{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T10:25:40Z","timestamp":1787135140430,"version":"build-2736575974"},"reference-count":17,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cVictor Babes\u201d University of Medicine and Pharmacy, Timisoara"},{"id":[{"id":"https:\/\/ror.org\/00afdp487","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background and Clinical Significance: Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) syndrome is a rare autosomal recessive disorder caused by biallelic variants in the TRNT1 gene, which encodes tRNA nucleotidyltransferase 1. The disease typically presents early in life with microcytic anemia, recurrent febrile episodes, developmental delay, and immune dysfunction. Because of its rarity and variable clinical expression, diagnosis may be challenging, and broad genetic testing can identify additional variants whose clinical significance requires careful interpretation. Case Presentation: We report a 4-month-old male infant with recurrent febrile episodes, severe recurrent microcytic anemia, recurrent infections, mild psychomotor developmental delay, and multisystem involvement. Genetic analysis identified two heterozygous TRNT1 variants inherited from different parents and confirmed to be in trans: a maternally inherited pathogenic frameshift variant, c.428_431del, p.(Asp143Glyfs12), and a paternally inherited missense variant, c.1246A&gt;G, p.(Lys416Glu), initially classified as a variant of uncertain significance and subsequently interpreted as likely pathogenic in the context of the clinical phenotype and segregation findings. These findings supported the diagnosis of TRNT1-related SIFD syndrome. An additional heterozygous pathogenic C7 variant, c.633_643del, p.(Ser212Hisfs4), was identified. No second pathogenic C7 allele was detected, and functional complement testing was not performed; therefore, complement component 7 deficiency could not be established. Conclusions: This case highlights the importance of early genetic evaluation in infants with recurrent fever, microcytic anemia, immune abnormalities, and multisystem involvement. It also emphasizes the need for cautious interpretation of additional monoallelic pathogenic variants detected by broad genetic panels when functional confirmation and a compatible inheritance pattern are lacking.<\/jats:p>","DOI":"10.3390\/diagnostics16162633","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:30:53Z","timestamp":1787131853000},"page":"2633","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early-Onset TRNT1-Related SIFD Syndrome with an Additional Monoallelic C7 Variant: A Pediatric Case Report"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6879-145X","authenticated-orcid":false,"given":"Iulius","family":"Juganaru","sequence":"first","affiliation":[{"name":"Department XI Pediatrics, Discipline I Pediatrics, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"},{"name":"1st Department of Pediatrics, Children\u2019s Emergency Hospital \u2018Louis \u021aurcanu\u2019, 300011 Timi\u0219oara, Romania"},{"name":"Research Center for Disturbance of Growth and Development in Children BELIEVE, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7362-3714","authenticated-orcid":false,"given":"Adriana","family":"Cojocaru","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 2nd Eftimie Murgu Square, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"Grigorita","sequence":"additional","affiliation":[{"name":"1st Department of Pediatrics, Children\u2019s Emergency Hospital \u2018Louis \u021aurcanu\u2019, 300011 Timi\u0219oara, Romania"},{"name":"Master\u2019s Program in Applied Auxology in Child and Adolescent Growth and Development, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niculina","family":"Mang","sequence":"additional","affiliation":[{"name":"Department XI Pediatrics, Discipline I Pediatrics, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"},{"name":"1st Department of Pediatrics, Children\u2019s Emergency Hospital \u2018Louis \u021aurcanu\u2019, 300011 Timi\u0219oara, Romania"},{"name":"Research Center for Disturbance of Growth and Development in Children BELIEVE, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Paun","sequence":"additional","affiliation":[{"name":"Department XI Pediatrics, Discipline I Pediatrics, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"},{"name":"1st Department of Pediatrics, Children\u2019s Emergency Hospital \u2018Louis \u021aurcanu\u2019, 300011 Timi\u0219oara, Romania"},{"name":"Research Center for Disturbance of Growth and Development in Children BELIEVE, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4599-0912","authenticated-orcid":false,"given":"Diana-Georgiana","family":"Basaca","sequence":"additional","affiliation":[{"name":"Department XI Pediatrics, Discipline I Pediatrics, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"},{"name":"1st Department of Pediatrics, Children\u2019s Emergency Hospital \u2018Louis \u021aurcanu\u2019, 300011 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8679-9655","authenticated-orcid":false,"given":"Laura Octavia","family":"Grigorita","sequence":"additional","affiliation":[{"name":"Department I\u2014Discipline of Anatomy and Embryology, Faculty of Medicine, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 2nd Eftimie Murgu Square, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7219-4014","authenticated-orcid":false,"given":"Lucian Ioan","family":"Cristun","sequence":"additional","affiliation":[{"name":"Ph.D. School Department, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2313-7643","authenticated-orcid":false,"given":"Otilia","family":"Marginean","sequence":"additional","affiliation":[{"name":"Department XI Pediatrics, Discipline I Pediatrics, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"},{"name":"1st Department of Pediatrics, Children\u2019s Emergency Hospital \u2018Louis \u021aurcanu\u2019, 300011 Timi\u0219oara, Romania"},{"name":"Research Center for Disturbance of Growth and Development in Children BELIEVE, \u2018Victor Babe\u0219\u2019 University of Medicine and Pharmacy Timi\u0219oara, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1182\/blood-2014-08-591370","article-title":"Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD)","volume":"124","author":"Chakraborty","year":"2014","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10875-022-01343-0","article-title":"Clinical and Therapeutic Aspects of Sideroblastic Anaemia with B-Cell Immunodeficiency, Periodic Fever and Developmental Delay (SIFD) Syndrome: A Systematic Review","volume":"43","author":"Maccora","year":"2023","journal-title":"J. Clin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.imlet.2020.06.012","article-title":"Biallelic TRNT1 variants in a child with B cell immunodeficiency, periodic fever and developmental delay without sideroblastic anemia (SIFD variant)","volume":"225","author":"Rigante","year":"2020","journal-title":"Immunol. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/j.1365-2141.2008.07290.x","article-title":"Recent advances in the understanding of inherited sideroblastic anaemia","volume":"143","author":"Camaschella","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.clim.2017.11.008","article-title":"Novel biallelic TRNT1 mutations resulting in sideroblastic anemia, combined B and T cell defects, hypogammaglobulinemia, recurrent infections, hypertrophic cardiomyopathy and developmental delay","volume":"188","author":"Lougaris","year":"2018","journal-title":"Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mendonca, L.O., Prado, A.I., Costa, I.M.C., Bandeira, M., Dyer, R., Barros, S.F., Kh\u00f6ler, K.F., Fonseca, L.A.M., Kalil, J., and Castro, F.M. (2021). Case Report: Expanding Clinical, Immunological and Genetic Findings in Sideroblastic Anemia With Immunodeficiency, Fevers and Development Delay (SIFD) Syndrome. Front Immunol., 12.","DOI":"10.3389\/fimmu.2021.586320"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Khalil, S.M., Aqel, S., Mudawi, D.S., Mobayed, H., and Al-Nesf, M.A. (2023). The first case report of complement component 7 deficiency in Qatar and a 10-year follow-up. Front Immunol., 14.","DOI":"10.3389\/fimmu.2023.1253301"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1046\/j.1365-2249.2003.02186.x","article-title":"Complement component C7 deficiency in a Spanish family","volume":"133","author":"Barroso","year":"2003","journal-title":"Clin. Exp. Immunol."},{"key":"ref_9","unstructured":"National Center for Biotechnology Information (2026, August 08). ClinVar; NM_182916.3(TRNT1):c.1246A>G (p.Lys416Glu), Variation ID: 963695 [Internet]. Bethesda (MD): National Library of Medicine (US), Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/963695\/."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Fatica, T., Naas, T., Liwak, U., Slaa, H., Souaid, M., Frangione, B., Kattini, R., Gaudreau-Lapierre, A., Trinkle-Mulcahy, L., and Chakraborty, P. (2023). TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins. Genes, 14.","DOI":"10.3390\/genes14051043"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.gendis.2020.01.005","article-title":"Novel biallelic TRNT1 mutations lead to atypical SIFD and multiple immune defects","volume":"7","author":"Yang","year":"2020","journal-title":"Genes. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.clicom.2024.02.003","article-title":"Case of Mitochondrial Encephalomyopathy secondary to COVID-19 in a Pediatric case of SIFD syndrome with a novel TRNT1 mutation","volume":"5","author":"Khojah","year":"2024","journal-title":"Clin. Immunol. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e276","DOI":"10.1111\/ajd.13527","article-title":"Neutrophilic dermatosis: A new skin manifestation and novel pathogenic variant in a rare autoinflammatory disease","volume":"62","author":"Bardou","year":"2021","journal-title":"Aust. J. Dermatol."},{"key":"ref_14","first-page":"1","article-title":"Congenital sideroblastic anemia associated with B cell immunodeficiency, periodic fevers, and developmental delay: A case report and review of mucocutaneous features","volume":"7","author":"fri","year":"2019","journal-title":"SAGE Open Med. Case Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1365-2567.2006.02364.x","article-title":"Molecular defects of the C7 gene in two patients with complement C7 deficiency","volume":"118","author":"Barroso","year":"2006","journal-title":"Immunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1136\/annrheumdis-2017-212401","article-title":"Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors","volume":"77","author":"Giannelou","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4341","DOI":"10.1007\/s10067-021-05653-3","article-title":"Etanercept as a successful therapy in autoinflammatory syndrome related to TRNT1 mutations: A case-based review","volume":"40","author":"Orlando","year":"2021","journal-title":"Clin. Rheumatol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/16\/2633\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T09:41:24Z","timestamp":1787132484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/16\/2633"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":17,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["diagnostics16162633"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16162633","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]}}}