This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and f...This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and further analysis identified seven novel mutants.The preponderance of variants was observed in exon 1 and exon 4,specifically within the nicotinamide adenine dinucleotide phosphate(NADPH)-binding region.Among the entire cohort,53 patients underwent initial surgery at Sichuan Provincial People’s Hospital(Chengdu,China).The external genitalia scores(EGS)of these participants varied from 2.0 to 11.0,with a mean of 6.8(standard deviation[s.d.]:2.5).Thirty patients consented to hormone testing.Their average testosterone-todihydrotestosterone(T/DHT)ratio was 49.3(s.d.:23.4).Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome;and their T/DHT ratios were below the diagnostic threshold.Furthermore,assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants.These mechanisms include interference with NADPH binding(c.356G>C,c.365A>G,c.492C>G,and c.662T>G)and destabilization of the protein structure(c.727C>T).The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts.Seven novel variations were identified,and the variant database for the SRD5A2 gene was expanded.These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.展开更多
46,XY disorders of sex development(DSD)is characterized by incomplete masculinization genitalia,with gonadal dysplasia and with/without the presence of Mullerian structures.At least 30 genes related to 46,XY DSD have ...46,XY disorders of sex development(DSD)is characterized by incomplete masculinization genitalia,with gonadal dysplasia and with/without the presence of Mullerian structures.At least 30 genes related to 46,XY DSD have been found.However,the clinical phenotypes of patients with different gene mutations overlap,and accurate diagnosis relies on gene sequencing technology.Therefore,this study aims to determine the prevalence of pathogenic mutations in a Chinese cohort with 46,XY DSD by the targeted nextgeneration sequencing(NGS)technology.Eighty-seven 46,XY DSD patients were enrolled from the Peking Union Medical College Hospital(Beijing,China).A total of fifty-four rare variants were identified in 60 patients with 46,XY DSD.The incidence of these rare variants was approximately 69.0%(60/87).Twenty-five novel variants and 29 reported variants were identified.Based on the American College of Medical Genetics and Genomics(ACMG)guidelines,thirty-three variants were classified as pathogenic or likely pathogenic variants and 21 variants were assessed as variants of uncertain significance.The overall diagnostic rate was about 42.5%based on the pathogenic and likely pathogenic variants.Androgen receptor{AR),steroid 5-alpha-reductase 2(SRD5A2)and nuclear receptor subfamily 5 Group A member 1(NR5A1)gene variants were identified in 21,13 and 13 patients,respectively.The incidence of these three gene variants was about 78.3%(47/60)in patients with rare variants.It is concluded that targeted NGS is an effective method to detect pathogenic mutations in 46,XY DSD patients and AR,SRD5A2,and NR5A1 genes were the most common pathogenic genes in our cohort.展开更多
This study aims to characterize the cell atlas of the epididymis derived from a 46,XY disorders of sex development(DSD)patient with a novel heterozygous mutation of the nuclear receptor subfamily 5 group A member 1(NR...This study aims to characterize the cell atlas of the epididymis derived from a 46,XY disorders of sex development(DSD)patient with a novel heterozygous mutation of the nuclear receptor subfamily 5 group A member 1(NR5A1)gene.Next-generation sequencing found a heterozygous c.124C>G mutation in NR5A1 that resulted in a p.Q42E missense mutation in the conserved DNA-binding domain of NR5A1.The patient demonstrated feminization of external genitalia and Tanner stage 1 breast development.The surgical procedure revealed a morphologically normal epididymis and vas deferens but a dysplastic testis.Microfluidic-based single-cell RNA sequencing(scRNA-seq)analysis found that the fibroblast cells were significantly increased(approximately 46.5%),whereas the number of main epididymal epithelial cells(approximately 9.2%),such as principal cells and basal cells,was dramatically decreased.Bioinformatics analysis of cell–cell communications and gene regulatory networks at the single-cell level inferred that epididymal epithelial cell loss and fibroblast occupation are associated with the epithelial-to-mesenchymal transition(EMT)process.The present study provides a cell atlas of the epididymis of a patient with 46,XY DSD and serves as an important resource for understanding the pathophysiology of DSD.展开更多
The clinical characteristics of patients with disorders of sex development（DSD）, and the diagnostic values of classic cytogenetic and molecular genetic assays for DSD were investigated. In the enrolled 56 cases, the...The clinical characteristics of patients with disorders of sex development（DSD）, and the diagnostic values of classic cytogenetic and molecular genetic assays for DSD were investigated. In the enrolled 56 cases, there were 9 cases of 46,XY DSD, 6 cases of Turner syndrome（TS）, one case of Super female syndrome, 25 cases of Klinefelter syndrome, 14 cases of 46,XX DSD, and one case of autosomal balanced rearrangements with hypospadias. The diagnosis of sex was made through physical examination, cytogenetic assay, ultrasonography, gonadal biopsy and hormonal analysis. PCR was used to detect SRY, ZFX, ZFY, DYZ3 and DYZ1 loci on Y and X chromosomes respectively. The DSD patients with the same category had similar clinical characteristics. The karyotypes in peripheral blood lymphocytes of all patients were identified. PCR-based analysis showed presence or absence of the X/Y-linked loci in several cases. Of the 9 cases of 46,XY DSD, 6 were positive for SRY, 9 for ZFX/ZFY, 9 for DYZ3 and 8 for DYZ1 loci. Of the 6 cases of TS, only 1 case with the karyotype of 45,X,/46,XX/46,XY was positive for all 5 loci. Of the 25 cases of Klinefelter syndrome, all were positive for all 5 loci. In one case of rare Klinefelter syndrome variants azoospermia factor（AZF） gene detection revealed the loss of the AZFa＋AZFb region. In 14 cases of 46,XX DSD, 7 cases were positive for SRY, 14 for ZFX, 7 for ZFY, 7 for ZYZ3, and 5 for DYZ1. PCR can complement and also confirm cytogenetic studies in the diagnosis of sex in cases of DSD.展开更多
Importance:Impaired growth is an important factor in patients with disorders of sex development(DSD).Objective:To profile the growth of children with 46,XY DSD.Methods:We compared heights between 46,XY DSD children an...Importance:Impaired growth is an important factor in patients with disorders of sex development(DSD).Objective:To profile the growth of children with 46,XY DSD.Methods:We compared heights between 46,XY DSD children and normal boys and obtained growth curves for DSD using the k-median coefficient of variation method.The study subjects were categorized into groups with good response and poor response to the human chorionic gonadotrophin(HCG)test according to testosterone levels and were compared height standard deviation scores(HtSDS)with normal boys.Results:A total of 571 children with noncongenital adrenal hyperplasia(CAH)46,XY DSD were enrolled in this study.The overall HtSDS for the DSD subjects were 0.031 1.202.The HtSDS of DSD boys were lower than those for normal boys among multiple age groups since early infancy.In children aged≥12 years,the HtSDS values were significantly lower than the normal reference values for boys of the same age in both the good and poor response groups(P=.025 and P=.003,respectively).The HtSDS in the poor response group was generally lower than the normal reference value(P=.017).The average HtSDS values in the poor response groups were lower than those in the good response groups across multiple age groups.Interpretation:Growth retardation was evident in boys with non-CAH 46,XY DSD in early childhood and puberty.The level of growth retardation was related to testosterone level.DSD-specific growth curves can improve our understanding of growth dynamics and minimize the scope for bias in the assessment of growth in these children.展开更多
Background:Disorders of sex development(DSD)is a group of sexual differentiation disorders resulting in genital anomalies with defects in gonadal hormone synthesis and/or incomplete genital development.These condition...Background:Disorders of sex development(DSD)is a group of sexual differentiation disorders resulting in genital anomalies with defects in gonadal hormone synthesis and/or incomplete genital development.These conditions result in problems concerning the sex assignment of the child.This study aims to describe the clinical features,diagnosis and management of children with DSD in southern Thailand.Methods:The medical records of 117 pediatric patients diagnosed with DSD during the period of 1991-2011 were retrospectively reviewed.Results:Disorders of sex development were categorized into 3 groups:sex chromosome abnormalities(53.0%),46,XX DSD(29.9%)and 46,XY DSD(17.1%).The two most common etiologies of DSD were Turner syndrome(36.8%)and congenital adrenal hyperplasia(29.9%).Ambiguous genitalia/intersex was the main problem in 46,XX DSD(94%)and 46,XY DSD(100%).Sex reassignment was done in 5 children(4.3%)at age of 3-5 years:from male to female in 4 children(1 patient with congenital adrenal hyperplasia,1 patient with 45,X/46,XY DSD,and 2 patients with 46,XX ovotesticular DSD)and from female to male in 1 patient with 46,XX ovotesticular DSD.Of the total 20 children with 46,XY DSD,16(80%)were raised as females.Conclusion:Management of DSD children has many aspects of concern.Sex assignment/reassignment depends on the phenotype(phallus size)of the external genitalia rather than the sex chromosome.展开更多
Sex determination is a complex biological process,through which the sex of an organism is established in a binary fate decision[1,2].There are two main determining mechanisms:1)genotypic sex determination(GSD),whereby...Sex determination is a complex biological process,through which the sex of an organism is established in a binary fate decision[1,2].There are two main determining mechanisms:1)genotypic sex determination(GSD),whereby the individual’s sex is determined by its genotype;and 2)environmental sex determination(ESD),where the sex is driven by different external factors,such as temperature,p H,and social interactions[1].展开更多
Disorders of sex development(DSD)are a group of rare complex clinical syndromes with multiple etiologies.Distinguishing the various causes of DSD is quite difficult in clinical practice,even for senior general physici...Disorders of sex development(DSD)are a group of rare complex clinical syndromes with multiple etiologies.Distinguishing the various causes of DSD is quite difficult in clinical practice,even for senior general physicians because of the similar and atypical clinical manifestations of these conditions.In addition,DSD are difficult to diagnose because most primary doctors receive insufficient training for DSD.Delayed diagnoses and misdiagnoses are common for patients with DSD and lead to poor treatment and prognoses.On the basis of the principles and algorithms of dynamic uncertain causality graph(DUCG),a diagnosis model for DSD was jointly constructed by experts on DSD and engineers of artificial intelligence.“Chaining”inference algorithm and weighted logic operation mechanism were applied to guarantee the accuracy and efficiency of diagnostic reasoning under incomplete situations and uncertain information.Verification was performed using 153 selected clinical cases involving nine common DSD-related diseases and three causes other than DSD as the differential diagnosis.The model had an accuracy of 94.1%,which was significantly higher than that of interns and third-year residents.In conclusion,the DUCG model has broad application prospects as a computer-aided diagnostic tool for DSDrelated diseases.展开更多
Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pe...Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pediatric patients with DSD.Methods:Choosing cases with CHD7 variants from DSD patients in Beijing Children’s Hospital to assess for the study.Prediction software tools were used to predict variant pathogenicity in these subjects.results:Among the 113 DSD patients,22 cases had CHD7 variants.Twenty-four different CHD7 variants were identified in the 22 DSD patients.Prediction software combined with ClinVar database information and their clinical manifestations revealed that,of the 18 patients with 46,XY DSD,two had CHARGE syndrome and two had Kallmann syndrome.Seven of the variants were highly categorized as“likely to be pathogenic”and seven as“suspected to be pathogenic”.Of the four patients with 46,XX DSD,three had ovotesticular DSD(c.305A>G,c.2788G>A,and c.3098G>A)and one had testicular DSD(c.2831G>A).Interpretation:A high frequency of CHD7 variants was found in the DSD patients,especially those with 46,XY DSD.Thus,the detection of a pathogenic CHD7 variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46,XY DSD patients,but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis.This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients.Further data are required to determine the connection between CHD7 variants and sex-reversal in patients with 46,XX DSD,and the accumulation of these data is essential and necessary for DSD research.展开更多
Forty-six XX disorder of sex development is an uncommon medical condition observed at times during the evaluation of a man＇s fertility. The following is a case series and literature review of phenotypically normal me...Forty-six XX disorder of sex development is an uncommon medical condition observed at times during the evaluation of a man＇s fertility. The following is a case series and literature review of phenotypically normal men diagnosed with this karyotype. Our goal is to comprehend the patients＇ clinical presentation as well as their laboratory results aiming to explore options available for their management. A formal literature review through PubMed and MEDLINE databases was performed using ＂46 XX man＂ as a word search. A total of 55 patients, including those conveyed in this article were diagnosed with a 46 XX karyotype during their fertility evaluation. The patients＇ mean age _＋ s.d. was 34 ＋ 10 years and their mean height ＋ s.d. was 166 ＋ 6.5 cm. Overall, they presented with hypergonadotropic hypogonadism. Sexual dysfunction, reduced hair distribution, and gynecomastia were reported in 20% （4120）, 25.8% （8/31）, and 42% （13131） of the patients, respectively. The SRYgene was detected in 36 （83.7%） and was absent in the remaining seven （16.3%） patients. We found that a multidisciplinary approach to management is preferred in 46 XX patients. Screening for remnants of the mullerian ducts and for malignant transformation in dysgenetic gonads is imperative. Hypogonadism should be addressed, while fertility options are in vitro fertilization with donor sperm or adoption.展开更多
Androgen insensitivity syndrome （AIS）, an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor （AR） gene, and is characterized by partial or complete inability of...Androgen insensitivity syndrome （AIS）, an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor （AR） gene, and is characterized by partial or complete inability of specific tissues to respond to androgens in individuals with the 46,XY karyotype. This study aimed to investigate AR gene mutations and to characterize genotype-phenotype correlations. Ten patients from unrelated families, aged 2-31 years, were recruited in the study. Based on karyotype, altered hormone profile, and clinical manifestations, nine patients were preliminarily diagnosed with complete AIS and one with partial AIS. Genetic analysis of AR gene revealed the existence of 10 different mutations, of which five were novel （c.2112 C〉G[p.STO4R], c.2290T〉A[p.Y764N], c.2626C〉T[p.Q876X], c.933dupC[p.K313Qfs＊28], and c.1067delC[p.A356Efs＊123]）; the other five were previously reported （c.1789G〉A[p.A597T], c.2566C〉T[p.R856C], c.2668G〉A[p.V890M], c.2679C〉T[p.P893L], and c.1605C〉G[p.Y535X]）. Regarding the distribution of these mutations, 60.0% were clustered in the ligand-binding domain of AR gene. Exons 1 and 8 of AR gene each accounted for 30.0% （3/10） of all mutations. Most of the truncation mutations were in exon 1 and missense mutations were mainly located in exons 4-8. Our study expands the spectrum of AR gene mutations and confirms the usefulness of AR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening.展开更多
基金supported by the Sichuan Science and Technology Program(No.2022JDZH0029 to JYY)the Special Fund for Clinical Research and Translational Medicine from Chinese Academy of Medical Sciences(No.2022-I2M-C&T-B-117 to JYY)the Sichuan Key Research and Development Project from the Department of Science and Technology of Sichuan Province(No.2022YFS0237 to YMT).
文摘This study was conducted retrospectively on a cohort of 68 patients with steroid 5α-reductase 2(SRD5A2)deficiency and 46,XY disorders of sex development(DSD).Whole-exon sequencing revealed 28 variants of SRD5A2,and further analysis identified seven novel mutants.The preponderance of variants was observed in exon 1 and exon 4,specifically within the nicotinamide adenine dinucleotide phosphate(NADPH)-binding region.Among the entire cohort,53 patients underwent initial surgery at Sichuan Provincial People’s Hospital(Chengdu,China).The external genitalia scores(EGS)of these participants varied from 2.0 to 11.0,with a mean of 6.8(standard deviation[s.d.]:2.5).Thirty patients consented to hormone testing.Their average testosterone-todihydrotestosterone(T/DHT)ratio was 49.3(s.d.:23.4).Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome;and their T/DHT ratios were below the diagnostic threshold.Furthermore,assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants.These mechanisms include interference with NADPH binding(c.356G>C,c.365A>G,c.492C>G,and c.662T>G)and destabilization of the protein structure(c.727C>T).The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts.Seven novel variations were identified,and the variant database for the SRD5A2 gene was expanded.These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.
基金This work was supported by the National Natural Science Foundation of China(No.81971375 and No.81771576)the National Key Research and Development Program of China(2016YFC0905100)+1 种基金the CAMS Innovation Fund for Medical Sciences(2016-I2M-1-002)the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(No.2017PT32020 and No.2018PT32001).
文摘46,XY disorders of sex development(DSD)is characterized by incomplete masculinization genitalia,with gonadal dysplasia and with/without the presence of Mullerian structures.At least 30 genes related to 46,XY DSD have been found.However,the clinical phenotypes of patients with different gene mutations overlap,and accurate diagnosis relies on gene sequencing technology.Therefore,this study aims to determine the prevalence of pathogenic mutations in a Chinese cohort with 46,XY DSD by the targeted nextgeneration sequencing(NGS)technology.Eighty-seven 46,XY DSD patients were enrolled from the Peking Union Medical College Hospital(Beijing,China).A total of fifty-four rare variants were identified in 60 patients with 46,XY DSD.The incidence of these rare variants was approximately 69.0%(60/87).Twenty-five novel variants and 29 reported variants were identified.Based on the American College of Medical Genetics and Genomics(ACMG)guidelines,thirty-three variants were classified as pathogenic or likely pathogenic variants and 21 variants were assessed as variants of uncertain significance.The overall diagnostic rate was about 42.5%based on the pathogenic and likely pathogenic variants.Androgen receptor{AR),steroid 5-alpha-reductase 2(SRD5A2)and nuclear receptor subfamily 5 Group A member 1(NR5A1)gene variants were identified in 21,13 and 13 patients,respectively.The incidence of these three gene variants was about 78.3%(47/60)in patients with rare variants.It is concluded that targeted NGS is an effective method to detect pathogenic mutations in 46,XY DSD patients and AR,SRD5A2,and NR5A1 genes were the most common pathogenic genes in our cohort.
基金supported by grants from the National Key Research and Development Program of China (No.2018YFC1003602 to HC and No.2018YFC1003504 to HJ)the National Natural Science Foundation of China (No.81871202 to HC and No.31900484 to GCX)+2 种基金Lo Kwee Seong Start Up Fund to KLE,Shanghai Sailing Program (No.20YF1422900 to YWZ)the Natural Science Foundation of Nantong (No.JC2021081 to JWS)Startup R&D funding from Nantong University (No.135419631032 to JWS and TDYX2021021 to JWS).
文摘This study aims to characterize the cell atlas of the epididymis derived from a 46,XY disorders of sex development(DSD)patient with a novel heterozygous mutation of the nuclear receptor subfamily 5 group A member 1(NR5A1)gene.Next-generation sequencing found a heterozygous c.124C>G mutation in NR5A1 that resulted in a p.Q42E missense mutation in the conserved DNA-binding domain of NR5A1.The patient demonstrated feminization of external genitalia and Tanner stage 1 breast development.The surgical procedure revealed a morphologically normal epididymis and vas deferens but a dysplastic testis.Microfluidic-based single-cell RNA sequencing(scRNA-seq)analysis found that the fibroblast cells were significantly increased(approximately 46.5%),whereas the number of main epididymal epithelial cells(approximately 9.2%),such as principal cells and basal cells,was dramatically decreased.Bioinformatics analysis of cell–cell communications and gene regulatory networks at the single-cell level inferred that epididymal epithelial cell loss and fibroblast occupation are associated with the epithelial-to-mesenchymal transition(EMT)process.The present study provides a cell atlas of the epididymis of a patient with 46,XY DSD and serves as an important resource for understanding the pathophysiology of DSD.
文摘The clinical characteristics of patients with disorders of sex development（DSD）, and the diagnostic values of classic cytogenetic and molecular genetic assays for DSD were investigated. In the enrolled 56 cases, there were 9 cases of 46,XY DSD, 6 cases of Turner syndrome（TS）, one case of Super female syndrome, 25 cases of Klinefelter syndrome, 14 cases of 46,XX DSD, and one case of autosomal balanced rearrangements with hypospadias. The diagnosis of sex was made through physical examination, cytogenetic assay, ultrasonography, gonadal biopsy and hormonal analysis. PCR was used to detect SRY, ZFX, ZFY, DYZ3 and DYZ1 loci on Y and X chromosomes respectively. The DSD patients with the same category had similar clinical characteristics. The karyotypes in peripheral blood lymphocytes of all patients were identified. PCR-based analysis showed presence or absence of the X/Y-linked loci in several cases. Of the 9 cases of 46,XY DSD, 6 were positive for SRY, 9 for ZFX/ZFY, 9 for DYZ3 and 8 for DYZ1 loci. Of the 6 cases of TS, only 1 case with the karyotype of 45,X,/46,XX/46,XY was positive for all 5 loci. Of the 25 cases of Klinefelter syndrome, all were positive for all 5 loci. In one case of rare Klinefelter syndrome variants azoospermia factor（AZF） gene detection revealed the loss of the AZFa＋AZFb region. In 14 cases of 46,XX DSD, 7 cases were positive for SRY, 14 for ZFX, 7 for ZFY, 7 for ZYZ3, and 5 for DYZ1. PCR can complement and also confirm cytogenetic studies in the diagnosis of sex in cases of DSD.
基金National Key Research and Development Program of China,Grant/Award Number:2016YFC0901505Research of Biological Medicine and Life Science Innovation,Capital Residents Health Project-Etiological Diagnosis of 46,XY DSD,Grant/Award Number:Z15110200390000。
文摘Importance:Impaired growth is an important factor in patients with disorders of sex development(DSD).Objective:To profile the growth of children with 46,XY DSD.Methods:We compared heights between 46,XY DSD children and normal boys and obtained growth curves for DSD using the k-median coefficient of variation method.The study subjects were categorized into groups with good response and poor response to the human chorionic gonadotrophin(HCG)test according to testosterone levels and were compared height standard deviation scores(HtSDS)with normal boys.Results:A total of 571 children with noncongenital adrenal hyperplasia(CAH)46,XY DSD were enrolled in this study.The overall HtSDS for the DSD subjects were 0.031 1.202.The HtSDS of DSD boys were lower than those for normal boys among multiple age groups since early infancy.In children aged≥12 years,the HtSDS values were significantly lower than the normal reference values for boys of the same age in both the good and poor response groups(P=.025 and P=.003,respectively).The HtSDS in the poor response group was generally lower than the normal reference value(P=.017).The average HtSDS values in the poor response groups were lower than those in the good response groups across multiple age groups.Interpretation:Growth retardation was evident in boys with non-CAH 46,XY DSD in early childhood and puberty.The level of growth retardation was related to testosterone level.DSD-specific growth curves can improve our understanding of growth dynamics and minimize the scope for bias in the assessment of growth in these children.
文摘Background:Disorders of sex development(DSD)is a group of sexual differentiation disorders resulting in genital anomalies with defects in gonadal hormone synthesis and/or incomplete genital development.These conditions result in problems concerning the sex assignment of the child.This study aims to describe the clinical features,diagnosis and management of children with DSD in southern Thailand.Methods:The medical records of 117 pediatric patients diagnosed with DSD during the period of 1991-2011 were retrospectively reviewed.Results:Disorders of sex development were categorized into 3 groups:sex chromosome abnormalities(53.0%),46,XX DSD(29.9%)and 46,XY DSD(17.1%).The two most common etiologies of DSD were Turner syndrome(36.8%)and congenital adrenal hyperplasia(29.9%).Ambiguous genitalia/intersex was the main problem in 46,XX DSD(94%)and 46,XY DSD(100%).Sex reassignment was done in 5 children(4.3%)at age of 3-5 years:from male to female in 4 children(1 patient with congenital adrenal hyperplasia,1 patient with 45,X/46,XY DSD,and 2 patients with 46,XX ovotesticular DSD)and from female to male in 1 patient with 46,XX ovotesticular DSD.Of the total 20 children with 46,XY DSD,16(80%)were raised as females.Conclusion:Management of DSD children has many aspects of concern.Sex assignment/reassignment depends on the phenotype(phallus size)of the external genitalia rather than the sex chromosome.
基金supported by grants from the National Key R&D Program of China(Grant No.2018YFA0800200)the Strategic Priority Research Program of the Chinese Academy of Sciences,China(Grant No.XDA16010207)+1 种基金the National Natural Science Foundation of China(Grant Nos.31830061,31425016,and 81530004)the State Key Laboratory of Membrane Biology,China
文摘Sex determination is a complex biological process,through which the sex of an organism is established in a binary fate decision[1,2].There are two main determining mechanisms:1)genotypic sex determination(GSD),whereby the individual’s sex is determined by its genotype;and 2)environmental sex determination(ESD),where the sex is driven by different external factors,such as temperature,p H,and social interactions[1].
基金This research was supported by the National Key Research and Development Program of China(No.2016YFC0901501)CAMS Innovation Fund for Medical Science(No.CAMS-2017-I2M–1-011)the Research Project of the Institute of Internet Industry,Tsinghua University,titled“DUCG theory and application of medical aided diagnosis-algorithm of introducing classification variables in DUCG.”。
文摘Disorders of sex development(DSD)are a group of rare complex clinical syndromes with multiple etiologies.Distinguishing the various causes of DSD is quite difficult in clinical practice,even for senior general physicians because of the similar and atypical clinical manifestations of these conditions.In addition,DSD are difficult to diagnose because most primary doctors receive insufficient training for DSD.Delayed diagnoses and misdiagnoses are common for patients with DSD and lead to poor treatment and prognoses.On the basis of the principles and algorithms of dynamic uncertain causality graph(DUCG),a diagnosis model for DSD was jointly constructed by experts on DSD and engineers of artificial intelligence.“Chaining”inference algorithm and weighted logic operation mechanism were applied to guarantee the accuracy and efficiency of diagnostic reasoning under incomplete situations and uncertain information.Verification was performed using 153 selected clinical cases involving nine common DSD-related diseases and three causes other than DSD as the differential diagnosis.The model had an accuracy of 94.1%,which was significantly higher than that of interns and third-year residents.In conclusion,the DUCG model has broad application prospects as a computer-aided diagnostic tool for DSDrelated diseases.
文摘Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7(CHD7)in disorders of sex development(DSD).Objective:We aimed to present the potential pathogenicity of CHD7 variants in pediatric patients with DSD.Methods:Choosing cases with CHD7 variants from DSD patients in Beijing Children’s Hospital to assess for the study.Prediction software tools were used to predict variant pathogenicity in these subjects.results:Among the 113 DSD patients,22 cases had CHD7 variants.Twenty-four different CHD7 variants were identified in the 22 DSD patients.Prediction software combined with ClinVar database information and their clinical manifestations revealed that,of the 18 patients with 46,XY DSD,two had CHARGE syndrome and two had Kallmann syndrome.Seven of the variants were highly categorized as“likely to be pathogenic”and seven as“suspected to be pathogenic”.Of the four patients with 46,XX DSD,three had ovotesticular DSD(c.305A>G,c.2788G>A,and c.3098G>A)and one had testicular DSD(c.2831G>A).Interpretation:A high frequency of CHD7 variants was found in the DSD patients,especially those with 46,XY DSD.Thus,the detection of a pathogenic CHD7 variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46,XY DSD patients,but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis.This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients.Further data are required to determine the connection between CHD7 variants and sex-reversal in patients with 46,XX DSD,and the accumulation of these data is essential and necessary for DSD research.
文摘Forty-six XX disorder of sex development is an uncommon medical condition observed at times during the evaluation of a man＇s fertility. The following is a case series and literature review of phenotypically normal men diagnosed with this karyotype. Our goal is to comprehend the patients＇ clinical presentation as well as their laboratory results aiming to explore options available for their management. A formal literature review through PubMed and MEDLINE databases was performed using ＂46 XX man＂ as a word search. A total of 55 patients, including those conveyed in this article were diagnosed with a 46 XX karyotype during their fertility evaluation. The patients＇ mean age _＋ s.d. was 34 ＋ 10 years and their mean height ＋ s.d. was 166 ＋ 6.5 cm. Overall, they presented with hypergonadotropic hypogonadism. Sexual dysfunction, reduced hair distribution, and gynecomastia were reported in 20% （4120）, 25.8% （8/31）, and 42% （13131） of the patients, respectively. The SRYgene was detected in 36 （83.7%） and was absent in the remaining seven （16.3%） patients. We found that a multidisciplinary approach to management is preferred in 46 XX patients. Screening for remnants of the mullerian ducts and for malignant transformation in dysgenetic gonads is imperative. Hypogonadism should be addressed, while fertility options are in vitro fertilization with donor sperm or adoption.
基金The authors are grateful to the patients and their family members for participating in this study. This study was supported by grants from the National Natural Science Foundation of China （81771645 and 81471432 to YQT）.
文摘Androgen insensitivity syndrome （AIS）, an X-linked recessive genetic disorder of sex development, is caused by mutations in the androgen receptor （AR） gene, and is characterized by partial or complete inability of specific tissues to respond to androgens in individuals with the 46,XY karyotype. This study aimed to investigate AR gene mutations and to characterize genotype-phenotype correlations. Ten patients from unrelated families, aged 2-31 years, were recruited in the study. Based on karyotype, altered hormone profile, and clinical manifestations, nine patients were preliminarily diagnosed with complete AIS and one with partial AIS. Genetic analysis of AR gene revealed the existence of 10 different mutations, of which five were novel （c.2112 C〉G[p.STO4R], c.2290T〉A[p.Y764N], c.2626C〉T[p.Q876X], c.933dupC[p.K313Qfs＊28], and c.1067delC[p.A356Efs＊123]）; the other five were previously reported （c.1789G〉A[p.A597T], c.2566C〉T[p.R856C], c.2668G〉A[p.V890M], c.2679C〉T[p.P893L], and c.1605C〉G[p.Y535X]）. Regarding the distribution of these mutations, 60.0% were clustered in the ligand-binding domain of AR gene. Exons 1 and 8 of AR gene each accounted for 30.0% （3/10） of all mutations. Most of the truncation mutations were in exon 1 and missense mutations were mainly located in exons 4-8. Our study expands the spectrum of AR gene mutations and confirms the usefulness of AR gene sequencing to support a diagnosis of AIS and to enable prenatal or antenatal screening.
