scholarly journals Intragenic Duplication of DMRT1 in a SRY-Negative Boy with 46,XX Disorder of Sex Development

2021 ◽  
Author(s):  
Veronica Bertini ◽  
Fulvia Baldinotti ◽  
Nina Tyutyusheva ◽  
Camillo Rosano ◽  
Cinzia Cosini ◽  
...  
Keyword(s):  
De Novo ◽  
Sex Differentiation ◽  
Disorders Of Sex Development ◽  
Comparative Genomic ◽  
Normal Male ◽  
Testicular Development ◽  
Targeted Next Generation Sequencing ◽  
Sex Development ◽  
Intragenic Duplication ◽  
Xx Males

Background. 46,XX disorders of sex development are rare. Approximately, 90% of XX males are SRY-positive, while testicular development in the absence of SRY takes place in a minority. Methods: A boy with 46,XX karyotype (SRY-negative; absence of SOX9 duplications) was investigated by targeted Next Generation Sequencing (NGS), Multiplex ligation-dependent probe amplification (MLPA), and Comparative Genomic Hybridization array (CGH-array). Results: The boy had normal male phenotype and normal prepubertal values of testicular hormones. He presented a heterozygous duplication of 49.626 bp, encompassing exons 2 and 3 of DMRT1. The result was arr[GRCh37] 9p24.3(845893_895518)x3. Since both breakpoints are harbored in the intronic regions, the duplication does not stop or shift the coding frame. Additional known pathogenic or uncertain variants in pro-testis gene cascade were not identified. Conclusions: This study report a boy with 46,XX testicular disorder of sex differentiation, showing a de novo partial intragenic duplication of DMRT1. This intragenic duplication may result in a gain of function, acting as primary pro-testis gene (or anti-ovary gene) in a 46,XX human foetus and permitting normal pre-pubertal endocrine testis function.

MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: bioinformatics consideration

2019 ◽  
Vol 28 (14) ◽  
pp. 2319-2329 ◽  
Author(s):  
Kohei Hamanaka ◽  
Atsushi Takata ◽  
Yuri Uchiyama ◽  
Satoko Miyatake ◽  
Noriko Miyake ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Genes ◽  
De Novo ◽  
Clinical Symptoms ◽  
Disorders Of Sex Development ◽  
Sequencing Data ◽  
Causative Gene ◽  
Sex Development ◽  
And Migration ◽  
Proliferation And Migration

AbstractDisorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In many DSD cases, genetic causes remain to be elucidated. Here, we performed a case–control exome sequencing study comparing gene-based burdens of rare damaging variants between 26 DSD cases and 2625 controls. We found exome-wide significant enrichment of rare heterozygous truncating variants in the MYRF gene encoding myelin regulatory factor, a transcription factor essential for oligodendrocyte development. All three variants occurred de novo. We identified an additional 46,XY DSD case of a de novo damaging missense variant in an independent cohort. The clinical symptoms included hypoplasia of Müllerian derivatives and ovaries in 46,XX DSD patients, defective development of Sertoli and Leydig cells in 46,XY DSD patients and congenital diaphragmatic hernia in one 46,XY DSD patient. As all of these cells and tissues are or partly consist of coelomic epithelium (CE)-derived cells (CEDC) and CEDC developed from CE via proliferaiton and migration, MYRF might be related to these processes. Consistent with this hypothesis, single-cell RNA sequencing of foetal gonads revealed high expression of MYRF in CE and CEDC. Reanalysis of public chromatin immunoprecipitation sequencing data for rat Myrf showed that genes regulating proliferation and migration were enriched among putative target genes of Myrf. These results suggested that MYRF is a novel causative gene of 46,XY and 46,XX DSD and MYRF is a transcription factor regulating CD and/or CEDC proliferation and migration, which is essential for development of multiple organs.

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.

scholarly journals Establishment of a Novel Human Fetal Adrenal Culture Model that Supports de Novo and Manipulated Steroidogenesis

2020 ◽  
Author(s):  
Cecilie Melau ◽  
John E Nielsen ◽  
Signe Perlman ◽  
Lene Lundvall ◽  
Lea Langhoff Thuesen ◽  
...  
Keyword(s):  
De Novo ◽  
Culture Media ◽  
Ex Vivo ◽  
Disorders Of Sex Development ◽  
Endocrine Function ◽  
Specific Response ◽  
Adrenal Tissue ◽  
Sex Development ◽  
Adrenal Steroidogenesis ◽  
Novel Approach

Abstract Context Disorders affecting adrenal steroidogenesis promote an imbalance in the normally tightly controlled secretion of mineralocorticoids, glucocorticoids, and androgens. This may lead to differences/disorders of sex development in the fetus, as seen in virilized girls with congenital adrenal hyperplasia (CAH). Despite the important endocrine function of human fetal adrenals, neither normal nor dysregulated adrenal steroidogenesis is understood in detail. Objective Due to significant differences in adrenal steroidogenesis between human and model species (except higher primates), we aimed to establish a human fetal adrenal model that enables examination of both de novo and manipulated adrenal steroidogenesis. Design and Setting Human adrenal tissue from 54 1st trimester fetuses were cultured ex vivo as intact tissue fragments for 7 or 14 days. Main Outcome Measures Model validation included examination of postculture tissue morphology, viability, apoptosis, and quantification of steroid hormones secreted to the culture media measured by liquid chromatography-tandem mass spectrometry. Results The culture approach maintained cell viability, preserved cell populations of all fetal adrenal zones, and recapitulated de novo adrenal steroidogenesis based on continued secretion of steroidogenic intermediates, glucocorticoids, and androgens. Adrenocorticotropic hormone and ketoconazole treatment of ex vivo cultured human fetal adrenal tissue resulted in the stimulation of steroidogenesis and inhibition of androgen secretion, respectively, demonstrating a treatment-specific response. Conclusions Together, these data indicate that ex vivo culture of human fetal adrenal tissue constitutes a novel approach to investigate local effects of pharmaceutical exposures or emerging therapeutic options targeting imbalanced steroidogenesis in adrenal disorders, including CAH.

TESTOSTERONE 5α-REDUCTION IN THE SKIN OF NORMAL SUBJECTS AND OF PATIENTS WITH ABNORMAL SEX DEVELOPMENT

1975 ◽  
Vol 79 (1) ◽  
pp. 164-176 ◽  
Author(s):  
Frédérique Kuttenn ◽  
Pierre Mauvais-Jarvis
Keyword(s):  
Conversion Rate ◽  
Reductase Activity ◽  
Human Subjects ◽  
Sex Differentiation ◽  
Normal Subjects ◽  
Normal Male ◽  
Skin Sample ◽  
Reduction Activity ◽  
Sex Development ◽  
Normal Men

ABSTRACT Human pubic skin was obtained from normal subjects and patients with abnormal sex differentiation. Skin samples (200 mg) supplemented with NADPH, were incubated for 1 h with labelled testosterone. The conversion of testosterone to dihydrotestosterone1), 3α- and 3β-androstanediol was calculated. This conversion averaged 14.9 ± 3.4 % (se) in 11 normal men and 3.6 ± 1.4 % (se) in 8 normal women. In 4 children as in 4 young hypogonadotrophic hypogonadal men, the conversion rate of testosterone to 5α-reduced metabolites was low (0.8 to 3.5%) and increased at puberty (13.5 to 19.2%). After administration of HCG for 3 months to 1 of the hypogonadal men, it reached 30.2 %. Inversely, the formation of dihydrotestosterone and androstanediols from testosterone was suppressed in 2 men treated with large doses of oestrogen. In 3 subjects with an incomplete form of testicular feminization syndrome, the conversion rate of testosterone to 5α-reduced metabolites was in the normal male range (6.4 to 18.3%), whereas it was low in one case of the complete form of the syndrome (1.5%). In 9 women with idiopathic hirsutism the rate of 5α-reduced metabolites recovered from testosterone was close to that of normal men (13.5 ± 5.5% (se). From theseresults, it is postulated that in human subjects, there is a good correlation between hair growth in skin from a sexual area and the extent of testosterone 5α-reduction in this tissue. Such an enzymatic activity might be induced by active androgens; this latter hypothesis is in good agreement with the increase of 5α-reduction activity observed at puberty or after treatment of young hypogonadal males. In addition, it is pointed out that a positive correlation is observed between the 5α-reductase activity present in each skin sample studied and the urinary 3α-androstanediol found for the same individual. This confirms our previous findings suggesting that the determination of urinary 3α-androstanediol might prove of clinical interest in the evaluation of the androgenic status in human subjects.

scholarly journals Ovotesticular Disorder of Sex Development: An Unusual Presentation

2019 ◽  
Vol 9 ◽  
pp. 34 ◽  
Author(s):  
Meltem Özdemir ◽  
Rasime Pelin Kavak ◽  
Ihsan Yalcinkaya ◽  
Kursat Guresci
Keyword(s):  
Unusual Case ◽  
Disorders Of Sex Development ◽  
Ambiguous Genitalia ◽  
Normal Male ◽  
Genital Organ ◽  
Rare Form ◽  
Disorder Of Sex Development ◽  
Breast Enlargement ◽  
Sex Development ◽  
Bilateral Breast Enlargement

Disorder of sex development is an inclusive term that refers to any problem where the genital organ is atypical in relation to chromosomes or gonads. Ovotesticular disorder of sex development, which is formerly known as “true hermaphroditism,” is the most rare form among all disorders of sex development in humans. It is characterized by the simultaneous presence of both ovarian and testicular tissues in the same individual and characteristically presents with ambiguous genitalia in neonates or infants. Herein, we present an unusual case of a 19-year-old individual with phenotypically nearly normal male genitalia who presented with the complaint of bilateral breast enlargement.

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 Delayed Recognition of Disorders of Sex Development (DSD): A Missed Opportunity for Early Diagnosis of Malignant Germ Cell Tumors

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Remko Hersmus ◽  
Hans Stoop ◽  
Stefan J. White ◽  
Stenvert L. S. Drop ◽  
J. Wolter Oosterhuis ◽  
...  
Keyword(s):  
Germ Cell ◽  
Early Recognition ◽  
Metastatic Cancer ◽  
Germ Cell Tumors ◽  
Disorders Of Sex Development ◽  
Ambiguous Genitalia ◽  
Normal Male ◽  
Testicular Dysgenesis Syndrome ◽  
Sex Development ◽  
Increased Risk

Disorders of sex development (DSD) are defined as a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. DSD patients with gonadal dysgenesis or hypovirilization, containing part of the Y chromosome (GBY), have an increased risk for malignant type II germ cell tumors (GCTs: seminomas and nonseminomas). DSD may be diagnosed in newborns (e.g., ambiguous genitalia), or later in life, even at or after puberty. Here we describe three independent male patients with a GCT; two were retrospectively recognized as DSD, based on the histological identification of both carcinomain situand gonadoblastoma in a single gonad as the cancer precursor. Hypospadias and cryptorchidism in their history are consistent with this conclusion. The power of recognition of these parameters is demonstrated by the third patient, in which the precursor lesion was diagnosed before progression to invasiveness. Early recognition based on these clinical parameters could have prevented development of (metastatic) cancer, to be treated by systemic therapy. All three patients showed a normal male 46,XY karyotype, without obvious genetic rearrangements by high-resolution whole-genome copy number analysis. These cases demonstrate overlap between DSD and the so-called testicular dysgenesis syndrome (TDS), of significant relevance for identification of individuals at increased risk for development of a malignant GCT.

scholarly journals Disorders of Sex Development in Wolf-Hirschhorn Syndrome: A Genotype-phenotype Correlation and MSX1 as Candidate Gene

2021 ◽  
Author(s):  
Khouloud Rjiba ◽  
Hedia Ayech ◽  
Wafa Slimani ◽  
Olfa KRAIEM ◽  
Afef Jelloul ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
Ventral Side ◽  
Comparative Genomic ◽  
Chromosome 4 ◽  
Phenotype Correlation ◽  
Androgen Synthesis ◽  
Sex Development ◽  
Genotype Phenotype Correlation ◽  
Spatiotemporal Regulation ◽  
One Year

Abstract Background: Wolf-Hirschhorn (WHS) is a set of congenital physical anomalies and mental retardation associated with a partial deletion of the short arm of chromosome 4.To establish a genotype-phenotype correlation; we carried out a molecular cytogenetic analysis on two Tunisian WHS patients. Patient 1was a boy of one-year-old presented typical WHS phenotype while patient 2, is a boy of two days presented an hypospadias, a micropenis and cryptorchidie in addition to the typical WHS phenotype. Both the comparative genomic hybridization (CGH array) and Fluorescence in Situ Hybridization (FISH) techniques were used.Results: Results of the analysis showed that patient 2 had a greater deletion size (4,8Mb) of chromosome 4 than patient 1 (3, 4 Mb). Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. If we analyze the uncommon deleted region between patient1 and patient 2 we found that the Muscle Segment Homeobox (MSX1) gene is included in this region. MSX1 is a critical transcriptional repressor factor, expressed in the ventral side of the developing anterior pituitary and implicated in gonadotrope differentiation. Msx acts as a negative regulatory pituitary development by repressing the gonadotropin releasing hormone (GnRH) genes during embryogenesis. We hypothesized that the deletion of MSX1 in our patient may deregulate the androgen synthesis. Conclusion: Based on the MSX1 gene function, its absence might be indirectly responsible for the hypospadias phenotype by contributing to the spatiotemporal regulation of GnRH transcription during development.

Targeting the Non-Coding Genome for the Diagnosis of Disorders of Sex Development

2021 ◽  
pp. 1-19
Author(s):  
Gabby Atlas ◽  
Rajini Sreenivasan ◽  
Andrew Sinclair
Keyword(s):  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Regulatory Elements ◽  
Gonadal Development ◽  
Comparative Genomic ◽  
Enhancer Activity ◽  
Sex Development ◽  
Genomic Regions

Disorders of sex development (DSD) are a complex group of conditions with highly variable clinical phenotypes, most often caused by failure of gonadal development. DSD are estimated to occur in around 1.7% of all live births. Whilst the understanding of genes involved in gonad development has increased exponentially, approximately 50% of patients with a DSD remain without a genetic diagnosis, possibly implicating non-coding genomic regions instead. Here, we review how variants in the non-coding genome of DSD patients can be identified using techniques such as array comparative genomic hybridization (CGH) to detect copy number variants (CNVs), and more recently, whole genome sequencing (WGS). Once a CNV in a patient’s non-coding genome is identified, putative regulatory elements such as enhancers need to be determined within these vast genomic regions. We will review the available online tools and databases that can be used to refine regions with potential enhancer activity based on chromosomal accessibility, histone modifications, transcription factor binding site analysis, chromatin conformation, and disease association. We will also review the current in vitro and in vivo techniques available to demonstrate the functionality of the identified enhancers. The review concludes with a clinical update on the enhancers linked to DSD.

scholarly journals Disorders of sex development: a genetic study of patients in a multidisciplinary clinic

2014 ◽  
Vol 3 (4) ◽  
pp. 180-192 ◽  
Author(s):  
Luigi Laino ◽  
Silvia Majore ◽  
Nicoletta Preziosi ◽  
Barbara Grammatico ◽  
Carmelilia De Bernardo ◽  
...  
Keyword(s):  
Sex Chromosome ◽  
Genetic Defect ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Molecular Study ◽  
Testicular Development ◽  
Androgen Synthesis ◽  
Sex Development ◽  
Dna Alterations ◽  
Definition Of

Sex development is a process under genetic control directing both the bi-potential gonads to become either a testis or an ovary, and the consequent differentiation of internal ducts and external genitalia. This complex series of events can be altered by a large number of genetic and non-genetic factors. Disorders of sex development (DSD) are all the medical conditions characterized by an atypical chromosomal, gonadal, or phenotypical sex. Incomplete knowledge of the genetic mechanisms involved in sex development results in a low probability of determining the molecular definition of the genetic defect in many of the patients. In this study, we describe the clinical, cytogenetic, and molecular study of 88 cases with DSD, including 29 patients with 46,XY and disorders in androgen synthesis or action, 18 with 46,XX and disorders in androgen excess, 17 with 46,XY and disorders of gonadal (testicular) development, 11 classified as 46,XX other, eight with 46,XX and disorders of gonadal (ovarian) development, and five with sex chromosome anomalies. In total, we found a genetic variant in 56 out of 88 of them, leading to the clinical classification of every patient, and we outline the different steps required for a coherent genetic testing approach. In conclusion, our results highlight the fact that each category of DSD is related to a large number of different DNA alterations, thus requiring multiple genetic studies to achieve a precise etiological diagnosis for each patient.

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