Activated PI3K-delta syndrome

Activated PI3K-delta syndrome is a disorder that impairs the immune system. Individuals with this condition often have low numbers of white blood cells (lymphopenia), particularly B cells and T cells. Normally, these cells recognize and attack foreign invaders, such as viruses and bacteria, to prevent infection. Beginning in childhood, people with activated PI3K-delta syndrome develop recurrent infections, particularly in the lungs, sinuses, and ears. Over time, recurrent respiratory tract infections can lead to a condition called bronchiectasis, which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems. People with activated PI3K-delta syndrome may also have chronic active viral infections, commonly Epstein-Barr virus or cytomegalovirus infections.

Another possible feature of activated PI3K-delta syndrome is abnormal clumping of white blood cells. These clumps can lead to enlarged lymph nodes (lymphadenopathy), or the white blood cells can build up to form solid masses (nodular lymphoid hyperplasia), usually in the moist lining of the airways or intestines. While lymphadenopathy and nodular lymphoid hyperplasia are noncancerous (benign), activated PI3K-delta syndrome also increases the risk of developing a form of cancer called B-cell lymphoma.

The prevalence of activated PI3K-delta syndrome is unknown.

Activated PI3K-delta syndrome is caused by mutations in the PIK3CD gene, which provides instructions for making a protein called p110 delta (p110δ). This protein is one piece (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K), which turns on signaling pathways within cells. The version of PI3K containing the p110δ subunit, called PI3K-delta, is specifically found in white blood cells, including B cells and T cells. PI3K-delta signaling is involved in the growth and division (proliferation) of white blood cells, and it helps direct B cells and T cells to mature (differentiate) into different types, each of which has a distinct function in the immune system.

PIK3CD gene mutations involved in activated PI3K-delta syndrome lead to production of an altered p110δ protein. A PI3K-delta enzyme containing the altered subunit is abnormally turned on (activated). Studies indicate that overactive PI3K-delta signaling alters the differentiation of B cells and T cells, leading to production of cells that cannot respond to infections and that die earlier than usual. Lack of functioning B cells and T cells makes it difficult for people with this disorder to fight off bacterial and viral infections. Overactivation of PI3K-delta signaling can also stimulate abnormal proliferation of white blood cells, leading to lymphadenopathy and nodular lymphoid hyperplasia in some affected individuals. An increase in B cell proliferation in combination with reduced immune system function may contribute to development of B-cell lymphoma.

Genetic Testing Information

• Genetic Testing Registry: Immunodeficiency 14

Patient Support and Advocacy Resources

• Disease InfoSearch
• National Organization for Rare Disorders (NORD)

Research Studies from ClinicalTrials.gov

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• IMMUNODEFICIENCY 14

Scientific Articles on PubMed

• PubMed

• Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debre M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17. Citation on PubMed or Free article on PubMed Central
• Crank MC, Grossman JK, Moir S, Pittaluga S, Buckner CM, Kardava L, Agharahimi A, Meuwissen H, Stoddard J, Niemela J, Kuehn H, Rosenzweig SD. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J Clin Immunol. 2014 Apr;34(3):272-6. doi: 10.1007/s10875-014-0012-9. Epub 2014 Mar 8. Citation on PubMed or Free article on PubMed Central
• Jou ST, Chien YH, Yang YH, Wang TC, Shyur SD, Chou CC, Chang ML, Lin DT, Lin KH, Chiang BL. Identification of variations in the human phosphoinositide 3-kinase p110delta gene in children with primary B-cell immunodeficiency of unknown aetiology. Int J Immunogenet. 2006 Oct;33(5):361-9. doi: 10.1111/j.1744-313X.2006.00627.x. Citation on PubMed
• Kracker S, Curtis J, Ibrahim MA, Sediva A, Salisbury J, Campr V, Debre M, Edgar JD, Imai K, Picard C, Casanova JL, Fischer A, Nejentsev S, Durandy A. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase delta syndrome. J Allergy Clin Immunol. 2014 Jul;134(1):233-6. doi: 10.1016/j.jaci.2014.02.020. Epub 2014 Apr 1. No abstract available. Citation on PubMed or Free article on PubMed Central
• 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 p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014 Jan;15(1):88-97. doi: 10.1038/ni.2771. Epub 2013 Oct 28. Citation on PubMed or Free article on PubMed Central