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• W1993346645 abstract "To the Editor: Newborn screening for severe T-cell immunodeficiency disorders has been recommended in the United States by using PCR quantitation and the measurement of T-cell receptor excision circles (TRECs) as a validated assay.1Routes J.M. Grossman W.J. Verbsky J. Laessig R.H. Hoffman G.L. Brokopp C.D. et al.Statewide newborn screening for severe T-cell lymphopenia.JAMA. 2009; 302: 2465-2470Crossref PubMed Scopus (163) Google Scholar TRECs are small episomal pieces of DNA that are formed during the rearrangement of T-cell receptor genes of thymocytes undergoing differentiation in the thymus. One particular TREC is the δRec-ψJα TREC produced by approximately 70% of all T cells that express the α/β T-cell receptor.1Routes J.M. Grossman W.J. Verbsky J. Laessig R.H. Hoffman G.L. Brokopp C.D. et al.Statewide newborn screening for severe T-cell lymphopenia.JAMA. 2009; 302: 2465-2470Crossref PubMed Scopus (163) Google Scholar Quantitation of these TRECs in peripheral blood T cells is a measure of recent emigrants from the thymus of naive T cells, a surrogate marker for thymopoiesis. In newborn screening, the TREC assay is performed on DNA isolated from the Guthrie card blood spots. Decreased TRECs as a measure of decreased thymopoiesis are seen in infants with congenital T-cell defects, such as severe combined immunodeficiency, and in infants with complete DiGeorge anomaly (DGA). DGA is a congenital disorder caused by the developmental defects of structures arising from the third and fourth pharyngeal pouches.2Ochs H.D. Nelson D.L. Stiehm E.R. Other well-defined immunodeficiency syndromes.in: Stiehm E.R. Ochs H.D. Winkelstein J.A. Immunologic disorders in infants & children. 5th ed. Elsevier Saunders, Philadelphia (Pa)2004: 505-579Google Scholar, 3McDonald-McGinn D.M. Sullivan K.E. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).Medicine. 2011; 90: 1-18Crossref PubMed Scopus (305) Google Scholar The prevalence of DGA is estimated as being 1:3000 to 1:6000 live births. The clinical manifestations of DGA include abnormal facial characters such as hypertelorism, low-set posteriorly rotated ears, micrognathia, bulbous tip of the nose, small “fish” mouth, congenital cardiac defects, velopharyngeal insufficiency, hypoparathyroidism, and thymic hypoplasia or aplasia. The major genetic defect in DGA is heterozygous deletion of 22q11.2, which accounts for 50% to 60% of patients.4Markert M.L. Devlin B.H. McCarthy E.A. Thymus transplantation.Clin Immunol. 2010; 135: 236-246Crossref PubMed Scopus (100) Google Scholar, 5Rope A.F. Cragun D.L. Saal H.M. Hopkin R.J. DiGeorge anomaly in the absence of chromosome 22q11.2 deletion.J Pediatr. 2009; 155: 560-565Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Most infants have thymic hypoplasia, which permits T-cell maturation and the development of adequate numbers of T cells to be protective.3McDonald-McGinn D.M. Sullivan K.E. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).Medicine. 2011; 90: 1-18Crossref PubMed Scopus (305) Google Scholar, 4Markert M.L. Devlin B.H. McCarthy E.A. Thymus transplantation.Clin Immunol. 2010; 135: 236-246Crossref PubMed Scopus (100) Google Scholar, 5Rope A.F. Cragun D.L. Saal H.M. Hopkin R.J. DiGeorge anomaly in the absence of chromosome 22q11.2 deletion.J Pediatr. 2009; 155: 560-565Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar This is known as partial DGA. In 1% of infants, there is thymus aplasia, that is, complete DGA. In this situation, T-cell development is markedly impaired; there are very low naive CD45RA+CD62L+ T-cell percentages (<5% of T cells) associated with profoundly depressed TREC levels. We present an infant in whom TRECs were initially markedly decreased but over time became normal. The clue to us that the child might have thymus function was the normal percentages of naive T cells in all flow cytometry assays. The patient presented at age 4 days in cardiac failure and respiratory distress. Interrupted aortic arch type B and ventricular septal defect were diagnosed. He experienced multiorgan failure with cardiogenic shock. After medical management and recovery, he underwent surgical repair of the interrupted aortic arch and closure of the ventricular septal defect at age 5 weeks. Unfortunately, he experienced subependymal hemorrhage and hypoxic ischemic encephalopathy of the basal ganglia, which resulted in severe neurologic impairment and seizure disorder. DGA was confirmed by demonstrating 22q11.2 microdeletion. The patient had persistent lymphopenia since initially hospitalized. The thymic shadow on the initial chest radiograph was absent. Immune evaluation at age 3 weeks prior to cardiac surgery demonstrated very low CD3+ T-cell numbers (316 cells/mm3) (Table I). TRECs were found to be markedly decreased at 5 and 7 copies/μL (normal ≥25; performed by M. W. B.).1Routes J.M. Grossman W.J. Verbsky J. Laessig R.H. Hoffman G.L. Brokopp C.D. et al.Statewide newborn screening for severe T-cell lymphopenia.JAMA. 2009; 302: 2465-2470Crossref PubMed Scopus (163) Google Scholar Markedly decreased CD3+ T cells and TRECs suggested the diagnosis of complete DGA. However, the normal naive CD4+CD45RA+ T-cell percentage of 86% (Table I) was not consistent with this diagnosis. The patient was started on prophylactic trimethoprim-sulfamethoxazole and antibody replacement. A second immune evaluation performed at age 3 months also showed low CD3+ T cells and normal naive CD4+ T-cell percentages (Table I). In vitro lymphoproliferative responses to PHA, concanavalin A, and alloantigens were markedly decreased. A third immune evaluation at age 4 months revealed similar findings as at age 3 months (Table I).Table IImmunologic studies of an infant with partial DGA who initially had decreased TRECsStudyAge3 wk3 mo4 mo8 moNormal for 3-6 moAbsolute lymphocyte count (cells/mm3)19703045299841123400-7600CD3 cells/mm3 (%)316 (16)365 (12)390 (13)1932 (47)2500-5500 (51-77)CD4 cells/mm3 (%)295 (15)182 (6)300 (10)986 (24)1800-4000 (35-56)CD8 cells/mm3 (%)78 (4)121 (4)180 (6)945 (23)590-1600 (12-23)CD19 cells/mm3 (%)98 (5)1064 (35)1439 (48)1151 (28)430-3000 (11-41)CD56 cells/mm3 (%)571 (29)1158 (38)450 (15)616 (15)70-830 (3-14)CD45RA+ of CD4 (%)8667708477-94CD45RO+ of CD4 (%)385044233-16CD27+ of CD19 (%)030025-40PHA (% NR)12.2124.0≥50Concanavalin A (% NR)25.084.4≥50Pokeweed mitogen (% NR)50.484.0≥50Alloantigens (% NR)20.340.7≥50IgG (mg/dL)429621196-525IgA (mg/dL)432412-31IgM (mg/dL)493739-92TRECs (copies/μL)5, 748, 96≥25∗Routes et al.1% NR, Percent normal response.∗ Routes et al.1Routes J.M. Grossman W.J. Verbsky J. Laessig R.H. Hoffman G.L. Brokopp C.D. et al.Statewide newborn screening for severe T-cell lymphopenia.JAMA. 2009; 302: 2465-2470Crossref PubMed Scopus (163) Google Scholar Open table in a new tab % NR, Percent normal response. At age 8 months, the absolute lymphocyte count was normal; CD3+ T-cell numbers increased to 1932 cells/mm3, naive CD4+CD45RA+ T-cell percentage was 84%, memory CD4+CD45RO+ T-cell percentage decreased to 23% (normal 3%-16%), and in vitro lymphoproliferative responses to PHA, concanavalin A, and pokeweed mitogen were normal. TRECs increased to 48 and 96 copies/μL. Subcutaneous gammaglobulin was discontinued, but daily trimethoprim-sulfamethoxazole was continued because of absent memory B cells, which are associated with selective antibody deficiency. In complete DGA, there is aplasia of the thymus and therefore absence of thymopoiesis. The diagnosis of athymia is supported by finding very low naive CD3+CD45RA+ T-cell numbers and very low TRECs.2Ochs H.D. Nelson D.L. Stiehm E.R. Other well-defined immunodeficiency syndromes.in: Stiehm E.R. Ochs H.D. Winkelstein J.A. Immunologic disorders in infants & children. 5th ed. Elsevier Saunders, Philadelphia (Pa)2004: 505-579Google Scholar, 3McDonald-McGinn D.M. Sullivan K.E. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).Medicine. 2011; 90: 1-18Crossref PubMed Scopus (305) Google Scholar, 6Zemble R. Prak E.L. McDonald K. McDonald-McGinn D. Zackai E. Sullivan K. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome).Clin Immunol. 2010; 136: 409-418Crossref PubMed Scopus (61) Google Scholar, 7Markert M.L. Sarzotti M. Ozaki D.A. Sempowski G.D. Rhein M.E. Hale L.P. et al.Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients.Blood. 2003; 102: 1121-1130Crossref PubMed Scopus (109) Google Scholar, 8Markert M.L. Devlin B.H. Alexieff M.J. Li J. McCarthy E.A. Gupton S.E. et al.Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants.Blood. 2007; 109: 4539-4547Crossref PubMed Scopus (168) Google Scholar Our patient had marked lymphopenia, decreased CD3+ T cells, and decreased in vitro lymphoproliferative responses to mitogens and very low but detectable TRECs. In contrast to these findings, our patient had normal percentages of CD4+CD45RA+ naive T cells, suggesting the diagnosis of partial DGA. Criteria for the identification of complete DGA in thymus transplantation studies include TRECs less than 100/100,000 T cells (normal 10,000/100,000 T cells) and decreased CD3+CD45RA+CD62L+ naive T cells (<50 cells/mm3 or <5%).4Markert M.L. Devlin B.H. McCarthy E.A. Thymus transplantation.Clin Immunol. 2010; 135: 236-246Crossref PubMed Scopus (100) Google Scholar, 7Markert M.L. Sarzotti M. Ozaki D.A. Sempowski G.D. Rhein M.E. Hale L.P. et al.Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients.Blood. 2003; 102: 1121-1130Crossref PubMed Scopus (109) Google Scholar, 8Markert M.L. Devlin B.H. Alexieff M.J. Li J. McCarthy E.A. Gupton S.E. et al.Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants.Blood. 2007; 109: 4539-4547Crossref PubMed Scopus (168) Google Scholar In partial DGA, T-cell percentages and numbers are often low for age.9Chinen J. Rosenblatt H.M. Smith E.O. Shearer W.T. Noroski L.M. Long-term assessment of T-cell populations in DiGeorge syndrome.J Allergy Clin Immunol. 2003; 111: 573-579Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar As a consequence, naive T-cell numbers may also be low for age but are more than 50 cells/mm3 or more than 5% of total T cells, values that are above the limits set for the diagnosis of complete DGA.8Markert M.L. Devlin B.H. Alexieff M.J. Li J. McCarthy E.A. Gupton S.E. et al.Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants.Blood. 2007; 109: 4539-4547Crossref PubMed Scopus (168) Google Scholar In our patient, there were extremely decreased TRECs (<25 copies/μL) consistent with severe T-cell lymphopenia, as seen in severe combined immunodeficiency and complete DGA. Measurement of naive CD45RA+ T cells should be performed if the diagnosis of complete DGA is being considered based on low TREC values in newborns. Finding naive T cells supports the diagnosis of partial DGA and suggests that CD3+ T-cell numbers and in vitro lymphoproliferative responses may improve over time as they did in our patient. Thus, for DGA infants with low but detectable TRECs identified in newborn screening studies, flow cytometry studies measuring CD45RA+ T cells should be performed to distinguish patients with complete DGA from patients with the more common partial DGA." @default.
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• W1993346645 title "Interpreting low T-cell receptor excision circles in newborns with DiGeorge anomaly: Importance of assessing naive T-cell markers" @default.
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