P450 Oxidoreductase Deficiency: A Systematic Review and Meta-analysis of Genotypes, Phenotypes, and Their Relationships.
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.
['Dean|Benjamin|B|', 'Chrisp|Georgina L|GL|', 'Quartararo|Maria|M|', 'Maguire|Ann M|AM|', 'Hameed|Shihab|S|', 'King|Bruce R|BR|', 'Munns|Craig F|CF|', 'Torpy|David J|DJ|', 'Falhammar|Henrik|H|', 'Rushworth|R Louise|RL|']
D000309:Adrenal Insufficiency D054882:Antley-Bixler Syndrome Phenotype D005260:Female D005838:Genotype D006801:Humans D008297:Male D009139:Musculoskeletal Abnormalities D009154:Mutation D010641:Phenotype
skeletal malformation maternal virilisation adrenal insufficiency disorders of sexual development mutation congenital adrenal hyperplasia