Journal of Shandong University (Health Sciences) ›› 2021, Vol. 59 ›› Issue (3): 107-112.doi: 10.6040/j.issn.1671-7554.0.2020.1386

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Activated phosphoinositide 3-kinase δ syndrome caused by a mutation in PIK3CD gene: a case report and literature review

HUANG Xiuli, LIU Bingju, SUN Lifeng   

  1. 3. Department of Pathology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China)
  • Published:2021-04-06

Abstract: Objective To explore the clinical features, gene mutations and treatment in patient with activated phosphoinositide 3-kinase δ syndrome(APDS). Methods The data of one patient who was diagnosed as APDS were retrospectively analyzed,and the related literatures were reviewed. The clinical features, gene mutations and treatment were summarized. Results The patient, a 9-year old Chinese girl, was hospitalized in Shandong Provincial Hospital Affiliated to Shandong First Medical University because of “recurrent cough for eight years, chronic diarrhea for three years and abnormal liver function for two years”. CT scan of the chest and abdomen demonstrated that she had hepatomegaly, splenomegaly, right middle lobe bronchiectasis and lymphoid hyperplasia, and the lung tissue in the middle lobe of the right lung was not dilated completely. The immunological features were inverted CD4+/CD8+ index, normal IgG level and increased IgM level. Sanger sequencing of PIK3CD gene confirmed a de novo mutation c.3061G>A(p.E1021K), which confirmed the diagnosis of APDS1. The child received IVIG and rapamycin treatments and experienced obvious improvement in diarrhea, lymphoproliferation, hepatomegaly, and splenomegaly. Recurrent respiratory infections were not occurred. The Wanfang Medical Database, CNKI Database and Pubmed Database were searched by keywords such as “activated phosphoinositide 3-kinase δ syndrome”“activated PI3Kδ syndrome” “PIK3CD”“PIK3R1”“APDS”. A total of 285 patients were reported all over the world, in which 43 patients were Chinese including this patient. There was only one patient with APSD2 type. Compared with the overseas patients, the incidence of bronchiectasis and higher IgM level of APDS patients in China was higher. No patients combined with malignant tumors. The hotspot mutations were c.3061 G>A(p. E1021K)in APDS1 and c.1425+1 G>(A, C, T)(p.434-475del)in APDS2, respectively. Conclusion APDS is a rare primary immunodeficiency disease characterized by antibody deficiency mainly. The patients have recurrent respiratory infections, bronchiectasis, non-neoplastic lymphoid hyperplasia, chronic diarrhea, autoimmune diseases, malignant tumor, developmental delay, CD4+/CD8+ inversion, high IgM level and variable IgG levels. IVIG can reduce respiratory tract infections and rapamycin was beneficial in the treatment of non-neoplastic lymphoproliferative. Hematopoietic stem cell transplantation can significantly improve clinical status and immune function.

Key words: Activated phosphoinositide 3-kinase δ syndrome, Immunodeficiency disease, Gene mutation, Recurrent respiratory infections, Bronchiectasis

CLC Number: 

  • R72
[1] Angulo I, Vadas O, Gawon F, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage[J]. Science, 2013, 342(6160): 866-871.
[2] Marie-Céline D, Lucie H, Pierre F, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene[J]. J Clin Invest, 2014, 124(9): 3923-3928.
[3] Jamee M, Moniri S, Zaki-Dizaji M, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome(APDS): a systematic review [J]. Clin Rev Allergy Immunol, 2020, 59(3): 323-333.
[4] Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phos phoinositide 3-kinase δsyndrome: a large patient cohort study[J]. J Allergy Clin Immunol, 2017, 139(2): 597-606.
[5] Olbrich P, Lorenz M, Daball PC, et al. Activated PI3Kδ syndrome type 2: two patients, a novel mutation, and review of the literature[J].Pediatr Allergy Immunol, 2016, 27(6): 640-644.
[6] Burke JE, Vadas O, Berndt A, et al. Dynamics of the phosphoinositide 3-kinase p110δ interaction with p85α and membranes reveals aspects of regulation distinct from p110α[J]. Structure, 2011, 19(8): 1127-1137.
[7] Lucas CL, Zhang Y, Venida A, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K[J]. J Exp Med, 2014, 211(13): 2537-2547.
[8] Thauland TJ, Pellerin L, Ohgami RS, et al. Case study: mechanism for increased follicular helper T cell development in activated PI3K delta syndrome[J]. Front Immunol,2019,10:753. doi: 10.3389/fimmu.2019.00753.
[9] Condliffe AM, Chandra A. Respiratory manifestations of the activated phosphoinositide 3-kinase delta syndrome[J]. Front Immunol, 2018, 9: 338. doi: 10.3389/fimmu.2018.00338.
[10] Zhang Q, Ma H, Ma J, et al. Clinical and genetic analysis of immunodeficiency-related diseases associated with PIK3CD mutations [J]. Pediatr Invest, 2018, 2(4): 257-262.
[11] Wang Y, Wang W, Liu L, et al. Report of a Chinese cohort with activated phosphoinositide 3-kinase δ syndrome [J]. J Clin Immunol, 2018, 38(8): 854-863.
[12] Li G, Liu H, Guan W, et al. A mutation in PIK3CD gene causing pediatric systemic lupus erythematosus: a case report[J]. Medicine(Baltimore), 2019, 98(18): e15329. doi: 10.1097/MD.0000000000015329.
[13] 刘辉,唐晓蕾,刘金荣,等. PIK3CD基因突变所致激活PI3Kδ综合征的临床特点和基因分析 [J].中华儿科杂志,2016,54(9): 698-702. LIU Hui, TANG Xiaolei, LIU Jinrong, et al. Clinical and genetic analysis for activated PI3K-δ syndrome by PIK3CD gene mutation [J]. Chinese Journal of Pediatrics, 2016, 54(9): 698-702.
[14] 唐文静,王薇,罗颖,等.PIK3CD基因突变致PI3Kδ过度活化综合征临床及免疫学特点分析[J].中华儿科杂志,2017, 55(1): 19-24. TANG Wenjing, WANG Wei, LUO Ying, et al. Clinical and immunological analysis of patients with activated phosphoinositide 3-kinase δ syndrome resulting from PIK3CD mutation[J]. Chinese Journal of Pediatrics, 2017, 55(1): 19-24.
[15] 郑静,肖阳阳,刘利群,等. PIK3CD基因突变致PI3K-δ过度活化综合征1例报告并文献复习[J].临床儿科杂志,2019, 37(4): 301-303. ZHENG Jing, XIAO Yangyang, LIU Liqun, et al. Activated PI3K-δ syndrome caused by PIK3CD gene mutation: a case report and literature review[J]. Journal of Clinical Pediatrics, 2019, 37(4): 301-303.
[16] 唐红霞,尹薇.激活PI3K-δ综合征合并关节炎1例并文献复习[J].临床儿科杂志,2018,36(11): 858-861. TANG Hongxia, YIN Wei. Activated phosphoinositide 3-kinase δ syndrome with arthritis:a case report and literature review[J]. Journal of Clinical Pediatrics, 2018, 36(11): 858-861.
[17] Luo Y, Xia Y, Wang W, et al. Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome[J]. Clin Immunol, 2018, 197: 60-67. doi: 10.1016/j.clim.2018.08.007.
[18] 杨秋韵,贾彦军,王艳平,等. 2型PI3Kδ过度活化综合征临床与免疫学特征分析[J].中华儿科杂志,2020, 58(5): 413-417. YANG Qiuyun, JIA Yanjun, WANG Yanping, et al. Clinical and immunological characteristics of a case with activated phosphoinositide 3 kinase δ syndrome 2 [J]. Chinese Journal of Pediatrics, 2020, 58(5): 413-417.
[19] Wang Y, Chen X, Yang Q, et al. E1021K homozygous mutation in PIK3CD leads to activated PI3K-Delta syndrome 1[J]. J Clin Immunol, 2020, 40(2): 378-387.
[20] Karanovic D, Michelow LC, Hayward AR, et al. Disseminated and congenital toxoplasmosis in a mother and child with activated PI3-kinase δ syndrome type 2(APDS2): case report and a literature review of toxoplasma infections in primary immunodeficiencies[J]. Front Immunol, 2019, 10: 77. doi: 10.3389/fimmu.2019.00077.
[21] Michalovich D, Nejentsev S. Activated PI3 kinase delta syndrome: from genetics to therapy [J]. Front Immunol, 2018, 9: 369. doi: 10.3389/fimmu.2018.00369.
[22] Coulter TI, Cant AJ. The treatment of activated PI3Kδ syndrome[J]. Front Immunol, 2018, 9: 2043. doi: 10.3389/fimmu.2018.02043.
[23] Maccari ME, Abolhassani H, Aghamohammadi A, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome: the European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry[J]. Front Immunol, 2018, 9: 543. doi: 10.3389/fimmu.2018.00543.
[24] Notarangelo LD. Hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: who, when, and how? [J]. J Allergy Clin Immunol, 2019, 143(1): 91-93.
[25] Rao VK, Webster S, Dalm VASH, et al. Effective “activated PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib [J]. Blood, 2017, 130(21): 2307-2316.
[26] Kracker S, Curtis J, Mohammad A, et al. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome[J]. J Allergy Clin Immunol, 2014, 134(1): 233-236.
[27] Okano T, Imai K, Tsujita Y, et al. Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase delta syndrome type 1 [J]. J Allergy Clin Immunol, 2019, 143(1): 266-275.
[28] Elgizouli M, Lowe DM, Speckmann C, et al. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency[J]. Clin Exp Immunol, 2016, 183(2): 221-229.
[29] Zou J, Duan XQ, Zheng GL, et al. A novel PIK3CD C896T mutation detected in bilateral sudden sensorineural hearing loss using next generation sequencing: an indication of primary immunodeficiency[J]. J Otol, 2016, 11(2): 78-83.
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