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Although more than 250 different deleterious variations have been described, no genotype\u2013phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2\u2009weeks of age, requiring replacement therapy with mineralocorticoids and glucocorticoids for 4\u2009months. For 3\u2009years, he did well without treatment. At almost 4\u2009years of age, the disorder was restarted. A long follow\u2010up showed the evolution of hypogonadotropic hypogonadism. Molecular studies on <jats:italic>NR0B1<\/jats:italic> revealed a novel and deleterious deletion\u2013insertion\u2013inversion\u2013deletion complex rearrangement sorted in the 5\u2032\u20103\u2032 direction, which is described as follows: (1) deletion of the intergenic region (between <jats:italic>TASL<\/jats:italic> and <jats:italic>NR0B1<\/jats:italic> genes) and 5\u2032 region, (2) insertion of a sequence containing 37\u2009bp at the junction of the intergenic region of the <jats:italic>TASL<\/jats:italic> gene and a part of exon 1 of the <jats:italic>NR0B1<\/jats:italic> gene, (3) inversion of a part of exon 1, (4) deletion of the final portion of exon 1 and exon 2 and beginning of the 3\u2032UTR region, (5) maintenance of part of the intergenic sequence (between genes <jats:italic>MAGEB1<\/jats:italic> and <jats:italic>NR0B1<\/jats:italic>, telomeric sense), (6) large posterior deletion, in the same sense. The path to molecular diagnosis was challenging and involved several molecular biology techniques. Evaluating the breakpoints in our patient, we assumed that it was a nonrecurrent rearrangement that had not yet been described. It may involve a repair mechanism known as nonhomologous end\u2010joining (NHEJ), which joins two ends of DNA in an imprecise manner, generating an \u201cinformation scar,\u201d represented herein by the 37\u2009bp insertion. In addition, the local Xp21 chromosome architecture with sequences capable of modifying the DNA structure could impact the formation of complex rearrangements.<\/jats:p>","DOI":"10.1002\/ajmg.a.63536","type":"journal-article","created":{"date-parts":[[2024,1,20]],"date-time":"2024-01-20T05:09:40Z","timestamp":1705727380000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["X\u2010linked congenital adrenal hypoplasia: Report of long clinical follow\u2010up and description of a new complex variant in the <i>NR0B1<\/i> gene"],"prefix":"10.1002","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0061-8217","authenticated-orcid":false,"given":"Adriana Mangue","family":"Esquiaveto\u2010Aun","sequence":"first","affiliation":[{"name":"Graduate Program in Child and Adolescent Health Faculty of Medical Sciences (FCM), UNICAMP  Campinas S\u00e3o Paulo 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