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BACKGROUND: 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. CASE PRESENTATION: 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 POR gene (NM_001395413.1): the patient harbored a paternal c.1187_1195dup (p.Pro396_Glu398dup) variant and two maternally inherited variants in cis, c.1447G>A (p.Gly483Ser) and c.1806 + 4_1806 + 28del. Protein structural modeling predicted that the p.Pro396_Glu398dup and p.Gly483Ser may disrupt the flavin adenine dinucleotide (FAD)-binding domain. RNA sequencing (RNA-seq) confirmed that the intronic variant c.1806 + 4_1806 + 28del caused aberrant splicing, resulting in partial intron retention and predicted impairment of the nicotinamide adenine dinucleotide phosphate (NADPH)-binding domain. According to American College of Medical Genetics and Genomics (ACMG) guidelines and incorporating functional evidence, c.1187_1195dup and c.1806 + 4_1806 + 28del were reclassified as likely pathogenic (LP), whereas c.1447G>A remained a variant of uncertain significance (VUS). CONCLUSIONS: 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.

RATIONALE: Cytochrome P450 oxidoreductase deficiency (PORD) is a rare autosomal recessive disorder caused by mutations in the POR gene, leading to impaired steroid hormone synthesis and a wide range of multisystem abnormalities. The condition is often associated with reproductive malformations and endocrine disorders, presenting clinically with symptoms such as infertility, menstrual irregularities, and adrenal dysfunction, and may be accompanied by skeletal malformations. Only a very limited number of patients have achieved successful pregnancies through assisted reproductive technology, and there is currently no standardized treatment strategy. PATIENT CONCERNS: A 29-year-old woman presented with "7 years of infertility without contraception." DIAGNOSES: Genetic analysis identified compound heterozygous POR mutations (c.1820A>G/c.1474G>A), confirming PORD. Pelvic imaging revealed uterus didelphys. Endocrine evaluation demonstrated insulin resistance and adrenal dysfunction, and the patient fulfilled the diagnostic criteria for polycystic ovary syndrome. INTERVENTIONS: Following unsuccessful long-protocol ovulation induction, a modified gonadotropin-releasing hormone antagonist protocol was implemented with metformin co-treatment for insulin sensitization. Stepwise glucocorticoid therapy (oral prednisone 5 mg/day → dexamethasone 0.5 mg/day → transition to hydrocortisone 20 mg/day during pregnancy) was administered for adrenal progesterone regulation. All embryos underwent vitrification, with subsequent single frozen-thawed blastocyst transfer. OUTCOMES: Ovarian stimulation yielded 24 oocytes, resulting in 7 blastocysts. Successful singleton implantation was achieved. The pregnancy progressed without maternal metabolic or fetal complications, culminating in term delivery (39 weeks and 4 days) of a healthy male neonate (birth weight 3250 g, Apgar scores 9/10). LESSONS: This case demonstrates that pregnancy attainment in complex PORD requires protocol individualization using gonadotropin-releasing hormone antagonists to mitigate premature luteinization, dynamic glucocorticoid titration to control adrenal steroid excess, and metabolic optimization addressing insulin resistance. The co-occurrence of POR mutations should be investigated in assisted reproductive technology failures with polycystic ovary syndrome-like presentations, particularly when accompanied by skeletal or genital tract anomalies.

BACKGROUND: Pathogenic POR variants cause P450 oxidoreductase deficiency, a rare steroidogenesis disorder. Missense changes are well characterized, but the clinical and molecular consequences of splicing defects remain unclear. METHODS: We identified a novel homozygous splice variant (c.1249-2A>C) in a patient with disorders of sex development and Antley-Bixler syndrome -like skeletal malformations. By reviewing 12 published cases and performing minigene assays on five variants (c.731 + 1G>A, c.732-2A>T, c.947 + 1G>A, c.948-30G>A, c.1249-2A>C), we characterized their splicing outcomes. Structural consequences were predicted using AlphaFold; nonsense-mediated mRNA degradation was assessed for c.1249-2A>C using cycloheximide block. RESULTS: c.731 + 1G>A and c.947 + 1G>A caused intron retention with premature termination, deleting FAD/NADPH-binding domains. c.732-2A>T and c.1249-2A>C skipped exons 8 and 12, which altered FAD-binding site conformation. c.1249-2A>C mRNA reduction was not rescued by cycloheximide, arguing against NMD and suggesting nuclear retention or intranuclear decay. We classified two variants as pathogenic (c.731 + 1G>A, c.947 + 1G>A), two as likely pathogenic (c.732-2A>T and the novel c.1249-2A>C), and one as likely benign (c.948-30G>A). CONCLUSION: Our findings establish that POR splicing variants, whether causing exon skipping or intron retention, disrupt essential domains and produce severe disease. Minigene-based functional testing enables precise variant classification and sharpens genotype-phenotype correlations, supporting improved diagnosis and informed genetic counseling.

BACKGROUND: Cytochrome P450 oxidoreductase deficiency (PORD) is an ultra-rare autosomal recessive disorder caused by mutations in the POR gene and characterized by highly heterogeneous skeletal, genital, and endocrine manifestations. Owing to this complexity, PORD remains frequently underrecognized in clinical practice, and integrated clinical-genetic syntheses remain limited. METHODS: A retrospective analysis was conducted on the clinical data of a PORD patient treated at Shenzhen Children's Hospital. Relevant literature was retrieved from PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI). Reported cases were analyzed with respect to sex, age, geographic distribution, clinical manifestations, and POR gene variants. RESULTS: The patient from our hospital, a 7-month-old infant, presented with characteristic features including frontal bossing, craniosynostosis, flat nasal bridge, proximal radioulnar synostosis, clitoromegaly, partial labial fusion, and steroid hormone abnormalities. Genetic testing identified compound heterozygous variants, p.G146fs*111, a novel mutation, and p.R457H. The patient underwent bilateral mandibular distraction osteogenesis and cranial reconstruction, which alleviated airway obstruction, swallowing difficulty, and craniosynostosis. A total of 50 eligible studies were identified, comprising 167 patients (male:female = 77:90). The major clinical findings were skeletal deformities in 124 cases (74.25%), gonadal deformities in 121 (72.46%), hormonal abnormalities or delayed puberty in 127 (76.05%), and adrenal insufficiency or crisis in 108 (64.67%). Additionally, ovarian cysts were observed in 36 female patients (40.00%). Among all patients, the allele frequency of the p.R457H variant was 27.25%, while that of the p.A287P variant was 14.97%. In the 22 Chinese patients, the allele frequency of the p.R457H variant reached 38.64%. CONCLUSION: We report the clinical features of a PORD patient carrying a novel POR mutation, p.G146fs*111. PORD typically presents with skeletal and genital malformations as well as adrenal insufficiency. Management requires multidisciplinary collaboration, including individualized steroid replacement, regular blood pressure monitoring, and surgical intervention when necessary. The p.R457H variant may represent a hotspot mutation in East Asian populations.

Humeroradial synostosis (HRS) is a rare congenital limb malformation, characterised by fusion of the humeral and radial bones, leading to functional disability of the elbow joint. HRS may be reported in familial or sporadic cases and observed either isolated or as part of a syndromic condition. According to an extensive review of the literature, a dozen known conditions may comprise an HRS. The present review aims to propose an updated classification based on molecular pathways (chondrogenesis and osteogenesis; limb development and patterning; genome regulation), combined with a concise overview of the conditions associated with HRS. This knowledge could guide molecular analyses, patient management and genetic counselling. As some cases remain unexplained, further genetic and epidemiological studies are required to evaluate the contribution of genetic and environmental factors in HRS physiopathology.