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 , and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in . 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 (for APDS1) or (for APDS2) identified by molecular genetic testing.

MANAGEMENT

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. 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. 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. 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 gain-of-function variant (for APDS1) or loss-of-function variant (for APDS2). Once the or pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.