Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
Medical Faculty, Institute of Molecular Medicine I, Heinrich-Heine-University, Düsseldorf, Germany.
Front Immunol. 2018 Oct 16;9:2400. doi: 10.3389/fimmu.2018.02400. eCollection 2018.
Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by lymphopenia, recurrent infections and induced lymphoproliferation and -lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of infections, immunoglobulin substitution (IVIG) and restoration of the immune system by hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with recurrent infections, CD4 lymphopenia and dysregulated immunoglobulin levels. Patient P1 developed a highly malignant B cell lymphoma at the age of 10 years and a second, independent Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed lymphoma in the absence of detectable EBV or other common viruses. Lymphoma development may be due to the lacking tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1] lymphoma proneness of STK4 deficient patients even in the absence of EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of recurrent infections, CD4 lymphopenia and lymphoma and unknown genetic make-up. Patient P2 experienced recurrent otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from Autoimmune Lymphoproliferative Syndrome (ALPS): elevated DNT cell number, non-malignant lymphadenopathy and hepatosplenomegaly, hematolytic anemia, hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (lymphadenopathy, elevated DNT cell number and increased Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active EBV infection and genetic testing identified a novel mutation. None of the patients harbored typically ALPS-associated mutations of the Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency.
丝氨酸/苏氨酸激酶 4（STK4）缺乏症是一种常染色体隐性遗传疾病，导致原发性免疫缺陷（PID），其特征通常为淋巴细胞减少、反复感染以及诱导的淋巴细胞增生和淋巴瘤。目前的治疗方案包括预防或治疗感染、免疫球蛋白替代治疗（IVIG）以及通过造血干细胞移植恢复免疫系统。在这里，我们报告了来自两个土耳其（患者 P1）和摩洛哥（患者 P2）近亲家庭的两名患者，他们因纯合突变而患有 PID。P1 携带先前报道的移码突变（c.1103delT，p.M368RfsX2），而 P2 携带新的剪接供体位点突变（P2；c.525+2T>G）。两名患者均在儿童时期出现反复感染、CD4 淋巴细胞减少和免疫球蛋白水平失调。患者 P1 在 10 岁时患有高度恶性 B 细胞淋巴瘤，5 年后又发生了第二个独立的霍奇金淋巴瘤。据我们所知，她是第一个报道在没有检测到 EBV 或其他常见病毒的情况下发生淋巴瘤的 STK4 缺陷病例。淋巴瘤的发生可能是由于 STK4 缺乏肿瘤抑制功能，也可能是由于缺乏 CD4+T 细胞导致免疫监视失调。我们的数据应引起医生的注意，[1]即使在没有 EBV 感染的情况下，STK4 缺陷患者也容易发生淋巴瘤，[2]在患有反复感染、CD4 淋巴细胞减少和淋巴瘤且遗传构成未知的儿科患者中，可能存在潜在的 STK4 缺乏。患者 P2 在儿童时期经常发生中耳炎，但当她 14 岁时就诊时，她表现出与自身免疫性淋巴增生综合征（ALPS）相似的临床和免疫特征：DNT 细胞数量升高、非恶性淋巴结病和肝脾肿大、溶血性贫血、高丙种球蛋白血症。患者 P1 也表现出 ALPS 样特征（淋巴结病、DNT 细胞数量升高和维生素 B12 水平升高），最初临床诊断为 ALPS 样。对 P2 的进一步检查显示其存在活跃的 EBV 感染，基因检测发现了一种新的突变。两名患者均未携带 Fas 受体介导的凋亡途径中典型的 ALPS 相关突变，且 Fas 介导的凋亡未受影响。所报告的病例报告扩展了 STK4 缺乏症的临床谱。
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