Abstract
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan–Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.
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Introduction
Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants, in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function (GOF) variants in the PIK3CD gene, while loss of function (LOF) variants in PIK3R1 have been reported to cause APDS2 [1,2,3,4]. The pathogenic variants PIK3CD and PIK3R1 result in the over activation of PI3-kinase. PI3-kinase plays a role in regulation of T and B cells, therefore, both APDS1 and APDS2 manifest as combined immunodeficiency. Clinical presentation of APDS typically begins in the first year of life as severe, recurrent infections. This progresses to include lymphoproliferation and sometimes malignant lymphoma; many patients also experience autoimmunity, bronchiectasis, and enteropathy [5].
Treatment for APDS often includes immunoglobulin replacement therapy to combat recurrent infection, as well as immunosuppressive agents such as rituximab, sirolimus, and tacrolimus to mitigate autoimmunity and lymphoproliferation [5]. Hematopoietic stem cell transplantation (HSCT) has also been undertaken in a minority of patients and has been shown to ameliorate symptoms, however, HSCT itself can also cause adverse complications and death [5,6,7,8].
Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan [6, 7]. Okano et al. [6] reported on APDS1 survival based on 23 Japanese and Taiwanese patients from 21 families, 9 of which had HSCT. Thirty-year survival was 83% with just 2 deaths, both due to HSCT. Elkaim et al. reported that the thirty-year survival rate of APDS2 was 83%, based on an international cohort of 36 patients [7].
We conducted a review of the medical literature for every published case of APDS with documented age at last report and a molecular diagnosis in PIK3CD or PIK3R1. We identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. A comprehensive survival analysis and study of causes of death for APDS was conducted. The results of this study show decreased survival compared to previous reports, which may be attributed to the sample size of this study being more than 7 × higher than prior studies.
Methods
Literature review and data extraction
Literature was reviewed for all reports of age of individuals with APDS. All individuals included in this analysis were published in English language peer-reviewed journals indexed in PubMed. Search terms utilized were PIK3CD, PIK3R1, PASLI, and APDS. This resulted in 116 papers that were all reviewed (PubMed last accessed 08-21-22). In order to be included in this study an individual had to have been reported to have a molecular diagnosis of pathogenic variant in either PIK3CD or PIK3R1. An additional requirement to be included in this study was the patient’s age at last report and whether the patient was alive or deceased at last report. Cause of death and whether the individual received HSCT were also noted, when available, but were not required for inclusion in the study. In total, 116 papers were reviewed, 61 of which reported on subjects that met the inclusion criteria for this study. Through this review of the medical literature, 193 individuals diagnosed with APDS1 through molecular genetic testing and pathogenic variant present in PIK3CD were extracted from the literature for whom age was reported. In addition, 63 individuals diagnosed with APDS2 through molecular genetic testing and pathogenic variant present in PIK3R1 were extracted from the literature for whom age was reported.
Kaplan–Meier survival analysis
Kaplan–Meier survival analysis was conducted using the R survival package to estimate the probability of survival over time plus the 95% confidence interval [9,10,11]. All-cause mortality was considered the endpoint. Any individual who was alive at last report was censored. A censored observation is one where the subject drops out of the study but survives at a given time point. Kaplan–Meier survival analysis was conducted using 1-year age bins from birth to the oldest patient age. The Mantel–Haenszel test was utilized to test if the conditional probability estimates from APDS1 and 2 were different from each other [12].
Results
We reviewed the literature for all reports of age of individuals with APDS. Through this review of the medical literature, 193 individuals diagnosed with APDS1 through molecular genetic testing and pathogenic variant present in PIK3CD were extracted from the literature for whom age was reported [1, 2, 6, 8, 13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54]. In addition, 63 individuals diagnosed with APDS2 through molecular genetic testing and pathogenic variant present in PIK3R1 were extracted from the literature for whom age was reported [3, 4, 7, 8, 26, 44, 55,56,57,58,59,60,61,62,63,64,65,66].
The median age of individuals reported with APDS1 was 13 years with an average of 17 years (range, 1–64 years). The median age of individuals reported with APDS2 was 14 years with an average of 16 years (range, 1–56 years). The age distribution was significantly different between the two groups due to there being disproportionately more individuals with APDS1 in the 5–15 year age range (p = 3.6E−10) (Fig. 1). Gender was not available for all individuals in the study. For APDS1, 103/182 (57%) individuals were reported as being male and 79/182 (43%) individuals were noted to be female. For APDS2, 20/39 (51%) individuals were reported as being male with 19/39 (49%) individuals were noted to be female.
Twenty-four individuals with APDS1 in this study were reported as being deceased. Age of death ranged from 1 to 64 years. The most common cause of death was tied between lymphoma (N = 5) and HSCT (N = 5) (Fig. 2). The range of ages for death by lymphoma was 1–27 years, while the range of ages for death by HSCT was 5–18 years. The next most common cause of death was sepsis with no further information specified (N = 3, age range 11–31 years). Additional causes of death included: varicella zoster pneumonitis (N = 1, age 12); acute myeloid leukemia (N = 1, age 22); lymphoproliferative disease (N = 1, age 11); gastric cancer (N = 1, age 64); IgA nephropathy (N = 1, age 57); respiratory failure (N = 1, age 39) (Fig. 2).
Six out of the 63 individuals with APDS2 in this study were reported as having died. Age of death ranged from 12 to 36 years. The cause of death was reported for 5/6 individuals who died with APDS2, and all of their deaths were attributed to lymphoma.
For APDS1, the same number of individuals were reported to die from HSCT and lymphoma (N = 5 each). However, HSCT and lymphoma did not occur at the same rate within this patient population. The number of individuals diagnosed with APDS1 who had HSCT was 27. With 5 deaths attributed to complications from HSCT, the resultant mortality rate for HSCT in this group of APDS1 cases was 18.5% (5/27). In contrast, the number of APDS1 patients who had lymphoma was 11, with 5 individuals having died from lymphoma, resulting in a rate of death for lymphoma of 45% (5/11). Hence, looking at mortality rate resulting from HSCT versus lymphoma reveals a significantly higher rate of death resulting from lymphoma than HSCT in this patient population.
The leading cause of death for APDS2 subjects in this study was lymphoma. In total, 10 subjects with APDS2 were reported as having had lymphoma, 5 of whom died from it. This is a death rate from lymphoma of 50%, which is similar to the lymphoma death rate in APDS1. There were 5 cases of APDS2 reported as having HSCT, and none of them were reported to have died from complications resulting from that procedure. Since the mortality rate for HSCT in APDS1 was 18.5%, it is possible that with an N = 5, there were not enough APDS2 cases who received HSCT in this study to observe any deaths. The overall mortality rate for HSCT in both the APDS1 and APDS2 cases was 15.6% (5/32).
The data on causes of death for both APDS1 and APDS2 was grouped by decade of age at death and the number of individuals with a cause of death (Fig. 2C, left panel), and the percentage of individuals who died resulting from a particular cause of death was plotted (Fig. 2C, right panel). Looking at the data from the perspective of causes of death in each decade of life revealed that in the first two decades of life (0–19 years), HSCT was the primary cause of death. In the third and fourth decades of life (20–39 years), lymphoma was the leading cause of death. This is most likely due to the age at which HSCT is performed and the age of onset for lymphoma in these cases.
Kaplan–Meier survival analysis was conducted that allowed for inclusion of individuals who were alive at last report as well as those who died during the timespan of the study. Kaplan–Meier survival analysis was conducted for all-cause mortality in 1-year age bins on subjects diagnosed with APDS1 and separately for subjects diagnosed with APDS2 (Fig. 3). The survival probability estimate for APDS1 at the age of 20 years was 87%, age of 30 years was 75%, and ages of 40 and 50 years were 69%. The survival probability estimate for APDS2 at the age of 20 years was 98%, age of 30 years was 72%, and ages of 40 and 50 years were 60%. The Mantel–Haenszel test showed that the survival probability estimates for APDS1 and APDS2 were not different from each other (p-value: 0.49). Consequently, Kaplan–Meier survival analysis was also conducted on the combined APDS1-2 cohort using age at last report for 256 individuals, since the combined cohort was largest and had the most power (Fig. 3). Because most of the individuals in the combined cohort had APDS1 the survival curve for APDS1-2 most closely reflected the survival curve for APDS1. For APDS1-2, the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%.
Discussion
Kaplan–Meier survival analysis and studies of mortality were conducted for 256 individuals who had genetically defined APDS1 or 2. Kaplan–Meier survival analysis on the combined APDS1-2 cohort using age at last report showed that the APDS1-2 the conditional survival rate is appreciably reduced beginning in the second decade of life. This reduced survival continues to decline over time: at the age of 20 years survival was 87%, 74% at age of 30 years, and 68% at ages of 40 and 50 years.
In this cohort of 256 individuals with APDS1 or APDS2, 30 deaths were noted. Of these, the cause of death was reported for 24 individuals. The most common cause of death was lymphoma with age of death from lymphoma ranging from 1 TO 27 years. The second most common cause of death was complications resulting from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%. The mortality rate for lymphoma was 47.6%, which is notably higher than the mortality rate for lymphoma in the general population. Of the individuals who reached older ages, the causes of death were gastric cancer (age 64 years), IgA nephropathy (age 57 years), and respiratory failure (age 39 years). Most deaths occurred before the age of 30 years; however, it is important to note that the age distribution of this cohort is highly skewed toward younger ages with 85% of the combined APDS cohort in this study being less than 30 years old.
Given that only 15% of the cohort was older than 30, this study has less power beyond the age of 30 years. This is reflected in the larger confidence intervals in the Kaplan–Meier curves post-30, as well as the dearth of deaths after age of 30 years in the chart in Fig. 2B. The chart could be misconstrued to indicate that there are fewer deaths after the age of 30 years; however, the data from this cohort simply does not provide the opportunity to make observations post-age of 30 years with as much sensitivity as below age of 30 years. Having noted this limitation, this cohort contained 38 individuals 30 years or older, which is larger than the total study size of the two previous survival analyses published for APDS.
There are two previously published survival analyses for APDS, one for APDS1 and one for APDS2 [6, 7]. With much smaller sample sizes than this study, just N = 23 for APDS1 [6] and N = 36 for APDS2 [7], both reported thirty-year survival was 83%. In this study with a much larger cohort, N = 256, the thirty-year survival was 74%. The lower survival rates in this study is likely due to the larger sample size of this cohort resulting in greater sensitivity to observe events and consequently in a more robust measure of survival rates.
Common variable immune deficiency (CVID) is a heterogenous group of primary immune deficiencies clinically defined as having reduced IgG, IgA, and/or IgM. There are multiple genetic causes of CVID with PIK3CD and PIK3R1 being among them [67]. Kaplan–Meier survival analysis of a large cohort of 411 subjects with genetically undefined CVID who were followed for four decades was reported [68]. The 30-years survival rate for this CVID cohort was 68% for females and 70% for males. This more closely resembles the 74% thirty-year survival rate that was found in this study of APDS.
The most common causes of death in the CVID cohort were respiratory failure from chronic lung disease (37%), cancer (primarily lymphoma) (29%), and severe infection (10%) [68]. In contrast, lymphoma was the most common cause of death in this APDS cohort and only one person with APDS was reported as having died due to respiratory failure from chronic lung disease. This could indicate that respiratory failure is a less frequent feature of APDS than heterogenous CVID; however, it could also be that respiratory failure from chronic lung disease occurs at older ages, and as we noted this APDS cohort has 38/256 individuals who were older than 30. Longer-term follow-up on APDS is warranted to better define survival and mortality at older ages.
The results of this study on survival and mortality in APDS suggest that traditional treatments for APDS appear to mitigate risk of death due to severe infection; however, new treatments are needed to mitigate the risk of death from lymphoma and other cancers.
Data availability
All data were extracted from published articles indexed in PubMed.
References
Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342:866–71.
Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15:88–97.
Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, Butrick M, Matthews H, Price S, Biancalana M, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211:2537–47.
Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, Cavazzana M, Picard C, Durandy A, Fischer A, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124:3923–8.
Jamee M, Moniri S, Zaki-Dizaji M, Olbrich P, Yazdani R, Jadidi-Niaragh F, Aghamahdi F, Abolhassani H, Condliffe AM, Aghamohammadi A, et al. Clinical, immunological, and genetic features in patients with activated pi3kdelta syndrome (APDS): a systematic review. Clin Rev Allergy Immunol. 2020;59:323–33.
Okano T, Imai K, Tsujita Y, Mitsuiki N, Yoshida K, Kamae C, Honma K, Mitsui-Sekinaka K, Sekinaka Y, Kato T, 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 Allergy Clin Immunol. 2019;143:266–75.
Elkaim E, Neven B, Bruneau J, Mitsui-Sekinaka K, Stanislas A, Heurtier L, Lucas CL, Matthews H, Deau MC, Sharapova S, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138(210–218): e219.
Nademi Z, Slatter MA, Dvorak CC, Neven B, Fischer A, Suarez F, Booth C, Rao K, Laberko A, Rodina J, et al. Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome. J Allergy Clin Immunol. 2017;139:1046–9.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.
Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med. 1998;17:857–72.
Wilson EB. Probable Inference, the Law of Succession, and Statistical Inference. J Am Stat Assoc. 1927;22:209–12.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.
Rao VK, Webster S, Dalm V, Sediva A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, et al. Effective “activated PI3Kdelta syndrome”-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood. 2017;130:2307–16.
Crank MC, Grossman JK, Moir S, Pittaluga S, Buckner CM, Kardava L, Agharahimi A, Meuwissen H, Stoddard J, Niemela J, et al. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J Clin Immunol. 2014;34:272–6.
Kracker S, Curtis J, Ibrahim MA, Sediva A, Salisbury J, Campr V, Debre M, Edgar JD, Imai K, Picard C, et al. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase delta syndrome. J Allergy Clin Immunol. 2014;134:233–6.
Hartman HN, Niemela J, Hintermeyer MK, Garofalo M, Stoddard J, Verbsky JW, Rosenzweig SD, Routes JM. Gain of function mutations of PIK3CD as a cause of primary sclerosing cholangitis. J Clin Immunol. 2015;35:11–4.
Chiriaco M, Brigida I, Ariganello P, Di Cesare S, Di Matteo G, Taus F, Cittaro D, Lazarevic D, Scarselli A, Santilli V, et al. The case of an APDS patient: defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment. Clin Immunol. 2017;178:20–8.
Elgizouli M, Lowe DM, Speckmann C, Schubert D, Hulsdunker J, Eskandarian Z, Dudek A, Schmitt-Graeff A, Wanders J, Jorgensen SF, et al. Activating PI3Kdelta mutations in a cohort of 669 patients with primary immunodeficiency. Clin Exp Immunol. 2016;183:221–9.
Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, Ohnishi H, Kato Z, Sekinaka Y, Zaha K, et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016;138(1672–1680):e1610.
Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL, Cunningham-Rundles C. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front Immunol. 2016;7:220.
Rae W, Ramakrishnan KA, Gao Y, Ashton-Key M, Pengelly RJ, Patel SV, Ennis S, Williams AP, Faust SN. Precision treatment with sirolimus in a case of activated phosphoinositide 3-kinase delta syndrome. Clin Immunol. 2016;171:38–40.
Rae W, Gao Y, Ward D, Mattocks CJ, Eren E, Williams AP. A novel germline gain-of-function variant in PIK3CD. Clin Immunol. 2017;181:29–31.
Heurtier L, Lamrini H, Chentout L, Deau MC, Bouafia A, Rosain J, Plaza JM, Parisot M, Dumont B, Turpin D, et al. Mutations in the adaptor-binding domain and associated linker region of p110delta cause activated PI3K-delta syndrome 1 (APDS1). Haematologica. 2017;102:e278–81.
Takeda AJ, Zhang Y, Dornan GL, Siempelkamp BD, Jenkins ML, Matthews HF, McElwee JJ, Bi W, Seeborg FO, Su HC, et al. Novel PIK3CD mutations affecting N-terminal residues of p110delta cause activated PI3Kdelta syndrome (APDS) in humans. J Allergy Clin Immunol. 2017;140(1152–1156):e1110.
Stray-Pedersen A, Sorte HS, Samarakoon P, Gambin T, Chinn IK, Coban Akdemir ZH, Erichsen HC, Forbes LR, Gu S, Yuan B, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous mendelian disorders. J Allergy Clin Immunol. 2017;139:232–45.
Wentink M, Dalm V, Lankester AC, van Schouwenburg PA, Scholvinck L, Kalina T, Zachova R, Sediva A, Lambeck A, Pico-Knijnenburg I, et al. Genetic defects in PI3Kdelta affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections. Clin Immunol. 2017;176:77–86.
Dulau Florea AE, Braylan RC, Schafernak KT, Williams KW, Daub J, Goyal RK, Puck JM, Rao VK, Pittaluga S, Holland SM, et al. Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD. J Allergy Clin Immunol. 2017;139:1032-1035.e1036.
Mettman D, Thiffault I, Dinakar C, Saunders C. Immunodeficiency-associated lymphoid hyperplasia as a cause of intussusception in a case of activated PI3K-delta syndrome. Front Pediatr. 2017;5:71.
Saettini F, Pelagatti MA, Sala D, Moratto D, Giliani S, Badolato R, Biondi A. Early diagnosis of PI3Kdelta syndrome in a 2 years old girl with recurrent otitis and enlarged spleen. Immunol Lett. 2017;190:279–81.
Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, Goodlad JR, Farmer G, Steele CL, Leahy TR, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(597–606): e594.
Hong CR, Lee S, Hong KT, Choi JY, Shin HY, Choi M, Kang HJ. Successful haploidentical transplantation with post-transplant cyclophosphamide for activated phosphoinositide 3-kinase delta syndrome. J Allergy Clin Immunol Pract. 2019;7(1034–1037):e1031.
Luo Y, Xia Y, Wang W, Li Z, Jin Y, Gong Y, He T, Li Q, Li C, Yang J. Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase delta syndrome. Clin Immunol. 2018;197:60–7.
Buchbinder D, Seppanen M, Rao VK, Uzel G, Nugent D. Clinical challenges: identification of patients with novel primary immunodeficiency syndromes. J Pediatr Hematol Oncol. 2018;40:e319–22.
Pham MN, Cunningham-Rundles C. Evaluation of lymphoproliferative disease and increased risk of lymphoma in activated phosphoinositide 3 kinase delta syndrome: a case report with discussion. Front Pediatr. 2018;6:402.
Lougaris V, Baronio M, Moratto D, Tampella G, Gazzurelli L, Facchetti M, Martire B, Cardinale F, Lanzarotto F, Bondioni MP, et al. A novel monoallelic gain of function mutation in p110delta causing atypical activated phosphoinositide 3-kinase delta syndrome (APDS-1). Clin Immunol. 2019;200:31–4.
Tessarin G, Rossi S, Baronio M, Gazzurelli L, Colpani M, Benvenuto A, Zunica F, Cardinale F, Martire B, Brescia L, et al. Activated phosphoinositide 3-kinase delta syndrome 1: clinical and immunological data from an italian cohort of patients. J Clin Med. 2020;9:3335.
Thauland TJ, Pellerin L, Ohgami RS, Bacchetta R, Butte MJ. Case study: mechanism for increased follicular helper T cell development in activated PI3K delta syndrome. Front Immunol. 2019;10:753.
Baleydier F, Ranza E, Schappi M, Rougemont AL, Merlini L, Ansari M, Blanchard-Rohner G. Activated phosphoinositide 3 kinase delta syndrome (APDS): a primary immunodeficiency mimicking lymphoma. J Pediatr Hematol Oncol. 2019;41:e521–4.
Cansever M, Zietara N, Chiang SCC, Ozcan A, Yilmaz E, Karakukcu M, Rohlfs M, Somekh I, Canoz O, Abdulrezzak U, et al. A rare case of activated phosphoinositide 3-kinase delta syndrome (APDS) presenting with hemophagocytosis complicated with hodgkin lymphoma. J Pediatr Hematol Oncol. 2020;42:156–9.
Wallace JG, Zambrano-Rodas P, Cordova-Calderon W, Estrada-Turriate S, Mendoza-Quispe D, Limache Ontiveros Y, Geha RS, Chou J, Platt CD. Dysregulated actin dynamics in activated PI3Kdelta syndrome. Clin Immunol. 2020;210:108311.
Ahmed AA, El Shahaway AA, Hussien SA. Activated PI3K-delta syndrome in an Egyptian pediatric cohort with primary immune deficiency. Allergol Immunopathol. 2020;48:686–93.
Kang JM, Kim SK, Kim D, Choi SR, Lim YJ, Kim SK, Park BK, Park WS, Kang ES, Ko YH, et al. Successful Sirolimus Treatment for Korean Patients with activated phosphoinositide 3-kinase delta syndrome 1: the first case Series in Korea. Yonsei Med J. 2020;61:542–6.
Lougaris V, Baronio M, Castagna A, Tessarin G, Rossi S, Gazzurelli L, Benvenuto A, Moratto D, Chiarini M, Cattalini M, et al. Paediatric MAS/HLH caused by a novel monoallelic activating mutation in p110delta. Clin Immunol. 2020;219:108543.
Diaz N, Juarez M, Cancrini C, Heeg M, Soler-Palacin P, Payne A, Johnston GI, Helmer E, Cain D, Mann J, et al. Seletalisib for activated pi3kdelta syndromes: open-label phase 1b and extension studies. J Immunol. 2020;205:2979–87.
Lu M, Gu W, Sheng Y, Wang J, Xu X. Case report: activating PIK3CD mutation in patients presenting with granulomatosis with polyangiitis. Front Immunol. 2021;12:670312.
Zhang X, Wang J, Zhu K, Jin Y, Fu H, Mao J. Activated phosphoinositide 3-kinase delta syndrome misdiagnosed as anti-neutrophil cytoplasmic antibody-associated vasculitis: a case report. J Int Med Res. 2021;49:3000605211013222.
Schworer SA, Francis OL, Johnson SM, Smith BD, Gold SH, Smitherman AB, Wu EY. Autoimmune cytopenia as an early and initial presenting manifestation in activated PI3 kinase delta syndrome: case report and review. J Pediatr Hematol Oncol. 2021;43:281–7.
Bloomfield M, Klocperk A, Zachova R, Milota T, Kanderova V, Sediva A. Natural course of activated phosphoinositide 3-kinase delta syndrome in childhood and adolescence. Front Pediatr. 2021;9:697706.
Marzollo A, Bresolin S, Colavito D, Cani A, Gaio P, Bosa L, Mescoli C, Rossini L, Barzaghi F, Perilongo G, et al. Case report: intestinal nodular lymphoid hyperplasia as first manifestation of activated PI3Kdelta syndrome due to a novel PIK3CD variant. Front Pediatr. 2021;9:703056.
Yin Z, Tian X, Zou R, He X, Chen K, Zhu C. Case report: first occurrence of plasmablastic lymphoma in activated phosphoinositide 3-kinase delta syndrome. Front Immunol. 2021;12:813261.
Wang W, Min Q, Lai N, Csomos K, Wang Y, Liu L, Meng X, Sun J, Hou J, Ying W, et al. Cellular mechanisms underlying B cell abnormalities in patients with gain-of-function mutations in the PIK3CD gene. Front Immunol. 2022;13:890073.
Wang Y, Wang W, Liu L, Hou J, Ying W, Hui X, Zhou Q, Liu D, Yao H, Sun J, et al. Report of a Chinese cohort with activated phosphoinositide 3-kinase delta syndrome. J Clin Immunol. 2018;38:854–63.
Kannan JA, Davila-Saldana BJ, Zhang K, Filipovich AH, Kucuk ZY. Activated phosphoinositide 3-kinase delta syndrome in a patient with a former diagnosis of common variable immune deficiency, bronchiectasis, and lymphoproliferative disease. Ann Allergy Asthma Immunol. 2015;115:452–4.
Goto F, Uchiyama T, Nakazawa Y, Imai K, Kawai T, Onodera M. Persistent impairment of T-Cell regeneration in a patient with activated PI3K delta syndrome. J Clin Immunol. 2017;37:347–50.
Lougaris V, Faletra F, Lanzi G, Vozzi D, Marcuzzi A, Valencic E, Piscianz E, Bianco A, Girardelli M, Baronio M, et al. Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. Clin Immunol. 2015;159:33–6.
Lawrence MG, Uzel G. 6-year-old boy with recurrent sinopulmonary infections and lymphadenopathy. J Allergy Clin Immunol Pract. 2015;3(461–463):e461.
Kuhlen M, Honscheid A, Loizou L, Nabhani S, Fischer U, Stepensky P, Schaper J, Klapper W, Siepermann M, Schuster F, et al. De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly. Clin Immunol. 2016;162:27–30.
Olbrich P, Lorenz M, Cura Daball P, Lucena JM, Rensing-Ehl A, Sanchez B, Fuhrer M, Camacho-Lovillo M, Melon M, Schwarz K, et al. Activated PI3Kdelta syndrome type 2: two patients, a novel mutation, and review of the literature. Pediatr Allergy Immunol. 2016;27:640–4.
Martinez-Saavedra MT, Garcia-Gomez S, Dominguez Acosta A, Mendoza Quintana JJ, Paez JP, Garcia-Reino EJ, Camps G, Martinez-Barricarte R, Itan Y, Boisson B, et al. Gain-of-function mutation in PIK3R1 in a patient with a narrow clinical phenotype of respiratory infections. Clin Immunol. 2016;173:117–20.
Asano T, Okada S, Tsumura M, Yeh TW, Mitsui-Sekinaka K, Tsujita Y, Ichinose Y, Shimada A, Hashimoto K, Wada T, et al. Enhanced AKT phosphorylation of circulating B cells in patients with activated PI3Kdelta syndrome. Front Immunol. 2018;9:568.
Petrovski S, Parrott RE, Roberts JL, Huang H, Yang J, Gorentla B, Mousallem T, Wang E, Armstrong M, McHale D, et al. Dominant splice site mutations in PIK3R1 cause hyper IgM syndrome, lymphadenopathy and short stature. J Clin Immunol. 2016;36:462–71.
Dominguez-Pinilla N, Allende LM, Rosain J, Gallego MDC, Chaves F, Deswarte C, Viedma E, de Inocencio Arocena J, Ruiz-Contreras J, Bustamante J, et al. Disseminated abscesses due to Mycoplasma faucium in a patient with activated PI3Kδ syndrome type 2. J Allergy Clin Immunol Pract. 2018;6:1796-1798.e1792.
Yazdani R, Hamidi Z, Babaha F, Azizi G, Fekrvand S, Abolhassani H, Aghamohammadi A. PIK3R1 mutation associated with hyper IgM (APDS2 Syndrome): a case report and review of the literature. Endocr Metab Immune Disord Drug Targets. 2019;19:941–58.
Karanovic D, Michelow IC, Hayward AR, DeRavin SS, Delmonte OM, Grigg ME, Dobbs AK, Niemela JE, Stoddard J, Alhinai Z, et al. Disseminated and congenital toxoplasmosis in a mother and child with activated PI3-kinase delta syndrome type 2 (APDS2): case report and a literature review of toxoplasma infections in primary immunodeficiencies. Front Immunol. 2019;10:77.
Ramirez L, Tamayo W, Ale H. APDS2 and SHORT syndrome in a teenager with PIK3R1 pathogenic variant. J Clin Immunol. 2020;40:1020–5.
Bravo García-Morato M, García-Miñaúr S, Molina Garicano J, Santos Simarro F, Del Pino Molina L, López-Granados E, Ferreira Cerdán A, Rodríguez Pena R. Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two. Clin Immunol. 2017;179:77–80.
Abolhassani H, Hammarstrom L, Cunningham-Rundles C. Current genetic landscape in common variable immune deficiency. Blood. 2020;135:656–67.
Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119:1650–7.
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PEB receives support from Baylor College of Medicine and NIH NINDS RO1 NS08372.
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JH analyzed investigation, data curation, and validation. PEB performed conceptualization, formal analysis, supervision, validation, and writing.
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Hanson, J., Bonnen, P.E. Systematic review of mortality and survival rates for APDS. Clin Exp Med 24, 17 (2024). https://doi.org/10.1007/s10238-023-01259-y
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DOI: https://doi.org/10.1007/s10238-023-01259-y