**4.1 Epidemiology and demographic**

124 Steroids – Basic Science

regulatory (stAR) protein, the steroidogenic enzyme P450ssc, 3HDS type 2, 17hydroxylase/17-20 lyase and 17β-hydroxysteroid dehydrogenase type 3 (17-HSD3)

(Gobinet et al., 2002; Miller et al., 2005), (Fig.1)

Fig. 1. Steroidogenic pathway and role of 17- HSD3

(Sinnecker types 5 and 4).

**4. 17β-hydroxysteroid dehydrogenase type 3 deficiency**

17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency (OMIM #264300), originally described as 17-ketosteroid reductase deficiency (Saez et al., 1971), is an autosomal recessive disorder which represents the most common defect of the biosynthesis of T in 46,XY DSD (Bertelloni et al., 2004; Mendonca et al., 2000). This disorder is due to an impaired conversion of Δ4-A into T in the testes (Bertelloni et al., 2009; Faienza et al., 2008). Deficiency in the 17-HSD3 enzyme can be caused by either homozygous or compound heterozygous mutations in the *HSD17B3* gene (Geissler et al., 1994). Mutations in the *HSD17B3* gene confer a spectrum of 46,XY disorders of sexual organ development ranging from completely undervirilized external female genitalia (Sinnecker type 5), predominantly female (Sinnecker type 4), ambiguous (Sinnecker type 3), to predominantly male with micropenis and hypospadias (Sinnecker type 2) (Boehmer et al., 1999; Sinnecker et al., 1996). The most frequent presentation of 17β-HSD3 deficiency is a 46,XY individual with female external genitalia, labial fusion and a blind ending vagina, with or without clitoromegaly The DSD affect 1 in 5,000 to 5,500 people (0.018%) (Parisi et al., 2007; Thyen et al., 2006). Although the precise incidence of 17β-HSD3 deficiency is unknown, a nation-wide survey in the Netherlands showed a minimal incidence of 17β-HSD3 deficiency of about 1:147.000 newborns, with a frequency of heterozygotes of 1 in 135 (Boehmer et al., 1999). The frequency of complete androgen insensitivity syndrome (CAIS) from the same population was 1 in 99,000, which indicates that the frequency of 17-HSD3 deficiency is 0.65 times that of CAIS (Boehmer et al., 1999). 17-HSD3 deficiency is rare in Western countries, whereas in areas of high consanguinity, such as among the Gaza Strip Arab population, the incidence of 17-HSD3 deficiency has been reported to be 1 in 100–300 people (Rosler et al., 1996, 2006). Of the known cases of 17-HSD3 deficiency, most of the patients have been reported in Europe, Asia, Australia and South America, whereas only 11 cases have been reported in the United States (Mains et al., 2008; Moeller § Adamski, 2009). In a recent study from a gender assessment team in the United States that looked at DSD over a 25-year period, no patient with 17-HSD3 deficiency was diagnosed (Paris et al., 2007). Moreover, in the United Kingdom DSD database, patients with 17β-HSD3 represent about the 4% of the total 46,XY DSD subjects (13/322) (Hughes, 2008). Probably the rate of 17-HSD3 deficiency in the United States is not so low, but many cases are misdiagnosed. In one study, patients who were later confirmed to have 17-HSD3 deficiency were initially misdiagnosed with AIS, and the rate of misdiagnosis was calculated to be 67% (Faisal et al., 2000). The risk of misdiagnosis is especially problematic because the clinical findings in 17-HSD3 deficiency may mimic AIS in childhood and 5-reductase deficiency in puberty (Lee et al., 2007). Thus, correct diagnosis should be made early so that treatment, management and genetic counseling can be specifically directed toward 17-HSD3 deficiency (Hiort et al., 2003; Johannsen et al., 2006).
