{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T22:59:47Z","timestamp":1781564387279,"version":"3.54.5"},"reference-count":12,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"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. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p><jats:italic>HNF4A<\/jats:italic>-MODY constitutes 5%\u201310% of MODY cases; however, treatment options remain unclearly recommended, and long-term follow-up of patients with <jats:italic>HNF4A<\/jats:italic>-MODY is lacking due to limited research. Here, we report a case carrying a new <jats:italic>de novo<\/jats:italic> variant of <jats:italic>HNF4A<\/jats:italic>. The patient had been using insulin for up to 25 years before genetic diagnosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case description<\/jats:title><jats:p>A 38-year-old man sought consultation due to an increased daily insulin requirement and inadequate glycemic control. At the age of 13, the patent\u2019s parents discovered that he had significantly elevated fasting blood glucose levels accompanied by weight loss. He was subsequently diagnosed with type 1 diabetes and began insulin therapy. At a routine follow-up at age 21, another physician observed that his pancreatic islet function remained preserved, with negative results for diabetes-related antibodies. Consequently, his diagnosis was revised to type 2 diabetes, and the antihyperglycemic therapy was added in metformin and acarbose. Before the current consultation, the patient\u2019s insulin dosage had gradually increased to 80 units per day; however, glycemic control remained unsatisfactory. Whole exome sequencing identified a heterozygous variant, c.272G &amp;gt; A (p.R91H), in exon 3 of the <jats:italic>HNF4A<\/jats:italic> gene (NM_175914.5) in the patient. The patient\u2019s treatment regimen was modified to include metformin at a dosage of 1.0 g twice daily, semaglutide at 0.5 mg once weekly, and insulin glargine was gradually discontinued. The patient achieved adequate glycemic control during follow-up.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This case emphasizes that spontaneous <jats:italic>HNF4A<\/jats:italic>-MODY is prone to misdiagnosis and the prolonged rate of pancreatic function decline in <jats:italic>HNF4A<\/jats:italic>-MODY. Glycemic control and complication progression could be acceptable in <jats:italic>HNF4A<\/jats:italic>-MODY cases treated with long-time insulin, but risks of hypoglycemic events, obesity, and atherosclerosis remain. Switching to GLP1RA treatment in <jats:italic>HNF4A<\/jats:italic>-MODY still yields a good effect after a prolonged disease course.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1509135","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T13:10:43Z","timestamp":1750079443000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: long-term misdiagnosis and follow-up of a patient with HNF4A-MODY carrying a new de novo mutation"],"prefix":"10.3389","volume":"16","author":[{"given":"Jing","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,16]]},"reference":[{"key":"B1","article-title":"Maturity-Onset Diabetes of the Young Overview","volume-title":"GeneReviews\u00ae [Internet]","author":"Naylor","year":"1993"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1738-y","article-title":"Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European 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(Lond)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00592-018-1232-x","article-title":"Screening of HNF1A and HNF4A mutation and clinical phenotype analysis in a large cohort of Chinese patients with maturity-onset diabetes of the young","volume":"56","author":"Wang","year":"2019","journal-title":"Acta Diabetol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13378","article-title":"Recognition of maturity-onset diabetes of the young in China","volume":"12","author":"Liang","year":"2021","journal-title":"J Diabetes Investig"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nature11966","article-title":"Multidomain integration in the structure of the HNF-4alpha nuclear receptor complex","volume":"495","author":"Chandra","year":"2013","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.v37.5","article-title":"A new screening strategy and whole-exome sequencing for the early diagnosis of maturity-onset diabetes of the young","volume":"37","author":"Liu","year":"2021","journal-title":"Diabetes Metab Res Rev"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-011-2418-8","article-title":"The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes","volume":"55","author":"Shields","year":"2012","journal-title":"Diabetologia"},{"key":"B11","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1097\/CM9.0000000000002321","article-title":"Prevalence of maturity-onset diabetes of the young in phenotypic type 2 diabetes in young adults: a nationwide, multi-center, cross-sectional survey in China","volume":"136","author":"Chen","year":"2023","journal-title":"Chin Med J (Engl)"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-013-3119-2","article-title":"De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed","volume":"57","author":"Stanik","year":"2014","journal-title":"Diabetologia"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1509135\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T13:10:44Z","timestamp":1750079444000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1509135\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,16]]},"references-count":12,"alternative-id":["10.3389\/fendo.2025.1509135"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1509135","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,16]]},"article-number":"1509135"}}