The purpose of this study was to characterize a large group of infants with complete DiGeorge anomaly and to evaluate the ability of thymus transplantation to reconstitute immune function in these infants. DiGeorge anomaly is characterized by varying defects of the heart, thymus, and parathyroid glands. Complete DiGeorge anomaly refers to the subgroup that is athymic (< 1%). The characteristics of 54 subjects at presentation and results from 44 consecutive thymus transplantations are reported. Remarkably, only 52% had 22q11 hemizygosity and only 57% had congenital heart disease requiring surgery. Thirty-one percent developed an atypical phenotype with rash and lymphadenopathy. To date, 33 of 44 subjects who received a transplant survive (75%) with post-transplantation follow-up as long as 13 years. All deaths occurred within 12 months of transplantation. All 25 subjects who were tested 1 year after transplantation had developed polyclonal T-cell repertoires and proliferative responses to mitogens. Adverse events developing after transplantation included hypothyroidism in 5 subjects and enteritis in 1 subject. In summary, diagnosis of complete DiGeorge anomaly is challenging because of the variability of presentation. Thymus transplantation was well tolerated and resulted in stable immunoreconstitution in these infants. (Blood. 2007; 109: [4539][4540][4541][4542][4543][4544][4545][4546][4547]

Complete DiGeorge syndrome is a fatal condition in which infants have no detectable thymus function. The optimal treatment for the immune deficiency of complete DiGeorge syndrome has not been determined. Safety and efficacy of thymus transplantation were evaluated in 12 infants with complete DiGeorge syndrome who had less than 20-fold proliferative responses to phytohemagglutinin. All but one had fewer than 50 T cells/mm 3 . Allogeneic postnatal cultured thymus tissue was transplanted. T-cell development was followed by flow cytometry, lymphocyte proliferation assays, and T-cell receptor V␤ (TCRBV) repertoire evaluation. Of the 12 patients, 7 are at home 15 months to 8.5 years after transplantation. All 7 survivors developed T-cell proliferative responses to mitogens of more than 100 000 counts per minute (cpm). By one year after transplantation, 6 of 7 patients developed antigen-specific proliferative responses. The TCRBV repertoire showed initial oligoclonality that progressed to polyclonality within a year. B-cell function developed in all 3 patients tested after 2 years. Deaths were associated with underlying congenital problems. Risk factors for death included tracheostomy, longterm mechanical ventilation, and cytomegalovirus infection. Adverse events in the first 3 months after transplantation included eosinophilia, rash, lymphadenopathy, development of CD4 ؊ CD8 ؊ peripheral T cells, elevated serum immunoglobulin E (IgE), and possible pulmonary inflammation. Adverse events related to the immune system occurring more than 3 months after transplantation included thrombocytopenia in one patient and hypothyroidism and alopecia in one other patient. Thymic transplantation is efficacious, well tolerated, and should be considered as treatment for infants with complete DiGeorge syndrome. (Blood.

Complete DiGeorge syndrome is a fatal congenital disorder characterized by athymia, hypoparathyroidism, and heart defects. Less than half of patients are 22q11 hemizygous. The goal of this study was to assess if immune suppression followed by postnatal thymus transplantation would lead to T-cell function in 6 infant patients who had host T cells at the time of transplantation. All infants had fewer than 50 recent thymic emigrants (CD3 ؉ CD45RA IntroductionDiGeorge syndrome is a congenital disorder characterized by defects in the third and fourth pharyngeal pouches, although abnormalities can be found extending from the first through sixth pharyngeal arches. 1 Typically, defects are found in the heart, parathyroid gland, and thymus. [2][3][4][5][6] The immune defect in DiGeorge syndrome usually is mild. In fewer than 1% of cases, there is profound immune deficiency secondary to athymia. 7 Athymic patients are categorized as having complete DiGeorge syndrome. 2,8 Patients with complete DiGeorge syndrome usually die within the first 2 years of life. 2 Severe recurrent infections are a major problem. 2 Peripheral blood testing can be used to identify those patients with DiGeorge syndrome who are athymic. Naive T cells (recent thymic emigrants) coexpress CD45RA and CD62L. 9 We define athymic patients as those having less than 50 naive T cells/cubic millimeter (mm 3 ). 10 In patients having a sufficient blood volume for testing, we also quantitate the number of T-cell receptor rearrangement excision circles (TRECs) in circulating T cells. [11][12][13] TRECs are episomal DNA circles that form when T-cell receptor (TCR) gene segments rearrange in the thymus. Athymic patients have less than 100 TRECs/100 000 T cells (normal value for a newborn is approximately 10 000 TRECs/100 000 T cells). 10 Most athymic patients with DiGeorge syndrome have very low proliferative responses to mitogens and very low T-cell numbers. These patients can be treated with postnatal allogeneic thymus transplantation without immunosuppression. 10 The mechanism of this experimental treatment is the migration of host bone marrow cells to slices of cultured donor thymus that are implanted into the patient's muscle. In the donor graft, the host bone marrow cells develop via thymopoiesis into host T cells that then emigrate out of the thymus into the peripheral blood.We report the results of postnatal allogeneic thymus transplantation in 6 athymic patients with DiGeorge syndrome who had some T cells and T-cell proliferative responses to mitogens. Because of their T-cell function, these patients would likely have rejected allotransplants if no immunosuppression had been given. Thus, all patients were initially treated with Thymoglobulin (rabbit antithymocyte globulin, Imtix-SangStat, Lyon, France). This treatment was immediately followed by postnatal cultured allogeneic thymus transplantation. The excellent clinical and immunologic results in this group of patients supports the use of Thymoglobulin together with thymus transplantation to effect normal...

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