46, XY individuals with impairment of 5α-reductase type 2 have normally virilized wolffian duct derived structures, with seminal vesicles (although small seminal vesicles have been reported as well), with vasa deferentia, epididymides and ejaculatory ducts and no müllerian duct derived structures (2, 124, 125 , ). However, differentiation of the urogenital sinus and genital tubercle is not observed, resulting in absence of the prostate and in ambiguous or in female external genitalia at birth (2, 124, 125 ). Affected 46, XY individuals are therefore often raised as girls. At puberty all affected individuals show some or a severe degree of virilization often resulting in deepening of the voice, an increased muscle mass, growth of the penis, scrotal development, testicular descent and sometimes leading to a gender change (2, 126.

Gynecomastia in adulthood does not occur. The additional virilization may result from the action of testosterone, because testosterone is available at high levels during puberty. In addition, some testosterone may be converted to 5α-dihydrotestosterone by some residual 5α-reductase activity and by the action of 5α-reductase type 1, which is expressed in non-genital skin, pubic skin, liver and certain brain regions. In the affected 46, XY individuals a typical female pubic hair pattern develops, while the facial and body hair amount is absent or reduced (3). This last observation points to a role for 5α-reductase type 2 in the normal development of this type of body hair. Male pattern baldness has never been observed. 5α-reductase type 2 deficient patients are usually infertile due to the absence or underdevelopment of the prostate and seminal vesicles, in addition to oligospermia or azoospermia due to maldescent of the testes. However, fertile patients have also been reported (2, 124 ). 46, XX female carriers have normal fertility, decreased body hair and delayed menarche, normal sebum production but no history of acne (2, 124 ). This suggests a role of 5α-reductase type 2 enzyme in females in the physiology and pathophysiology of body hair growth, menarche and follicular development (124 ).

A reflection of defective or absence 5α-reductase type 2 enzyme activity can be obtained in patients serum and urine samples by measuring testosterone levels (elevated), 5α-dihydrotestosterone levels (decreased) and by measuring the ratio of testosterone/5α-dihydrotestosterone (increased after hCG stimulation) (2). Furthermore in cultured genital skin fibroblasts (if available) the conversion of testosterone to 5α-dihydrotestosterone can be assessed and is an option for establishing a defective enzyme. In broken cell preparations at pH 5.5 the type 2 isozyme activity is measured more specifically and can be compared with a preparation from a normal person (2).

Genetic analysis of 5α-reductase type 2 deficiency has become possible since the cloning of the cDNA (12). The gene is located on chromosome 2 at locus 2p23. The enzyme is encoded by 5 exons and the most reliable approach to detect gene mutations is the sequencing of each individual exon and the flanking intron sequences [Figure 11].

Interestingly worldwide 42 different mutations have been detected in the 5α-reductase type 2 gene in patients with the syndrome of 5α-reductase type 2 deficiency in several different ethnic groups [Figure 11] (2, 3, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138,).. Identical mutations have been reported in different ethnic groups and some of them can be considered to be due to a founder effect and some to have occurred de novo (2, 124). The mutations were found in all five exons of the gene and comprise of 33 amino acid substitutions (78.5%), one complete gene deletion (12), two small deletions resulting in either a premature stopcodon or in an inframe amino acid residue deletion, 5 nonsense mutations and one splice donor site mutation in intron 4, resulting in aberrant splicing [Figure 11]. The majority of the reported patients are homozygous for one of the mutations. A smaller number of patients appeared to be compound heterozygous, while also a small group of patients are heterozygous (2, 124 ).

In general male carriers of a single mutant allele have a normal fertility as is the case for female carriers. The largest investigated kindreds were found in the Dominican Republic, in Turkey and in New Guinea (2, 124 ). In all three kindreds the high incidence can be directly related to a founder affect in geographical isolated populations with a high degree of inbreeding. A relatively large number loss of function mutations in the Type II steroid 5α-reductase has been identified in the male pseudohermaphroditism syndrome. This rare autosomal recessive disorder is characterized by impaired enzymatic activity. In a recent paper on somatic mutations in the gene coding for Type II steroid 5α-reductase recurrent de novo mutations in prostate cancer were reported resulting in increased 5α-reductase activity (139). This finding indicates a role for increased 5α-dihydrotestosterone levels in the prostate, during prostate cancer progression in a subset of patients.