Atypical Presentations of Hypomorphic X-Linked SCID

IL2RG mutations are associated with X-linked Severe Combined Immunodeficiency (X SCID). There is increasing awareness of Hypomorphic SCID associated with IL2RG variants; we present 3 novel mutations of this gene with variable presentations. Chart review was performed for patients with hypomorphic SCID due to pathogenic IL2RG variants. Plasmablast differentiation was performed from peripheral blood mononuclear cells using CD40L and IL-21 stimulation for 6 days followed by staining for plasmablast markers (CD19+/CD27+/CD38+) and surface immunoglobulins. Patient 1 is a 7-year-old Honduran boy with history of recurrent sinopulmonary infections including recent CMV pneumonitis, bronchiectasis, chronic lung disease, food allergies, unilateral retinal detachment, and hydrocephalus s/p VP shunt. Immunologic testing showed elevated lymphocyte numbers with decreased memory B cells, normal immunoglobulins, absent vaccine responses, and poor proliferation to mitogens. Whole genome testing showed two mosaic mutations in IL2RG: c. 568C>T (20%), c. 589T>C (87%). He is on prophylaxis with azithromycin and trimethoprim/sulfamethoxazole, immunoglobulin, and awaiting definitive treatment. Patient 2 is a 10-year-old with recurrent sinopulmonary disease with bronchiectasis. He had normal TRECs, normal lymphocyte numbers with normal mitogen proliferation to PHA, normal immunoglobulin levels, but absent vaccine responses, and abnormal plasmablast differentiation (0.12% CD27+/CD38+ at day 6 post in vitro activation) and profoundly decreased expression of surface IgG and IgA in vitro. Genetic testing showed a hemizygous IL2RG c.32T>C mutation, as well as CFTR mutations (c.1972dup and c.1977_1985del, in cis). He is maintained on immunoglobulin replacement. Patient 3 is a 40-year-old who had recurrent infections beginning in childhood, and extranodal B-cell lymphoma at age 26 years. He had pan-lymphopenia, and genetic testing showed IL2RG c.982C>T, p.R328X. He underwent successful bone marrow transplantation from a matched sibling at age 36. Hypomorphic X-SCID due to novel or mosaic variants in IL2RG can present with variable symptoms including malignancy and variable lymphocyte phenotype including normal T, B, and NK cell counts, and should be considered in males with opportunistic or persistent infections. Download : Download high-res image (159KB)Download : Download full-size imageFigure 1. Patient 2 Figure 1. Patient 2