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.

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 1 was a boy of one-year-old, presented a typical WHS phenotype while patient 2, is a boy of two days presented an hypospadias, a micropenis and a cryptorchidie in addition to the typical WHS phenotype. Both the array comparative genomic hybridization (array CGH) 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. Msx1 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.

scholarly journals Disorders of sex development in Wolf–Hirschhorn syndrome: a genotype–phenotype correlation and MSX1 as candidate gene

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Khouloud Rjiba ◽  
Hédia Ayech ◽  
Olfa Kraiem ◽  
Wafa Slimani ◽  
Afef Jelloul ◽  
...  
Keyword(s):  
Disorders Of Sex Development ◽  
Ventral Side ◽  
Comparative Genomic ◽  
Chromosome 4 ◽  
Phenotype Correlation ◽  
Pituitary Development ◽  
Androgen Synthesis ◽  
Sex Development ◽  
Genotype Phenotype Correlation ◽  
Spatiotemporal Regulation

AbstractBackgroundWolf–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 1 was a boy of 1-year-old, presented a typical WHS phenotype while patient 2, is a boy of 2 days presented an hypospadias, a micropenis and a cryptorchidie in addition to the typical WHS phenotype. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used.ResultsResults of the analysis showed that patient 2 had a greater deletion size (4.8 Mb) 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.MSX1is a critical transcriptional repressor factor, expressed in the ventral side of the developing anterior pituitary and implicated in gonadotrope differentiation.Msx1acts as a negative regulatory pituitary development by repressing the gonadotropin releasing hormone (GnRH) genes during embryogenesis. We hypothesized that the deletion ofMSX1in our patient may deregulate the androgen synthesis.ConclusionBased on theMSX1gene function, its absence might be indirectly responsible for the hypospadias phenotype by contributing to the spatiotemporal regulation ofGnRHtranscription during development.

Spectrum of Pathogenic Variants in SRD5A2 in Indian Children with 46,XY Disorders of Sex Development and Clinically Suspected Steroid 5α-Reductase 2 Deficiency

2019 ◽  
Vol 13 (5-6) ◽  
pp. 228-239
Author(s):  
Anil Kumar ◽  
Rajni Sharma ◽  
Mohammed Faruq ◽  
Varun Suroliya ◽  
Manoj Kumar ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Wide Spectrum ◽  
Disorders Of Sex Development ◽  
Pathogenic Variant ◽  
Compound Heterozygous ◽  
Phenotype Correlation ◽  
Indian Children ◽  
Sex Development ◽  
Pathogenic Variants ◽  
Genotype Phenotype Correlation

The aim of this study was to assess the prevalence of pathogenic variants in the <i>SRD5A2</i> gene in children with 46,XY disorders of sex development (DSD) with normal to high serum testosterone levels and absence of Müllerian structures on imaging and to evaluate the genotype-phenotype correlation. Seventy-five patients with 46,XY DSD and probable clinical diagnosis of 5α-reductase 2 deficiency or androgen insensitivity syndrome were enrolled. Genetic analysis was done for pathogenic variants in <i>SRD5A2</i>, and the genotype-phenotype correlation was studied. As a result, 10 pathogenic or likely pathogenic biallelic variants in <i>SRD5A2, </i>either homozygous or compound heterozygous, were identified in 25 of 75 (33.3%) patients. The hCG stimulated testosterone: dihydrotestosterone (T:DHT) ratio was elevated in all patients with pathogenic variants in <i>SRD5A2</i> and in nearly 90% of those without pathogenic variants in <i>SRD5A2</i> in whom this was assessed. The missense pathogenic variant p.R246Q was a hotspot. One novel pathogenic variant p.Y178*, and a variant p.F194I, not previously reported in patients with 5α-reductase 2 deficiency, were identified. The missense variant p.F194I was predicted as deleterious and damaging by in silico analysis and as likely to reduce the enzyme activity by protein modeling. In conclusion, pathogenic variants in <i>SRD5A2 </i>can be detected in a wide spectrum of Indian patients with 46,XY DSD. Molecular genetic analysis should be considered as a first-line test as the T:DHT ratio lacks specificity and a hotspot variant is present in a vast majority.

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.

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.

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.

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 Integrating clinical and genetic approaches in the diagnosis of 46,XY disorders of sex development

2018 ◽  
Vol 7 (12) ◽  
pp. 1480-1490 ◽  
Author(s):  
Zofia Kolesinska ◽  
James Acierno Jr ◽  
S Faisal Ahmed ◽  
Cheng Xu ◽  
Karina Kapczuk ◽  
...  
Keyword(s):  
Clinical Diagnosis ◽  
Clinical Assessment ◽  
Disorders Of Sex Development ◽  
Integrated Approach ◽  
Androgen Insensitivity Syndrome ◽  
Definitive Diagnosis ◽  
Comparative Genomic ◽  
Routine Practice ◽  
Variant Of Uncertain Significance ◽  
Sex Development

46,XY differences and/or disorders of sex development (DSD) are clinically and genetically heterogeneous conditions. Although complete androgen insensitivity syndrome has a strong genotype–phenotype correlation, the other types of 46,XY DSD are less well defined, and thus, the precise diagnosis is challenging. This study focused on comparing the relationship between clinical assessment and genetic findings in a cohort of well-phenotyped patients with 46,XY DSD. The study was an analysis of clinical investigations followed by genetic testing performed on 35 patients presenting to a single center. The clinical assessment included external masculinization score (EMS), endocrine profiling and radiological evaluation. Array-comparative genomic hybridization (array-CGH) and sequencing of DSD-related genes were performed. Using an integrated approach, reaching the definitive diagnosis was possible in 12 children. The correlation between clinical and genetic findings was higher in patients with a more severe phenotype (median EMS 2.5 vs 6; P = 0.04). However, in 13 children, at least one variant of uncertain significance was identified, and most times this variant did not correspond to the original clinical diagnosis. In three patients, the genetic studies guided further clinical assessment which resulted in a reclassification of initial clinical diagnosis. Furthermore, we identified eight patients harboring variants in more than one DSD genes, which was not seen in controls (2.5%; P = 0.0003). In summary, taking into account potential challenges in reaching the definitive diagnosis in 46,XY DSD, only integrated approach seems to be the best routine practice.

scholarly journals OR27-01 Combining Clinical and Genetic Approaches in Diagnosing a Large Brazilian Cohort of Patients with 46,XY Differences/Disorders of Sex Development (DSD)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nathalia Lisboa Rosa Almeida Gomes ◽  
Rafael Loch Batista ◽  
Mirian Yumie Nishi ◽  
Antonio Marcondes Lerario ◽  
Thatiana Evilen Silva ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Massively Parallel Sequencing ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
Unknown Etiology ◽  
Androgen Synthesis ◽  
Sex Development ◽  
Liquid Chromatography Tandem Mass ◽  
Phenotype Heterogeneity

Abstract Background: It is recommended a multidisciplinary approach consisted of clinical, hormonal and genetic workups for diagnosing 46,XY DSD. However, no previous study has quantified how useful is this combined approach. Objectives: To retrospectively review the clinical and genetic findings for diagnosing a large cohort of patients with 46,XY DSD from a single Brazilian center. Methods: 247 non-syndromic 46,XY DSD individuals (159 sporadic and 88 familial cases from 39 families) were studied. Clinical and hormonal data were collected from medical files. Testosterone (T), androstenedione (A) were measured by immunoradiometric or immunofluorimetric assays and dihydrotestosterone (DHT) by RIA after celite chromatography or by liquid chromatography tandem mass spectrometry; T/DHT and T/A ratios were calculated. Analysis of sensitivity (SE), specificity (SP) of T/DHT was performed, being the molecular diagnosis considered the gold standard for diagnosing SRD5A2 deficiency. A T/A&gt;0.8 was considered indicative of 17ß-HSDB3 deficiency. The patients were clinically classified into four subgroups: 1) androgen insensitivity syndrome (AIS), 2) gonadal dysgenesis (GD); 3) defects in androgen synthesis (DAS) and 4) DSD of unknown etiology. Molecular studies were performed by Sanger sequencing and/ or massively parallel sequencing (MPS). Results: The median age at first visit was 14 years (range 0.1 to 59 years). The molecular diagnosis was established in 96.5% of the cases with AIS (n=28/29), in 96% of the subjects with DAS (n=46/48), in 36% of the patients with GD (n=21/57) and in 26.7% (n=15/56) with DSD of unknown etiology. The best cut-off for T/DHT in basal state and hCG stimulated was 12.5 (SE=100%; SP=78.57%) and 24 (SE=87.5%; SP=95.7%) respectively. A T/A&lt;0.8 was observed in 13/16 (81%) of the patients with molecular diagnosis of 17ß-HSDB3 deficiency and also in 1/49 patients with other diagnose. Classification according to the phenotype matched with the genetic diagnosis in most cases. The molecular evaluation allowed that 16% (9/56) of the patients that were classified as DSD of unknow etiology had a definitive diagnosis, including six GD cases, two individuals with SRD5A2 deficiency and one with 17ß-HSDB3 deficiency. A clear AIS phenotype of five patients allowed us to consider and prove the pathogenicity of two synonymous and one promoter region variants as the cause of AIS. The combination of clinical and molecular diagnosis led to an increase in 8% the diagnosis in a total of 116 index-cases (58.5%) with a molecular diagnosis. Conclusion: Considering the phenotype heterogeneity, pitfalls of the hormonal assessment and number of genes involved, it is reasonable to consider MPS as a first test for diagnosing patients with 46,XY DSD. However, the combination of clinical and molecular diagnosis is more accurate than either strategies alone in diagnosing 46,XY DSD.

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