Hypomorphic defects in RAG1 underlie leaky SCID, ranging from Omenn syndrome to atypical presentations of combined immunodeficiency. Hypomorphic RAG1 mutations also cause an atypical SCID characterized by chronic CMV infection, autoimmunity and expansion of TCRγδ T cells.
We report the clinical course and outcome of a child with hypomorphic RAG1 defects.
A 16-month-old girl with failure to thrive presented with pneumonia and ARDS due to H1N1 Influenza. A month later, she developed CMV and Pneumocystis jirovecii pneumonia, hepatosplenomegaly, autoimmune hemolytic anemia (AHIA) and pancreatitis. Previously, she had suffered from bronchiolitis requiring O2-therapy and had developed vaccine-related disease after Rotavirus and VZV vaccine. Her work-up showed moderate T and B lymphopenia with normal NK cells, excess of memory T and of TCRγδ T cells (53% of T cells), hypergammaglobulinemia, absent thymus on CT scan, and restricted TCR-V-beta repertoire. Whole exome sequencing revealed compound heterozygous missense mutations in RAG1 (p.R410Q, p.H612R). She received haploidentical HSCT after myeloablative conditioning, resulting in full engraftment. Three months post-HSCT she experienced graft loss with CMV reactivation and recurrence of AHIA, not responding to unconditioned stem cell boost and a course of bortezomib. She then developed fulminant hemophagocytic lymphohistiocytosis which was sadly fatal despite high dose steroid therapy, a second haploidentical HSCT and extensive antiviral therapy.
We report a patient presenting with life-threatening flu, which led to the diagnosis of leaky SCID associated with AIHA, pancreatitis and HLH. This highlights the importance of timely diagnosis of SCID and the wide spectrum of presentation of hypomorphic RAG mutations.