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.

Disorders of sex development in children in KwaZulu-Natal Durban South Africa: 20-year experience in a tertiary centre

2017 ◽  
Vol 30 (1) ◽  
Author(s):  
Yasmeen Ganie ◽  
Colleen Aldous ◽  
Yusentha Balakrishna ◽  
Rinus Wiersma
Keyword(s):  
Sex Chromosome ◽  
Disorders Of Sex Development ◽  
Sub Saharan Africa ◽  
Tertiary Referral Centre ◽  
Endocrine Society ◽  
Androgen Synthesis ◽  
Tertiary Centre ◽  
Sex Development ◽  
Aetiological Diagnosis ◽  
African Patients

AbstractBackground:The objective of the study was to describe the prevalence, clinical characteristics and aetiological diagnosis in children with disorders of sex development (DSDs) presenting to a tertiary referral centre.Methods:This is a retrospective review of all cases of DSD referred to the Paediatric Endocrine Unit in Inkosi Albert Luthuli Central Hospital (IALCH) from January 1995 to December 2014.Results:A total of 416 children (15.1%; CI: 13.8%–16.5%) were diagnosed with DSD. The aetiological diagnosis based on the current classification [Lawson Wilkins Paediatric Endocrine Society (LWPES) and European Society for Paediatric Endocrinology (ESPE)] was sex chromosome DSD in 9.5% (n=33), 46 XX DSD in 33% (n=114) and 46 XY DSD in 57.5% (n=199). The most common diagnoses in descending order were a disorder in androgen synthesis and action (not classified) in 53% (n=182), ovotesticular DSD in 22% (n=75) and congenital adrenal hyperplasia (CAH) in 10% (n=36). Overall the median age of presentation was 10 months (IQR: 1 month–4.5 years). There was a significant relationship (p<0.001) between the age of presentation and aetiological diagnosis. The majority (97%) of African patients had a diagnosis of 46 XX DSD. Prematurity was present in 47% (n=83) of children with 46 XY DSD (p<0.001).Conclusions:DSD is not an uncommon diagnosis in African patients in sub-Saharan Africa. The most common aetiological diagnosis is 46 XY DSD in androgen synthesis and action, followed by ovotesticular DSD. CAH is only the third most common disorder.

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 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 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 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.

Observational study of disorders of sex development in Yaounde, Cameroon

2020 ◽  
Vol 33 (3) ◽  
pp. 417-423
Author(s):  
Suzanne Ngo Um Sap ◽  
Ritha Mbono Betoko ◽  
Martine Etoa Etoga ◽  
Pierre Yves Mure ◽  
Yves Morel ◽  
...  
Keyword(s):  
Sex Chromosome ◽  
Disorders Of Sex Development ◽  
Central Africa ◽  
Main Diagnosis ◽  
Pediatric Endocrinology ◽  
Endocrine Society ◽  
Sex Development ◽  
Mother And Child ◽  
Study Population ◽  
Sub Saharan

AbstractIntroductionAccording to the current classification of the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Pediatric Endocrinology (ESPE) of Disorders of Sex Development (DSD), etiologies vary around the world. Ethnic or genetic diversity probably explains this variability. We therefore conducted the present study on etiologies of DSDs in a country from central Africa.MethodsWe carried out an observational retrospective study at the Pediatric Endocrinology Unit of the Mother and Child Centre of the Chantal Biya Foundation in Yaounde, Cameroon from May 2013 to December 2019. All patients diagnosed with a DSD were included, and incomplete files excluded.ResultsWe included 80 patients diagnosed with DSD during the study period. The 46,XX DSD were the most frequent in our study population (n = 41, 51.25%), with congenital adrenal hyperplasia (CAH) as the main diagnosis. The 46,XY DSD accounted for 33.75% and sex chromosome DSD group represented 15% of the study population.ConclusionsDSDs are not an exceptional diagnosis in a Sub-Saharan context. 46,XX DSD are the most prevalent diagnosis in our setting. The diagnosis of all these affections is late compared to other centers, justifying advocacy for neonatal screening of DSDs in our context.

scholarly journals Etiology and Clinical Presentation of Disorders of Sex Development in Kenyan Children and Adolescents

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Prisca Amolo ◽  
Paul Laigong ◽  
Anjumanara Omar ◽  
Stenvert Drop
Keyword(s):  
Children And Adolescents ◽  
Sex Chromosome ◽  
Clinical Laboratory ◽  
Molecular Genetic ◽  
Management Strategies ◽  
Disorders Of Sex Development ◽  
Ambiguous Genitalia ◽  
Molecular Genetic Analysis ◽  
High Rate ◽  
Sex Development

Objective. The purpose of this study was to describe baseline data on etiological, clinical, laboratory, and management strategies in Kenyan children and adolescents with Disorders of Sex Development (DSD). Methods. This retrospective study included patients diagnosed with DSD who presented at ages 0–19 years from January 2008 to December 2015 at the Kenyatta National (KNH) and Gertrude’s Children’s (GCH) Hospitals. After conducting a search in the data registry, a structured data collection sheet was used for collection of demographic and clinical data. Data analysis involved description of the frequency of occurrence of various variables, such as etiologic diagnoses and patient characteristics. Results. Data from the records of 71 children and adolescents were reviewed at KNH (n = 57, 80.3%) and GCH (n = 14, 19.7%). The mean age at the time of diagnosis was 2.7 years with a median of 3 months. Thirty-nine (54.9%) children had karyotype testing done. The median age (IQR) of children with reported karyotypes and those without was 3.3 years (1.3–8.9) and 8.3 years (3.6–12.1), respectively (p=0.021). Based on karyotype analysis, 19 (48.7%) of karyotyped children had 46,XY DSD and 18 (46.2%) had 46,XX DSD. There were two (5.1%) children with sex chromosome DSD. Among the 71 patients, the most common presumed causes of DSD were ovotesticular DSD (14.1%) and CAH (11.3%). Majority (95.7%) of the patients presented with symptoms of DSD at birth. The most common presenting symptom was ambiguous genitalia, which was present in 66 (93.0%) patients either in isolation or in association with other symptoms. An ambiguous genitalia was initially observed by the patient’s mother in 51.6% of 62 cases despite the high rate (84.7%) of delivery in hospital. Seventeen (23.9%) of the cases had a gender reassignment at final diagnosis. A psychologist/psychiatrist or counselor was involved in the management of 23.9% of the patients. Conclusion. The commonest presumed cause of DSD was ovotesticular DSD in contrast to western studies, which found CAH to be more common. Investigation of DSD cases is expensive and needs to be supported. We would have liked to do molecular genetic analysis outside the country but financial challenges made it impossible. A network for detailed diagnostics in resource-limited countries would be highly desirable. There is a need to train health care workers and medical students for early diagnosis. Psychological evaluation should be carried out for all patients at diagnosis and support given for families.

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.

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