CVID4 D81.4

Rare immunodeficiency syndrome caused by a homozygous mutation in theTNFRSF13C gene (606269). TNFRSF13C encodes the B-cell activating BAFF receptor on chromosome 22q13.

The disease name CVID"Common Variable Immunodeficiency" refers to a group of diseases from the group of "primary immunodeficiency diseases (PID)". CVID is characterized by a more or less pronounced deficiency of the three antibody classes IgG, IgA and IgM . The antibody deficiency leads to recurrent and often severe infections , mainly affecting the ears, sinuses, respiratory tract and skin. In the majority of cases, the diagnosis is not made until the third to fourth decade of life. Severe and repeated infections can cause permanent damage to the airways (bronchiectasis).

In CVID4, a mutation in theTNFRSF13C gene (606269) results in decreased or absent expression of the BAFF receptor and consequent insufficiency of BAFF.

Homozygous deletions in the BAFFR gene (606269.0001) were detected (Warnatz et al. 2009).

Warnatz et al (2009) reported on a 57-year-old man born to consanguineous parents with lifelong chronic sinusitis and a first pneumonia at age 37. At age 57, a clinical diagnosis of CVID was made after recurrent pneumonia. His 80-year-old sister presented with severe herpes zoster infection at age 70 and later pneumonia. Laboratory testing in both individuals revealed low serum IgG and IgM levels but normal serum and mucosal IgA levels. Both patients showed a T-cell-dependent antigenic response to the vaccine but no T-cell-independent humoral response. None of the patients developed lymphoproliferative or autoimmune disorders.

Studies of B lymphocytes from both individuals showed undetectable surface expression of the BAFF receptor associated with an inability to bind BAFF . Both individuals also exhibited severe and persistent B-cell lymphopenia and decreased numbers of memory B cells. Phenotyping of B cell surface proteins revealed a developmental arrest of B cells at the transitional stage to mature follicular B cells.

1. Bonilla FA et al (2016) International Consensus Document (ICON): Common variable immunodeficiency disorders. J Allergy Clin Immunol Pract 4: 38-59.

2. Gereige JD et al (2019) Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity. Front Immunol 10:2753.

3. Warnatz K et al (2009) B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc Nat Acad Sci 106: 13945-13950.