Diagnostic challenges and management advances in cytochrome P450 oxidoreductase deficiency, a rare form of congenital adrenal hyperplasia, with 46, XX karyotype.

Cytochrome P450 oxidoreductase deficiency (PORD) is a rare form of congenital adrenal hyperplasia that can manifest with skeletal malformations, ambiguous genitalia, and menstrual disorders caused by cytochrome P450 oxidoreductase (POR) mutations affecting electron transfer to all microsomal cytochrome P450 and some non-P450 enzymes involved in cholesterol, sterol, and drug metabolism. With the advancement of molecular biology and medical genetics, increasing numbers of PORD cases were reported, and the clinical spectrum of PORD was extended with studies on underlying mechanisms of phenotype-genotype correlations and optimum treatment. However, diagnostic challenges and management dilemma still exists because of unawareness of the condition, the overlapping manifestations with other disorders, and no clear guidelines for treatment. Delayed diagnosis and management may result in improper sex assignment, loss of reproductive capacity because of surgical removal of ruptured ovarian macro-cysts, and life-threatening conditions such as airway obstruction and adrenal crisis. The clinical outcomes and prognosis, which are influenced by specific POR mutations, the presence of additional genetic or environmental factors, and management, include early death due to developmental malformations or adrenal crisis, bilateral oophorectomies after spontaneous rupture of ovarian macro-cysts, genital ambiguity, abnormal pubertal development, and nearly normal phenotype with successful pregnancy outcomes by assisted reproduction. Thus, timely diagnosis including prenatal diagnosis with invasive and non-invasive techniques and appropriate management is essential to improve patients' outcomes. However, even in cases with conclusive diagnosis, comprehensive assessment is needed to avoid severe complications, such as chromosomal test to help sex assignment and evaluation of adrenal function to detect partial adrenal insufficiency. In recent years, it has been noted that proper hormone replacement therapy can lead to decrease or resolve of ovarian macro-cysts, and healthy babies can be delivered by in vitro fertilization and frozen embryo transfer following adequate control of multiple hormonal imbalances. Treatment may be complicated with adverse effects on drug metabolism caused by POR mutations. Unique challenges occur in female PORD patients such as ovarian macro-cysts prone to spontaneous rupture, masculinized genitalia without progression after birth, more frequently affected pubertal development, and impaired fertility. Thus, this review focuses only on 46, XX PORD patients to summarize the potential molecular pathogenesis, differential diagnosis of classic and non-classic PORD, and tailoring therapy to maintain health, avoid severe complications, and promote fertility.

Clinical characteristics of cytochrome P450 oxidoreductase deficiency: a nationwide survey in Japan.

Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis that causes various symptoms such as skeletal malformations, disorders of sex development, and adrenal insufficiency. The aim of this study was to elucidate the clinical characteristics, especially age at diagnosis and treatment, of PORD from the perinatal period to adulthood in Japan. The first questionnaire was sent to 183 council members of the Japanese Society for Pediatric Endocrinology on 1 September 2018. The response rate was 65%, and a total of 39 patients with PORD were examined at 20 hospitals. The second questionnaire was sent in November 2018 to the council members examining these 39 patients with PORD. The response rate was 77%, and we received clinical information on 30 of the 39 patients. The two novel clinical findings were the age at diagnosis and the treatment of Japanese patients with PORD. In many cases, PORD can be diagnosed at <3 months of age. Hydrocortisone as the primary treatment during infancy can be used daily or in stressful situations; however, because patients with PORD generally have mild to moderate adrenal insufficiency, some might be able to avoid hydrocortisone treatment. Patients with PORD should be carefully followed up, and treatment should be optimized as for patients with other types of adrenal insufficiency. Other characteristics in the present study were similar to those described in previous reports.

[Advance in clinical research on Antley-Bixler syndrome].

Antley-Bixler syndrome (ABS) is a rare childhood disorder affecting skeletal development. Some patients may also have genital anomalies and impaired steroidogenesis. Diagnostic criteria for ABS has not been fully established, though craniosynostosis, midface hypoplasia and elbow synostosis are minimum requirements. The etiology of ABS is complex, which included autosomal dominant form caused by FGFR2 gene mutations, autosomal recessive form caused by POR gene mutations, and high oral dose of fluconazole during pregnancy. Patients may die from dyspnea due to upper respiratory tract obstruction. This review summarizes research progress on the clinical features, etiology, differential diagnosis, treatment and prevention of ABS.

Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: case report and literature review.

BACKGROUND: Cytochrome P450 oxidoreductase deficiency (PORD) is a rare disease exhibiting a variety of clinical manifestations. It can be difficult to differentiate with other diseases such as 21-hydroxylase deficiency (21-OHD), polycystic ovary syndrome (PCOS) and Antley-Bixler syndrome (ABS). Nearly 100 cases of PORD have been reported worldwide. However, the genetic characters and clinical management are still unclear, especially in China. CASE PRESENTATION: In this study, we report a 27-year-old female Chinese patient who first presented with amenorrhea and recurrence of large ovary cyst. She was misdiagnosed with PCOS and non-classical 21-OHD due to ovary cysts and elevated 17-hydroxy-progesterone. The patient's complaining of a mild difficulty of bending the metacarpophalangeal joints reminded us to consider PORD, which usually presents with skeletal deformities and sexual dysfunction. The diagnosis of PORD was confirmed by genetic analyses, which showed the patient harboring a homozygous missense mutation in the POR gene (R457H) and her parents carrying the heterozygous mutation. The patient was treated with low-dose corticosteroids and estrogen/progesterone sequential therapy, and her ovarian cyst gradually reduced with regular menstruation in the follow-up. Moreover, the clinical and genetic characteristics of 104 previously reported PORD cases were also summarized and analyzed. CONCLUSIONS: PORD is a very rare disease which can be easily misdiagnosed in mild cases. Clinicians should keep in mind of this disease in patients with sexual dysfunction, especially combined with special skeletal deformities. Our data could provide a consciously understanding of this disease for clinic practicers. Low-dose corticosteroids combined with estrogen/progesterone sequential therapy will be effective in PORD patients with recurrence of large ovary cyst. The fact that the reported PORD patients in China carrying an identical variant R457H in POR gene also give us a viewpoint that R457H mutation in POR gene maybe important in causing PORD in Chinese as same as in Japanese.

Multidisciplinary Treatment of Antley-Bixler Syndrome.

Antley-Bixler syndrome is a rare form of craniosynostosis characterized by unique clinical features that present particular challenges to long-term treatment. Typical craniofacial features include midface hypoplasia, trapezoidocephaly, frontal bossing, ocular proptosis, low-set protrusive ears, and choanal atresia. A staged surgical approach including fronto-orbital and midface advancements is required for intracranial pressure reduction, globe protection, airway patency, and malocclusion. In this case report, the combined, longitudinal surgical and orthodontic treatment strategies employed to correct severe facial deformity in a long-term 21-year survivor of Antley-Bixler syndrome are reviewed.

Foot anomalies in Antley-Bixler syndrome: three case reports.

Multiple joint contractures, including radiohumeral synostosis, are the hallmark of Antley-Bixler syndrome (ABS). The detailed description of the skeletal aberration, however, focused in feet is scarce. We carried out the scrutiny for foot lesion in three ABS patients with POR (nicotinamide adenine dinucleotide phosphate-oxidase-cytochrome P450 oxidoreductase) gene mutations, one of whom had undergone surgical intervention for difficulty in walking. Radiographs in all three patients showed middle cuneiform-second metatarsal synostosis and the fourth brachymetapody, irrespective of the severity of their systemic manifestations. In addition, talocalcaneal synostosis, lateral cuneiform-cuboid synostosis, defects of middle phalanx, and distal phalanx-middle phalanx synostosis were found in at least two patients. In conclusion, we found distinctive constellations of foot abnormalities in the patients of ABS with POR gene mutation, which may be useful in planning the treatment strategy, as well as in the diagnostic process.