scholarly journals Alternative (backdoor) androgen production and masculinization in the human fetus

2018 ◽  
Author(s):  
Peter J O’Shaughnessy ◽  
Jean Philippe Antignac ◽  
Bruno Le Bizec ◽  
Marie-Line Morvan ◽  
Konstantin Svechnikov ◽  
...  
Keyword(s):  
Human Fetus ◽  
High Resolution Mass Spectrometry ◽  
Fetal Liver ◽  
Critical Role ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Androgen Synthesis ◽  
Sex Development ◽  
First Time ◽  
Genital Tubercle

AbstractMasculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway. The fetal testes are essential for canonical androgen production but little is known about the synthesis of backdoor androgens despite their known critical role in masculinization. In this study, we have measured plasma and tissue levels of endogenous steroids in second trimester human male fetuses using multi-dimensional and high-resolution mass-spectrometry. Results show that androsterone is the principal backdoor androgen in the fetal circulation and that DHT is undetectable (<1ng/ml). Backdoor pathway intermediates are found primarily in the placenta and fetal liver with significant androsterone levels also in the fetal adrenal. Backdoor intermediates, including androsterone, are mostly undetectable in the fetal testes. This is consistent with transcript levels of enzymes involved in the backdoor pathway (SRD5A1, AKR1C2/4, CYP17A1), as measured by qPCR. These data identify androsterone as the predominant backdoor androgen in the human fetus and show that it is formed primarily in non-gonadal tissue with placental progesterone the likely substrate. Masculinization of the human fetus depends, therefore, on androgen synthesis by both the fetal testes and non-gonadal tissues leading to DHT formation at the genital tubercle. Our findings provide, for the first time, a solid basis to explain why placental insufficiency is associated with disorders of sex development in humans

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.

scholarly journals The first clinical presentation of disorders of sex development 46 XY due to mutation in Steroidogenic factor 1 (SF1) in Russian Literature

2016 ◽  
Vol 62 (1) ◽  
pp. 55-59
Author(s):  
Natalia Yur'evna Kalinchenko ◽  
Tatiana Aleksandrovna Anosova ◽  
Vitaliy Alekseevich Ioutsi ◽  
Anatoly Nikolaevich Tiulpakov
Keyword(s):  
Molecular Genetic ◽  
Critical Role ◽  
Disorders Of Sex Development ◽  
Russian Literature ◽  
Molecular Genetic Analysis ◽  
Heterozygous Mutation ◽  
Steroidogenic Factor 1 ◽  
Sex Development ◽  
And Function ◽  
First Time

Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a critical role in different processes of sex development. Homozygous mutations in SF1 result in adrenal failure and complete testicular disgenesis in 46,XY individuals. According to recent studies heterozygous mutations in SF1 are associated with milder phenotype: they are found in children with 46,XY disorders of sex development (DSD) but with apparently normal adrenal structure and function. Here we present for the first time in Russian literature a case of SF1 deficiency. Molecular genetic analysis of NR5A1 gene revealed a novel heterozygous mutation c.951delC p.H317QfsX17. This clinical case demonstrates the importance of molecular genetic studies in DSD 46,XY, especially severe forms.

scholarly journals Characterising SRD5A2 Gene Variants in 37 Indonesian Patients with 5-Alpha-Reductase Type 2 Deficiency

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Nanis S. Marzuki ◽  
Firman P. Idris ◽  
Hannie D. Kartapradja ◽  
Alida R. Harahap ◽  
Jose R. L. Batubara
Keyword(s):  
Autosomal Recessive ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Compound Heterozygous ◽  
Phenotypic Characteristics ◽  
Sex Development ◽  
Srd5a2 Gene ◽  
Diagnostic Approaches ◽  
Autosomal Recessive Condition

The 5-alpha-reductase type 2 deficiency (5ARD2) is an autosomal recessive condition associated with impairment in the conversion of testosterone to dihydrotestosterone. This condition leads to undervirilisation in 46,XY individuals. To date, there have been more than 100 variations identified in the gene responsible for 5ARD2 development (steroid 5-alpha-reductase 2, SRD5A2). However, few studies have examined the molecular characterisation of Indonesian 5ARD2 cases. In the current study, we analysed 37 subjects diagnosed with 46,XY DSD (disorders of sex development) with confirmed variations in the SRD5A2 gene. We examined results from testosterone/dihydrotestosterone (T/DHT) and urinary etiocholanolone/androsterone (Et/An) ratios, as well as from molecular and clinical analyses. Twelve variants in the SRD5A2 gene were identified, and 6 of which were novel, namely, c.34–38delGinsCCAGC, p.Arg50His, p.Tyr136∗, p.Gly191Arg, p.Phe194Ile, and p.Ile253Val variants. Moreover, we determined that 20 individuals contained harmful mutations, while the remaining 17 variants were benign. Those containing harmful mutations exhibited more severe phenotypes with median external genitalia masculinisation scores (EMS) of 3 (1.5–9) and were more likely to be diagnosed at a later age, reared as female, and virilised at pubertal age. In addition, the respective sensitivities for detecting severe 5ARD2 cases using T/DHT (cutoff: 10) and urinary Et/An ratios (cutoff: 0.95) were 85% and 90%, whereas mild cases were only identified with 64.7% and 47.1% sensitivity, respectively. Although we were unable to identify clear correlations between genotypic and phenotypic characteristics in this study, we clearly showed that individuals who were homozygous or compound heterozygous for any of the harmful mutations were more likely to exhibit classic 5ARD2 phenotypes, lower EMS, female assignment at birth, and virilisation during puberty. These results serve to inform the development of improved clinical and molecular 5ARD2 diagnostic approaches, specifically in Indonesian patients.

scholarly journals Comprehensive Transcriptome Analysis of Hypothalamus Reveals Genes Associated With Disorders of Sex Development in Pigs

2020 ◽  
Author(s):  
Shuwen Tan ◽  
Yi Zhou ◽  
Haiquan Zhao ◽  
Jinhua Wu ◽  
Hui Yu ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Rna Isolation ◽  
Functional Enrichment ◽  
Regulation Mechanism ◽  
Normal Female ◽  
Sex Development ◽  
Mirna Expression Profiles ◽  
Hormone Biosynthesis

Abstract Background Disorders of sex development (DSD) is a chronic autoimmune disease characterized by systemic inflammation, pathological osteogenesis, and endocrine abnormality. However, its genetic etiology remains mostly unknown. In addition, little research focuses on the regulation mechanism from the view of transcriptomics in the hypothalamic-pituitary-gonadal axis (HPGA). The hypothalamus is the integrated center of the HPGA mediating neural, hormonal, and environmental stimulus to sex development. Methods Three XX-DSD (SRY-negative) pig (DSD) and three NF pigs (five months old, 40 kg ± 5 kg) were selected by external genitalia observation and sex determining region Y gene (SRY) detection. The hypothalamus were sampled for RNA isolation, and the mRNA, lncRNA and miRNA expression profiles were analyzed by sequencing. Results A total of 1,258 lncRNAs, 1,086 mRNAs, and 61 microRNAs were found to differentially express in XX-DSD pigs compared with normal female pigs. Many genes in hormone biosynthesis and secretion pathway are significantly up-regulated, and the up-regulation of GNRH1, KISS1 and AVP may be the candidate genes leading the abnormal secretion of GnRH. Next, we predicted the lncRNA-miRNA-mRNA co-expression triplets and constructed three competing endogenous RNA (ceRNA) potentially associated with DSD. Functional enrichment suggested TCONS_00340886, TCONS_00000204 and miR-181a were related to GnRH secretion. Conclusions Our research revealed the first transcriptomic profile in the hypothalamus of XX-DSD pigs and provided new insight in coding and non-coding RNAs that may be associated with DSD in pigs.

scholarly journals MAMLD1 and Differences/Disorders of Sex Development: An Update

2021 ◽  
pp. 1-12
Author(s):  
Mami Miyado ◽  
Maki Fukami ◽  
Tsutomu Ogata
Keyword(s):  
Leydig Cell ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Gene Interactions ◽  
Testicular Function ◽  
Ovarian Dysfunction ◽  
Causative Gene ◽  
Fetal Testis ◽  
Sex Development ◽  
Age Dependent

<i>MAMLD1</i> (alias <i>CXorf6</i>) was first documented in 2006 as a causative gene of 46,XY differences/disorders of sex development (DSD). <i>MAMLD1</i>/<i>Mamld1</i> is expressed in the fetal testis and is predicted to enhance the expression of several Leydig cell-specific genes. To date, hemizygous <i>MAMLD1</i> variants have been identified in multiple 46,XY individuals with hypomasculinized external genitalia. Pathogenic <i>MAMLD1</i> variants are likely to cause genital abnormalities at birth and are possibly associated with age-dependent deterioration of testicular function. In addition, some <i>MAMLD1</i> variants have been identified in 46,XX individuals with ovarian dysfunction. However, recent studies have raised the possibility that <i>MAMLD1</i> variants cause 46,XY DSD and ovarian dysfunction as oligogenic disorders. Unsolved issues regarding MAMLD1 include the association between <i>MAMLD1</i> variants and 46,XX testicular DSD, gene-gene interactions in the development of <i>MAMLD1</i>-mediated DSD, and intracellular functions of MAMLD1.

scholarly journals AMH and AMHR2 Involvement in Congenital Disorders of Sex Development

2021 ◽  
pp. 1-9
Author(s):  
Franco G. Brunello ◽  
Rodolfo A. Rey
Keyword(s):  
Molecular Genetic ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Fetal Life ◽  
Fallopian Tubes ◽  
Female Fetus ◽  
Sequencing Technologies ◽  
Sex Development ◽  
Mullerian Ducts ◽  
Gene Maps

Anti-müllerian hormone (AMH) is 1 of the 2 testicular hormones involved in male development of the genitalia during fetal life. When the testes differentiate, AMH is secreted by Sertoli cells and binds to its specific receptor type II (AMHR2) on the müllerian ducts, inducing their regression. In the female fetus, the lack of AMH allows the müllerian ducts to form the fallopian tubes, the uterus, and the upper part of the vagina. The human <i>AMH</i> gene maps to 19p13.3 and consists of 5 exons and 4 introns spanning 2,764 bp. The <i>AMHR2</i> gene maps to 12q13.13, consists of 11 exons, and is 7,817 bp long. Defects in the AMH pathway are the underlying etiology of a subgroup of disorders of sex development (DSD) in 46,XY patients. The condition is known as the persistent müllerian duct syndrome (PMDS), characterized by the existence of a uterus and fallopian tubes in a boy with normally virilized external genitalia. Approximately 200 cases of patients with PMDS have been reported to date with clinical, biochemical, and molecular genetic characterization. An updated review is provided in this paper. With highly sensitive techniques, AMH and AMHR2 expression has also been detected in other tissues, and massive sequencing technologies have unveiled variants in <i>AMH</i> and <i>AMHR2</i> genes in hitherto unsuspected conditions.

scholarly journals 46 XY DISORDER

2016 ◽  
Vol 23 (10) ◽  
pp. 1202-1208
Author(s):  
Muhammad Naveed Najeeb ◽  
Sadiq Hussain Malik ◽  
Sheikh Khurram Salam Sehgal ◽  
Ameer Ahmad Malik ◽  
Saqib Mehmood
Keyword(s):  
Physical Examination ◽  
Study Design ◽  
Gonadal Dysgenesis ◽  
Disorders Of Sex Development ◽  
Serum Testosterone ◽  
Androgen Insensitivity Syndrome ◽  
Base Line ◽  
Reductase Deficiency ◽  
Androgen Synthesis ◽  
Sex Development

Objectives: The Disorders of Sex Development are classified as 46, XY DSD,46, XX DSD and Chromosomal DSD according to the chromosomal constitution of the affectedpersons. 46, XY DSD is further classified into Androgen Synthetic Defect, Androgen InsensitivitySyndrome Gonadal Dysgenesis, 5-Alpha Reductase Deficiency, Persistent Mullerian DuctSyndrome and Isolated Hypospadias according to the pathophysiology of the disease. Theaim of present study was to classify 46, XY patients into their subclasses on the basis of theirhormonal profile and physical examination. Study Design: Observational descriptive study.Setting: Biochemistry Department University of Health Sciences for Karyotyping and Geneticassessment, and its allied institution Biochemistry Department Quaid-e-Azam Medical CollegeBahawalpur for hormonal analysis, along with Pediatric Medicine Departments of Quaid-e-AzamMedical College / Bahawal Victoria Hospital Bahawalpur for collection of Sample and clinicalassessments. Period: June 2015 to December 2015. Study Design: Observational descriptivestudy. Material and Methods: 53 patients with 46, XY DSD were recruited. Complete clinicalhistory and data of each patient was recorded in the research proforma. Genitals examinedfor the phallus length and size, position of urinary meatus, palpation of gonads and shape ofthe labioscrotal folds. Ultrasonography examination of each patient was performed to look forundescended testes and for the presence of either male or female internal reproductive organs.Results: Base line levels of serum Testosterone Dihydrotestosterone Luteinizing hormone,Follicle stimulating hormone, 17-OH-Progesteron and Anti-mullerian hormones were measuredby ELISA technique. Testosterone and DHT were measured again after hCG stimulation. Onthe basis of physical examination, ultrasonographic findings and hormonal profile diagnosisof the types of 46, XY DSD was possible in 27 (51%) of patients. Androgen synthesis defect asa cause of 46, XY DSD was diagnosed in 7(13%) patients, Androgen insensitivity syndrome in6(11%) patients, 5-Alpha reductase deficiency in 3(6%) patients, Gonadal Dysgenesis in 3 (6%),Persistent Mullerian Duct Syndrome in 3(6%) and Isolated Hypospadias in 2 (4%) patients.There were 26 (49%) patients which remain undiagnosed with the algorithm of diagnosis usedin the present study.

scholarly journals Disorders of Sex Development of Adrenal Origin

2021 ◽  
Vol 12 ◽  
Author(s):  
Gabriela P. Finkielstain ◽  
Ana Vieites ◽  
Ignacio Bergadá ◽  
Rodolfo A. Rey
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Special Focus ◽  
Adrenal Hyperplasia ◽  
Hydroxylase Deficiency ◽  
Trophic Effect ◽  
Salt Wasting ◽  
Sex Development ◽  
21 Hydroxylase Deficiency

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

Molecular Characteristics of Sequence Variants in GATA4 in Patients with 46,XY Disorders of Sex Development without Cardiac Defects

2019 ◽  
Vol 13 (5-6) ◽  
pp. 240-245
Author(s):  
Jin-Ho Choi ◽  
Yena Lee ◽  
Arum Oh ◽  
Gu-Hwan Kim ◽  
Han-Wook Yoo
Keyword(s):  
Heart Defects ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Pathogenic Mutation ◽  
Luciferase Reporter ◽  
Molecular Characteristics ◽  
Sequence Variants ◽  
Sex Development ◽  
Stimulation Tests

A <i>GATA4</i> haploinsufficiency has been well described in patients with congenital heart defects (CHDs), whilst only a few studies have reported mutations related to a 46,XY disorder of sex development (DSD) phenotype. This study investigated the clinical phenotypes and molecular characteristics of two 46,XY DSD patients harboring <i>GATA4</i> variants. Mutation analysis was performed using a targeted gene panel or whole-exome sequencing. The transactivation activity of each variant protein was examined by in vitro luciferase reporter assay using the <i>AMH</i> and <i>SRY</i> promoters. Subject 1 presented with a micropenis and hypospadias. Subject 2 showed complete female external genitalia with a 46,XY karyotype. Both patients were responsive to hCG stimulation tests and did not manifest CHD. A novel heterozygous variant, c.643A>G (p.R215G), in <i>GATA4</i> was identified in Subject 1, whereas Subject 2 harbored a previously reported variant, c.1220C>A (p.P407Q), in <i>GATA4</i> and a previously known pathogenic mutation, i.e., c.226C>T (p.Q76*) in the <i>AR</i> gene. The reporter assays using the <i>SRY</i> and <i>AMH</i> promoters revealed decreased transcriptional activity of both p.P407Q and p.R215G. However, the <i>GATA4</i> p.P407Q variant was classified as likely benign. In conclusion, it is essential to integrate clinical features and endocrine findings when interpreting sequence variants.

scholarly journals Disorders of Sex Development: Can You Be Sure This Baby Is A Boy or Girl? We Must See Beyond The Diagnosis

2019 ◽  
Vol 10 (2) ◽  
pp. 103-110
Author(s):  
Mohammed Shadrul Alam ◽  
Mirza Kamrul Zahid ◽  
Paritosh Kumar Palit ◽  
Abhi Kumar Chakraborty ◽  
Nirupama Saha ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Sex Development ◽  
Newborn Children

Throughout the pregnancy, the parents have anticipated whether their child will be a boy or a girl. No part of a newborn baby’s anatomy arouses as much interest initially as the external genitalia. Most newborn children have the typical features of a boy or girl, but in some cases the baby’s sex can’t be clearly identified. Infants born with ambiguous or abnormal genitalia may have indeterminate phenotypic sex.1 Disorders of sex development (DSDs), formerly termed intersex conditions, are congenital conditions in which development of the chromosomal, gonadal, or anatomic sex is atypical and may affect up to 1:1000 individuals in the population.2 J Shaheed Suhrawardy Med Coll, December 2018, Vol.10(2); 103-110

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