{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T05:05:55Z","timestamp":1779944755116,"version":"3.53.1"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"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>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency and elevated adrenocorticotropic hormone (ACTH) levels. Variants in\n                      <jats:italic>TXNRD2<\/jats:italic>\n                      , which encodes mitochondrial thioredoxin reductase 2, have recently been implicated in FGD; however, the phenotypic and mutational spectrum remain extremely limited.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Whole-genome sequencing (WGS) was performed in a proband from a Saudi family who presented in early childhood with clinical and biochemical features consistent with FGD (Low basal and stimulated cortisol of &amp;lt; 5 nmol\/l and extremely elevated ACTH levels of &amp;gt; 2500 pg\/ml) and seizure disorder requiring medical treatment and with basal ganglia changes noted on brain MRI at presentation. WGS identified a novel likely pathogenic\n                      <jats:italic>TXNRD2<\/jats:italic>\n                      variant with no other potential variant in FGD-associated genes. Population frequency, segregation analysis, evolutionary conservation, and\n                      <jats:italic>in silico<\/jats:italic>\n                      pathogenicity predictions were assessed for the identified variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      WGS identified a novel missense homozygous\n                      <jats:italic>TXNRD2<\/jats:italic>\n                      (NM_001282512) variant (c.575C&amp;gt;T (p.Pro192Leu) in the proband, and in the heterozygous state in both parents, supporting autosomal recessive inheritance. This variant has not been reported in a local population database of &amp;gt; 18000 exomes, is extremely rare in international population databases (minor allele frequency 0.00000479), and affects a highly conserved residue. The variant was consistently predicted by multiple\n                      <jats:italic>in silico<\/jats:italic>\n                      tools to have deleterious effects on protein structure and function. No pathogenic, likely pathogenic, or VUS was found in other genes involved in FGD, including\n                      <jats:italic>MC2R, MRAP, STAR, CYP11A1, NNT, MCM4, or SGPL1.<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This report adds another patient with a novel variant to the few previously described patients and expands the genetic spectrum of the very rare\n                      <jats:italic>TXNRD2<\/jats:italic>\n                      -associated FGD, supporting the role of mitochondrial redox dysregulation in adrenal insufficiency.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1834727","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:43:59Z","timestamp":1779943439000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Familial glucocorticoid deficiency due to a novel TXNRD2 variant: expanding the spectrum of a rare genetic cause"],"prefix":"10.3389","volume":"17","author":[{"given":"Ibrahim","family":"Al Alwan","sequence":"first","affiliation":[{"name":"College of Medicine, King Saud Bin Abdulaziz University for Health Sciences","place":["Riyadh, Saudi Arabia"]},{"name":"Department of Pediatrics, King Abdullah International Medical Research Center (KAIMRC)","place":["Riyadh, Saudi Arabia"]},{"name":"Pediatric Endocrinology Division, Department of Pediatrics, King Abdullah Specialist Children\u2019s Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs 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