Diagnosing APDS

APDS is a progressive and underdiagnosed inborn error of immunity (IEI) with diverse symptoms. It can be less difficult to uncover if you know what to look for.

APDS is inherited in an autosomal dominant manner, meaning that a person needs a causative variant from only one parent to have it themselves. ^1-4

De novo variants have also been observed, and while the prevalence has not been fully assessed, a large cohort suggests that around 20% of APDS patients may have de novo variants. ^1-5

APDS may be difficult to trace based on clinical history as symptoms can vary even within the same family. ¹

Steps to Diagnose APDS

1
Recognize the clinical manifestations of APDS - especially in combination: ^6-8

Immune deficiency

Severe, recurrent sinopulmonary infections^6,9
Severe, recurrent, and persistent herpesvirus, especially EBV, CMV^9-11,6,12
Recalcitrant or rare infections (bacterial, viral, and fungal), including abscesses, skin lesions/ infections, eye infections, and oral ulcerations^6,9-11
Low IgA or IgG levels^6,11
High IgM levels^6,11

Immune
dysregulation ^6,11

Autoimmunity, particularly cytopenias
Lymphoproliferation
Lymphoma
Enteropathy, including failure to thrive

Immune deficiency and/or dysregulation ^14-16

End organ damage (e.g., bronchiectasis)

Neurodevelopmental ^6,10

Neurodevelopmental delay (current or historical)
Failure to thrive

A personal or family history of any of these symptoms should raise suspicion of Pls such as APDS. ^9,15

2
Recognize the common timeline of pathologies seen in APDS ^6,14,15

A suboptimal response to treatment should raise suspicion of an IEI, like APDS ¹³

*Onset of all symptoms is heterogenous and typically progressive, varying from patient to patient

3
Make A Differential Diagnosis

According to Nicholas Hartog, MD “Patients may have multiple complications though lack of a unified diagnosis.” Some individuals may have been initially diagnosed with other primary immunodeficiencies such as Common Variable Immune Deficiency (CVID) or Hyper IgM Syndromes. Individuals whose main symptoms are autoimmune cytopenias, lymphadenopathy, splenomegaly, hepatomegaly, nodular lymphoid hyperplasia or lymphoma may have been initially diagnosed with hematological disorders such as Autoimmune Lymphoproliferative Syndrome (ALPS), Evans syndrome, or simply refractory cytopenias.

Initial diagnoses for 39 patients with APDS ⁹

4
Confirm your Suspicion with a genetic test

Genetic testing is available from various clinical laboratories and the cost of genetic testing may be covered by insurance or other sources. NavigateAPDS offers an additional option for accessing genetic testing.

Access the navigateAPDS genetic test - a fast, Sponsored genetic panel

Pharming Healthcare, Inc. provides financial support for the sponsored genetic testing program and information about the program to healthcare professionals and others. Tests and services, however, are performed by Invitae (now part of Labcorp). Healthcare professionals must confirm that patients meet certain criteria to use the program. Pharming Healthcare, Inc., and other third parties, including commercial organizations, may receive information about patients, the healthcare professionals ordering tests and the test results, but at no time is any patient identifiable information provided to Pharming Healthcare, Inc. Also, for tests involving patients covered under governmental health insurance programs such as Medicare and Medicaid, no information regarding the healthcare professional ordering the test is provided to Pharming Healthcare, Inc. Genetic testing and counseling are available in the US, Canada, and Puerto Rico. Healthcare professionals and patients who participate in the sponsored genetic testing program have no obligation to recommend, purchase, order, prescribe, promote, administer, use, or support any other products or services from Invitae (now part of Labcorp), or from third parties or commercial organizations. Patients who participate in the sponsored genetic testing program are free to use the information received through the program to inform their and their physician’s healthcare decision-making in any way they deem appropriate.

Learn more about the navigateAPDS genetic testing program and eligibility criteria.

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

Stay informed

PI is also referred to as an Inborn Error of Immunity (IEI).

References:

1. 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 2. AAngulo 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 3. 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 4. 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 5. 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 6. Coulter TI, et al. J Allergy Clin Immunol. 2017;139(2):597-606.e4. 7. Walter JE, et al. J Allergy Clin Immunol Pract. 2016;4(6):1089-1100. 8. Kubala SA, et al. Poster presented at: CIS 2021 Annual Meeting; April 14-17, 2021 9. Jamee M, et al. Clin Rev Allergy Immunol. 2020;59(3):323-333. 10. Maccari ME, et al. Front Immunol. 2018;9:543. 11. Elkaim E, et al. J Allergy Clin Immunol. 2016;138(1):210-218. 12. Carpier JM, Lucas CL.Front Immunol. 2018;8:200 13. Castagnoli R, et al. World Allergy Organ J. 2021;14(2):100513 14. Angulo I, et al. Science. 2013;342(6160):866-871 15. Lucas CL, et al. Nat Immunol. 2014;15(1):88-97. 16. Condliffe AM, Chandra A. Front Immunol. 2018;9:338.

Diagnosing APDS

APDS is a progressive and underdiagnosed inborn error of immunity (IEI) with diverse symptoms. It can be less difficult to uncover if you know what to look for.

Steps to Diagnose APDS

1
Recognize the clinical manifestations of APDS - especially in combination: ^6-8

Immune deficiency

Immune
dysregulation ^6,11

Immune deficiency and/or dysregulation ^14-16

Neurodevelopmental ^6,10

A personal or family history of any of these symptoms should raise suspicion of Pls such as APDS. ^9,15

2
Recognize the common timeline of pathologies seen in APDS ^6,14,15

A suboptimal response to treatment should raise suspicion of an IEI, like APDS ¹³

3
Make A Differential Diagnosis

Initial diagnoses for 39 patients with APDS ⁹

4
Confirm your Suspicion with a genetic test

Access the navigateAPDS genetic test - a fast, Sponsored genetic panel

Learn more about the navigateAPDS genetic testing program and eligibility criteria.

Stay informed

References:

Site Map:

APDS Resources:

Diagnosing APDS

APDS is a progressive and underdiagnosed inborn error of immunity (IEI) with diverse symptoms. It can be less difficult to uncover if you know what to look for.

Steps to Diagnose APDS

1 Recognize the clinical manifestations of APDS - especially in combination: 6-8

Immune deficiency

Immune dysregulation 6,11

Immune deficiency and/or dysregulation 14-16

Neurodevelopmental 6,10

A personal or family history of any of these symptoms should raise suspicion of Pls such as APDS. 9,15

2 Recognize the common timeline of pathologies seen in APDS 6,14,15

A suboptimal response to treatment should raise suspicion of an IEI, like APDS 13

3 Make A Differential Diagnosis

Initial diagnoses for 39 patients with APDS 9

4 Confirm your Suspicion with a genetic test

Access the navigateAPDS genetic test - a fast, Sponsored genetic panel

Learn more about the navigateAPDS genetic testing program and eligibility criteria.

Stay informed

References:

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1
Recognize the clinical manifestations of APDS - especially in combination: ^6-8

Immune
dysregulation ^6,11

Immune deficiency and/or dysregulation ^14-16

Neurodevelopmental ^6,10

A personal or family history of any of these symptoms should raise suspicion of Pls such as APDS. ^9,15

2
Recognize the common timeline of pathologies seen in APDS ^6,14,15

A suboptimal response to treatment should raise suspicion of an IEI, like APDS ¹³

3
Make A Differential Diagnosis

Initial diagnoses for 39 patients with APDS ⁹

4
Confirm your Suspicion with a genetic test