{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T15:54:46Z","timestamp":1765554886928,"version":"3.48.0"},"reference-count":19,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background: Hemoglobin Rothschild (Hb Rothschild), NM_000518.5(HBB):c.112T&gt;C, is an ultra-rare low-oxygen-affinity hemoglobin variant that persistently causes reduced peripheral oxygen saturation on pulse oximetry despite normal arterial oxygenation. Fewer than ten cases have been reported worldwide, and only one involved a child\u2014an asymptomatic carrier identified incidentally. Methods: The patient underwent clinical examination, growth assessment, blood tests, hemoglobin electrophoresis, chest CT, abdominal ultrasound, echocardiography, and pulmonary perfusion scintigraphy. Whole genome sequencing (WGS) of the proband and parents was performed, followed by bioinformatic analysis and ACMG-based variant interpretation. A PRISMA-guided PubMed literature review was conducted. Results: We report on the first pediatric case exhibiting a symptomatic clinical course. A 4-year-old boy was referred for chronically low peripheral oxygen saturation (SpO2), 78\u201386%, on pulse oximetry and recurrent lower respiratory tract infections. Early developmental history revealed episodes of apnea in infancy, perioral cyanosis, poor exercise tolerance, and low weight gain. Repeated cardiopulmonary assessments, chest computed tomography (CT), echocardiography, and pulmonary perfusion scintigraphy yielded unremarkable findings. Arterial blood gas analysis consistently showed normal arterial partial pressure of oxygen (PaO2), excluding true hypoxemia. Hemoglobin electrophoresis revealed an abnormal HbD fraction; WGS identified a heterozygous variant NM_000518.5(HBB):c.112T&gt;C inherited from the patient\u2019s asymptomatic father. This variant increases the partial pressure of oxygen at which hemoglobin is 50% saturated (p50), thereby decreasing hemoglobin\u2019s oxygen affinity and shifting the oxyhemoglobin dissociation curve to the right. These alterations explain the discordance between low peripheral oxygen saturation (SpO2) and preserved oxygen delivery to tissues. Conclusions: This case expands the clinical spectrum of Hb Rothschild and demonstrates that symptomatic presentation may occur in early childhood. Awareness of low-affinity hemoglobin variants is essential to avoid misdiagnosis and unnecessary cardiopulmonary interventions. Early genetic testing facilitates accurate diagnosis and appropriate counseling.<\/jats:p>","DOI":"10.3390\/diagnostics15243181","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T15:27:20Z","timestamp":1765553240000},"page":"3181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["First Symptomatic Pediatric Case of Hb Rothschild (HBB: c.112T&gt;C, p.Trp38Arg): Low-Oxygen-Affinity Hemoglobin Presenting with Persistent Pseudohypoxemia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3422-956X","authenticated-orcid":false,"given":"Ekaterina","family":"Nuzhnaya","sequence":"first","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics, 1 Moskvorechye Street, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0972-5118","authenticated-orcid":false,"given":"Andrey","family":"Marakhonov","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics, 1 Moskvorechye Street, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6137-6138","authenticated-orcid":false,"given":"Artem","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Russian Children\u2019s Clinical Hospital, a Branch of Pirogov Russian National Research Medical University, 117 Leninsky Prospekt, Moscow 119571, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9443-0485","authenticated-orcid":false,"given":"Yulia","family":"Lashkova","sequence":"additional","affiliation":[{"name":"Russian Children\u2019s Clinical Hospital, a Branch of Pirogov Russian National Research Medical University, 117 Leninsky Prospekt, Moscow 119571, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Kuznetsov","sequence":"additional","affiliation":[{"name":"Russian Children\u2019s Clinical Hospital, a Branch of Pirogov Russian National Research Medical University, 117 Leninsky Prospekt, Moscow 119571, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7447-0625","authenticated-orcid":false,"given":"Tatiana","family":"Kulichenko","sequence":"additional","affiliation":[{"name":"Russian Children\u2019s Clinical Hospital, a Branch of Pirogov Russian National Research Medical University, 117 Leninsky Prospekt, Moscow 119571, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-574X","authenticated-orcid":false,"given":"Ksenya","family":"Zabudskaya","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics, 1 Moskvorechye Street, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1285-9093","authenticated-orcid":false,"given":"Oxana","family":"Ryzhkova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics, 1 Moskvorechye Street, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2391-481X","authenticated-orcid":false,"given":"Nikolay","family":"Zernov","sequence":"additional","affiliation":[{"name":"Biotech Campus LLC, Moscow 117997, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7041-045X","authenticated-orcid":false,"given":"Natalia","family":"Semenova","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution, Research Centre for Medical Genetics, 1 Moskvorechye Street, Moscow 115522, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1002\/ajh.10394","article-title":"Hemoglobinopathy case finding by pulse oximetry","volume":"74","author":"Bruns","year":"2003","journal-title":"Am. J. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1002\/ajh.22074","article-title":"Erratum to: Unexpectedly low pulse oximetry measurements associated with variant hemoglobins: A systematic review","volume":"86","author":"Verhovsek","year":"2011","journal-title":"Am. J. Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bain, B.J. (2011). Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. Br. J. Haematol., 153.","DOI":"10.1111\/j.1365-2141.2011.08694.x"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1055\/s-0032-1312612","article-title":"Oxygen Saturation in Pulse Oximetry in Hemoglobin Anomalies","volume":"224","author":"Zur","year":"2012","journal-title":"Klin. P\u00e4diatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/0022-2836(80)90090-X","article-title":"Hemoglobin Rothschild (\u03b237(C3)Trp \u2192 Arg): A high\/low affinity hemoglobin mutant","volume":"144","author":"Sharma","year":"1980","journal-title":"J. Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fomenko, A., Kolokowski, T., Heyse, D., Petkova, P., Hassan, M., Rezazadegan, K., Walther, N., and Dellweg, D. (2022). Hemoglobin Rothschild\u2014Unimpaired physical performance and oxygen uptake\u2014A case report with literature review. Respir. Med. Case Rep., 38.","DOI":"10.1016\/j.rmcr.2022.101681"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1080\/03630269.2017.1324796","article-title":"Detection of Hb Rothschild HBB: C.[112T > A or 112T > C], Through High Index of Suspicion on Abnormal Pulse Oximetry","volume":"41","author":"Alli","year":"2017","journal-title":"Hemoglobin"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1080\/16078454.2022.2140998","article-title":"A Case Hb Rothschild (HBB: C.112T > A) with low pulse oximetry: A first familial presentation in China","volume":"27","author":"Li","year":"2022","journal-title":"Hematology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.arbres.2019.05.009","article-title":"Una causa infrecuente de saturaci\u00f3n arterial de ox\u00edgeno baja: Hemoglobinopat\u00eda de Rothschild","volume":"55","year":"2019","journal-title":"Arch. Bronconeumol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1097\/MPH.0b013e31817e4a19","article-title":"Dyshemoglobinemias and pulse oximetry: A therapeutic challenge","volume":"30","author":"Hladik","year":"2008","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_12","first-page":"72","article-title":"Low-oxygen-affinity hemoglobinopathy Hemoglobin Sunshine Seth: A case report and literature review","volume":"44","author":"Chang","year":"2023","journal-title":"Chin. J. Hematol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1002\/ajh.25425","article-title":"How we diagnose and manage altered oxygen affinity hemoglobin variants","volume":"94","author":"Yudin","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"453","DOI":"10.3109\/03630268708998005","article-title":"Hemoglobin Chico [beta 66(E10)Lys----Thr]: A new variant with decreased oxygen affinity","volume":"11","author":"Shih","year":"1987","journal-title":"Hemoglobin"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, M., Wang, K., Xu, X., Ji, W., Guo, Y., Gao, W., and Liu, T. (2025). Case Report: Hemoglobin titusville: A specific case of cyanosis. Front. Cardiovasc. Med., 12.","DOI":"10.3389\/fcvm.2025.1537704"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/BF03010939","article-title":"Haemoglobin Hammersmith precludes monitoring with conventional pulse oximetry","volume":"41","author":"Lang","year":"1994","journal-title":"Can. J. Anaesth. J. Can. Anesth."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1097\/00000542-199402000-00029","article-title":"Unexpectedly low pulse oximeter readings in a boy with unstable hemoglobin K\u00f6ln","volume":"80","author":"Katoh","year":"1994","journal-title":"Anesthesiology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/(SICI)1096-8652(199811)59:3<181::AID-AJH1>3.0.CO;2-I","article-title":"Low pulse oximeter-measured hemoglobin oxygen saturations with hemoglobin Cheverly","volume":"59","author":"Hohl","year":"1998","journal-title":"Am. J. Hematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/ijlh.13885","article-title":"The hemoglobinopathies, molecular disease mechanisms and diagnostics","volume":"44","author":"Harteveld","year":"2022","journal-title":"Int. J. Lab. Hematol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/24\/3181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T15:31:45Z","timestamp":1765553505000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/15\/24\/3181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":19,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["diagnostics15243181"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics15243181","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]}}}