Immunodeficiency, Common Variable, 10

A number sign (#) is used with this entry because common variable immunodeficiency-10 (CVID10) is caused by heterozygous mutation in the NFKB2 gene (164012) on chromosome 10q24.

Common variable immunodeficiency-10 is an autosomal dominant primary immunodeficiency characterized by childhood-onset of recurrent infections, hypogammaglobulinemia, and decreased numbers of memory and marginal zone B cells. Some patients may develop autoimmune features and have circulating autoantibodies. An unusual feature is central adrenal insufficiency (summary by Chen et al., 2013).

For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

Quentien et al. (2012) reported 4 patients from 3 French families with a combination of both ACTH deficiency and CVID. All patients had childhood-onset recurrent infections associated with hypogammaglobulinemia and decreased numbers of B-cell memory switched lymphocytes. ACTH deficiency was diagnosed between 5 and 15 years; clinical symptoms included hypoglycemia. Three of the 4 patients had a hypoplastic pituitary on brain imaging. One patient also had a subnormal growth hormone (GH; 139250) response to stimulation, suggesting that secretion of other pituitary hormones may also be affected. All patients lacked pituitary autoantibodies and had no mutations in any candidate genes tested. Family studies showed additional variably affected members in 2 of the families. The parents in 2 families were unaffected. In a follow-up, Brue et al. (2014) noted that 1 of the patients reported by Quentien et al. (2012) had developed central thyroid-stimulating hormone (TSH; see 188540) deficiency.

Chen et al. (2013) reported a mother and her 2 children with childhood-onset common variable immunodeficiency. All had a history of recurrent infections since childhood, particularly of the upper and lower respiratory tracts, as well as asthma. One child had autoimmune features, including alopecia areata, vitiligo, and trachyonychia, and both children had autoantibodies to thyroid peroxidase and glutamate decarboxylase, respectively. Laboratory studies showed hypogammaglobulinemia, poor antibody response to antigens, and decreased numbers of memory and marginal zone B cells. All patients also had low ACTH and cortisol levels that did not response to synthetic ACTH, indicating central adrenal insufficiency. An unrelated patient had a similar disorder, with recurrent infections, central adrenal insufficiency, alopecia totalis, trachyonychia, and psoriasiform dermatitis confirmed by biopsy.

Liu et al. (2014) reported 2 sibs, born of unrelated Greek Cypriot parents, with CVID10. The older sib presented at age 14 months with severe chickenpox, but was not diagnosed with CVID until age 9 years. She had a history of recurrent infections, alopecia totalis, idiopathic thrombocytopenic purpura (ITP), and central adrenal insufficiency. The younger sib presented at 5 months of age with meningococcal meningitis and was diagnosed with CVID at age 7. As a young adult, he developed an inflammatory condition of the central nervous system resulting in visual disturbances due to maculoretinopathy, gait disturbances, spasticity, hypomania, and swallowing difficulties. He died from surgical complications of gastrostomy placement. Laboratory studies showed hypogammaglobulinemia and decreased numbers of B cells, switched memory B cells, and NK cells. There were normal numbers of circulating T cells, but decreased numbers of T follicular helper cells. Family history revealed that the father had chronic sinusitis and bronchiectasis and died at age 39 years; his plasma immunoglobulin levels were normal on 3 occasions and DNA was not available.

Lee et al. (2014) reported a mother and her 2 sons with severe B-cell deficiency, hypogammaglobulinemia, recurrent infections, and alopecia areata. The mother reported a lifelong history of recurrent infections and was diagnosed with CVID at age 40. Her sons were diagnosed at age 20 years and 1 year, respectively; both had had chronic sinusitis since childhood. All had severe B-cell deficiency with an absence of mature and transitional B cells. Bone marrow biopsy of 1 patient showed an arrest in early B-cell development. However, there was evidence of circulating serum Ig, as well as antibodies to specific antigens. Numbers of circulating T cells were normal, but there was a reduction in follicular helper T cells and regulatory T cells.

Brue et al. (2014) reported a boy who presented with hypogammaglobulinemia at age 18 months. At age 4 years, he developed alopecia totalis associated with onychodystrophy. At age 7, he showed severe hypoglycemia and was found to have decreased cortisol due to ACTH deficiency. Brain MRI showed a hypoplastic anterior pituitary. Both of his parents were unaffected.

The transmission pattern of CVID10 in the family reported by Chen et al. (2013) was consistent with autosomal dominant inheritance.

In 4 patients from 2 unrelated families with autosomal dominant common variable immunodeficiency with central adrenal insufficiency, Chen et al. (2013) identified 2 different heterozygous truncating mutations in the NFKB2 gene (164012.0001 and 164012.0002). The mutation in the first family was found by exome sequencing; the second patient was ascertained from a cohort of 33 patients with CVID who were tested for variants in the NFKB2 gene. Both mutations caused a truncation in the C terminus of the protein, removing the conserved phosphorylation sites required for activation of p100 to p52. Cell lines carrying the mutations lacked the phosphorylated signal observed in control cells, and immunoblot analysis and immunofluorescence microscopy of transformed B cells from the patients showed decreased p52 nuclear translocation. These findings indicated that the mutant truncated proteins could not be processed by the proteasome, resulting in reduced protein activation and nuclear translocation. The immunologic phenotype in the patients was similar to that observed in mice with a truncating mutation in the same region of the Nfkb2 gene (Tucker et al., 2007). Chen et al. (2013) postulated functional haploinsufficiency as the pathologic mechanism because some p52 was found to be translocated to the nucleus in patient cells.

In 2 sibs, born of unrelated Greek Cypriot parents, with CVID10, Liu et al. (2014) identified a heterozygous deletion in the NFKB2 gene (164012.0003). The mutation was found by whole-exome sequencing.

In a mother and her 2 sons with CVID10 and alopecia areata, Lee et al. (2014) identified a heterozygous missense mutation in the NFKB2 gene (D865G; 164012.0004). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies in HEK293 cells showed that the mutation resulted in near absence of proper phosphorylation and processing of NFKB2 p100 to p52 in response to MAP3K14 (604655). Patient cells showed a similar defect in p100 processing, and there was decreased nuclear translocation of p65 (RELA; 164014). The findings indicated that the mutant p100 acts in a dominant-negative manner to impair canonical signaling, while also compromising noncanonical signaling by haploinsufficiency.

In patients from 3 French families with CVID10 with variable ACTH deficiency originally reported by Quentien et al. (2012), Brue et al. (2014) identified 3 different heterozygous mutations in the NFKB2 gene (164012.0004-164012.0006). The mutations were found by whole-exome sequencing and were absent from unaffected parents in several cases. Another patient with the disorder and a de novo heterozygous NFKB2 mutation (R853X; 164012.0002) was subsequently identified. All mutations occurred in the C-terminal region near signals required for processing of the NFKB2 protein by the noncanonical pathway. The findings indicated that inhibition of proper NFKB2 processing can have long-term deleterious effects on central endocrine function.

Using chemical mutagenesis, Tucker et al. (2007) generated mice with a mutant Nfkb2 allele that they termed Lym1. The Lym1 mutation was a T-to-A change at base 2854, resulting in substitution of tyr868 with a stop codon in the C-terminal phosphorylation site of Nfkb2. The mutation prevented processing of the inhibitory precursor, p100, into the active subunit, p52, thus preventing activation of RelA dimers. Mutant mice exhibited a complex phenotype with immunologic abnormalities, including disorganized splenic architecture, absence of peripheral lymph nodes, disrupted B-cell development, and inflammatory lesions in the lung and liver. The phenotype was more severe in homozygous mutant mice compared to heterozygous mice, and was more severe than in mice carrying a targeted deletion of Nfkb2. Tucker et al. (2007) concluded that NFKB2 has a key role in regulation of RELA (164014) activation and suggested overlap in the function of NFKB members in canonical and noncanonical pathway signaling.