Replacing defective thymus function.

PURPOSE OF REVIEW: Transplantation of cultured postnatal allogeneic thymus has been successful for treating athymia, mostly associated with complete DiGeorge syndrome, for more than 20 years. Advances in molecular genetics provide opportunities for widening the range of athymic conditions that can be treated while advances in cell culture and organ/tissue regeneration may offer the prospect of alternative preparations of thymic tissue. There are potential broader applications of this treatment outside congenital athymia. RECENT FINDINGS: At the same time as further characterization of the cultured thymus product in terms of thymic epithelial cells and lymphoid composition, preclinical studies have looked at de-novo generation of thymic epithelial cells from stem cells and explored scaffolds for delivering these as three-dimensional structures. In the era of newborn screening for T-cell lymphopaenia, a broadening range of defects leading to athymia is being recognized and new assays should allow differentiation of these from haematopoietic cell defects, pending their genetic/molecular characterization. Evidence suggests that the tolerogenic effect of transplanted thymus could be exploited to improve outcomes after solid organ transplantation. SUMMARY: Thymus transplantation, the accepted standard treatment for complete DiGeorge syndrome is also appropriate for other genetic defects leading to athymia. Improved strategies for generating thymus may lead to better outcomes and broader application of this treatment.

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects.

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype-phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.