Mutations in NFKB2 have been identified to cause an autosomal dominant form of common variable immune deficiency (CVID) as well as combined immune deficiency. Literature reports have been limited to small numbers of symptomatic patients with NFKB2 mutations and their family members. We sought to better characterize the disease phenotype associated with deleterious NFKB2 mutations in an international cohort.
Clinical and laboratory data were collected on each subject. Each subject was categorized based on specific mutation attributes, laboratory results, and diagnoses. We calculated the prevalence of clinical features for patients with NF-kB2-associated CVID and those without CVID.
We included 34 subjects with NFKB2 mutations in our study. All patients had heterozygous mutations at sites downstream from the active p52 sequence of NFKB2, with the majority near the C-terminus. Of these, 24 patients were clinically diagnosed with CVID. Of the patients diagnosed with CVID, 96% of patients had recurrent or unusual infections and 79% had non-infectious disease involving two or more organ systems. With respect to non-infectious features, there was a high prevalence of dermatologic (58%), endocrine (42%), lymphoproliferative (38%), neurologic (38%), gastrointestinal (33%), and hematologic disease involving autoimmune cytopenias (21%). Similar clinical features were found in the subjects without CVID, although at a lower prevalence.
Heterozygous mutations in NFKB2 are associated with CVID in addition to wide-ranging multi-organ disease. Our international cohort of patients with NFKB2 mutations describes a broad clinical phenotype that represents variable expressivity and penetrance of a monogenic disorder.