Two 3β- hydroxysteroid dehydrogenase isoforms, type 1 (HSD3B1) and type 2 (HSD3B2), exist. HSD3B2 is mainly expressed in adrenals and gonads while HSD3B1 is expressed in the placenta and peripheral tissues. HSD3B2 deficiency (OMIM +201810) is a rare cause of CAH.
HSD3B2 is a nicotinamide adenine dinucleotide (NAD+)- dependent enzyme anchored to the membrane of the endoplasmic reticulum and mitochondria. HSD3B2 catalyses the conversion of ∆5 to ∆4 steroids and HSD3B2 deficiency affects all three steroidogenic pathways (mineralocorticoids, glucocorticoids, and androgens). A broad phenotypic spectrum has been reported. Classic HSD3B2 deficiency presents with either salt- wasting or non- salt- wasting. Affected males show a variable impairment of gonadal steroidogenesis leading to different degrees of 46,XY DSD. Affected 46,XX individuals manifest only with adrenal symptoms and normal or mildly virilized external genitalia. Isolated premature pubarche and primary hypogonadism has been reported in infants and children of both sexes. A non- classic variant has also been described, manifesting with hirsutism and menstrual irregularities (Table 1). The 3β- hydroxysteroid dehydrogenase type 1 and 2 isoforms, are encoded by the HSD3B1 and HSD3B2 genes, respectively. Mutations in the HSD3B2 (GeneID 3284, GenbankID NC_ 000001.9) gene cause 3β- hydroxysteroid dehydrogenase deficiency. HSD3B2 is located on chromosome 1p13.1, in close proximity to the highly homologous HSD3B1 gene. It consists of one untranslated and 3 translated exons. Mutation analysis is performed by PCR amplification of HSD3B2 of exons 2 to 4 covering intron- exon boundaries followed by direct DNA sequencing of the PCR products (Figure 1). Over 40 mutations have been reported so far, which are distributed over the entire genomic region. An overall good genotype- phenotype correlation has been described for the salt- loss phenotype, with completely inactivating mutations associated with the salt- wasting form and partly inactivating mutations allowing for some residual aldosterone synthesis. A poor correlation with gonadal steroidogenesis has been observed.
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.
