{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:17:53Z","timestamp":1784557073895,"version":"3.55.0"},"reference-count":0,"publisher":"Bioscientifica","license":[{"start":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["edm.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"\n Summary<\/jats:title>\n \n Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for\n POMC<\/jats:italic>\n gene transcription and terminal differentiation of POMC-expressing cells.\n TBX19<\/jats:italic>\n gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 \u03bcg\/dL; normal range (NR): 7.8\u201326.2) and plasma ACTH levels within the normal range (22.1 pg\/mL; NR: 4.7\u201348.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 \u00d7 10\n \u22125<\/jats:sup>\n , no homozygous) was found in exon 2 of the\n TBX19<\/jats:italic>\n gene. The effect of this was assessed by an\n in vitro<\/jats:italic>\n splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient.\n <\/jats:p>\n <\/jats:sec>\n \n Learning points<\/jats:title>\n \n \n Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases.<\/jats:p>\n <\/jats:list-item>\n \n \n In vitro<\/jats:italic>\n splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Establishing a diagnosis due to a\n TBX19<\/jats:italic>\n mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:sec>","DOI":"10.1530\/edm-21-0128","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T07:11:13Z","timestamp":1633504273000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-2","source":"Crossref","is-referenced-by-count":4,"title":["Missplicing due to a synonymous, T96= exonic substitution in the T-box transcription factor TBX19 resulting in isolated ACTH deficiency"],"prefix":"10.1530","volume":"2021","author":[{"given":"Ashwini","family":"Maudhoo","sequence":"first","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avinaash","family":"Maharaj","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Buonocore","sequence":"additional","affiliation":[{"name":"2Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Angel","family":"Martos-Moreno","sequence":"additional","affiliation":[{"name":"3Department of Endocrinology, Hospital Infantil Universitario Ni\u00f1o Jes\u00fas, Instituto de Investigaci\u00f3n La Princesa, Madrid, Spain"},{"name":"4Department of Pediatrics, Universidad Aut\u00f3noma de Madrid, Madrid, Spain"},{"name":"5Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Argente","sequence":"additional","affiliation":[{"name":"3Department of Endocrinology, Hospital Infantil Universitario Ni\u00f1o Jes\u00fas, Instituto de Investigaci\u00f3n La Princesa, Madrid, Spain"},{"name":"4Department of Pediatrics, Universidad Aut\u00f3noma de Madrid, Madrid, Spain"},{"name":"5Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain"},{"name":"6CEI UAM\u2009+\u2009CSIC, IMDEA Food Institute, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C","family":"Achermann","sequence":"additional","affiliation":[{"name":"2Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li F","family":"Chan","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lou A","family":"Metherell","sequence":"additional","affiliation":[{"name":"1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Endocrinology, Diabetes & Metabolism Case Reports"],"original-title":[],"link":[{"URL":"https:\/\/edm.bioscientifica.com\/view\/journals\/edm\/2021\/1\/EDM21-0128.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/edm.bioscientifica.com\/downloadpdf\/journals\/edm\/2021\/1\/EDM21-0128.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:47:46Z","timestamp":1784555266000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/edm\/article\/3806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,1]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1530\/edm-21-0128","relation":{},"ISSN":["2052-0573"],"issn-type":[{"value":"2052-0573","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,1]]}}}