Clinical Guidance

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

Source: GeneReviews — "Activated PI3K Delta Syndrome"

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 .

Source: GeneReviews — "Activated PI3K Delta Syndrome"

Diagnostic Criteria

No consensus clinical diagnostic criteria for activated PI3K delta syndrome (APDS) have been published.

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

Source: GeneReviews — "Activated PI3K Delta Syndrome"

Differential Diagnosis

Table 4. Genes of Interest in the Differential Diagnosis of Activated PI3K Delta Syndrome

Management Guidelines

No clinical practice guidelines for activated PI3K delta syndrome (APDS) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with APDS, the evaluations summarized (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

System/Concern | Evaluation | Comment

General

| Comprehensive physical exam | To assess for presence of lymphadenopathy, splenomegaly, hepatomegaly

Infection history

| • Detailed review of infection history

• EBV, CMV, HSV PCR in blood relevant serologic testing

• JCV PCR if patient received rituximab1

| To identify patterns indicative of immunodeficiency

Immunodeficiency

| • CBC w/differential

• Immunoglobulin levels (IgG, IgA, IgM, IgE)

• Lymphocyte subset analysis incl nave/memory T cells B-cell subsets

• Vaccine-specific antibody titers

| To evaluate immune function identify immunodeficiency

Lymphoproliferation

| Imaging studies (e.g., ultrasound, CT, MRI) | To detect organomegaly lymphadenopathy

• B-cell clonality studies by V-beta spectratyping

• LDH, EBV/CMV PCR

| To evaluate for susceptibility to lymphoproliferative disorders

Pulmonary

| • Spirometry

• Consider chest CT

| To detect underlying respiratory issues

Gastrointestinal

| • Endosc...

Source: GeneReviews — "Activated PI3K Delta Syndrome"

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.

Source: GeneReviews — "Activated PI3K Delta Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 8. Activated PI3K Delta Syndrome: Recommended Surveillance

Source: GeneReviews — "Activated PI3K Delta Syndrome"