Palmisani Elena, Miano Maurizio, Grossi Alice, Lanciotti Marina, Lupia Michela, Terranova Paola, Ceccherini Isabella, Montanari Eugenia, Calvillo Michaela, Pierri Filomena, Micalizzi Concetta, Maggiore Rosario, Guardo Daniela, Zanardi Sabrina, Facchini Elena, Maggio Angela, Mastrodicasa Elena, Corti Paola, Russo Giovanna, Pillon Marta, Farruggia Piero, Cesaro Simone, Barone Angelica, Tosetti Francesca, Ramenghi Ugo, Crescenzio Nicoletta, Bleesing Jack, Dufour Carlo, Fioredda Francesca
Haematology Unit-IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Genetic Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Hemasphere. 2023 Feb 22;7(3):e845. doi: 10.1097/HS9.0000000000000845. eCollection 2023 Mar.
Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte homeostasis classically due to mutation of FAS, FASL, and CASP10 genes (ALPS-FAS/CASP10). Despite recent progress, about one-third of ALPS patients does not carry classical mutations and still remains gene orphan (ALPS-U, undetermined genetic defects). The aims of the present study were to compare the clinical and immunological features of ALPS-FAS/CASP10 versus those of ALPS-U affected subjects and to deepen the genetic characteristics of this latter group. Demographical, anamnestic, biochemical data were retrieved from medical record of 46 ALPS subjects. An enlarged panel of genes (next-generation sequencing) was applied to the ALPS-U group. ALPS-U subjects showed a more complex phenotype if compared to ALPS-FAS/CASP10 group, characterized by multiorgan involvement ( = 0.001) and positivity of autoimmune markers ( = 0.02). Multilineage cytopenia was present in both groups without differences with the exception of lymphocytopenia and autoimmune neutropenia that were more frequent in ALPS-U than in the ALPS-FAS/CASP10 group ( = 0.01 and = 0.04). First- and second-line treatments were able to control the symptoms in 100% of the ALPS-FAS/CASP10 patients, while 63% of ALPS-U needed >2 lines of treatment and remission in some cases was obtained only after target therapy. In the ALPS-U group, we found in 14 of 28 (50%) patients 19 variants; of these, 4 of 19 (21%) were known as pathogenic and 8 of 19 (42%) as likely pathogenic. A characteristic flow cytometry panel including CD3CD4-CD8-+TCRαβ+, CD3+CD25+/CD3HLADR+, TCR αβ+ B220+, and CD19+CD27+ identified the ALPS-FAS/CASP10 group. ALPS-U seems to represent a distinct entity from ALPS-FAS/CASP10; this is relevant for management and tailored treatments whenever available.
自身免疫性淋巴细胞增生综合征（ALPS）是一种淋巴细胞稳态的遗传性疾病，典型病因是FAS、FASL和CASP10基因（ALPS-FAS/CASP10）发生突变。尽管最近取得了进展，但约三分之一的ALPS患者没有携带经典突变，仍然属于基因未明类型（ALPS-U，未确定的遗传缺陷）。本研究的目的是比较ALPS-FAS/CASP10患者与ALPS-U患者的临床和免疫学特征，并深入了解后一组的遗传特征。从46例ALPS患者的病历中获取人口统计学、既往史和生化数据。对ALPS-U组应用了一组扩大的基因（二代测序）。与ALPS-FAS/CASP10组相比，ALPS-U患者表现出更复杂的表型，其特征为多器官受累（P = 0.001）和自身免疫标志物阳性（P = 0.02）。两组均存在多系血细胞减少，除淋巴细胞减少和自身免疫性中性粒细胞减少在ALPS-U组比ALPS-FAS/CASP10组更常见外（P = 0.01和P = 0.04），其他方面无差异。一线和二线治疗能够使100%的ALPS-FAS/CASP10患者症状得到控制，而63%的ALPS-U患者需要超过2线治疗，部分病例仅在靶向治疗后才获得缓解。在ALPS-U组中，我们在28例患者中的14例（50%）发现了19种变异；其中，19种中的4种（21%）已知为致病性变异，19种中的8种（42%）可能为致病性变异。一个包括CD3CD4-CD8-+TCRαβ+、CD3+CD25+/CD3HLADR+、TCR αβ+ B220+和CD19+CD27+的特征性流式细胞术检测组合可识别ALPS-FAS/CASP10组。ALPS-U似乎代表了一种与ALPS-FAS/CASP10不同的疾病实体；这对于管理和在有条件时进行个体化治疗具有重要意义。
