Abstract
DiGeorge syndrome (DGS) presents with a wide spectrum of thymic pathologies. Nationwide neonatal screening programs of lymphocyte production using T-cell recombination excision circles (TREC) have repeatedly identified patients with DGS. We tested what proportion of DGS patients could be identified at birth by combined TREC and kappa-deleting element recombination circle (KREC) screening. Furthermore, we followed TREC/KREC levels in peripheral blood (PB) to monitor postnatal changes in lymphocyte production.MethodsTREC/KREC copies were assessed by quantitative PCR (qPCR) and were related to the albumin control gene in dry blood spots (DBSs) from control (n = 56), severe immunodeficiency syndrome (SCID, n = 10) and DGS (n = 13) newborns. PB was evaluated in DGS children (n = 32), in diagnostic samples from SCID babies (n = 5) and in 91 controls.ResultsAll but one DGS patient had TREC levels in the normal range at birth, albeit quantitative TREC values were significantly lower in the DGS cohort. One patient had slightly reduced KREC at birth. Postnatal DGS samples revealed reduced TREC numbers in 5 of 32 (16%) patients, whereas KREC copy numbers were similar to controls. Both TREC and KREC levels showed a more pronounced decrease with age in DGS patients than in controls (p<0.0001 for both in a linear model). DGS patients had higher percentages of NK cells at the expense of T cells (p<0.0001). The patients with reduced TREC levels had repeated infections in infancy and developed allergy and/or autoimmunity, but they were not strikingly different from other patients. In 12 DGS patients with paired DBS and blood samples, the TREC/KREC levels were mostly stable or increased and showed similar kinetics in respective patients.ConclusionsThe combined TREC/KREC approach with correction via control gene identified 1 of 13 (8%) of DiGeorge syndrome patients at birth in our cohort. The majority of patients had TREC/KREC levels in the normal range.
Highlights
DiGeorge syndrome is a complex disorder caused by an embryopathy; it presents with a number of clinical symptoms arising from the disturbed development of the 3rd and 4th pharyngeal arches, chief amongst which are congenital heart, great vessel and parathyroid gland defects as well as a typical malformation of the face and soft palate
The analysis of control gene amplification in DiGeorge syndrome (DGS) and SCID patients showed no difference between long- and short-term stored dry blood spots (DBSs)
T cell receptor excision circle (TREC)/ kappa-deleting element recombination circles (KREC) copy numbers are expressed per one microgram of DNA, the DNA concentration being assessed by quantitative PCR (qPCR)
Summary
DiGeorge syndrome is a complex disorder caused by an embryopathy; it presents with a number of clinical symptoms arising from the disturbed development of the 3rd and 4th pharyngeal arches, chief amongst which are congenital heart, great vessel and parathyroid gland defects as well as a typical malformation of the face and soft palate. The thymus is the location of the T-lymphocyte maturation and selection process In children, it is a dominant place of Tlymphocyte development and a source of naıve T cells [4]. In DiGeorge syndrome, the immunodeficiency is caused by dysplasia of the thymus, and it would be logical to expect abnormal development of T-cells in the thymus and abnormal TREC levels. This assumption was partially proven to be correct with the introduction of SCID (severe combined immune deficiency) screening, performed during the last 2 years in an increasing number of countries, the USA in particular [6, 7]. We tested whether addition of KREC could add more information both at birth and during the postnatal period in DiGeorge syndrome patients
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