TY - JOUR
T1 - P450 Oxidoreductase Deficiency
T2 - A Systematic Review and Meta-analysis of Genotypes, Phenotypes, and Their Relationships
AU - Dean, Benjamin
AU - Chrisp, Georgina L.
AU - Quartararo, Maria
AU - Maguire, Ann M.
AU - Hameed, Shihab
AU - King, Bruce R.
AU - Munns, Craig F.
AU - Torpy, David J.
AU - Falhammar, Henrik
AU - Rushworth, R. Louise
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
KW - adrenal insufficiency
KW - congenital adrenal hyperplasia
KW - disorders of sexual development
KW - maternal virilisation
KW - mutation
KW - skeletal malformation
UR - http://www.scopus.com/inward/record.url?scp=85081076375&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgz255
DO - 10.1210/clinem/dgz255
M3 - Article
C2 - 31825489
AN - SCOPUS:85081076375
VL - 105
SP - 1
EP - 11
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 3
ER -