Compound heterozygous variants in POR gene identified by whole‐exome sequencing in a Chinese pedigree with cytochrome P450 oxidoreductase deficiency
Open accessAbstract
Abstract Importance Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations. This condition specifically leads to disordered steroidogenesis, which can affect the development of the reproductive system, skeleton, and other parts of the body. The severe form of PORD is difficult to differentiate with Antley‐Bixler syndrome (ABS). The genetic characters and clinical evaluation of PORD are still unclear in China. Objective To perform an exome analysis and identify the pathogenic cause in order to assist clinicians to obtain a proper evaluation on the genetic condition. Methods The proband underwent detailed physical evaluations. DNA of the proband and his parents was isolated and whole‐exome sequencing (WES) was performed. Variants were analyzed and evaluation according to the ACMG guideline. Results A 1‐year‐old Chinese boy with midface hypoplasia, choanal stenosis, multiple joint contractures, micropenis and right cryptorchidism was misdiagnosed with Crouzon syndrome. By trio‐whole‐exome sequencing, we identified an unreported compound heterozygous mutation (c.667C>T, p.R223* and c.1370G>A, p.R457H) in POR in the proband. This mutation was inherited from healthy heterozygous parents, supporting the diagnosis of PORD, which was further confirmed by biochemical characteristics. Interpretation We have identified a pathogenic variant with an unreported compound heterozygous POR mutation, which expands the clinical and genetic spectra of PORD and emphasizes the usefulness of WES for genetic diagnosis.
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The clinical phenotype exhibits significant variability depending on the specific POR mutations, contributing to frequent misdiagnosis or underdiagnosis in clinical practice.
“Notably, the clinical phenotype exhibits significant variability depending on the specific POR mutations, contributing to frequent misdiagnosis or underdiagnosis in clinical practice (7).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [7]
The Discussion says POR mutations cause wide phenotypic variability, from mild to severe. The Abstract Results report that the patient was misdiagnosed with Crouzon syndrome. The paper does not establish that misdiagnosis is frequent or address underdiagnosis in clinical practice; page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredElevated steroid hormone levels and the presence of genital anomalies in PORD provide key diagnostic clues for differentiation from Antley-Bixler syndrome.
“Elevated steroid hormone levels and the presence of genital anomalies in PORD provide key diagnostic clues for differentiation (7).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [7]
The Discussion explicitly identifies genital anomalies as a way to differentiate PORD from Antley–Bixler syndrome. The Results (Laboratory abnormalities; page unavailable) report elevated progesterone in this patient, but other measured steroid hormones were normal; the paper does not identify broadly elevated steroid hormone levels as a differential clue. (LLM, conf=0.86)
Experimental — accuracy not yet measuredReduced activity of hepatic CYP enzymes including CYP1A2, CYP2C19, and CYP3A4 can significantly alter drug metabolism in PORD patients.
“Furthermore, the reduced activity of hepatic CYP enzymes—including CYP1A2, CYP2C19, and CYP3A4—can significantly alter drug metabolism in PORD patients (7).”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [7]
The Discussion says the R457H mutation can inactivate CYP1A2, CYP2C19, and CYP3A4, enzymes important for drug metabolism. It describes altered drug metabolism and medication risks as possibilities for patients with that mutation, rather than establishing a significant effect across PORD patients generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMutations in POR reduce or abolish the activity of its dependent enzymes, leading to clinical manifestations including genital abnormalities, steroid hormone dysregulation, infertility in both sexes, and skeletal malformations resembling Antley-Bixler syndrome.
“Mutations in POR reduce or abolish the activity of its dependent enzymes, leading to a broad spectrum of clinical manifestations. These include genital abnormalities, steroid hormone dysregulation, infertility in both sexes, and skeletal malformations resembling Antley-Bixler syndrome.”
From Case Report: Integrating clinical presentation and genetic analysis in P450 oxidoreductase deficiency: a novel mutation and systematic review (2026) · cites this paper as [7]
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Zhang, C., Zhao, Z., Du, Y., Huang, Q., Liu, Y., Fu, G., & Xu, J. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1791297
- Authors
- Hao, C., Guo, J., Guo, R., Qi, Z., Li, W., & Ni, X.
- Affiliations
- Capital Medical University (CN)
- Corresponding author
- Li, Wei
- Ni, Xin
- Venue
- Pediatric Investigation
- Publisher
- Wiley
- Published
- 2018-06
- Volume
- 2
- Issue
- 2
- Pages
- 90-95
- ISSN
- 2096-3726 (ISSN-L)
- 2574-2272
- PMC
- PMC7331414
- OpenAlex
- W2883243962
- Cited by
- 13
- References
- 16
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 3 · 2022: 1 · 2019: 3 · 2018: 2
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pediatric Investigation (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81670789)
- Beijing Municipal Science and Technology Commission
- Beijing Municipal Administration of Hospitals (QML20161201)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- POR gene, compound heterozygosity, steroidogenesis disorders, Antley-Bixler syndrome, midface hypoplasia, cryptorchidism, micropenis, joint contractures, choanal stenosis, genetic diagnosis, Chinese pedigree
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