title: Persistent low thymic activity and non-cardiac mortality in children with chromosome 22q11.2 microdeletion and partial DiGeorge syndrome.
abstract: A subgroup of patients with 22q11.2 microdeletion and partial DiGeorge syndrome (pDGS) appears to be susceptible to non-cardiac mortality (NCM) despite sufficient overall CD4(+) T cells. To detect these patients, 20 newborns with 22q11.2 microdeletion and congenital heart disease were followed prospectively for 6 years. Besides detailed clinical assessment, longitudinal monitoring of naive CD4(+) and cytotoxic CD3(+)CD8(+) T cells (CTL) was performed. To monitor thymic activity, we analysed naive platelet endothelial cell adhesion molecule-1 (CD31(+)) expressing CD45RA(+)RO(-)CD4(+) cells containing high numbers of T cell receptor excision circle (T(REC))-bearing lymphocytes and compared them with normal values of healthy children (n = 75). Comparing two age periods, low overall CD4(+) and naive CD4(+) T cell numbers were observed in 65%/75%, respectively, of patients in period A (< 1 year) declining to 22%/50%, respectively, of patients in period B (> 1/< 7 years). The percentage of patients with low CTLs (< P10) remained robust until school age (period A: 60%; period B: 50%). Low numbers of CTLs were associated with abnormally low naive CD45RA(+)RO(-)CD4(+) T cells. A high-risk (HR) group (n = 11) and a standard-risk (SR) (n = 9) group were identified. HR patients were characterized by low numbers of both naive CD4(+) and CTLs and were prone to lethal infectious and lymphoproliferative complications (NCM: four of 11; cardiac mortality: one of 11) while SR patients were not (NCM: none of nine; cardiac mortality: two of nine). Naive CD31(+)CD45RA(+)RO(-)CD4(+), naive CD45RA(+)RO(-)CD4(+) T cells as well as T(RECs)/10(6) mononuclear cells were abnormally low in HR and normal in SR patients. Longitudinal monitoring of naive CD4(+) and cytotoxic T cells may help to discriminate pDGS patients at increased risk for NCM.
authors.affiliation: Division of Immunology/Hematology/BMT, University Children's Hospital, Zürich, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Eberle
authors.forename: C
authors.initials: C
authors.lastname: Berger
authors.forename: S
authors.initials: S
authors.lastname: Junge
authors.forename: S
authors.initials: S
authors.lastname: Dougoud
authors.forename: E Valsangiacomo
authors.initials: EV
authors.lastname: Büchel
authors.forename: M
authors.initials: M
authors.lastname: Riegel
authors.forename: A
authors.initials: A
authors.lastname: Schinzel
authors.forename: R
authors.initials: R
authors.lastname: Seger
authors.forename: T
authors.initials: T
authors.lastname: Güngör
mesh_terms: D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D006330:Heart Defects, Congenital / Q000150:complications / Q000235:genetics / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D017404:In Situ Hybridization, Fluorescence; D007231:Infant, Newborn; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009894:Opportunistic Infections / Q000150:complications / Q000276:immunology; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013950:Thymus Gland / Q000002:abnormalities* / Q000276:immunology
chemical_list: D007136:Immunoglobulins