RARE DISEASE
Activated PI3K-delta syndrome
Activated PI3K-delta syndrome
Activated PI3K-delta syndrome
Synonyms: APDS, Senescent T-cells-lymphadenopathy-immunodeficiency syndrome due to p110delta-activating mutation
Synonyms: APDS, Senescent T-cells-lymphadenopathy-immunodeficiency syndrome due to p110delta-activating mutation
Synonyms: APDS, Senescent T-cells-lymphadenopathy-immunodeficiency syndrome due to p110delta-activating mutation
Drug discovery
4
drugs
With orphan designations
Overview
Activated PI3K-delta syndrome (APDS) is a rare autosomal dominant primary immunodeficiency caused by gain-of-function mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), leading to hyperactive PI3Kδ signaling. Clinical features include recurrent sinopulmonary infections, lymphoproliferation (lymphadenopathy, splenomegaly), bronchiectasis, autoimmune complications, and increased lymphoma risk. Diagnosis involves genetic testing and immunophenotyping showing skewed B/T-cell subsets. Management combines supportive care, targeted PI3Kδ inhibitors (e.g., leniolisib), and immunosuppressants [1][6][18].
Burden
High morbidity: Recurrent infections (96–100% of patients), progressive lung damage, chronic fatigue, and pain [4][16].
Autoimmunity (e.g., cytopenias, arthritis) in ~50% and lymphoma risk (up to 25%) [1][7][16].
Significant quality-of-life impacts: 70–80% require lifelong therapies; caregivers report elevated physical/emotional strain [4][9].
Therapies
Supportive: Immunoglobulin replacement, antimicrobial prophylaxis, and bronchiectasis management [8][13].
Targeted: Leniolisib (FDA-approved PI3Kδ inhibitor) reduces lymphoproliferation and immune dysregulation; sirolimus (mTOR inhibitor) for refractory cases [3][18].
Curative: Hematopoietic stem cell transplantation (HSCT) in severe/early-onset disease [6][8].
Categories: rare genetic diseases, rare immunological diseases
Research Papers
121 drug discovery papers about Activated PI3K-delta syndrome, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
121 drug discovery papers about Activated PI3K-delta syndrome, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-13 | Case Report: Activated phosphoinositide 3-kinase δ syndrome mimicking Hyper-IgM syndrome: early hepatosplenomegaly as a key diagnostic clue.
APDS is a combined immunodeficiency disorder, characterized by impaired antibody production and lymphoproliferation, with a high risk of malignancy and autoimmunity. The disease may be caused by autosomal dominant gain-of-function variants in the PIK3CD or loss-of-function variants in the PIK3R1 gene. We report an 11-year-old girl with a history of recurrent respiratory infections, lymphoproliferation, and hepatosplenomegaly from early childhood. She was diagnosed with Hyper-IgM syndrome (HIGM) because of decreased IgA and IgG but increased IgM, and was treated with immunoglobulin replacement therapy, but there was no improvement in respiratory symptoms, and hepatosplenomegaly remained marked. Immunologic testing showed that, in addition to a reduced peripheral B-cell count, there was also a reduced CD4+ T-cell count and an inverted CD4/CD8 ratio, suggesting a diagnosis other than classical HIGM. The patient was diagnosed with APDS, confirmed by whole-exome sequencing, identifying the PIK3CD c.3061G>A p.(Glu1021Lys) variant. The patient maintained on immunoglobulin replacement therapy and corticosteroid therapy, with subsequent addition of sirolimus, and showed a rapid response with improvement in chronic productive cough, enlarged lymph nodes, and hepatosplenomegaly after 2 months. After 6 months of treatment, lymphodenopathy had resolved, and the liver and spleen returned to normal size. Early hepatosplenomegaly and lymphadenopathy are important warning signs of APDS in children with a Hyper IgM-like phenotype. This is particularly relevant in patients with CD4+ T-cell lymphopenia, an inverted CD4/CD8 ratio, and marked B-cell lymphopenia. Sirolimus improved lymphoproliferative manifestations and partially controlled chronic respiratory and gastrointestinal disease but did not eliminate the need for immunoglobulin replacement therapy.
2026-08-27 | APDS treatment in Germany: decision criteria, costs and contribution of leniolisib to outcomes.
Activated PI3 Kinase Delta Syndrome (APDS) is a rare inborn error of immunity. To better classify the contribution of a potential new therapeutic precision agent, leniolisib, medically relevant decision criteria were assessed upon which an outcomes model was built. Two online surveys and two roundtable discussions with 6 medical and scientific experts were conducted to obtain and discuss clinical and cost components. Based on the discussion results, key decision outcomes were modelled in an outcomes model. Key decision therapeutic criteria of physicians were reliably found in two rounds of Maximum Difference Scaling, with efficacy being most important, followed by safety, disease severity, and quality of life impact. Relevant clinical outcomes in APDS, that were considered well quantifiable, were frequency of infections, lymphoproliferation, bronchiectasis, lymphoma, and mortality. For these outcomes, relevant improvements versus current standard of care were estimated for the new therapeutic precision agent leniolisib. Expert assessments in the online surveys, which were carried out by the 6 participants independently, showed low variance across participants. Ratings resulted in a projected reduction of mortality by use of leniolisib of ~16% at an age of 40 years (95% CI: [9%; 22%]). This age is currently reached only by 65% of APDS patients. Other changes were expected for costs, immunoglobulin replacement, treatment of lymphoma and other malignancies, bronchiectasis, and advanced lung disease, as well as allogeneic hematopoietic cell transplantation (alloHCT). Decision criteria of physicians for treating APDS are well in line with other therapeutic areas, with efficacy considered to be most relevant. Based on currently available data on leniolisib therapy, mortality and several patient-relevant morbidity endpoints are expected to improve in future clinical practice in Germany. Leniolisib may significantly modify the course of disease in APDS patients.
2026-06-16 | A review of PI3K/AKT/mTOR inhibitors from traditional Chinese medicine: potential and perspective for activated phosphoinositide 3-kinase δ syndrome.
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a primary immunodeficiency caused by hyperactivation of the PI3K/AKT/mTOR pathway, resulting in severe lymphoproliferation, recurrent infections, autoimmunity, and malignancy. However, current therapies, including immunosuppressants and hematopoietic stem cell transplantation, are constrained by limited efficacy, high costs, donor scarcity, or adverse effects such as metabolic complications from chronic rapamycin use. In this review, we systematically synthesize preclinical evidence on traditional Chinese medicine (TCM) agents that target the PI3K/AKT/mTOR pathway. Our goal is to establish a hypothesis-driven framework for APDS drug discovery. Through a comprehensive PubMed, CNKI, and Wanfang databases up to October 30, 2025, we identified 332 eligible studies, compiling a repository of 5 herbs, 99 extracts, and 56 formulas. These agents, rich in flavonoids, terpenoids, alkaloids, and polysaccharides, exhibit multifaceted pharmacological activities such as antitumor, anti-inflammatory, and immunomodulatory effects. Notably, 15 candidates show promise in ameliorating lymphoproliferation, infection, and gastrointestinal dysfunction in disease models with pathophysiological overlap with APDS. However, we emphasize that all current evidence is derived from non-APDS experimental systems; direct validation in patient-derived immune cells or APDS-mutant models remains absent. This review therefore provides a prioritized, evidence-based repository of testable hypotheses and a translational roadmap, advocating for rigorous functional validation, isoform-specific mechanistic dissection, and integration with conventional therapies to bridge the gap between traditional medicine and precision immunotherapy for APDS.
2026-06-02 | Activated PIK3CD drives marginal zone B cell development from early transitional progenitors by enhancing ADAM10 expression.
Activated PI3K-delta syndrome (APDS) is a human monogenic primary immunodeficiency disorder caused by mutations in the gene encoding the p110δ catalytic subunit of phosphoinositide 3-kinase, PIK3CD. APDS is characterized by complex immune phenotypes, including increased serum IgM, susceptibility to encapsulated bacterial respiratory infections, poor vaccine response, and autoimmune disorders. Impaired B cell development and responses, involving an expansion at the transient transitional T1 stage and a strikingly selective expansion of autoreactive marginal zone B cells, may be largely responsible for these phenotypes, although little is known about the precise underlying mechanisms. In this study, we used a mouse model of activated PI3Kδ syndrome to investigate the role of altered PI3Kδ signaling specifically within the spleen marginal zone B cell development. Here, we report that hyperactive P110δ leads to an increase in the proportion of spleen marginal zone B cell precursors with enhanced surface ADAM10 levels, as early as the T1 stage of B cell development. Using single-cell RNA sequencing (scRNA-seq), we also identified divergent cell differentiation at the T1 stage. The ADAM10 inhibitor suppresses marginal zone B cells differentiation and also partially reverses the imbalance of transitional T1 and T2 stage. These findings inform understanding of the mechanism underlying imbalanced marginal zone B cell development in APDS from a shallow perspective, and provide a preliminary platform for future investigation of strategies to target autoimmune B cells in this disease.
2026-04-27 | Case Report: Recurrent pulmonary infections with neck masses: a diagnostic challenge and literature review.
This article presents a case characterized by recurrent pulmonary infections and a poor therapeutic response. Initially, cystic fibrosis (CF) or Primary ciliary dyskinesia was suspected; however, the patient subsequently sought medical attention for a neck mass. The mass was initially misdiagnosed as lymphoma, but a comprehensive examination and assessment ultimately confirmed the diagnosis of activated phosphoinositide 3-kinase delta syndrome type I(APDS1). Through the patient's tortuous diagnostic journey, this report aims to enhance clinicians' understanding of this rare primary immunodeficiency disorder. Clinical picture: The patient is a female adopted child who has experienced recurrent lung infections since the age of 6 months. On average, she has required hospitalization 2-3 times annually, with conventional anti-infection treatments proving less effective. Throughout her illness, she was admitted to another hospital for sinusitis and breast cysts, although the specifics of her treatment remain unclear. Subsequently, she presented to our hospital with symptoms of coughing, yellow sputum, and hemoptysis. During her hospitalization, a new neck mass was identified. Key inspection: Imaging assessment revealed a chest CT indicating pulmonary infection and bronchiectasis with mucus plug formation. Neck CT and MRI suggested a potential diagnosis of lymphoma. Pathogen testing through nucleic acid analysis for respiratory pathogens yielded positive results for mycoplasma and adenovirus influenzae. Laboratory and abdominal ultrasound did not identify any abnormalities in the pancreas. A peripheral blood immunological assessment demonstrated significantly diminished cellular and humoral immune functions. Following the resection of the cervical mass, the initial pathological diagnosis was lymphoma; however, tests for T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangements returned negative results. After a multidisciplinary consultation and subsequent pathological re-examination, the diagnosis was revised to infectious mononucleosis. Genetic testing revealed a heterozygous mutation in the PIK3CD gene. Final diagnosis: Activated phosphatidylinositol 3-kinase δ syndrome type I (APDS1). Treatment and prognosis: Following diagnosis, the child was administered rapamycin-targeted therapy in conjunction with compound sulfamethoxazole to prevent infections, with regular monitoring of rapamycin blood concentrations. Subsequent follow-up indicated a significant reduction in the frequency of pulmonary infection episodes, a decrease in the size of the enlarged lymph nodes in the neck, and effective control of the condition.
antibodies
2024-12-12 | Case Report: Early-onset or recalcitrant cytopenias as presenting manifestations of activated PI3Kδ syndrome.
Patients with recurrent, chronic, or refractory cytopenias represent a challenging subgroup that may harbor an underlying diagnosis, such as an inborn error of immunity (IEI). Patients with IEIs such as activated phosphoinositide 3-kinase delta syndrome (APDS), frequently have hematologic manifestations, but these are not often reported as presenting symptoms. As a result, IEIs may be overlooked in patients presenting with early and/or recalcitrant cytopenias. Here, we describe the diagnostic journey and management of three patients who presented to a pediatric hematologist/oncologist with early-onset or recalcitrant cytopenias and were ultimately diagnosed with APDS. Patients presented with early-onset and/or refractory cytopenias, with two of the three developing multilineage cytopenias. Prior to an APDS diagnosis, two patients underwent a total of approximately 20 procedures, including biopsies, invasive endoscopies, and imaging, with one undergoing eight differential diagnoses that were ruled out through additional testing. Recalcitrant cytopenias, a history of infection, and a family history of lymphoproliferation, infection, or autoimmunity raised suspicion of an underlying IEI, leading to genetic testing. Genetic testing identified a pathogenic variant of PIK3CD in each patient, resulting in the diagnosis of APDS. Following these diagnoses, two patients underwent modifications in the management of care with the administration of intravenous immunoglobulin therapy (IVIG), the mTOR inhibitor sirolimus, or surgical procedures. These treatment modifications either improved or resolved the cytopenias. The third patient showed improvement in immune thrombocytopenia with IVIG 1 month prior to receiving a definitive diagnosis. Following diagnosis, follow-up genetic testing of family members led to the identification of additional cases of APDS. These cases highlight the importance of early genetic evaluation in patients with early-onset or recalcitrant cytopenias and demonstrate the challenges of differential diagnosis. In addition, these cases demonstrate beneficial changes in management and outcomes that can follow a definitive diagnosis, including the identification of targeted treatment options. Collectively, this case series supports the notion that underlying IEIs should be considered in the workup of early-onset or recalcitrant cytopenias, particularly in patients who present with a combination of hematologic and immunologic manifestations that are refractory to treatment, manifest at an unusually young age, or can be tied to family history.
2023-08-22 | Activated PI3Kδ syndrome - reviewing challenges in diagnosis and treatment.
Activated PI3Kδ syndrome (APDS) is a rare inborn error of immunity (IEI) characterized primarily by frequent infections, lymphoproliferation and autoimmunity. Since its initial description in 2013, APDS has become part of the growing group of nearly 500 IEIs affecting various components of the immune system. The two subtypes of APDS - APDS1 and APDS2 - are caused by variants in the PIK3CD and PIK3R1 genes, respectively. Due to the rarity of the disease and the heterogeneous clinical picture, many patients are not diagnosed until years after symptom onset. Another challenge is the large number of PIK3CD and PIK3R1 variants whose functional significance for developing APDS is inconclusive. Treatment of APDS has so far been mostly symptom-oriented with immunoglobulin replacement therapy, immunosuppressive therapies and antibiotic or antiviral prophylaxes. Additionally, allogeneic stem cell transplantation as well as new targeted therapies are options targeting the root cause that may improve patients' quality of life and life expectancy. However, the clinical course of the disease is difficult to predict which complicates the choice of appropriate therapies. This review article discusses diagnostic procedures and current and future treatment options, and highlights the difficulties that physicians, patients and their caretakers face in managing this complex disease. This article is based on cohort studies, the German and US guidelines on the management of primary immunodeficiencies as well as on published experience with diagnosis and compiled treatment experience for APDS.
2022-07-11 | Case Report: Successful Treatment With Monoclonal Antibodies in One APDS Patient With Prolonged SARS-CoV-2 Infection Not Responsive to Previous Lines of Treatment.
We described the case of a patient affected by activated PI3K-kinase delta syndrome (APDS) and a long-lasting and pauci-symptomatic SARS-CoV-2 infection, treated with multiple therapeutic agents including remdesivir and SARS-CoV-2-neutralizing monoclonal antibodies. We detected the clearance of the virus 105 days from the first positive swab and 7 days after monoclonal antibody administration. At genotyping, the SARS-CoV-2 virus resulted as wild type on all samples tested. This case shows the monoclonal antibodies' good tolerability and efficacy in reducing viral shedding in long-lasting infections refractory to other treatments.
2019-07-17 | CD57 identifies T cells with functional senescence before terminal differentiation and relative telomere shortening in patients with activated PI3 kinase delta syndrome.
Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.
2018-03-07 | Exhaustion of the CD8+ T Cell Compartment in Patients with Mutations in Phosphoinositide 3-Kinase Delta
Pathogenic gain-of-function mutations in the gene encoding phosphoinositide 3-kinase delta (PI3Kδ) cause Activated PI3Kδ Syndrome (APDS), a disease characterized by humoral immunodeficiency, lymphadenopathy and an inability to control persistent viral infections including EBV and CMV. Understanding the mechanisms leading to impaired immune response is important to optimally treat APDS patients. Immunosenescence of CD8+ T cells was suggested to contribute to APDS pathogenesis. However, the constitutive activation of T cells in APDS may also result in T cell exhaustion. Therefore, we studied exhaustion of the CD8+ T cell compartment in APDS patients and compared them to healthy controls and HIV patients, as a control for exhaustion. The subset distribution of the T cell compartment of APDS patients was comparable to HIV patients with decreased naive CD4+ and CD8+ T cells and increased effector CD8+ T cells. Like in HIV+ patients, expression of activation markers and inhibitory receptors CD160, CD244 and PD-1 on CD8+ T cells was increased in APDS patients, indicating exhaustion. EBV-specific CD8+ T cells from APDS patients exhibited an exhausted phenotype that resembled HIV-specific CD8+ T cells in terms of inhibitory receptor expression. Inhibition of PD-1 on EBV-specific CD8+ T cells from APDS patients enhanced in vitro proliferation and effector cytokine production. Based on these results, we conclude that total and EBV-specific CD8+ T cells from APDS patients are characterized by T cell exhaustion. Furthermore, PD-1 checkpoint inhibition may provide a possible therapeutic approach to support the immune system of APDS patients to control EBV and CMV.
cell therapies
2026-02-04 | αβT/CD19-depleted Allogeneic Stem Cell Transplantation in Adults with Inborn Errors of Immunity.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is successful in pediatric patients with inborn errors of immunity (IEI), but its use in adults is complicated by pre-existing organ damage and increased risk of treatment-related mortality. Ex vivo graft engineering using αβTCR/CD19 depletion has shown promising safety profiles in pediatric IEI, yet evidence in adults is limited. We assessed the feasibility and outcomes of αβTCR/CD19-depleted allo-HSCT in adults with IEI, focusing on engraftment, immune reconstitution, and clinical outcomes. We included 9 adults with IEI and 1 with VEXAS (age 21-51). IEIs included CTLA4HI, APDS, DOCK8, ALPS, DADA2, CVID2, and HA20, with Immune Deficiency and Dysregulation Activity (IDDA) scores of 17-92. αβTCR/CD19-depleted allografts from related, unrelated or haplo-identical donors were used after antithymocyte globulin (ATG) and myeloablative conditioning (thiotepa, melphalan, and fludarabine). Post-transplant immunoprophylaxis included mycophenolate mofetil; 4/10 patients received additional transplant-associated immunosuppression. All patients achieved primary engraftment. One patient with secondary rejection successfully underwent a second allo-HSCT. 5 patients developed grade 2-4 acute GvHD; no chronic GvHD was observed. One patient with GvHD died from COVID-19. All remaining 9 patients were successfully tapered off immunosuppression and showed improved IDDA scores. At 6 months NK, γδT, B and CD8 + T cells normalized; CD4 + numbers reached 149 cells/µl at 1 year. Most patients were successfully vaccinated and could stop immunoglobulin substitution. In conclusion, ex vivo graft engineering using αβTCR/CD19 depletion was feasible in adults with IEI. Clinical outcomes are encouraging, but need to be confirmed in larger studies.
2023-11-02 | Future Directions in the Diagnosis and Treatment of APDS and IEI: a Survey of German IEI Centers.
The diagnosis and treatment of inborn errors of immunity (IEI) is a major challenge as the individual conditions are rare and often characterized by a variety of symptoms, which are often non disease-specific. Ideally, patients are treated in dedicated centers by physicians who specialize in the management of primary immune disorders. In this study, we used the example of Activated PI3Kδ syndrome (APDS), a rare IEI with an estimated prevalence of 1:1,000,000. We conducted surveys by questionnaire and interviewed physicians at different IEI centers in Germany. We queried structural aspects of IEI care in Germany, diagnostic procedures in IEI care (including molecular diagnostics), distribution of APDS patients, APDS symptoms and severity, treatment algorithms in APDS, the role of stem cell transplantation and targeted therapies in IEI with focus on APDS. We were especially interested in how genetic diagnostics may influence treatment decisions, e.g. with regard to targeted therapies. Most centers care for both pediatric and adult patients. A total of 28 APDS patients are currently being treated at the centers we surveyed. Patient journeys vary considerably, as does severity of disease. Genetic diagnosis continues to gain importance - whole genome sequencing is likely to become routine in IEI in the next few years. According to the experts interviewed, stem cell transplantation and - with new molecules being approved - targeted therapies, will gain in importance for the treatment of APDS and IEI in general.
2023-02-13 | Successful haploidentical hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: Case report and literature review.
Activated phosphoinositide 3-kinase δ syndrome (APDS), a recently described primary immunodeficiency,is caused by autosomal dominant mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta(PIK3CD) gene encoding the p110δ catalytic subunit of PI3Kδ (APDS1) or the PIK3R1 gene that encodes the p85α regulatory subunit of PI3Kδ (APDS2). Gain-of-function mutation of PIK3CD in APDS1 leads to p110δ hyperactivity, with the result of the hyperphosphorylation of downstream mediators of Akt and mammalian target of rapamycin that cause a series of clinical symptoms. Few cases with APDS were reported in Asia. We report a 6-year-old patient with a recurrent respiratory infection, cryptosporidium enteritis, lymphoproliferation, high serum immunoglobulin-M level, anemia, and inverted CD4+/CD8+ ratio. The whole exome sequencing confirmed a heterozygous missense mutation c.3061G>A（p.E1021K）in patient and her mother. Her mutant gene is inherited from her mother, but her mother has not any clinical symptoms. Activated phosphoinositide 3-kinase δ syndrome. The patient was received immunoglobulin (Ig) replacement therapy, antibiotics, and rapamycin treatment. Through effectively controlling infection and optimal timing of transplantation by adjusting the conditioning regimen, haploidentical Hematopoietic Stem Cell Transplantation(haplo-HSCT) from her brother was successfully performed. The patient is in good condiion with a good quality of life after 20 months of follow-up. We reported a rare APDS1 case with PIK3CD E1021K gene mutation, Successfully treated with haplo-HSCT. This case provided a reference for treating APDS with haplo-HSCT.
2022-06-20 | Generation of human induced pluripotent stem cell line from peripheral blood mononuclear cells from an activated phosphoinositide 3-kinase δ syndrome patient.
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a rare autosomal dominant primary immunodeficiency disease (PID) which was caused by the acquired mutation of PIK3CD gene. In this study, we generated a human induced pluripotent stem cell (hiPSC) line CHCMUi001-A from the peripheral blood mononuclear cells (PBMCs) of a APDS patient, who has a heterozygous mutation (c.3061 G > A) in the PIK3CD gene. This iPSC line presented a normal karyotype and exhibited characteristics of pluripotent stem cells. This iPSC line can be very useful for not only studying disease mechanisms but also developing new potential clinical treatments for APDS patients.
2022-06-08 | Activated Phosphoinositide 3-Kinase δ Syndrome: a Large Pediatric Cohort from a Single Center in China.
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a primary immunodeficiency first described in 2013, which is caused by gain-of-function mutations in PIK3CD or PIK3R1, and characterized by recurrent respiratory tract infections, lymphoproliferation, herpesvirus infection, autoimmunity, and enteropathy. We sought to review the clinical phenotypes, immunological characteristics, treatment, and prognosis of APDS in a large genetically defined Chinese pediatric cohort. Clinical records, radiology examinations, and laboratory investigations of 40 APDS patients were reviewed. Patients were contacted via phone call to follow up their current situation. Sinopulmonary infections and lymphoproliferation were the most common complications in this cohort. Three (10.3%) and five (12.5%) patients suffered localized BCG-induced granulomatous inflammation and tuberculosis infection, respectively. Twenty-seven patients (67.5%) were affected by autoimmunity, while malignancy (7.5%) was relatively rare to be seen. Most patients in our cohort took a combined treatment of anti-infection prophylaxis, immunoglobulin replacement, and immunosuppressive therapy such as glucocorticoid or rapamycin administration. Twelve patients underwent hematopoietic stem cell transplantation (HSCT) and had a satisfying prognosis. Clinical spectrum of APDS is heterogeneous. This cohort's high incidence of localized BCG-induced granulomatous inflammation and tuberculosis indicates Mycobacterial susceptibility in APDS patients. Rapamycin is effective in improving lymphoproliferation and cytopenia. HSCT is an option for those who have severe complications and poor response to other treatments.
gene therapies
2025-05-15 | Case Report: Activated PI3-kinase-δ syndrome and ovarian malignancies: a case series from the European ESID-APDS registry.
Activated phosphoinositide-3-kinase-delta (PI3Kδ) syndrome (APDS) is an autosomal dominant inborn error of immunity (IEI) characterized by combined immunodeficiency and immune dysregulation with increased risk for lymphoma and other non-lymphoid malignancies. We describe five patients with ovarian malignancies among 110 female APDS patients participating in the European Society for Immunodeficiencies (ESID) registry and identified three additional cases in the literature. These findings document a relevant predisposition to these non-hematological malignancies in APDS patients.
2025-04-25 | Massively Scalable Generation, Discovery, and Clinical (Re)Classification of Inborn Errors of Immunity Using Cutting-Edge Genome Engineering
Clinical next-generation sequencing (NGS) is a pillar of diagnosis for inborn errors of immunity (IEI). However, for each pathogenic variant identified, these methods yield hundreds of variants of uncertain significance (VUS), creating ambiguity in clinical management. Here, we present a high-throughput framework to precisely generate genetic variants at endogenous loci and map them with the clinically established functional readout. Loss-of-function (LOF) variants in PIK3CD or PIK3R1 can lead to immune deficiency and/or the multisystem SHORT syndrome, while gain-of-function (GOF) variants lead to lymphoproliferation, autoimmunity, and infection—the activated PI3K-delta syndrome (APDS). In primary human T cells from multiple healthy donors, we performed saturation CRISPR base-editor screening of PIK3CD and PIK3R1 coupled with the clinical APDS-diagnostic flow cytometric assay to measure phosphorylated AKT and S6 after T cell receptor (TCR) stimulation. We successfully detected most known pathogenic variants and found >100 variants which were clearly novel GOF or LOF mutations. We individually validated 30 of these variants and show that many GOF, including those already associated with APDS, are sensitive to leniolisib, an FDA-approved PI3Kδ inhibitor for APDS. Next, we used structural modeling to map variant effects to defined regions in the PI3Kδ protein complex, identifying variant “hotspots” associated with pathogenic AKT/S6 signaling. Finally, we acquired peripheral blood samples from patients harboring germline mutations in PIK3CD or PIK3R1. We find that both exhibit pathogenic AKT/S6 signaling and leniolisib sensitivity at similar effect sizes as our screen-identified novel GOFs, emphasizing the clinical predictive value of our variant classification approach. We leveraged multiple precision genome editing approaches to correct the causative SNVs in these patient samples, improving signaling defects. Thousands of new functional annotations from our screens will be incorporated into public databases and used for variant reclassification, substantially broadening the population of previously undiagnosed patients who can immediately benefit from this precision medicine approach. This proof-of-concept study is part of the Human Immune Variome Project, an effort to functionally classify variants across hundreds of genes implicated in IEIs, to remove ambiguity related to clinical management and treatment. Figure 1.
small molecules
2026-09-13 | Case Report: Activated phosphoinositide 3-kinase δ syndrome mimicking Hyper-IgM syndrome: early hepatosplenomegaly as a key diagnostic clue.
APDS is a combined immunodeficiency disorder, characterized by impaired antibody production and lymphoproliferation, with a high risk of malignancy and autoimmunity. The disease may be caused by autosomal dominant gain-of-function variants in the PIK3CD or loss-of-function variants in the PIK3R1 gene. We report an 11-year-old girl with a history of recurrent respiratory infections, lymphoproliferation, and hepatosplenomegaly from early childhood. She was diagnosed with Hyper-IgM syndrome (HIGM) because of decreased IgA and IgG but increased IgM, and was treated with immunoglobulin replacement therapy, but there was no improvement in respiratory symptoms, and hepatosplenomegaly remained marked. Immunologic testing showed that, in addition to a reduced peripheral B-cell count, there was also a reduced CD4+ T-cell count and an inverted CD4/CD8 ratio, suggesting a diagnosis other than classical HIGM. The patient was diagnosed with APDS, confirmed by whole-exome sequencing, identifying the PIK3CD c.3061G>A p.(Glu1021Lys) variant. The patient maintained on immunoglobulin replacement therapy and corticosteroid therapy, with subsequent addition of sirolimus, and showed a rapid response with improvement in chronic productive cough, enlarged lymph nodes, and hepatosplenomegaly after 2 months. After 6 months of treatment, lymphodenopathy had resolved, and the liver and spleen returned to normal size. Early hepatosplenomegaly and lymphadenopathy are important warning signs of APDS in children with a Hyper IgM-like phenotype. This is particularly relevant in patients with CD4+ T-cell lymphopenia, an inverted CD4/CD8 ratio, and marked B-cell lymphopenia. Sirolimus improved lymphoproliferative manifestations and partially controlled chronic respiratory and gastrointestinal disease but did not eliminate the need for immunoglobulin replacement therapy.
2026-08-27 | APDS treatment in Germany: decision criteria, costs and contribution of leniolisib to outcomes.
Activated PI3 Kinase Delta Syndrome (APDS) is a rare inborn error of immunity. To better classify the contribution of a potential new therapeutic precision agent, leniolisib, medically relevant decision criteria were assessed upon which an outcomes model was built. Two online surveys and two roundtable discussions with 6 medical and scientific experts were conducted to obtain and discuss clinical and cost components. Based on the discussion results, key decision outcomes were modelled in an outcomes model. Key decision therapeutic criteria of physicians were reliably found in two rounds of Maximum Difference Scaling, with efficacy being most important, followed by safety, disease severity, and quality of life impact. Relevant clinical outcomes in APDS, that were considered well quantifiable, were frequency of infections, lymphoproliferation, bronchiectasis, lymphoma, and mortality. For these outcomes, relevant improvements versus current standard of care were estimated for the new therapeutic precision agent leniolisib. Expert assessments in the online surveys, which were carried out by the 6 participants independently, showed low variance across participants. Ratings resulted in a projected reduction of mortality by use of leniolisib of ~16% at an age of 40 years (95% CI: [9%; 22%]). This age is currently reached only by 65% of APDS patients. Other changes were expected for costs, immunoglobulin replacement, treatment of lymphoma and other malignancies, bronchiectasis, and advanced lung disease, as well as allogeneic hematopoietic cell transplantation (alloHCT). Decision criteria of physicians for treating APDS are well in line with other therapeutic areas, with efficacy considered to be most relevant. Based on currently available data on leniolisib therapy, mortality and several patient-relevant morbidity endpoints are expected to improve in future clinical practice in Germany. Leniolisib may significantly modify the course of disease in APDS patients.
2026-06-16 | A review of PI3K/AKT/mTOR inhibitors from traditional Chinese medicine: potential and perspective for activated phosphoinositide 3-kinase δ syndrome.
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a primary immunodeficiency caused by hyperactivation of the PI3K/AKT/mTOR pathway, resulting in severe lymphoproliferation, recurrent infections, autoimmunity, and malignancy. However, current therapies, including immunosuppressants and hematopoietic stem cell transplantation, are constrained by limited efficacy, high costs, donor scarcity, or adverse effects such as metabolic complications from chronic rapamycin use. In this review, we systematically synthesize preclinical evidence on traditional Chinese medicine (TCM) agents that target the PI3K/AKT/mTOR pathway. Our goal is to establish a hypothesis-driven framework for APDS drug discovery. Through a comprehensive PubMed, CNKI, and Wanfang databases up to October 30, 2025, we identified 332 eligible studies, compiling a repository of 5 herbs, 99 extracts, and 56 formulas. These agents, rich in flavonoids, terpenoids, alkaloids, and polysaccharides, exhibit multifaceted pharmacological activities such as antitumor, anti-inflammatory, and immunomodulatory effects. Notably, 15 candidates show promise in ameliorating lymphoproliferation, infection, and gastrointestinal dysfunction in disease models with pathophysiological overlap with APDS. However, we emphasize that all current evidence is derived from non-APDS experimental systems; direct validation in patient-derived immune cells or APDS-mutant models remains absent. This review therefore provides a prioritized, evidence-based repository of testable hypotheses and a translational roadmap, advocating for rigorous functional validation, isoform-specific mechanistic dissection, and integration with conventional therapies to bridge the gap between traditional medicine and precision immunotherapy for APDS.
2026-06-02 | Activated PIK3CD drives marginal zone B cell development from early transitional progenitors by enhancing ADAM10 expression.
Activated PI3K-delta syndrome (APDS) is a human monogenic primary immunodeficiency disorder caused by mutations in the gene encoding the p110δ catalytic subunit of phosphoinositide 3-kinase, PIK3CD. APDS is characterized by complex immune phenotypes, including increased serum IgM, susceptibility to encapsulated bacterial respiratory infections, poor vaccine response, and autoimmune disorders. Impaired B cell development and responses, involving an expansion at the transient transitional T1 stage and a strikingly selective expansion of autoreactive marginal zone B cells, may be largely responsible for these phenotypes, although little is known about the precise underlying mechanisms. In this study, we used a mouse model of activated PI3Kδ syndrome to investigate the role of altered PI3Kδ signaling specifically within the spleen marginal zone B cell development. Here, we report that hyperactive P110δ leads to an increase in the proportion of spleen marginal zone B cell precursors with enhanced surface ADAM10 levels, as early as the T1 stage of B cell development. Using single-cell RNA sequencing (scRNA-seq), we also identified divergent cell differentiation at the T1 stage. The ADAM10 inhibitor suppresses marginal zone B cells differentiation and also partially reverses the imbalance of transitional T1 and T2 stage. These findings inform understanding of the mechanism underlying imbalanced marginal zone B cell development in APDS from a shallow perspective, and provide a preliminary platform for future investigation of strategies to target autoimmune B cells in this disease.
2026-04-27 | Case Report: Recurrent pulmonary infections with neck masses: a diagnostic challenge and literature review.
This article presents a case characterized by recurrent pulmonary infections and a poor therapeutic response. Initially, cystic fibrosis (CF) or Primary ciliary dyskinesia was suspected; however, the patient subsequently sought medical attention for a neck mass. The mass was initially misdiagnosed as lymphoma, but a comprehensive examination and assessment ultimately confirmed the diagnosis of activated phosphoinositide 3-kinase delta syndrome type I(APDS1). Through the patient's tortuous diagnostic journey, this report aims to enhance clinicians' understanding of this rare primary immunodeficiency disorder. Clinical picture: The patient is a female adopted child who has experienced recurrent lung infections since the age of 6 months. On average, she has required hospitalization 2-3 times annually, with conventional anti-infection treatments proving less effective. Throughout her illness, she was admitted to another hospital for sinusitis and breast cysts, although the specifics of her treatment remain unclear. Subsequently, she presented to our hospital with symptoms of coughing, yellow sputum, and hemoptysis. During her hospitalization, a new neck mass was identified. Key inspection: Imaging assessment revealed a chest CT indicating pulmonary infection and bronchiectasis with mucus plug formation. Neck CT and MRI suggested a potential diagnosis of lymphoma. Pathogen testing through nucleic acid analysis for respiratory pathogens yielded positive results for mycoplasma and adenovirus influenzae. Laboratory and abdominal ultrasound did not identify any abnormalities in the pancreas. A peripheral blood immunological assessment demonstrated significantly diminished cellular and humoral immune functions. Following the resection of the cervical mass, the initial pathological diagnosis was lymphoma; however, tests for T-cell receptor (TCR) and immunoglobulin (IG) gene rearrangements returned negative results. After a multidisciplinary consultation and subsequent pathological re-examination, the diagnosis was revised to infectious mononucleosis. Genetic testing revealed a heterozygous mutation in the PIK3CD gene. Final diagnosis: Activated phosphatidylinositol 3-kinase δ syndrome type I (APDS1). Treatment and prognosis: Following diagnosis, the child was administered rapamycin-targeted therapy in conjunction with compound sulfamethoxazole to prevent infections, with regular monitoring of rapamycin blood concentrations. Subsequent follow-up indicated a significant reduction in the frequency of pulmonary infection episodes, a decrease in the size of the enlarged lymph nodes in the neck, and effective control of the condition.
antibodies
2024-12-12 | Case Report: Early-onset or recalcitrant cytopenias as presenting manifestations of activated PI3Kδ syndrome.
Patients with recurrent, chronic, or refractory cytopenias represent a challenging subgroup that may harbor an underlying diagnosis, such as an inborn error of immunity (IEI). Patients with IEIs such as activated phosphoinositide 3-kinase delta syndrome (APDS), frequently have hematologic manifestations, but these are not often reported as presenting symptoms. As a result, IEIs may be overlooked in patients presenting with early and/or recalcitrant cytopenias. Here, we describe the diagnostic journey and management of three patients who presented to a pediatric hematologist/oncologist with early-onset or recalcitrant cytopenias and were ultimately diagnosed with APDS. Patients presented with early-onset and/or refractory cytopenias, with two of the three developing multilineage cytopenias. Prior to an APDS diagnosis, two patients underwent a total of approximately 20 procedures, including biopsies, invasive endoscopies, and imaging, with one undergoing eight differential diagnoses that were ruled out through additional testing. Recalcitrant cytopenias, a history of infection, and a family history of lymphoproliferation, infection, or autoimmunity raised suspicion of an underlying IEI, leading to genetic testing. Genetic testing identified a pathogenic variant of PIK3CD in each patient, resulting in the diagnosis of APDS. Following these diagnoses, two patients underwent modifications in the management of care with the administration of intravenous immunoglobulin therapy (IVIG), the mTOR inhibitor sirolimus, or surgical procedures. These treatment modifications either improved or resolved the cytopenias. The third patient showed improvement in immune thrombocytopenia with IVIG 1 month prior to receiving a definitive diagnosis. Following diagnosis, follow-up genetic testing of family members led to the identification of additional cases of APDS. These cases highlight the importance of early genetic evaluation in patients with early-onset or recalcitrant cytopenias and demonstrate the challenges of differential diagnosis. In addition, these cases demonstrate beneficial changes in management and outcomes that can follow a definitive diagnosis, including the identification of targeted treatment options. Collectively, this case series supports the notion that underlying IEIs should be considered in the workup of early-onset or recalcitrant cytopenias, particularly in patients who present with a combination of hematologic and immunologic manifestations that are refractory to treatment, manifest at an unusually young age, or can be tied to family history.
2023-08-22 | Activated PI3Kδ syndrome - reviewing challenges in diagnosis and treatment.
Activated PI3Kδ syndrome (APDS) is a rare inborn error of immunity (IEI) characterized primarily by frequent infections, lymphoproliferation and autoimmunity. Since its initial description in 2013, APDS has become part of the growing group of nearly 500 IEIs affecting various components of the immune system. The two subtypes of APDS - APDS1 and APDS2 - are caused by variants in the PIK3CD and PIK3R1 genes, respectively. Due to the rarity of the disease and the heterogeneous clinical picture, many patients are not diagnosed until years after symptom onset. Another challenge is the large number of PIK3CD and PIK3R1 variants whose functional significance for developing APDS is inconclusive. Treatment of APDS has so far been mostly symptom-oriented with immunoglobulin replacement therapy, immunosuppressive therapies and antibiotic or antiviral prophylaxes. Additionally, allogeneic stem cell transplantation as well as new targeted therapies are options targeting the root cause that may improve patients' quality of life and life expectancy. However, the clinical course of the disease is difficult to predict which complicates the choice of appropriate therapies. This review article discusses diagnostic procedures and current and future treatment options, and highlights the difficulties that physicians, patients and their caretakers face in managing this complex disease. This article is based on cohort studies, the German and US guidelines on the management of primary immunodeficiencies as well as on published experience with diagnosis and compiled treatment experience for APDS.
2022-07-11 | Case Report: Successful Treatment With Monoclonal Antibodies in One APDS Patient With Prolonged SARS-CoV-2 Infection Not Responsive to Previous Lines of Treatment.
We described the case of a patient affected by activated PI3K-kinase delta syndrome (APDS) and a long-lasting and pauci-symptomatic SARS-CoV-2 infection, treated with multiple therapeutic agents including remdesivir and SARS-CoV-2-neutralizing monoclonal antibodies. We detected the clearance of the virus 105 days from the first positive swab and 7 days after monoclonal antibody administration. At genotyping, the SARS-CoV-2 virus resulted as wild type on all samples tested. This case shows the monoclonal antibodies' good tolerability and efficacy in reducing viral shedding in long-lasting infections refractory to other treatments.
2019-07-17 | CD57 identifies T cells with functional senescence before terminal differentiation and relative telomere shortening in patients with activated PI3 kinase delta syndrome.
Premature T-cell immunosenescence with CD57+ CD8+ T-cell accumulation has been linked to immunodeficiency and autoimmunity in primary immunodeficiencies including activated PI3 kinase delta syndrome (APDS). To address whether CD57 marks the typical senescent T-cell population seen in adult individuals or identifies a distinct population in APDS, we compared CD57+ CD8+ T cells from mostly pediatric APDS patients to those of healthy adults with similarly prominent senescent T cells. CD57+ CD8+ T cells from APDS patients were less differentiated with more CD27+ CD28+ effector memory T cells showing increased PD1 and Eomesodermin expression. In addition, transition of naïve to CD57+ CD8+ T cells was not associated with the characteristic telomere shortening. Nevertheless, they showed the increased interferon-gamma secretion, enhanced degranulation and reduced in vitro proliferation typical of senescent CD57+ CD8+ T cells. Thus, hyperactive PI3 kinase signaling favors premature accumulation of a CD57+ CD8+ T-cell population, which shows most functional features of typical senescent T cells, but is different in terms of differentiation and relative telomere shortening. Initial observations indicate that this specific differentiation state may offer the opportunity to revert premature T-cell immunosenescence and its potential contribution to inflammation and immunodeficiency in APDS.
2018-03-07 | Exhaustion of the CD8+ T Cell Compartment in Patients with Mutations in Phosphoinositide 3-Kinase Delta
Pathogenic gain-of-function mutations in the gene encoding phosphoinositide 3-kinase delta (PI3Kδ) cause Activated PI3Kδ Syndrome (APDS), a disease characterized by humoral immunodeficiency, lymphadenopathy and an inability to control persistent viral infections including EBV and CMV. Understanding the mechanisms leading to impaired immune response is important to optimally treat APDS patients. Immunosenescence of CD8+ T cells was suggested to contribute to APDS pathogenesis. However, the constitutive activation of T cells in APDS may also result in T cell exhaustion. Therefore, we studied exhaustion of the CD8+ T cell compartment in APDS patients and compared them to healthy controls and HIV patients, as a control for exhaustion. The subset distribution of the T cell compartment of APDS patients was comparable to HIV patients with decreased naive CD4+ and CD8+ T cells and increased effector CD8+ T cells. Like in HIV+ patients, expression of activation markers and inhibitory receptors CD160, CD244 and PD-1 on CD8+ T cells was increased in APDS patients, indicating exhaustion. EBV-specific CD8+ T cells from APDS patients exhibited an exhausted phenotype that resembled HIV-specific CD8+ T cells in terms of inhibitory receptor expression. Inhibition of PD-1 on EBV-specific CD8+ T cells from APDS patients enhanced in vitro proliferation and effector cytokine production. Based on these results, we conclude that total and EBV-specific CD8+ T cells from APDS patients are characterized by T cell exhaustion. Furthermore, PD-1 checkpoint inhibition may provide a possible therapeutic approach to support the immune system of APDS patients to control EBV and CMV.
cell therapies
2026-02-04 | αβT/CD19-depleted Allogeneic Stem Cell Transplantation in Adults with Inborn Errors of Immunity.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is successful in pediatric patients with inborn errors of immunity (IEI), but its use in adults is complicated by pre-existing organ damage and increased risk of treatment-related mortality. Ex vivo graft engineering using αβTCR/CD19 depletion has shown promising safety profiles in pediatric IEI, yet evidence in adults is limited. We assessed the feasibility and outcomes of αβTCR/CD19-depleted allo-HSCT in adults with IEI, focusing on engraftment, immune reconstitution, and clinical outcomes. We included 9 adults with IEI and 1 with VEXAS (age 21-51). IEIs included CTLA4HI, APDS, DOCK8, ALPS, DADA2, CVID2, and HA20, with Immune Deficiency and Dysregulation Activity (IDDA) scores of 17-92. αβTCR/CD19-depleted allografts from related, unrelated or haplo-identical donors were used after antithymocyte globulin (ATG) and myeloablative conditioning (thiotepa, melphalan, and fludarabine). Post-transplant immunoprophylaxis included mycophenolate mofetil; 4/10 patients received additional transplant-associated immunosuppression. All patients achieved primary engraftment. One patient with secondary rejection successfully underwent a second allo-HSCT. 5 patients developed grade 2-4 acute GvHD; no chronic GvHD was observed. One patient with GvHD died from COVID-19. All remaining 9 patients were successfully tapered off immunosuppression and showed improved IDDA scores. At 6 months NK, γδT, B and CD8 + T cells normalized; CD4 + numbers reached 149 cells/µl at 1 year. Most patients were successfully vaccinated and could stop immunoglobulin substitution. In conclusion, ex vivo graft engineering using αβTCR/CD19 depletion was feasible in adults with IEI. Clinical outcomes are encouraging, but need to be confirmed in larger studies.
2023-11-02 | Future Directions in the Diagnosis and Treatment of APDS and IEI: a Survey of German IEI Centers.
The diagnosis and treatment of inborn errors of immunity (IEI) is a major challenge as the individual conditions are rare and often characterized by a variety of symptoms, which are often non disease-specific. Ideally, patients are treated in dedicated centers by physicians who specialize in the management of primary immune disorders. In this study, we used the example of Activated PI3Kδ syndrome (APDS), a rare IEI with an estimated prevalence of 1:1,000,000. We conducted surveys by questionnaire and interviewed physicians at different IEI centers in Germany. We queried structural aspects of IEI care in Germany, diagnostic procedures in IEI care (including molecular diagnostics), distribution of APDS patients, APDS symptoms and severity, treatment algorithms in APDS, the role of stem cell transplantation and targeted therapies in IEI with focus on APDS. We were especially interested in how genetic diagnostics may influence treatment decisions, e.g. with regard to targeted therapies. Most centers care for both pediatric and adult patients. A total of 28 APDS patients are currently being treated at the centers we surveyed. Patient journeys vary considerably, as does severity of disease. Genetic diagnosis continues to gain importance - whole genome sequencing is likely to become routine in IEI in the next few years. According to the experts interviewed, stem cell transplantation and - with new molecules being approved - targeted therapies, will gain in importance for the treatment of APDS and IEI in general.
2023-02-13 | Successful haploidentical hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: Case report and literature review.
Activated phosphoinositide 3-kinase δ syndrome (APDS), a recently described primary immunodeficiency,is caused by autosomal dominant mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta(PIK3CD) gene encoding the p110δ catalytic subunit of PI3Kδ (APDS1) or the PIK3R1 gene that encodes the p85α regulatory subunit of PI3Kδ (APDS2). Gain-of-function mutation of PIK3CD in APDS1 leads to p110δ hyperactivity, with the result of the hyperphosphorylation of downstream mediators of Akt and mammalian target of rapamycin that cause a series of clinical symptoms. Few cases with APDS were reported in Asia. We report a 6-year-old patient with a recurrent respiratory infection, cryptosporidium enteritis, lymphoproliferation, high serum immunoglobulin-M level, anemia, and inverted CD4+/CD8+ ratio. The whole exome sequencing confirmed a heterozygous missense mutation c.3061G>A（p.E1021K）in patient and her mother. Her mutant gene is inherited from her mother, but her mother has not any clinical symptoms. Activated phosphoinositide 3-kinase δ syndrome. The patient was received immunoglobulin (Ig) replacement therapy, antibiotics, and rapamycin treatment. Through effectively controlling infection and optimal timing of transplantation by adjusting the conditioning regimen, haploidentical Hematopoietic Stem Cell Transplantation(haplo-HSCT) from her brother was successfully performed. The patient is in good condiion with a good quality of life after 20 months of follow-up. We reported a rare APDS1 case with PIK3CD E1021K gene mutation, Successfully treated with haplo-HSCT. This case provided a reference for treating APDS with haplo-HSCT.
2022-06-20 | Generation of human induced pluripotent stem cell line from peripheral blood mononuclear cells from an activated phosphoinositide 3-kinase δ syndrome patient.
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a rare autosomal dominant primary immunodeficiency disease (PID) which was caused by the acquired mutation of PIK3CD gene. In this study, we generated a human induced pluripotent stem cell (hiPSC) line CHCMUi001-A from the peripheral blood mononuclear cells (PBMCs) of a APDS patient, who has a heterozygous mutation (c.3061 G > A) in the PIK3CD gene. This iPSC line presented a normal karyotype and exhibited characteristics of pluripotent stem cells. This iPSC line can be very useful for not only studying disease mechanisms but also developing new potential clinical treatments for APDS patients.
2022-06-08 | Activated Phosphoinositide 3-Kinase δ Syndrome: a Large Pediatric Cohort from a Single Center in China.
Activated phosphoinositide 3-kinase δ syndrome (APDS) is a primary immunodeficiency first described in 2013, which is caused by gain-of-function mutations in PIK3CD or PIK3R1, and characterized by recurrent respiratory tract infections, lymphoproliferation, herpesvirus infection, autoimmunity, and enteropathy. We sought to review the clinical phenotypes, immunological characteristics, treatment, and prognosis of APDS in a large genetically defined Chinese pediatric cohort. Clinical records, radiology examinations, and laboratory investigations of 40 APDS patients were reviewed. Patients were contacted via phone call to follow up their current situation. Sinopulmonary infections and lymphoproliferation were the most common complications in this cohort. Three (10.3%) and five (12.5%) patients suffered localized BCG-induced granulomatous inflammation and tuberculosis infection, respectively. Twenty-seven patients (67.5%) were affected by autoimmunity, while malignancy (7.5%) was relatively rare to be seen. Most patients in our cohort took a combined treatment of anti-infection prophylaxis, immunoglobulin replacement, and immunosuppressive therapy such as glucocorticoid or rapamycin administration. Twelve patients underwent hematopoietic stem cell transplantation (HSCT) and had a satisfying prognosis. Clinical spectrum of APDS is heterogeneous. This cohort's high incidence of localized BCG-induced granulomatous inflammation and tuberculosis indicates Mycobacterial susceptibility in APDS patients. Rapamycin is effective in improving lymphoproliferation and cytopenia. HSCT is an option for those who have severe complications and poor response to other treatments.
gene therapies
2025-05-15 | Case Report: Activated PI3-kinase-δ syndrome and ovarian malignancies: a case series from the European ESID-APDS registry.
Activated phosphoinositide-3-kinase-delta (PI3Kδ) syndrome (APDS) is an autosomal dominant inborn error of immunity (IEI) characterized by combined immunodeficiency and immune dysregulation with increased risk for lymphoma and other non-lymphoid malignancies. We describe five patients with ovarian malignancies among 110 female APDS patients participating in the European Society for Immunodeficiencies (ESID) registry and identified three additional cases in the literature. These findings document a relevant predisposition to these non-hematological malignancies in APDS patients.
2025-04-25 | Massively Scalable Generation, Discovery, and Clinical (Re)Classification of Inborn Errors of Immunity Using Cutting-Edge Genome Engineering
Clinical next-generation sequencing (NGS) is a pillar of diagnosis for inborn errors of immunity (IEI). However, for each pathogenic variant identified, these methods yield hundreds of variants of uncertain significance (VUS), creating ambiguity in clinical management. Here, we present a high-throughput framework to precisely generate genetic variants at endogenous loci and map them with the clinically established functional readout. Loss-of-function (LOF) variants in PIK3CD or PIK3R1 can lead to immune deficiency and/or the multisystem SHORT syndrome, while gain-of-function (GOF) variants lead to lymphoproliferation, autoimmunity, and infection—the activated PI3K-delta syndrome (APDS). In primary human T cells from multiple healthy donors, we performed saturation CRISPR base-editor screening of PIK3CD and PIK3R1 coupled with the clinical APDS-diagnostic flow cytometric assay to measure phosphorylated AKT and S6 after T cell receptor (TCR) stimulation. We successfully detected most known pathogenic variants and found >100 variants which were clearly novel GOF or LOF mutations. We individually validated 30 of these variants and show that many GOF, including those already associated with APDS, are sensitive to leniolisib, an FDA-approved PI3Kδ inhibitor for APDS. Next, we used structural modeling to map variant effects to defined regions in the PI3Kδ protein complex, identifying variant “hotspots” associated with pathogenic AKT/S6 signaling. Finally, we acquired peripheral blood samples from patients harboring germline mutations in PIK3CD or PIK3R1. We find that both exhibit pathogenic AKT/S6 signaling and leniolisib sensitivity at similar effect sizes as our screen-identified novel GOFs, emphasizing the clinical predictive value of our variant classification approach. We leveraged multiple precision genome editing approaches to correct the causative SNVs in these patient samples, improving signaling defects. Thousands of new functional annotations from our screens will be incorporated into public databases and used for variant reclassification, substantially broadening the population of previously undiagnosed patients who can immediately benefit from this precision medicine approach. This proof-of-concept study is part of the Human Immune Variome Project, an effort to functionally classify variants across hundreds of genes implicated in IEIs, to remove ambiguity related to clinical management and treatment. Figure 1.
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Drug Discovery Landscape
4 orphan drug designations for Activated PI3K-delta syndrome, including 2 approved therapies.
4 orphan drug designations for Activated PI3K-delta syndrome, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Leniolisib [Joenja] | small molecules | EMA | Approved | Pharming Technologies B.V. |
Seletalisib | small molecules | EMA | UCB Biopharma | |
leniolisib [Joenja] | small molecules | FDA | Approved | Pharming Technologies B.V. |
seletalisib | small molecules | FDA | UCB, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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