Activated PI3K Delta Syndrome

Clinical characteristics.

Activated PI3K delta syndrome (APDS) is characterized by a spectrum of clinical manifestations involving the immune system leading to increased susceptibility to infections (e.g., otitis media, sinusitis, bronchitis, and pneumonia), autoimmune/autoinflammatory manifestations including autoimmune cytopenias, gastrointestinal manifestations resembling Crohn-like colitis, intussusception, and lymphoproliferation (e.g., lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia), and an increased risk of developing B-cell lymphomas and other malignancies. Short stature, growth delays, and neurodevelopmental delays are also reported.

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. The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2.

Diagnosis/testing.

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.

Management.

Targeted therapies: 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. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is recommended for individuals with lymphoproliferative disease or organomegaly when leniolisib is unavailable; it is also used off-label due to its immunosuppressive and antiproliferative properties. 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.

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. Leniolisib or sirolimus targeted therapies for lymphoproliferation. Glucocorticoids for acute management of autoimmune complications; other immunosuppressive agents for chronic management of autoimmune manifestations. Bronchodilators and inhaled steroids for chronic lung disease; pulmonary hygiene and preventative pulmonary care to decrease risk of respiratory infections. Nutritional support and dietary modifications for gastrointestinal manifestations; anti-inflammatory medications including high-dose glucocorticoids for treatment of inflammatory bowel disease (which may also improve gut function and enhance absorption of targeted therapies); consider assisted enteral/parenteral nutrition for severe cases. Developmental interventions and educational support to address developmental delays and cognitive impairments. Offer counseling to address psychosocial impacts.

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.

Evaluation of relatives at risk: Molecular genetic testing for the APDS pathogenic variant identified in the proband is recommended for all at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Detailed clinical and laboratory evaluations to assess for possible clinical features related to APDS is recommended for family members found to have an APDS pathogenic variant.

Genetic counseling.

APDS is an autosomal dominant disorder. Approximately 80% of individuals diagnosed with APDS have an affected parent and 20% of individuals have the disorder as the result of a de novo PIK3CD gain-of-function variant (for APDS1) or de novo PIK3R1 loss-of-function variant (for APDS2). Once the PIK3CD or PIK3R1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

APDS types 1 (APDS1) and 2 (APDS2) are characterized by a spectrum of clinical manifestations primarily involving the immune system, leading to increased susceptibility to infections, autoimmunity, and lymphoproliferation. APDS should be considered in probands with the following suggestive findings:

Clinical findings

• Recurrent infections. Individuals with APDS commonly experience recurrent sinopulmonary infections from early childhood. These infections include:
  • Otitis media (frequent middle ear infections that may lead to conductive hearing loss);
  • Sinusitis (persistent sinus infections that are often difficult to treat);
  • Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis).
• Lymphoproliferation is a hallmark of APDS and can present as:
  • Lymphadenopathy (often generalized and can be persistent);
  • Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism);
  • Nodular lymphoid hyperplasia.
    Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract.
• Autoimmune manifestations vary widely and can include:
  • Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia);
  • Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and intussusception). Symptoms of chronic diarrhea and abdominal pain are common.
• Growth delay. Some individuals may experience growth delay, which can be secondary to chronic infections and autoimmune manifestations.

Note: The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2. Growth delay and short stature are notable features of APDS2, while gastrointestinal complications, such as chronic diarrhea and enteropathy, are also more frequently reported in APDS2 compared to APDS1. APDS2 is also associated with delayed tooth eruption due to its overlap with SHORT syndrome, a feature not typically seen in APDS1. Both types share B-cell abnormalities, but APDS2 is characterized by a higher incidence of B-cell lymphopenia, increased transitional B cells, and decreased serum IgA and IgG levels, with increased IgM levels being common to both [Elkaim et al 2016, Oh et al 2021, Maccari et al 2023].

Laboratory findings. The diagnosis of APDS types 1 and 2 can be supported by a range of laboratory findings that reflect the underlying immune dysfunction. Findings include abnormalities in immunoglobulin levels, lymphocyte populations, and specific cellular responses. It is critical to interpret these laboratory results in the context of the clinical presentation.

• Immunoglobulin levels
  • Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation.
  • There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections.
  • Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines).
• Lymphocyte populations
  • Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation.
  • Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [Li et al 2024].
• Functional assays
  • T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished.
  • A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia.
• Tissue biopsy findings. Critical pathologic findings in biologic specimens include nodular lymphoid hyperplasia in airway mucosal and gastrointestinal tract biopsies.

Imaging findings

• Lymphadenopathy and hepatosplenomegaly are common findings on ultrasound and computerized tomography (CT) with evidence of increased fluorodeoxyglucose uptake on positron emission tomography (PET) scans.
• Bronchiectasis and mosaic attenuation can be identified on CT chest imaging.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

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 (see Table 1).

Molecular Diagnosis

The molecular diagnosis of APDS is established in a proband with suggestive findings and one of the following identified by molecular genetic testing (see Table 1):

• A heterozygous pathogenic (or likely pathogenic) gain-of-function variant involving PIK3CD (for APDS1; ~75% of affected individuals) [Jamee et al 2020]
• A heterozygous pathogenic (or likely pathogenic) loss-of-function variant involving PIK3R1 (for APDS2; ~25% of affected individuals) [Jamee et al 2020]

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in PIK3CD or PIK3R1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of APDS, molecular genetic testing approaches can include use of single gene testing or a multigene panel.

• Single-gene testing. Sequence analysis of PIK3CD and PIK3R1 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications, although no deletions or duplications of these genes have been detected in APDS to date.
• An immunodeficiency, inborn errors of immunity or cytopenia multigene panel that includes some or all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of APDS has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of PIK3CD and PIK3R1 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Activated PI3K Delta Syndrome

Clinical Description

Activated PI3K delta syndrome (APDS) is a rare inborn error of immunity characterized primarily by frequent infections, lymphoproliferation, and autoimmune manifestations. To date, at least 250 individuals have been identified with a pathogenic variant in PIK3CD (for APDS1) or PIK3R1 (for APDS2) [Elkaim et al 2016, Coulter et al 2017, Carpier & Lucas 2018, Maccari et al 2018, Jamee et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

It is important to note that the severity and presence of these clinical findings can vary widely among affected individuals. Some may present with mild symptoms, while others experience severe manifestations that significantly impact quality of life. The variability within the spectrum of APDS highlights the importance of individualized care and management strategies.

Table 2.

Activated PI3K Delta Syndrome: Frequency of Select Features

Sinopulmonary infections. Recurrent sinopulmonary infections are nearly universal in individuals with APDS. These infections often begin in childhood and are a hallmark of the disease. Common infections include pneumonia, otitis media, and sinusitis. These infections are typically caused by both respiratory viruses and bacterial pathogens, reflecting the underlying B-cell dysfunction. Prophylactic antibiotics and immunoglobulin replacement therapy are commonly used to reduce the frequency and severity of infections.

Bronchiectasis. Bronchiectasis is a significant complication in individuals with APDS, primarily resulting from recurrent and chronic respiratory infections. The clinical features of bronchiectasis are multifaceted and can substantially impact individuals' quality of life and clinical outcomes.

A hallmark of bronchiectasis in APDS is a chronic productive cough associated with increased frequency of respiratory infections, including pneumonia and bronchitis. These recurrent infections contribute to the progressive destruction and dilation of bronchial walls, perpetuating the cycle of infection and inflammation. Individuals often develop symptoms of obstructive lung disease, including dyspnea, wheezing, and hemoptysis.

High-resolution computed tomography (HRCT) is the imaging modality of choice for diagnosing and evaluating the extent of bronchiectasis. Typical findings on HRCT include bronchial dilatation, lack of tapering of the bronchi, and bronchial wall thickening. Chronic bronchiectasis can lead to several severe complications, including respiratory failure, group 3 pulmonary hypertension leading to cor pulmonale (right-sided heart failure secondary to lung disease).

Lymphoproliferation. Lymphoproliferation in the context of APDS is a hallmark clinical feature characterized by the abnormal proliferation of lymphoid tissue. This may manifest as the following:

• Lymphadenopathy. Enlarged lymph nodes are common, often presenting as generalized lymphadenopathy. This can be extensive and may involve multiple lymph node regions.
• Splenomegaly. Enlargement of the spleen is frequently observed, contributing to abdominal discomfort and potential hypersplenism.
• Tonsillar and adenoidal hypertrophy. Enlargement of the tonsils and adenoids can lead to obstructive symptoms, including sleep apnea and difficulty breathing.
• Mucosal nodular lymphoid hyperplasia. This can occur in the respiratory and gastrointestinal tracts, potentially causing airway obstruction and gastrointestinal symptoms.
• Hepatomegaly. Liver enlargement is also noted in some affected individuals, which may be associated with portal hypertension and other complications.
• Malignancy risk. There is an increased risk of developing B-cell lymphomas and other malignancies, which necessitates vigilant monitoring.

Growth deficiency. Poor growth is observed in approximately half of individuals with APDS [Jamee et al 2020]. It is often multifactorial, resulting from chronic infections, gastrointestinal issues, and possibly metabolic demands due to lymphoproliferation and immune dysregulation. Growth delay is especially common in APDS2 [Maccari et al 2023].

Herpes group virus infection. Herpes virus infections are a significant complication in APDS, affecting up to 49% of individuals [Coulter et al 2017]. These infections include Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella zoster (VZV), and cytomegalovirus (CMV). Chronic active viral infections are common and can lead to further complications such as lymphoproliferation and increased risk of malignancies.

Enteropathy. Enteropathy is a significant complication of APDS, reported in up to half of affected individuals and characterized by chronic diarrhea, abdominal pain, and histologic findings such as Crohn-like colitis and nodular lymphoid hyperplasia [Elkaim et al 2016, Maccari et al 2018, Qiu et al 2022, Vanselow et al 2023a, Rao et al 2024a]. Enteropathy is more common in APDS2 compared to APDS1 [Maccari et al 2023]. The gastrointestinal involvement contributes to malnutrition and growth deficiency.

Lymphoma. Lymphoma is a significant concern in APDS, with an incidence of approximately 12.8% in APDS1 and up to 28% in APDS2 [Elkaim et al 2016]. The most common lymphoma type in APDS is diffuse large B-cell lymphoma. However, there is increased risk of both Hodgkin and non-Hodgkin lymphomas, which is attributed to chronic immune activation and lymphoproliferation. This necessitates vigilant monitoring and early intervention.

Autoimmune cytopenias. Autoimmune cytopenias, such as autoimmune hemolytic anemia and immune thrombocytopenia, are common in APDS, occurring in about 19%-30% of affected individuals [Jamee et al 2020]. These cytopenias often present later in the disease course and can be challenging to manage, requiring immunosuppressive therapies or targeted treatment with leniolisib (see Targeted Therapies) [Schworer et al 2021].

Autoimmune and autoinflammatory disease. Autoimmune and autoinflammatory manifestations are prevalent in many affected individuals [Coulter et al 2017]. These can include autoimmune endocrinopathy, enteropathy, arthritis, and vasculitis. At times, individuals may have already received B-cell depleting therapies (e.g., rituximab) prior to their diagnosis of APDS. This may delay the diagnosis of APDS because the hypogammaglobulinemia can be attributed to B-cell depletion caused by rituximab and the characteristic B-cell immunophenotype of APDS cannot be characterized (low naïve B cells and increased transitional B cells).

Following molecular genetic testing, the pAKT/pS6 functional assay (see Suggestive Findings) can help characterize the immunophenotype following use of immunomodulation. To date, the pAKT/pS6 assay is available on a research basis with plans for Clinical Laboratory Improvement Amendments (CLIA) validation.

Neurodevelopmental delays. Neurodevelopmental delays occur in approximately 19% of individuals with APDS1 and 31% with APDS2 [Coulter et al 2017]. These can manifest as mild cognitive impairment, speech and language delays, and motor developmental delays. The exact mechanisms remain under investigation, but this underscores the need for early developmental assessments and interventions.

Dental manifestations. APDS2 is associated with delayed tooth eruption, due to its overlap with SHORT syndrome (see Genetically Related Disorders). This feature is not typically seen in APDS1.

Phenotype Correlations by Gene

APDS1 is caused by a heterozygous pathogenic gain-of-function variant in PIK3CD, and APDS2 is caused by a heterozygous loss-of-function pathogenic variant in PIK3R1. The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2 [Elkaim et al 2016, Oh et al 2021, Maccari et al 2023].

• Growth delay and short stature are notable features of APDS2 and are more common in APDS2 than in APDS1.
• Gastrointestinal complications, such as chronic diarrhea and enteropathy, are more frequently reported in APDS2 compared to APDS1.
• APDS2 is associated with delayed tooth eruption due to its overlap with SHORT syndrome, a feature not typically seen in APDS1.
• APDS2 is characterized by a higher incidence of B-cell lymphopenia, increased transitional B cells, and decreased serum IgA and IgG levels.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified to date.

Penetrance

Penetrance in APDS is believed to approach 100%. However, there is considerable clinical variability, with presentations ranging from nearly asymptomatic with mild laboratory findings to severe manifestations of the disease [Jamee et al 2020].

Prevalence

The estimated prevalence of APDS is around one in one million [Vanselow et al 2023a, Lougaris et al 2024].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with APDS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Activated PI3K Delta Syndrome: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

Targeted Therapies

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Table 6.

Activated PI3K Delta Syndrome: Targeted Treatment

Role of HSCT in APDS. Hematopoietic stem cell transplantation (HSCT) is emerging as a curative approach for individuals with APDS, particularly those with severe or refractory disease [Okano et al 2019, Dimitrova et al 2022, Vanselow et al 2023b]. It is generally reserved for individuals with severe manifestations such as recurrent, refractory infections, severe lymphoproliferation, or life-threatening complications like cytopenias or enteropathy unresponsive to conventional treatments. Additionally, HSCT can be considered in individuals whose immune dysregulation does not respond to therapies like sirolimus or leniolisib, or for those with progressive organ damage such as bronchiectasis or liver fibrosis caused by chronic immune dysregulation. However, the risk-vs-benefit ratio of HSCT has to be weighed in regard to both the extent of underlying comorbidities (which may preclude HSCT) and donor-related factors (degree of HLA matching).

Studies on HSCT outcomes in APDS provide helpful insights on the role of this treatment modality. In a cohort of 23 individuals, nine underwent HSCT with varying conditioning regimens, achieving an overall survival rate of 86.1% over 30 years despite challenges such as graft failure, viral reactivation, and treatment-related mortality [Okano et al 2019]. Survivors showed significant improvements in immune function and clinical manifestations [Vanselow et al 2023b], highlighting HSCT as a curative strategy, particularly for refractory immune dysregulation and severe lymphoproliferation, noting long-term improvements in immune function despite early complications like graft-vs-host disease. In another cohort, the two-year cumulative incidence of graft failure following first HSCT was 17% overall but 42% if mTOR inhibitors were used in the first year post-HCT, compared to 9% without mTOR inhibitors [Dimitrova et al 2022].

Successful HSCT requires careful pre-transplant optimization, including stabilizing individuals with mTOR inhibitors or PI3Kδ inhibitors as bridging therapies. Conditioning regimens such as fludarabine and treosulfan are critical to balance effective engraftment with minimizing toxicity. HLA-matched donors are ideal, but haploidentical or mismatched donors have also been used with heightened risks. Post-transplant complications, including viral reactivation, graft failure, and transplant-related mortality, remain significant challenges, necessitating early identification and prompt intervention.

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 7).

Table 7.

Activated PI3K Delta Syndrome: Treatment of Manifestations

Role of glucocorticoids in APDS. Glucocorticoids are a cornerstone in the management of gastrointestinal inflammation in APDS. By controlling inflammation, they can improve gut function and potentially enhance the absorption of other medications, such as leniolisib and sirolimus, whose bioavailability may be compromised in the presence of chronic inflammation. In the authors' experience, there have been cases of persistent diarrhea in individuals with APDS despite underwhelming endoscopic findings of inflammation or nodular lymphoid hyperplasia. In these cases, the authors have used off-label high-dose glucocorticoids, typically 1-2 mg/kg/day of methyl prednisolone but up to 5 mg/kg single pulse doses (initiating an intravenous dose, then switching to oral as appropriate) and weaning thereafter. Understandably, the use of glucocorticoids must be carefully balanced due to their potential adverse effects.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended.

Table 8.

Activated PI3K Delta Syndrome: Recommended Surveillance

Evaluation of Relatives at Risk

Molecular genetic testing for the APDS pathogenic variant identified in the proband is recommended for all at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Detailed clinical and laboratory evaluation to assess for possible clinical features related to APDS is recommended for family members who have an APDS pathogenic variant.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The use of sirolimus in pregnancy is not recommended due to limited safety data and potential risks to the developing fetus. Animal studies have shown sirolimus to be harmful to the developing fetus. Therefore, contraception is recommended for females of reproductive age. The same applies for leniolisib, given that animal studies have shown that it interferes with organogenesis. Both leniolisib and sirolimus should therefore be discontinued in individuals planning for pregnancy.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

There are currently two clinical trials evaluating the safety and efficacy of leniolisib in individuals age one to six years (NCT05693129) and four to 11 years old (NCT05438407).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Activated PI3K delta syndrome (APDS) is inherited in an autosomal dominant manner. APDS1 is caused by a heterozygous PIK3CD gain-of-function variant, and APDS2 is caused by a heterozygous PIK3R1 loss-of-function variant.

Risk to Family Members

Parents of a proband

• Approximately 80% of individuals diagnosed with APDS have an affected parent [Elkaim et al 2016].
• Approximately 20% of individuals diagnosed with APDS have the disorder as the result of a de novo PIK3CD gain-of-function variant (for APDS1) or a de novo PIK3R1 loss-of-function variant (for APDS2) [Elkaim et al 2016].
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical evaluation for features of APDS. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, de novo occurrence of an APDS-related gene cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the PIK3CD or PIK3R1 pathogenic variant identified in the proband, the risk to the sibs is 50%.
• Although penetrance of APDS is high among sibs who inherit a PIK3CD or PIK3R1 pathogenic variant, significant intrafamilial clinical variability may be observed; heterozygous sibs may be almost clinically asymptomatic with mild laboratory findings or have severe disease manifestations [Coulter et al 2017, Maccari et al 2023, Yang et al 2023].
• If the proband has a known PIK3CD or PIK3R1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with APDS has a 50% chance of inheriting a PIK3CD or PIK3R1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the APDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PIK3CD encodes phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (also called phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit delta), the p110δ subunit of PI3K. PIK3R1 encodes phosphatidylinositol 3-kinase regulatory subunit alpha (also called phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha), the regulatory p85α unit of PI3K. Pathogenic variants identified in activated PI3K delta syndrome (APDS) typically lead to a gain of function of PIK3CD or loss of function of PIK3R1 with subsequent increased expression of p110δ or decreased expression of p85α. This leads to hyperactivation of the PI3K-AKT-mTOR signaling pathway. This hyperactivation alters normal lymphocyte development and function, leading to the immunodeficiency observed in APDS. Specifically, it causes an increase in transitional B cells and a reduction in naïve B and T cells. This dysregulation contributes to both the immunodeficiency and the autoimmune manifestations seen in affected individuals.

Mechanism of disease causation

• PIK3CD (associated with APDS1). Gain-of-function pathogenic variants that enhance the enzymatic activity of the p110δ protein, a catalytic subunit of PI3K
• PIK3R1 (associated with APDS2). Loss-of-function pathogenic variants affecting the regulatory subunit p85α of PI3K, altering PI3K signaling pathways

Author Notes

Gulbu Uzel, MD (vog.hin.diain@lezug), is actively involved in clinical research regarding individuals with activated PI3K delta syndrome (APDS). Dr Uzel would be happy to communicate with persons who have any questions regarding diagnosis of APDS or other considerations.

Keith Sacco, MD (ten.shn@occas.htiek), is also interested in hearing from clinicians treating families affected by immune dysregulation in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Uzel to inquire about review of PIK3R1 or PIK3CD variants of uncertain significance.

Revision History

• 30 January 2025 (gm) Review posted live
• 15 July 2024 (ks) Original submission

Literature Cited

• Baynes KC, Beeton CA, Panayotou G, Stein R, Soos M, Hansen T, Simpson H, O'Rahilly S, Shepherd PR, Whitehead JP. Natural variants of human p85 alpha phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity. Diabetologia. 2000;43:321-31. [PubMed: 10768093]

• Cant AJ, Chandra A, Munro E, Rao VK, Lucas CL. PI3Kδ pathway dysregulation and unique features of its inhibition by leniolisib in activated PI3Kδ syndrome and beyond. J Allergy Clin Immunol Pract. 2024;12:69-78. [PMC free article: PMC10872751] [PubMed: 37777067]

• Carpier JM, Lucas CL. Epstein-Barr virus susceptibility in activated PI3Kδ syndrome (APDS) immunodeficiency. Front Immunol. 2018;8:2005. [PMC free article: PMC5776011] [PubMed: 29387064]

• Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, Goodlad JR, Farmer G, Steele CL, Leahy TR, Doffinger R, Baxendale H, Bernatoniene J, Edgar JD, Longhurst HJ, Ehl S, Speckmann C, Grimbacher B, Sediva A, Milota T, Faust SN, Williams AP, Hayman G, Kucuk ZY, Hague R, French P, Brooker R, Forsyth P, Herriot R, Cancrini C, Palma P, Ariganello P, Conlon N, Feighery C, Gavin PJ, Jones A, Imai K, Ibrahim MA, Markelj G, Abinun M, Rieux-Laucat F, Latour S, Pellier I, Fischer A, Touzot F, Casanova JL, Durandy A, Burns SO, Savic S, Kumararatne DS, Moshous D, Kracker S, Vanhaesebroeck B, Okkenhaug K, Picard C, Nejentsev S, Condliffe AM, Cant AJ. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139:597-606.e4. [PMC free article: PMC5292996] [PubMed: 27555459]

• Dimitrova D, Nademi Z, Maccari ME, Ehl S, Uzel G, Tomoda T, Okano T, Imai K, Carpenter B, Ip W, Rao K, Worth AJJ, Laberko A, Mukhina A, Neven B, Moshous D, Speckmann C, Warnatz K, Wehr C, Abolhassani H, Aghamohammadi A, Bleesing JJ, Dara J, Dvorak CC, Ghosh S, Kang HJ, Markelj G, Modi A, Bayer DK, Notarangelo LD, Schulz A, Garcia-Prat M, Soler-Palacin P, Karakukcu M, Yilmaz E, Gambineri E, Menconi M, Masmas TN, Holm M, Bonfim C, Prando C, Hughes S, Jolles S, Morris EC, Kapoor N, Koltan S, Paneesha S, Steward C, Wynn R, Duffner U, Gennery AR, Lankester AC, Slatter M, Kanakry JA. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome. J Allergy Clin Immunol. 2022;149:410-421.e7. [PMC free article: PMC8611111] [PubMed: 34033842]

• Elkaim E, Neven B, Bruneau J, Mitsui-Sekinaka K, Stanislas A, Heurtier L, Lucas CL, Matthews H, Deau MC, Sharapova S, Curtis J, Reichenbach J, Glastre C, Parry DA, Arumugakani G, McDermott E, Kilic SS, Yamashita M, Moshous D, Lamrini H, Otremba B, Gennery A, Coulter T, Quinti I, Stephan JL, Lougaris V, Brodszki N, Barlogis V, Asano T, Galicier L, Boutboul D, Nonoyama S, Cant A, Imai K, Picard C, Nejentsev S, Molina TJ, Lenardo M, Savic S, Cavazzana M, Fischer A, Durandy A, Kracker S. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138:210-8.e9. [PubMed: 27221134]

• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]

• Jamee M, Moniri S, Zaki-Dizaji M, Olbrich P, Yazdani R, Jadidi-Niaragh F, Aghamahdi F, Abolhassani H, Condliffe AM, Aghamohammadi A, Azizi G. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): a systematic review. Clin Rev Allergy Immunol. 2020;59:323-33. [PubMed: 31111319]

• Kang JM, Kim SK, Kim D, Choi SR, Lim YJ, Kim SK, Park BK, Park WS, Kang ES, Ko YH, Choe YH, Lee JW, Kim YJ. Successful sirolimus treatment for Korean patients with activated phosphoinositide 3-kinase delta syndrome 1: the first case series in Korea. Yonsei Med J. 2020;61:542-6. [PMC free article: PMC7256007] [PubMed: 32469178]

• Li Q, Wang W, Wu Q, Zhou Q, Ying W, Hui X, Sun B, Hou J, Qian F, Wang X, Sun J. Phenotypic and immunological characterization of patients with activated PI3Kdelta syndrome 1 presenting with autoimmunity. J Clin Immunol. 2024;44:102. [PMC free article: PMC11026262] [PubMed: 38634985]

• Lougaris V, Piane FL, Cancrini C, Conti F, Tommasini A, Badolato R, Trizzino A, Zecca M, De Rosa A, Barzaghi F, Pignata C. Activated phosphoinositde 3-kinase (PI3Kδ) syndrome: an Italian point of view on diagnosis and new advances in treatment. Ital J Pediatr. 2024;50:103. [PMC free article: PMC11106885] [PubMed: 38769568]

• Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15:88-97. [PMC free article: PMC4209962] [PubMed: 24165795]

• Maccari ME, Abolhassani H, Aghamohammadi A, Aiuti A, Aleinikova O, Bangs C, Baris S, Barzaghi F, Baxendale H, Buckland M, Burns SO, Cancrini C, Cant A, Cathébras P, Cavazzana M, Chandra A, Conti F, Coulter T, Devlin LA, Edgar JDM, Faust S, Fischer A, Garcia-Prat M, Hammarström L, Heeg M, Jolles S, Karakoc-Aydiner E, Kindle G, Kiykim A, Kumararatne D, Grimbacher B, Longhurst H, Mahlaoui N, Milota T, Moreira F, Moshous D, Mukhina A, Neth O, Neven B, Nieters A, Olbrich P, Ozen A, Pachlopnik Schmid J, Picard C, Prader S, Rae W, Reichenbach J, Rusch S, Savic S, Scarselli A, Scheible R, Sediva A, Sharapova SO, Shcherbina A, Slatter M, Soler-Palacin P, Stanislas A, Suarez F, Tucci F, Uhlmann A, van Montfrans J, Warnatz K, Williams AP, Wood P, Kracker S, Condliffe AM, Ehl S. 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. Front Immunol. 2018;9:543. [PMC free article: PMC5863269] [PubMed: 29599784]

• Maccari ME, Wolkewitz M, Schwab C, Lorenzini T, Leiding JW, Aladjdi N, Abolhassani H, Abou-Chahla W, Aiuti A, Azarnoush S, Baris S, Barlogis V, Barzaghi F, Baumann U, Bloomfield M, Bohynikova N, Bodet D, Boutboul D, Bucciol G, Buckland MS, Burns SO, Cancrini C, Cathébras P, Cavazzana M, Cheminant M, Chinello M, Ciznar P, Coulter TI, D'Aveni M, Ekwall O, Eric Z, Eren E, Fasth A, Frange P, Fournier B, Garcia-Prat M, Gardembas M, Geier C, Ghosh S, Goda V, Hammarström L, Hauck F, Heeg M, Heropolitanska-Pliszka E, Hilfanova A, Jolles S, Karakoc-Aydiner E, Kindle GR, Kiykim A, Klemann C, Koletsi P, Koltan S, Kondratenko I, Körholz J, Krüger R, Jeziorski E, Levy R, Le Guenno G, Lefevre G, Lougaris V, Marzollo A, Mahlaoui N, Malphettes M, Meinhardt A, Merlin E, Meyts I, Milota T, Moreira F, Moshous D, Mukhina A, Neth O, Neubert J, Neven B, Nieters A, Nove-Josserand R, Oksenhendler E, Ozen A, Olbrich P, Perlat A, Pac M, Schmid JP, Pacillo L, Parra-Martinez A, Paschenko O, Pellier I, Sefer AP, Plebani A, Plantaz D, Prader S, Raffray L, Ritterbusch H, Riviere JG, Rivalta B, Rusch S, Sakovich I, Savic S, Scheible R, Schleinitz N, Schuetz C, Schulz A, Sediva A, Semeraro M, Sharapova SO, Shcherbina A, Slatter MA, Sogkas G, Soler-Palacin P, Speckmann C, Stephan JL, Suarez F, Tommasini A, Trück J, Uhlmann A, van Aerde KJ, van Montfrans J, von Bernuth H, Warnatz K, Williams T, Worth AJJ, Ip W, Picard C, Catherinot E, Nademi Z, Grimbacher B, Forbes Satter LR, Kracker S, Chandra A, Condliffe AM, Ehl S; European Society for Immunodeficiencies Registry Working Party. Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity. J Allergy Clin Immunol. 2023;152:984-96.e10. [PubMed: 37390899]

• Oh J, Garabedian E, Fuleihan R, Cunningham-Rundles C. Clinical manifestations and outcomes of activated phosphoinositide 3-kinase delta syndrome from the USIDNET cohort. J Allergy Clin Immunol Pract. 2021;9:4095-102. [PMC free article: PMC8578310] [PubMed: 34352450]

• Okano T, Imai K, Tsujita Y, Mitsuiki N, Yoshida K, Kamae C, Honma K, Mitsui-Sekinaka K, Sekinaka Y, Kato T, Hanabusa K, Endo E, Takashima T, Hiroki H, Yeh TW, Tanaka K, Nagahori M, Tsuge I, Bando Y, Iwasaki F, Shikama Y, Inoue M, Kimoto T, Moriguchi N, Yuza Y, Kaneko T, Suzuki K, Matsubara T, Maruo Y, Kunitsu T, Waragai T, Sano H, Hashimoto Y, Tasaki K, Suzuki O, Shirakawa T, Kato M, Uchiyama T, Ishimura M, Tauchi T, Yagasaki H, Jou ST, Yu HH, Kanegane H, Kracker S, Durandy A, Kojima D, Muramatsu H, Wada T, Inoue Y, Takada H, Kojima S, Ogawa S, Ohara O, Nonoyama S, Morio T. Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase delta syndrome type 1. J Allergy Clin Immunol. 2019;143:266-75. [PubMed: 29778502]

• Qiu L, Wang Y, Tang W, Yang Q, Zeng T, Chen J, Chen X, Zhang L, Zhou L, Zhang Z, An Y, Tang X, Zhao X. Activated phosphoinositide 3-kinase delta syndrome: a large pediatric cohort from a single center in China. J Clin Immunol. 2022;42:837-50. [PubMed: 35296988]

• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]

• Rao VK, Kulm E, Grossman J, Buchbinder D, Chong H, Bradt J, Webster S, Sediva A, Dalm VA, Uzel G. Long-term treatment with selective PI3Kdelta inhibitor leniolisib in adults with activated PI3Kdelta syndrome. Blood Adv. 2024a;8:3092-108. [PMC free article: PMC11222951] [PubMed: 38593221]

• Rao VK, Kulm E, Sediva A, Plebani A, Schuetz C, Shcherbina A, Dalm VA, Trizzino A, Zharankova Y, Webster S, Orpia A, Korholz J, Lougaris V, Rodina Y, Radford K, Bradt J, Relan A, Holland SM, Lenardo MJ, Uzel G. Interim analysis: open-label extension study of leniolisib for patients with APDS. J Allergy Clin Immunol. 2024b;153:265-274.e9. [PMC free article: PMC10841669] [PubMed: 37797893]

• Rao VK, Webster S, Sediva A, Plebani A, Schuetz C, Shcherbina A, Conlon N, Coulter T, Dalm VA, Trizzino A, Zharankova Y, Kulm E, Korholz J, Lougaris V, Rodina Y, Radford K, Bradt J, Kucher K, Relan A, Holland SM, Lenardo MJ, Uzel G. A randomized, placebo-controlled phase 3 trial of the PI3Kdelta inhibitor leniolisib for activated PI3Kdelta syndrome. Blood. 2023;141:971-83. [PMC free article: PMC10163280] [PubMed: 36399712]

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]

• Schworer SA, Francis OL, Johnson SM, Smith BD, Gold SH, Smitherman AB, Wu EY. Autoimmune cytopenia as an early and initial presenting manifestation in activated pi3 kinase delta syndrome: case report and review. J Pediatr Hematol Oncol. 2021;43:281-7. [PMC free article: PMC8542580] [PubMed: 34054047]

• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]

• Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, Klein C, Morio T, Oksenhendler E, Picard C, Puel A, Puck J, Seppänen MRJ, Somech R, Su HC, Sullivan KE, Torgerson TR, Meyts I. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42:1473-507. [PMC free article: PMC9244088] [PubMed: 35748970]

• Tharin Z, Richard C, Derangère V, Ilie A, Arnould L, Ghiringhelli F, Boidot R, Ladoire S. PIK3CA and PIK3R1 tumor mutational landscape in a pan-cancer patient cohort and its association with pathway activation and treatment efficacy. Sci Rep. 2023;13:4467. [PMC free article: PMC10024711] [PubMed: 36934165]

• Vanselow S, Hanitsch L, Hauck F, Korholz J, Maccari ME, Meinhardt A, Sogkas G, Schuetz C, Grimbacher B. Future directions in the diagnosis and treatment of APDS and IEI: a survey of German IEI centers. Front Immunol. 2023a;14:1279652. [PMC free article: PMC10588788] [PubMed: 37868971]

• Vanselow S, Wahn V, Schuetz C. Activated PI3Kdelta syndrome - reviewing challenges in diagnosis and treatment. Front Immunol. 2023b;14:1208567. [PMC free article: PMC10432830] [PubMed: 37600808]

• Wang Y, Wang W, Liu L, Hou J, Ying W, Hui X, Zhou Q, Liu D, Yao H, Sun J, Wang X. Report of a Chinese cohort with activated phosphoinositide 3-kinase delta syndrome. J Clin Immunol. 2018;38:854-63. [PubMed: 30499059]

• Wang S, Wang W, Zhang X, Gui J, Zhang J, Guo Y, Liu Y, Han L, Liu Q, Li Y, Sun N, Liu Z, Du J, Tai J, Ni X. A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation. Orphanet J Rare Dis. 2021;16:208. [PMC free article: PMC8106842] [PubMed: 33964933]

• Yang X, Xi R, Bai J, Pan Y. Successful haploidentical hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: case report and literature review. Medicine (Baltimore). 2023;102:e32816. [PMC free article: PMC9902017] [PubMed: 36749229]