Upper limb malformations in DiGeorge syndrome

We report on upper limb anomalies in two children with a complete DiGeorge sequence: conotruncal defects, hypocalcemia, thymic aplasia, and facial anomalies. One child had preaxial polydactyly, and the other had club hands with hypoplastic first metacarpal. In both patients, molecular analysis documented a 22qll deletion. To our knowledge, limb anomalies have rarely been reported in DiGeorge syndrome, and they illustrate the variable clinical expression of chromosome 22qll deletions. © 1995 Wiley-Liss, Inc.     

Preimplantation genetic diagnosis of DiGeorge syndrome

We report the first case of preimplantation genetic diagnosis used in order to avoid chromosomal imbalance in the progeny of a woman mildly affected by DiGeorge syndrome and carrier of a microdeletion of chromosome 22q11.2. In total, seven embryos were biopsied in three separate treatments and analysed by fluorescent in-situ hybridization (FISH). Of these, four were carrying the deletion, two were normal and in one the analysis was inconclusive. The diagnostic procedure was performed within 5 h. This allowed the biopsied embryos to be transferred the same day as the biopsy was taken (day 3). Two embryos were transferred in the third treatment, but no pregnancy was established. Patients with a 22q11 microdeletion, who have a 50% risk of transmitting the deletion to their offspring, can now be offered preimplantation genetic diagnosis using FISH for the detection of a 22q11 deletion.      

Long-term assessment of T-cell populations in DiGeorge syndrome

BACKGROUND: Patients with DiGeorge syndrome present with a broad range of T-cell deficiency. Partial DiGeorge syndrome (pDGS) is a preferred designation for patients with detectable T-cell function. Among immunology experts, there is no uniform opinion on the necessity of T-cell precautions for pDGS patients. Few studies have addressed the natural course of their immune function over time. OBJECTIVE: The objective of this study was to describe the natural history of immune parameters in pDGS. METHODS: We reviewed the medical records of 45 pDGS patients. Peripheral blood T-cell subsets counts and percentages were recorded at 1, 6, 12, 18, 24, 30, 48, 60, 72, 96, and 120 months of age, and the rates of change of T-cell measurements over the follow-up period (slopes) were calculated for each individual. Humoral immunity was evaluated by quantification of immunoglobulins and by testing antibody titers to recall antigens. RESULTS: T-cell subsets counts from pDGS patients were generally lower than those of age-matched normal populations but were not severely depressed (ie, CD4+ T-cell percentage less than 15%). The median of the slopes for CD3+, CD4+, and CD8+ T-cell percentages were -0.7%, -0.8%, and -0.1%/month, respectively, in the first year of age and 0.1%/month for each subpopulation from 12 to 120 months of age. Lymphoproliferative responses to phytohemagglutinin were adequate at all ages. Immunoglobulin deficiencies or inadequate production of specific antibodies were not detected. CONCLUSIONS: In our pDGS patient cohort, a significant deterioration of T-cell number or function did not occur over time. Clinical implications of this finding include the possibility of discontinuing T-cell deficiency precautions and frequency of reevaluations of pDGS patients with stable and adequate immune function.     

Selective polysaccharide antibody deficiency in familial DiGeorge syndrome.

A family including three children with DiGeorge syndrome is described. One child died in the neonatal period from cardiac anomalies accompanying complete DiGeorge syndrome. The two surviving siblings shared a common set of pharyngeal pouch anomalies and immunodeficiency consistent with partial DiGeorge syndrome, and other morphologic anomalies characteristic of the velocardiofacial syndrome with which familial DiGeorge syndrome is associated (reviewed in reference 1). Both had normal karyotypes. Both presented with recurrent otitis media and sinopulmonary infections, CD4+ T cell lymphopenia, and defective DCH skin test responses to recall T cell antigens. Both had low serum IgM levels and IgG4 levels at the lower limits of normal. Immunization with bacterial polysaccharides resulted in impaired IgG antibody responses to the same set of antigens (H. influenzae polyribophosphate and S. pneumoniae capsular serotypes 9N and 14), while responses to protein antigens were intact. Both siblings were treated successfully with intravenous gamma globulin. The pattern of selective antibody deficiency in these patients with familial DiGeorge syndrome suggests a heritable lesion in certain regulatory antipolysaccharide CD4+ T cell subpopulations.     

DiGeorge syndrome: part of CATCH 22.

DiGeorge syndrome (DGS) comprises thymic hypoplasia, hypocalcaemia, outflow tract defects of the heart, and dysmorphic facies. It results in almost all cases from a deletion within chromosome 22q11. We report the clinical findings in 44 cases. We propose that DiGeorge syndrome should be seen as the severe end of the clinical spectrum embraced by the acronym CATCH 22 syndrome; Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcaemia resulting from 22q11 deletions.     

Immunologic reconstitution in 22q deletion (DiGeorge) syndrome

Adoptive transfer of mature T cells (ATMTC) through bone marrow (BM) transplantation, first attempted over 20 years ago, has recently emerged as a successful therapy for complete 22q deletion syndrome (22qDS). This provides a potential option to thymic transplantation (TT) for immune reconstitution in 22qDS. Compared to thymic transplant, ATMTC is an easier procedure to accomplish and is available at more centers. However, there are differences in the nature of the T-cell reconstitution that results. Predictably, more naïve T cells and recent thymic emigrants are present in patients treated with thymus transplant. There are no significant differences in mortality between the two procedures, but the number of patients is too limited to conclude that the procedures are equally effective. Adoptive transfer should be pursued as a reasonable treatment for 22qDS patients requiring immune reconstitution when thymus transplant is not available.     

Long-term results of bone marrow transplantation in complete DiGeorge syndrome

BACKGROUND: Therapeutic options for DiGeorge syndrome (DGS) with profound T-cell deficiency are very limited. Thymic transplantation has shown promising results but is not easily available. Hematopoietic cell transplantation (HCT) has been successful in restoring immune competence in the short term. OBJECTIVE: Present the long-term follow-up of 2 patients with complete DGS who received bone marrow transplants in the neonatal period from HLA-matched siblings, and perform a multicenter survey to document the status of other patients with DGS who have undergone HCT. METHODS: Immune function assessment by immunophenotyping, lymphocyte proliferation, T-cell receptor excision circles, single nucleotide polymorphism mapping arrays, spectratyping, cytogenetics, and fluorescence in situ hybridization were used. RESULTS: Among reported patients with DGS receiving HCT, survival is greater than 75%. Our patients are in their 20s and in good health. Their hematopoietic compartment shows continuous engraftment with mixed chimerism, normal T-cell function, and humoral immunity. Circulating T cells exhibit a memory phenotype with a restricted repertoire and are devoid of T-cell receptor excision circles. CONCLUSION: These features suggest that T-cell reconstitution has occurred predominantly through expansion of the donors' mature T-cell pool. Although restricted, their immune systems are capable of providing substantial protection to infection and respond to vaccines. We conclude that bone marrow transplant achieves long-lived reconstitution of immune function in complete DGS and is a good alternative to thymic transplantation in patients with a suitable donor. CLINICAL IMPLICATIONS: Bone marrow transplant in complete DGS using an HLA-matched sibling donor provides long-lasting immunity and is a suitable and more available alternative to thymic transplantation.