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PEDIATRICS Vol. 113 No. 2 February 2004, pp. e122-e127

ELECTRONIC ARTICLE

Nonmyeloablative Hematopoietic Stem Cell Transplant for X-Linked Hyper-Immunoglobulin M Syndrome With Cholangiopathy

David A. Jacobsohn, MD, ScM*, Karan M. Emerick, MD{ddagger}, Paul Scholl, MB, B. Chir§, Hector Melin-Aldana, MD||, Maurice O’Gorman, PhD||, Reggie Duerst, MD* and Morris Kletzel, MD*

* Department of Pediatrics, Division of Hematology/Oncology/Transplant
{ddagger} Department of Pediatrics, Division of Gastroenterology and Hepatology
§ Department of Pediatrics, Division of Immunology/Rheumatology
|| Department of Pathology and Laboratory Medicine, Northwestern University, The Feinberg School of Medicine, Chicago, Illinois

Objective. 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.

Methods. 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.

Results. 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.

Conclusions. 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.

Key Words: stem cell transplant • nonmyeloablative • immunodeficiency • hyper-IgM • cholangiopathy

Abbreviations: X-HIM, X-linked hyper-immunoglobulin M • IVIG, intravenous immunoglobulin • G-CSF, granulocyte colony-stimulating factor • HSCT, hematopoietic stem cell transplantation • VNTR, variable-number tandem repeats • H&E, hematoxylin and eosin • CBD, common bile duct • ERCP, endoscopic retrograde cholangiopancreatography • GVHD, graft-versus-host disease • CSA, cyclosporin A • PBSC, peripheral blood stem cells • MNC, mononuclear cell

Received for publication Aug 5, 2003; Accepted Oct 7, 2003.