DSD Due to 5α-Reductase 2 Deficiency - from Diagnosis to Long Term Outcome

Elaine M.F. Costa; Sorahia Domenice; Maria Helena Sircili; Marlene Inacio; Berenice B. Mendonca

doi:10.1055/s-0032-1324727

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2012; 30(05): 427-431
DOI: 10.1055/s-0032-1324727

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

DSD Due to 5α-Reductase 2 Deficiency - from Diagnosis to Long Term Outcome

Elaine M.F. Costa

¹Division of Endocrinology Unit, Hormone and Molecular Genetics Laboratory, Medical School, University of São Paulo

²Division of Endocrinology, Hospital das Clinicas of the University of São Paulo, School of Medicine, São Paulo, Brazil

,

Sorahia Domenice

¹Division of Endocrinology Unit, Hormone and Molecular Genetics Laboratory, Medical School, University of São Paulo

²Division of Endocrinology, Hospital das Clinicas of the University of São Paulo, School of Medicine, São Paulo, Brazil

,

Maria Helena Sircili

¹Division of Endocrinology Unit, Hormone and Molecular Genetics Laboratory, Medical School, University of São Paulo

²Division of Endocrinology, Hospital das Clinicas of the University of São Paulo, School of Medicine, São Paulo, Brazil

,

Marlene Inacio

¹Division of Endocrinology Unit, Hormone and Molecular Genetics Laboratory, Medical School, University of São Paulo

²Division of Endocrinology, Hospital das Clinicas of the University of São Paulo, School of Medicine, São Paulo, Brazil

,

Berenice B. Mendonca

¹Division of Endocrinology Unit, Hormone and Molecular Genetics Laboratory, Medical School, University of São Paulo

²Division of Endocrinology, Hospital das Clinicas of the University of São Paulo, School of Medicine, São Paulo, Brazil

› Author Affiliations

Abstract

Most of the patients with 5α-RD 2 deficiency are reared in the female social sex due to their severely undervirilized external genitalia but ~60% who have not been submitted to orchiectomy in childhood undergo male social sex change at puberty. In our cohort of 30 cases from 18 families, all subjects were registered in the female social sex except for two children—one who had an affected uncle and the other who was diagnosed before being registered. The majority of the patients were satisfied with the long-term results of their treatment and surprisingly, penile length was not associated with satisfactory or unsatisfactory sexual activity.

Steroid 5α-RD2 deficiency should be included in the differential diagnosis of all newborns with 46,XY DSD with normal testosterone production before gender assignment or any surgical intervention because these patients should be considered males at birth.

Keywords

5α-reductase 2 deficiency - disorders of sexual development - outcome

Full Text

References

References
1 Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974; 186 (4170) 1213-1215
2 Walsh PC, Madden JD, Harrod MJ, Goldstein JL, MacDonald PC, Wilson JD. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974; 291 (18) 944-949
3 Nowakowski H, Lenz W. Genetic aspects in male hypogonadism. Recent Prog Horm Res 1961; 17: 53-95
4 Imperato-McGinley J, Zhu YS. Androgens and male physiology the syndrome of 5alpha-reductase-2 deficiency. Mol Cell Endocrinol 2002; 198 (1–2) 51-59
5 Maimoun L, Philibert P, Cammas B , et al. Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. J Clin Endocrinol Metab 2011; 96 (2) 296-307
6 Cai LQ, Zhu YS, Katz MD , et al. 5 alpha-reductase-2 gene mutations in the Dominican Republic. J Clin Endocrinol Metab 1996; 81 (5) 1730-1735
7 Byne W. Developmental endocrine influences on gender identity: implications for management of disorders of sex development. Mt Sinai J Med 2006; 73 (7) 950-959
8 Bahceci M, Ersay AR, Tuzcu A, Hiort O, Richter-Unruh A, Gokalp D. A novel missense mutation of 5-alpha reductase type 2 gene (SRD5A2) leads to severe male pseudohermaphroditism in a Turkish family. Urology 2005; 66 (2) 407-410
9 Ocal G, Adiyaman P, Berberoğlu M , et al. Mutations of the 5alpha-steroid reductase type 2 gene in six Turkish patients from unrelated families and a large pedigree of an isolated Turkish village. J Pediatr Endocrinol Metab 2002; 15 (4) 411-421
10 Boudon C, Lobaccaro JM, Lumbroso S , et al. A new deletion of the 5 alpha-reductase type 2 gene in a Turkish family with 5 alpha-reductase deficiency. Clin Endocrinol (Oxf) 1995; 43 (2) 183-188
11 Canto P, Vilchis F, Chávez B , et al. Mutations of the 5 alpha-reductase type 2 gene in eight Mexican patients from six different pedigrees with 5 alpha-reductase-2 deficiency. Clin Endocrinol (Oxf) 1997; 46 (2) 155-160
12 Vilchis F, Canto P, Chávez B, Ulloa-Aguirre A, Méndez JP. Molecular analysis of the 5 alpha-steroid reductase type 2 gene in a family with deficiency of the enzyme. Am J Med Genet 1997; 69 (1) 69-72
13 Vilchis F, Méndez JP, Canto P, Lieberman E, Chávez B. Identification of missense mutations in the SRD5A2 gene from patients with steroid 5alpha-reductase 2 deficiency. Clin Endocrinol (Oxf) 2000; 52 (3) 383-387
14 Hafez M, Mazen I, Ghali I, Sultan C, Lumbroso S. A new mutation of 5-alpha-reductase type 2 (A62E) in a large Egyptian kindred. Horm Res 2003; 59 (6) 281-284
15 Imperato-McGinley J, Miller M, Wilson JD, Peterson RE, Shackleton C, Gajdusek DC. A cluster of male pseudohermaphrodites with 5 alpha-reductase deficiency in Papua New Guinea. Clin Endocrinol (Oxf) 1991; 34 (4) 293-298
16 Griffin J , et al. The androgen resistance syndrome: Steroid 5a-reductase 2 deficiency, testicular feminization, and related disorders., in The metabolic and molecular bases of inherited disease, B.A. Scriver CR, Sly WS, Vale D, Editor 2000, McGraw-Hill: New York.
17 Thigpen AE, Davis DL, Milatovich A , et al. Molecular genetics of steroid 5 alpha-reductase 2 deficiency. J Clin Invest 1992; 90 (3) 799-809
18 Cohen-Kettenis PT. Gender change in 46,XY persons with 5alpha-reductase-2 deficiency and 17beta-hydroxysteroid dehydrogenase-3 deficiency. Arch Sex Behav 2005; 34 (4) 399-410
19 Warne GL, Raza J. Disorders of sex development (DSDs), their presentation and management in different cultures. Rev Endocr Metab Disord 2008; 9 (3) 227-236
20 Jenkins EP, Andersson S, Imperato-McGinley J, Wilson JD, Russell DW. Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase. J Clin Invest 1992; 89 (1) 293-300
21 Russell DW, Wilson JD. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem 1994; 63: 25-61
22 Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW. Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest 1993; 92 (2) 903-910
23 Silver RI, Wiley EL, Thigpen AE, Guileyardo JM, McConnell JD, Russell DW. Cell type specific expression of steroid 5 alpha-reductase 2. J Urol 1994; 152 (2 Pt 1) 438-442
24 Mendonca BB, Inacio M, Costa EM , et al. Male pseudohermaphroditism due to steroid 5alpha-reductase 2 deficiency. Diagnosis, psychological evaluation, and management. Medicine (Baltimore) 1996; 75 (2) 64-76
25 Mendoca B, Costa E, Belgorosky A, Rivarola M, Domenice S. 46,XY DSD due to impaired androgen production. Best Pract Res Clin Endocrinol Meta B 2010; 24 (2) 243-262
26 Berra M, Williams EL, Muroni B , et al. Recognition of 5α-reductase-2 deficiency in an adult female 46XY DSD clinic. Eur J Endocrinol 2011; 164 (6) 1019-1025
27 Ng WK, Taylor NF, Hughes IA, Taylor J, Ransley PG, Grant DB. 5 alpha-reductase deficiency without hypospadias. Arch Dis Child 1990; 65 (10) 1166-1167
28 Cai LQ, Fratianni CM, Gautier T, Imperato-McGinley J. Dihydrotestosterone regulation of semen in male pseudohermaphrodites with 5 alpha-reductase-2 deficiency. J Clin Endocrinol Metab 1994; 79 (2) 409-414
29 Hochberg Z, Chayen R, Reiss N , et al. Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5 alpha-reductase 2 deficiency. J Clin Endocrinol Metab 1996; 81 (8) 2821-2827
30 Mendonça BB, Batista MC, Arnhold IJ , et al. Male pseudohermaphroditism due to 5 alpha reductase deficiency associated with gynecomastia. Rev Hosp Clin Fac Med Sao Paulo 1987; 42 (2) 66-68
31 Chávez B, Valdez E, Vilchis F. Uniparental disomy in steroid 5alpha-reductase 2 deficiency. J Clin Endocrinol Metab 2000; 85 (9) 3147-3150
32 Hiort O, Sinnecker GH, Willenbring H, Lehners A, Zöllner A, Struve D. Nonisotopic single strand conformation analysis of the 5 alpha-reductase type 2 gene for the diagnosis of 5 alpha-reductase deficiency. J Clin Endocrinol Metab 1996; 81 (9) 3415-3418
33 Thiele S, Hoppe U, Holterhus PM, Hiort O. Isoenzyme type 1 of 5alpha-reductase is abundantly transcribed in normal human genital skin fibroblasts and may play an important role in masculinization of 5alpha-reductase type 2 deficient males. Eur J Endocrinol 2005; 152 (6) 875-880
34 Imperato-McGinley J, Peterson RE, Gautier T, Sturla E. Male pseudohermaphroditism secondary to 5 alpha-reductase deficiency—a model for the role of androgens in both the development of the male phenotype and the evolution of a male gender identity. J Steroid Biochem 1979; 11 (1B) 637-645
35 Walter KN, Kienzle FB, Frankenschmidt A , et al. Difficulties in diagnosis and treatment of 5alpha-reductase type 2 deficiency in a newborn with 46,XY DSD. Horm Res Paediatr 2010; 74 (1) 67-71
36 Bertelloni S, Scaramuzzo RT, Parrini D, Baldinotti F, Tumini S, Ghirri P. Early diagnosis of 5alpha-reductase deficiency in newborns. Sex Dev 2007; 1 (3) 147-151
37 Imperato-McGinley J, Gautier T, Pichardo M, Shackleton C. The diagnosis of 5 alpha-reductase deficiency in infancy. J Clin Endocrinol Metab 1986; 63 (6) 1313-1318
38 Imperato-McGinley J. 5 alpha-reductase-2 deficiency. Curr Ther Endocrinol Metab 1997; 6: 384-387
39 Perry RJ, Novikova E, Wallace AM, Donaldson MD. Pitfalls in the diagnosis of 5α-reductase type 2 deficiency during early infancy. Horm Res Paediatr 2011; 75 (5) 380-382
40 Hackel C, Oliveira LE, Ferraz LF , et al. New mutations, hotspots, and founder effects in Brazilian patients with steroid 5alpha-reductase deficiency type 2. J Mol Med (Berl) 2005; 83 (7) 569-576
41 Wilson JD, Griffin JE, Russell DW. Steroid 5 alpha-reductase 2 deficiency. Endocr Rev 1993; 14 (5) 577-593
42 Nicoletti A, Baldazzi L, Balsamo A , et al. SRD5A2 gene analysis in an Italian population of under-masculinized 46,XY subjects. Clin Endocrinol (Oxf) 2005; 63 (4) 375-380
43 Mazen I, Gad YZ, Hafez M, Sultan C, Lumbroso S. Molecular analysis of 5alpha-reductase type 2 gene in eight unrelated egyptian children with suspected 5alpha-reductase deficiency: prevalence of the G34R mutation. Clin Endocrinol (Oxf) 2003; 58 (5) 627-631
44 Vilchis F, Ramos L, Méndez JP, Benavides S, Canto P, Chávez B. Molecular analysis of the SRD5A2 in 46,XY subjects with incomplete virilization: the P212R substitution of the steroid 5alpha-reductase 2 may constitute an ancestral founder mutation in Mexican patients. J Androl 2010; 31 (4) 358-364
45 Maimoun L, Philibert P, Bouchard P , et al. Primary amenorrhea in four adolescents revealed 5α-reductase deficiency confirmed by molecular analysis. Fertil Steril 2011; 95 (2) 804-805 , e1–e5
46 Mendonca BB, Domenice S, Arnhold IJ, Costa EM. 46,XY disorders of sex development (DSD). Clin Endocrinol (Oxf) 2009; 70 (2) 173-187
47 Costa EM, Mendonca BB, Inácio M, Arnhold IJ, Silva FA, Lodovici O. Management of ambiguous genitalia in pseudohermaphrodites: new perspectives on vaginal dilation. Fertil Steril 1997; 67 (2) 229-232
48 Khen-Dunlop N, Lortat-Jacob S, Thibaud E, Clément-Ziza M, Lyonnet S, Nihoul-Fekete C. Rokitansky syndrome: clinical experience and results of sigmoid vaginoplasty in 23 young girls. J Urol 2007; 177 (3) 1107-1111
49 Dénes FT, Cocuzza MA, Schneider-Monteiro ED , et al. The laparoscopic management of intersex patients: the preferred approach. BJU Int 2005; 95 (6) 863-867
50 Sircili MH, , e Silva FA, Costa EM. , et al. Long-term surgical outcome of masculinizing genitoplasty in large cohort of patients with disorders of sex development. J Urol 2010; 184 (3) 1122-1127
51 Sircili MH, de Mendonca BB, Denes FT, Madureira G, Bachega TA , e Silva FA. Anatomical and functional outcomes of feminizing genitoplasty for ambiguous genitalia in patients with virilizing congenital adrenal hyperplasia. Clinics (Sao Paulo) 2006; 61 (3) 209-214
52 Powell CR, Mcaleer I, Alagiri M, Kaplan GW. Comparison of flaps versus grafts in proximal hypospadias surgery. J Urol 2000; 163 (4) 1286-1288 , discussion 1288–1289
53 Ferro F, Zaccara A, Spagnoli A, Lucchetti MC, Capitanucci ML, Villa M. Skin graft for 2-stage treatment of severe hypospadias: back to the future?. J Urol 2002; 168 (4 Pt 2) 1730-1733 , discussion 1733
54 Nihoul-Fékété C, Thibaud E, Lortat-Jacob S, Josso N. Long-term surgical results and patient satisfaction with male pseudohermaphroditism or true hermaphroditism: a cohort of 63 patients. J Urol 2006; 175 (5) 1878-1884
55 Hughes IA, Houk C, Ahmed SF, Lee PA ; LWPES Consensus Group; ESPE Consensus Group. Consensus statement on management of intersex disorders. Arch Dis Child 2006; 91 (7) 554-563
56 Migeon CJ, Wisniewski AB, Gearhart JP , et al. Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics 2002; 110 (3) e31
57 Mendonca BB Male pseudohermaphroditism in http://WWW.ENDOTEXT.ORG website, M. New, Editor 2007, MDTEXT.COM, INC, S. DARTMOUTH,MA.