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Classifications

IUIS Category

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Inheritance

1

Autosomal dominant HP:0000006

APDS1 and APDS2 are autosomal dominant; both inherited and de novo pathogenic variants occur.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:39899769 SUPPORT Other

"APDS is an autosomal dominant disorder."

GeneReviews explicitly states the inheritance pattern.

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Subtypes

2

APDS1 (PIK3CD-related) MONDO:0014222

PIK3CD hgnc:8977

APDS1 is caused by heterozygous gain-of-function variants in PIK3CD, which encodes the catalytic p110delta PI3K subunit. It is the most common APDS subtype and classically presents with childhood-onset respiratory infections, lymphoproliferation, and antibody deficiency with a hyper-IgM pattern.

Show evidence (2 references)

PMID:39899769 SUPPORT Other

"APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1."

Current GeneReviews defines APDS1 as PIK3CD gain-of-function disease and APDS2 as PIK3R1 loss-of-function disease.

PMID:31111319 SUPPORT Other

"Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively."

Systematic review explicitly defines APDS1 as the PIK3CD-related subtype.

APDS2 (PIK3R1-related) MONDO:0014453

PIK3R1 hgnc:8979

APDS2 is caused by heterozygous PIK3R1 variants, most often splice defects that impair the inhibitory p85alpha regulatory subunit and produce net PI3Kdelta gain of function. The core immune phenotype overlaps strongly with APDS1, although growth delay and neurodevelopmental features are reported more often in this subtype.

Show evidence (2 references)

PMID:39899769 SUPPORT Other

"APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1."

Current GeneReviews defines the two APDS subtypes and their distinct variant mechanisms.

PMID:31111319 SUPPORT Other

"Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively."

Systematic review explicitly defines APDS2 as the PIK3R1-related subtype.

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Pathophysiology

7

PI3K-delta pathway hyperactivation

Germline gain-of-function variants in the PIK3CD catalytic subunit (APDS1) or loss-of-function variants in the inhibitory PIK3R1 regulatory subunit (APDS2) create constitutive PI3K-delta signaling with increased downstream AKT and mTOR activity. Persistent pathway activation disrupts lymphocyte homeostasis and underlies the precision-medicine rationale for PI3K-delta inhibition.

B cell CL:0000236 CD4-positive alpha-beta T cell CL:0000624 CD8-positive alpha-beta T cell CL:0000625

PIK3CD hgnc:8977 PIK3R1 hgnc:8979

phosphatidylinositol 3-kinase/protein kinase B signal transduction GO:0043491 ↑ INCREASED TOR signaling GO:0031929 ↑ INCREASED

Downstream

Defective B-cell maturation and humoral immunity Constitutive PI3K-delta signaling directly disrupts B-cell maturation and humoral function.

Senescent T-cell skewing Constitutive PI3K-delta signaling drives premature effector differentiation and T-cell senescence.

Chronic lymphoproliferation Constitutive lymphocyte signaling promotes persistent benign lymphoid expansion.

Immune dysregulation and autoimmunity Persistent PI3K-delta activation distorts lymphocyte homeostasis and tolerance, producing autoimmune manifestations.

Short stature Growth impairment is enriched in APDS2, but the intermediates connecting PIK3R1-related pathway dysregulation to stature remain unresolved.

Neurodevelopmental delay Neurodevelopmental delay is associated with APDS, especially APDS2, but a specific causal route from PI3K-pathway hyperactivation has not been established.

Show evidence (2 references)

PMID:29675019 SUPPORT Human Clinical

"CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation."

Patient peripheral blood B cells show constitutive AKT hyperphosphorylation, directly supporting pathway hyperactivation in APDS.

PMID:28972011 SUPPORT Human Clinical

"Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients."

Directly links APDS-causing variants to increased PI3Kdelta-AKT-S6 signaling and shows reversibility with selective PI3Kdelta inhibition.

Defective B-cell maturation and humoral immunity

Hyperactive PI3K-delta signaling skews B-cell development toward expanded transitional cells while impairing maturation into class-switched memory B cells and efficient IgG production. Clinically this produces a hyper-IgM pattern in many patients together with reduced antibody quality and poor polysaccharide vaccine responses.

B cell CL:0000236 class-switched memory B cell CL:0000972

B cell differentiation GO:0030183 ↓ DECREASED isotype switching GO:0045190 ↓ DECREASED

Downstream

Recurrent respiratory infections Humoral immune deficiency predisposes to recurrent sinopulmonary infection.

Progressive airway injury Repeated infection caused by humoral immune failure drives cumulative structural airway damage.

Show evidence (2 references)

PMID:29675019 SUPPORT Human Clinical

"Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production."

Abstract directly supports defective IgG production as a core humoral defect in APDS.

PMID:31111319 SUPPORT Other

"The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4+ T cells in 64.8% of APDS patients."

Systematic review supports the common hyper-IgM pattern and widespread B-cell deficiency in APDS.

Senescent T-cell skewing

APDS promotes accumulation of senescent effector T cells and depletion of naive and long-lived memory T-cell pools, creating an exhausted effector-skewed T-cell compartment.

CD4-positive alpha-beta T cell CL:0000624 CD8-positive alpha-beta T cell CL:0000625

cellular senescence GO:0090398 ↑ INCREASED activation-induced cell death of T cells GO:0006924 ↑ INCREASED

Downstream

Impaired antiviral control Senescent, naive-cell-depleted T-cell compartments have reduced control of latent herpesviruses.

Show evidence (1 reference)

PMID:28972011 SUPPORT Human Clinical

"Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS])."

Precision-therapy study explicitly describes senescent T-cell accumulation as a direct consequence of APDS-causing PI3Kdelta gain of function.

Impaired antiviral control

Dysfunctional T-cell immunity weakens control of latent herpesviruses, especially EBV and CMV, predisposing to persistent viremia, lymphadenitis, and lymphoma.

CD4-positive alpha-beta T cell CL:0000624 CD8-positive alpha-beta T cell CL:0000625

defense response to virus GO:0051607 ↓ DECREASED

Downstream

Herpesvirus susceptibility Impaired antiviral T-cell control directly produces recurrent or persistent herpesvirus disease.

Lymphoma Defective antiviral control and EBV persistence contribute to APDS-associated lymphoma risk.

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"The immunodeficiency phenotype in APDS can be predominantly antibody deficiency, with recurrent sinopulmonary tract infections, or combined immunodeficiency, with a predisposition to herpesvirus in addition to bacterial infections."

Review directly supports impaired antiviral control as a distinct downstream consequence of APDS T-cell dysfunction.

Immune dysregulation and autoimmunity

PI3K-delta hyperactivation also disrupts immune tolerance, producing autoimmune and autoinflammatory complications. Autoimmune cytopenias are the dominant hematologic autoimmune manifestation.

Downstream

Autoimmune thrombocytopenia Loss of immune tolerance produces immune-mediated platelet destruction.

Autoimmune hemolytic anemia Loss of immune tolerance produces autoimmune erythrocyte destruction.

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"Cytopenias are the most common autoimmune manifestation (accounting for 76% of all autoimmune complications) and include immune thrombocytopenia purpura (ITP) and autoimmune haemolytic anaemia (AIHA) (3, 15, 19)."

Review evidence identifies autoimmune cytopenias as the dominant autoimmune APDS complication.

Chronic lymphoproliferation

Benign lymphoid hyperplasia is a dominant APDS manifestation and presents as persistent lymphadenopathy, splenomegaly, tonsillar or adenoidal enlargement, and nodal disease at sites of chronic infection.

lymphocyte CL:0000542

leukocyte proliferation GO:0070661 ↑ INCREASED

Downstream

Lymphadenopathy Persistent benign lymphoid hyperplasia presents clinically as lymph node enlargement.

Splenomegaly Persistent benign lymphoid hyperplasia also produces splenic enlargement.

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Consistent with the two published cohorts, chronic non-neoplastic lymphoproliferation was reported in the majority of patients (87%)."

The combined APDS1/APDS2 registry identifies chronic benign lymphoproliferation as a dominant APDS process.

Progressive airway injury

Recurrent sinopulmonary infection together with airway obstruction from lymphoid hyperplasia promotes mosaic attenuation, bronchiolitis, and established bronchiectasis.

epithelial cell of tracheobronchial tree CL:0002202

inflammatory response GO:0006954 ↑ INCREASED

Downstream

Bronchiectasis Chronic airway injury and remodeling produce established bronchiectasis.

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."

Combined APDS1/APDS2 registry imaging documents substantial structural airway damage beginning early in life.

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Pathograph

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Phenotypes

11

Blood 4

Autoimmune thrombocytopenia HP:0001973

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"Cytopenias are the most common autoimmune manifestation (accounting for 76% of all autoimmune complications) and include immune thrombocytopenia purpura (ITP) and autoimmune haemolytic anaemia (AIHA) (3, 15, 19)."

Review explicitly identifies immune thrombocytopenia as one of the defining autoimmune cytopenias in APDS.

Autoimmune hemolytic anemia HP:0001890

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"Cytopenias are the most common autoimmune manifestation (accounting for 76% of all autoimmune complications) and include immune thrombocytopenia purpura (ITP) and autoimmune haemolytic anaemia (AIHA) (3, 15, 19)."

Review explicitly identifies autoimmune hemolytic anemia as one of the defining autoimmune cytopenias in APDS.

Decreased circulating IgG FREQUENT Decreased circulating IgG concentration HP:0004315

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Immunologically, hypogammaglobulinemia with increased IgM levels was frequent."

The APDS1/APDS2 registry review supports frequent hypogammaglobulinemia without importing an APDS1-only percentage.

Lymphoma OCCASIONAL HP:0002665

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"B cell lymphomas are the most common malignancy and are often associated with EBV infection."

The clinical review supports the dominant lymphoma lineage and its frequent EBV association.

Context-specific annotations (2)

APDS1 13%

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"An increased risk for lymphoma was also highlighted with 13% among the APDS1 patients and 28% in the APDS2 cohort."

Registry review provides the APDS1-specific observed proportion.

APDS2 28%

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"An increased risk for lymphoma was also highlighted with 13% among the APDS1 patients and 28% in the APDS2 cohort."

Registry review provides the APDS2-specific observed proportion.

Cardiovascular 2

Lymphadenopathy FREQUENT HP:0002716

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"Lymphadenopathy occurs most frequently (61%), followed by splenomegaly (47%) and hepatomegaly (29%) (15)."

Review quantifies lymphadenopathy as the most frequent form of benign lymphoproliferation in APDS.

Splenomegaly FREQUENT HP:0001744

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"Lymphadenopathy occurs most frequently (61%), followed by splenomegaly (47%) and hepatomegaly (29%) (15)."

Review quantifies splenomegaly as a frequent manifestation of APDS-associated lymphoproliferation.

Immune 1

Recurrent respiratory infections VERY_FREQUENT HP:0002205

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"As in the previously reported cohorts, recurrent respiratory infections were by far the most frequent manifestation, occurring in 96% of the patients."

The combined APDS1/APDS2 registry supports recurrent respiratory infection as the cardinal early phenotype of APDS.

Nervous System 1

Neurodevelopmental delay HP:0012758

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."

Registry data document neurodevelopmental delay in both subtypes with a higher observed proportion in APDS2.

Context-specific annotations (2)

APDS1 19%

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."

Registry review provides the APDS1-specific neurodevelopmental-delay proportion.

APDS2 31%

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."

Registry review provides the APDS2-specific neurodevelopmental-delay proportion.

Respiratory 1

Bronchiectasis FREQUENT HP:0002110

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."

Combined APDS1/APDS2 registry imaging supports bronchiectasis as a frequent structural complication.

Context-specific annotations (2)

APDS1 24/40 (60%)

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients."

Registry CT data provide the APDS1-specific observed proportion.

APDS2 4/15 (27%)

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients."

Registry CT data provide the APDS2-specific observed proportion.

Growth 1

Short stature HP:0004322

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."

Registry data quantify growth impairment as an APDS2-enriched feature.

Context-specific annotations (2)

APDS1

Growth impairment occurs in APDS1, but this registry passage does not provide a separate APDS1 percentage.

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."

Registry wording places growth impairment across APDS while identifying APDS2 enrichment, without an APDS1-specific percentage.

APDS2 45%

Growth impairment is enriched in APDS2.

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."

Registry review provides the APDS2-specific growth-impairment proportion.

Other 1

Herpesvirus susceptibility FREQUENT Recurrent viral infections HP:0004429

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Acute viral infections (with varicella and herpes simplex) as well as chronic viral infections/reactivations were frequently documented in APDS1 and APDS2 patients (Figure 1A)."

Combined registry data support viral susceptibility in both APDS1 and APDS2 without importing an APDS1-only frequency.

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Genetic Associations

2

PIK3CD (Causative)

Gene: PIK3CD hgnc:8977 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:31111319 SUPPORT Other

"Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively."

Systematic review identifies PIK3CD gain-of-function as the APDS1 disease gene.

PMID:31111319 SUPPORT Other

"The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations."

Defines the dominant APDS1 hotspot variant pattern.

PIK3R1 (Causative)

Gene: PIK3R1 hgnc:8979 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:31111319 SUPPORT Other

"Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively."

Systematic review identifies PIK3R1 as the causative gene for APDS2.

PMID:31111319 SUPPORT Other

"The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations."

Defines the dominant recurrent APDS2 splice hotspot.

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Medical Actions

6

Immunoglobulin replacement therapy

Category: Therapeutic Action: immunoglobulin replacement therapy Ontology label: Pharmacotherapy NCIT:C15986

Intravenous or subcutaneous immunoglobulin replacement is commonly used as supportive therapy for antibody deficiency and prevention of recurrent bacterial infections.

Target Phenotypes: recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:31111319 SUPPORT Other

"The majority of APDS patients were placed on long-term immunoglobulin replacement therapy."

Systematic review supports immunoglobulin replacement as standard-of-care supportive treatment.

Sirolimus

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

mTOR inhibition with sirolimus is an off-label pathway-directed option for lymphoproliferation or organomegaly when leniolisib is unavailable. Registry responses were strongest for lymphoproliferation and less consistent for bowel inflammation and cytopenias. Headache, anorexia, renal toxicity, aphthous ulcers, and liver toxicity led to treatment interruption in some registry participants.

Mechanism Target:

INHIBITS PI3K-delta pathway hyperactivation — Sirolimus inhibits the downstream mTOR arm of the hyperactive PI3K-delta-AKT-mTOR pathway.

Show evidence (1 reference)

PMID:38148368 SUPPORT Other

"The mTOR inhibitor sirolimus has been used effectively for some clinical manifestations of this condition, however the arrival of specific PI3Kδ inhibitor leniolisib has shown promising early results and may provide a more targeted approach."

The review explicitly identifies sirolimus as an mTOR inhibitor used in APDS.

Target Phenotypes: lymphadenopathy HP:0002716

Show evidence (3 references)

PMID:29599784 SUPPORT Human Clinical

"Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well."

Registry outcomes define the main clinical benefit and the limitations of rapamycin treatment.

PMID:38148368 SUPPORT Other

"The mTOR inhibitor sirolimus has been used effectively for some clinical manifestations of this condition, however the arrival of specific PI3Kδ inhibitor leniolisib has shown promising early results and may provide a more targeted approach."

Review supports sirolimus as an established pathway-directed treatment for selected APDS manifestations.

PMID:29599784 SUPPORT Human Clinical

"Two patients (No. 7, 13) suffered from side effects (severe headaches, anorexia, renal toxicity) that led to the complete interruption of the treatment, whereas in three cases, the therapy was paused because of side effects (aphthous ulcers, liver toxicity, renal toxicity) but could be started again."

Registry treatment data document clinically meaningful sirolimus toxicity and treatment interruption.

Leniolisib

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: leniolisib CHEBI:229649

Selective oral PI3Kdelta inhibition directly targets the causal signaling lesion in APDS and is recommended as first-line therapy for significant lymphoproliferative disease. The current U.S. label indicates Joenja for adults and pediatric patients 12 years and older; 70 mg twice daily is the recommended dose for patients weighing at least 45 kg, with no recommended dose below 45 kg. The current label warns of postmarketing hypersensitivity, including anaphylaxis. In the pivotal 12-week phase 3 trial, both lymph-node size and naive-B-cell coprimary outcomes improved versus placebo.

Mechanism Target:

INHIBITS PI3K-delta pathway hyperactivation — Leniolisib selectively inhibits the causal hyperactive PI3K-delta signaling node.

Show evidence (1 reference)

PMID:36399712 SUPPORT Human Clinical

"Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ."

The pivotal trial directly states the drug-target relationship.

Target Phenotypes: lymphadenopathy HP:0002716

Show evidence (7 references)

url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217759s005lbl.pdf SUPPORT Other

"JOENJA is a kinase inhibitor indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older."

The May 2025 U.S. prescribing information establishes the current labeled APDS indication and age threshold.

url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217759s005lbl.pdf SUPPORT Other

"The recommended dosage of JOENJA in adult and pediatric patients 12 years of age and older weighing 45 kg or greater is 70 mg administered orally twice daily approximately 12 hours apart, with or without food. There is no recommended dosage for patients weighing less than 45 kg."

The current label supplies the weight-qualified dosing recommendation and explicitly states the lack of a recommended dose below 45 kg.

PMID:39899769 SUPPORT Other

"Leniolisib, a selective PI3K delta (PI3Kδ) inhibitor, has shown promise in clinical trials by directly targeting the overactive PI3Kδ signaling pathway, a hallmark of the condition, and is therefore recommended as a first-line treatment of significant lymphoproliferative disease, including..."

Current GeneReviews recommends leniolisib as first-line treatment for significant lymphoproliferation.

+ 4 more references

Hematopoietic stem cell transplantation

Category: Therapeutic Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Allogeneic hematopoietic stem cell transplantation is reserved for severe or treatment-refractory disease, including progressive organ damage, refractory infection, or immune dysregulation. In an international cohort, two-year overall survival was 86% and graft-failure-free survival was 68%; graft instability and poor graft function remain important limitations.

Target Phenotypes: combined immunodeficiency HP:0005387

Show evidence (3 references)

PMID:34033842 SUPPORT Human Clinical

"With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity."

The largest international HCT cohort provides balanced survival and graft-failure-free outcome estimates.

PMID:34033842 SUPPORT Human Clinical

"Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT."

The cohort directly identifies major limitations that qualify the potentially curative role of HCT.

PMID:39899769 SUPPORT Other

"Allogenic hematopoietic stem cell transplant (HSCT) is reserved for individuals with severe or treatment-refractory APDS, including progressive organ damage, recurrent refractory infections, or severe immune dysregulation unresponsive to pharmacologic therapy."

Current GeneReviews defines the clinical circumstances in which HSCT is reserved across APDS1 and APDS2.

Antibiotic prophylaxis

Category: Therapeutic Action: antibiotic prophylaxis Ontology label: Antibiotic Therapy NCIT:C15620

Long-term prophylactic antibiotics are used in patients with recurrent bacterial sinopulmonary infections to reduce infectious burden alongside immunoglobulin replacement therapy.

Target Phenotypes: recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:39899769 SUPPORT Other

"Supportive care: Regular intravenous or subcutaneous immunoglobulin replacement therapy to prevent recurrent bacterial infections and improve immune function; long-term prophylactic antibiotics can be considered to reduce the frequency of bacterial infections; individuals with recurrent herpes..."

Current GeneReviews supports long-term antibacterial prophylaxis as an option within APDS supportive care.

Multisystem, viral, and malignancy surveillance

Category: Monitoring Action: clinical assessment Ontology label: Clinical Evaluation NCIT:C124351

Longitudinal follow-up should assess infections and herpesvirus burden, immune function, lymphoproliferation and blood counts, autoimmunity, respiratory function, and gastrointestinal/liver status at least annually. GeneReviews also recommends chest CT or MRI every three to five years and baseline then periodic liver ultrasonography. Persistent or changing lymphadenopathy warrants clinical evaluation because benign lymphoproliferation can be difficult to distinguish from lymphoma.

Show evidence (2 references)

PMID:39899769 SUPPORT Other

"Surveillance: Annually assess infection risk (blood/sputum cultures for EBV, CMV, and HSV), immune function (immunoglobulin levels, CD4+, CD8+, B-cell subsets, response to vaccines), lymphoproliferative status (CBC, B-cell counts), autoimmunity (ANA screen, TSH, TPO), respiratory function..."

Current GeneReviews provides a structured multisystem surveillance schedule including viral, lymphoproliferative, pulmonary, and liver monitoring.

PMID:29599784 SUPPORT Human Clinical

"Benign lymphoproliferation may be difficult to distinguish from malignant disease, the risk of which is increased in APDS patients."

Registry evidence supports careful reassessment of lymphoproliferation for malignant transformation.

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Biochemical Markers

3

Elevated serum IgM (Abnormal)

Context: Hyper-IgM is the dominant serologic pattern in APDS and reflects impaired class-switch recombination and abnormal B-cell maturation.

Pathograph Readouts

Readout Of Defective B-cell maturation and humoral immunity Positive Diagnostic

Elevated IgM reports impaired immunoglobulin class switching and abnormal B-cell maturation.

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"A hyper IgM-like pattern is the most common immunoglobulin profile reported (low IgG, low IgA and high IgM). This is explained by the fact that PI3Kδ signalling pathways are involved in immunoglobulin class switching (25) with class switched memory B cells reduced in APDS."

The review links elevated IgM to the class-switching and B-cell maturation defect.

Show evidence (1 reference)

PMID:31111319 SUPPORT Other

"The predominant immunologic phenotype was hyper-IgM syndrome (48.1%)."

Systematic review shows that a hyper-IgM pattern is the most common humoral abnormality in APDS.

Enhanced AKT phosphorylation in circulating B cells (Abnormal)

Context: Constitutive phospho-AKT in peripheral blood CD19-positive B cells is a functional biomarker of hyperactive PI3K-delta signaling and falls with selective p110delta inhibition.

Pathograph Readouts

Readout Of PI3K-delta pathway hyperactivation Positive Diagnostic

Enhanced AKT phosphorylation reports excessive PI3K-delta-AKT pathway activity.

Show evidence (1 reference)

PMID:29675019 SUPPORT Human Clinical

"The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor."

Normalization with a selective p110-delta inhibitor identifies pAKT as a functional readout of pathway hyperactivation.

Show evidence (1 reference)

PMID:29675019 SUPPORT Human Clinical

"The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor."

Functional assay evidence shows constitutive AKT activation in APDS B cells and reversibility with pathway inhibition.

Reduced class-switched memory B cells (Abnormal)

Context: Loss of switched-memory B cells is a recurrent APDS immunophenotype and contributes to defective long-lived humoral immunity.

Pathograph Readouts

Readout Of Defective B-cell maturation and humoral immunity Negative Diagnostic

Reduced class-switched memory B cells report impaired B-cell maturation and immunoglobulin class switching.

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"A hyper IgM-like pattern is the most common immunoglobulin profile reported (low IgG, low IgA and high IgM). This is explained by the fact that PI3Kδ signalling pathways are involved in immunoglobulin class switching (25) with class switched memory B cells reduced in APDS."

The review identifies reduced switched-memory B cells as a readout of impaired immunoglobulin class switching.

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"A hyper IgM-like pattern is the most common immunoglobulin profile reported (low IgG, low IgA and high IgM). This is explained by the fact that PI3Kδ signalling pathways are involved in immunoglobulin class switching (25) with class switched memory B cells reduced in APDS."

Review explicitly links impaired class switching to reduced switched-memory B cells in APDS.

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Diagnosis

6

Molecular genetic testing

Molecular diagnosis is established by identifying a heterozygous pathogenic gain-of-function variant in PIK3CD (APDS1) or a heterozygous pathogenic loss-of-function variant in PIK3R1 (APDS2). Panel-based or exome sequencing is appropriate given the clinical overlap with common variable immunodeficiency, hyper-IgM syndrome, and combined immunodeficiency. PTEN loss-of-function APDS-like immunodeficiency is a related but out-of-scope entity for this APDS1/APDS2 entry.

molecular genetic testing NCIT:C19770

Results: Heterozygous pathogenic gain-of-function PIK3CD variant (APDS1) or loss-of-function PIK3R1 variant (APDS2)

Show evidence (2 references)

PMID:39899769 SUPPORT Other

"The clinical diagnosis of APDS can be established in a proband based on suggestive clinical findings, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in PIK3CD (for APDS1) or PIK3R1 (for APDS2) identified by molecular..."

Current GeneReviews defines molecular APDS diagnosis using PIK3CD for APDS1 and PIK3R1 for APDS2, without including PTEN in the APDS subtype definition.

PMID:31111319 SUPPORT Other

"It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels."

Systematic review identifies the cardinal clinical triggers that should prompt PIK3CD/PIK3R1 genetic testing.

Serum immunoglobulin profiling

Serum immunoglobulin levels are abnormal in most patients. The most common pattern is elevated IgM with low IgG and IgA, but subclass deficiency, selective IgA deficiency, and hypogammaglobulinaemia are also described. Normal immunoglobulin levels do not exclude the diagnosis.

serum immunoglobulin measurement NCIT:C64430

Markers: IgM, IgG, IgA

Results: Elevated IgM with low IgG or IgA in most patients; pattern varies

Show evidence (2 references)

PMID:29599784 SUPPORT Human Clinical

"Immunologically, hypogammaglobulinemia with increased IgM levels was frequent."

The combined APDS1/APDS2 registry supports a frequent hyper-IgM/hypogammaglobulinemia pattern without generalizing APDS1-only percentages.

PMID:34422726 SUPPORT Other

"A hyper IgM-like pattern is the most common immunoglobulin profile reported (low IgG, low IgA and high IgM). This is explained by the fact that PI3Kδ signalling pathways are involved in immunoglobulin class switching (25) with class switched memory B cells reduced in APDS."

Review explains the immunological basis for the hyper-IgM pattern and notes that normal levels do not exclude APDS.

Lymphocyte subset analysis

Flow cytometric quantification of lymphocyte subsets typically reveals B cell lymphopenia, CD4+ T cell reduction with an inverted CD4/CD8 ratio, and expanded transitional B cells with reduced class-switched memory B cells. Extended phenotyping supports the diagnosis and reflects underlying immune dysregulation.

lymphocyte subset flow cytometry NCIT:C16585

Results: B cell lymphopenia; reduced CD4+ T cells; inverted CD4/CD8 ratio; expanded transitional B cells; reduced class-switched memory B cells

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"Lymphocyte subset testing typically reveals B cell lymphopenia, CD4+ T cell reduction, with an inverted CD4/CD8 ratio."

Review summarizes the characteristic lymphocyte subset pattern as a key diagnostic feature of APDS.

Vaccine response assessment

Measurement of specific antibody responses to pneumococcal polysaccharide and protein-conjugate vaccines reveals impaired humoral immunity in the majority of patients with APDS, analogous to other combined immunodeficiencies.

vaccine-specific antibody measurement NCIT:C64430

Results: Impaired polysaccharide and/or conjugate vaccine responses

Show evidence (1 reference)

PMID:34422726 SUPPORT Other

"Vaccine responses are often impaired (3, 16). Defective anti-polysaccharide vaccine responses were detected in 52 of 58 patients (90%) and defective anti-peptide antibody responses in 14 of 42 (33%) (15)."

Review documents near-universal impairment of vaccine responses in APDS, supporting their use as a diagnostic marker.

Thoracic CT imaging

High-resolution CT of the thorax can show mosaic attenuation reflecting small-airway disease and established bronchiectasis. The 90% estimate for mosaic attenuation comes from an APDS1 cohort, whereas bronchiectasis is documented in combined APDS1/APDS2 registry data. CT is relevant to staging airway injury and pulmonary surveillance.

high-resolution thoracic computed tomography NCIT:C17204

Results: Mosaic attenuation (well quantified in APDS1) and/or bronchiectasis

Show evidence (2 references)

PMID:27555459 SUPPORT Human Clinical

"Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%)."

The APDS1 cohort documents mosaic attenuation and bronchiectasis; its percentages are not generalized to APDS2.

PMID:29599784 SUPPORT Human Clinical

"The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."

Combined APDS1/APDS2 registry CT data establish bronchiectasis across the operational disease scope.

Enhanced phospho-AKT in circulating B cells

Flow cytometric measurement of AKT phosphorylation at Ser473 in CD19+ peripheral blood B cells is a supportive functional biomarker of PI3K-delta hyperactivation. Enhanced pAKT, particularly in CD10+ immature B cells, may help distinguish PI3K-pathway hyperactivation from common variable immunodeficiency and CD40L-related hyper-IgM syndrome, but the assay remains incompletely validated. Because this functional abnormality can also occur in PTEN-related APDS-like immunodeficiency, it complements but does not replace subtype-defining molecular testing.

phospho-AKT flow cytometry NCIT:C16585

Results: Elevated phospho-AKT (Ser473) in CD19+ B cells, most pronounced in CD10+ immature B cells; normalized by p110delta inhibitor

Show evidence (1 reference)

PMID:29675019 SUPPORT Human Clinical

"These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies."

Functional flow cytometry distinguishes PI3K-pathway hyperactivation from other antibody deficiencies but does not by itself separate APDS1/2 from PTEN-related APDS-like disease.

🩻

Imaging Findings

2

Mosaic attenuation on thoracic CT VERY_FREQUENT

In the APDS1 cohort supplying the frequency estimate, thoracic CT frequently showed mosaic attenuation, reflecting heterogeneous small-airway involvement in chronic lung disease.

Ct APDS1

Mosaic attenuation of the lung lung UBERON:0002048

Show evidence (1 reference)

PMID:27555459 SUPPORT Human Clinical

"Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%)."

APDS1 cohort imaging establishes mosaic attenuation as a very frequent thoracic imaging pattern in that subtype; the estimate is not generalized to APDS2.

Bronchiectasis on thoracic CT FREQUENT

CT demonstrates established bronchial dilatation and structural airway damage in a substantial proportion of patients with pulmonary involvement.

Ct

Bronchiectasis HP:0002110 lung UBERON:0002048 bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."

Combined APDS1/APDS2 registry CT data support bronchiectasis as a frequent imaging finding.

📈

Progression

2

Early disease

Age: Infancy through childhood

Recurrent respiratory infections typically appear first, followed by chronic lymphoproliferation and then gastrointestinal manifestations and cytopenias.

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias."

The combined APDS1/APDS2 registry establishes the usual sequence of early and later manifestations.

Variable later course

Age: Childhood through adulthood

Most manifestations develop by age 15, but APDS has variable penetrance and timing, including documented adult-onset and asymptomatic courses.

Show evidence (1 reference)

PMID:29599784 SUPPORT Human Clinical

"Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented."

Registry natural-history data qualify the typical pediatric course with late-onset and asymptomatic presentations.

📊

Related Datasets

1

Role of activated PI3K-delta signaling in humoral immunity geo:GSE171795

We report the high-throughput profiling of murine naive B cells, germinal center (dark zone and light zone) B cells, and plasma cells transcriptome. By obtaining over 5 million bases of sequence, we generated genome-wide expression maps of cell subsets from WT mice and aPIK3CD mice. We find that activated PIK3CD signaling lead to significant alteration in gene expression of plasma cells.

mouse BULK RNA SEQ n=32

PMID:34586341

Identified by GEO DataSets index search for Activated PI3K-delta syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

🔬

Clinical Trials

3

NCT02435173 PHASE_III COMPLETED

Completed phase 2/3 leniolisib program with an open-label dose-finding part followed by a randomized blinded placebo-controlled efficacy and safety part in genetically confirmed APDS. The schema records the highest confirmatory phase because the ClinicalTrials.gov record lists both phase 2 and phase 3.

Target Phenotypes: lymphadenopathy HP:0002716

Show evidence (2 references)

clinicaltrials:NCT02435173 SUPPORT Human Clinical

"This study was designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e., patients with Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (APDS/PASLI)."

The ClinicalTrials.gov record establishes the intervention, genetically activated APDS population, and lymphadenopathy target.

PMID:36399712 SUPPORT Human Clinical

"Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks."

The peer-reviewed pivotal trial confirms phase 3 design, enrollment, dose, and treatment duration.

NCT05438407 PHASE_III ACTIVE_NOT_RECRUITING

Active, non-recruiting open-label phase 3 pediatric leniolisib study in patients aged four to 11 years, followed by a long-term extension; status recorded from ClinicalTrials.gov on 2026-07-19.

Show evidence (1 reference)

clinicaltrials:NCT05438407 SUPPORT Human Clinical

"This is a 2-part, prospective, open-label, single arm, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and efficacy of leniolisib in at least 15 pediatric patients (aged 4 to 11 years) with activated phosphoinositide 3-kinase delta (PI3Kδ)..."

The registry record establishes the pediatric age range, intervention, design, and outcome domains.

NCT05693129 PHASE_III ACTIVE_NOT_RECRUITING

Active, non-recruiting open-label phase 3 pediatric leniolisib study in patients aged one to six years, followed by a long-term extension; status recorded from ClinicalTrials.gov on 2026-07-19.

Show evidence (1 reference)

clinicaltrials:NCT05693129 SUPPORT Human Clinical

"This is a 2-part, prospective, open-label, single arm, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and efficacy of leniolisib in at least 15 pediatric patients (aged 1 to 6 years) with activated phosphoinositide 3-kinase delta (PI3Kδ)..."

The registry record establishes the younger pediatric age range, intervention, design, and outcome domains.

{ }

Source YAML

click to show

name: Activated PI3K-delta syndrome
creation_date: "2026-04-12T17:07:22Z"
category: Mendelian
synonyms:
- APDS
- Activated phosphoinositide 3-kinase delta syndrome
disease_term:
  preferred_term: Activated PI3K-delta syndrome
  term:
    id: MONDO:0018338
    label: activated PI3K-delta syndrome
parents:
- Primary Immunodeficiency
- Combined immunodeficiency
classifications:
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      IUIS 2022 phenotypic classification Table 1 (combined immunodeficiencies).
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee."
      explanation: >-
        APDS is assigned to IUIS Table 1 (combined immunodeficiency) in the
        IUIS phenotypic IEI classification.
description: >-
  Activated PI3K-delta syndrome (APDS) is a rare autosomal dominant combined
  immunodeficiency comprising APDS1, caused by heterozygous gain-of-function
  variants in PIK3CD, and APDS2, caused by heterozygous loss-of-function
  variants in PIK3R1. Both mechanisms produce net hyperactivation of
  PI3K-delta-AKT-mTOR signaling. The resulting immune dysregulation drives
  recurrent sinopulmonary infection, non-neoplastic lymphoproliferation,
  hyper-IgM humoral abnormalities, reduced switched-memory B cells,
  herpesvirus susceptibility, autoimmunity, and progressive airway damage
  including bronchiectasis. PTEN loss-of-function immunodeficiency is described
  as APDS-like (APDS-L) in some literature but is not included in this entry's
  APDS1/APDS2 subtype scope.
references:
- reference: PMID:39899769
  title: "Activated PI3K Delta Syndrome."
  tags:
  - GeneReviews
  findings:
  - statement: Current GeneReviews operationally defines APDS as APDS1 caused by PIK3CD gain of function and APDS2 caused by PIK3R1 loss of function.
    supporting_text: "APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1."
    evidence:
    - reference: PMID:39899769
      reference_title: "Activated PI3K Delta Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1."
      explanation: Current GeneReviews defines the operational APDS1/APDS2 scope.
- reference: PMID:37178059
  title: "Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan."
  findings:
  - statement: Some literature distinguishes PTEN loss-of-function immunodeficiency as APDS-like rather than APDS1 or APDS2.
    supporting_text: "In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF)."
    evidence:
    - reference: PMID:37178059
      reference_title: "Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF), APDS2 (PIK3R1-LOF) and APDS-L (PTEN-LOF)."
      explanation: The Japanese guideline supplies the alternate APDS-like nomenclature for PTEN loss of function.
has_subtypes:
- name: APDS1
  display_name: APDS1 (PIK3CD-related)
  subtype_term:
    preferred_term: immunodeficiency 14
    term:
      id: MONDO:0014222
      label: immunodeficiency 14
  description: >-
    APDS1 is caused by heterozygous gain-of-function variants in PIK3CD, which
    encodes the catalytic p110delta PI3K subunit. It is the most common APDS
    subtype and classically presents with childhood-onset respiratory
    infections, lymphoproliferation, and antibody deficiency with a hyper-IgM
    pattern.
  genes:
  - preferred_term: PIK3CD
    term:
      id: hgnc:8977
      label: PIK3CD
  evidence:
  - reference: PMID:39899769
    reference_title: "Activated PI3K Delta Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1."
    explanation: Current GeneReviews defines APDS1 as PIK3CD gain-of-function disease and APDS2 as PIK3R1 loss-of-function disease.
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively."
    explanation: Systematic review explicitly defines APDS1 as the PIK3CD-related subtype.
- name: APDS2
  display_name: APDS2 (PIK3R1-related)
  subtype_term:
    preferred_term: immunodeficiency 36 with lymphoproliferation
    term:
      id: MONDO:0014453
      label: immunodeficiency 36 with lymphoproliferation
  description: >-
    APDS2 is caused by heterozygous PIK3R1 variants, most often splice defects
    that impair the inhibitory p85alpha regulatory subunit and produce net
    PI3Kdelta gain of function. The core immune phenotype overlaps strongly
    with APDS1, although growth delay and neurodevelopmental features are
    reported more often in this subtype.
  genes:
  - preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  evidence:
  - reference: PMID:39899769
    reference_title: "Activated PI3K Delta Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1."
    explanation: Current GeneReviews defines the two APDS subtypes and their distinct variant mechanisms.
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively."
    explanation: Systematic review explicitly defines APDS2 as the PIK3R1-related subtype.
inheritance:
- name: Autosomal dominant
  description: >-
    APDS1 and APDS2 are autosomal dominant; both inherited and de novo
    pathogenic variants occur.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:39899769
    reference_title: "Activated PI3K Delta Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "APDS is an autosomal dominant disorder."
    explanation: GeneReviews explicitly states the inheritance pattern.
progression:
- phase: Early disease
  age_range: Infancy through childhood
  notes: >-
    Recurrent respiratory infections typically appear first, followed by
    chronic lymphoproliferation and then gastrointestinal manifestations and
    cytopenias.
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias."
    explanation: The combined APDS1/APDS2 registry establishes the usual sequence of early and later manifestations.
- phase: Variable later course
  age_range: Childhood through adulthood
  notes: >-
    Most manifestations develop by age 15, but APDS has variable penetrance and
    timing, including documented adult-onset and asymptomatic courses.
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented."
    explanation: Registry natural-history data qualify the typical pediatric course with late-onset and asymptomatic presentations.
pathophysiology:
- name: PI3K-delta pathway hyperactivation
  description: >-
    Germline gain-of-function variants in the PIK3CD catalytic subunit (APDS1)
    or loss-of-function variants in the inhibitory PIK3R1 regulatory subunit
    (APDS2) create constitutive PI3K-delta signaling with increased downstream
    AKT and mTOR activity. Persistent pathway activation disrupts lymphocyte
    homeostasis and underlies the precision-medicine rationale for PI3K-delta
    inhibition.
  genes:
  - preferred_term: PIK3CD
    term:
      id: hgnc:8977
      label: PIK3CD
  - preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: CD4-positive alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  - preferred_term: TOR signaling
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: INCREASED
  evidence:
  - reference: PMID:29675019
    reference_title: "Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation."
    explanation: Patient peripheral blood B cells show constitutive AKT hyperphosphorylation, directly supporting pathway hyperactivation in APDS.
  - reference: PMID:28972011
    reference_title: "Effective \"activated PI3Kδ syndrome\"-targeted therapy with the PI3Kδ inhibitor leniolisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients."
    explanation: Directly links APDS-causing variants to increased PI3Kdelta-AKT-S6 signaling and shows reversibility with selective PI3Kdelta inhibition.
  downstream:
  - target: Defective B-cell maturation and humoral immunity
    causal_link_type: DIRECT
    description: Constitutive PI3K-delta signaling directly disrupts B-cell maturation and humoral function.
    evidence:
    - reference: PMID:28972011
      reference_title: "Effective \"activated PI3Kδ syndrome\"-targeted therapy with the PI3Kδ inhibitor leniolisib."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS])."
      explanation: Human APDS data connect causal PI3K-delta activation with transitional B-cell accumulation and immune deficiency.
  - target: Senescent T-cell skewing
    causal_link_type: DIRECT
    description: Constitutive PI3K-delta signaling drives premature effector differentiation and T-cell senescence.
    evidence:
    - reference: PMID:28972011
      reference_title: "Effective \"activated PI3Kδ syndrome\"-targeted therapy with the PI3Kδ inhibitor leniolisib."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS])."
      explanation: The precision-therapy study directly links APDS-causing PI3K-delta activation to senescent T-cell accumulation.
  - target: Chronic lymphoproliferation
    causal_link_type: DIRECT
    description: Constitutive lymphocyte signaling promotes persistent benign lymphoid expansion.
    evidence:
    - reference: PMID:28972011
      reference_title: "Effective \"activated PI3Kδ syndrome\"-targeted therapy with the PI3Kδ inhibitor leniolisib."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS])."
      explanation: Human APDS data directly connect pathway activation with lymphadenopathy and immune-cell expansion.
  - target: Immune dysregulation and autoimmunity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered lymphocyte differentiation
    - loss of immune tolerance
    description: Persistent PI3K-delta activation distorts lymphocyte homeostasis and tolerance, producing autoimmune manifestations.
    evidence:
    - reference: PMID:36399712
      reference_title: "A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ."
      explanation: The phase 3 report identifies hyperactive PI3K-delta as causal and autoimmunity as part of the resulting APDS phenotype.
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Growth impairment is enriched in APDS2, but the intermediates connecting PIK3R1-related pathway dysregulation to stature remain unresolved.
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."
      explanation: Registry association supports APDS2-enriched growth impairment while leaving the causal intermediates unresolved.
  - target: Neurodevelopmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Neurodevelopmental delay is associated with APDS, especially APDS2, but a specific causal route from PI3K-pathway hyperactivation has not been established.
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."
      explanation: Registry association supports a neurodevelopmental phenotype but not a resolved molecular-to-clinical mechanism.
- name: Defective B-cell maturation and humoral immunity
  description: >-
    Hyperactive PI3K-delta signaling skews B-cell development toward expanded
    transitional cells while impairing maturation into class-switched memory B
    cells and efficient IgG production. Clinically this produces a hyper-IgM
    pattern in many patients together with reduced antibody quality and poor
    polysaccharide vaccine responses.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: class-switched memory B cell
    term:
      id: CL:0000972
      label: class switched memory B cell
  biological_processes:
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
    modifier: DECREASED
  - preferred_term: isotype switching
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  evidence:
  - reference: PMID:29675019
    reference_title: "Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production."
    explanation: Abstract directly supports defective IgG production as a core humoral defect in APDS.
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The predominant immunologic phenotype was hyper-IgM syndrome (48.1%). Immunologic profiling showed decreased B cells in 74.8% and CD4+ T cells in 64.8% of APDS patients."
    explanation: Systematic review supports the common hyper-IgM pattern and widespread B-cell deficiency in APDS.
  downstream:
  - target: Recurrent respiratory infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired antibody production
    - poor polysaccharide vaccine responses
    description: Humoral immune deficiency predisposes to recurrent sinopulmonary infection.
    evidence:
    - reference: PMID:29675019
      reference_title: "Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production."
      explanation: The human phenotype couples antibody-production failure with recurrent respiratory infection.
  - target: Progressive airway injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - recurrent lower-respiratory infection
    - chronic airway inflammation and remodeling
    description: Repeated infection caused by humoral immune failure drives cumulative structural airway damage.
    evidence:
    - reference: PMID:36399712
      reference_title: "A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality."
      explanation: Clinical evidence supports infection and bronchiectasis as linked APDS manifestations; recurrent infection and airway inflammation are the specified intermediates.
- name: Senescent T-cell skewing
  description: >-
    APDS promotes accumulation of senescent effector T cells and depletion of
    naive and long-lived memory T-cell pools, creating an exhausted
    effector-skewed T-cell compartment.
  cell_types:
  - preferred_term: CD4-positive alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  - preferred_term: activation-induced cell death of T cells
    term:
      id: GO:0006924
      label: activation-induced cell death of T cells
    modifier: INCREASED
  evidence:
  - reference: PMID:28972011
    reference_title: "Effective \"activated PI3Kδ syndrome\"-targeted therapy with the PI3Kδ inhibitor leniolisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS])."
    explanation: Precision-therapy study explicitly describes senescent T-cell accumulation as a direct consequence of APDS-causing PI3Kdelta gain of function.
  downstream:
  - target: Impaired antiviral control
    causal_link_type: DIRECT
    description: Senescent, naive-cell-depleted T-cell compartments have reduced control of latent herpesviruses.
    evidence:
    - reference: PMID:37178059
      reference_title: "Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections."
      explanation: The clinical guideline directly associates T-cell senescence and naive-cell loss with EBV/CMV susceptibility.
- name: Impaired antiviral control
  description: >-
    Dysfunctional T-cell immunity weakens control of latent herpesviruses,
    especially EBV and CMV, predisposing to persistent viremia,
    lymphadenitis, and lymphoma.
  cell_types:
  - preferred_term: CD4-positive alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: defense response to virus
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The immunodeficiency phenotype in APDS can be predominantly antibody deficiency, with recurrent sinopulmonary tract infections, or combined immunodeficiency, with a predisposition to herpesvirus in addition to bacterial infections."
    explanation: Review directly supports impaired antiviral control as a distinct downstream consequence of APDS T-cell dysfunction.
  downstream:
  - target: Herpesvirus susceptibility
    causal_link_type: DIRECT
    description: Impaired antiviral T-cell control directly produces recurrent or persistent herpesvirus disease.
    evidence:
    - reference: PMID:37178059
      reference_title: "Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "T-cell dysfunction due to increased senescence is associated with a decrease in CD4-positive T lymphocytes and CD45RA-positive naive T lymphocytes, along with increased susceptibility to Epstein-Barr virus/cytomegalovirus infections."
      explanation: The guideline supports herpesvirus susceptibility as the clinical consequence of impaired T-cell control.
  - target: Lymphoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic EBV infection
    - impaired immune surveillance
    description: Defective antiviral control and EBV persistence contribute to APDS-associated lymphoma risk.
    evidence:
    - reference: PMID:34422726
      reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The frequency of lymphoma appears higher in patients with a history of chronic viral infections, with chronic EBV reported in almost half of the patients who developed lymphoma (15)."
      explanation: The review directly supports chronic viral infection and EBV as intermediates contributing to lymphoma risk.
- name: Immune dysregulation and autoimmunity
  description: >-
    PI3K-delta hyperactivation also disrupts immune tolerance, producing
    autoimmune and autoinflammatory complications. Autoimmune cytopenias are
    the dominant hematologic autoimmune manifestation.
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cytopenias are the most common autoimmune manifestation (accounting for 76% of all autoimmune complications) and include immune thrombocytopenia purpura (ITP) and autoimmune haemolytic anaemia (AIHA) (3, 15, 19)."
    explanation: Review evidence identifies autoimmune cytopenias as the dominant autoimmune APDS complication.
  downstream:
  - target: Autoimmune thrombocytopenia
    causal_link_type: DIRECT
    description: Loss of immune tolerance produces immune-mediated platelet destruction.
    evidence:
    - reference: PMID:34422726
      reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cytopenias are the most common autoimmune manifestation (accounting for 76% of all autoimmune complications) and include immune thrombocytopenia purpura (ITP) and autoimmune haemolytic anaemia (AIHA) (3, 15, 19)."
      explanation: The review identifies immune thrombocytopenia as a principal APDS autoimmune manifestation.
  - target: Autoimmune hemolytic anemia
    causal_link_type: DIRECT
    description: Loss of immune tolerance produces autoimmune erythrocyte destruction.
    evidence:
    - reference: PMID:34422726
      reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cytopenias are the most common autoimmune manifestation (accounting for 76% of all autoimmune complications) and include immune thrombocytopenia purpura (ITP) and autoimmune haemolytic anaemia (AIHA) (3, 15, 19)."
      explanation: The review identifies autoimmune hemolytic anemia as a principal APDS autoimmune manifestation.
- name: Chronic lymphoproliferation
  description: >-
    Benign lymphoid hyperplasia is a dominant APDS manifestation and presents as
    persistent lymphadenopathy, splenomegaly, tonsillar or adenoidal
    enlargement, and nodal disease at sites of chronic infection.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  biological_processes:
  - preferred_term: leukocyte proliferation
    term:
      id: GO:0070661
      label: leukocyte proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with the two published cohorts, chronic non-neoplastic lymphoproliferation was reported in the majority of patients (87%)."
    explanation: The combined APDS1/APDS2 registry identifies chronic benign lymphoproliferation as a dominant APDS process.
  downstream:
  - target: Lymphadenopathy
    causal_link_type: DIRECT
    description: Persistent benign lymphoid hyperplasia presents clinically as lymph node enlargement.
    evidence:
    - reference: PMID:34422726
      reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Lymphadenopathy occurs most frequently (61%), followed by splenomegaly (47%) and hepatomegaly (29%) (15)."
      explanation: The clinical review identifies lymphadenopathy as the most frequent APDS lymphoproliferative manifestation.
  - target: Splenomegaly
    causal_link_type: DIRECT
    description: Persistent benign lymphoid hyperplasia also produces splenic enlargement.
    evidence:
    - reference: PMID:34422726
      reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Lymphadenopathy occurs most frequently (61%), followed by splenomegaly (47%) and hepatomegaly (29%) (15)."
      explanation: The clinical review identifies splenomegaly as a frequent APDS lymphoproliferative manifestation.
- name: Progressive airway injury
  description: >-
    Recurrent sinopulmonary infection together with airway obstruction from
    lymphoid hyperplasia promotes mosaic attenuation, bronchiolitis, and
    established bronchiectasis.
  cell_types:
  - preferred_term: epithelial cell of tracheobronchial tree
    term:
      id: CL:0002202
      label: epithelial cell of tracheobronchial tree
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."
    explanation: Combined APDS1/APDS2 registry imaging documents substantial structural airway damage beginning early in life.
  downstream:
  - target: Bronchiectasis
    causal_link_type: DIRECT
    description: Chronic airway injury and remodeling produce established bronchiectasis.
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."
      explanation: Combined-subtype registry imaging directly documents bronchiectasis as the structural endpoint of APDS lung disease.
phenotypes:
- name: Recurrent respiratory infections
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Recurrent upper and lower sinopulmonary infections are the dominant early
    clinical manifestation and often begin in infancy or early childhood.
  phenotype_term:
    preferred_term: recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As in the previously reported cohorts, recurrent respiratory infections were by far the most frequent manifestation, occurring in 96% of the patients."
    explanation: The combined APDS1/APDS2 registry supports recurrent respiratory infection as the cardinal early phenotype of APDS.
- name: Herpesvirus susceptibility
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Impaired antiviral control predisposes many patients to persistent or
    recurrent herpesvirus disease, especially EBV and CMV viremia or
    lymphadenitis.
  phenotype_term:
    preferred_term: recurrent herpesvirus infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute viral infections (with varicella and herpes simplex) as well as chronic viral infections/reactivations were frequently documented in APDS1 and APDS2 patients (Figure 1A)."
    explanation: Combined registry data support viral susceptibility in both APDS1 and APDS2 without importing an APDS1-only frequency.
- name: Lymphadenopathy
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Persistent or recurrent lymph node enlargement is part of the dominant
    benign lymphoproliferative phenotype.
  phenotype_term:
    preferred_term: lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lymphadenopathy occurs most frequently (61%), followed by splenomegaly (47%) and hepatomegaly (29%) (15)."
    explanation: Review quantifies lymphadenopathy as the most frequent form of benign lymphoproliferation in APDS.
- name: Splenomegaly
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Splenic enlargement is a common manifestation of benign lymphoid
    hyperplasia in APDS and tracks with the broader lymphoproliferative
    phenotype.
  phenotype_term:
    preferred_term: splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lymphadenopathy occurs most frequently (61%), followed by splenomegaly (47%) and hepatomegaly (29%) (15)."
    explanation: Review quantifies splenomegaly as a frequent manifestation of APDS-associated lymphoproliferation.
- name: Bronchiectasis
  category: Respiratory
  frequency: FREQUENT
  description: >-
    Progressive airway remodeling with bronchiectasis is a major long-term
    consequence of recurrent infection and chronic inflammatory lung injury.
    Registry data suggest that bronchiectasis is more frequent in APDS1 than
    APDS2, although it occurs in both subtypes.
  phenotype_term:
    preferred_term: bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."
    explanation: Combined APDS1/APDS2 registry imaging supports bronchiectasis as a frequent structural complication.
  phenotype_contexts:
  - subtype: APDS1
    frequency: "24/40 (60%)"
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients."
      explanation: Registry CT data provide the APDS1-specific observed proportion.
  - subtype: APDS2
    frequency: "4/15 (27%)"
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients."
      explanation: Registry CT data provide the APDS2-specific observed proportion.
- name: Autoimmune thrombocytopenia
  category: Hematologic
  description: >-
    Immune thrombocytopenia is a characteristic autoimmune hematologic
    complication of APDS and reflects loss of immune tolerance.
  phenotype_term:
    preferred_term: autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cytopenias are the most common autoimmune manifestation (accounting for 76% of all autoimmune complications) and include immune thrombocytopenia purpura (ITP) and autoimmune haemolytic anaemia (AIHA) (3, 15, 19)."
    explanation: Review explicitly identifies immune thrombocytopenia as one of the defining autoimmune cytopenias in APDS.
- name: Autoimmune hemolytic anemia
  category: Hematologic
  description: >-
    Autoimmune hemolytic anemia is a recurrent autoimmune cytopenia in APDS and
    reflects breakdown of peripheral immune tolerance.
  phenotype_term:
    preferred_term: autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cytopenias are the most common autoimmune manifestation (accounting for 76% of all autoimmune complications) and include immune thrombocytopenia purpura (ITP) and autoimmune haemolytic anaemia (AIHA) (3, 15, 19)."
    explanation: Review explicitly identifies autoimmune hemolytic anemia as one of the defining autoimmune cytopenias in APDS.
- name: Decreased circulating IgG
  category: Immunologic
  frequency: FREQUENT
  description: >-
    Reduced serum IgG is common and accompanies broader antibody production
    defects and poor vaccine responses.
  phenotype_term:
    preferred_term: decreased circulating IgG concentration
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  reports_on:
  - target: Defective B-cell maturation and humoral immunity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced circulating IgG reports impaired B-cell maturation, class switching, and antibody production.
    evidence:
    - reference: PMID:29675019
      reference_title: "Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production."
      explanation: Human APDS data identify defective IgG production as a diagnostic readout of the humoral immune defect.
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunologically, hypogammaglobulinemia with increased IgM levels was frequent."
    explanation: The APDS1/APDS2 registry review supports frequent hypogammaglobulinemia without importing an APDS1-only percentage.
- name: Lymphoma
  category: Oncologic
  frequency: OCCASIONAL
  description: >-
    B-cell lymphoma is the dominant malignancy complication in APDS and is
    often associated with chronic EBV infection.
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "B cell lymphomas are the most common malignancy and are often associated with EBV infection."
    explanation: The clinical review supports the dominant lymphoma lineage and its frequent EBV association.
  phenotype_contexts:
  - subtype: APDS1
    frequency: "13%"
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An increased risk for lymphoma was also highlighted with 13% among the APDS1 patients and 28% in the APDS2 cohort."
      explanation: Registry review provides the APDS1-specific observed proportion.
  - subtype: APDS2
    frequency: "28%"
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "An increased risk for lymphoma was also highlighted with 13% among the APDS1 patients and 28% in the APDS2 cohort."
      explanation: Registry review provides the APDS2-specific observed proportion.
- name: Short stature
  category: Growth
  description: >-
    Short stature and growth impairment occur across APDS but are enriched in
    APDS2.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."
    explanation: Registry data quantify growth impairment as an APDS2-enriched feature.
  phenotype_contexts:
  - subtype: APDS1
    notes: Growth impairment occurs in APDS1, but this registry passage does not provide a separate APDS1 percentage.
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."
      explanation: Registry wording places growth impairment across APDS while identifying APDS2 enrichment, without an APDS1-specific percentage.
  - subtype: APDS2
    frequency: "45%"
    notes: Growth impairment is enriched in APDS2.
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."
      explanation: Registry review provides the APDS2-specific growth-impairment proportion.
- name: Neurodevelopmental delay
  category: Neurologic
  description: >-
    Neurodevelopmental delay is reported in both subtypes but was more frequent
    in APDS2 in the international registry.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."
    explanation: Registry data document neurodevelopmental delay in both subtypes with a higher observed proportion in APDS2.
  phenotype_contexts:
  - subtype: APDS1
    frequency: "19%"
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."
      explanation: Registry review provides the APDS1-specific neurodevelopmental-delay proportion.
  - subtype: APDS2
    frequency: "31%"
    evidence:
    - reference: PMID:29599784
      reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Non-immunological characteristics included neurodevelopmental delay (19% of APDS1 and 31% of APDS2) and growth impairment, especially among APDS2 patients (45%)."
      explanation: Registry review provides the APDS2-specific neurodevelopmental-delay proportion.
imaging_findings:
- name: Mosaic attenuation on thoracic CT
  modality: CT
  subtype: APDS1
  imaging_finding_term:
    preferred_term: Mosaic attenuation of the lung
  description: >-
    In the APDS1 cohort supplying the frequency estimate, thoracic CT frequently
    showed mosaic attenuation, reflecting heterogeneous small-airway involvement
    in chronic lung disease.
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  diagnostic: false
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27555459
    reference_title: "Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%)."
    explanation: APDS1 cohort imaging establishes mosaic attenuation as a very frequent thoracic imaging pattern in that subtype; the estimate is not generalized to APDS2.
- name: Bronchiectasis on thoracic CT
  modality: CT
  imaging_finding_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  description: >-
    CT demonstrates established bronchial dilatation and structural airway
    damage in a substantial proportion of patients with pulmonary involvement.
  located_in:
    preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  phenotype_term:
    preferred_term: bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  diagnostic: false
  frequency: FREQUENT
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."
    explanation: Combined APDS1/APDS2 registry CT data support bronchiectasis as a frequent imaging finding.
biochemical:
- name: Elevated serum IgM
  presence: Abnormal
  context: >-
    Hyper-IgM is the dominant serologic pattern in APDS and reflects impaired
    class-switch recombination and abnormal B-cell maturation.
  readouts:
  - target: Defective B-cell maturation and humoral immunity
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated IgM reports impaired immunoglobulin class switching and abnormal B-cell maturation.
    evidence:
    - reference: PMID:34422726
      reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A hyper IgM-like pattern is the most common immunoglobulin profile reported (low IgG, low IgA and high IgM). This is explained by the fact that PI3Kδ signalling pathways are involved in immunoglobulin class switching (25) with class switched memory B cells reduced in APDS."
      explanation: The review links elevated IgM to the class-switching and B-cell maturation defect.
  evidence:
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The predominant immunologic phenotype was hyper-IgM syndrome (48.1%)."
    explanation: Systematic review shows that a hyper-IgM pattern is the most common humoral abnormality in APDS.
- name: Enhanced AKT phosphorylation in circulating B cells
  presence: Abnormal
  context: >-
    Constitutive phospho-AKT in peripheral blood CD19-positive B cells is a
    functional biomarker of hyperactive PI3K-delta signaling and falls with
    selective p110delta inhibition.
  readouts:
  - target: PI3K-delta pathway hyperactivation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Enhanced AKT phosphorylation reports excessive PI3K-delta-AKT pathway activity.
    evidence:
    - reference: PMID:29675019
      reference_title: "Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor."
      explanation: Normalization with a selective p110-delta inhibitor identifies pAKT as a functional readout of pathway hyperactivation.
  evidence:
  - reference: PMID:29675019
    reference_title: "Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor."
    explanation: Functional assay evidence shows constitutive AKT activation in APDS B cells and reversibility with pathway inhibition.
- name: Reduced class-switched memory B cells
  presence: Abnormal
  context: >-
    Loss of switched-memory B cells is a recurrent APDS immunophenotype and
    contributes to defective long-lived humoral immunity.
  readouts:
  - target: Defective B-cell maturation and humoral immunity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced class-switched memory B cells report impaired B-cell maturation and immunoglobulin class switching.
    evidence:
    - reference: PMID:34422726
      reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "A hyper IgM-like pattern is the most common immunoglobulin profile reported (low IgG, low IgA and high IgM). This is explained by the fact that PI3Kδ signalling pathways are involved in immunoglobulin class switching (25) with class switched memory B cells reduced in APDS."
      explanation: The review identifies reduced switched-memory B cells as a readout of impaired immunoglobulin class switching.
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A hyper IgM-like pattern is the most common immunoglobulin profile reported (low IgG, low IgA and high IgM). This is explained by the fact that PI3Kδ signalling pathways are involved in immunoglobulin class switching (25) with class switched memory B cells reduced in APDS."
    explanation: Review explicitly links impaired class switching to reduced switched-memory B cells in APDS.
genetic:
- name: PIK3CD
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: APDS1
  gene_term:
    preferred_term: PIK3CD
    term:
      id: hgnc:8977
      label: PIK3CD
  notes: >-
    Heterozygous gain-of-function variants in the catalytic p110delta subunit
    cause APDS1. The p.Glu1021Lys hotspot accounts for most reported APDS1
    cases in published series.
  evidence:
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively."
    explanation: Systematic review identifies PIK3CD gain-of-function as the APDS1 disease gene.
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations."
    explanation: Defines the dominant APDS1 hotspot variant pattern.
- name: PIK3R1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: APDS2
  gene_term:
    preferred_term: PIK3R1
    term:
      id: hgnc:8979
      label: PIK3R1
  notes: >-
    Heterozygous variants in the p85alpha regulatory subunit cause APDS2 by
    relieving normal inhibition of PI3Kdelta. Exon 11 splice-site mutations
    leading to p.434-475 deletion are the major recurrent APDS2 lesions.
  evidence:
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Activated phosphoinositide 3-kinase delta syndrome (APDS) is a novel primary immunodeficiency (PID) caused by heterozygous gain of function mutations in PI3Kδ catalytic p110δ (PIK3CD) or regulatory p85α (PIK3R1) subunits leading to APDS1 and APDS2, respectively."
    explanation: Systematic review identifies PIK3R1 as the causative gene for APDS2.
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The c.3061 G>A (p. E1021K) mutation in APDS1 with 85% frequency and c.1425+1 G> (A, C, T) (p.434-475del) mutation in APDS2 with 79% frequency were hotspot mutations."
    explanation: Defines the dominant recurrent APDS2 splice hotspot.
treatments:
- name: Immunoglobulin replacement therapy
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    Intravenous or subcutaneous immunoglobulin replacement is commonly used as
    supportive therapy for antibody deficiency and prevention of recurrent
    bacterial infections.
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The majority of APDS patients were placed on long-term immunoglobulin replacement therapy."
    explanation: Systematic review supports immunoglobulin replacement as standard-of-care supportive treatment.
- name: Sirolimus
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    mTOR inhibition with sirolimus is an off-label pathway-directed option for
    lymphoproliferation or organomegaly when leniolisib is unavailable. Registry
    responses were strongest for lymphoproliferation and less consistent for
    bowel inflammation and cytopenias. Headache, anorexia, renal toxicity,
    aphthous ulcers, and liver toxicity led to treatment interruption in some
    registry participants.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_phenotypes:
  - preferred_term: lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  target_mechanisms:
  - target: PI3K-delta pathway hyperactivation
    treatment_effect: INHIBITS
    description: Sirolimus inhibits the downstream mTOR arm of the hyperactive PI3K-delta-AKT-mTOR pathway.
    evidence:
    - reference: PMID:38148368
      reference_title: "Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The mTOR inhibitor sirolimus has been used effectively for some clinical manifestations of this condition, however the arrival of specific PI3Kδ inhibitor leniolisib has shown promising early results and may provide a more targeted approach."
      explanation: The review explicitly identifies sirolimus as an mTOR inhibitor used in APDS.
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well."
    explanation: Registry outcomes define the main clinical benefit and the limitations of rapamycin treatment.
  - reference: PMID:38148368
    reference_title: "Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mTOR inhibitor sirolimus has been used effectively for some clinical manifestations of this condition, however the arrival of specific PI3Kδ inhibitor leniolisib has shown promising early results and may provide a more targeted approach."
    explanation: Review supports sirolimus as an established pathway-directed treatment for selected APDS manifestations.
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients (No. 7, 13) suffered from side effects (severe headaches, anorexia, renal toxicity) that led to the complete interruption of the treatment, whereas in three cases, the therapy was paused because of side effects (aphthous ulcers, liver toxicity, renal toxicity) but could be started again."
    explanation: Registry treatment data document clinically meaningful sirolimus toxicity and treatment interruption.
- name: Leniolisib
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Selective oral PI3Kdelta inhibition directly targets the causal signaling
    lesion in APDS and is recommended as first-line therapy for significant
    lymphoproliferative disease. The current U.S. label indicates Joenja for
    adults and pediatric patients 12 years and older; 70 mg twice daily is the
    recommended dose for patients weighing at least 45 kg, with no recommended
    dose below 45 kg. The current label warns of postmarketing hypersensitivity,
    including anaphylaxis. In the pivotal 12-week phase 3 trial, both lymph-node
    size and naive-B-cell coprimary outcomes improved versus placebo.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: leniolisib
      term:
        id: CHEBI:229649
        label: leniolisib
  target_phenotypes:
  - preferred_term: lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  target_mechanisms:
  - target: PI3K-delta pathway hyperactivation
    treatment_effect: INHIBITS
    description: Leniolisib selectively inhibits the causal hyperactive PI3K-delta signaling node.
    evidence:
    - reference: PMID:36399712
      reference_title: "A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ."
      explanation: The pivotal trial directly states the drug-target relationship.
  evidence:
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217759s005lbl.pdf
    reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217759s005lbl.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JOENJA is a kinase inhibitor indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older."
    explanation: The May 2025 U.S. prescribing information establishes the current labeled APDS indication and age threshold.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217759s005lbl.pdf
    reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217759s005lbl.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The recommended dosage of JOENJA in adult and pediatric patients 12 years of age and older weighing 45 kg or greater is 70 mg administered orally twice daily approximately 12 hours apart, with or without food. There is no recommended dosage for patients weighing less than 45 kg."
    explanation: The current label supplies the weight-qualified dosing recommendation and explicitly states the lack of a recommended dose below 45 kg.
  - reference: PMID:39899769
    reference_title: "Activated PI3K Delta Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Leniolisib, a selective PI3K delta (PI3Kδ) inhibitor, has shown promise in clinical trials by directly targeting the overactive PI3Kδ signaling pathway, a hallmark of the condition, and is therefore recommended as a first-line treatment of significant lymphoproliferative disease, including lymphadenopathy and splenomegaly."
    explanation: Current GeneReviews recommends leniolisib as first-line treatment for significant lymphoproliferation.
  - reference: url:https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217759s005lbl.pdf
    reference_title: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217759s005lbl.pdf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hypersensitivity reaction(s), including anaphylaxis, have been reported in postmarketing setting. If a clinically significant hypersensitivity reaction occurs, discontinue JOENJA and institute appropriate therapy [see Adverse Reactions (6.2)]."
    explanation: The May 2025 prescribing information adds the postmarketing hypersensitivity and anaphylaxis warning.
  - reference: PMID:36399712
    reference_title: "A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS."
    explanation: Randomized phase 3 evidence demonstrates improvement in both coprimary outcomes and acceptable short-term tolerability.
  - reference: PMID:28972011
    reference_title: "Effective \"activated PI3Kδ syndrome\"-targeted therapy with the PI3Kδ inhibitor leniolisib."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively."
    explanation: Early interventional study shows direct clinical improvement in APDS lymphoproliferation with leniolisib.
  - reference: PMID:39561927
    reference_title: "A randomised, placebo-controlled, phase III trial of leniolisib in activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS): Adolescent and adult subgroup analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a 12-week phase III randomised placebo-controlled trial, leniolisib, a selective PI3Kδ inhibitor, was well-tolerated and met both co-primary endpoints (change from Baseline in log10-transformed sum of product of diameters of index lymph nodes and percentage of naïve/total B cells at Day 85)."
    explanation: Phase III trial evidence confirms leniolisib efficacy on both lymphadenopathy and naive-B-cell restoration.
- name: Hematopoietic stem cell transplantation
  action_category: THERAPEUTIC
  therapeutic_modality: CELL_THERAPY
  description: >-
    Allogeneic hematopoietic stem cell transplantation is reserved for severe
    or treatment-refractory disease, including progressive organ damage,
    refractory infection, or immune dysregulation. In an international cohort,
    two-year overall survival was 86% and graft-failure-free survival was 68%;
    graft instability and poor graft function remain important limitations.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_phenotypes:
  - preferred_term: combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:34033842
    reference_title: "International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity."
    explanation: The largest international HCT cohort provides balanced survival and graft-failure-free outcome estimates.
  - reference: PMID:34033842
    reference_title: "International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT."
    explanation: The cohort directly identifies major limitations that qualify the potentially curative role of HCT.
  - reference: PMID:39899769
    reference_title: "Activated PI3K Delta Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Allogenic hematopoietic stem cell transplant (HSCT) is reserved for individuals with severe or treatment-refractory APDS, including progressive organ damage, recurrent refractory infections, or severe immune dysregulation unresponsive to pharmacologic therapy."
    explanation: Current GeneReviews defines the clinical circumstances in which HSCT is reserved across APDS1 and APDS2.
- name: Antibiotic prophylaxis
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Long-term prophylactic antibiotics are used in patients with recurrent
    bacterial sinopulmonary infections to reduce infectious burden alongside
    immunoglobulin replacement therapy.
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_phenotypes:
  - preferred_term: recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:39899769
    reference_title: "Activated PI3K Delta Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Supportive care: Regular intravenous or subcutaneous immunoglobulin replacement therapy to prevent recurrent bacterial infections and improve immune function; long-term prophylactic antibiotics can be considered to reduce the frequency of bacterial infections; individuals with recurrent herpes simplex or herpes zoster virus can receive prophylactic acyclovir or valganciclovir."
    explanation: Current GeneReviews supports long-term antibacterial prophylaxis as an option within APDS supportive care.
- name: Multisystem, viral, and malignancy surveillance
  action_category: MONITORING
  description: >-
    Longitudinal follow-up should assess infections and herpesvirus burden,
    immune function, lymphoproliferation and blood counts, autoimmunity,
    respiratory function, and gastrointestinal/liver status at least annually.
    GeneReviews also recommends chest CT or MRI every three to five years and
    baseline then periodic liver ultrasonography. Persistent or changing
    lymphadenopathy warrants clinical evaluation because benign
    lymphoproliferation can be difficult to distinguish from lymphoma.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:39899769
    reference_title: "Activated PI3K Delta Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Surveillance: Annually assess infection risk (blood/sputum cultures for EBV, CMV, and HSV), immune function (immunoglobulin levels, CD4+, CD8+, B-cell subsets, response to vaccines), lymphoproliferative status (CBC, B-cell counts), autoimmunity (ANA screen, TSH, TPO), respiratory function (including pulmonary function tests), and gastrointestinal status (liver function tests); CT or MRI of the chest every three to five years; colonoscopy symptomatically as needed; liver ultrasound at baseline and every two to three years; psychiatric assessments as needed."
    explanation: Current GeneReviews provides a structured multisystem surveillance schedule including viral, lymphoproliferative, pulmonary, and liver monitoring.
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Benign lymphoproliferation may be difficult to distinguish from malignant disease, the risk of which is increased in APDS patients."
    explanation: Registry evidence supports careful reassessment of lymphoproliferation for malignant transformation.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Molecular diagnosis is established by identifying a heterozygous pathogenic
    gain-of-function variant in PIK3CD (APDS1) or a heterozygous pathogenic
    loss-of-function variant in PIK3R1 (APDS2). Panel-based or exome sequencing
    is appropriate given the clinical overlap with common variable
    immunodeficiency, hyper-IgM syndrome, and combined immunodeficiency. PTEN
    loss-of-function APDS-like immunodeficiency is a related but out-of-scope
    entity for this APDS1/APDS2 entry.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Heterozygous pathogenic gain-of-function PIK3CD variant (APDS1) or loss-of-function PIK3R1 variant (APDS2)
  evidence:
  - reference: PMID:39899769
    reference_title: "Activated PI3K Delta Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical diagnosis of APDS can be established in a proband based on suggestive clinical findings, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in PIK3CD (for APDS1) or PIK3R1 (for APDS2) identified by molecular genetic testing."
    explanation: Current GeneReviews defines molecular APDS diagnosis using PIK3CD for APDS1 and PIK3R1 for APDS2, without including PTEN in the APDS subtype definition.
  - reference: PMID:31111319
    reference_title: "Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It should be suspected in patients with history of recurrent respiratory infections, lymphoproliferation, and raised IgM levels."
    explanation: Systematic review identifies the cardinal clinical triggers that should prompt PIK3CD/PIK3R1 genetic testing.
- name: Serum immunoglobulin profiling
  description: >-
    Serum immunoglobulin levels are abnormal in most patients. The most common pattern
    is elevated IgM with low IgG and IgA, but subclass deficiency, selective IgA
    deficiency, and hypogammaglobulinaemia are also described. Normal immunoglobulin
    levels do not exclude the diagnosis.
  diagnosis_term:
    preferred_term: serum immunoglobulin measurement
    term:
      id: NCIT:C64430
      label: Protein or Enzyme Type Measurement
  results: Elevated IgM with low IgG or IgA in most patients; pattern varies
  markers: IgM, IgG, IgA
  evidence:
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunologically, hypogammaglobulinemia with increased IgM levels was frequent."
    explanation: The combined APDS1/APDS2 registry supports a frequent hyper-IgM/hypogammaglobulinemia pattern without generalizing APDS1-only percentages.
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A hyper IgM-like pattern is the most common immunoglobulin profile reported (low IgG, low IgA and high IgM). This is explained by the fact that PI3Kδ signalling pathways are involved in immunoglobulin class switching (25) with class switched memory B cells reduced in APDS."
    explanation: Review explains the immunological basis for the hyper-IgM pattern and notes that normal levels do not exclude APDS.
- name: Lymphocyte subset analysis
  description: >-
    Flow cytometric quantification of lymphocyte subsets typically reveals B cell
    lymphopenia, CD4+ T cell reduction with an inverted CD4/CD8 ratio, and expanded
    transitional B cells with reduced class-switched memory B cells. Extended
    phenotyping supports the diagnosis and reflects underlying immune dysregulation.
  diagnosis_term:
    preferred_term: lymphocyte subset flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  results: B cell lymphopenia; reduced CD4+ T cells; inverted CD4/CD8 ratio; expanded transitional B cells; reduced class-switched memory B cells
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Lymphocyte subset testing typically reveals B cell lymphopenia, CD4+ T cell reduction, with an inverted CD4/CD8 ratio."
    explanation: Review summarizes the characteristic lymphocyte subset pattern as a key diagnostic feature of APDS.
- name: Vaccine response assessment
  description: >-
    Measurement of specific antibody responses to pneumococcal polysaccharide and
    protein-conjugate vaccines reveals impaired humoral immunity in the majority of
    patients with APDS, analogous to other combined immunodeficiencies.
  diagnosis_term:
    preferred_term: vaccine-specific antibody measurement
    term:
      id: NCIT:C64430
      label: Protein or Enzyme Type Measurement
  results: Impaired polysaccharide and/or conjugate vaccine responses
  evidence:
  - reference: PMID:34422726
    reference_title: "Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vaccine responses are often impaired (3, 16). Defective anti-polysaccharide vaccine responses were detected in 52 of 58 patients (90%) and defective anti-peptide antibody responses in 14 of 42 (33%) (15)."
    explanation: Review documents near-universal impairment of vaccine responses in APDS, supporting their use as a diagnostic marker.
- name: Thoracic CT imaging
  description: >-
    High-resolution CT of the thorax can show mosaic attenuation reflecting
    small-airway disease and established bronchiectasis. The 90% estimate for
    mosaic attenuation comes from an APDS1 cohort, whereas bronchiectasis is
    documented in combined APDS1/APDS2 registry data. CT is relevant to staging
    airway injury and pulmonary surveillance.
  diagnosis_term:
    preferred_term: high-resolution thoracic computed tomography
    term:
      id: NCIT:C17204
      label: Computed Tomography
  results: Mosaic attenuation (well quantified in APDS1) and/or bronchiectasis
  evidence:
  - reference: PMID:27555459
    reference_title: "Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%)."
    explanation: The APDS1 cohort documents mosaic attenuation and bronchiectasis; its percentages are not generalized to APDS2.
  - reference: PMID:29599784
    reference_title: "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The registry data confirmed the previously described (5, 6) high incidence of bronchiectasis (28 patients out of the 55 who underwent a CT-scan), which was documented early in life (age range: 2–39 years; mean: 11.2 years)."
    explanation: Combined APDS1/APDS2 registry CT data establish bronchiectasis across the operational disease scope.
- name: Enhanced phospho-AKT in circulating B cells
  description: >-
    Flow cytometric measurement of AKT phosphorylation at Ser473 in CD19+ peripheral
    blood B cells is a supportive functional biomarker of PI3K-delta
    hyperactivation. Enhanced pAKT, particularly in CD10+ immature B cells, may
    help distinguish PI3K-pathway hyperactivation from common variable
    immunodeficiency and CD40L-related hyper-IgM syndrome, but the assay remains
    incompletely validated. Because this functional abnormality can also occur
    in PTEN-related APDS-like immunodeficiency, it complements but does not
    replace subtype-defining molecular testing.
  diagnosis_term:
    preferred_term: phospho-AKT flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  results: Elevated phospho-AKT (Ser473) in CD19+ B cells, most pronounced in CD10+ immature B cells; normalized by p110delta inhibitor
  evidence:
  - reference: PMID:29675019
    reference_title: "Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies."
    explanation: Functional flow cytometry distinguishes PI3K-pathway hyperactivation from other antibody deficiencies but does not by itself separate APDS1/2 from PTEN-related APDS-like disease.
clinical_trials:
- name: NCT02435173
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Completed phase 2/3 leniolisib program with an open-label dose-finding part
    followed by a randomized blinded placebo-controlled efficacy and safety
    part in genetically confirmed APDS. The schema records the highest
    confirmatory phase because the ClinicalTrials.gov record lists both phase 2
    and phase 3.
  target_phenotypes:
  - preferred_term: lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: clinicaltrials:NCT02435173
    reference_title: "An Open-label, Non-randomized, Within-patient Dose-finding Study Followed by a Randomized, Subject, Investigator and Sponsor Blinded Placebo Controlled Study to Assess the Efficacy and Safety of CDZ173 (Leniolisib) in Patients With APDS/PASLI (Activated Phosphoinositide 3-kinase Delta Syndrome/ p110δ-activating Mutation Causing Senescent T Cells, Lymphadenopathy and Immunodeficiency)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study was designed to explore CDZ173, a selective PI3Kδ inhibitor, in patients with genetically activated PI3Kδ, i.e., patients with Activated phosphoinositide 3-kinase delta syndrome/ p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (APDS/PASLI)."
    explanation: The ClinicalTrials.gov record establishes the intervention, genetically activated APDS population, and lymphadenopathy target.
  - reference: PMID:36399712
    reference_title: "A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks."
    explanation: The peer-reviewed pivotal trial confirms phase 3 design, enrollment, dose, and treatment duration.
- name: NCT05438407
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Active, non-recruiting open-label phase 3 pediatric leniolisib study in
    patients aged four to 11 years, followed by a long-term extension; status
    recorded from ClinicalTrials.gov on 2026-07-19.
  evidence:
  - reference: clinicaltrials:NCT05438407
    reference_title: "An Open-label, Single Arm Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Leniolisib in Pediatric Patients Aged 4 to 11 Years With Activated Phosphoinositide 3-Kinase Delta Syndrome Followed by an Open-label Long-term Extension"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a 2-part, prospective, open-label, single arm, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and efficacy of leniolisib in at least 15 pediatric patients (aged 4 to 11 years) with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS)."
    explanation: The registry record establishes the pediatric age range, intervention, design, and outcome domains.
- name: NCT05693129
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Active, non-recruiting open-label phase 3 pediatric leniolisib study in
    patients aged one to six years, followed by a long-term extension; status
    recorded from ClinicalTrials.gov on 2026-07-19.
  evidence:
  - reference: clinicaltrials:NCT05693129
    reference_title: "An Open-label, Single Arm Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Leniolisib in Pediatric Patients (Aged 1 to 6 Years) With APDS (Activated Phosphoinositide 3-Kinase Delta Syndrome) Followed by an Open-label Long-term Extension"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a 2-part, prospective, open-label, single arm, multicenter study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and efficacy of leniolisib in at least 15 pediatric patients (aged 1 to 6 years) with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS)"
    explanation: The registry record establishes the younger pediatric age range, intervention, design, and outcome domains.
datasets:
- accession: geo:GSE171795
  title: Role of activated PI3K-delta signaling in humoral immunity
  description: We report the high-throughput profiling of murine naive B cells, germinal center (dark zone and light zone) B cells, and plasma cells transcriptome. By obtaining over 5 million bases of sequence, we generated genome-wide expression maps of cell subsets from WT mice and aPIK3CD mice. We find that activated PIK3CD signaling lead to significant alteration in gene expression of plasma cells.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 32
  publication: PMID:34586341
  notes: Identified by GEO DataSets index search for Activated PI3K-delta syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

📚

References & Deep Research

References

2

PMID:39899769

Activated PI3K Delta Syndrome.

1 finding

Current GeneReviews operationally defines APDS as APDS1 caused by PIK3CD gain of function and APDS2 caused by PIK3R1 loss of function.

"APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1."

Show evidence (1 reference)

PMID:39899769 SUPPORT Other

"APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1."

Current GeneReviews defines the operational APDS1/APDS2 scope.

PMID:37178059

Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan.

1 finding

Some literature distinguishes PTEN loss-of-function immunodeficiency as APDS-like rather than APDS1 or APDS2.

"In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF),..."

Show evidence (1 reference)

PMID:37178059 SUPPORT Other

"In 2014, loss-of-function (LOF) mutation of p85α (responsible gene: PIK3R1), a regulatory subunit of p110δ, was identified as a causative gene, followed in 2016 by the identification of the LOF mutation of PTEN, which dephosphorylates PIP3, leading to the differentiation of APDS1 (PIK3CD-GOF),..."

The Japanese guideline supplies the alternate APDS-like nomenclature for PTEN loss of function.

Deep Research

1

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Activated PI3K-delta Syndrome. Core disease mechanisms, molecular and cell...

Asta Scientific Corpus Retrieval 20 citations 2026-04-12T10:08:20.951047

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Activated PI3K-delta Syndrome. Core disease mechanisms, molecular and cell...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Activated PI3K-delta syndrome

Authors: Unknown authors
Year: 2020
Venue: Definitions
URL: https://www.semanticscholar.org/paper/2d9cd678f1ad514aad537ed315a6394d425c888a
DOI: 10.32388/q6iuae
Citations: 4
Influential citations: 1
Summary: People with activated PI3K-delta syndrome develop recurrent infections, particularly in the lungs, sinuses, and ears, and may have chronic active viral infections, commonly Epstein-Barr virus or cytomegalovirus infections.
Evidence snippets:
Snippet 1 (score: 0.431) > Activated PI3K-delta syndrome

[2] The Interlinking Metabolic Association between Type 2 Diabetes Mellitus and Cancer: Molecular Mechanisms and Therapeutic Insights

Authors: Abutaleb Asiri, A. A. Al Qarni, Ahmed Bakillah
Year: 2024
Venue: Diagnostics
URL: https://www.semanticscholar.org/paper/e4de6095f95951d23b6467a7a213148e94c4125a
DOI: 10.3390/diagnostics14192132
PMID: 39410536
PMCID: 11475808
Citations: 14
Summary: An overview of shared molecular mechanisms between diabetes and cancer as well as established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management are discussed.
Evidence snippets:
Snippet 1 (score: 0.428) > T2DM and cancer are complex diseases that share common mechanisms including obesity, inflammatory stress, chronic hyperglycemia, and insulin resistance. These mechanisms are involved in the association with tumor development and progression by promoting cell growth, proliferation, migration, and invasion as well as inhibiting apoptosis in tumor cells. Understanding these mechanisms linking both diseases is crucial for developing effective methods for diagnosis, prevention, and treatment. Furthermore, certain pathways such as the PI3K/AKT/mTOR pathway, which are associated with glucose metabolism, frequently exhibit molecular alterations in various cancer subtypes. To overcome the impact of drug resistance and toxicities, a therapeutic combination targeting these specific pathways could provide a promising intervention strategy to reduce the burden impact in both diseases. However, the inhibition of PI3K/AKT/mTOR by small molecule inhibitors may lead to insulin resistance in cancer cells, posing a significant challenge that could worsen disease outcomes. Identifying predictive biomarkers for effective treatments involving PI3K/AKT/mTOR inhibitors is essential to anticipate potential complications. Moreover, antidiabetic drugs appear to reduce cancer risk. Understanding the precise mechanism by which these treatments prevent cancer may help identify novel strategies to treat cancer patients and prevent the disease's incidence. Further research into the cellular and molecular interactions driving the intricate relationship between T2DM and cancer is essential. This will enhance our understanding and improve the clinical outcomes of patients affected by both diseases.

[3] Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective

Authors: L. Berglund
Year: 2023
Venue: Journal of Clinical Immunology
URL: https://www.semanticscholar.org/paper/2ea3bdb89da3e207aeaea857a20bbc6a3fb0dfac
DOI: 10.1007/s10875-023-01626-0
PMID: 38148368
PMCID: 10751257
Citations: 17
Summary: Key aspects of PI3K pathway biology are summarized and potential options for nuanced modulation of the PI3K pathway in APDS from a clinical perspective are discussed, highlighting differences from PI3K inhibition in haematological malignancies.
Evidence snippets:
Snippet 1 (score: 0.427) > Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective

[4] Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes

Authors: Vyanka Redenbaugh, T. Coulter
Year: 2021
Venue: Frontiers in Pediatrics
URL: https://www.semanticscholar.org/paper/7dc479c651fab24017fc959690b058a1262fda47
DOI: 10.3389/fped.2021.702872
PMID: 34422726
PMCID: 8374435
Citations: 26
Influential citations: 2
Summary: The common manifestations such as sinopulmonary infections, bronchiectasis, lymphoproliferation, susceptibility to herpesvirus, malignancy, as well as more rare non-immune features such as short stature and neurodevelopmental abnormalities are discussed.
Evidence snippets:
Snippet 1 (score: 0.419) > Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes

[5] Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer

Authors: M. G. de Matos, Mafalda Pinto, A. Gonçalves, Sule Canberk, M. J. Bugalho et al.
Year: 2025
Venue: PeerJ
URL: https://www.semanticscholar.org/paper/655de68f1a7e8137dcba8a2046f14dee4f07594d
DOI: 10.7717/peerj.18801
PMID: 39850836
PMCID: 11756370
Citations: 4
Summary: The knowledge of genetic and molecular biomarkers has achieved a high level of complexity, and the difficulties related to its applicability determine that their implementation in clinical practice is not yet a reality.
Evidence snippets:
Snippet 1 (score: 0.416) > Knowledge of molecular mechanisms implicated in thyroid carcinogenesis has been attained in recent years. Thyroid neoplasm result from alterations in gene expression patterns, which occur due to a gradual accumulation of genetic and epigenetic events. These changes are associated with specific tumor phenotypes and are implicated in disease etiology. Molecular alterations induce the activation of different signaling pathways, such as the mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K/AKT/mTOR), which are involved in and promote carcinogenesis (Hsiao & Nikiforov, 2014). In a few years, the knowledge of molecular mechanisms implicated in thyroid carcinogenesis changed from understanding signaling pathways and identification of a few genes mutations to the knowledge of the main genes implicated in thyroid carcinogenesis, reviewed by De Leo et al. (2024). Genetic changes in thyroid neoplasms were divided in early/driver molecular alterations and late/progression events. Late/ progression events may be associated with early/driver molecular alterations and represent the evolution from well-differentiated to high-grade and undifferentiated carcinoma, being (Pozdeyev et al., 2018). Most frequent gene mutations present in follicular-cell derived thyroid tumors are BRAF, RAS, and TERTp mutations, associate with clinically relevant clinicopathologic features, as shown in Table 3.

[6] Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Authors: T. Coulter, Anita Chandra, C. Bacon, J. Babar, J. Curtis et al.
Year: 2017
Venue: The Journal of Allergy and Clinical Immunology
URL: https://www.semanticscholar.org/paper/a890b4b187a0ade1f6ba97b4787f8700c0f6d4a1
DOI: 10.1016/j.jaci.2016.06.021
PMID: 27555459
PMCID: 5292996
Citations: 403
Influential citations: 30
Summary: The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease and clinical trials of selective PI3K&dgr; inhibitors offer new prospects for APDS treatment.
Evidence snippets:
Snippet 1 (score: 0.410) > Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

[7] Correlation of DRD2 mRNA expression levels with deficit syndrome severity in chronic schizophrenia patients receiving clozapine treatment

Authors: Liang Liu, Yin Luo, Guofu Zhang, Chunhui Jin, Zhenhe Zhou et al.
Year: 2017
Venue: Oncotarget
URL: https://www.semanticscholar.org/paper/d84ac1f938cd73189ef4e9ba5c4718bfa34825f0
DOI: 10.18632/oncotarget.21230
PMID: 29156812
PMCID: 5689702
Citations: 5
Summary: A correlation was observed between increased deficit syndrome severity and elevated expression levels of DRD2 in PBLs of chronic schizophrenia patients receiving long-term clozapine treatment.
Evidence snippets:
Snippet 1 (score: 0.408) > Schizophrenia is a complex, severe, chronic psychiatric disorder with a heterogeneous clinical phenotype [1]. The prevalence of schizophrenia is approximately 1.1% of the population over the age of 18, and 25 million people worldwide are currently affected by this disorder [2]. However, at present, schizophrenia is primarily diagnosed using criterion-based approaches, such as the criteria from the International Classification of Diseases, Tenth Edition (ICD-10), and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) [3]. Biomarkers for the diagnosis, prognosis or therapeutic efficacy of schizophrenia are currently being examined extensively. > Many efforts have been made to investigate the etiology of this disease, including studies focused on genetics, early environmental factors, psychology and neurobiology [4][5][6][7]. Gene-environmental interactions have been found to play a crucial role in the development of schizophrenia [8,9]. Considering these various factors, the development of genomics and molecular biology improved the understanding of the molecular pathophysiology of schizophrenia, especially the related neuronal signaling pathways and the influences of antipsychotic drugs on them [10][11][12][13]. The phosphoinositide-3 kinase -protein kinase B (PI3K-Akt) pathway is an important downstream intracellular pathway of DRD2, which is associated with the function and development of central nervous system and the pathophysiology of schizophrenia [10][11][12][13][14][15]. PI3K-Akt pathway is also the intracellular downstream pathway of glutamate, serotonin, dysbindin, disrupted in schizophrenia-1 (DISC-1), and neuregulin 1 (NRG1), which are all the targets for mood stabilizers and antipsychotic drugs [10,15,16]. Almost all aspects of the cell developments, such as growth, proliferation, metabolism and apoptosis, were modulated by PI3K-Akt pathway.

[8] Activated PI3 Kinase Delta Syndrome: Molecular Pathogenesis and Emerging Therapeutics

Authors: Elias A Alraqibah
Year: 2025
Venue: Cureus
URL: https://www.semanticscholar.org/paper/64ca180c8b4dba5605a150d357db50ba117d38b7
DOI: 10.7759/cureus.90448
PMID: 40978950
PMCID: 12446750
Summary: An in-depth exploration of the genetic and molecular mechanisms underlying Activated PI3 kinase delta syndrome is provided, highlighting the complex interplay between immunodeficiency and autoimmunity.
Evidence snippets:
Snippet 1 (score: 0.406) > Activated PI3 Kinase Delta Syndrome: Molecular Pathogenesis and Emerging Therapeutics

[9] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

Authors: I. Condò
Year: 2022
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
DOI: 10.3390/ijms23126525
PMID: 35742964
PMCID: 9223693
Citations: 15
Influential citations: 2
Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
Evidence snippets:
Snippet 1 (score: 0.404) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[10] Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome

Authors: Takaki Asano, S. Okada, M. Tsumura, Tzu-wen Yeh, Kanako Mitsui-Sekinaka et al.
Year: 2018
Venue: Frontiers in Immunology
URL: https://www.semanticscholar.org/paper/d7a2168f57e26dccb1c4815aa7a08a5f2ff6d03a
DOI: 10.3389/fimmu.2018.00568
PMID: 29675019
PMCID: 5895775
Citations: 24
Summary: The results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.
Evidence snippets:
Snippet 1 (score: 0.402) > Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome

[11] The Diabetes Syndrome – A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms

Authors: A. W. Rachfal, S. Grant, S. Schwartz
Year: 2021
Venue: International Journal of General Medicine
URL: https://www.semanticscholar.org/paper/4c088a6a8b613c15e817f7491d24022497b7f5c4
DOI: 10.2147/IJGM.S305156
PMID: 33776471
PMCID: 7987256
Citations: 6
Summary: The “Diabetes Syndrome”, an overarching group of interrelated conditions linked by these overlapping mechanisms, can be viewed as a conceptual framework that can facilitate understanding of the inter-relationships of superficially disparate conditions.
Evidence snippets:
Snippet 1 (score: 0.401) > Although many pathways lead to hyperglycemia in diabetes -the so-called "Egregious Eleven" (Listed in Table 1) -β-cell dysfunction is the core defect. 1,2 Four basic pathophysiologic mechanisms damage the β-cell, namely, genes and epigenetic changes, inflammation, an abnormal environment [especially fuel excess], and insulin resistance (IR). 1,2 2][3] The interplay between these pathophysiologic mechanisms influences the specific risk of development and progression of complications in an individual patient. [6][7][8][9][10][11][12][13][14][15] In clinical practice we often encounter these common diseases, frequently within one individual patient and they are treated as independent conditions. However, we believe their epidemiologic associations is, in part, due to the same underlying pathophysiologies driving β-cell damage and diabetic complications. That is, the same pathophysiologic mechanisms that damage the β-cell and promote diabetesspecific complications also have key roles in the pathogenesis of these diseases. ][9][10][11][12][13][14][15] However, we propose these connections go beyond mere epidemiologic links due to overlapping pathophysiology. In fact, these conditions occur together in enough frequency and have common overlapping pathophysiologic drivers that we have created a conceptual framework called "The Diabetes Syndrome". The name is inspired by the Greek meaning of syndromē (sun-[together] + dramein [to run]) as the conditions, indeed, run together (Figure 1). This article will describe the shared pathophysiologic and etiologic factors across these prevalent and related diseases within the Diabetes Syndrome conceptual framework discussed within the context of the 4 basic pathophysiologic mechanisms -genes and epigenetic changes, abnormal environment, inflammation, and IR -with a focus on commonalities between these diseases and DM. In brief, genetics can mediate susceptibility to damage from abnormal external and internal environmental factors, including inflammation and IR. All these mechanisms can promote epigenetic changes.

[12] Identification of Key Biomarkers Related to Lipid Metabolism in Acute Pancreatitis and Their Regulatory Mechanisms Based on Bioinformatics and Machine Learning

Authors: Liang Zhang, Yujie Jiang, Taojun Jin, Mingxian Zheng, Yixuan Yap et al.
Year: 2025
Venue: Biomedicines
URL: https://www.semanticscholar.org/paper/e7ce2244e2bc25df76718a7b46e860a9c0478c01
DOI: 10.3390/biomedicines13092132
PMID: 41007695
PMCID: 12467098
Citations: 3
Summary: Findings are crucial for a deeper understanding of lipid metabolism pathways in AP and for the early implementation of preventive clinical measures, such as the control of blood lipid levels.
Evidence snippets:
Snippet 1 (score: 0.401) > FFAs have activated inflammatory cytokines, including tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-1β, and monocyte chemoattractant protein (MCP)-1, which exacerbate the inflammatory cascade in AP [12,13]. These findings suggest that lipid metabolism disorders are closely linked to the regulation of the local immune micro-environment of the pancreas. Abnormal expression of specific lipid metabolism-related genes may play a crucial role in AP progression. Notably, ACSL4, a gene involved in cell membrane lipid synthesis, has been shown to be central to AP pathology and may serve as a potential therapeutic target [14]. However, the molecular mechanisms by which lipid metabolism abnormalities regulate AP development remain unclear. A systematic analysis of the expression patterns of relevant genes and their regulatory mechanisms could enhance our understanding of AP pathogenesis and inform personalized treatment strategies. > Advancements in high-throughput sequencing and computational biology have made machine learning and bioinformatics essential tools for exploring disease diagnosis, treatment, and underlying pathological mechanisms. In this study, we conducted a systematic analysis of AP-related lipid metabolism core genes and their regulatory mechanisms by integrating gene expression data, gene enrichment analysis, machine learning, protein interaction networks, and metabolic pathway analysis [15][16][17][18]. We then experimentally validated the candidate genes using an AP mouse model to ensure the reliability and clinical translational value of the identified biomarkers. > This study aims to identify key lipid metabolism-related genes involved in the pathogenesis of acute pancreatitis and elucidate their core regulatory mechanisms through integrative bioinformatics, machine learning, and animal experiments.

[13] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
Year: 2016
Venue: Molecular Psychiatry
URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
DOI: 10.1038/mp.2016.89
PMID: 27240529
PMCID: 4995546
Citations: 77
Influential citations: 2
Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
Evidence snippets:
Snippet 1 (score: 0.400) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[14] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
Year: 2023
Venue: Frontiers in Pharmacology
URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
DOI: 10.3389/fphar.2023.1290253
PMID: 38026943
PMCID: 10662320
Citations: 3
Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
Evidence snippets:
Snippet 1 (score: 0.397) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[15] Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations

Authors: C. B. Machado, Flávia Melo Cunha de Pinho Pessoa, E. L. da Silva, Laudreísa da Costa Pantoja, Rita Almeida Ribeiro et al.
Year: 2021
Venue: Pharmaceutics
URL: https://www.semanticscholar.org/paper/ee6315b5b8c029d8612812666dfaa8cd566c577f
DOI: 10.3390/pharmaceutics13101604
PMID: 34683897
PMCID: 8540545
Citations: 4
Summary: Overall, regimens of KI treatment are clinically manageable, and results are especially effective when allied with tumor genetic profiles, giving rise to encouraging future prospects of an era where chemotherapy-free treatment regimens are a reality for many oncologic patients.
Evidence snippets:
Snippet 1 (score: 0.395) > Other relevant PI3K inhibitors with FDA approval to treat hematological malignancies include the pan-PI3K inhibitor with preferential activity towards PI3K-α/-δ copanlisib, the PI3K-γ/-δ inhibitor duvelisib and the recently approved PI3K-δ/Casein kinase 1 epsilon (CSNK1E) inhibitor umbralisib [134][135][136]. > The high prevalence of clinical trials evaluating PI3K inhibition as therapeutics for B-cell malignancies speaks to the favorable outcomes, especially when combined with chemo-immunotherapy treatment regimens, achieved in these studies, with ORRs reaching results as high as 75% of the treated population. Treatment efficacy, however, is diverse among different malignant B-cell subtypes, and patients afflicted with R/R diffuse large B-cell lymphoma (DLBCL) had generally lower rates of response to PI3K inhibition. Even among DLBCL patients, molecular profiles distinguishing the cell of origin in activated B-cell-like (ABC) DLBCL and germinal center B-cell-like (GCB) DLBCL represent a further stratification when predicting patient outcome to PI3K inhibition treatment [85,88,90,94,96,97,102,106]. > Mechanisms involved in tumor-acquired PI3K-inhibitor resistance are not fully elucidated yet, with no common mutation characterized across patient cohorts with progressive disease after idelalisib treatment [137]. However, analyses in human and murine models signal towards upregulation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) pathways in neoplastic cells resistant to PI3K-δ inhibition, which are major cellular mechanisms responsible for the regulation of proliferation, differentiation and cell death [138][139][140].

[16] Activated phosphoinositide 3‐kinase delta syndrome: Pathogenesis, clinical manifestations, and treatment

Authors: Ke Zhu, Qifan Li, Lingli Han, Jinqiao Sun
Year: 2024
Venue: Pediatric Discovery
URL: https://www.semanticscholar.org/paper/9856bc849611542f204bcc3f97ab7b9ee6e2df39
DOI: 10.1002/pdi3.2504
PMID: 40625457
PMCID: 12118235
Citations: 2
Summary: Targeted therapies, such as the mTOR inhibitor sirolimus and the elective Phosphoinositide 3‐kinase delta inhibitor leniolisib, have emerged as promising options, demonstrating both safety and effectiveness.
Evidence snippets:
Snippet 1 (score: 0.395) > Activated phosphoinositide 3‐kinase delta syndrome: Pathogenesis, clinical manifestations, and treatment

[17] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
Year: 2025
Venue: Pathophysiology
URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
DOI: 10.3390/pathophysiology32010009
PMID: 39982365
PMCID: 12077258
Citations: 24
Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
Evidence snippets:
Snippet 1 (score: 0.394) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[18] Chemotherapy and Mechanisms of Resistance in Breast Cancer

Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
Year: 2012
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
DOI: 10.5772/24629
Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
Evidence snippets:
Snippet 1 (score: 0.393) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[19] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
Year: 2020
Venue: Current Neuropharmacology
URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
DOI: 10.2174/1570159X17666191021141057
PMID: 31631822
PMCID: 7327943
Citations: 12
Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
Evidence snippets:
Snippet 1 (score: 0.391) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[20] Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: expanding the phenotype

Authors: P. Zhao, Juan Huang, Huicong Fu, Jia-li Xu, T. Li et al.
Year: 2024
Venue: Pediatric Rheumatology
URL: https://www.semanticscholar.org/paper/06f3fe8bbc9cdd6bae66177a0b4cd2c218da308a
DOI: 10.1186/s12969-024-00955-7
PMID: 38287413
PMCID: 10823743
Citations: 11
Summary: This study expands the spectrums of clinical phenotype and genotype of APDS, and demonstrates that WES has a high molecular diagnostic yield for patients with immunodeficiency related symptoms, such as respiratory infections, multiple ecchymosis, ANCA-associated vasculitis, multiple ileocecal polyps, hepatosplenomegaly, and lymphoid hyperplasia.
Evidence snippets:
Snippet 1 (score: 0.391) > Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: expanding the phenotype

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Activated PI3K-delta Syndrome. Core disease mechanisms, molecular and cell...

Relevant Papers

[1] Activated PI3K-delta syndrome

[2] The Interlinking Metabolic Association between Type 2 Diabetes Mellitus and Cancer: Molecular Mechanisms and Therapeutic Insights

[3] Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective

[4] Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes

[5] Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer

[6] Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

[7] Correlation of DRD2 mRNA expression levels with deficit syndrome severity in chronic schizophrenia patients receiving clozapine treatment

[8] Activated PI3 Kinase Delta Syndrome: Molecular Pathogenesis and Emerging Therapeutics

[9] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

[10] Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome

[11] The Diabetes Syndrome – A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms

[12] Identification of Key Biomarkers Related to Lipid Metabolism in Acute Pancreatitis and Their Regulatory Mechanisms Based on Bioinformatics and Machine Learning

[13] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

[14] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

[15] Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations

[16] Activated phosphoinositide 3‐kinase delta syndrome: Pathogenesis, clinical manifestations, and treatment

[17] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

[18] Chemotherapy and Mechanisms of Resistance in Breast Cancer

[19] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

[20] Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: expanding the phenotype

Notes