SUMMARY
1. PIK3CD gain of function mutation is an autosomal dominant disease characterized by a CVID, combine immunodeficiency or hyper IgM phenotype, autoimmunity and increased risk of malignancy (B cell lymphoma). Onset of symptoms occurs around infancy to early childhood.
2. PIK3CD gain of function mutations result in overactivity of the PI3K signaling pathway with hyperactivation of mammalian target of rapamycin (mTOR) and increased terminal effector T cell differentiation (however these cells exhibit evidence of senescence and have impaired IL-2 secretion and proliferation).
3. Clinically patients suffer from recurrent sinopulmonary infections, bacterial skin infections and abscesses, warts, failure to thrive and CMV/EBV viremia. Autoimmune manifestations include cytopenia, inflammatory bowel disease and autoimmune primary sclerosing cholangitis. Patients may also develop EBV/CMV induced lymphoproliferation, hepatosplenomegaly and malignancy (lymphoma).
4. Patients may have reduced IgG or IgA levels and impaired responses to protein or polysaccharide vaccinations. Patients may also have reduced T and B cells, an advanced naïve to memory T cell ratio and reduced NK cell cytotoxicity.
5. Normal or elevated IgM appears to be a key laboratory finding.
6. Patients require uninterrupted immunoglobulin replacement therapy for the antibody deficiency component of their disease.
7. Treatment with Rapamycin to inhibit mTOR can improve autoimmune disease and partially restore naïve T cell numbers
OVERVIEW
PIK3CD gain of function mutation is an autosomal dominant disease characterized by a CVID, combine immunodeficiency or hyper IgM phenotype, autoimmunity and increased risk of malignancy (B cell lymphoma). Onset of symptoms occurs around infancy to early childhood.
Clinically patients suffer from recurrent sinopulmonary infections, bacterial skin infections and abscesses, warts, failure to thrive and CMV/EBV viremia. Autoimmune manifestations include cytopenia, inflammatory bowel disease and autoimmune primary sclerosing cholangitis. Patients may also develop EBV/CMV induced lymphoproliferation, hepatosplenomegaly and malignancy (lymphoma).
Patients may have reduced IgG or IgA levels and impaired responses to protein or polysaccharide vaccinations. Normal or elevated IgM appears to be a key laboratory finding. Patients may also have reduced T and B cells, an advanced naïve to memory T cell ratio and reduced NK cell cytotoxicity.
PATHOGENESIS
PIK3CD gain of function mutations result in overactivity of the PI3K signaling pathway with hyperactivation of mammalian target of rapamycin (mTOR) and increased terminal effector T cell differentiation (however these cells exhibit evidence of senescence and have impaired IL-2 secretion and proliferation). The majority of the reported cases to date were due to the missense mutation E1021K.
DIFFERENTIAL DIAGNOSIS
Other conditions that cause a CVID phenotype with autoimmunity include CTLA-4 deficiency, LRBA deficiency and STAT3 gain of function mutations. Hyper IgM syndromes, combined immunodeficiencies and “leaky” SCID would also be on the differential.
EVALUATION
Papillon-Lefevre syndrome should be suspected in patients presenting with hyperkeratosis of the palms and soles as well as severe gingival inflammation resulting in loss of dentition.
Step 1: Quantitative and Functional humoral/cell-mediated Evaluation
- Quantitative immunoglobulins (IgG, IgM, IgA)
- Antibody titers to vaccine antigens
- Flow cytometry for B-cell, T-cell, and NK cell numbers
- Lymphocyte flow cytometry for B-cell subpopulations
- Lymphocyte proliferation to Mitogens/Antigens
- Patients can have have low to normal IgG, and gA levels. IgM levels are often elevated – this can be a useful clinical clue. Specific vaccine titers to protein (tetanus, diphtheria) and polysaccharide antigens (strep pneumoniae) may be reduced. B and T cell numbers may be reduced. The naïve to memory T cell ratio is advanced. Lymphocyte proliferation to mitogens/antigens is reduced.
Step 2: Genetic Testing
- PIK3CD mutation analysis
- Individual gene sequencing is commercially available. Testing could also be accomplished by whole exome sequencing.
MANAGEMENT
Replacement of serum IgG with monthly IVIG or weekly subcutaneous (SC) Ig is the cornerstone of therapy (400-600 mg/kg per month). Patients who maintain trough IgG levels above 700-900mg/dl have fewer infectious complications. SCIg is ideal for patients who benefit from maintaining steady serum levels of immunoglobulins or who are unable to tolerate IVIG due to adverse side effects (headache, chills, nausea, thrombotic events).
The addition of prophylactic antibiotics can be considered in patients who continue to have infections despite appropriate immunoglobulin replacement.
Rapamycin therapy (to inhibit the mTOR pathway) can be very effective in addressing the autoimmune manifestations of this disease and also partially restores the naïve T cell compartment.
RESOURCES
Diagnostic Resources
1. Quantitative Immunoglobulin levels and specific antibody responses to vaccines (readily available at many academic centers and commercial laboratories)
2. Lymphocyte Subsets by Flow Cytometry for T-cell (CD3, CD4, CD8), B-cell (CD19), and NK cell (CD16/56). A CBC with differential needs to be ordered with each test in order to calculate absolute lymphocyte numbers.
- This test is commonly available at many academic centers as well as commercial laboratories
3. Switched Memory B-cells (CD27+IgM-IgD-) by Flow Cytometry
- Children’s Hospital of Philadelphia – Basic Lymphocyte Panel (have pdf of CHOP immunology test requisition and CHOP b cell panel sample requirements)
- Cincinnati Children’s Diagnostic Immunology Laboratory
4. PI3CKD gene sequencing
- Cincinnati Childrens molecular genetics
Literature Resources
1. Angulo 2013
Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage
2. Lukas 2014
Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency