Table 1

Primary and secondary causes of hypogammaglobulinemia to be distinguished from common variable immunodeficiency


Diagnosis (examples)

Primary immunodeficiencies


X-chromosomal agammaglobulinemia (BTK), rare AR forms

Class switch recombination deficiencies

X-chromosomal form: CD40L

Autosomal recessive forms: CD40, AID, UNG

X-chromosome lymphoproliferative

SAP, XIAP deficiency


Combined immunodeficiency

Hypomorphic variants of severe combined immunodeficiencies

Other forms of combined immunodeficiency (ORAI, STIM, DOCK8 a.o.)

Other defined primary immunodeficiencies

WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome DiGeorge syndrome

Chromosomal instability syndromes

Ataxia telangiectasia (ATM)

Nijmegen breakage syndrome (NBS1)

ICF (immunodeficiency, chromosomal instability, facial abnormalities) syndrome (DNMT3B)

Secondary cause


Chronic lymphatic leukemia

Immunodeficiency and thymoma (Good syndrome)

Malignant lymphoma

Protein loss

Loss of immunoglobulins (for example, renal or gastrointestinal protein loss, severe burns, lymphangiectasis)

Hyperkatabolism of immunoglobulins (for example, myotonic dystrophy types 1 and 2)

Drug induced

Anticonvulsants (carbamazepine, valproic acid, phenytoine)


Gold salts




Antimalarial agents (very rare)

Methotrexate (very rare)

Alkylating agents (cyclophosphamid, chlorambucil)

Anti-CD20 (rituximab)



Congenital cytomegalovirus, rubella or Toxoplasma gondii infection, neonatal HIV infection

Ebstein-Barr virus infection

AID, activation-induced cytidine deaminase; a.o., and others; AR, autosomal recessive; ATM, ataxia telangiectasia mutated; BTK, Bruton agammaglobulinemia tyrosine kinase; DNMT3B, DNA (cytosine-5-)-methyltransferase 3 beta; DOCK8, dedicator of cytokinesis 8; NBS1, Nijmegen breakage syndrome 1; ORAI, ORAI calcium release-activated calcium modulator 1; SAP, SLAM associated protein/SH2 domain protein 1A; STIM, stromal interaction molecule 1; UNG, uracil-DNA glycosylase; XIAP, X-linked inhibitor of apoptosis.

Salzer et al. Arthritis Research & Therapy 2012 14:223   doi:10.1186/ar4032