scholarly journals The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency

2009 ◽  
Vol 161 (2) ◽  
pp. 237-242 ◽  
Author(s):  
Birgit Köhler ◽  
Lin Lin ◽  
Inas Mazen ◽  
Cigdem Cetindag ◽  
Heike Biebermann ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Mutational Analysis ◽  
Disorders Of Sex Development ◽  
Inhibin B ◽  
Binding Motif ◽  
Undescended Testes ◽  
Gender Assignment ◽  
Steroidogenic Factor 1 ◽  
Sex Development ◽  
Penoscrotal Hypospadias

ObjectiveHypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias.Design and methodsMutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network.ResultsHeterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients.ConclusionsSF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common.

scholarly journals Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development

2014 ◽  
Vol 170 (5) ◽  
pp. 759-767 ◽  
Author(s):  
Sally Tantawy ◽  
Inas Mazen ◽  
Hala Soliman ◽  
Ghada Anwar ◽  
Abeer Atef ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Direct Sequencing ◽  
Disorders Of Sex Development ◽  
Missense Mutations ◽  
Coding Region ◽  
Steroidogenic Factor 1 ◽  
Sex Development ◽  
Gene Coding ◽  
Future Fertility

ObjectiveSteroidogenic factor 1 (SF1, NR5A1) is a key transcriptional regulator of genes involved in the hypothalamic–pituitary–gonadal axis. Recently, SF1 mutations were found to be a frequent cause of 46,XY disorders of sex development (DSD) in humans. We investigate the frequency of NR5A1 mutations in an Egyptian cohort of XY DSD.DesignClinical assessment, endocrine evaluation and genetic analysis of 50 Egyptian XY DSD patients (without adrenal insufficiency) with a wide phenotypic spectrum.MethodsMolecular analysis of NR5A1 gene by direct sequencing followed by in vitro functional analysis of the two novel missense mutations detected.ResultsThree novel heterozygous mutations of the coding region in patients with hypospadias were detected. p.Glu121AlafsX25 results in severely truncated protein, p.Arg62Cys lies in DNA-binding zinc finger, whereas p.Ala154Thr lies in the hinge region of SF1 protein. Transactivation assays using reporter constructs carrying promoters of anti-Müllerian hormone (AMH), CYP11A1 and TESCO core enhancer of Sox9 showed that p.Ala154Thr and p.Arg62Cys mutations result in aberrant biological activity of NR5A1. A total of 17 patients (34%) harboured the p.Gly146Ala polymorphism.ConclusionWe identified two novel NR5A1 mutations showing impaired function in 23 Egyptian XY DSD patients with hypospadias (8.5%). This is the first study searching for NR5A1 mutations in oriental patients from the Middle East and Arab region with XY DSD and no adrenal insufficiency, revealing a frequency similar to that in European patients (6.5–15%). We recommend screening of NR5A1 in patients with hypospadias and gonadal dysgenesis. Yearly follow-ups of gonadal function and early cryoconservation of sperms should be performed in XY DSD patients with NR5A1 mutations given the risk of future fertility problems due to early gonadal failure.

scholarly journals Heterozygous Missense Mutations in Steroidogenic Factor 1 (SF1/Ad4BP, NR5A1) Are Associated with 46,XY Disorders of Sex Development with Normal Adrenal Function

2007 ◽  
Vol 92 (3) ◽  
pp. 991-999 ◽  
Author(s):  
Lin Lin ◽  
Pascal Philibert ◽  
Bruno Ferraz-de-Souza ◽  
Daniel Kelberman ◽  
Tessa Homfray ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
De Novo ◽  
Mutational Analysis ◽  
Case Reports ◽  
Disorders Of Sex Development ◽  
Adrenal Function ◽  
Testicular Function ◽  
Missense Mutations ◽  
Steroidogenic Factor 1 ◽  
Sex Development

Abstract Context: Steroidogenic factor 1 (SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 (Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Müllerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46,XY individuals with female external genitalia, Müllerian structures (uterus), and primary adrenal failure. Objective: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46,XY gonadal dysgenesis/impaired androgenization (now termed 46,XY disorders of sex development) with normal adrenal function. Methods and Patients: The study included mutational analysis of NR5A1 in 30 individuals with 46,XY disorders of sex development, followed by functional studies of SF1 activity. Results: Heterozygous missense mutations in NR5A1 were found in four individuals (four of 30, 13%) with this phenotype. These mutations (V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding (V15M, M78I, G91S), altered subnuclear localization (V15M, M78I), or disruption of the putative ligand-binding pocket (L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change. Conclusions: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46,XY individuals.

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

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.

Comparison between two inhibin B ELISA assays in 46,XY testicular disorders of sex development (DSD) with normal testosterone secretion

2018 ◽  
Vol 31 (2) ◽  
pp. 191-194
Author(s):  
Guilherme Guaragna-Filho ◽  
Antônio Ramos Calixto ◽  
Georgette Beatriz De Paula ◽  
Laurione Cândido De Oliveira ◽  
André Moreno Morcillo ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
Inhibin B ◽  
Enzyme Linked Immunosorbent Assay ◽  
Specific Patient ◽  
Testosterone Secretion ◽  
Sex Development ◽  
Interclass Correlation ◽  
Bland Altman Method ◽  
Partial Androgen Insensitivity Syndrome

Abstract Background: Inhibin B is a hormone produced by the Sertoli cells that can provide important information for the investigation of disorders of sex development (DSD) with 46,XY karyotype. The aim of this study is to compare two enzyme-linked immunosorbent assay (ELISA) assays for dosage of serum inhibin B in patients with 46,XY DSD with normal testosterone secretion. Methods: Twenty-nine patients with 46,XY DSD and normal testosterone secretion (partial androgen insensitivity syndrome [PAIS] [n=8]; 5α-reductase deficiency [n=7] and idiopathic 46,XY DSD [n=14]) were included. Molecular analysis of the AR and SRD5A2 genes were performed in all patients and the NR5A1 gene analysis in the idiopathic group. Measurements of inhibin B were performed by two second-generation ELISA assays (Beckman-Coulter and AnshLabs). Assays were compared using the interclass correlation coefficient (ICC) and the Bland-Altman method. Results: ICC was 0.915 [95% confidence interval (CI): 0.828–0.959], however, a discrepancy was observed between trials, which is more evident among higher values when analyzed by the Bland-Altman method. Conclusions: It is recommended to perform the inhibin B measurement always using the same ELISA kit when several evaluations are required for a specific patient.

Disorders of sex development

2017 ◽  
Author(s):  
David F.M. Thomas
Keyword(s):  
Disorders Of Sex Development ◽  
Ambiguous Genitalia ◽  
Surgical Reconstruction ◽  
Adrenal Hyperplasia ◽  
Specialist Care ◽  
Gender Assignment ◽  
Developmental Abnormalities ◽  
Sex Development

The aetiology of disorders of sex development (DSD) is multifactorial and includes chromosomal defects, developmental abnormalities of the gonads, and defects of hormonal synthesis and expression. Infants born with ambiguous genitalia require urgent investigation because of the risk of hyponatraemia associated with congenital adrenal hyperplasia (CAH) and to permit an informed decision on gender assignment. CAH is the commonest form of DSD, accounting for around 80% of all infants born with ambiguous genitalia. Despite controversy regarding timing and consent, feminizing genitoplasty in early childhood remains the accepted management for girls with significant clitoromegaly. Surgical reconstruction for 46XY DSD is guided by several factors, notably the size of the phallus and gonadal phenotype. The majority of individuals with disorders of sex development will require ongoing specialist care and long-term multidisciplinary follow-up and support.

Gender Assignment, Reassignment and Outcome in Disorders of Sex Development: Update of the 2005 Consensus Conference

2016 ◽  
Vol 85 (2) ◽  
pp. 112-118 ◽  
Author(s):  
Heino F.L. Meyer-Bahlburg ◽  
Katharine Baratz Dalke ◽  
Sheri A. Berenbaum ◽  
Peggy T. Cohen-Kettenis ◽  
Melissa Hines ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
Consensus Conference ◽  
Gender Assignment ◽  
Sex Development

scholarly journals THE ROLE OF UROLOGISTS IN MANAGEMENT OF DISORDERS OF SEX DEVELOPMENT

2012 ◽  
Vol 19 (1) ◽  
Author(s):  
Ilham Wahyudi ◽  
Irfan Wahyudi ◽  
Kanadi Sumadipradja ◽  
Jose RL Batubara ◽  
Arry Rodjani
Keyword(s):  
Multidisciplinary Team ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
Therapeutic Management ◽  
Gender Assignment ◽  
Disorder Of Sex Development ◽  
Sex Development ◽  
Diagnostic Management ◽  
One Year

Objective: To evaluate disorder of sex development (DSD) profile at Cipto Mangunkusumo Hospital (RSCM), the management profile, and the role of urologist on diagnostic and therapeutic management. Material & method: We retrospectively collected data from medical record of all DSD cases managed by pediatric endocrinologist, urologist, obstetric gynaecologist at RSCM from January 2002 up to December 2009. 2006 IICP criteria was used as classification. The management profile and the role of urologist were evaluated. Results: there were 133 DSD cases with the majority of cases was congenital adrenal hyperplasia (CAH) followed by androgen insensitivity syndrome (AIS). Most of the cases were diagnosed before one year old and other on pubertal period. Karyotyping, laboratory examination, ultrasonography, genitography, uretrocystoscopy, kolposcopy, diagnostic laparascopy were performed as diagnostic management. Gender assignment was performed by multidisciplinary team. Masculinizing surgery, feminizing surgery, and gonadectomy was done as therapeutic management. Conclusion: The majority case on RSCM’s DSD profile was CAH. The management was performed by multidisciplinary team. Gender assignment decision should be based upon thorough diagnostic evaluation. The urologist has important role on diagnostic and therapeutic management. Keywords: Disorder of sex development, diagnostic management, gender assignment, therapeutic management, urologist.

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