Treatment of X-Linked Severe Combined Immunodeficiency by in Utero Transplantation of Paternal Bone Marrow

Abstract

EVERE combined immunodeficiency is a congenital syndrome due to various genetic abnormalities that cause susceptibility to infection, failure to thrive, lymphoid hypoplasia, very low levels of T lymphocytes, and hypogammaglobulinemia.1,2 Untreated, the disorder is usually fatal within the first year of life.We report the successful treatment of a fetus with the X-linked variant of severe combined immunodeficiency by the in utero transplantation of paternal bone marrow that was enriched with hematopoietic cell progenitors. CASE REPORTThe patient, 11 months old at this writing, is the second son of a 28-year-old woman known to carry a mutation found in X-linked severe combined immunodeficiency.Her first son died at seven months of age of severe combined immunodeficiency, confirmed by autopsy and molecular analysis.Studies of his DNA identified a splice-donor-site mutation in the gene for the common g chain of the interleukin-2 receptor ( IL2RG ) in complementary DNA at position 868( ϩ 5) in intron 6.The woman became pregnant again.Analysis of DNA obtained at 12 weeks' gestation by chorionic-villus sampling showed that the fetus was an affected male.After extensive nondirective counseling the family decided in favor of prenatal treatment.Bone marrow was harvested under general anesthesia from the 30-year-old father of the fetus.After enrichment of the bone mar-S row with CD34 ϩ cells (hematopoietic cell progenitors), the fetus received three transplants of 14.8 million, 2.0 million, and 1.8 million cells (114 million, 8.9 million, and 6.2 million cells per kilogram of estimated fetal weight), respectively, by percutaneous, ultrasound-guided, intraperitoneal injection at 16, 17.5, and 18.5 weeks' gestation.At delivery by cesarean section, the infant appeared normal except for a mild macular rash.A biopsy of the rash revealed no evidence of graft-versus-host disease, such as infiltrating lymphocytes, apoptotic keratinocytes, or vacuolar changes of the basal epithelium.The rash resolved with a seven-day course of methylprednisolone at a dose of 1 mg per kilogram of body weight per day intramuscularly.