{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T19:38:09Z","timestamp":1768073889003,"version":"3.49.0"},"reference-count":26,"publisher":"The Endocrine Society","issue":"1","license":[{"start":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T00:00:00Z","timestamp":1749254400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"The Japanese Society for Pediatric Endocrinology Future Development"},{"DOI":"10.13039\/501100003478","name":"The Ministry of Health, Labour and Welfare of Japan","doi-asserted-by":"publisher","award":["23FC1041"],"award-info":[{"award-number":["23FC1041"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Agency"},{"name":"Medical Research and Development","award":["24ek0109743h0001"],"award-info":[{"award-number":["24ek0109743h0001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Primary adrenal insufficiency (PAI) is a rare, life-threatening condition, and at times is associated with differences of sexual differentiation (DSD). Cytochrome P450 enzymes, which are essential for steroidogenesis in adrenals and gonads, have heme in their active center. CPOX encodes an enzyme coproporphyrinogen oxidase (CPOX) that is involved in the synthesis of heme.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aims to report the identification of biallelic inactivating CPOX variants in 3 unrelated patients with PAI and their clinical characteristics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We report 3 patients with childhood-onset PAI, including 2 with 46,XY DSD. All 3 had adrenal hypoplasia. Additionally, they commonly had severe neonatal jaundice; 2 developed skin blisters in the areas exposed to phototherapy and 2 showed severe neonatal anemia requiring transfusions. Exome sequencing was performed to explore the genetic basis of the patients. The pathogenicity of the identified variants was confirmed with targeted mRNA and proteomic analyses of the patient-derived peripheral blood cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified biallelic rare CPOX variants in each patient, including c.2T &amp;gt; G, p.Arg426*, c.1277G &amp;gt; A, and p.Tyr429Cysfs33*. The 3 patients commonly had the start codon-altering c.2T &amp;gt; G variant. Analysis of the mRNA and proteome of peripheral blood cells from 1 patient (c.2T &amp;gt; G and p.Arg426*) showed that CPOX mRNA expression was comparable to controls; however, CPOX protein expression was significantly decreased to 1%.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We provided genetic evidence linking CPOX deficiency and PAI with 46,XY DSD, suggesting that the heme synthesis pathway plays an important role in human steroidogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgaf329","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T07:52:41Z","timestamp":1749196361000},"page":"e83-e91","source":"Crossref","is-referenced-by-count":2,"title":["Coproporphyrinogen Oxidase Deficiency Causes Primary Adrenal Insufficiency and 46,XY DSD"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4390-5685","authenticated-orcid":false,"given":"Misa","family":"Honda","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Keio University School of Medicine , Shinjuku-ku, Tokyo 160-8582 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0940-4517","authenticated-orcid":false,"given":"Satoshi","family":"Narumi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Keio University School of Medicine , Shinjuku-ku, Tokyo 160-8582 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1751-6527","authenticated-orcid":false,"given":"Kosei","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Okayama University Hospital , Kitaku, Okayama 700-8558 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshimitsu","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital , Showa-ku Nagoya City, Aichi 466-8650 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Department of Applied Genomics, Kazusa DNA Research Institute , Kisarazu City, Chiba 292-0818 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3328-9571","authenticated-orcid":false,"given":"Osamu","family":"Ohara","sequence":"additional","affiliation":[{"name":"Department of Applied Genomics, Kazusa DNA Research Institute , Kisarazu City, Chiba 292-0818 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