**4.2.1 Birth**

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).

17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency:

to differentiate between them (Bertelloni et al., 2009a).

detection of anabolic steroid residues in urine (Van Poucke et al., 2005).

2009b).

**4.2.3 Prenatal** 

structure (Bertelloni et al., 2009b).

**4.3 Endocrine findings** 

molecular genetics study.

al., 1992).

Diagnosis, Phenotypic Variability and Molecular Findings 127

It appeared to be related to the functional inactivity of 17-HSD3 during puberty and increased aromatization of 4-A to produce excessive estrogens; however, the *HSD17B3*  gene was not studied for defects in this study (Balducci et al., 1985; Bertelloni et al.,

Recently, the first case of prenatally identified 17-HSD3 deficiency was reported in a child with discordance between 46,XY karyotype and female external genitalia with phallic

The phenotype of 17-HSD3 deficiency is clinically indistinguishable from that of AIS or 5-reductase 2 deficiency. In fact, the majority of the subjects had a misdiagnosis of AIS or 5α-reductase deficiency before adequate assessment, and these two latter DSD represent the principal differential diagnoses in infancy and adolescence, respectively (Balducci et al., 1985; Bertelloni et al., 2009a; Lee et al., 2007) (Fig. 2). 17-HSD3 however, can be reliably diagnosed by systematic endocrine evaluation (Fig. 2) and the diagnosis confirmed by

The characteristic hormonal profile of 17-HSD3 deficiency is of increased concentrations of 4-A and reduced levels of T (Faisal et al., 2000)**.** In particular**,** a diagnostic hallmark of 17- HSD3 deficiency is a decreased serum T/4-A ratio (<0.8-0.9) after human corionic gonadotropin (hCG) stimulation in prepubertal subjects, while baseline values seems to be informative in early infancy and adolescence (Rosler et al., 1996). A normal ratio above 0.8 after hCG stimulation raises the suspicion of other diagnoses such as androgen receptor mutation. An elevated T/DHT raises the suspicion of a 5-reductase type 2 deficiency. However, low basal T/4-A ratio is not specific for 17-HSD3 deficiency, being sometimes also found in patients with other defects in T synthesis or with Leydig cell hypoplasia. The clinical phenotype of Leydig cell hypoplasia may also resemble that of 17β-HSD3 deficiency before puberty, but the absence of all testicular androgens (baseline and after hCG stimulation) and the lack of pubertal development or isosexual pubertal arrest should allow

A diagnostic tool could be represented by the urinary ketosteroid analysis performed by means gas chromatography tandem mass spectrometry, a high sensitive technique for the

The DHT levels in 17- HSD-3 deficiency can be decreased, normal or high, while the

Elevated serum LH and FSH levels at baseline and after GnRH test administration, indicating the impairment of the pituitary regulatory control by gonadal hormones, have been found in these subjects (Mendonca et al., 2000). Increased serum LH causes elevated 4-A levels, allowing the formation of some T either in extra glandular tissues or in the testes, when some residual enzyme activity is present (Andersson et al., 1996). Elevation of FSH may also be due to a damage to the spermatogenic tubules as a result of long term cryptorchidism as documented in histological specimens from adult subjects. However, FSH levels have been reported to be normal in some subjects (Van Poucke et al., 2005; Rosler et

dehydroepiandrosterone (DHEA) levels are typically high (Mendonca et al., 2000).

Those subjects who come to medical attention in childhood have some degree of virilization or inguinal hernia with testes present along the inguinal canals or labioscrotal folds (Andersson et al., 1996; Bohmer et al., 1999; Lee et al., 2007). Less often patients have ambiguous external genitalia (Can et al., 1998; Eckstein et al., 1989), male genitalia with a micropenis (Ulloa-Aguirre et al., 1985) or hypospadias (Andersson et al., 1996). In these patients, the male sex is assigned at birth and they are raised accordingly (Rosler et al., 1996).

The degree of virilization can vary from Sinnecker stage 5 to stage 2 as mentioned above. This is speculated to be due to the partial activity of 17-HSD3 in the testes and extratesticular T conversion by other members of the family, such as 17-HSD5 (Lee et al., 2007; Qiu et al., 2004).

On examination, a separate urethral and vaginal opening is noted in many subjects, although a short urogenital sinus is reported in some (Bertelloni et al., 2006; Lee et al, 2007). Blind ending vagina that have length ranging from 1 to 7 cm has been reported in this condition (Faienza et al., 2007; Mendonca et al., 2000).

Although these findings are not specific for 17-HSD-3 deficiency and can be seen in other 46,XY DSD, they should raise suspicion for 17 HSD3 deficiency.
