是早发性、慢性、非恶性淋巴组织增生、自身免疫表现和对淋巴瘤的易感性。大多数ALPS患者携带编码FAS的TNFRSF6基因的杂合子种系（ALPS-FAS）或体细胞突变（ALPS-sFAS）。虽然ALPS的临床特征已被描述之前，长期随访的发病率和死亡率的数据是稀缺的。我们对90例ALPS-FAS和ALPS-sFAS患者的临床和遗传特征进行了回顾性分析，监测时间中位数为20.5年。在83%的先证者中发现了TNFRSF6的杂合种系突变。在17%的索引病例中发现了体细胞TNFRSF6突变（均位于FAS的细胞内结构域内）。60%的细胞外结构域突变的ALPS-FAS患者具有影响TNFRSF6第二等位基因的体细胞突变;这些患者的发病年龄较晚。没有发现其他基因型与表型的相关性。长期分析证实了淋巴细胞增生在成年期有自发缓解的趋势，但自身免疫表现的结果好坏参半。我们观察到显著的和潜在的危及生命的疾病和治疗相关的发病率，包括脾切除术后脓毒症的高风险，这需要对ALPS患者进行仔细的长期监测。我们还注意到男性患者的疾病相关症状发生率明显高于女性患者。（血。2011; 118（18）：4798 - 4807）
Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder characterized by early-onset, chronic, nonmalignant lymphoproliferation, autoimmune manifestations, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline (ALPS-FAS) or somatic mutations (ALPS-sFAS) of the TNFRSF6 gene coding for FAS. Although the clinical features of ALPS have been described previously, long-term follow-up data on morbidity and mortality are scarce. We performed a retrospective analysis of clinical and genetic features of 90 ALPS-FAS and ALPS-sFAS patients monitored over a median period of 20.5 years. Heterozygous germline mutations of TNFRSF6 were identified in 83% of probands. Somatic TNFRSF6 mutations were found in 17% of index cases (all located within the intracellular domain of FAS). Sixty percent of the ALPS-FAS patients with mutations in the extracellular domain had a somatic mutation affecting the second allele of TNFRSF6; age at onset was later in these patients. No other genotype-phenotype correlations could be found. Long-term analysis confirmed a trend toward spontaneous remission of lymphoproliferation in adulthood but mixed outcomes for autoimmune manifestations. We observed significant and potentially life-threatening disease and treatment-related morbidity, including a high risk of sepsis after splenectomy that calls for careful long-term monitoring of ALPS patients. We also noted a significantly greater occurrence of disease-related symptoms in male than in female patients. (Blood. 2011;118(18):4798-4807)