Combined homozygous 21 hydroxylase with heterozygous P450 oxidoreductase mutation in a Saudi boy presented with hypertension.

Congenital adrenal hyperplasia (CAH) comprises a group of inherited autosomal recessive disorders characterised by defective cortisol biosynthesis, compensatory increases in corticotrophin secretion and adrenocortical hyperplasia. The characteristics of the biochemical and clinical phenotype depend on the specific enzymatic defect. 21-hydroxylase deficiency is estimated to account for 90%-95% of all CAH cases. Although there are many variants of CAH, a new variant is found secondary to a mutation in the gene encoding the protein P450 oxidoreductase (POR) in which the electron is granted to all microsomal P450 enzymes type II. In 2004, it was discovered that this new CAH disease was attributable to the POR gene mutation. POR facilitates electron transfer from Nicotinamide adenine dinucleotide phosphate (NADPH) to key enzymes involved in steroid and sterol synthesis and metabolism. POR deficiency causes partial and combined impairment of the key enzymes involved in steroidogenesis: P450c17 (17α-hydroxylase/17,20 lyase), P450c21 (21-hydroxylase) and P450aro (aromatase). Clinically, mutant POR manifests with disordered sex development, adrenal insufficiency and skeletal malformations. However, each enzyme may be differently compromised in the same patient. This difference in the clinical manifestations secondary to the variability in enzymatic impairments ranges from ambiguous genitalia in both sexes, adrenal insufficiency associated or not to bone malformations, to abnormal laboratory results in the neonatal screening test of asymptomatic newborns. We report here a case of a 46, XY patient with normal male genitalia associated with hypertension not related to fludrocortisone in which genetic study showed that a homozygous mutation in the CYP21A2 also carries the heterozygous missense variant of unclear pathogenicity in the POR gene.Although there are many variants of CAH, a new variant is found secondary to a mutation in the gene encoding the protein P450 oxidoreductase (POR) which therefore the electron is granted to all microsomal P450 enzymes type II. In 2004, it was mentioned by Fluck and his colleagues that this new CAH disease was attributable to the POR gene mutation.POR facilitates electron transfer from NADPH to key enzymes involved in steroid and sterol synthesis and metabolism.POR deficiency causes partial and combined impairment of the key enzymes involved in steroidogenesis: P450c17 (17α- hydroxylase/17,20 lyase), P450c21 (21-hydroxylase) and P450aro (aromatase).Clinically, Mutant POR manifests with disordered sex development, adrenal insufficiency and skeletal malformations.However, each enzyme may be differently compromised in the same patient. This difference in the clinical manifestations secondary to the variability in enzymatic impairments, it is ranging from ambiguous genitalia in both sexes, adrenal insufficiency associated or not to bone malformations, to abnormal laboratory results in the neonatal screening test of asymptomatic newborns. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.