Immunodeficiency, Common Variable 12, with Autoimmunity

CVID12 with autoimmunity, also called common variable immunodeficiency 12, with autoimmunity, is a rare autosomal dominant complex immunodeficiency syndrome caused by a heterozygous mutation in the NFKB1 gene (164011) on chromosome 4q24.

The affected gene, NFKB1, encodes a transcription factor that regulates the expression of target genes involved in the immune system, defining the phenotype as a disorder of immune regulation (Fliegauf et al. 2015; Lorenzini et al. 2020).

The age of onset and the severity of the disease are very different. Mostly, the symptoms of the disease became evident in the 3-4th decade of life. Occasionally already in childhood.

Immunodeficiency is characterized by recurrent broncho-pulmonary infections and is associated with hypogammaglobulinemia. Approximately 50% of patients develop autoimmune features. Some had skin and/or nail infections. Features of autoimmunity were: thrombocytopenia, autoimmune hemolytic anemia, and alopecia. One patient developed lymphoma. <20% of patients developed malignancies, most commonly solid tumors, including lymphoma.

Nijenhuis et al (2001) reported on a Dutch family in which 6 individuals in 3 generations suffered from common variable immunodeficiency. The age at onset of symptoms varied widely: in one patient, recurrent respiratory and gastrointestinal infections occurred before the age of 2 years, whereas in the others, the diagnosis was made in adulthood and symptoms appeared in the 4th decade of life or later. Features included recurrent infections and chronic obstructive pulmonary disease. One patient had recurrent skin lesions and inflammatory bowel disease. All patients had decreased serum immunoglobulins with normal B and T cell counts. Ten other family members had dysgammaglobulinemia without overt CVID, although some had mild symptoms of immunodeficiency.

Later, some patients in this family were found to have isolated IgA deficiency (Finck et al. 2006).

1. Finck A et al. (2006) Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q. Europ J Hum Genet. 14: 867-875
2. Fliegauf M et al (2015) Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency. Am J Hum Genet. 97: 389-403.
3. Lorenzini T et al. (2020) Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. J Allergy Clin Immun 146: 901-911.
4. Nijenhuis T et al (2001) Common variable immunodeficiency (CVID) in a family: an autosomal dominant mode of inheritance. Neth J Med 59: 134-139.
5. Schipp C et al. (2016) Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans. Haematologica 101: e392-e396.
6. Tuijnenburg Pet al. (2018) Loss-of-function nuclear factor kappaB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. J Allergy Clin Immun 142: 1285-1296.