P450 Oxidoreductase Deficiency: A Systematic Review and Meta-analysis of Genotypes, Phenotypes, and Their Relationships

Abstract

Context P450 oxidoreductase deficiency (PORD) is a rare genetic disorder that is associated with significant morbidity. However there has been limited analysis of reported PORD cases. Objective To determine, based on the cohort of reported PORD cases, genotype-phenotype relationships for skeletal malformations, maternal virilisation in pregnancy, adrenal insufficiency, and disorders of sexual development (DSD). Data Sources PubMed and Web of Science from January 2004 to February 2018. Study Selection Published case reports/series of patients with PORD. Eligible patients were unique, had biallelic mutations, and their clinical features were reported. Data Extraction Patient data were manually extracted from the text of case reports/series. A malformation score, representing the severity of skeletal malformations, was calculated for each patient. Data Synthesis Of the 211 patients published in the literature, 90 were eligible for inclusion. More than 60 unique mutations were identified in this cohort. Four groups of mutations were identified, through regression modeling, as having significantly different skeletal malformation scores. Maternal virilization in pregnancy, reported for 21% of patients, was most common for R457H mutations. Adrenal insufficiency occurred for the majority of patients (78%) and was typically mild, with homozygous R457H mutations being the least deficient. DSD affected most patients (72%), but were less common for males (46XY) with homozygous R457H mutations. Conclusions PORD is a complex disorder with many possible mutations affecting a large number of enzymes. By analyzing the cohort of reported PORD cases, this study identified clear relationships between genotype and several important phenotypic features.

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

“…A recently published review showed that PORD is a complex disorder with many possible mutations affecting a large number of enzymes and the most common mutations were R457H(25%) and A287P(24%) in 180 individual POR mutations from 90 patients [6]. 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.…”

“…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) .…”

“…In 2004, mutations in POR gene disrupting steroid biosynthesis were rstly reported [4,5]. Up to now over 100 cases and more than 50 different POR mutations have been reported (6). 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].…”

“…Up to now over 100 cases and more than 50 different POR mutations have been reported (6). 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].…”

Biological Application and Disease of Oxidoreductase Enzymes

“…Both TCA cycle and respiratory chain can be affected by succinate dehydrogenase deficiency. Deficiency of oxidoreductase enzymes involved in Krebs cycle affects all carbohydrate, protein, fat, and nucleic acid metabolism as it is a common pathway for metabolism of the above macromolecules [60].…”