{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:00:00Z","timestamp":1791306000077,"version":"4.3.1"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"3","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:p>Primary adrenal insufficiency (PAI) is potentially life threatening, but rare. In children, genetic defects prevail whereas adults suffer more often from acquired forms of PAI. The spectrum of genetic defects has increased in recent years with the use of next-generation sequencing methods and now has reached far beyond genetic defects in all known enzymes of adrenal steroidogenesis. Cofactor disorders such as P450 oxidoreductase (<jats:italic>POR<\/jats:italic>) deficiency manifesting as a complex form of congenital adrenal hyperplasia with a broad clinical phenotype have come to the fore. In patients with isolated familial glucocorticoid deficiency (FGD), in which no mutations in the genes for the ACTH receptor (<jats:italic>MC2R<\/jats:italic>) or its accessory protein MRAP have been found, non-classic steroidogenic acute regulatory protein (<jats:italic>StAR<\/jats:italic>) and<jats:italic>CYP11A1<\/jats:italic>mutations have been described; and more recently novel mutations in genes such as nicotinamide nucleotide transhydrogenase (<jats:italic>NNT<\/jats:italic>) and thioredoxin reductase 2 (<jats:italic>TRXR2<\/jats:italic>) involved in the maintenance of the mitochondrial redox potential and generation of NADPH important for steroidogenesis and ROS detoxication have been discovered. In addition, whole exome sequencing approach also solved the genetics of some syndromic forms of PAI including IMAGe syndrome (<jats:italic>CDKN1C<\/jats:italic>), Irish traveler syndrome (<jats:italic>MCM4<\/jats:italic>), MIRAGE syndrome (<jats:italic>SAMD9<\/jats:italic>); and most recently a syndrome combining FGD with steroid-resistant nephrotic syndrome and ichthyosis caused by mutations in the gene for sphingosine-1-phosphate lyase 1 (<jats:italic>SGPL1<\/jats:italic>). This review intends do give an update on novel genetic forms of PAI and their suggested mechanism of disease. It also advocates for advanced genetic work-up of PAI (especially in children) to reach a specific diagnosis for better counseling and treatment.<\/jats:p>","DOI":"10.1530\/eje-17-0128","type":"journal-article","created":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T00:30:27Z","timestamp":1493339427000},"page":"R99-R111","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":70,"title":["MECHANISMS IN ENDOCRINOLOGY: Update on pathogenesis of primary adrenal insufficiency: beyond steroid enzyme deficiency and autoimmune adrenal destruction"],"prefix":"10.1093","volume":"177","author":[{"given":"Christa E","family":"Fl\u00fcck","sequence":"first","affiliation":[{"name":"Departments of Pediatrics and Clinical Research, Bern University Children\u2019s Hospital Inselspital, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"key":"ref611","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1210\/jc.2009-0467","article-title":"Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency","volume":"94","year":"2009","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref231","first-page":"107","article-title":"Management of endocrine disease quality of life and complications of primary adrenal insufficiency a of","journal-title":"epidemiology review European Journal Endocrinology"},{"key":"ref391","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1210\/jcem-56-6-1243","article-title":"Primary cortisol resistance: a family study","volume":"56","year":"1983","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref441","first-page":"63","article-title":"Oxidative stress adrenocortical insufficiency of","journal-title":"Journal Endocrinology"},{"key":"ref521","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/ng.3569","article-title":"SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7","volume":"48","year":"2016","journal-title":"Nature Genetics"},{"key":"ref381","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/2458","article-title":"Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse.","volume":"20","year":"1998","journal-title":"Nature Genetics"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1210\/en.2013-1241","article-title":"Deficiency of ALADIN impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis","volume":"154","year":"2013","journal-title":"Endocrinology"},{"key":"ref461","doi-asserted-by":"publisher","first-page":"201499","DOI":"10.1210\/jc.2013-3844","article-title":"reductase mutation associated with familial glucocorticoid deficiency of and","author":"TXNRD","journal-title":"Journal Clinical Endocrinology Metabolism"},{"key":"ref151","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.1172\/JCI116853","article-title":"Hereditary isolated glucocorticoid deficiency is associated with abnormalities of the adrenocorticotropin receptor gene","volume":"92","year":"1993","journal-title":"Journal of Clinical Investigation"},{"key":"ref271","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1016\/S0140-6736(13)61684-0","article-title":"Adrenal insufficiency","volume":"383","year":"2014","journal-title":"Lancet"},{"key":"ref01","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1159\/000363107","article-title":"Novel insight into etiology, diagnosis and management of primary adrenal insufficiency","volume":"82","year":"2014","journal-title":"Hormone Research in Paediatrics"},{"key":"ref191","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1093\/hmg\/10.3.283","article-title":"Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene","volume":"10","year":"2001","journal-title":"Human Molecular Genetics"},{"key":"ref301","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1056\/NEJM198511073131903","article-title":"Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. 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