**3.1 Disorders of sexual development**

Disorders of sexual development (DSDs) are congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical (Houk et al., 2006; Hughes et al., 2006). These disorders are classified into three major categories: sex chromosome DSD, 46,XX DSD and 46,XY DSD. This designation was proposed to replace the former term of pseudohermaphroditism, according to the consensus statement on management of intersex disorders (Hughes et al., 2006). 46,XY DSD are a heterogeneous group of clinical conditions characterized by 46,XY karyotype, either normal or dysgenetic testes and female or ambiguous phenotype of external (and possibly internal) genitalia (Hughes et al., 2006). This disorder can have several etiologies, but more frequently is due to a disruption in androgen production and/or action. Defects in androgen action and metabolism include mutations in the androgen receptor gene (complete, partial or mild androgen insensivity syndrome-AIS and Kennedy syndrome), or in the steroid 5-reductase type 2 gene, encoding the enzyme which convert T into DHT in the uro-genital tract (Quigley et al., 1995; Wilson et al., 1993). Instead, disorders of androgens biosynthesis are rare and usually due to alteration of enzyme involved in the conversion of cholesterol to T, such as the steroidogenic acute

17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency:

**4.1 Epidemiology and demographic** 

Johannsen et al., 2006).

**4.2 Clinical features** 

**4.2.1 Birth** 

woman have been described (Pang et al., 1987).

Diagnosis, Phenotypic Variability and Molecular Findings 125

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;

The characteristic phenotype of 17-HSD3 deficiency is a 46,XY individual with testes and male wolffian-duct derived urogenital structure (e.g. epydidymus, vas deferens and seminals vesicles), but with undervirilization of the external genitalia. Patients show a phenotypic variability ranging from undervirilization of the external genitalia with or without clitoromegaly and/or labial fusion, to complete female external genitalia and a blind-ending vagina; testes may be situated in the abdomen or in the inguinal channels or in the labia majora (Grumbach et al., 1998). Gynecomastia, likely as consequence of high 4-A levels and its conversion to estrogens in peripheral tissues, is not usually present (Andersson et al, 1996; Balducci et al., 1985; Mendonca et al., 2000). Two late-onset variants of uncertain pathophysiology, one of which is characterized by gynecomastia in boys (Rogers et al., 1985; Castro-Magana et al., 1993) and the other by polycystic disease in

Patients with mutations in the *HSD17B3* gene may go unnoticed at birth as they commonly have female external genitalia (Balducci et al., 1985; Lee et al., 2007; Rosler et al., 1996). These children are usually assigned the female gender and grow up as such, and the diagnosis may be missed until adolescence (Andersson et al., 1996; Balducci et al., 1985; Bohmer et al.,

1999; Faienza et al., 2007; Lee et al., 2007; Mendonca et al., 2000; Rosler et al., 2006).

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
