DiGeorge syndrome, which falls within a wider phenotypic spectrum associated with deletions of 22q11.2, is associated with a number of endocrine disorders. These include hypoparathyroidism, hypothyroidism and growth hormone deficiency. We report an unusual case of autoimmune hyperthyroidism (Graves' disease) presenting in a 3 year-old male with DiGeorge syndrome. The development of endocrine specific autoimmune disease in a syndrome associated with immune deficiency and the spectrum of endocrine autoimmunity associated with deletions of 22q11.2 are described. Paediatricians and patients with 22q11.2 deletions should be particularly aware of the risks of developing disorders of thyroid function.
"For example, AIRE expression in the thymus requires cross-talk between developing thymocytes and stromal cells, and this process is dependent on an organized thymic microenvironment  . A higher incidence of autoimmune phenomena, including autoimmune cytopenias   autoimmune arthritis , and autoimmune endocrinopathies , can be observed in DiGeorge syndrome (DGS)   in which abnormal thymic development may result in impaired expression of AIRE and, potentially, of other transcription factors that regulate expression of organ-specific antigens in the thymus resulting in defective central tolerance  . However, it should be mentioned that in DGS autoimmunity may also be explained by exaggerated chronic inflammatory responses, " bystander " activation of autoreactive T cells and " molecular mimicry " . "
[Show abstract][Hide abstract] ABSTRACT: The thymus is a specialized organ that provides an inductive environment for the development of T cells from multipotent hematopoietic progenitors. Self-nonself discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Tolerance represents a state of immunologic nonresponsiveness in the presence of a particular antigen. The immune system becomes tolerant to self-antigens through the two main processes, central and peripheral tolerance. Central tolerance takes place within the thymus and represents the mechanism by which T cells binding with high avidity self-antigens, which are potentially autoreactive, are eliminated through so-called negative selection. This process is mostly mediated by medullary thymic epithelia cells (mTECs) and medullary dendritic cells (DCs). A remarkable event in the process is the expression of tissue-specific antigens (TSA) by mTECs driven by the transcription factor autoimmune regulator (AIRE). Mutations in this gene result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a rare autosomal recessive disease (OMIM 240300). Thus far, this syndrome is the paradigm of a genetically determined failure of central tolerance and autoimmunty. Patients with APECED have a variable pattern of autoimmune reactions, involving different endocrine and nonendocrine organs. However, although APECED is a monogenic disorder, it is characterized by a wide variability of the clinical expression, thus implying a further role for disease-modifying genes and environmental factors in the pathogenesis. Studies on this polyreactive autoimmune syndrome contributed enormously to unraveling several issues of the molecular basis of autoimmunity. This review focuses on the developmental, functional, and molecular events governing central tolerance and on the clinical implication of its failure.
International Reviews Of Immunology 10/2012; 31(5):344-62. DOI:10.3109/08830185.2012.697230 · 4.10 Impact Factor
"Immune deficiency in these patients seems to be associated to an increased incidence of autoimmune diseases [106–108], in particular cytopenias [109, 110], arthritis , and endocrinopathies . "
[Show abstract][Hide abstract] ABSTRACT: Primary immunodeficiencies (PIDs) are disorders of the immune system, which lead to increased susceptibility to infections. T-cell defects, which may affect T-cell development/function, are approximately 11% of reported PIDs. The pathogenic mechanisms are related to molecular alterations not only of genes selectively expressed in hematopoietic cells but also of the stromal component of the thymus that represents the primary lymphoid organ for T-cell differentiation. With this regard, the prototype of athymic disorders due to abnormal stroma is the Nude/SCID syndrome, first described in mice in 1966. In man, the DiGeorge Syndrome (DGS) has long been considered the human prototype of a severe T-cell differentiation defect. More recently, the human equivalent of the murine Nude/SCID has been described, contributing to unravel important issues of the T-cell ontogeny in humans. Both mice and human diseases are due to alterations of the FOXN1, a developmentally regulated transcription factor selectively expressed in skin and thymic epithelia.
"In the 22q11.2 DS, autoimmune disease may occur in up to 30% of patients and includes autoimmune cytopenias, autoimmune endocrinopathies, and autoimmune arthritis.15–18 Previous studies reported cases of autoimmune hemolytic anemia and immune thrombocytopenia, but only a few patients with Evans syndrome have been described.15,16,19–21 "
[Show abstract][Hide abstract] ABSTRACT: We report a case of an 8-year-old male patient with Evans syndrome and severe hypogammaglobulinemia, subsequently in whom the 22q11.2 deletion syndrome (22q11.2 DS) was diagnosed. No other clinical sign of 22q11.2 DS was present with the exception of slight facial dysmorphism. The case is of particular interest because it suggests the need to research chromosome 22q11.2 deletion in patients who present with autoimmune cytopenia and peculiar facial abnormalities, which could be an atypical presentation of an incomplete form of 22q11.2 DS.
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