Steroid 17α- hydroxylase (CYP17A1) deficiency (17OHD, OMIM #202110) accounts for about 1% of all CAH cases. CYP17A1 facilitates two distinct enzymatic reactions, 17α- hydroxylase and 17,20- lyase, relying on electron transfer facilitated by the enzyme P450 oxidoreductase (POR) for its catalytic activity. Cytochrome b5 (CYB5A) is required as an additional allosteric factor for an efficient 17,20- lyase reaction. 17OHD results in both cortisol and sex steroid deficiency. In addition, the mineralocorticoid precursors DOC and corticosterone accumulate. The accumulation of the weak glucocorticoid corticosterone prevents adrenal crisis in the majority of 17OHD patients. Increased DOC concentrations lead to severe hypokalaemic hypertension. Deficient sex steroid synthesis results in male undervirlization (46,XY DSD) and in primary amenorrhea in 46,XX individuals. Absent pubertal development is observed in both sexes, with biochemical signs of hypergonadotropic hypogonadism (Table 1). Isolated 17,20- lyase deficiency is a rare variant with largely preserved 17α- hydroxylase activity. This variant manifests with impaired sex steroid biosynthesis only, but neither with evidence of mineralocorticoid excess nor glucocorticoid deficiency. The CYP17A1 gene (GeneID 1586; GenbankID NC_ 000010.9) is located on chromosome 10 (10q24.3) and consists of 8 exons (Figure 1) encoding a 508 amino acid protein. Over 70 CYP17A1- inactivating mutations exist. There is no mutational a hot spot in most large populations. Therefore, sequencing of the entire coding region is commonly necessary for molecular genetic diagnosis. Exceptions have been described (i.e. in Brazil) where the p.Met1Thr and p.Tyr329X mutations account for 82% of mutant alleles, in Canadian Mennonites and Dutch Frieslanders, as well as in Japan and in East Asia. Mutations causing isolated 17,20- lyase deficiency result in amino acid substitutions located within the area of the CYP17A1 molecule interacting with the cofactor cytochrome b5. However, urine steroid metabolome analysis from patients carrying such CYP17A1 mutations provided evidence for impaired 17α- hydroxylation, which means that this condition does not represent true but apparent isolated 17,20 lyase deficiency. Apparently isolated 17,20- lyase deficiency might be mimicked by POR deficiency due to mutations in the POR gene while mutations in CYB5A represent true 17,20 lyase deficiency.
Table1. Differential diagnosis of congenital adrenal hyperplasia— clinical, biochemical, and genetic characteristics
Fig1. Genomic organization of genes causing different forms of congenital adrenal hyperplasia. (1) Genes encoding steroidogenic Cytochrome P450 type II enzymes: (a) The 21- hydroxylase (CYP21A2) gene consists of 10 exons and it is typically amplified in two overlapping fragments. (b) The 17- hydroxylase (CYP17A1) gene consists of 8 exons and different strategies have been employed either amplifying the gene in five or in two fragments. (2) Genes encoding steroidogenic Cytochrome P450 type I enzymes: (c) The 11- hydroxylase (CYP11B1) gene consists of 9 exons and is usually amplified in three overlapping fragments, although non- overlapping strategies have been described. (d) The P450 side chain cleavage (CYP11A1) gene consists of 9 exons and it is usually amplified in small non- overlapping fragments, although different PCR strategies have been described. (e) The aldosterone synthase (CYP11B2) gene consists of 9 exons normally amplified in either two overlapping fragments or three non- overlapping fragments. (3) Genes encoding hydroxysteroid dehydrogenases: (f) The hydroxysteroid dehydrogenase type 2 (HSD3B2) gene has 4 exons; exon 1 and the 5- prime part of exon 2 are not translated. (4) Gene encoding the electron donor of steroidogenic cytochrome P450 type II: (g) The P450 oxidoreductase (POR) gene has 15 translated exons and an untranslated exon (1U). PCR amplification is performed in several small fragments. (5) Gene encoding for a cholesterol transporter: (h) The steroid acute regulatory protein (StAR) gene consists of 7 exons commonly amplified in five fragments.
