Complex Multisystem Phenotype With Immunodeficiency Associated WithNBASMutations: Reports of Three Patients and Review of the Literature

Abstract

Objectives:Mutations in the neuroblastoma-amplified sequence (NBAS) gene were originally described in patients with skeletal dysplasia or isolated liver disease of variable severity. Subsequent publications reported a more complex phenotype. Among multisystemic clinical symptoms, we were particularly interested in the immunological consequences of theNBASdeficiency. Methods:Clinical and laboratory data of 3 patients ages 13, 6, and 5 in whom bi-allelicNBASmutations had been detected via next-generation sequencing were characterized. Literature review of 23 publications describing 74 patients was performed. Results:We report three Russian patients with compound heterozygous mutations of theNBASgene who had combined immunodeficiency characterized by hypogammaglobulinemia, low T-cells, and near-absent B-cells, along with liver disease, skeletal dysplasia, optic-nerve atrophy, and dysmorphic features. Analysis of the data of 74 previously reported patients who carried variousNBASmutations demonstrated that although the most severe form of liver disease seems to require disruption of the N-terminal or middle part ofNBAS, mutations of variable localizations in the gene have been associated with some form of liver disease, as well as immunological disorders. Conclusions:NBASdeficiency has a broad phenotype, and referral to an immunologist should be made in order to screen for immunodeficiency.