scholarly journals Disorders of Sex Development: Classification, Review, and Impact on Fertility

2020 ◽  
Vol 9 (11) ◽  
pp. 3555
Author(s):  
Pedro Acién ◽  
Maribel Acién
Keyword(s):  
Sex Determination ◽  
Klinefelter Syndrome ◽  
Sex Differentiation ◽  
Disorders Of Sex Development ◽  
Androgen Excess ◽  
Adrenal Steroid ◽  
Sex Development ◽  
Male Phenotype ◽  
Kallman Syndrome

In this review, the elements included in both sex determination and sex differentiation are briefly analyzed, exposing the pathophysiological and clinical classification of disorders or anomalies of sex development. Anomalies in sex determination without sex ambiguity include gonadal dysgenesis, polysomies, male XX, and Klinefelter syndrome (dysgenesis and polysomies with a female phenotype; and sex reversal and Klinefelter with a male phenotype). Other infertility situations could also be included here as minor degrees of dysgenesis. Anomalies in sex determination with sex ambiguity should (usually) include testicular dysgenesis and ovotesticular disorders. Among the anomalies in sex differentiation, we include: (1) males with androgen deficiency (MAD) that correspond to those individuals whose karyotype and gonads are male (XY and testes), but the phenotype can be female due to different hormonal abnormalities. (2) females with androgen excess (FAE); these patients have ovaries and a 46,XX karyotype, but present varying degrees of external genital virilization as a result of an enzyme abnormality that affects adrenal steroid biosynthesis and leads to congenital adrenal hyperplasia; less frequently, this can be caused by iatrogenia or tumors. (3) Kallman syndrome. All of these anomalies are reviewed and analyzed herein, as well as related fertility problems.

scholarly journals Transcriptional Regulation of the Y-Linked Mammalian Testis-Determining Gene SRY

2021 ◽  
pp. 1-9
Author(s):  
Naoki Okashita ◽  
Makoto Tachibana
Keyword(s):  
Sex Determination ◽  
Sex Differentiation ◽  
Disorders Of Sex Development ◽  
Sex Reversal ◽  
Cis Acting ◽  
Male Development ◽  
Sex Development ◽  
Epigenetic Modifier ◽  
Male Sex ◽  
Testis Determining Gene

Mammalian male sex differentiation is triggered during embryogenesis by the activation of the Y-linked testis-determining gene <i>SRY</i>. Since insufficient or delayed expression of <i>SRY</i> results in XY gonadal sex reversal, accurate regulation of <i>SRY</i> is critical for male development in XY animals. In humans, dysregulation of <i>SRY</i> may cause disorders of sex development. Mouse <i>Sry</i> is the most intensively studied mammalian model of sex determination. <i>Sry</i> expression is controlled in a spatially and temporally stringent manner. Several transcription factors play a key role in sex determination as trans-acting factors for <i>Sry</i> expression. In addition, recent studies have shown that several epigenetic modifications of <i>Sry</i> are involved in sex determination as cis-acting factors for <i>Sry</i> expression. Herein, we review the current understanding of transcription factor- and epigenetic modifier-mediated regulation of <i>SRY</i>/<i>Sry</i> expression.

scholarly journals Multidisciplinary Management of Disorders of Sex Development in Indonesia, A Prototype in Developing Country

2017 ◽  
Vol 3 (1) ◽  
pp. 17 ◽  
Author(s):  
Nurin Aisyiyah Listyasari ◽  
Ardy Santosa ◽  
Achmad Zulfa Juniarto ◽  
Sultana MH Faradz
Keyword(s):  
Quality Of Life ◽  
Disorders Of Sex Development ◽  
Multidisciplinary Management ◽  
Improve Quality ◽  
Gender Assignment ◽  
Androgen Excess ◽  
Comprehensive Management ◽  
Sex Development ◽  
Management Protocol

Background : Disorder of sex development (DSD) patients require comprehensive management to improve quality of life. A standardized management protocol for patients in Indonesia is not yet available resulting in patients infrequently received a proper diagnosis. This study reported a multidisciplinary management DSD in Indonesia based on minimal diagnostic facilities and expertise in developing country.Objectives : The purpose of the study is to review the management of DSD patients in Indonesia relates to providing appropriate gender assignment and to improving patients quality of life.Methodology : We analyzed the records of DSD patient admitted to the division of Human Genetics Center for Biomedical Research (CEBIOR) Faculty of Medicine Diponegoro University, Semarang, Indonesia from May 2004 - December 2015. Data were collected and analyzed for physical examination, family pedigree karyotyping, hormonal assays and  psychosocial.  Other examination such as ultrasonography, Xray and Cytoscopy were also recorded for selected cases. Bimonthly, Sexual Adjustment Team (SAT) meeting was recorded.Results : From the total 617 DSD cases we found 426 cases (69,04 %) with 46, XY DSD, 117 cases (18,96%) with 46,XX DSD and 74 cases (12%) with sex chromosome DSD. Most of the patients in the group of 46, XY DSD are Unknown Male Undervirilization (UMU) with 256 cases (60.09%). As the majority cases of 46, XX DSD was Congenital Adrenal Hyperplasia with 81 cases (69.23%). The remaining cases were Androgen Action Disorder (AAD) with 140 cases (32.86%), 46, XY DSD Gonadal Dysgenesis with 30 cases (7.04%), Androgen Excess Disorders with 3 cases (2.56%), Defect of Mullerian Development with 19 cases (16,24%), 3 cases (2.56%) of Androgen Excess and 3 cases (2.56%) of 46, XX Gonadal Dysgenesis.Conclusion : Comprehensive management for DSD Patients help patient in diagnosis, gender assignment and support patient to improve quality of life. This multidisciplinary of DSD team is the only team in Indonesia that can be used as a model for other center in Indonesia as well as other developing countries with minimal diagnostic facilities.

scholarly journals Shifting syndromes: Sex chromosome variations and intersex classifications

2018 ◽  
Vol 48 (1) ◽  
pp. 125-148 ◽  
Author(s):  
David Andrew Griffiths
Keyword(s):  
Lived Experience ◽  
Classification System ◽  
Consensus Statement ◽  
Sex Chromosome ◽  
Disorders Of Sex Development ◽  
Current Drive ◽  
Medical Community ◽  
New Classification ◽  
Sex Development

The 2006 ‘Consensus statement on management of intersex disorders’ recommended moving to a new classification of intersex variations, framed in terms of ‘disorders of sex development’ or DSD. Part of the rationale for this change was to move away from associations with gender, and to increase clarity by grounding the classification system in genetics. While the medical community has largely accepted the move, some individuals from intersex activist communities have condemned it. In addition, people both inside and outside the medical community have disagreed about what should be covered by the classification system, in particular whether sex chromosome variations and the related diagnoses of Turner and Klinefelter’s syndromes should be included. This article explores initial descriptions of Turner and Klinefelter’s syndromes and their subsequent inclusion in intersex classifications, which were increasingly grounded in scientific understandings of sex chromosomes that emerged in the 1950s. The article questions the current drive to stabilize and ‘sort out’ intersex classifications through a grounding in genetics. Alternative social and historical definitions of intersex – such as those proposed by the intersex activists – have the potential to do more justice to the lived experience of those affected by such classifications and their consequences.

177. A MECHANISM UNDERLYING DISORDERS OF SEX DEVELOPMENT CAUSED BY DAX1 DUPLICATION

2009 ◽  
Vol 21 (9) ◽  
pp. 95
Author(s):  
L. Ludbrook ◽  
R. Sekido ◽  
R. Lovell-Badge ◽  
V. Harley
Keyword(s):  
Sex Determination ◽  
Disorders Of Sex Development ◽  
Nuclear Hormone Receptor ◽  
Testicular Development ◽  
Transcriptional Level ◽  
Sox9 Expression ◽  
Transgenic Mouse Line ◽  
Sex Development

The DAX1 protein is an orphan nuclear hormone receptor expressed in developing and adult hypothalamic, pituitary, adrenal and gonadal tissues. In humans, duplication of the DAX1 gene at locus Xp21 causes Disorders of Sex Development (DSD), whereby XY individuals develop as females, due to the failure of testicular development. DAX1 acts as a co-factor for nuclear receptor-mediated transcription of steroidogenic genes. In mice, overexpression of a Dax1 transgene causes delayed testis cord formation, a milder phenotype than that seen in human (1). Exactly how DAX1 duplication interferes with typical testicular development is unclear but a ‘window' of DAX1 activity was proposed (2). In order to identify the mechanism of DAX1 action when overexpressed in the developing XY gonad, we have used both in vivo and in vitro approaches. We hypothesised that, when present in excess, DAX1 must repress the action of early testis-forming genes. We investigated the effect of Dax1 over expression, using the Dax1 transgenic mouse line, Dax1812 (1), on expression of Sox9, a critical testis-forming gene. Immunostaining of Dax1812 gonads revealed reduced Sox9 expression, suggesting excess Dax1 antagonises Sox9 upregulation during the early stages of sex determination. To determine whether antagonism of Sox9 was occurring at the transcriptional level we assessed the effect of excess Dax1 on the activity of the Testis-Specific Enhancer of Sox9 (TES), which drives Sox9 transcription in the developing XY gonad (3). In combination, the in vivo and in vitro evidence strongly suggests that Dax1, when present in excess, can repress Sox9 expression through TES and that this repression occurs through inhibition of Steroidogenic Factor-1 activity. With this work we have identified a potential mechanism for disruption of the male-specific sex determination pathway caused by DAX1 duplication and leading to DSD in XY individuals.

Nuclear receptor action involved with sex differentiation

2003 ◽  
Vol 75 (11-12) ◽  
pp. 1771-1784 ◽  
Author(s):  
I. A. Hughes ◽  
Howard Martin ◽  
Jarmo Jääskeläinen ◽  
C. L. Acerini
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Reproductive Tract ◽  
Sex Differentiation ◽  
Disorders Of Sex Development ◽  
Nuclear Hormone Receptor ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Sex Development ◽  
Sequence Of Events

Sex determination and differentiation in the male is an orderly sequence of events coordinated by genetic and hormonal factors operating in a time- and concentration-dependent manner. The constitutive sex in mammals is female. Disorders of fetal sex development have provided the means to identify testis-determining genes and the molecular mechanisms of hormone action. Thus, the androgen receptor, a nuclear hormone receptor critical for androgen-induced male sex differentiation, displays unique intra-receptor and protein-protein interactions which, when disturbed, can result in extreme forms of sex reversal. Polymorphic variants are associated with milder disorders of sex development. Against this genetic background, endocrine active substances may further contribute to the underlying causes of an increase in male reproductive tract disorders.

scholarly journals ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling

2018 ◽  
Vol 115 (21) ◽  
pp. 5474-5479 ◽  
Author(s):  
Abigail Harris ◽  
Pam Siggers ◽  
Silvia Corrochano ◽  
Nick Warr ◽  
Danielle Sagar ◽  
...  
Keyword(s):  
Sex Determination ◽  
Wnt Signaling ◽  
Disorders Of Sex Development ◽  
Ovary Development ◽  
Sex Development ◽  
Mutual Antagonism ◽  
Testis Determination ◽  
Direct Target ◽  
Canonical Wnt ◽  
Xy Female

Mammalian sex determination is controlled by the antagonistic interactions of two genetic pathways: The SRY-SOX9-FGF9 network promotes testis determination partly by opposing proovarian pathways, while RSPO1/WNT-β-catenin/FOXL2 signals control ovary development by inhibiting SRY-SOX9-FGF9. The molecular basis of this mutual antagonism is unclear. Here we show that ZNRF3, a WNT signaling antagonist and direct target of RSPO1-mediated inhibition, is required for sex determination in mice. XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal, or related defects. These abnormalities are associated with ectopic WNT/β-catenin activity and reduced Sox9 expression during fetal sex determination. Using exome sequencing of individuals with 46,XY disorders of sex development, we identified three human ZNRF3 variants in very rare cases of XY female presentation. We tested two missense variants and show that these disrupt ZNRF3 activity in both human cell lines and zebrafish embryo assays. Our data identify a testis-determining function for ZNRF3 and indicate a mechanism of direct molecular interaction between two mutually antagonistic organogenetic pathways.

scholarly journals Contemporary Demographic, Treatment, and Geographic Distribution Patterns for Disorders of Sex Development

2017 ◽  
Vol 57 (3) ◽  
pp. 311-318
Author(s):  
Rohit Tejwani ◽  
Ruiyang Jiang ◽  
Steven Wolf ◽  
Deanna W. Adkins ◽  
Brian J. Young ◽  
...  
Keyword(s):  
Regional Variation ◽  
Nationwide Inpatient Sample ◽  
Disorders Of Sex Development ◽  
Distribution Patterns ◽  
International Classification Of Diseases ◽  
Tertiary Referral ◽  
Sex Development ◽  
Classification Of Diseases ◽  
State Regional

This study aimed to describe the demographic characteristics, hospital utilizations, patterns of inpatient surgical management, and the overall state/regional variation in surgery rate among patients with disorders of sex development (DSD). We analyzed the Nationwide Inpatient Sample from 2001 to 2012 for patients younger than 21 years. DSD-related diagnoses and procedures were identified via International Classification of Diseases, Ninth Revision (ICD-9) codes. We identified a total of 43,968 DSD-related admissions. Of these, 73.4% of the admissions were designated as female and 642 (1.9%) were inpatient surgical admissions. Among neonates, less than 1% underwent any type of genital surgery. Nonsurgical admissions were associated with longer length of stay and higher cost. There was no significant regional variation in the rate of DSD surgeries, but we observed higher concentrations of DSD surgeries in states associated with tertiary referral centers.

scholarly journals Cis-Regulatory Control of Mammalian Sex Determination

2021 ◽  
pp. 1-18
Author(s):  
Meshi Ridnik ◽  
Stefan Schoenfelder ◽  
Nitzan Gonen
Keyword(s):  
Sex Determination ◽  
Cell Fate ◽  
Developmental Disorders ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Regulatory Elements ◽  
Regulatory Control ◽  
Male Factor ◽  
Cis Acting ◽  
Sex Development

Sex determination is the process by which an initial bipotential gonad adopts either a testicular or ovarian cell fate. The inability to properly complete this process leads to a group of developmental disorders classified as disorders of sex development (DSD). To date, dozens of genes were shown to play roles in mammalian sex determination, and mutations in these genes can cause DSD in humans or gonadal sex reversal/dysfunction in mice. However, exome sequencing currently provides genetic diagnosis for only less than half of DSD patients. This points towards a major role for the non-coding genome during sex determination. In this review, we highlight recent advances in our understanding of non-coding, cis-acting gene regulatory elements and discuss how they may control transcriptional programmes that underpin sex determination in the context of the 3-dimensional folding of chromatin. As a paradigm, we focus on the <i>Sox9</i> gene, a prominent pro-male factor and one of the most extensively studied genes in gonadal cell fate determination.

Boy born after gender preselection following successive gestational androgen excess of maternal luteoma and female disorders of sex development

2009 ◽  
Vol 91 (6) ◽  
pp. 2732.e5-2732.e7 ◽  
Author(s):  
Chi-Huang Chen ◽  
I-Ching Chen ◽  
Yu-Chi Wang ◽  
Jah-Yao Liu ◽  
Gwo-Jang Wu ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
Androgen Excess ◽  
Sex Development

scholarly journals Variants of STAR, AMH and ZFPM2/FOG2 May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of NR5A1

2020 ◽  
Vol 21 (22) ◽  
pp. 8554
Author(s):  
Idoia Martínez de LaPiscina ◽  
Rana AA Mahmoud ◽  
Kay-Sara Sauter ◽  
Isabel Esteva ◽  
Milagros Alonso ◽  
...  
Keyword(s):  
Sex Determination ◽  
Broad Spectrum ◽  
Clinical Characteristics ◽  
Phenotypic Expression ◽  
Disorders Of Sex Development ◽  
Organ Function ◽  
Transactivation Activity ◽  
Sex Development ◽  
Genetic Features ◽  
Mode Of Inheritance

Variants of NR5A1 are often found in individuals with 46,XY disorders of sex development (DSD) and manifest with a very broad spectrum of clinical characteristics and variable sex hormone levels. Such complex phenotypic expression can be due to the inheritance of additional genetic hits in DSD-associated genes that modify sex determination, differentiation and organ function in patients with heterozygous NR5A1 variants. Here we describe the clinical, biochemical and genetic features of a series of seven patients harboring monoallelic variants in the NR5A1 gene. We tested the transactivation activity of novel NR5A1 variants. We additionally included six of these patients in a targeted diagnostic gene panel for DSD and identified a second genetic hit in known DSD-causing genes STAR, AMH and ZFPM2/FOG2 in three individuals. Our study increases the number of NR5A1 variants related to 46,XY DSD and supports the hypothesis that a digenic mode of inheritance may contribute towards the broad spectrum of phenotypes observed in individuals with a heterozygous NR5A1 variation.

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