Lymphedema in patients with X-linked severe combined immunodeficiency

Background: IL2RG and JAK3 mutations cause T-cell–negative, B-cell–positive, natural killer cell–negative severe combined immunodeficiency (SCID). Cell therapies such as hematopoietic stem cell transplantation (or gene therapy for IL2RG deficiency) can effectively restore T-cell immunity but—when performed without myeloablation—may leave residual immune defects. These include persistent B-cell dysfunction, poor innate lymphoid cell recovery, and poor reconstitution of secondary lymphoid organs. Severe/recurrent warts may also occur in the long term. Objective: We present 3 IL2RG SCID cases complicated by lymphedema and discuss possible hypotheses of this rare complication. Methods: We describe 3 patients with IL2RG SCID who developed lymphedema: 2 after unconditioned cell therapy and 1 with a hypomorphic mutation who remained untreated. Clinical presentation, immunologic data, imaging, and transplant history were reviewed and compared with published data. Results: Lymphedema affected the lower limbs and varied in severity, with one case complicated by recurrent dermohypodermitis and Streptococcus mitis sepsis. Conclusion: Lymphedema is a rare but potentially disabling complication of IL2RG/JAK3 SCID, affecting long-term quality of life. Hypothetically, low/absent levels of innate lymphoid cells—particularly lymphoid tissue inducer cells, a subset of innate lymphoid cells—may be a contributing factor in the pathogenesis of lymphedema in IL2RG/JAK3 SCID.