{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:38:58Z","timestamp":1792442338683,"version":"4.5.0"},"reference-count":36,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Slovenian Research Agency","doi-asserted-by":"publisher","award":["P3-0343"],"award-info":[{"award-number":["P3-0343"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the NNT gene. The patients were followed until the ages of 21.6, 20.2, and 4.2 years. PAI was diagnosed in the eldest two brothers after an Addisonian crisis and the third was diagnosed at the age of 4.5 months in the asymptomatic stage due to the genetic screening of family members. Whole exome sequencing with a targeted interpretation of variants in genes related to PAI was performed in all the patients. The urinary steroid metabolome was determined by gas chromatography\u2013mass spectrometry in the asymptomatic patient. The three patients, who were homozygous for c.1575dup in the NNT gene, developed isolated glucocorticoid deficiency. The urinary steroid metabolome showed normal excretion of cortisol metabolites. The adolescent patients had slow pubertal progression with low\u2013normal testicular volume, while testicular endocrine function was normal. Bone mineral density was in the range for osteopenia in both grown-up siblings. Echocardiography revealed no structural or functional heart abnormalities. This article is among the first with a comprehensive and chronologically-detailed description of patients with NNT deficiency.<\/jats:p>","DOI":"10.3390\/genes13050717","type":"journal-article","created":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T01:55:51Z","timestamp":1650506151000},"page":"717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Long-Term Follow-Up of Three Family Members with a Novel NNT Pathogenic Variant Causing Primary Adrenal Insufficiency"],"prefix":"10.3390","volume":"13","author":[{"given":"Tjasa","family":"Krasovec","sequence":"first","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7843-8107","authenticated-orcid":false,"given":"Jaka","family":"Sikonja","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3304-5120","authenticated-orcid":false,"given":"Mojca","family":"Zerjav Tansek","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marusa","family":"Debeljak","sequence":"additional","affiliation":[{"name":"Clinical Institute of Special Laboratory Diagnostics, University Children\u2019s Hospital, University Medical Centre Ljubljana, Vrazov Trg 1, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasa","family":"Ilovar","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0154-3547","authenticated-orcid":false,"given":"Katarina","family":"Trebusak Podkrajsek","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Clinical Institute of Special Laboratory Diagnostics, University Children\u2019s Hospital, University Medical Centre Ljubljana, Vrazov Trg 1, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bertok","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tine","family":"Tesovnik","sequence":"additional","affiliation":[{"name":"Clinical Institute of Special Laboratory Diagnostics, University Children\u2019s Hospital, University Medical Centre Ljubljana, Vrazov Trg 1, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3080-4838","authenticated-orcid":false,"given":"Jernej","family":"Kovac","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Clinical Institute of Special Laboratory Diagnostics, University Children\u2019s Hospital, University Medical Centre Ljubljana, Vrazov Trg 1, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasna","family":"Suput Omladic","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7232-9532","authenticated-orcid":false,"given":"Michaela F.","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Laboratory for Translational Hormone Analytics, Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Feulgenstra\u00dfe 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan A.","family":"Wudy","sequence":"additional","affiliation":[{"name":"Laboratory for Translational Hormone Analytics, Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Feulgenstra\u00dfe 12, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0836-5114","authenticated-orcid":false,"given":"Magdalena","family":"Avbelj Stefanija","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0273-4732","authenticated-orcid":false,"given":"Tadej","family":"Battelino","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Primoz","family":"Kotnik","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5246-9869","authenticated-orcid":false,"given":"Urh","family":"Groselj","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Ljubljana, Vrazov Trg 2, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children\u2019s Hospital, University Medical Centre Ljubljana, Bohoriceva Ulica 20, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"88","DOI":"10.4274\/jcrpe.galenos.2020.2020.0132","article-title":"Pediatric primary adrenal insufficiency: A 21-year single center experience","volume":"13","year":"2021","journal-title":"J. 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