Sequential transplantation of allogeneic hematopoietic stem cells and liver in x-linked hyper-IgM syndrome: the role of CMV prophylaxis with letermovir

X-linked hyper-IgM syndrome (XHIM) is a rare inborn error of immunity caused by CD40 ligand deficiency, resulting in combined humoral and cellular immune dysfunction with susceptibility to opportunistic infections, particularly Cryptosporidium-associated sclerosing cholangitis. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, yet outcomes worsen significantly once advanced liver disease develops. We report the clinical course of a 19-year-old patient with XHIM who underwent HSCT from an 8/10 HLA-mismatched unrelated donor because of progressive sclerosing cholangitis. Early after transplantation, he developed severe cholestasis and persistent fever. Cryptosporidium parvum infection poorly responsive to antimicrobial therapy was diagnosed and resolved only after immunosuppression tapering, paralleling T-cell immune recovery. Despite successful engraftment, progressive cholangiopathy required liver transplantation 6 months after HSCT. Given the high CMV risk and severe cytopenias, letermovir prophylaxis was administered for 100 days post-transplantation. After discontinuation, recurrent CMV reactivations occurred and resolved only following further immunosuppression tapering and subsequent T-cell immune reconstitution. At 3-year follow-up, the patient was clinically well, with full donor chimerism, stable liver function, sustained immune recovery allowing discontinuation of immunoglobulin replacement therapy. This case highlights the importance of early HSCT in XHIM, the central role of immune reconstitution in opportunistic infection control, and the potential utility of extended letermovir prophylaxis in high-risk liver transplant recipients.