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

Abstract

BackgroundCytochrome 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 presentationIn 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.ConclusionsPORD 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.

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

“…The features of DSD in patients with PORD (75%) have been previously described [3]. The pathogenic mechanisms of DSD are associated with impaired syntheses of testosterone and dihydrotestosterone and conversion of these androgens to estrogens.…”

“…results in various symptoms such as skeletal malformations, disorders of sex development (DSD), and adrenal insufficiency. PORD was first reported in 2004, and more than 100 cases have since been reported worldwide [3]. Comprehensive genetic studies of Japanese [4] and Caucasian [5] patients with PORD have been published; however, the clinical characteristics, especially the age at diagnosis and treatment of PORD, have not been fully elucidated.…”

Successful Live Birth in a Chinese Woman with P450 Oxidoreductase Deficiency through Frozen-thawed Embryo Transfer

“…Several phenotypic features were very common in PORD women but occurred across a range of mutations, including of high serum concentrations of P (100%), pregnenolone (100%), 17OHP (96%), corticosterone (83%) and deoxycorticosterone (DOC)(70%), DSD(78%), ovarian cysts(39%), skeletal malformations(84%), and adrenal insu ciency(78%) with most of mild cases [6]. For lateonset PORD primary amenorrhea/oligomenorrhea or infertility could be the main clinical manifestation [7,8,9], but little is known about the optimal way to investigate and treat patients with adult-onset PORD. Our case presented with features of high P and 17OHP, primary amenorrhea, ovarian cyst, minor skeletal malformation and no obvious sign of adrenal insu ciency.…”

“…Chinese patients [4,6,8,13,14]. The mutation of c.1370G>A in POR gene leads to a conversion of arginine at amino acid position 457 to histidine (R457H) which supports only 3% of 17-hydroxylase activity, no detectable 17,20 lyase activity [4,5], and only 1% of aromatase activity [15] The c.1196_1204del mutation in POR gene was rstly reported in two unrelated Turkish PORD patients(HGMD ID:CD117091) and cause a loss of three amino acid p.Pro399_Glu401del (P399_E401del) (16) .…”

“…Patients with PORD occur mostly in neonates and children, and have a range of skeletal malformations, glucocorticoid de ciency and disorders of sexual development (DSD) [6]. Although one pair of POR mutations can impair all microsomal cytochrome P450 enzymes, each enzyme is affected to a different extent (depending on the locations of the POR gene mutations), resulting in high clinical variability of PORD, such as it has been reported that young girls or women only had incomplete pubertal development, primary amenorrhea, oligomenorrhea or infertility with or without skeletal malformations [7,8,9]. The clinical course of PORD in adulthood and the long-term consequence for female fertility remain unknown.…”