Nonmyeloablative hematopoietic stem cell transplant for X-linked hyper-immunoglobulin m syndrome with cholangiopathy

X-linked hyper-immunoglobulin M (X-HIM) syndrome is a rare genetic immunodeficiency syndrome caused by mutations in the gene encoding CD40 ligand (CD40L, CD154). Allogeneic hematopoietic stem cell transplantation (HSCT) offers the prospect of immune reconstitution in X-HIM syndrome. Standard HSCT using high-dose chemoradiotherapy can be followed by serious hepatic problems, including veno-occlusive disease, graft-versus-host disease, and/or drug-induced hepatotoxicity. In patients whose liver function is compromised before HSCT, such as in X-HIM syndrome caused by cholangiopathy and hepatitis related to opportunistic infections, there is a higher likelihood of hepatotoxicity. We explored nonmyeloablative HSCT in 2 patients with X-HIM syndrome. Nonmyeloablative HSCT without liver transplant for X-HIM syndrome, to our knowledge, has not been described previously.

Two children with X-HIM syndrome and persistent infections had documented cholangiopathy on liver biopsy. Both children underwent nonmyeloablative HSCT from HLA-matched siblings with fludarabine, busulfan, and anti-thymocyte globulin as their preparative regimen. Graft-versus-host disease prophylaxis consisted of cyclosporine.

Both children are >2 years after their HSCT. One remains a mixed chimera, and the other shows 100% donor chimerism. Both children are now free of infections and are no longer dependent on intravenous gammaglobulin. Both show response to immunizations. Both have had resolution of their cholangiopathy.

Nonmyeloablative HSCT from HLA-matched siblings can offer immune reconstitution without hepatotoxicity in patients with X-HIM syndrome and preexisting cholangiopathy. Even with stable mixed chimerism after allogeneic HSCT, patients may be able to enjoy a normal phenotype. Nonmyeloablative HSCT warrants additional study in X-HIM syndrome.