**4.3 Endocrine findings**

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 molecular genetics study.

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

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

The DHT levels in 17- HSD-3 deficiency can be decreased, normal or high, while the dehydroepiandrosterone (DHEA) levels are typically high (Mendonca et al., 2000).

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 al., 1992).

17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency:

**Clinical presentation** 

ambiguous genitalia, pubertal virilization

ambiguous genitalia at

clitoromegaly, pubertal virilization, male gender role, and many reassigned as males if raised as girls

female external genitalia, palpable gonads, clitoral enlargement and virilization at puberty

pubertal virilization, mild clitoromegaly, voice

inguinal hernia, failure of breast development, facial and body hair growth, voice changes, clitoral

birth to mild

46,XY DSD;

46,XY DSD;

46,XY DSD;

enlargement

virilization, mild clitoromegaly, voice

14,15 years 46,XY DSD; pubertal

changes

changes

**Phenotype** 

hirsutism, clitoromegaly, failure to menstruate

46,XY DSD; female prepubertal external genitalia, pubertal virilization, severe hair growth, voice changes and clitoral enlargement (6 months, child diagnosed because of family history)

16 years 46,XY DSD;

4–16 years 46,XY DSD;

4–43 years 46,XY DSD;

**Age of diagnosis** 

6 months, 11 years

Newborn– 12 years

4 months– 15 years

8, 23, 34 years 15 years

Diagnosis, Phenotypic Variability and Molecular Findings 129

South Asian

Arab, Dutch, Brazilian, Portuguese

Spanish, Italian, Lebanese

English, German

Dutch, Brazilian

English, German

**Ethnicity Mutation Mutation** 

Iranian p.Ser65Leu missense/

**type Effect** 

p.Ala56Thr missense/

p.Arg80Gln missense/

p.Arg80Trp missense/

c.325+4,A-T splice

c.326–1,G-C splice

p.Asn130Ser missense/

severe impairment of enzyme activity

inactivates enzyme

severe impairment of enzyme

Dutch p.Asn74Thr missense Boehmer et al., 1999

impaired enzyme activity (NADPH binding site)

complete loss of enzyme activity (NADPH binding site)

junction/ disrupts splice acceptor site

junction

**Reference** 

1996

Andersson et al.,

Lee et al., 2007 Moghrabi et al., 1998

Mendonca et al., 2000 Geissler et al., 1994 Boehmer et al., 1999 Roesler et al.,

Roesler et al., 1992 Mendonca et al.,

McKeever et al., 2002 Faienza et al.,

Bilbao et al., 1998

Mendonca et al.,

Boehmer et al., 1999 Andersson et al.,

Mendonca et al., 2000 Geissler et al., 1994 Boehmer et al., 1999 Andersson et al.,

Mendonca et al., 1999 Moghrabi et al.,

Lee et al., 2007 Bertelloni et al., 2009 Moghrabi et al., 1998

1996

1999

2007

2000

1996

1996

1998

Fig. 2. A diagnostic algorithm to elucidate the various etiologies of 46,XY DSD. The diagram shows the importance of hCG stimulation in the diagnosis of 46,XY DSD. Upon hCG stimulation, if the T/4-A ratio is >0.8, the diagnosis of 17- HSD3 can be suspected; if the T/DHT ratio is >20, a diagnosis of 5-reductase deficiency can be suspected. If the response of T is >100 ng/dl, androgen insensivity syndrome (AIS) is possible. However, if the response is <100 ng/dl, causes of gonadal dysgenesis should be sought. Once a diagnosis is suspected, molecular genetic studies can be used for definitive diagnosis.
