Atypical presentation and manifestations in X-linked agammaglobulinemia patients with novel BTK mutations

Abstract

X-linked agammaglobulinemia (XLA) is a rare immunodeficiency caused by defects in the Bruton tyrosine kinase (BTK) gene, characterized by impaired B-cell development, reduced immunoglobulin production, and increased susceptibility to bacterial infections at an early age. Some XLA patients show atypical presentations, with most reports concentrating on the diagnosis at a relatively old age. They presented with infections at late age or with unusual pathogens; however, other atypical manifestations have only rarely been reported. Methods: Description of patients with XLA and novel mutations in BTK who presented with atypical manifestations or developed noninfectious complications. Results: Four patients presented unique manifestations unusual for XLA. The first with Granulomatous Dermatitis, the second with acute demyelinating encephalomyelitis, the third with “Crohn's disease like” localized protein-losing enteropathy, and the last patient with idiopathic thrombocytopenic purpura, which is an unexpected finding in a patient devoid of endogenous immunoglobulins. Mutations in BTK were found in all domains of the gene; 1 resulted in a stop codon and 3 were missense mutations. Conclusions: Early recognition of atypical presentations and manifestations of patients with XLA is crucial for timely initiation of life-saving therapy, which may include anti-bacterial and anti-inflammatory treatments in addition to immunoglobulin. Statement of novelty: In this study we present unique inflammatory and autoimmune phenomenons in XLA patients that were not described previously and are somewhat unexpected. These should alert the immunologist for the possibility of XLA diagnosis.