Primary antibody deficiencies

PADs present clinically with recurrent and severe bacterial infections. These typically involve the upper and lower respiratory tracts (otitis media, sinusitis, bronchitis, and pneumonia) and the gastrointestinal tract; conjunctivitis, skin infections, and invasive infections such as meningitis, sepsis, septic arthritis, and empyema are also commonly seen at presentation.

The clinical spectrum is heterogeneous, ranging from infantile to adult-onset disease. Agammaglobulinemias such as typically present in the first two years of life, once transplacentally acquired maternal IgG has waned; affected individuals are usually recognised before five years of age.

, the most clinically significant PAD, is typically diagnosed during adult life in approximately 70% of cases, generally between 20 and 40 years of age. The presentation is predominantly nonsyndromic; however, several entities additionally show autoimmunity, granulomatous disease, lymphoproliferation, or an increased risk of malignancy.

Estimated prevalence is around 1/600 for selective IgA deficiency in white populations and 1/25,000 to 1/50,000 for common variable immunodeficiency. PADs account for approximately 50% of all primary immunodeficiency diagnoses.

A large number of genes have been associated with primary antibody deficiencies. The genetic forms encompass agammaglobulinemias, CVID-phenotype disorders, hyper-IgM syndromes, and isotype deficiencies. Selective IgA deficiency is most frequent overall but often asymptomatic; is the most common symptomatic PAD. Examples include (BTK; ~85% of agammaglobulinemias), CVID (TNFRSF13B, NFKB1, CTLA4), and X-linked (CD40LG; class-switch defect).

The genetic conditions associated with primary antibody deficiencies follow heterogeneous inheritance patterns. X-linked, autosomal recessive, and autosomal dominant modes are all represented across the spectrum, with multifactorial contributions described for selective IgA deficiency. De novo variants have been documented in several autosomal dominant immune dysregulation entities (e.g. CTLA4 haploinsufficiency).

• Where primary antibody deficiency is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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