{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T06:04:26Z","timestamp":1780380266965,"version":"3.54.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Congenital analbuminemia (CAA) is an ultrarare autosomal recessive disorder caused by biallelic pathogenic variants in the\n                      <jats:italic>ALB<\/jats:italic>\n                      gene, leading to absent or severely reduced serum albumin. Although historically considered a benign biochemical condition, emerging evidence suggests that pediatric CAA may be associated with clinically relevant multisystem manifestations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a longitudinal integrative study involving five children from two kindreds, all with genetically confirmed CAA. Their clinical features were thoroughly documented, along with extended coagulation tests and immunological profiling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All patients presented with persistent hypoalbuminemia, early-onset edema, gastrointestinal morbidity (frequently leading to misdiagnosis as protein-losing enteropathy), antenatal complications, recurrent respiratory infections, and dyslipidemia. Genetic testing revealed an\n                      <jats:italic>ALB<\/jats:italic>\n                      splice-site mutation (c.1428\u2009+\u20092T\u2009&amp;gt;\u2009C) in one kindred and a novel homozygous frameshift insertion (p.Glu69Ter) in the second. Coagulation profiling identified a reproducible prothrombotic signature, including elevated fibrinogen, D-dimer, and strikingly increased FXI activity, with one patient suffering life-threatening cerebral thrombosis. Immunological evaluation demonstrated preserved leukocyte and lymphocyte counts, preserved or elevated IgG levels, variable antigen-specific vaccine responses, reduced kappa-deleting recombination excision circle values in the tested patients, and skewing of CD4\u207a T cells toward effector memory subsets, consistent with immune dysregulation rather than frank immunodeficiency.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides detailed multisystem phenotyping of pediatric CAA and supports the view that CAA may present with clinically relevant gastrointestinal, metabolic, infectious, and hemostatic manifestations beyond isolated hypoalbuminemia. Early molecular diagnosis may reduce unnecessary invasive investigations and facilitate individualized monitoring for infectious and thrombotic complications. Larger multicenter studies with longitudinal follow-up and functional validation are required to confirm these findings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2026.1810945","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:41:52Z","timestamp":1780378912000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genomic diagnosis and multisystem phenotyping in pediatric congenital analbuminemia: clinical, coagulation, and immune signatures"],"prefix":"10.3389","volume":"14","author":[{"given":"Asena Pinar","family":"Sefer","sequence":"first","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Recep Tayyip Erdogan University","place":["Rize, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melek","family":"Yorgun Altunbas","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baran","family":"Erman","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Hacettepe University","place":["Ankara, T\u00fcrkiye"]},{"name":"Can Sucak Research Laboratory for Translational Immunology, Hacettepe University","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salim","family":"Can","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alper","family":"Bulutoglu","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satanay","family":"Hubrack","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Sidra Medicine, Research Branch","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Sidra Medicine, Research Branch","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Makhlouf","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Sidra Medicine, Research Branch","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis R.","family":"Saraiva","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Sidra Medicine, Research Branch","place":["Doha, Qatar"]},{"name":"College of Health & Life Sciences, Hamad Bin Khalifa University","place":["Doha, Qatar"]},{"name":"Department of Comparative Medicine, Yale University School of Medicine","place":["New Haven, CT, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gizem","family":"Onder","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Health Science Institute, Ac\u0131badem Mehmet Ali Ayd\u0131nlar University","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozden","family":"Hatirnaz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Health Science Institute, Ac\u0131badem Mehmet Ali Ayd\u0131nlar University","place":["Istanbul, T\u00fcrkiye"]},{"name":"Rare Diseases and Orphan Drugs Application and Research Center-ACURARE, Ac\u0131badem University","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayse Merve","family":"Usta","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Pediatrics, Sar\u0131yer Hamidiye Etfal Training and Research Hospital","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilek","family":"Guller","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Pediatrics, Sar\u0131yer Hamidiye Etfal Training and Research Hospital","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilek","family":"Baser","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamze","family":"Akgun","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umran","family":"Aba","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Hacettepe University","place":["Ankara, T\u00fcrkiye"]},{"name":"Can Sucak Research Laboratory for Translational Immunology, Hacettepe University","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahmi Kutay","family":"Erdogan","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Hacettepe University","place":["Ankara, T\u00fcrkiye"]},{"name":"Can Sucak Research Laboratory for Translational Immunology, Hacettepe University","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer Faruk","family":"Beser","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Istanbul University Cerrahpasa","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fugen","family":"Cullu Cokugras","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Istanbul University Cerrahpasa","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Demirbas Ar","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology, Hepatology and Nutrition, Bal\u0131kesir Ataturk City Hospital","place":["Ankara, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nafiye","family":"Urganci","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Pediatrics, Sar\u0131yer Hamidiye Etfal Training and Research Hospital","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oguz Salih","family":"Dincer","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Pediatrics, School of Medicine, Recep Tayyip Erdogan University","place":["Rize, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sevgi","family":"Bilgic Eltan","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safa","family":"Baris","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif","family":"Karakoc-Aydiner","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernice","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Sidra Medicine, Research Branch","place":["Doha, Qatar"]},{"name":"College of Health & Life Sciences, Hamad Bin Khalifa University","place":["Doha, Qatar"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"Ozen","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, Marmara University","place":["Istanbul, T\u00fcrkiye"]},{"name":"The Isil Berat Barlan Center for Translational Medicine","place":["Istanbul, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5494","DOI":"10.1016\/j.bbagen.2013.04.019","article-title":"Congenital analbuminaemia: molecular defects and biochemical and clinical aspects","volume":"1830","author":"Minchiotti","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"B2","doi-asserted-by":"publisher","first-page":"336","DOI":"10.3389\/fgene.2019.00336","article-title":"Diagnosis, phenotype, and molecular genetics of congenital analbuminemia","volume":"10","author":"Minchiotti","year":"2019","journal-title":"Front Genet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e0300130","DOI":"10.1371\/journal.pone.0300130","article-title":"Performance evaluation of different albumin assays for the detection of analbuminemia","volume":"19","author":"Zhang","year":"2024","journal-title":"PLoS One"},{"key":"B4","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1007\/s00431-004-1492-z","article-title":"Congenital analbuminaemia: biochemical and clinical implications. A case report and literature review","volume":"163","author":"Koot","year":"2004","journal-title":"Eur J Pediatr"},{"key":"B5","doi-asserted-by":"publisher","first-page":"407","DOI":"10.3390\/biom13030407","article-title":"Alterations in the plasma protein expression pattern in congenital analbuminemia\u2014a systematic review","volume":"13","author":"Foster","year":"2023","journal-title":". Biomolecules"},{"key":"B6","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1093\/clinchem\/48.6.844","article-title":"Molecular diagnosis of analbuminemia: a novel mutation identified in two Amerindian and two Turkish families","volume":"48","author":"Galliano","year":"2002","journal-title":"Clin Chem"},{"key":"B7","first-page":"e20","article-title":"Perinatal and childhood morbidity and mortality in congenital analbuminemia","volume":"17","author":"Toye","year":"2012","journal-title":"Paediatr Child Health"},{"key":"B8","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.thromres.2022.08.008","article-title":"Association of low serum albumin with venous thrombosis in pediatric patients","volume":"218","author":"Bhasin","year":"2022","journal-title":"Thromb Res"},{"key":"B9","first-page":"85","article-title":"Coronary artery bypass surgery in a patient with analbuminemia","volume":"38","author":"Demirsoy","year":"2011","journal-title":"Tex Heart Inst J"},{"key":"B10","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1007\/BF01486844","article-title":"Turnover of autologous alpha 1-antitrypsin in a patient with congenital analbuminemia","volume":"61","author":"Weigand","year":"1983","journal-title":"Klin Wochenschr"},{"key":"B11","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1111\/j.1399-0004.1976.tb01606.x","article-title":"Analbuminemia in an American Indian girl","volume":"9","author":"Boman","year":"1976","journal-title":"Clin Genet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1684\/abc.2023.1806","article-title":"Congenital analbuminemia associated with compound heterozygous novel nucleotide variations in a young adult with coronary thrombosis","volume":"81","author":"Amri","year":"2023","journal-title":"Ann Biol Clin (Paris)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1002\/humu.20754","article-title":"Mutations and polymorphisms of the gene of the major human blood protein, serum albumin","volume":"29","author":"Minchiotti","year":"2008","journal-title":"Hum Mutat"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1016\/j.jaci.2015.04.049","article-title":"Practice parameter for the diagnosis and management of primary immunodeficiency","volume":"136","author":"Bonilla","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1016\/j.jaip.2019.02.004","article-title":"The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity","volume":"7","author":"Seidel","year":"2019","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B16","first-page":"399","volume":"36","year":"2009","journal-title":"Transfus Med Hemother"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1814","DOI":"10.3906\/sag-2010-176","article-title":"Reference values for T and B lymphocyte subpopulations in Turkish children and adults","volume":"51","author":"Besci","year":"2021","journal-title":"Turk J Med Sci"},{"key":"B18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1007\/s10875-024-01658-0","article-title":"A novel homozygous germline mutation in transferrin receptor 1 (TfR1) leads to combined immunodeficiency and provides new insights into iron-immunity axis","volume":"44","author":"Aba","year":"2024","journal-title":"J Clin Immunol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1373\/clinchem.2007.089748","article-title":"Analbuminemia produced by a novel splicing mutation","volume":"53","author":"Dolcini","year":"2007","journal-title":"Clin Chem"},{"key":"B20","doi-asserted-by":"publisher","first-page":"700","DOI":"10.3349\/ymj.2019.60.7.700","article-title":"Congenital analbuminemia in a Korean male diagnosed with single nucleotide polymorphism in the ALB gene: the first case reported in Korea","volume":"60","author":"Kim","year":"2019","journal-title":"Yonsei Med J"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.3390\/ijms23031159","article-title":"Variations in the human serum albumin gene: molecular and functional aspects","volume":"23","author":"Caridi","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"9761","DOI":"10.1038\/s41598-022-13174-5","article-title":"Association of FXI activity with thrombo-inflammation, extracellular matrix, lipid metabolism and apoptosis in venous thrombosis","volume":"12","author":"Pallares Robles","year":"2022","journal-title":"Sci Rep"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2878","DOI":"10.1182\/blood-2009-05-219915","article-title":"Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology","volume":"114","author":"Cushman","year":"2009","journal-title":"Blood"},{"key":"B24","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1056\/NEJM200003093421004","article-title":"High levels of coagulation factor XI as a risk factor for venous thrombosis","volume":"342","author":"Meijers","year":"2000","journal-title":"N Engl J Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3090","DOI":"10.1111\/jth.15545","article-title":"Oxidative stress mediated platelet activation in patients with congenital analbuminemia: effect of albumin infusion","volume":"19","author":"Baratta","year":"2021","journal-title":"J Thromb Haemost"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.3389\/fimmu.2019.01595","article-title":"Striking a balance-cellular and molecular drivers of memory T cell development and responses to chronic stimulation","volume":"10","author":"Hope","year":"2019","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"4496","DOI":"10.3390\/ijms22094496","article-title":"Hypoalbuminemia as surrogate and culprit of infections","volume":"22","author":"Wiedermann","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s13613-020-00697-1","article-title":"Role of albumin in the preservation of endothelial glycocalyx integrity and the microcirculation: a review","volume":"10","author":"Aldecoa","year":"2020","journal-title":"Ann Intensive Care"},{"key":"B29","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1053\/j.gastro.2019.03.021","article-title":"Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis","volume":"157","author":"Fernandez","year":"2019","journal-title":"Gastroenterology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"e0182997","DOI":"10.1371\/journal.pone.0182997","article-title":"Anticoagulant action of low, physiologic, and high albumin levels in whole blood","volume":"12","author":"Paar","year":"2017","journal-title":"PLoS One"}],"container-title":["Frontiers in Pediatrics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1810945\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:41:53Z","timestamp":1780378913000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fped.2026.1810945\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,2]]},"references-count":30,"alternative-id":["10.3389\/fped.2026.1810945"],"URL":"https:\/\/doi.org\/10.3389\/fped.2026.1810945","relation":{},"ISSN":["2296-2360"],"issn-type":[{"value":"2296-2360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,2]]},"article-number":"1810945"}}