{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:19:18Z","timestamp":1787894358927,"version":"build-2784847793"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"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>Cytochrome P450 oxidoreductase deficiency (PORD) is an ultra-rare autosomal recessive disorder within the congenital adrenal hyperplasia (CAH) spectrum, characterized by a broad clinical spectrum involving steroidogenesis defects, genital anomalies, and skeletal abnormalities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      We report a phenotypically female neonate with a 46,XY karyotype whose postnatal diagnostic evaluation was initiated after newborn screening revealed elevated 17-hydroxyprogesterone (17-OHP) concentration. The patient presented with mild hypertelorism, mild nasal hypoplasia, and low-set bilateral ears, along with female external genitalia consistent with disorder of sex development (DSD) and anal atresia. Radiological evaluation revealed femoral bowing and subsequent fracture. The craniofacial and skeletal abnormalities were consistent with the features of Antley-Bixler syndrome (ABS). Endocrine evaluation revealed elevated progesterone, markedly reduced testosterone, and secondary hyperaldosteronism. Genetic analysis identified three novel variants in the\n                      <jats:italic>POR<\/jats:italic>\n                      gene (NM_001395413.1): the patient harbored a paternal c.1187_1195dup (p.Pro396_Glu398dup) variant and two maternally inherited variants in\n                      <jats:italic>cis<\/jats:italic>\n                      , c.1447G&amp;gt;A (p.Gly483Ser) and c.1806\u00a0+\u00a04_1806\u00a0+\u00a028del. Protein structural modeling predicted that the p.Pro396_Glu398dup and p.Gly483Ser may disrupt the flavin adenine dinucleotide (FAD)\u2013binding domain. RNA sequencing (RNA-seq) confirmed that the intronic variant c.1806\u00a0+\u00a04_1806\u00a0+\u00a028del caused aberrant splicing, resulting in partial intron retention and predicted impairment of the nicotinamide adenine dinucleotide phosphate (NADPH)\u2013binding domain. According to American College of Medical Genetics and Genomics (ACMG) guidelines and incorporating functional evidence, c.1187_1195dup and c.1806\u00a0+\u00a04_1806\u00a0+\u00a028del were reclassified as likely pathogenic (LP), whereas c.1447G&amp;gt;A remained a variant of uncertain significance (VUS).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study describes a neonate with PORD caused by three novel POR variants and expands the known clinical spectrum of PORD by identifying rare manifestations including anal atresia and hearing loss. RNA-seq provided valuable functional evidence for variant interpretation and facilitated accurate molecular diagnosis. These findings highlight the importance of integrating genetic phasing, transcript-level functional analysis, and comprehensive clinical evaluation for precise diagnosis and counseling in rare endocrine disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1896956","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T04:35:06Z","timestamp":1787891706000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel compound heterozygous POR variants in a neonate with Antley-Bixler syndrome and 46,XY DSD: a case report and literature review"],"prefix":"10.3389","volume":"17","author":[{"given":"Wenting","family":"Zhang","sequence":"first","affiliation":[{"name":"Neonatal Disease Screening Center, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, Guangdong, China"]},{"name":"Dongguan Key Laboratory of Screening, Diagnosis and Treatment of Neonatal Genetic and Metabolic Diseases","place":["Dongguan, Guangdong, China"]},{"name":"Central Laboratory, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Zeng","sequence":"additional","affiliation":[{"name":"Neonatal Disease Screening Center, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, Guangdong, China"]},{"name":"Dongguan Key Laboratory of Screening, Diagnosis and Treatment of Neonatal Genetic and Metabolic Diseases","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjin","family":"Li","sequence":"additional","affiliation":[{"name":"Neonatal Disease Screening Center, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, Guangdong, China"]},{"name":"Dongguan Key Laboratory of Screening, Diagnosis and Treatment of Neonatal Genetic and Metabolic Diseases","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cailian","family":"Xie","sequence":"additional","affiliation":[{"name":"Neonatal Disease Screening Center, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, Guangdong, China"]},{"name":"Dongguan Key Laboratory of Screening, Diagnosis and Treatment of Neonatal Genetic and Metabolic Diseases","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihao","family":"Sun","sequence":"additional","affiliation":[{"name":"Neonatal Disease Screening Center, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, Guangdong, China"]},{"name":"Dongguan Key Laboratory of Screening, Diagnosis and Treatment of Neonatal Genetic and Metabolic Diseases","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guizhen","family":"Lyu","sequence":"additional","affiliation":[{"name":"Dongguan Molecular Diagnostic Technology and Infectious Disease Medical Test Engineering Research Center, Dongguan Labway Clinical Laboratory Co., Ltd.","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tizhen","family":"Yan","sequence":"additional","affiliation":[{"name":"Central Laboratory, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, China"]},{"name":"Institute of Reproduction and Genetics, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, Guangdong, China"]},{"name":"Dongguan Key Laboratory of Reproduction and Birth Defects Prevention and Control, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Huang","sequence":"additional","affiliation":[{"name":"Neonatal Disease Screening Center, Dongguan Maternal and Child Health Care Hospital","place":["Dongguan, Guangdong, 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