Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life

Wisniewski, Amy B.; Batista, Rafael Loch; Costa, Elaine Maria Frade; Finlayson, Courtney; Sircili, Maria Helena Palma; Dénes, Francisco Tibor; Domenice, Sorahia; Mendonca, Berenice B.

doi:10.1210/er.2019-00049

Cited by 83 publications

(80 citation statements)

References 263 publications

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“…As molecular diagnosis is valuable for 46,XY DSD management, it is fast becoming the first-line approach for DSD newborns. 12,[38][39][40] However, genetic testing is still not available everywhere. As important as molecular advancement is also to make this genetic test easy and feasible for any newborn, anywhere in the world.…”

Section: The 5α-reductases Enzymes and 5α-reductases Genesmentioning

confidence: 99%

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

Batista¹,

Mendonca²

2020

TACG

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The conversion of testosterone into dihydrotestosterone is catalyzed by the 5αreductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported in the early 70s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge on the molecular bases of androgen milieu. Methods: We searched for SRD5A2 allelic variants (AV) in the literature (PubMed, Embase, MEDLINE) and websites (ensembl, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous or compound heterozygous were included. The included cases were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender reassignment, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using the CONSURF platform. For categorical variables, we used X2 test and Cramer's V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 44 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). Sixty-nine percent were assigned as female. There were 70% of homozygous allelic variants and 30% compound heterozygous. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along with all exons with exon 1 (33%) and exon 4 (25%) predominance. Allelic variants in the exon 4 (NADPH-binding domain) resulted in lower virilization (p<0.0001). The codons 55, 65, 196, 235 and 246 are hotspots making up 25% of all allelic variants. Most of them (76%) were located at conserved aa. However, allelic variants at non-conserved aa were more frequently indels (28% vs 6%; p<0.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change from female to male occurred in Turkey and the highest in Brazil. External genitalia virilization was similar between those who changed and those who kept their assigned gender. The gender change rate was significantly different across the countries (V=0.44; p<0.001) even with similar virilization scores. Conclusion: 5ARD2 deficiency has a worldwide distribution. Allelic variants at the NADPHligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries. Molecular diagnosis influenced on sex assignment, favoring male sex assignment in newborns with 5α-reductase type 2 deficiency.

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Section: The 5α-reductases Enzymes and 5α-reductases Genesmentioning

confidence: 99%

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

Batista¹,

Mendonca²

2020

TACG

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“…Usually, the initial diagnostic approach of patients with DSD is based on the karyotype (35). In 46,XY individuals, the etiology of DSD is classified into: disorders of gonadal development (or gonadal dysgenesis), disorders of androgen synthesis (in non-dysgenetic gonads), disorders of androgen action, and disorders of AMH synthesis or action (resulting in the Persistent Müllerian Duct Syndrome, PMDS) (36). Gonadal dysgenesis and isolated disorders of androgen or AMH synthesis represent early fetal-onset forms of primary hypogonadism resulting in 46,XY DSD (31).…”

Section: Hypogonadism and Endocrine-related Dsdmentioning

confidence: 99%

“…Germ cell number is significantly decreased, and gonadal tumor risk is increased (38,72,73). The trend for male assignment in these cases has increased over the last decades (74), and the surgical repair of hypospadias and management of tumor risk have become the main challenges in the management (36). At the age of puberty, replacement with testosterone leads to satisfactory development of secondary sex characteristics and growth, but infertility is the rule in adulthood (71).…”

Section: Gonadal Dysgenesis In 46xy Patientsmentioning

confidence: 99%

Male Hypogonadism and Disorders of Sex Development

2020

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Disorders of Sex Development (DSD) are congenital anomalies in which there is a discordance between chromosomal, genetic, gonadal, and/or internal/external genital sex. In XY individuals, the process of fetal sex differentiation can be disrupted at the stage of gonadal differentiation, resulting in gonadal dysgenesis, a form of early fetal-onset primary hypogonadism characterized by insufficient androgen and anti-Müllerian hormone (AMH) production, which leads to the development of ambiguous or female genitalia. The process of sex differentiation can also be disrupted at the stage of genital differentiation, due to isolated defects in androgen or AMH secretion, but not both. These are forms of fetal-onset hypogonadism with dissociated gonadal dysfunction. In this review, we present a perspective on impaired testicular endocrine function, i.e., fetal-onset male hypogonadism, resulting in incomplete virilization at birth.

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“…However, this has become a very controversial practice [ 74 ]. The decision to conduct genital surgery and gender assignment at birth is fraught with bioethical concerns centered around the patient’s rights to decide their own genital sex and gender identity [ 75 , 76 ]. In addition, DSDs can be induced by environmental rather than purely genetic factors, especially during gestation.…”

Section: Disorders Of Sex Developmentmentioning

confidence: 99%

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

Estermann

Smith

2020

IJMS

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The gonads are unique among the body’s organs in having a developmental choice: testis or ovary formation. Gonadal sex differentiation involves common progenitor cells that form either Sertoli and Leydig cells in the testis or granulosa and thecal cells in the ovary. Single-cell analysis is now shedding new light on how these cell lineages are specified and how they interact with the germline. Such studies are also providing new information on gonadal maturation, ageing and the somatic-germ cell niche. Furthermore, they have the potential to improve our understanding and diagnosis of Disorders/Differences of Sex Development (DSDs). DSDs occur when chromosomal, gonadal or anatomical sex are atypical. Despite major advances in recent years, most cases of DSD still cannot be explained at the molecular level. This presents a major pediatric concern. The emergence of single-cell genomics and transcriptomics now presents a novel avenue for DSD analysis, for both diagnosis and for understanding the molecular genetic etiology. Such -omics datasets have the potential to enhance our understanding of the cellular origins and pathogenesis of DSDs, as well as infertility and gonadal diseases such as cancer.

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Management of 46,XY Differences/Disorders of Sex Development (DSD) Throughout Life

Cited by 83 publications

References 263 publications

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

Male Hypogonadism and Disorders of Sex Development

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

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