Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement
Novel SAMD9 Mutation in a Patient With Immunodeficiency, Neutropenia, Impaired Anti-CMV Response, and Severe Gastrointestinal Involvement
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DOI：
10.3389/fimmu.2019.02194
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发表时间：
2019-09-18
影响因子：
7.3
通讯作者：
Fronkova, Eva
中科院分区：
文献类型：
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作者：
Formankova, Renata;Kanderova, Veronika;Fronkova, Eva
含有9的无菌α基序结构域（SAMD9）基因突变已在严重多系统疾病MIRAGE综合征患者中被描述，但也在没有其他全身性症状的骨髓衰竭患者中被描述。造血干细胞移植（HSCT）在疾病治疗中的作用尚不清楚。在这里，我们提出了一个SAMD9 （c.2471）突变的患者G >A, p.R824Q)，表现为明显的胃肠道受累和免疫缺陷，但没有任何MIRAGE综合征典型的肾上腺功能不全的迹象。他在3个月大时患有严重的巨细胞病毒感染，T淋巴细胞对巨细胞病毒的功能反应发展迟缓，T细胞深度活化，B淋巴细胞计数明显减少，淋巴细胞增殖反应受损。培养的T细胞表现出略低的钙通量和降低的存活率。6个月大时，患者出现严重的中性粒细胞减少症，需要给予G-CSF。尽管BM中只有轻微的形态学和免疫表型紊乱，但在18个月大时，78%的BM细胞显示单体7。令人惊讶的是，CD3刺激后的T细胞增殖和细胞凋亡在随访期间正常化，可能反映了单体7的逐渐发展。在其他突出症状中，他有吞咽困难，需要经皮内镜胃造口术（PEG），频繁的胃肠道感染和肛周糜烂。他患有反复感染和周期性反复发烧，炎症标志物升高。在26个月大时，他接受了造血干细胞移植，血液学和免疫学实验室参数显著改善。然而，他继续遭受其他疾病的折磨，随后，他在移植后440天死于败血症。该SAMD9突变的致病性得到了实验证实。突变体SAMD9的表达导致转染细胞的增殖明显减少，细胞死亡明显增加。结论：我们描述了一种新的SAMD9突变，患者有突出的胃肠道和免疫症状，但没有肾上腺发育不全。因此，SAMD9突变应被认为是儿科患者肠病的原因。移植治疗结果的不足进一步质疑了HSCT在SAMD9突变和多系统参与患者管理中的作用。
Mutations in the Sterile alpha motif domain containing 9 (SAMD9) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in SAMD9 (c.2471 G >A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months Frontiers of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel SAMD9 mutation was confirmed experimentally. Expression of mutant SAMD9 caused a significant decrease in proliferation and increase in cell death of the transfected cells.Conclusion: We describe a novel SAMD9 mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with SAMD9 mutations and multisystem involvement.