DiGeorge syndrome: an historical review of clinical and cytogenetic features.

It is now over 28 years since Dr Angelo DiGeorge' commented on a paper by Dr Max Cooper and colleagues2 regarding the congenital absence of the thymus. At the 1965 Society for Pediatric Research (SPR) meeting, Dr Cooper gave a paper showing that the lymphoid system of the chicken consisted of two different components, the bursal system and the thymic system. Ablation of the bursal system caused agammaglobulinaemia but did not affect cellular immunity. However, thymectomy impaired cellular immunity. In his comment, Dr DiGeorge noted that there was a group of infants with congenital absence of the thymus who might represent a human homologue of the thymectomised chicks. DiGeorge and his co-worker, Dr James Arey, had noted three infants with congenital absence of the parathyroids who also had no evidence of thymic tissue. As DiGeorge stated, "the concurrent absence of both structures is not surprising if one recognizes that both are derived from common primordia. Furthermore, this association has been previously recorded although its physiologic significance has not been recognized."' Just before the 1965 SPR meeting, DiGeorge and colleagues (Drs Harold Lischner, Catherine Dacou-Voutetakis, and Hope Punnett) were in the process of studying a fourth infant with congenital hypoparathyroidism who was predicted to have absence of the thymus. In addition to the absence of the thymic shadow on chest radiograph, the infant had abnormal cellular immunity with persistent candidiasis, negative monilial skin test, and failure to reject a homologous skin graft, although the lymphocyte count, plasma cell numbers in lymph nodes, and serum immunoglobulins were normal. The infant was also noted to be 'runted' in spite of adequate control of serum calcium levels. DiGeorge suggested that all infants with congenital hypoparathyroidism should be studied for defects in cellular immunity. This was contrary to the prevailing notion that patients with absent thymus would have normal immunoglobulins and normal total peripheral blood lymphocyte counts. As DiGeorge had mentioned, thymic aplasia was first noted by Harrington3 in 1829 and later in association with congenital hypoparathyroidism by Lobdell4 in 1959. In spite of those earlier papers and the lack of a published paper by DiGeorge, Dr Robert A Good dubbed this association 'DiGeorge syndrome'.5 DiGeorge's first published paper on the subject actually did not appear until 1968 in the British Defects: Original Article Series with the proceedings of a Sanibel Island meeting on the development of the immune system.6 For additional information about the early history of DGS, I refer you to DiGeorge's paper.6 After several additional case reports ofDGS and evaluation of 18 additional cases, Dr Harold Lischner outlined the first categorisation of third and fourth branchial pouch defects in an editorial comment.7 Lischner suggested three categories. The first is the III-IV pharyngeal pouch syndrome which he defined as "congenital malformation, hypoplasia (with normal histology), or absence of the thymus and/or parathyroid glands, including significant maldescent of those organs so that they are located in the neck or other abnormal sites." Additional anomalies were noted, especially of the great vessels, micrognathia, ear defects, oesophageal atresia, blunted nose, thyroid anomalies, and endocardial cushion. DiGeorge syndrome was defined as those cases of the IIIIV pharyngeal pouch syndrome in which no thymic tissue was noted on careful postmortem examination, even in an ectopic position. The third category was partial DiGeorge syndrome in which the cases of III-IV pharyngeal pouch syndrome had defective cell mediated immunity or thymic hypoplasia by reduced thymic weight (<2 g). In addition, Lischner noted seven generalisations about partial DGS which still hold true.7 (1) Cell mediated immunity is grossly depressed. (2) Most lymphocytes in the peripheral blood and lymph nodes will be B cells. (3) The absolute lymphocyte count will usually be slightly or moderately depressed but may be normal. (4) Responsiveness of peripheral blood lymphocytes to phytohaemagglutinin in vitro may be depressed but not consistently. (5) Lymph nodes will be grossly depleted on lymphocytes in the deep cortical areas. (6) There may be some depression of antibody responses to specific immunisation, thought to be the result of the required interaction of T lymphocytes with B lymphocytes. (7) Serum immunoglobulins will be within or near the normal range. Although by 1979, DiGeorge had evaluated Institute for Molecular Genetics and Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Texas 77030, USA. F Greenberg