APDS Diagnosis for Hematologists & Oncologists

Hematologists/oncologists may encounter patients with primary immunodeficiencies
like APDS with the following manifestations:

Lymphoproliferation 1,2

  • Includes lymphadenopathy, splenomegaly, hepatomegaly, and/or nodular lymphoid hyperplasia

Autoimmune cytopenias 1,2

  • A substantial portion (>15%) of patients with autoimmune cytopenias have underlying primary immunodeficiencies such as APDS3-4
  • Patients with primary immunodeficiencies are at a much higher risk for autoimmunity3
  • Autoimmune cytopenia: 120x higher
  • Pediatric autoimmune hemolytic anemia (AIHA): 830x higher
  • Immune thrombocytopenic purpura (ITP): 60x higher

Malignancy (primarily lymphoma) 1,2

  • Lymphoma was the initial diagnosis for 21% of patients with APDS5
  • Risk of lymphoma is 8-10x higher among patients with primary immunodeficiencies6
  • Lymphoma treatment failure could indicate a primary immunodeficiency7

Primary immunodeficiencies like APDS should be considered in a differential diagnosis for unusual or refractory lymphoproliferation, autoimmune cytopenias, or malignancy 7-8

Clinical Suspicion

  • Recurrent or refractory ITP or AIHA
  • Adenopathy or splenomegaly
  • Multiple autoimmune cytopenias
  • Unusual lymphoma presentation (E.g. in children)

Genetic Testing

Primary immunodeficiency genetic panel

The only way to diagnose APDS and other primary immunodeficiencies is through genetic testing. 12

APDS can resemble autoimmune lymphoproliferative syndrome (ALPS) and should be considered a differential diagnosis. 10-11

Lymphadenopathy, splenomegaly, cytopenias, and lymphoma are
common manifestations of both APDS and ALPS. Physicians of patients with probable but not definitive ALPS may consider referring to an immunologist for genetic testing, or ordering a primary immunodeficiency genetic testing panel.

Genetic testing of patients with hematological manifestations may reveal underlying primary immunodeficiencies that have treatment options specific to the particular gene identified. 4-8

In a study of 80 patients with pediatric Evans syndrome, 40% were discovered to have variants in genes involved with primary immunodeficiency, of which 29 patients were identified with variants that have targeted treatment options. 4


Learn about a sponsored, no-charge genetic test and counseling for APDS.

APDS is inherited in an autosomal dominant manner, meaning that a person needs a pathalogical variant from only one parent to have it themselves.
photo of family to show inheritance gene of APDS

De novo variants have also been observed, and while the prevalence has not been fully assessed, a large cohort suggests that around 20% of patients may have de novo variants. 2,13-16

However, APDS may be difficult to trace based on clinical history as symptoms can vary even within the same family.13

As there is a 50% of chance of APDS being passed from parent to child, family members of patients with APDS should also be genetically tested.

Family members of diagnosed APDS patients should also be genetically tested and counseled.

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  1. Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606.e4. doi:10.1016/j.jaci.2016.06.021
  2. Elkaim E, Neven B, Bruneau J, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study. J Allergy Clin Immunol. 2016;138(1):210-218.e9. doi:10.1016/j.jaci.2016.03.022
  3. Fischer A, Provot J, Jais JP, Alcais A, Mahlaoui N; members of the CEREDIH French PID study group. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388-1393.e8. doi:10.1016/j.jaci.2016.12.978
  4. Hadjadj J, Aladjidi N, Fernandes H, et al. Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes. Blood. 2019;134(1):9-21. doi:10.1182/blood-2018-11-887141
  5. Jamee M, Moniri S, Zaki-Dizaji M, et al. Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review. Clin Rev Allergy Immunol. 2020;59(3):323-333. doi:10.1007/s12016-019-08738-9
  6. Mayor PC, Eng KH, Singel KL, et al. Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry. J Allergy Clin Immunol. 2018;141(3):1028-1035. doi:10.1016/j.jaci.2017.05.024
  7. Shapiro RS. Malignancies in the setting of primary immunodeficiency: Implications for hematologists/oncologists. Am J Hematol. 2011;86(1):48-55. doi:10.1002/ajh.21903
  8. Rotz SJ, Ware RE, Kumar A. Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults [published correction appears in Pediatr Blood Cancer. 2019 Apr;66(4):e27581]. Pediatr Blood Cancer. 2018;65(10):e27260. doi:10.1002/pbc.27260
  9. Sánchez-Ramón S, Bermúdez A, González-Granado LI, et al. Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs, Diagnosis, and Management. Front Immunol. 2019;10:586. Published 2019 Mar 26. doi:10.3389/fimmu.2019.00586
  10. Kulm E, et al. Oral abstract presented at: 62nd Annual ASH Meeting; December 5-8, 2020.
  11. Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118(22):5741-5751. doi:10.1182/blood-2011-07-325217
  12. Chinn IK, et al. J Allergy Clin Immunol. 2020;145(1):46-69.
  13. Lucas CL, Kuehn HS, Zhao F, et al. 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(1):88-97. doi:10.1038/ni.2771
  14. Angulo I, Vadas O, Garçon F, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866-871. doi:10.1126/science.1243292
  15. Lucas CL, Zhang Y, Venida A, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211(13):2537-2547. doi:10.1084/jem.20141759
  16. Deau MC, Heurtier L, Frange P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene [published correction appears in J Clin Invest. 2015 Apr;125(4):1764-5]. J Clin Invest. 2014;124(9):3923-3928. doi:10.1172/JCI75746