Novel phenotypes and genotypes in Antley-Bixler syndrome caused by cytochrome P450 oxidoreductase deficiency: based on the first cohort of Chinese children
Open accessAbstract
Background: Antley-Bixler syndrome (ABS) caused by P450 oxidoreductase deficiency (PORD) is a congenital adrenal hyperplasia with skeletal malformations and disordered sex development in both sexes. There have been no reports of ABS caused by PORD in Chinese children. Methods: We described the clinical and genetic characteristics of eight Chinese children with ABS caused by PORD and compared them with those of subjects in previous studies. Results: Eight patients, aged 6 months–17.8 years, showed strikingly similar craniofacial malformations. We first described four unreported features: lower eyelid fat pads (4/8), prominent lower eyelid-zygoma transverse line (4/8), underdeveloped or absent antihelix (5/8) and single earlobe crease (5/8). Five 46, XY patients presented various degrees of undervirilization, while three 46, XX cases showed masculinization. Basal endocrine measurements revealed the following consistent results: normal cortisol; elevated adrenocorticotropic hormone, progesterone, pregnenolone, 17-hydroxypropgesterone, and corticosterone; and decreased or normal testosterone/oestradiol. We identified three previously reported variants and four novel variants (c.51719_51710delGGCCCCTGTGinsC, p.D210G, p.Y248X and p.R554X) of POR . The most prevalent variant was p.R457H (8/16). The hydrocortisone dosages of patients differed because of variable degrees of adrenal insufficiency. Conclusions: We described novel phenotypes and genotypes of ABS caused by PORD. The variant p.R457H was the most prevalent in this cohort. All subjects had combined characteristics of 17-hydroxylase and 21-hydroxylase deficiency. Steroid replacement therapy for patients with PORD requires individually tailored dosing.
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Dean B et al. reported that patients homozygous for p.R457H did not display more pronounced skeletal defects than those carrying p.R457H in combination with other variants or compared to carriers of p.A287P.
“Although earlier studies suggested that the p.R457H variant is associated with more severe skeletal involvement, a study by Dean B et al. reported that patients homozygous for p.R457H did not display more pronounced skeletal defects than those carrying p.R457H in combination with other variants or compared to carriers of p.A287P (17, 34).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [34]
The Discussion (page unavailable) says patients with p.R457H tend to have severe skeletal phenotypes, whereas patients with p.A287P are less severely affected—the opposite of the claimed comparison. The Results’ Mutational analysis identifies one p.R457H homozygote but does not report the claimed skeletal-severity comparison with compound heterozygotes. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredIn female PORD patients, fetal CYP17A1 deficiency promotes accumulation of adrenal 17α-hydroxyprogesterone, which is shunted into the backdoor pathway to produce elevated levels of dihydrotestosterone.
“In female patients, fetal CYP17A1 deficiency promotes accumulation of adrenal 17α-hydroxyprogesterone, which is then shunted into the “backdoor pathway” to produce elevated levels of the potent androgen dihydrotestosterone (Figure 7) (34).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [34]
The Discussion (page not available) links prenatal masculinization in female PORD patients to possible activation of a backdoor androgen pathway, and the Results report elevated 17-OHP. The paper does not establish that fetal CYP17A1 deficiency causes adrenal 17-OHP to be converted through that pathway into elevated DHT. Its DHT measurements were taken after birth and were decreased or normal, so they do not resolve the fetal claim. (LLM, conf=0.86)
Experimental — accuracy not yet measuredApproximately half of all PORD patients require lifelong hydrocortisone replacement, while others may only need supplemental doses during periods of physiologic stress.
“While approximately half of all PORD patients require lifelong hydrocortisone replacement, others may only need supplemental doses during periods of physiologic stress (21, 28, 34).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [34]
Earlier studies suggested that the p.R457H variant is associated with more severe skeletal involvement.
“Although earlier studies suggested that the p.R457H variant is associated with more severe skeletal involvement, a study by Dean B et al. reported that patients homozygous for p.R457H did not display more pronounced skeletal defects than those carrying p.R457H in combination with other variants or compared to carriers of p.A287P (17, 34).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [34]
In PORD, impaired function of enzymes such as CYP17A1, CYP19A1, and CYP21A2 disrupts the synthesis of testosterone and dihydrotestosterone, as well as the conversion of androgens to estrogens, resulting in a spectrum of genital anomalies.
“In PORD, impaired function of enzymes such as CYP17A1, CYP19A1, and CYP21A2 disrupts the synthesis of testosterone and dihydrotestosterone, as well as the conversion of androgens to estrogens, resulting in a spectrum of genital anomalies (4, 32, 34, 59).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [34]
Patients carrying the p.R457H variant tend to exhibit more severe skeletal manifestations and a higher incidence of maternal virilization during pregnancy than those with the p.A287P variant.
“Accordingly, patients carrying the p.R457H variant tend to exhibit more severe skeletal manifestations and a higher incidence of maternal virilization during pregnancy than those with the p.A287P variant.”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [34]
p.A287P reduces 17α-hydroxylase and 17,20-lyase activities to approximately 20% and 10% of wild-type levels, respectively, while largely sparing CYP19A1 function.
“The p.R457H variant leads to a near-complete loss of CYP19A1 and CYP17A1 activities, whereas p.A287P reduces 17α-hydroxylase and 17,20-lyase activities to approximately 20% and 10% of wild-type levels, respectively, while largely sparing CYP19A1 function (34).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [34]
The p.R457H variant leads to a near-complete loss of CYP19A1 and CYP17A1 activities.
“The p.R457H variant leads to a near-complete loss of CYP19A1 and CYP17A1 activities, whereas p.A287P reduces 17α-hydroxylase and 17,20-lyase activities to approximately 20% and 10% of wild-type levels, respectively, while largely sparing CYP19A1 function (34).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [34]
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Cites
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594 · see citing works
Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome
Flück, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonça, B. B., Fujieda, K., & Miller, W. L. (2004) · Nature Genetics · doi:10.1038/ng1300 · Cited by 509 · see citing works
Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Vliet, G. V., Sack, J., Flück, C. E., et al. (2005) · The American Journal of Human Genetics · doi:10.1086/429417 · Cited by 336 · see citing works
Genotype-Phenotype Analysis in Congenital Adrenal Hyperplasia due to P450 Oxidoreductase Deficiency
Krone, N., Reisch, N., Idkowiak, J., Dhir, V., Ivison, H. E., Hughes, B. A., Rose, I. T., O'Neil, D. M., Vijzelaar, R., Smith, M. J., et al. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0640 · Cited by 163 · cited 2× · see citing works
“Twenty-four of 27 patients with PORD were found to have adrenal insufficiency after ACTH stimulation, 13 received permanent hydrocortisone replacement, and the remaining 11 required hydrocortisone treatment only during stress [17].”
BackgroundModulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase
Pandey, A. V., Kempná, P., Hofer, G., Mullis, P. E., & Flück, C. E. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0245 · Cited by 132 · see citing works
Genetic and clinical features of P450 oxidoreductase deficiency
Scott, R. R., & Miller, W. L. (2008) · Hormone Research in Paediatrics · doi:10.1159/000114857 · Cited by 115 · see citing works
Scott, R. R., Gomes, L. G., Huang, N., Van Vliet, G., & Miller, W. L. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-2345 · Cited by 79 · see citing works
P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms
Burkhard, F. Z., Parween, S., Udhane, S. S., Flück, C. E., & Pandey, A. V. (2017) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.04.003 · Cited by 79 · see citing works
Tomalik-Scharte, D., Maiter, D., Kirchheiner, J., Ivison, H. E., Fuhr, U., & Arlt, W. (2010) · European Journal of Endocrinology · doi:10.1530/eje-10-0764 · Cited by 77 · see citing works
Flagged first, then by citations
Research works printed but not linked: 10
- [2]Antley R Bixler D Trapezoidocephaly, midfacial hypoplasia and cartilage abnormalities with multiple synostoses and skeletal fractures Birth Defects Orig Artic Ser 1975 11 2 397 401 1227559
- [5]Aguilar A Wu S De Luca F P450 oxidoreductase expressed in rat chondrocytes modulates chondrogenesis via cholesterol- and Indian hedgehog-dependent mechanisms Endocrinology 2009 150 6 2732 2739 10.1210/en.2009-0043 19264869 · DOI · Paper page
- [7]Arlt W P450 oxidoreductase deficiency and Antley-Bixler syndrome Rev Endocr Metab Disord 2007 8 4 301 307 10.1007/s11154-007-9056-y 17960482 · DOI
- [8]Bai Y Li J Wang X Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review J Ovarian Res 2017 10 1 16 10.1186/s13048-017-0312-9 28288674 PMC5348910 · DOI · Paper page
- [10]Idkowiak J Cragun D Hopkin RJ Arlt W Adam MP Ardinger HH Pagon RA Wallace SE Bean LJH Stephens K Cytochrome P450 Oxidoreductase deficiency GeneReviews((R)) 1993 Seattle (WA) University of Washington 20301592
- [11]McCall AA Kirsch CF Ishiyama G Ishiyama A Otologic findings in Antley-Bixler syndrome: a clinical and radiologic case report Int J Pediatr Otorhinolaryngol 2007 71 7 1139 1143 10.1016/j.ijporl.2007.02.016 17482285 · DOI
- [12]Arlt W Walker EA Draper N Ivison HE Ride JP Hammer F Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study Lancet (London, England) 2004 363 9427 2128 2135 10.1016/S0140-6736(04)16503-3 15220035 · DOI · Paper page
- [14]Idkowiak J O'Riordan S Reisch N Malunowicz EM Collins F Kerstens MN Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 oxidoreductase deficiency J Clin Endocrinol Metab 2011 96 3 E453 E462 10.1210/jc.2010-1607 21190981 PMC3124345 · DOI · Paper page
- [15]Fukami M Nishimura G Homma K Nagai T Hanaki K Uematsu A Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients J Clin Endocrinol Metab 2009 94 5 1723 1731 10.1210/jc.2008-2816 19258400 · DOI · Paper page
- [20]Sahakitrungruang T Huang N Tee MK Agrawal V Russell WE Crock P Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients J Clin Endocrinol Metab 2009 94 12 4992 5000 10.1210/jc.2009-1460 19837910 PMC2795645 · DOI · Paper page
Cited by
Sorted by citations
Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency
Zhang, J., Woo, K. L., Hai, Y., Wang, S., Lin, Y., Huang, Y., Peng, X., Wu, H., Zhang, S., Yan, L., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1020880 · Cited by 10 · see citing works
Zhang, C., Zhao, Z., Du, Y., Huang, Q., Liu, Y., Fu, G., & Xu, J. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1791297
“In female patients, fetal CYP17A1 de fi ciency promotes accumulation of adrenal 17 a -hydroxyprogesterone, which is then shunted into the “ backdoor pathway ” to produce elevated levels of the potent androgen dihydrotestosterone (Figure 7) (34).”
Influential
- Authors
- Fan, L., Ren, X., Song, Y., Su, C., Fu, J., & Gong, C.
- Affiliations
- Capital Medical University (CN)
- Children's Hospital of Zhejiang University (CN)
- Corresponding author
- Gong, Chunxiu
- Venue
- Orphanet Journal of Rare Diseases
- Published
- 2019-12
- Volume
- 14
- Issue
- 1
- Pages
- 299-299
- ISSN
- 1750-1172 (ISSN-L)
- PMC
- PMC6937861
- OpenAlex
- W2997945876
- Cited by
- 22
- References
- 9
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 1 · 2023: 7 · 2022: 3 · 2021: 2
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Orphanet Journal of Rare Diseases (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- The Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority (XTYB201808)
- The Public Health Project for Residents in Beijing (Z151100003915103)
- The National Key Research and Development Program of China (2016YFC0901505)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- Antley-Bixler syndrome, P450 oxidoreductase deficiency, congenital adrenal hyperplasia, novel variants, craniofacial anomalies, earlobe crease, antihelix, disorders of sex development, adrenal insufficiency, steroid replacement therapy, Chinese children
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Child, Child, Preschool, Cytochrome P-450 Enzyme System, Female, Genotype, Humans, Infant, Male, Phenotype, Cohort Studies, Asian People, Antley-Bixler Syndrome Phenotype
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