Abstract

Introduction Heterozygous c-terminal variants in NFκB2 have been associated to early onset CVID, central adrenal insufficiency and ectodermal dysplasia. Affected natural killer (NK) cell function has only been described for one case in literature. We present a patient with early onset CVID, complete alopecia and severe systemic recurrent CMV infection associated with functional NK cell deficiency. Case Description
 A previously healthy girl with no family history of endocrine or immunologic diseases presented at 2 years of age with hair loss progressing to alopecia totalis; trachyonychia, psoriatic-like dermatitis and atopic dermatitis. Subsequently she developed recurrent bacterial upper and lower respiratory infections. Immunologic evaluation at 6 yrs showed hypogammaglobulinemia (IgG 180, IgA < 4, IgM 4), low B cells with almost only naïve B cells (98%). Antibody titers to tetanus and pneumococcal vaccines were not protective. T and NK cell numbers were normal, however, T-cell proliferation to PHA was slightly decreased. The diagnosis of CVID was established, and IVIG replacement started. She remained free of infections until 9 years of age when she developed CMV pneumonia that recovered after prolonged ganciclovir treatment. She persisted with recurrent respiratory infections despite IVIG, requiring prophylactic antibiotics. NK cell function was assessed by chromium release assay and demonstrated absent NK cell function. A heterozygous non-sense mutation in NFκB2 gene [c.2608C>T (NM_002502.5, p.Gln870] was identified by Whole exome sequencing (WES). At 12 yrs she was admitted with severe gastroenteritis with generalized intestinal edema, acute renal failure and massive urinary protein loss. Quantitative CMV PCR was positive in blood (>2 x 106 copies) and renal biopsy. Renal histology showed tubular atrophy, interstitial inflammation and discrete focal glomerular mesangial proliferation, suggestive of minimal change nephropathy. She required critical level care and was treated with systemic steroids, IVIG, broad-spectrum antibiotics, valgancyclovir and hyperimmune CMV immunoglobulin leading to full clinical recovery. Pituitary function was studied and demonstrated reduced serum cortisol and ACTH levels and thus glucocorticoid replacement was initiated. Discussion As previously reported, heterozygous NFκB2 mutations can cause CVID, endocrine dysfunction and ectodermal dysplasia. In our patient, the main clinical manifestation was immunodeficiency and skin alterations. Pituitary hormone deficiency was detected after her mutation was identified. Decreased NK cell function potentially explains her susceptibility to invasive CMV infections. To our knowledge, this is the second report of NFκB2 mutation associated with abnormal NK cell function, suggesting NK cell function should be assessed in patients with mutations in non-canonical NFkB pathway.