Long‐term outcomes and molecular analysis of a large cohort of patients with 46,<scp>XY</scp> disorder of sex development due to partial gonadal dysgenesis

Gomes, Nathália Lisboa; Lerário, Antônio Marcondes; Machado, Aline Zamboni; Moraes, Daniela; Silva, Thatiana Evilen da; Arnhold, Ivo Jorge Prado; Batista, Rafael Loch; Júnior, José Antônio Diniz Faria; Costa, Elaine Maria Frade; Nishi, Mirian Yumie; Inácio, Marlene; Domenice, Sorahia; Mendonca, Berenice B.

doi:10.1111/cen.13717

Cited by 17 publications

(16 citation statements)

References 53 publications

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“…In this study we found pathogenic/ likely pathogenic variants in DHX37 in patients with 46,XY GD at a frequency of 14%, which is slightly higher than the frequency of NR5A1 defects (11%) in our whole cohort (24,27). Considering only the ETRS phenotype (micropenis and absence of uni or bilateral testicular tissue) this frequency increases to 50% (7/14 families).…”

Section: Frequency Of the Dhx37 Variants In Our 46xy Dsd Cohortmentioning

confidence: 41%

Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum

Silva

Gomes

Lerário

et al. 2019

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context 46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS). Objective To report a gene for 46,XY GD etiology, especially for ETRS. Design Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing. Setting Tertiary Referral Center for differences/disorders of sex development (DSD). Patients and Interventions We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology. Results We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells. Conclusion This strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.

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Section: Frequency Of the Dhx37 Variants In Our 46xy Dsd Cohortmentioning

confidence: 41%

Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum

Silva

Gomes

Lerário

et al. 2019

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…Consequently, gender change from female to male is common in this 46,XY DSD condition [31]. Gender change from female to male is also reported among other 46,XY DSD conditions but in a lower frequency [6,8,34,35]. In our analysis, there were no differences in the sexual life parameters comparing male individuals assigned as male with those who changed from female to male, except by individuals who changed from female to male gender reported more active sex life than those assigned as male (p > 0.04; Table 2).…”

Section: Discussionmentioning

confidence: 51%

Aspects of Sexual Life, Sexual Orientation and Fertility Desire in a Large Cohort of Individuals With 46,xy Differences of Sex Development

Batista

Inácio

Brito

et al. 2021

Preprint

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Purpose: To analyze aspects of the sexual life, sexual orientation, and fertility desire among 46,XY DSD people, including those who changed their gender. Methods: It is a cross-sectional study including 127 adults (> 16 years of age) with 46,XY DSD (83 females; 44 males) from a single tertiary center. Results: Sexual fantasies and masturbation practice were more frequent in 46,XY DSD males, whereas orgasm and sexual life satisfaction were similar in both genders. More 46,XY DSD men than women had a long-term romantic relationship. 46,XY DSD women with prenatal androgen exposure reported more fear of being romantically rejected. External genitalia appearance at birth did not impact the sexuality of 46,XY DSD women after surgical genital treatment has been completed. Overall, the sexual life was similar between 46,XY men assigned as males and those who changed to the male gender. Regarding sexual orientation, most self-reported as heterosexual (91% and 92% of women and men, respectively). The desire for fertility had a similar prevalence in both genders, but more women than men considered infertility a barrier to a long-term romantic relationship. A total of 12 (7 males) had children; 10 out of 12 have adopted children. Conclusion: Fertility desire was common among 46,XY DSD people, regardless of gender. Prenatal androgen exposure reduced the desire for motherhood in 46,XY women. 46 XY DSD people who changed from female to male gender presented similar sexual parameters as those assigned as males. Among females, virilized genitalia at birth did not affect sexuality once the surgical treatment is completed.

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“…Molecular diagnosis was possible in 33% of the patients with 46, XY gonadal dysgenesis, and NR5A1 variants were the most prevalent molecular defects. 17 Through these studies, it was possible to identify a new mutation and a deletion of the entire coding sequence in genes related to Congenital Hypogonadotropic Hypogonadism (CHH). 18 In short Stature Homeobox (SHOX) haploinsufficiency studies, the target panel confirmed changes in known genes and identified two new deletions that were not previously detected through the classical diagnosis, the MPLA followed by Sanger.…”

Section: Discussionmentioning

confidence: 99%

Targeted massively parallel sequencing panel to diagnose genetic endocrine disorders in a tertiary hospital

Narcizo

Cardoso

Benedetti

et al. 2022

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Long‐term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis

Cited by 17 publications

References 53 publications

Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum

Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum

Aspects of Sexual Life, Sexual Orientation and Fertility Desire in a Large Cohort of Individuals With 46,xy Differences of Sex Development

Targeted massively parallel sequencing panel to diagnose genetic endocrine disorders in a tertiary hospital

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