Complete DiGeorge Syndrome Research Articles

Complete DiGeorge Syndrome Due to CHD7 Mutation

Complete DiGeorge Syndrome Due to CHD7 Mutation

Unrelated donor lymphocyte infusions as a treatment of immunodeficiency in complete DI George syndrome

Complete DiGeorge syndrome (DGS) is a rare congenital disorder characterized by number of developmental defects and T-cell deficiency. We present an infant with multiple anomalies (choanal and esophageal atresia, coloboma, tracheobronchomalacia, etc.), diagnosed at the age of 2 months with complete DGS (absence of T cells, no response to mitogens, absent thymus), treated with unrelated donor lymphocyte infusion (DLI). During first 7 months of age he required long-term ventilation, suffered recurrent infections, and sepsis.

Parathyroid Gland Transplantation without Posttransplantation Immunosuppression

RATIONALE: Determine if combined thymus and parathyroid gland transplantation in a patient with DiGeorge syndrome will result in function of both organs. METHODS: The patient had both athymia with a total T cell count of 29 cells/μL and profound hypoparathyroidism with a parathyroid hormone level below the limit of detection. Allogeneic postnatal cultured thymus and a maternal parathyroid gland were transplanted after conditioning with 3 doses of rabbit antithymocyte globulin. The mother, thymus donor, and patient had partial HLA matching. RESULTS: The parathyroid hormone level was normal when first tested on day +17 and has since remained normal. The patient weaned off all calcium supplementation. On day +139, she developed a bacterial infection of her central line, during which she maintained ionized calcium levels above 1.10 mmol/L without the requirement for calcium supplementation. At day +213, her ionized calcium levels remain within normal limits (1.24 mmol/L). Thymic function has been excellent. A thymus graft biopsy performed on day +80 showed evidence of thymopoiesis. Naïve T cells were detectable in the blood on day +86, with progressively increasing numbers over time (naïve CD4+ 114 cells/μL and naïve CD8+ 42 cells/μL on day +202). The total T cell count increased over time (258 cells/μL on day +202), as well. Normal PHA responses were seen on days +157 and +202. The patient did not require any posttransplantation immunosuppression. CONCLUSIONS: Parathyroid transplantation, when combined with thymus transplantation in this patient with complete DiGeorge syndrome, led to parathyroid function without posttransplantation immunosuppression.

Sa.110. Atypical Complete DiGeorge Syndrome Presenting with Hypogammaglobulinemia, Lymphadenopathy, Rash, and Eosinophilia

Sa.110. Atypical Complete DiGeorge Syndrome Presenting with Hypogammaglobulinemia, Lymphadenopathy, Rash, and Eosinophilia

Minitransplant Using Repeated Unrelated Donor Lymphocyte Infusions as a Treatment of Immunodeficiency in Complete DiGeorge Syndrome.

Complete DiGeorge syndrome (DGS) is a congenital disorder characterized by developmental defects of the heart, parathyroid glands and thymus associated with T-cell deficiency. Peripheral expansion of mature donor T cells thus represents a rational therapy. We present an infant with complete DGS treated with unrelated donor lymphocyte infusion (DLI). A Caucasian boy with multiple anomalies including choanal and esophageal atresia, congenital heart defects, retinal coloboma, tracheobronchomalacia, and gastroesofageal reflux was diagnosed with complete DGS at the age of 2 months. Lymphocyte subsets showed absence of T cells (0.0021x106/mL T cells, 1.9x106/mL lymphocytes at diagnosis) with no response to mitogens and absence of thymus. Microdeletion 22q11 was not found. During first 7 months of age he required long-term ventilation. At the same time, he suffered recurrent infections and sepsis. He had no sibling and no fully matched unrelated donor was available. At the age of six months the first dose of DLI (1x106/kg CD3+; 2x105/kg CD34+) was administered from an unrelated donor (mismatched for B and Cw alleles) with no conditioning regimen and no graft versus host disease (GVHD) prophylaxis. Although several units of blood products were not irradiated by mistake (9 in total, 8 times prior the 1st DLI), there was no proof of their engraftment. On day +10 after first DLI the boy developed severe isolated skin acute GVHD (stage 3–4) complicated with sepsis, cardiopulmonary instability and capillary leak syndrome, treated with antithymocyte globulin (rATG), cyclosporin A (CsA) and corticosteroids with a complete resolution of GVHD. Ventilation support was terminated at the age of 7 months. On day +36 after 1st DLI he was given the 2nd DLI (0.9x106/kg CD3+) from the same donor with no conditioning and with GVHD prophylaxis consisting of continued CsA. Severe documented complications were EBV infection 4 weeks after application (peripheral expansion of CD8+ donor cells started, treated with CsA withdrawal and 2 doses of rituximab). Isolated cholestatic liver GVHD manifested 1 month after second DLI, progressed to stage 4 over 3 weeks, successfully treated with corticosteroids, CsA and rATG. Since day+19 after 1st DLI, the donor genotype was documented in FACS-sorted T cells. Response to mitogens appeared and is now comparable to healthy controls. We used 7-color flow cytometry in subsequent specimens (three at the time of this abstract submission) to specify the developmental stage of the engrafted T cells. Central memory (CD27posCD45RAneg) stages dominate in the peripheral blood CD4 and CD8 cells (64 to 81% and 52 to 95%, respectively), which was higher than in control blood. Effector memory cells are increased in CD4 subset but decreased in CD8, whereas naive cells are decreased or normal. The patient, age 13 months, is now 6 months after 2nd DLI still on immunosupression (CsA and steroids), slowly started to gain his developmental milestones. We believe that infusions of small doses of DLI from an unrelated donor represent an adequate therapy for complete DiGeorge syndrome. Supported by NI 7410-3, MSM0021620812

Patients with Complete Digeorge Syndrome and Cutaneous Manifestations: A Histopathologic and Immunohistochemical Study

BACKGROUND: DiGeorge Syndrome is a congenital anomaly with a constellation of findings including thymic hypoplasia. Approximately 1 in 250 patients has complete DiGeorge syndrome with athymia. Many athymic patients develop severe eczema/erythroderma associated with oligoclonal circulating T cells. DESIGN: Nine biopsies from eight athymic patients with severe rash and circulating oligoclonal T cells were studied. Immunohistochemistry with CD3, CD4, CD8 and TIA‐1 was performed. RESULTS: The stratum corneum showed parakeratosis (78%), most commonly confluent. Neutrophilic abscesses were commonly identified (44%). The epidermis exhibited exocytosis (100%), spongiosis (89%), dyskeratosis (89%), acanthosis (56%), and satellitosis (44%). Dermal changes included perivascular (56%), perifollicular (33%), and perieccrine (11%) lymphocytic infiltrates. Eosinophils were identified (78%); most commonly in both the dermis and epidermis. The majority of lymphocytes were CD3 positive with a slight CD4 over CD8 predominance in the dermis and epidermis. 67% of cases contained TIA‐1 positive cells. CONCLUSION: Skin lesions from patients with complete DiGeorge syndrome who develop a rash that clinically resembles severe eczema/erythroderma display a constellation of histologic findings. The presence of dyskeratinocytes, satellitosis, and parakeratotic scale with neutrophils distinguishes these lesions from eczema and other spongiotic disorders. The pathophysiologic role of the inflammatory cells in this entity requires additional study.

Treatment of Complete DiGeorge Syndrome by Repeat Transfusions of Blood Lymphocytes from an HLA-Identical Sibling Donor.

DiGeorge syndrome (DGS) is a congenital disorder characterized by facial dysmorphies, hypoparathyroidism, cardio-vascular malformations and variable T-cell deficiency due to thymic hypoplasia. We present a male infant with complete absence of T-cells and thymus successfully treated by repeat blood lymphocyte transfusions. According to previous experience of bone marrow transplantation in a similar patient, T-cell reconstitution is possible by peripheral expansion of mature donor cells, independent of stem cell engraftment. Our patient received at the age of four months an initial transfusion of blood lymphocytes from his HLA-identical brother, containing 1x108 T-cells/ kg. Ten days later he developed mild cutaneous GvHD, which resolved spontaneously without immunosuppressive therapy. Lymphocyte transfusions were repeated three times at 4 weeks intervals without reappearance of GvHD. T-cells developed within two months after the first transfusion and since then remain at levels between 500–1000/μl with a proportion of 25% disclosing a CD45RA+ phenotype. In chimerism analysis T-cells are exclusively of donor origin. The T-cell receptor repertoire is similarly diverse as in the donor. After more than 2 years of follow up the boy is not suffering from severe infections and shows no signs of autoimmune disease. Following immunization, antibody titres normalized. Conclusion: In infants with complete DGS transfusions of blood lymphocytes from a matched family donor may lead to long-lasting engraftment of functional T cells and stable chimerism and represents a potentially helpful therapeutic option.

Thymic transplantation for complete DiGeorge syndrome: Medical and surgical considerations

Background/purpose Complete DiGeorge syndrome results in the absence of functional T cells. Our program supports the transplantation of allogeneic thymic tissue in infants with DiGeorge syndrome to reconstitute immune function. This study reviews the multidisciplinary care of these complex infants. Methods From 1991 to 2001, the authors evaluated 16 infants with complete DiGeorge syndrome. All infants received multidisciplinary medical and surgical support. Clinical records for the group were reviewed. Results Four infants died without receiving a thymic transplantation, and 12 children survived to transplantation. The mean age at time of transplantation was 2.7 months (range, 1.1 to 4.4 months). All 16 infants had significant comorbidity including congenital heart disease (16 of 16), hypocalcemia (14 of 16), gastroesophageal reflux disease or aspiration (13 of 16), CHARGE complex (4 of 16), and other organ involvement (14 of 16). Nontransplant surgical procedures included central line placement (15 of 16), fundoplication or gastrostomy (10 of 16), cardiac repair (10 of 16), bronchoscopy or tracheostomy (6 of 16), and other procedures (12 of 16). Complications were substantial, and 5 of the 12 transplanted infants died of nontransplant-related conditions. All surviving infants have immune reconstitution, with follow-up from 2 to 10 years. Conclusions Although the transplantation of thymic tissue can restore immune function in infants with complete DiGeorge syndrome, these children have substantial comorbidity. Care of these children requires coordinated multidisciplinary support.

Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome

AbstractComplete 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+CD62L+) per cubic millimeter (mm3) and all had some proliferative response to the mitogen phytohemagglutinin. Four infants had rash, lymphadenopathy, and oligoclonal populations of T cells in the periphery. Five of 6 patients are alive at the follow-up interval of 15 months to 30 months. The 5 surviving patients developed a mean of 983 host CD3+ T cells/mm3 (range, 536/mm3-1574/mm3), a mean of 437 recent thymic emigrants/mm3 (range, 196/mm3-785/mm3), and normal proliferative responses to phytohemaglutinin (follow-up from day 376 to day 873). The TCR repertoire became polyclonal in patients who presented with oligoclonal T cells. All patients had thymopoiesis on allograft biopsy. Postnatal thymus transplantation after treatment with Thymoglobulin shows promise as therapy for infants with complete DiGeorge syndrome who have significant proliferative responses to mitogens or who develop rash, lymphadenopathy, and oligoclonal T cells.

Complete DiGeorge syndrome: Development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases

BackgroundFive patients with DiGeorge syndrome presented with infections, skin rashes, and lymphadenopathy after the newborn period. T-cell counts and function varied greatly in each patient. Initial laboratory testing did not suggest athymia in these patients. ObjectiveThe purpose of this study was to determine whether the patients had significant immunodeficiency. MethodsResearch testing of peripheral blood included immunoscope evaluation of T-cell receptor β variable gene segment repertoire diversity, quantification of T-cell receptor rearrangement excision circles, and detection of naive T cells (expressing CD45RA and CD62L). ResultsThe patients were classified as having DiGeorge syndrome on the basis of syndromic associations and heart, parathyroid, and immune abnormalities. Immunoscope evaluation revealed that the T-cell repertoires were strikingly oligoclonal in all patients. There were few recent thymic emigrants, as indicated by the very low numbers of naive T cells (<50/mm3) and the absence of T-cell receptor rearrangement excision circles. These studies showed that all 5 patients were athymic. Two patients died, one from infection. No thymus was found during the complete autopsy performed on one patient. ConclusionPatients with DiGeorge syndrome, skin rash, and lymphadenopathy should undergo analysis of naive T-cell numbers and of T-cell receptor β variability segment repertoire to determine whether they are athymic, even if they have T cells with mitogen responsiveness. It is important for physicians to realize that patients with complete DiGeorge syndrome remain profoundly immunodeficient after development of these atypical features (rash, lymphadenopathy, and oligoclonal T cells). Prompt diagnosis is necessary for appropriate management.

Sarcoidosis in 3 adolescent patients with DiGeorge syndrome

Rationale Three adolescent patients with DiGeorge syndrome developed sarcoidosis. Two of these patients were also being treated with growth hormone (GH). Methods Retrospective chart reviews were conducted. Results The first patient is a 13 year old male with complete Digeorge syndrome who received 2 fetal thymus transplants in infancy and developed respiratory symptoms thought to be asthma at 5.5 years. He began GH and continued intermittently through age 11 years. Lymph node biopsies at age 8 and 11 years showed noncaseating granulomas leading to the diagnosis of sarcoidosis. The second patient is a 16 year old male with partial Digeorge syndrome who developed splenomegaly near the end of his first decade of life. He later developed diffuse adenopathy and respiratory symptoms. Lymph node and splenic tissue at 14.9 years showed noncaseating granulomas. He has been treated with GH since age 15 years. The first two patients responded to treatment with steroids. The third patient is a 19 year old female with partial Digeorge syndrome who developed skin nodules and lymphadenopathy at age 17 years. A skin nodule biopsy revealed granulomatous dermatitis consistent with sarcoidosis. She responded to treatment with hydroxychloroquine. Conclusions Patients with Digeorge syndrome are at risk for developing sarcoidosis.

Histologic and molecular assessment of human thymus.

Most work describing the histopathology of normal human thymus has focused on pediatric thymus because of tissue availability and high thymopoietic activity. However, pathologic examination of the thymus can provide information about immune status that is relevant to the clinical care of patients of all ages. Understanding age-related changes in the relative abundance and composition of anatomic compartments within the thymus is critical for evaluation of the thymus in normal adults and patients with diseases that affect the thymus. The purpose of this review is to acquaint diagnostic pathologists with some of the newer histologic, flow cytometric, and molecular techniques for assessment of non-neoplastic thymus. Diagnostic criteria are presented for assessment of thymic function and for determining the mechanisms underlying thymic hyperplasia. Accurate assessment of thymic function is critical for the diagnosis and treatment of patients with complete DiGeorge syndrome and can complement the clinical care of patients with a variety of disorders that affect the immune system.

Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients

AbstractComplete 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/mm3. Allogeneic postnatal cultured thymus tissue was transplanted. T-cell development was followed by flow cytometry, lymphocyte proliferation assays, and T-cell receptor Vβ (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, long-term 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.

Impaired thymic output and restricted T-cell repertoire in two infants with immunodeficiency and early-onset generalized dermatitis

We evaluated the T-cell repertoire and the thymic output in two infants, one with Omenn Syndrome (OS) and another with complete DiGeorge Syndrome (DGS), who developed generalized dermatitis. The patients shared common T-cell abnormalities, as demonstrated by the low response to mitogenic stimulation, by an unusual usage of specific T-cell receptor (TCR) segments, and by a reduction of TCR diversity in both alpha/beta and gamma/delta populations. Furthermore, they both showed an impaired thymic function, as assessed by the low number of TCR recombination excision circles, which are formed from excised DNA during the rearrangement of TCR genes. These data indicated that generalized erythrodermia may be present in different forms of T-cell immunodeficiency and may reflect intrinsic defects in either V(D)J recombination or in thymic development, leading to the peripheral expansion of T-cell clonotypes, that bear peculiar TCR chains.

Complete DiGeorge syndrome: Persistence of profound immunodeficiency

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. (J Pediatr 1998;132:15-21)

Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus.

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.

The ontogeny of human lymphocyte recirculation: high endothelial cell antigen (HECA‐452) and CD44 homing receptor expression in the development of the immune system

In the present report we have studied the expression of a lymphocyte homing receptor, the CD44 antigen, and of HECA-452, a high endothelial-specific antigen, during the development of the human immune system. We found that prothymocyte immigrants of the thymus already expressed the CD44 antigen. Similarly, the first peripheral T lymphocytes in fetal lymph nodes, tonsils and gut-associated lymphoid tissue were also CD44+. Cortical thymocytes and germinal center cells were CD44-. CD44 antigen expression was, thus, not limited to mature recirculating lymphocytes. This suggests that CD44 may not only be involved in recirculation of mature lymphocytes but also in the migration of prothymocytes to their site of maturation, i.e. the thymus. High endothelial venules (HEV) were not demonstrable at the early onset of lymphocyte immigration into the developing lymphoid organs. However, when large-scale influx of lymphocytes occurred, it paralleled HEV development. HECA-452 antigen expression preceded the morphological transformation of endothelium into a HEV phenotype. Expression of this antigen therefore, independently reflected the specialized nature of high endothelium. In a patient with complete DiGeorge's syndrome normal HEV developed, indicating that the presence of T lymphocytes is not a requirement for HEV development. Interestingly, a subpopulation of venules located in the thymic medulla near the cortico-medullary junction expressed the HECA-452 antigen. These vessels, which had flat or intermediately high endothelium, are probably involved in lymphocyte migration to the thymus.

Thymosin-induced leukocyte histamine release reaction in an infant with DiGeorge syndrome

A limited number of T-cell responses but no change in clinical condition were recorded in a patient with complete DiGeorge syndrome treated with thymosin for a 59-day period. A striking rise in IgE was observed, probably reflecting the appearance of reaginic antibodies to some constituent of thymosin. Although no local or systemic anaphylactic reactions were observed, the patient's serum caused a significant increase in histamine release from normal leukocytes in the presence of thymosin. Thus, allergic reactions to thymosin may complicate therapy of thymic deficiency diseases.

681 THYMOSIN TREATMENT OF DI GEORGE SYNDROME

A 2½-month-old infant with complete DiGeorge syndrome was treated with bovine thymosin fraction V. Initial evaluation revealed normal numbers of blood lymphocytes, 29% EAC rosettes, 41% sIg lymphocytes and no T-rosettes. T-rosettes rose to 15% upon in vitro incubation with thymosin. There was no in vitro response to PHA, PWM, SLO, candida or allogeneic cells, and delayed skin reactivity to SKSD, candida and DNCB was absent. IgG, A, M and E were 175 mg%, 15 mg%, 40 mg% and 10 Iu/ml respectively. He received 10 mg/day of thymosin for 21 days, followed by 20 mg/day for an additional 17 days, and weekly injections of the same dose thereafter. During therapy the lymphocyte count did not change, but T-rosettes rose to 26% while EAC rosettes and sIg lymphocytes decreased to 14% and 10% respectively. Lymphocytes remained unreactive in vitro to PHA, PWM, candida and allogeneic cells, but reacted to SLO (S.I.=42). Delayed skin reactions remained negative. IgG, A and M were 120 mg%, 20 mg% and 62 mg% at 4 months of age, while IgE rose to 255 Iu/ml. No specific antibodies were detected. He died of sepsis at 4½ months of age. In the postmortem no thymus or parathyroids could be found, and the lymphoid tissue revealed depleted T-dependent areas with poorly developed germinal centers. Similar partial reconstitution of T-cell functions, presumably resulting from the maturation of null-cells, have been observed in other immunodeficiencies treated with thymic extracts.

Parathyroid transplantation.

AbstractThis is a review of our current experience with the technique of parathyroid transplantation in man. We have performed 68 autografts and 2 allografts. The indications for parathyroid autotransplantation include primary and secondary parathyroid hyperplasia, repeat neck exploration for persistent or recurrent hyperparathyroidism, and total thyroidectomy for carcinoma. Indications for allotransplantation include the unsuccessful medical management of hypoparathyroidism and complete DiGeorge's syndrome. Graft function was successful in a high percentage of cases as documented by a normal serum calcium concentration with the grafted parathyroid tissue as the only source of parathyroid hormone, by detecting high concentrations of PTH in the antecubital vein draining the grafted arm and, histologically, by light and electron microscopy of the grafts.