{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:06:28Z","timestamp":1785855988437,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T00:00:00Z","timestamp":1669075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health (\u201cRicerca Corrente 2021\u201d)","award":["5XMILR19"],"award-info":[{"award-number":["5XMILR19"]}]},{"name":"5X1000 Gaslini","award":["5XMILR19"],"award-info":[{"award-number":["5XMILR19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In addition, immune-dysregulation, secondary to marrow failure, has been reported as being, in some cases, the most evident and early sign of the disease and making the diagnosis of both groups of disorders challenging. Dyskeratosis congenita is a disorder characterized by premature telomere erosion, typically showing marrow failure, nail dystrophy and leukoplakia, although incomplete genetic penetrance and phenotypes with immune-dysregulation features have been described. We report on a previously healthy 17-year-old girl, with a cousin successfully treated for acute lymphoblastic leukemia, who presented with leukopenia and neutropenia. The diagnostic work-up showed positive anti-neutrophil antibodies, leading to the diagnosis of autoimmune neutropenia, a slightly low NK count and high TCR-\u03b1\u03b2+-double-negative T-cells. A next-generation sequencing (NGS) analysis showed the 734C&gt;A variant on exon 6 of the TINF2 gene, leading to the p.Ser245Tyr. The telomere length was short on the lymphocytes and granulocytes, suggesting the diagnosis of an atypical telomeropathy showing with immune-dysregulation. This case underlines the importance of an accurate diagnostic work-up of patients with immune-dysregulation, who should undergo NGS or whole exome sequencing to identify specific disorders that deserve targeted follow-up and treatment.<\/jats:p>","DOI":"10.3390\/ijms232314535","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T08:25:28Z","timestamp":1669105528000},"page":"14535","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Autoimmune Neutropenia and Immune-Dysregulation in a Patient Carrying a TINF2 Variant"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8607-4200","authenticated-orcid":false,"given":"Benedetta","family":"Chianucci","sequence":"first","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4570-3485","authenticated-orcid":false,"given":"Alice","family":"Grossi","sequence":"additional","affiliation":[{"name":"Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6555-7219","authenticated-orcid":false,"given":"Gianluca","family":"Dell'Orso","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplant Unit, Department of Hematology and Oncology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Palmisani","sequence":"additional","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Lanciotti","sequence":"additional","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Terranova","sequence":"additional","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"Pierri","sequence":"additional","affiliation":[{"name":"Hematopoietic Stem Cell Transplant Unit, Department of Hematology and Oncology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Lupia","sequence":"additional","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9516-9148","authenticated-orcid":false,"given":"Luca","family":"Arcuri","sequence":"additional","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marica","family":"Laurino","sequence":"additional","affiliation":[{"name":"Hematology and Cellular Therapy Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8732-1955","authenticated-orcid":false,"given":"Isabella","family":"Ceccherini","sequence":"additional","affiliation":[{"name":"Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3718-8217","authenticated-orcid":false,"given":"Fabian","family":"Beier","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology, Hemostaseology, Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, 52047 Aachen, Germany"},{"name":"Center for Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD), 53127 Bonn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Dufour","sequence":"additional","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Fioredda","sequence":"additional","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-1704","authenticated-orcid":false,"given":"Maurizio","family":"Miano","sequence":"additional","affiliation":[{"name":"Haematology Unit, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.blre.2010.03.002","article-title":"Pathophysiology and management of inherited bone marrow failure syndromes","volume":"24","author":"Shimamura","year":"2010","journal-title":"Blood Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/j.1365-2559.2010.03612.x","article-title":"The pathology of bone marrow failure","volume":"57","author":"Leguit","year":"2010","journal-title":"Histopathology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s12185-012-1249-9","article-title":"Inherited bone marrow failure syndromes in 2012","volume":"97","author":"Sakaguchi","year":"2013","journal-title":"Int. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1002\/pbc.26092","article-title":"Bone marrow transplantation for CVID-like humoral immune deficiency associated with red cell aplasia","volume":"63","author":"Sayour","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"a005769","DOI":"10.1101\/mcs.a005769","article-title":"Aplastic anemia in a patient with CVID due to NFKB1 haploinsufficiency","volume":"6","author":"Sklarz","year":"2020","journal-title":"Mol. Case Stud."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1002\/ajh.23435","article-title":"Immunological profile of Fanconi anemia: A multicentric retrospective analysis of 61 patients","volume":"88","author":"Korthof","year":"2013","journal-title":"Am. J. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/j.1399-3038.2010.01136.x","article-title":"Dyskeratosis congenita: A combined immunodeficiency with broad clinical spectrum-a single-center pediatric experience","volume":"22","author":"Jyonouchi","year":"2011","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e26599","DOI":"10.1002\/pbc.26599","article-title":"Impaired immune function in children and adults with Fanconi anemia","volume":"64","author":"Myers","year":"2017","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/bjh.15915","article-title":"Impaired cellular and humoral immunity is a feature of Diamond-Blackfan anaemia; experience of 107 unselected cases in the United Kingdom","volume":"186","author":"Iskander","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5222","DOI":"10.1172\/JCI120216","article-title":"Short telomere syndromes cause a primary T cell immunodeficiency","volume":"128","author":"Wagner","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1007\/s10875-017-0396-4","article-title":"Common Variable Immunodeficiency Caused by FANC Mutations","volume":"37","author":"Sekinaka","year":"2017","journal-title":"J. Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.jaci.2012.11.052","article-title":"Common variable immunodeficiency as the initial presentation of dyskeratosis congenita","volume":"132","author":"Allenspach","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1399-0004.2007.00923.x","article-title":"Dyskeratosis congenita: A genetic disorder of many faces","volume":"73","author":"Kirwan","year":"2008","journal-title":"Clin. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E221","DOI":"10.1002\/ajh.24187","article-title":"Autoimmune neutropenia of infancy: Data from the Italian neutropenia registry","volume":"90","author":"Farruggia","year":"2015","journal-title":"Am. J. Hematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"789","DOI":"10.3324\/haematol.2016.142760","article-title":"Old and new faces of neutropenia in children","volume":"101","author":"Dufour","year":"2016","journal-title":"Haematologica"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5644","DOI":"10.1182\/bloodadvances.2020002793","article-title":"Late-onset and long-lasting autoimmune neutropenia: An analysis from the Italian Neutropenia Registry","volume":"4","author":"Fioredda","year":"2020","journal-title":"Blood Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"E328","DOI":"10.1002\/ajh.26625","article-title":"TACI variants as underlying condition in autoimmune neutropenia: Description of four cases","volume":"97","author":"Fioredda","year":"2022","journal-title":"Am. J. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/ajh.25353","article-title":"Idiopathic neutropenia of infancy: Data from the Italian Neutropenia Registry","volume":"94","author":"Farruggia","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/pbc.23108","article-title":"Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica)","volume":"57","author":"Fioredda","year":"2011","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Grossi, A., Miano, M., Lanciotti, M., Fioredda, F., Guardo, D., Palmisani, E., Terranova, P., Santamaria, G., Caroli, F., and Caorsi, R. (2021). Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients. Genes, 12.","DOI":"10.3390\/genes12091299"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.bcmd.2015.01.002","article-title":"Ser245Tyr TINF2 mutation in a long-term survivor after a second myeloablative SCT following late graft failure for Aplastic Anaemia","volume":"55","author":"Miano","year":"2015","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41525-019-0104-9","article-title":"Reanalysing genomic data by normalized coverage values uncovers CNVs in bone marrow failure gene panels","volume":"4","author":"Lauhasurayotin","year":"2019","journal-title":"NPJ Genom. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1093\/hmg\/ddy269","article-title":"Whole exome sequencing analysis in severe chronic obstructive pulmonary disease","volume":"27","author":"Qiao","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","first-page":"1310862","article-title":"TINF2Gene Mutation in a Patient with Pulmonary Fibrosis","volume":"2016","author":"Hoffman","year":"2016","journal-title":"Case Rep. Pulmonol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1002\/ajh.26242","article-title":"Genetic screening of children with marrow failure. The role of primary Immunodeficiencies","volume":"96","author":"Miano","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1016\/j.jaci.2016.10.053","article-title":"Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations","volume":"140","author":"Bahrami","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s10875-020-00930-3","article-title":"Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance","volume":"41","author":"Rosain","year":"2021","journal-title":"J. Clin. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fped.2018.00282","article-title":"Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2","volume":"6","author":"Lee","year":"2018","journal-title":"Front. Pediatr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1093\/hmg\/ddx098","article-title":"Mutations in XLF\/NHEJ1\/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening","volume":"26","author":"Carrillo","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1097\/MPH.0000000000001545","article-title":"Combined Immunodeficiency, Hemolytic Anemia, and Growth Retardation Secondary to a Homozygous Mutation in the NHEJ1 Gene","volume":"42","author":"Naseem","year":"2020","journal-title":"J. Pediatr. Hematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/j.1399-0004.2010.01605.x","article-title":"Telomere length measurement can distinguish pathogenic from non-pathogenic variants in the shelterin component, TIN2","volume":"81","author":"Vulliamy","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3594","DOI":"10.1182\/blood-2008-05-153445","article-title":"TINF2 mutations result in very short telomeres: Analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes","volume":"112","author":"Walne","year":"2008","journal-title":"Blood"},{"key":"ref_33","first-page":"1323","article-title":"A novel homozygous RTEL1 variant in a consanguineous Lebanese family: Phenotypic heterogeneity and disease anticipation","volume":"138","author":"Masri","year":"2019","journal-title":"Qual. Life Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"754029","DOI":"10.3389\/fimmu.2021.754029","article-title":"Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure","volume":"12","author":"Grossi","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"E2358","DOI":"10.1073\/pnas.1720427115","article-title":"Diagnostic utility of telomere length testing in a hospital-based setting","volume":"115","author":"Alder","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","first-page":"19","article-title":"The short and long telomere syndromes: Paired paradigms for molecular medicine","volume":"33","author":"Armanios","year":"2015","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/bmt.2010.65","article-title":"Disease-specific hematopoietic cell transplantation: Nonmyeloablative conditioning regimen for dyskeratosis congenita","volume":"46","author":"Dietz","year":"2011","journal-title":"Bone Marrow Transplant."},{"key":"ref_38","first-page":"S37","article-title":"Unrelated donor marrow transplantation for inborn errors","volume":"21","author":"Miano","year":"1998","journal-title":"Bone Marrow Transplant."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5607","DOI":"10.1182\/blood-2010-11-322149","article-title":"Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase","volume":"117","author":"Parry","year":"2011","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/bjh.15495","article-title":"Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita","volume":"183","author":"Fioredda","year":"2018","journal-title":"Br. J. Haematol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/23\/14535\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:24:18Z","timestamp":1760145858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/23\/14535"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,22]]},"references-count":40,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232314535"],"URL":"https:\/\/doi.org\/10.3390\/ijms232314535","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,22]]}}}