Diagnosing APDS

APDS is a progressive and rare inborn error of immunity (IEI) with diverse symptoms. Knowing what to look for may help you uncover it.1,2

APDS is inherited in an autosomal dominant pattern, meaning that a person needs a pathological variant from only one parent to have it themselves.1
APDS may be difficult to trace based on clinical history as symptoms can vary even within the same family.2

Steps to Diagnosing APDS

1
Recognize the clinical manifestations of APDS

Immune deficiency

  • Severe, recurrent sinopulmonary infections1
  • Severe, recurrent, and persistent herpesvirus, especially EBV, CMV1
  • Recalcitrant or rare infections (bacterial, viral, and fungal), including abscesses, skin lesions/ infections, eye infections, and oral ulcerations1,3
  • Low IgA or IgG levels3
  • High IgM levels3

Immune dysregulation1

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

Immune deficiency and/or dysregulation4

  • End organ damage (e.g., bronchiectasis)

Neurodevelopment1,4

  • 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.5

2
Recognize the common timeline of pathologies seen in APDS1,5

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

Onset of all symptoms is heterogeneous and typically progressive, varying from patient to patient.

3
Make A Differential Diagnosis

Some individuals may be misdiagnoised 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 be misdiagnosed with hematological disorders such as Autoimmune Lymphoproliferative Syndrome (ALPS) and Evans syndrome.

Initial diagnoses for 39 patients with APDS5

Adapted from Jamee M, et al.5
CVID: common variable immunodeficiency; CID: combined immunodeficiency; HIGM: hyper IgM syndromes; XLA: X-linked agammaglobulinemia; ALPS: autoimmune lymphoproliferative syndrome.

4
Confirm your Suspicion with a genetic test

Access the navigateAPDS genetic test - a fast genetic panel

The navigateAPDS testing program helps eliminate barriers to genetic testing and increases certainty in obtaining a correct diagnosis by enabling patients suspected of having APDS, and their family members, to have access to genetic testing and counseling.

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

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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.

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

References:

1. Redenbaugh V, Coulter T. Disorders related to PI3Kδ hyperactivation: Characterizing the clinical and immunological features of activated PI3-kinase delta syndromes. Front Pediatr. 2021;9:702872. 2. Vanselow S, et al. Activated PI3Kδ syndrome – reviewing challenges in diagnosis and treatment. Front Immunol. 2023;14:1208567. 3. Coulter TI, 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. 4. Nunes-Santos CJ, et al. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676–1687. 5. Jamee 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.

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