DiGeorge syndrome

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DiGeorge syndrome Primary immunodeficiency disease caused by failure of the thymus to develop properly, resulting in a deficiency of T cells. 

Budarf M. L., Konkle B. A., Ludlow L. B., et al. Identification of a patient with Bemard-Souli-er syndrome and a deletion in the DiGeorge/velo-cardiofacial chromosomal region in 22q 11.2. Hum Mol Genet 1995 4, 763-6. 

Primary immunodeficiency diseases (PIDs) are defects of the immune system that are due to genetic abnormalities or some failure in normal embryological development. They are usually apparent at birth or develop shortly thereafter. Approximately 70 PIDs have been described, including those specihc for humoral immunity (e.g., X-linked agammaglobulinemia, immune globulin [Ig] A dehciency), cellular immunity (e.g., DiGeorge s syndrome), or both (e.g., severe combined immunodehciency syndrome). 

By promoting the formation of T lymphocytes, thymic factors are used to enhance T-lymphocytic functions. Thymic factors have been used with some success in clinical trials in patients with severe combined immunodeficiency, DiGeorge s or Nezelof s syndrome, and viral disorders. Studies with thymodulin show promise in treating symptoms in asthmatics and patients with allergic rhinitis. The primary consideration in the use of thymic factors for immunodeficiency states is the presence of T-lymphocyte precursors. 

In addition to its antiviral actions, interferon has an antiproliferative effect and modifies the functions of macrophages and natural killer cells. Thymosin, a protein synthesized by the epithelioid component of the thymus, may be potentially valuable in patients with DiGeorge s syndrome or other T cell deficiency states. Levamisole augments T cell-mediated immunity and may be of value in the immunodeficiency associated with Hodgkin s disease. 

A great variety of patients with primary immunodeficiency disorders have now been studied with both bioassay procedures (Bach et al., 1972, 1975 Incefy et al, 1977 Lewis et al, 1978 Iwata et al., 1981). Serum thymic hormone levels are lower than age-matched normal levels for all patients studied with DiGeorge s syndrome, and a high proportion of patients with severe combined immunodeficiency. In patients vdth the complete Di-George s syndrome, thymic hormone levels are always undetectable, whereas in the partial form, FTS-like bioactivity is measurable but lower than normal. In some cases in which thymus grafi ing was utilized as a therapeutic modality, serum FTS-like bioactivity became detectable as early as 1 day after transplantation (Incefy et al., 1977) and eventually returned to normal (Lewis et al, 1978). These results have suggested that the increase in serum thymic hormone levels resulted from production by the transplanted thymus. In patients with SCID, regardless of the bioassay employed, thymic hormone levels were found to be either undetectable or much lower than that of age-matched normal donors. In rare cases serum FTS-like bioactivity... 

Diseases Associated with Normal Serum Thymic Hormone Bioactivity. In contrast to patients with SCID or DiGeorge s syndrome, infants with Bruton s agammaglobulinemia all have exhibited normal serum thymic hormone bioactivity. This result is consistent with the concept that primary disorders of B cell development are not associated with dysfunction of the endocrine thymus. There are several other human diseases that are unex-... 

The initial Taj RIA that employs rabbit hetero mtiserum has been used to evaluate serum levels in children with primary immunodeficiency disorders (D. Wara et al., 1982). With this assay, 11 of 13 children with combined immunodeficiency, 5 to 7 children with ataxia-telangiectasia and all 3 patients with Wiscott-Aldrich syndrome exhibited serum Taj levels below the mean of the normal age-matched donors. Such findings were similar to those reported using the Bach-Dardenne bioassay (Iwata et al., 1981). A major inconsistency, however, was in children with DiGeorge s syndrome. Whereas all such children manifested low serum thymic hormone bioactivity, only 3 of 6 exhibited levels below the mean of normals using the Taj RIA and serum levels were actually quite high in 2. 

In contrast to DiGeorge s syndrome, thymus transplantation has usually not been successful in patients with SCID (van Bekkum, 1973 Hong, 1976), although occasional T cell reconstitution has been noted (Murphy et al., 1976). In a more rational approach, thymus tissue has been transplanted in conjunction with fetal liver as a source of stem cells for treatment of SCID,... 

Thymus transplantation has also been employed experimentally in a variety of conditions including chronic mucocutaneous candidiasis, ataxia-telangiectsia, and Wiscott-Aldrich syndrome, but in these cases results have generally been disappointing (reviewed in Pahwa et al., 1979 Skotnicki et al., 1984). Thus, the only immunodeficiency state that has clearly demonstrated a lasting improvement of T cell immunity following thymus transplantation is DiGeorge s syndrome. 

The rapidity of immune reconstitution in patients with DiGeorge s syndrome following fetal thymic transplants suggested that humoral products released from the transplanted tissues were responsible for the beneficial... 

By far the most important clinical application of the thymic hormones is their potential therapeutic use in selected patients with primary immunodeficiency disorders (e.g., DiGeorge s syndrome), infections, cancer, and autoimmune disorders. The overwhelming evidence available to date indicates that thymic hormones exert immunorestorative effects when administered to patients with impaired T cell immunity. However, it remains for future clinical investigations to identify the most active preparations, to firmly establish the optimal dosages and sehedules for their administration, and to determine which clinical conditions will benefit from their use. 

D. Thymosin Thymosin is a protein hormone from the thymus gland that stimulates the maturation of pre-T cells and promotes the formation of T cells from ordinary lymphoid stem cells. Thymosin-containing preparations have been used in DiGeorge s syndrome (thymic aplasia), but their efficacy in other immune deficiency states has not been established. 

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