Correction of Immunodeficiency Associated with NEMO Mutation by Umbilical Cord Stem Cell Transplantation Using a Reduced-Intensity Conditioning Regimen.

X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is a developmental and immunologic disorder caused by hypomorphic mutations in the nuclear factor-κB essential modulator (NEMO) gene. NEMO is the regulatory subunit of the IκB kinase (IKK) complex, which phosphorylates and degrades NF-κB inhibitor α (IκBα), causing NF-κB activation. Following the identification of amorphic NEMO mutations causing familial incontinentia pigmenti (IP), hypomorphic mutations in NEMO have been identified in XL-EDA-ID patients. Affected boys are susceptible to infections with various microorganisms, mostly pyogenic bacteria and mycobacteria. Stem cell transplantation (SCT) is thought to be the only curative treatment, but successful SCT has not yet been reported. We here report the first successful treatment of the disorder by SCT. The patient was a 3-year-old boy. His mother and maternal grandmother had been diagnosed with IP. He had frequent episodes of enterocolitis, and Enterobacter aerogenes sepsis. Mutation analysis revealed NEMO mutation (1167 insC) in both the patient and his mother. Flow cytometry analysis showed lower NEMO expression in each PBMC lineage, and CD40L induced less up-regulation of CD23, CD54, CD86, and CD95 in the patient’s cells. The patient did not have an HLA-matched related or unrelated bone marrow donor. At 3 years of age, an unrelated UCSCT was performed after written consent was obtained from his parents. Pretransplant conditioning consisted of fludarabin (30 mg/m²/d) from day -7 to day -3, melpharan (70 mg/m²/d) from day -6 to day -5, and rabbit anti-T-lymphocyte globulin (ATG) (2.5 mg/kg/d) from day -5 to day -1. The patient received 4.6 × 10⁷ total nucleated cells/kg from a male donor. The recipient and donor were one antigen mismatched by serology and four loci mismatched by DNA typing. Following uneventful engraftment, NEMO protein expression was normalized and cytokine response was significantly improved. Lineage-specific genetic analysis confirmed full donor chimerism. Six months after UCSCT, the patient is in perfect performance status. This outcome shows that correction of immunodeficiency associated with NEMO mutation is possible by SCT, and UCSCT with a reduced-intensity regimen can be a suitable therapy for affected patients.