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The only way to definitively diagnose APDS is through genetic testing1,2
APDS is inherited in an autosomal dominant manner, meaning that a person needs a pathological variant from only one parent to have it themselves,1-4 although studies in one large cohort suggests that around 20% of APDS patients may have de novo variants.5 Even within families, APDS may be difficult to trace due to the wide variety of clinical manifestations.
The heterogeneity of APDS symptomology frequently results in numerous referrals, with some patients seeing up to 6 different specialists over a period of 7-8 years on average, while receiving various symptomatic treatments, before diagnosis.
The presence of a combination of clinical symptoms and laboratory features, as follows, would make a possible diagnosis of APDS more likely6,7:
Reducing the time to diagnosis for APDS increases the chances of preventing further manifestation of the symptoms.
| Laboratory test | Typical APDS findings |
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Complete blood count with differential |
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Ig levels |
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Vaccine challenge |
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Flow cytometry |
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Haematologists/oncologists may encounter patients with primary immunodeficiencies like APDS with the following manifestations:
Lymphoproliferation1,2
Autoimmune cytopenias1,2
Malignancy (primarily lymphoma)1,2
Genetic screening should be considered for these patients. In addition, patients with the following should raise clinical suspicion and be referred for genetic testing for APDS:
Patients with APDS can be misdiagnosed with autoimmune lymphoproliferative syndrome (ALPS) as lymphadenopathy, splenomegaly, cytopenias and lymphoma are common manifestations of both conditions.5,6 Patients with probable but not definitive ALPS should be referred for genetic testing to confirm the diagnosis.
Genetic testing is the only way to diagnose APDS; existing CVID patients should be screened for APDS
As genetic testing is the only way to definitively diagnose APDS,1,2 people with at least two of the following complications should be considered for genetic testing:3,4
Genetic testing may lead to targeted therapies
Genetic testing of patients with haematological manifestations may reveal underlying primary immunodeficiencies that have treatment options specific to the particular gene identified.1-5 In a study of 80 patients with paediatric 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.1 Even for patients with PIDs without dedicated therapies, a specific diagnosis provides HCPs with guidance on the potential development of manifestations and allows prospective monitoring for these, such as assessments for enteropathy and malignancy. Genetic diagnosis also allows patients access to specific monogenetic support groups, so they can be part of a community of people who share exactly the same condition. Furthermore, patients can receive appropriate family planning counselling, allowing arrangements to be made as required.1-5
APDS is inherited in an autosomal dominant manner.1-5 However, 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.
As nearly half (40%) of patients diagnosed with APDS have a family history of PI,6 a careful family history may be especially useful in diagnosis;5,6 however, symptoms frequently do not present in the same manner within a family.7
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.4
APD-INT-2022-0039 Date of preparation: July 2022
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