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

Costa, Elaine Maria Frade; Domenice, Sorahia; Sircili, Maria Helena Palma; Inácio, Marlene; Mendonca, Berenice B.

doi:10.1055/s-0032-1324727

Cited by 57 publications

(7 citation statements)

References 47 publications

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“…Our study confirms prepubertal presentation in approximately half of the SRD5A2 deficiency patients, (6,23,24), inaccuracy of T/DHT ratio and female to male gender change in half of the patients with initial female sex assignment (48-50%) (3,25). The latter observation suggests that gender role change is not universal in SRD5A2 deficiency patients with initial female sex assignment (23,26).…”

Section: Discussionsupporting

confidence: 82%

“…Inaccurate results are not uncommon with basal or human chorionic gonadotropin (hCG)-stimulated total testosterone (T) to dihydrotestosterone (DHT) ratio, the commonly used tests for diagnosis of SRD5A2 deficiency (3). Urinary steroid profiling (ratio of 5α to 5β steroid metabolites), a more reliable biochemical test, is a less available and laborious test with limited diagnostic accuracy in younger infants (< 3 months of age) (4).…”

Section: Introductionmentioning

confidence: 99%

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Homozygous p.Val89Leu plays an important pathogenic role in 5α-reductase type 2 deficiency patients with homozygous p.Arg246Gln in SRD5A2

Arya¹,

Tiwari²,

Lila³

et al. 2020

European Journal of Endocrinology

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Objective: To evaluate the pathogenic role of few benign variants and hypomorphic pathogenic variants in SRD5A2 Design and methods: We retrospectively analyzed phenotype and genotype in 23 Indian patients with genetically proven steroid 5α-reductase 2 (SRD5A2) deficiency. The interactions of the SRD5A2 enzymes resulting due to the most common benign variant (p.Val89Leu), the most common (hypomorphic) pathogenic variant (p.Arg246Gln) and the double variants ( p.Val89Leu and p.Arg246Gln) in SRD5A2 were compared with that of the wild-type enzyme (WT) by molecular dynamics (MD) simulation. Results: The majority (n=19, 82.61%) of patients presented for atypical genitalia and had male gender identity (16/20). Including the two novel ones (p.Leu83Pro, p.Ala28Leufs*103), a total of nine different pathogenic variants were observed. p.Arg246Gln was the most common pathogenic variant (n=12). Homozygous p.Arg246Gln (n=9) variant was associated with milder undervirilization (Sinnecker score of ≤3a: 8/9 vs 6/14, p=0.04) and had concurrent homozygous p.Val89Leu in all patients. Interestingly, asymptomatic fathers of two index patients were homozygous for p.Arg246Gln which questioned the pathogenicity of the variation as a sole factor. Unlike all symptomatic homozygous p.Arg246Gln patients who were also homozygous for p.Val89Leu, asymptomatic homozygous p.Arg246Gln fathers were heterozygous for p.Val89Leu. On MD simulation SRD5A2 p.Val89Leu-Testeosterone (T) and SRD5A2 p.Arg246Gln-T complexes, but not SRD5A2 p.Val89Leu and p.Arg246Gln-T complex, demonstrated close interaction between NADPH and T as that of SRD5A2 WT-T. Conclusions: p.Arg246Gln may not be pathogenic as a sole variation even in the homozygous state; additional contribution of homozygous p.Val89Leu variant may be essential for the pathogenicity of p.Arg246Gln in SRD5A2.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Homozygous p.Val89Leu plays an important pathogenic role in 5α-reductase type 2 deficiency patients with homozygous p.Arg246Gln in SRD5A2

Arya¹,

Tiwari²,

Lila³

et al. 2020

European Journal of Endocrinology

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“…Men with XY DSD conditions are reported to be more satisfied after surgical corrections of genitals, although repeated surgical procedures and complications may have a negative impact on sexual function (Callens et al, 2015;Callens et al, 2013). In a study on persons with 5a-RD2 deficiency, penile length was not associated with satisfaction of sexual activity (Costa, Domenice, Sircili, Inacio, & Mendonca, 2012). In men with PAIS, sexual function was reported to be seriously impaired (Bouvattier et al, 2006).…”

Section: Satisfaction With Genitals and Genital Functionmentioning

confidence: 99%

Sexuality in Adults with Differences/Disorders of Sex Development (DSD): Findings from the dsd-LIFE Study

Kreukels

Cohen‐Kettenis

Roehle

et al. 2019

Journal of Sex & Marital Therapy

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For various reasons, sexuality of individuals with differences/disorders of sex development (DSD) may be affected. The aim of the study was to describe sexual activity, satisfaction with sex life, satisfaction with genital function, and sexual problems in people with different DSD conditions. Data were collected from 1,040 participants in Europe. Many people with a variety of DSD conditions do not appear to be satisfied with their sex life, experience a variety of sexual problems, and are less sexually active than the general population; therefore sexuality should be explicitly addressed in the care of people with DSD.

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“…With a thorough understanding of anticipated events at puberty, an initial male sex assignment should be considered. Long-term follow up has shown that many affected individuals who live as male are participating in long-term, heterosexual relationships (37). If fertility is desired, most of these couples will require assisted methods of reproduction (38).…”

Section: Managementmentioning

confidence: 99%

The effect of 5α-reductase-2 deficiency on human fertility

Kang

Imperato‐McGinley

Zhu

et al. 2014

Fertility and Sterility

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A most interesting and intriguing male disorder of sexual differentiation is due to 5α-reductase-2 isoenzyme deficiency. These males are born with ambiguous external genitalia due to a deficiency in their ability to catalyze the conversion of testosterone to dihydrotestosterone (DHT). DHT is a potent androgen responsible for differentiation of the urogenital sinus and genital tubercle into the external genitalia, urethra and prostate. Affected males are born with a clitoral-like phallus, bifid scrotum, hypospadias, blind shallow vaginal pouch from incomplete closure of the urogenital sinus and a rudimentary prostate. At puberty, the surge in mainly testosterone production prompts virilization, causing most to choose gender reassignment to male. Fertility is a challenge for affected men for several reasons. Uncorrected cryptorchidism is associated with low sperm production, and there is evidence of defective transformation of spermatogonia into spermatocytes. The underdeveloped prostate and consequent low semen volumes affect sperm transport. Additionally, semen may not liquefy due to a lack of prostate-specific antigen. In this review, we discuss the 5α-reductase-2 deficiency syndrome and its impact on human fertility.

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

Cited by 57 publications

References 47 publications

Homozygous p.Val89Leu plays an important pathogenic role in 5α-reductase type 2 deficiency patients with homozygous p.Arg246Gln in SRD5A2

Homozygous p.Val89Leu plays an important pathogenic role in 5α-reductase type 2 deficiency patients with homozygous p.Arg246Gln in SRD5A2

Sexuality in Adults with Differences/Disorders of Sex Development (DSD): Findings from the dsd-LIFE Study

The effect of 5α-reductase-2 deficiency on human fertility

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