title: Newborn Screening for Severe Primary Immunodeficiency Diseases in Sweden-a 2-Year Pilot TREC and KREC Screening Study.
abstract: Newborn screening for severe primary immunodeficiencies (PID), characterized by T and/or B cell lymphopenia, was carried out in a pilot program in the Stockholm County, Sweden, over a 2-year period, encompassing 58,834 children. T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) were measured simultaneously using a quantitative PCR-based method on DNA extracted from dried blood spots (DBS), with beta-actin serving as a quality control for DNA quantity. Diagnostic cutoff levels enabling identification of newborns with milder and reversible T and/or B cell lymphopenia were also evaluated. Sixty-four children were recalled for follow-up due to low TREC and/or KREC levels, and three patients with immunodeficiency (Artemis-SCID, ATM, and an as yet unclassified T cell lymphopenia/hypogammaglobulinemia) were identified. Of the positive samples, 24 were associated with prematurity. Thirteen children born to mothers treated with immunosuppressive agents during pregnancy (azathioprine (n = 9), mercaptopurine (n = 1), azathioprine and tacrolimus (n = 3)) showed low KREC levels at birth, which spontaneously normalized. Twenty-nine newborns had no apparent cause identified for their abnormal results, but normalized with time. Children with trisomy 21 (n = 43) showed a lower median number of both TREC (104 vs. 174 copies/μL blood) and KREC (45 vs. 100 copies/3.2 mm blood spot), but only one, born prematurely, fell below the cutoff level. Two children diagnosed with DiGeorge syndrome were found to have low TREC levels, but these were still above the cutoff level. This is the first large-scale screening study with a simultaneous detection of both TREC and KREC, allowing identification of newborns with both T and B cell defects.
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital Solna, SE-17176, Stockholm, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-17176, Stockholm, Sweden.
authors.forename: Michela
authors.initials: M
authors.lastname: Barbaro
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital Solna, SE-17176, Stockholm, Sweden.|Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, SE-17177, Stockholm, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Ohlsson
authors.affiliation: Department of Clinical Immunology, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden.|ImmunoDeficiencyCenter Leipzig (IDCL) at Hospital St. Georg Leipzig, Delitzscher Strasse 141, 04129, Leipzig, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Borte
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital Solna, SE-17176, Stockholm, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Jonsson
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital Solna, SE-17176, Stockholm, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-17176, Stockholm, Sweden.
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Zetterström
authors.affiliation: Department of Clinical Immunology, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden.|Department of Immunopathology, SA Pathology, Women's and Children's Hospital Campus, North Adelaide, South Australia, 5006, Australia.|Robinson Research Institute and Discipline of Paediatrics, School of Medicine, University of Adelaide, North Adelaide, South Australia, 5006, Australia.
authors.forename: Jovanka
authors.initials: J
authors.lastname: King
authors.affiliation: Department of Clinical Technology and Intervention, Karolinska Institutet, SE-14186, Stockholm, Sweden.|Department of Pediatrics, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden.
authors.forename: Jacek
authors.initials: J
authors.lastname: Winiarski
authors.affiliation: Centre for Inherited Metabolic Diseases, Karolinska University Hospital Solna, SE-17176, Stockholm, Sweden. ulrika.vondebeln@karolinska.se.|Department of Medical Biochemistry and Biophysics, Division of Molecular Metabolism, Karolinska Institutet, SE-17177, Stockholm, Sweden. ulrika.vondebeln@karolinska.se.
authors.forename: Ulrika
authors.initials: U
authors.lastname: von Döbeln
authors.affiliation: Department of Clinical Immunology, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden. lennart.hammarstrom@ki.se.
authors.forename: Lennart
authors.initials: L
authors.lastname: Hammarström
mesh_terms: D005260:Female; D005820:Genetic Testing / Q000379:methods; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D015997:Neonatal Screening / Q000379:methods; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011995:Recombination, Genetic; D012307:Risk Factors; D017384:Sequence Deletion; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis* / Q000235:genetics; D013548:Sweden
chemical_list: D011948:Receptors, Antigen, T-Cell
keywords: KREC; Newborn screening; TREC; primary immunodeficiency diseases; severe combined immunodeficiency