**4.8 Gender behavior**

132 Steroids – Basic Science

Two missense mutations, the 239 G to A resulting in an Arg to Gln (R80Q) substitution, which is the most frequent alteration described in the Arab population living in the Gaza Strip (Boehmer et al.,1999; Mains et al., 2008; Rosler et al., 1996), and the 238 C to T resulting in an Arg to Trp (R80W) substitution (Bilbao et al, 1998; Faienza et al., 2007) involve the same arginine residue in exon 3 at position 80. This site has been extensively studied by systematic replacement of the wild-type arginine at position 80 and has been shown to be extremely important for both forming the salt bridge with the terminal phosphate moiety of the NADPH, as well as providing for a hydrophobic pocket for the purine ring of the adenosine portion of the NADPH (McKeever et al., 2002). Thus, this arginin is critical for cofactor binding and the substitution by different amino acids results in alteration of

One polymorphic substitution (G289S) has been described in a heterozygous form in apparently normal individuals. This polymorphism does not impair the kinetic properties of the normal enzyme (Moghrabi et al., 1998). A possible role of the G289S variation has been

Most gene alterations severely compromise the enzyme activity, but the R80Q mutation results in a 17-HSD3 residual enzyme activity (20%), showing a significantly lower reaction

Haplotype analysis of genetic markers flanking the *HSD17B3* gene has been performed to establish the ancient or *de novo* occurrence of mutations described in European, North American, Latin American, Australian and Arab populations (Boehmer et al., 1999). Dutch, German, white Australian and white American patients carrying the 325+4,A –T mutation share the same genetic markers and seem to have a common European ancestor. A founder effect was also demonstrated for the R80Q mutation that is common in Dutch, Arab (in Gaza), white Brazilian, and white Portuguese patients. As this mutation is associated with a specific haplotype, a common ancestor introduced during the Phoenician migration has been hypothesized (Rosler et al., 2006). An additional founder effect has been suggested for 655–1,G-T mutation found in Greeks, Turks and Syrians patients that may have spread to the Mediterranean area during Ottoman Empire (Boehmer et al., 1999). On the contrary, patients harboring the 326-1,G-C and the c.Pro282Leu mutations have a different marker

No phenotype-genotype correlation has been noted in 17-HSD3 deficiency, as exemplified by members of the same family who have different phenotypes despite the same genotype (Lee et al., 2007). A variable T/4-A ratio after human chorionic gonadotropin (hCG) stimulation was also seen despite the same homozygous mutation in different subjects of the same pedigree. This can be attributed to the extratesticular ability of some subjects to

Imaging studies that reveal the absence of mullerian structures and persistent wolffian structures also point to the diagnosis of 17-HSD3 deficiency, but this is not pathognomonic as 5-reductase type 2 deficiency will also have similar findings. Histological evidence from

cofactor preference, switching from NADPH to NADH (Payne § Hales, 2004).

genotype suggesting that these are the novo mutations (Boehmer et al., 1999).

convert 4-A to T by other enzymes such as 17-HSD5 (Qiu et al., 2004).

demonstrate in prostate cancer (Margiotti et al., 2002).

**4.6 Genotype-phenotype correlation** 

**4.7 Imaging studies** 

velocity as compared to the normal enzyme (Geissler et al., 1994).

**4.5 Worldwide distribution of ancient and** *de novo* **mutations** 

In the absence of a correct diagnosis before puberty, most patients with 17-HSD deficiency are raised as females and undergo virilization during adolescence due to extratesticular conversion of 4-A to T, secondary to some residual function of the enzyme and increased substrate availability in 4-A at puberty (Andersson et al., 1996). In cases with partial virilization, early post-natal diagnosis and consequence successful androgen treatment may result in a male sex assignment and in a nearly normal male phenotype in adulthood. Gonadectomy is recommended before puberty for those individuals who have been raised as females and wish to remain so. In these subjects, female sex characteristics should be induced or maintained with appropriate hormone replacement therapy (Hiort et al., 2003). Vaginal dilation using the modified Frank's procedure or vaginal reconstruction surgery may be necessary to create a vaginal cavity with adequate capacity for sexual relations (Castro-Magana et al., 1993). The patient and family will need appropriate psychological counseling to accept the diagnosis and the infertility that accompanies it (Gooren, 2002). In patients with a male attitude, it is possible to achieve adequate male development without medical intervention, when corrective surgery has been judged to be warranted (Boehmer et al., 1999; Farkas § Rosler, 1993; Rosler et al., 1996). Exogenous T treatment does not seem to yield additional benefits in adulthood (Mendonca et al., 2000; Farkas § Rosler, 1993), while pre-operative T administration may result in a better cosmetic appearance of the external genitalia (Farkas § Rosler., 1993). Gender role changes have been reported in 39-60% of cases of 17-HSD3 deficiency who have been raised as girls (Wilson, 1999). Genetic and endocrine evidence indicates that androgens play an important role in male gender behavior and identity. However the fact that many individuals with mutations of the 5-reductase and 17-HSD3 encoding genes do not change their gender role behavior implies that other

17β-Hydroxysteroid Dehydrogenase Type 3 Deficiency:

irreplaceable in confirming the diagnosis.

H.P., Blethen, S.L., Mendonca,

Sciarra, F. § Boscherini, B. (1985).

*Journal of Pediatrics*, 30, pp. 32–38.

*Endocrinology Investigation*, 32, pp. 666-670.

**6. References** 

444.

pp. 3-10.

Diagnosis, Phenotypic Variability and Molecular Findings 135

adolescent girl should also arouse suspicion. Since there are unique clinical implications based on the diagnosis of this condition, it is important to be as prompt and accurate as possible. In conclusion, endocrine evaluation is an important tool for the selection of patients with a suspected 17-HSD3 deficiency. In these patients, mutational analysis of the *HSD17B3* gene, supported by a knowledge of the ethnic distribution of mutations, is

Adamski, J., Carstensen, J., Husen, B., Kaufmann, M., de Launoit, Y., Leenders, F., Markus,

Andersson, S., Geissler, W.M., Wu, L., Davis, D.L., Grumbach, M.M., New, M.I., Schwarz,

B.B., Bloise, W., Witchel, S.F., Cutler, G.B. Jr, Griffin, J.E., Wilson, J.D. § Russel, D.W. (1996).

Familial male pseudohermaphroditism with gynaecomastia due to 17 beta-hydroxysteroid

Baulieu, E.E. (1991). Neurosteroids: a new function in the brain. *Biology of the Cell,* 71 (1-2),

Bertelloni, S., Federico, G. § Hiort, O. (2004). 17 -Hydroxysteroid dehydrogenase-3

Bertelloni, S., Maggio, M.C., Federico, G., Baroncelli, G. § Hiort, O. (2006). 17beta-

Bertelloni, S., Dati, E. § Hiort, O. (2009a). Diagnosis of 17β-hydroxysteroid dehydrogenase deficiency: a review. *Expert Review of Endocrinology and Metabolism,* 4, pp. 53-65. Bertelloni, S., Balsamo, A., Giordani, L., Fischetto, R., Russo, G., Delvecchio, M., Gennari, M.,

Bilbao, J.R., Loridan, L., Audì, L., Gonzalo, E.§ Castaño, L. (1998). A novel missense (R80W)

pseudohermaphroditism. *European Journal of Endocrinology*, 139, pp. 330-333. Boehmer, A.L., Brinkmann, A.O., Sandkuijl, L.A., Halley, D.J., Niermeijer, M.F., Andersson,

female sex reversal*. Gynecological Endocrinology*, 22, pp. 488–494.

*the New York Academy of Sciences*, 784, pp. 124–136.

M. § Jungblut, P.W. (1996). New 17 beta-hydroxysteroid dehydrogenases. Molecular and cell biology of the type IV porcine and human enzymes. *Annals of* 

Molecular genetics and pathophysiology of 17 beta-hydroxysteroid dehydrogenase 3 deficiency. *The Journal of Clinical Endocrinology § Metabolism,* 81, pp. 130–136. Balducci, R., Toscano, V., Wright, F., Bozzolan, F., Di Piero, G., Maroder, M., Panei, P.,

dehydrogenase deficiency. A report of 3 cases. *Clinical Endocrinology*, 23, pp. 439–

deficiency: genetics, clinical findings, diagnosis and molecular biology. *The Italian* 

hydroxysteroid dehydrogenase-3 deficiency: a rare endocrine cause of male-to-

Nicoletti, A., Maggio, M.C., Concolino, D., Cavallo, L., Cicognani, A., Chiumello, G., Hiort, O., Baroncelli, G.I. § Faienza, M.F. (2009b). 17beta-hydroxysteroid dehydrogenase-3 deficiency: from pregnancy to adolescence. *Journal of* 

mutation in 17 hydroxysteroid dehydrogenase type 3 gene associated with male

S., de Jong, F.H., Kayserili, H., de Vroede, M.A., Otten, B.J., Rouwe, C.W., Mendonca, B.B., Rodrigues, C., Bode, H.H., de Ruiter, P.E., Delemarre-van de Waal, H.A. § Drop, S.L. (1999). 17beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution

factors (social, psychological or biological) contribute to modulating human sexual behavior. Because gender-appropriate rearing, and not the chromosomal, gonadal or genital factors plays a crucial role in gender identity development, early diagnosis and treatment if patients with the 17-HSD3 deficiency is very important.
