CVID10D81.0

Recurrent infections as early as childhood, often associated with hypogammaglobulinemia and decreased numbers of memory B-cell lymphocytes. Pathways for the immunodeficiency syndrome are recurrent infections, especially of the upper and lower respiratory tract. Autoimmune phenomena such as vitiligo, alopecia areata (including maligna), and autoimmunologic thyroid disease are not uncommon. Furthermore, trachyonychia

psoriasiform dermatitis and idiopathic thrombocytopenic purpura (ITP).

ACTH deficiency is common and is diagnosed between the ages of 5 and 16 years. Furthermore, clinical symptoms include hypoglycemia. About 75% of patients have a hypoplastic pituitary gland.

Hypogammaglobulinemia, decreased antibody response to antigens, decreased number of memory and marginal zone B cells. Signs of central adrenal insufficiency may occur.

Quentien et al (2012) reported 4 patients from 3 French families with a combination of ACTH deficiency and CVID. All patients had recurrent infections in childhood associated with hypogammaglobulinemia and decreased numbers of memory B-cell lymphocytes. ACTH deficiency was diagnosed between 5 and 15 years of age; clinical symptoms included hypoglycemia. Brain imaging revealed a hypoplastic pituitary gland in three of the four patients. 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 had no pituitary autoantibodies and had no mutations in any of the candidate genes tested. Family studies revealed that 2 of the families had additional members who were differentially affected. The parents in 2 families were not affected.

Chen et al (2013) reported on a mother and her 2 children with childhood-onset common variable immunodeficiency. All children suffered from recurrent infections, particularly upper and lower respiratory tract infections, and asthma since childhood. One child had autoimmune features, including alopecia areata, vitiligo, and trachyonychia, and both children had autoantibodies to thyroid peroxidase. Laboratory tests revealed hypogammaglobulinemia, poor antibody response to antigens, and decreased numbers of memory and marginal zone B cells. All patients had low ACTH and cortisol levels that did not respond to synthetic ACTH, indicating central adrenal insufficiency.

Liu et al (2014) reported two siblings with CVID10 born to unrelated Greek Cypriot parents. The older sibling presented with severe chickenpox at 14 months of age but was not diagnosed with CVID until she was 9 years old. She had a history of recurrent infections, alopecia totalis, idiopathic thrombocytopenic purpura (ITP), and central adrenal insufficiency. The younger sibling developed meningococcal meningitis at 5 months of age and was diagnosed with CVID at 7 years of age. Laboratory tests revealed hypogammaglobulinemia and decreased B-cell counts. The number of circulating T cells was normal, but the number of follicular T helper cells was decreased.

Lee et al (2014) reported a mother and her two sons with severe B-cell deficiency, hypogammaglobulinemia, recurrent infections, and alopecia areata. The mother reported a lifetime history of recurrent infections and was diagnosed with CVID at age 40. Evidence included severe B-cell deficiency with an absence of mature B cells and transitional cells. The number of circulating T cells was normal, but the number of follicular helper T cells and regulatory T cells was reduced.

Brue et al (2014) reported on a boy who was diagnosed with hypogammaglobulinemia at 18 months of age. At the age of 4 years, he developed alopecia totalis associated with onychodystrophy. At the age of 7 years, he showed severe hypoglycemia. Cortisol levels were decreased due to ACTH deficiency. MRI of the brain showed a hypoplastic anterior pituitary.

Aird et al (2019) reported on a 13-year-old girl who developed progressive hair loss, trachyonychia, psoriatic dermatitis, and atopic dermatitis at age 2 years. She had recurrent sinopulmonary infections and was diagnosed with hypogammaglobulinemia at age 6 years. At age 9, she developed cytomegalovirus (CMV) pneumonia. Evidence included decreased serum cortisol and ACTH levels. At the age of 12 years, reactivation of CMV infection occurred, which was associated with progressive nephrotic syndrome. Bioptically, focal segmental glomerulosclerosis was diagnosed. The patient developed Pneumocystis jiroveci pneumonia and fungal infection of the lung at 13 years of age and died of multiorgan failure.

1. Aird A et al (2019) Novel heterozygous mutation in NFKB2 is associated with early onset CVID and a functional defect in NK cells complicated by disseminated CMV infection and severe nephrotic syndrome. Front Pediat 7: 303.
2. Brue T et al (2014) Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies. BMC Med Genet 15: 139.
3. Chen K et al (2013) Germline mutations in NFKB2 implicate the noncanonical NF-kappa-B pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 93: 812-824.
4. Lee CE et al (2014) Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood 124: 2964-2972.
5. Liu Y et al (2014) Novel NFKB2 mutation in early-onset CVID J Clin Immun 34: 686-690.
6. Quentien MH et al (2012) Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections. J Clin Endocr Metab 97: E121-E128.
7. Tucker E et al (2007) A novel mutation in the Nfkb2 gene generates an NF-kappa-B2 'super repressor. J Immun 179: 7514-7522.