{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T09:40:55Z","timestamp":1792402855066,"version":"4.4.0"},"reference-count":27,"publisher":"Walter de Gruyter GmbH","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"Abstract<\/jats:title>\n \n Objectives<\/jats:title>\n \n Familial glucocorticoid deficiency type 4 (FGD4) is a rare autosomal recessive form of primary adrenal insufficiency caused by biallelic variants in the\n NNT<\/jats:italic>\n gene and characterized predominantly by isolated glucocorticoid deficiency. Neurological presentations may obscure the underlying adrenal disorder. We describe a pediatric case with a novel\n NNT<\/jats:italic>\n variant not previously associated with FGD4 and review the reported clinical and genetic spectrum.\n <\/jats:p>\n <\/jats:sec>\n \n Case presentation<\/jats:title>\n \n A 10-year-old girl presented with a 4-year history of epilepsy and longstanding diffuse hyperpigmentation. A homozygous frameshift variant in\n NNT<\/jats:italic>\n (c.645delT; p.Phe215Leufs*17) was identified in the appendix to the previous whole-exome sequencing report and confirmed by Sanger sequencing; both parents were heterozygous carriers. The variant was classified as pathogenic according to ACMG criteria. The patient also had primary hypothyroidism, symptomatic epilepsy, and metabolic encephalopathy. During follow-up with glucocorticoid and thyroxine replacement therapy and continued antiepileptic treatment seizure frequency decreased, hyperpigmentation improved, and communication, attention, and social interaction improved.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n This case expands the mutational spectrum of\n NNT<\/jats:italic>\n -related FGD4 and emphasizes the importance of considering adrenal insufficiency in pediatric patients presenting with seizures and hyperpigmentation. Early recognition and diagnosis of adrenal insufficiency enable timely hormone replacement therapy and may reduce the risk of neurological and metabolic complications.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1515\/jpem-2026-0001","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T08:56:37Z","timestamp":1792400197000},"source":"Crossref","is-referenced-by-count":0,"title":["Delayed diagnosis of familial glucocorticoid deficiency type 4 in a child with epilepsy: a case report and literature review"],"prefix":"10.1515","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-110X","authenticated-orcid":false,"given":"Ni","family":"Zhen","sequence":"first","affiliation":[{"name":"Department of Pediatrics , Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai , China"},{"name":"Department of Endocrine and Metabolism Disease , Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenli","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiya","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine , Shanghai , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,10,20]]},"reference":[{"key":"2026101908563196589_j_jpem-2026-0001_ref_001","doi-asserted-by":"crossref","unstructured":"Di Dato, F, Capalbo, D, Mirra, R, Del Vecchio Blanco, F, Salerno, M, Iorio, R. Case report: neonatal cholestasis as early manifestation of primary adrenal insufficiency. Front Pediatr 2021;9:767858. https:\/\/doi.org\/10.3389\/fped.2021.767858.","DOI":"10.3389\/fped.2021.767858"},{"key":"2026101908563196589_j_jpem-2026-0001_ref_002","unstructured":"Lipi\u0144ski, P, Kot, K, Jankowska, I, Szalecki, MA. Cortisol deficiency as a rare cause of neonatal cholestasis. Dev Period Med 2018;22:280\u20133."},{"key":"2026101908563196589_j_jpem-2026-0001_ref_003","doi-asserted-by":"crossref","unstructured":"Meimaridou, E, Kowalczyk, J, Guasti, L, Hughes, CR, Wagner, F, Frommolt, P, et al.. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet 2012;44:740\u20132. https:\/\/doi.org\/10.1038\/ng.2299.","DOI":"10.1038\/ng.2299"},{"key":"2026101908563196589_j_jpem-2026-0001_ref_004","doi-asserted-by":"crossref","unstructured":"Richards, S, Aziz, N, Bale, S, Bick, D, Das, S, Gastier-Foster, J, et al.. 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. Genet Med 2015;17:405\u201324. https:\/\/doi.org\/10.1038\/gim.2015.30.","DOI":"10.1038\/gim.2015.30"},{"key":"2026101908563196589_j_jpem-2026-0001_ref_005","doi-asserted-by":"crossref","unstructured":"Maharaj, AV. Familial glucocorticoid deficiency: the changing landscape of an eponymous syndrome. Front Endocrinol 2023;14:1268345. https:\/\/doi.org\/10.3389\/fendo.2023.1268345.","DOI":"10.3389\/fendo.2023.1268345"},{"key":"2026101908563196589_j_jpem-2026-0001_ref_006","doi-asserted-by":"crossref","unstructured":"Roucher-Boulez, F, Mallet-Motak, D, Samara-Boustani, D, Jilani, H, Ladjouze, A, Souchon, PF, et al.. NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects. Eur J Endocrinol 2016;175:73\u201384. https:\/\/doi.org\/10.1530\/eje-16-0056.","DOI":"10.1530\/EJE-16-0056"},{"key":"2026101908563196589_j_jpem-2026-0001_ref_007","doi-asserted-by":"crossref","unstructured":"Novoselova, TV, Rath, SR, Carpenter, K, Pachter, N, Dickinson, JE, Price, G, et al.. NNT pseudoexon activation as a novel mechanism for disease in two siblings with familial glucocorticoid deficiency. J\u00a0Clin Endocrinol Metab 2015;100:E350\u20134. https:\/\/doi.org\/10.1210\/jc.2014-3641.","DOI":"10.1210\/jc.2014-3641"},{"key":"2026101908563196589_j_jpem-2026-0001_ref_008","doi-asserted-by":"crossref","unstructured":"Weinberg-Shukron, A, Abu-Libdeh, A, Zhadeh, F, Carmel, L, Kogot-Levin, A, Kamal, L, et al.. Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress. J\u00a0Med Genet 2015;52:636\u201341. https:\/\/doi.org\/10.1136\/jmedgenet-2015-103078.","DOI":"10.1136\/jmedgenet-2015-103078"},{"key":"2026101908563196589_j_jpem-2026-0001_ref_009","doi-asserted-by":"crossref","unstructured":"Hershkovitz, E, Arafat, M, Loewenthal, N, Haim, A, Parvari, R. Combined adrenal failure and testicular adrenal rest tumor in a patient with nicotinamide nucleotide transhydrogenase deficiency. J\u00a0Pediatr Endocrinol Metab 2015;28:1187\u201390. https:\/\/doi.org\/10.1515\/jpem-2015-0075.","DOI":"10.1515\/jpem-2015-0075"},{"key":"2026101908563196589_j_jpem-2026-0001_ref_010","doi-asserted-by":"crossref","unstructured":"Krasovec, T, Sikonja, J, Zerjav Tansek, M, Debeljak, M, Ilovar, S, Trebusak Podkrajsek, K, et al.. Long-term follow-up of three family members with a novel NNT pathogenic variant causing primary adrenal insufficiency. 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