Complete DiGeorge syndrome is characterized by the clinical triad of cardiac malformation, hypocalcemia, and T cell immunodeficiency due to congenital athymia. We describe an infant with complete DiGeorge syndrome who at presentation had no circulating T cells detectable by flow cytometry. The patient spontaneously developed circulating T cells but these cells did not proliferate in response to mitogens. The T cell receptor Vbeta repertoire was severely restricted. All T cells were host, not maternal, as assessed by fluorescent in situ hybridization evaluation of 22q11 hemizygosity. At autopsy, this patient had no grossly detectable thymus tissue and no microscopic evidence for thymopoiesis. These findings suggest that appearance of T cells in infants with complete DiGeorge syndrome may represent oligoclonal expansions of a small number of T cells that may have matured extrathymically and which do not respond in vitro to mitogen stimulation.

OBJECTIVE:DiGeorge syndrome is characterized by developmental defects of the heart, parathyroid glands, and thymus. The objective of this study was to determine whether T-cell function spontaneously improves in patients with DiGeorge syndrome who have profoundly depressed T-cell proliferative responses to mitogens at presentation, regardless of the T-cell count. STUDY DESIGN:We conducted a retrospective chart review of eight patients with DiGeorge syndrome who had no proliferative responses to mitogens on presentation. RESULTS:Despite lack of responsiveness of the patients' peripheral blood lymphocytes to mitogens, T cells were occasionally detected, and the patients' cells often responded to IL-2 and in mixed lymphocyte reactions. Unresponsiveness to mitogens and clinical immunodeficiency persisted without immune-based therapy. One patient is alive and well after immunoreconstitution from thymic transplantation. The others either died early of complications of their disease such as gastroesophageal reflux with aspiration (2 patients) or infection (2 patients) or died after attempts at immunorestorative therapy with IL-2, thymus transplantation, or bone marrow transplantation (3 patients). CONCLUSION:Eight patients with DiGeorge syndrome who were first seen with no mitogen responsiveness did not improve spontaneously. We recommend HLA-identical bone marrow transplantation or thymic transplantation for these patients as soon as the diagnosis is confirmed.

Transplantation of cultured postnatal human thymus was performed in a patient with complete DiGeorge syndrome. Biopsy of the graft 3 mo after implantation revealed normal CD1+ thymocytes in thymic cortical epithelial regions and CD1- thymocytes in thymic medullary epithelial regions, respectively. HLA analysis of graft thymocyte and thymic microenvironment components demonstrated that developing thymocytes and thymic macrophages were recipient derived, while thymic epithelial components were of donor origin. The patient, who initially had no T cells and had profoundly defective T cell function, developed normal T cell responses to mitogens and Ags, tolerance to donor in a mixed lymphocyte reaction, and normal Ab titers after tetanus toxoid and pneumovax immunization. Thus, transplantation of cultured postnatal human thymic tissue in humans can form functional chimeric thymic tissue, and may provide a strategy to reconstitute the peripheral T cell pool in select congenital and acquired immune deficiency syndromes.

Objective: To determine the relative frequencies of the different genetic forms of severe combined immunodeficiency (SCID) and whether there are distinctive characteristics of the particular genotypes.Study design: The demographic, genetic, and immunologic features of 108 infants with SCID who were treated consecutively at Duke University Medical Center were analyzed.Results: Eighty-nine subjects were boys and 19 were girls; there were 84 white infants, 16 black infants, and 8 Hispanic infants, Forty-nine had X-linked SCID with mutations of common cytokine receptor gamma chain (gamma(c)), 16 had adenosine deaminase (ADA) deficiency, 8 had Janus kinase 3 (Jak3) deficiency, 21 had unknown autosomal recessive mutations, 1 had reticular dysgenesis, 1 had cartilage hair hypoplasia, and 12 (all boys) had SCID of undetermined type, Deficiency of ADA caused the most profound lymphopenia; gamma(c) or Jak3 deficiency resulted in the most B cells and fewest natural kilter (NK) cells; NK cells and function were highest in autosomal recessive and unknown types of SCID.Conclusions: Different SCID genotypes are associated with distinctive lymphocyte characteristics. The presence of NK function in ADA-deficient, autosomal recessive, and unknown type SCIDs, and low NK function in a majority of gamma(c) and Jak3 SCIDs indicates that some molecular lesions aff ect T, B, and NK cells (gamma(c) and Jak3), others primarily T cells (ADA deficiency), and others just T and B cells.

A 10 year old black male with CGD and a history of multiple iavasive bacterial and fengal infections presented with one week of fever and an enlarging chest wall mass.Prior history included multiple life threatening infections including Aspergillns pneumonia, Staph Aureus hepatic abscess and Candida Albicans endocarditis and retinitis.He had chronic renal insufficiency from repeated courses of Amphoteriein B and took daily trimethoprim/sulfamethoxazole, itraconazole and three times a week gamma-lFN.Exam showed a nontender raised 8 X 10 cm area of induration and discoloration on his right anterior chest wall.Chest CT

Expression of Unique Cell Surface Proteins on B Cells of Patients with Severe Combined lmmunodefieiency (SCID) SE Schiff

From May 1992 to March 1993, 50 infants with severe combined immunodeficiency (SCID) were given bone marrow transplants at Duke University Medical Center. None received chemotherapy for conditioning or for graft-versus-host disease (GVHD) prophylaxis. Forty-one received haploidentical parental marrow depleted of T cells by soybean lectin and sheep red blood cell resetting, and nine received HLA-identical marrow. Forty (80%) survived from 1 week to almost 11 years posttransplantation, including nine of nine (100%) HLA-identical marrow recipients and 31 of 41 haploidentical recipients. T-cell function was present within 2 weeks after transplantation of unfractionated HLA-identical marrow, but not until 3 to 4 months after T-cell-depleted haploidentical marrow stem cells. All 37 patients who are more than 4 months posttransplantation have good T-cell function, and all but one have 100% donor T cells. B-cell function developed slowly or not at all in some recipients of haploidentical marrow. Fourteen (four HLA-identical and 10 haploidentical recipients) have some donor B cells; 19 patients are receiving intravenous immune globulin (IVIG) therapy.

T cell-depleted haploidentical (parental) bone marrow stem cell transplants are given to most infants with the syndrome of severe combined immunodeficiency (SCID) because they have no available HLA-identical sibling potential donors. Since they usually do not undergo cytoreduction prior to transplantation, these children later demonstrate mixed hematopoietic chimerism. Most often, T cells (but usually not B lymphocytes, macrophages, or other hematopoietic cells) can be shown to be of donor type. The origin of natural killer (NK) cells in such chimeras has not been reported. Two lymphocyte lines derived from the CD16+ fraction of an adenosine deaminase (ADA)-deficient male SCID's blood mononuclear cells (MNC) 13 months following maternal marrow stem cell transplantation demonstrated typical phenotypic and functional characteristics of NK cells after expansion. Karyotyping showed both lines to be XX. Thus, NK cell engraftment can occur in SCID infants who have not been conditioned, even when significant NK cell function is present before transplantation.

Transplacentally acquired lymphoid chimerism was detected in two infants with severe combined immunodeficiency (SCID) by two-colour cytofluorographic studies. These cells had no demonstrable function in studies in vitro. Following T cell-depleted maternal bone marrow stem cell transplantation, evidence of T cell function was detected 20 and 50 days later, and transient B cell function was detected 50 days later. These immune functions appeared much sooner than the 90-120 days usually required for T cell function and the 2-2.5 years for B cell function to develop after haplo-identical stem cell transplants into SCID infants without transplacental engraftment. The presence of maternal lymphoid chimerism did not interfere with haplo-identical marrow cell engraftment, even though no pre-transplant immunosuppression was given. This observation suggests that the transplanted maternal marrow stem cell in some way conferred reactivity on the engrafted but apparently non-functional mature T cells that had entered the fetal circulation transplacentally.