Chromosomal Disorders of Sex Development

2018 ◽  
Author(s):  
R. J McKinlay Gardner ◽  
David J Amor
Keyword(s):  
Sexual Development ◽  
De Novo ◽  
Chromosome Abnormality ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Sequential Process ◽  
Chromosomal Disorders ◽  
Sex Development ◽  
Development Proceeds

Chromosomal sex is, for the most part, congruently XX female and XY male. The XX and XY embryo are built on a fundamentally similar outline plan, and only as development proceeds do certain modifications evolve. If at any point in this sequential process some genetic instruction is faulty, inappropriate, or cannot be acted on, the direction of anatomical sexual development may proceed imperfectly or completely incongruently. This chapter reviews the conditions of ambiguous/incomplete/indeterminate development of the internal and external genitalia, where the basis of this is a chromosome abnormality, usually of the X or the Y chromosome. The key role of the SRY male-determining gene in a number of these conditions is noted. The de novo or familial origin of these disorders is discussed, with particular reference to possible risks of recurrence.

scholarly journals The evolving role of whole-exome sequencing in the management of disorders of sex development

2021 ◽  
Author(s):  
Yardena Tenenbaum Rakover ◽  
Osnat Admoni ◽  
Gadir Elias-Assad ◽  
Shira London ◽  
Marie Noufi Barhoum ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Sex Development ◽  
Pathogenic Variants ◽  
Extensive Evaluation ◽  
Whole Exome

Objective: Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal and anatomical sex is atypical. Despite wide laboratory and imaging investigations, the etiology of DSD is unknown in over 50% of patients. Methods: We evaluated the etiology of DSD by whole-exome sequencing (WES) at a mean age of 10 years in nine patients for whom extensive evaluation, including hormonal, imaging and candidate gene approaches, had not identified an etiology. Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient presented with labia majora fusion. In seven patients (78%), pathogenic variants were identified for RXFP2, HSD17B3, WT1, BMP4, POR, CHD7 and SIN3A. In two patients, no causative variants were found. Mutations in three genes were reported previously with different phenotypes: an 11-year-old boy with a novel de novo variant in BMP4; such variants are mainly associated with microphthalmia and in few cases with external genitalia anomalies in males, supporting the role of BMP4 in the development of male external genitalia; a 12-year-old boy with a known pathogenic variant in RXFP2, encoding insulin-like 3 hormone receptor, and previously reported in adult men with cryptorchidism; an 8-year-old boy with syndromic DSD had a de novo deletion in SIN3A. Conclusions: Our findings of molecular etiologies for DSD in 78% of our patients indicate a major role for WES in early DSD diagnosis and management, and highlights the importance of rapid molecular diagnosis in early infancy for sex of rearing decisions.

scholarly journals Disorders of Sex Development in Individuals Harbouring MAMLD1 Variants: WES and Interactome Evidence of Oligogenic Inheritance

2020 ◽  
Vol 11 ◽  
Author(s):  
Lele Li ◽  
Fenqi Gao ◽  
Lijun Fan ◽  
Chang Su ◽  
Xuejun Liang ◽  
...  
Keyword(s):  
Sexual Development ◽  
Disorders Of Sex Development ◽  
Specific Gene ◽  
Causative Role ◽  
Sex Development ◽  
Whole Exome ◽  
Clinical Series ◽  
Oligogenic Inheritance ◽  
Mode Of Inheritance

Mastermind-like domain-containing 1 (MAMLD1) has been shown to play an important role in the process of sexual development and is associated with 46,XY disorders of sex development (DSDs). However, the causative role of MAMLD1 variations in DSDs remains disputable. In this study, we have described a clinical series on children from unrelated families with 46,XY DSD harbouring MAMLD1 variants. Whole exome sequencing (WES) was performed for each patient. WES data were filtered using common tools and disease customisation algorithms, including comparison against lists of known and candidate MAMLD1-related and DSD-related genes. Lastly, we investigated the hypothesis that MAMLD1-related DSD may follow an oligogenic mode of inheritance. Forty-three potentially deleterious/candidate variants of 18 genes (RET, CDH23, MYO7A, NOTCH2, MAML1, MAML2, CYP1A1, WNT9B, GLI2, GLI3, MAML3, WNT9A, FRAS1, PIK3R3, FREM2, PTPN11, EVC, and FLNA) were identified, which may have contributed to the patient phenotypes. MYO7A was the most commonly identified gene. Specific gene combinations were also identified. In the interactome analysis, MAMLD1 exhibited direct connection with MAML1/2/3 and NOTCH1/2. Through NOTCH1/2, the following eight genes were shown to be associated with MAMLD1:WNT9A/9B, GLI2/3, RET, FLNA, PTPN11, and EYA1. Our findings provide further evidence that individuals with MAMLD1-related 46,XY DSD could carry two or more variants of known DSD-related genes, and the phenotypic outcome of affected individuals might be determined by multiple genes.

scholarly journals Genetic Analysis for the Diagnosis of Disorders of Sexual Development in Indonesia

2016 ◽  
Vol 2 (2) ◽  
pp. 44
Author(s):  
Sultana MH Faradz
Keyword(s):  
Sexual Development ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Gonadal Development ◽  
Androgen Insensitivity Syndrome ◽  
Medical Professionals ◽  
Adrenal Hyperplasia ◽  
Disorders Of Sexual Development ◽  
Sex Development

Disorders of sex development (DSD) is defined by congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical, while in clinical practice this term means any abnormality of the external genitalia. DSD patients have been managed by a multidisciplinary gender team in our center as collaboration between Dr. Kariadi province referral hospital and Faculty of Medicine Diponegoro University. Diagnosis should be established by specific physical examination hormonal, chromosomal and DNA studies; and imaging for most of the cases depending on indication.Since 2004 the involvement of molecular and cytogenetic analysis so far can diagnosed many of the DSD cases. Most of the genetically proven cases were Congenital Adrenal hyperplasia, Androgen Insensitivity syndrome and sex chromosomal DSD that lead abnormal gonadal development.  Many of them remain undiagnosed, further testing such as advanced DNA study should be carried out in collaboration with other center in overseas.The novel genes were found in some cases that contributed for the management of DSD.  Information for medical professionals, patients, family members and community about the availability and necessity of DSD diagnosis should be delivered to improve DSD management and patient quality of life.

scholarly journals The Evaluation of Parental Acceptance Towards Children with Sex Chromosomal Disorders of Sex Development Using A Mixed-Method

2021 ◽  
Vol 7 (1) ◽  
pp. 14-21
Author(s):  
Iit Fitrianingrum ◽  
Annastasia Ediati ◽  
Tri Indah Winarni ◽  
Sultana MH Faradz
Keyword(s):  
Mixed Method ◽  
Quantitative Data ◽  
Sex Chromosome ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Parental Acceptance ◽  
Chromosomal Disorders ◽  
Social And Emotional ◽  
Self Blame ◽  
Sex Development

Background: Sex chromosomal Disorder of sex development (DSD) is an atypical abnormality of external genitalia which is mismatched with its sex chromosome traits. The condition of children with DSD affects the dynamics in the family. Parents’ reactions after discovering this health problem vary greatly, such as being in a state of shock, confusion, or self-blame. However, parents’ acceptance is extremely important for better quality of caring, to the healthy social and emotional child development, and to make the best decisions regarding gender assignment.Objective: To describe the acceptance process of parents that have children with sex chromosomes mosaicism DSD.Methods: This study used a mixed-method with a sequential explanatory approach, which was preceded by quantitative data collection followed by qualitative. The total respondents consisted of 14 mothers and 12 fathers of 14 sex chromosome mosaicism DSD patients with XX/XY, X/XY, XYY or XXY variants. Quantitative data were collected using the Indonesian version of the Parental Acceptance-Rejection Questionnaire (PARQ), and interviews were conducted to determine the acceptance process.Results: Most acceptance cases were based on the surgical stage completion in which a higher number of mothers (71.43%) than fathers (50%).Conclusion: It is uneasy for parents to accept children with sex chromosome mosaicisms DSD, hence the fathers struggle more than mothers in accepting those affected. To the best of our knowledge this is the first study in Indonesia to help parent understand and accept their child condition.

scholarly journals OR15-07 Novel Genes Involved in Sex Differentiation Identified by Whole-Exome Sequencing in a Cohort of Children with Disorders of Sex Development

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Yardena Tenenbaum Rakover ◽  
Osnat Admoni ◽  
Ghadir Elias Assad ◽  
Shira London ◽  
Marie Noufi Barhoum ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
De Novo Mutation ◽  
Novel Genes ◽  
Sex Development ◽  
First Case ◽  
Whole Exome

Abstract Background: Disorders of sex development (DSD) are classified as a congenital discrepancy between external genitalia, gonadal and chromosomal sex. Despite extensive laboratory and imaging investigations, the etiology of DSD is unknown in more than 50% of patients and the diagnosis is often delayed to the second decade of life. Our objective was to evaluate the etiology of DSD by whole-exome sequencing (WES) in children in whom hormonal and candidate gene approaches had not identified the etiology. Methods: Nine patients diagnosed with DSD (eight 46,XY and one 46,XX) were enrolled. Patients underwent hormonal evaluation, including ACTH, GnRH and hCG tests. Candidate genes were sequenced in accordance with the hormonal results. WES was performed for the probands and their parents. Results: The eight 46,XY patients presented with micropenis, cryptorchidism and hypospadias at birth and the 46,XX patient with fusion of the labia majora. In six of the nine patients (66%), a pathogenic mutation was identified by WES that explained the phenotype: four known DSD-causing genes—POR, CHD7, HSD17B3 and WT1—and two novel genes—BMP4 and RFXP2. In three patients, variants of unknown significance were found. An 11-y-old boy had a novel de-novo mutation in BMP4. In humans, mutations in this gene, encoding bone morphogenetic protein 4, are associated with autosomal dominant microphthalmia. BMP4 is expressed in the urethral epithelium and has a role in the development of external genitalia and the pituitary. This is the first report of a BMP4 mutation in a child with DSD. A 12-y-old boy had a mutation in RFXP2, encoding insulin-like 3 hormone receptor, which has been previously reported in adult males with cryptorchidism. This is the first case of an RFXP2 mutation in a child with DSD. Conclusions: WES has a crucial role in early diagnosis of the etiology of DSD, making extensive endocrine testing unnecessary, and has important implications for sex of rearing decisions.

Psychological Adjustment and Sexual Development of Adolescents With Disorders of Sex Development

2010 ◽  
Vol 47 (5) ◽  
pp. 463-471 ◽  
Author(s):  
Eva Kleinemeier ◽  
Martina Jürgensen ◽  
Anke Lux ◽  
Pia-Marie Widenka ◽  
Ute Thyen
Keyword(s):  
Psychological Adjustment ◽  
Sexual Development ◽  
Disorders Of Sex Development ◽  
Sex Development

The role of anti-Mullerian and inhibin B hormones in the evaluation of 46,XY disorders of sex development

2014 ◽  
Vol 27 (9-10) ◽  
Author(s):  
Mona Hafez ◽  
Soha M. Abd El Dayem ◽  
Fatma El Mougy ◽  
Abeer Atef ◽  
Manal Kandil ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
Inhibin B ◽  
Sex Development

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.

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 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.

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