XY Disorders Of Sex Development Research Articles

Phenotypic and biochemical characteristics and molecular basis in 36 Chinese patients with androgen receptor variants

BackgroundAndrogen insensitive syndrome (AIS) is a rare genetic disease resulting from androgen receptor (AR) mutations and one of the causes of 46, XY disorder of sexual development (DSD). This study aimed to describe the clinical features and molecular defects of 36 Chinese patients with AR variants and investigate the functional alterations of novel variants in vitro.Material and methodsSubjects with AR variants were identified from 150 Chinese 46, XY DSD patients using targeted next-generation sequencing. In-silico and functional assays were performed to evaluate the transcriptional activity and nuclear localization of novel AR variants.ResultsEight novel and fifteen reported AR variants were identified. 30.6% (11/36) of patients harbored additional variants other than AR. Mutations in the Arg841 residue were found in 7 unrelated patients. Postpubertal serum gonadotropin levels were significantly elevated in patients with complete AIS (CAIS) compared with those in patients with partial AIS (PAIS) (P < 0.05). All the novel variants initially predicted to be uncertain significance by in-silico analyses were reclassified as likely pathogenic for defective AR transcriptional activity in vitro, except p.L295P, which was found in an atypical patient with oligogenic mutations and reclassified as likely benign. c.368_369 ins T was observed to interfere with nuclear translocation.ConclusionsCompared with PAIS patients, postpubertal CAIS patients had higher gonadotropin levels. Arg841 was disclosed as the location of recurrent mutations in Chinese AIS patients. Functional assays are important for reclassifying the novel AR variants and re-examining the diagnosis of AIS in specific patients with oligogenic mutations, instead of in-silico analysis.

Quality of Life and Psychological Well-being in Children and Adolescents with Disorders of Sex Development

Objective:The aim of this study was to assess the quality of life (QoL) and psychological well-being in child and adolescent with disorders of sex development (DSD).Methods:Sixty-two cases, aged 2-18 years, who were followed by a multidisciplinary DSD team were included. All participants and their parents were requested the complete the Pediatric Quality Of Life Inventory (PedsQL) and the Strengths and Difficulties Questionnaire. The psychiatric diagnoses of the patients were evaluated according to Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Turkish Version.Results:There was no significant difference between the 46,XX DSD and 46,XY DSD groups for both child and parent in Total PedsQL score. In the subscale scores, the PedsQL Physical Functionality Score reported by children was significantly lower for the 46,XX DSD group than for the 46,XY DSD group (p=0.01). There was a psychiatric diagnosis in 25.8% of cases. The PedsQL School Functionality Score reported by children in the group with psychiatric diagnosis was significantly lower than the group without psychiatric diagnosis (p=0.018). In the group with psychiatric diagnosis, the PedsQL Total Score and the subscale scores (Emotional Functionality Score, Social Functionality Score, School Functionality) reported by parents were significantly lower than in parents of the group without psychiatric diagnosis.Conclusion:This study emphasized that psychiatric disorders in DSD patients negatively affect the QoL. Psychiatric support and counseling from a multidisciplinary team are very important for families affected by DSD.

Poremećaji polne diferencijacije - iskustvo tercijernog centra

Introduction/aim: Disorders of sex development (DSD) comprise a heterogeneous group of congenital conditions with a difference between chromosomal, gonadal sex and the appearance of the external genitalia. The frequency of DSD is 1: 4,500-5,500 newborns per year. Congenital adrenal hyperplasia (CAH) due to the deficiency of the 21-hydroxylase enzyme is one of the most common and best-known causes of DSD. Other forms of CAH, as well as other causes of DSD, occur with significantly lower individual frequencies and are thus more challenging to diagnose and treat. The aim of the study was to analyse the etiology and clinical characteristics of DSD, as well as changes in the diagnostic and therapeutic approach to DSD in the tertiary center during the previous 13 years. Methods: The study was conducted in the form of a retrospective cohort study which included all patients investigated for DSD at the Department of Endocrinology of Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic" during the period from December 2007 until November 2020. Children with DSD caused by CAH due to 21-hydroxylase deficiency were not included in this study. Results: The study included a total of 31 children with DSD: 24 children (77%) had 46XY DSD, 3 (10%) had 46XX DSD, and 4 children (13%) had chromosomal DSD. A definitive diagnosis of specific etiology has been made in 25 children (81%), and the most common etiology of DSD was gonadal dysgenesis (55%), followed by the androgen insensitivity syndrome (10%) and atypical forms of CAH (7%). During the period 2 (2016-2020) more children with DSD (n = 18) were examined compared to the period 1 (2007-2015) and the specific etiological diagnosis was established in a larger number of children with DSD (89%) compared to the period 1 (69%). Also, during period 2 (2016-2020) genital surgery was performed in a significantly lesser number of children (11%) and at a later age (average age 6.8 years) than in period 1 (64%, average age 4.8 years; p &lt;0.05). Conclusion: During the latter period (2016-2020), there has been an increase in the number of investigated children as well as the percentage of DSD with established specific etiology. Also, the diagnosis is increasingly being made on the basis of genetic analysis, and genitoplasty is performed in a decreasing number of children and at a later age. A holistic and multidisciplinary approach is required for the evaluation treatment of children with DSD.

Proximal hypospadias and 46XY disorder of sex development; which patient with hypospadias needs to be investigated?

Aim: This study examines the distribution of genital abnormalities based on physical examination of our patients with 46, XY disorders of sex development (46, XY DSD), and aims to define severity and frequency of hypospadias in 46, XY DSD. Hypospadias is a relatively prevalent congenital anomaly. Although genetic, environmental and hormonal factors are considered to be responsible, etiology is not clarified in several hypospadias cases. Materials and Methods: Clinical, laboratory and genetic records of all cases with 46, XY DSD, who were evaluated by the sex determination monitoring board were retrospectively reviewed. In the diagnosis, hypospadias cases were examined in terms of the place of hypospadias and coexisting other external genital findings. Results: There were 72 patients with 46, XY DSD. 5-α reductase deficiency [n=32 (44.4%)] was the most commonly encountered diagnosis followed by androgen insensitivity syndrome [n=26, (36.1%)]. Proximal hypospadias were presented in 44.4% (n: 32) of the cases and only 6 of them (18.8%) were isolated hypospadias. In 81.2% of these cases, at least one of the anomalies such as cordi, bifid scrotum, undescended testis and micropenis accompanied proximal hypospadias. None of the distal hypospadias cases were referral clinic finding. Conclusions: 46 XY DSD is a heterogeneous group of patients with a varying age of presentation and a diverse clinical profile. It can be stated that proximal hypospadias is the most common referral clinic finding of 46, XY DSD, and the risk of 46, XY DSD increases with the intensifying degree of hypospadias and the presence of coexisting genital abnormalities such as cordi, bifid scrotum, undescended testis and micropenis.

Clinical, Etiological and Laboratory Profile of Children with Disorders of Sexual Development (DSD)-Experience from a Tertiary Pediatric Endocrine Unit in Western India.

Objectives:To present the clinical profile, diagnostic work-up, and management of children with Disorders of Sexual Development (DSD).Materials and Methods:A retrospective study from a tertiary pediatric endocrine unit of western India. We included 39 patients who presented over a period of 9 years from June 2009 to June 2018.Results:Nineteen patients (48.7%) were diagnosed with 46 XY DSD, 16 (41%) with 46 XX DSD, and 4 (10.3%) with sex chromosomal DSD. Out of 46 XY DSD, androgen insensitivity was observed in 8 (42.1%) patients, 5 alpha-reductase deficiency in 5 (26.3%), gonadal dysgenesis in 3 (15.8%), ovotesticular DSD in 2 (10.5%) and 17 beta-hydroxylase (17γ-HSD3) deficiency in 1 (5.3%). Congenital adrenal hyperplasia was the most common cause in 46 XX DSD observed in 11 (68.75%) out of 16 patients, ovotesticular DSD was seen in 4 (25%) patients and testicular DSD in 1 (6.25%) patient. In sex chromosomal DSD 3 (75%) patients had mixed gonadal dysgenesis and 1 (25%) had ovotesticular DSD out of a total of 4 patients. At presentation gender of rearing was assigned as male in 16 (41%) patients, female in 20 (51.3%) patients, and no gender was assigned in 3 (7.7%). The gender of rearing was changed after diagnosis in 6 (16.7%) children.Conclusion:CAH was the most common etiology of 46 XX DSD whereas androgen insensitivity among 46 XY DSD. Assigning the sex of rearing should not be hurried and should be done only after diagnosis and parental counseling. A multidisciplinary and systematic approach is required for children with DSD.

Gonadal dysgenesis 46,XY DSD associated with variants in the MAP3K1 gene

Disorders of sex development (DSDs) are congenital conditions in which phenotype does not correspond to chromosomal and gonadal sex. To date, the etiology of DSD is established only in half of the cases. With the development of modern methods of molecular genetic diagnostics in the last decade, a number of new regulators of gonad differentiation have been discovered, whose expression disorders can lead to DSD. Among these factors, Mitogen-activated triple protein kinase 1 (MAP3K1). A distinctive feature of studying the detected variants in the MAP3K1 gene that they lead to activation of MAP3K1. It does not allow using generally accepted pathogenicity assessment algorithms. However, the frequency of detection of changes in MAP3K1 is up to 18% of all cases of DSD, according to literature, which emphasizes the importance of studying each identified case, establishing the relationship of the disease with the identified genetic disorders. In this article, we present a clinical, hormonal, and molecular genetic description of 7 cases of DSD associated with variants in MAP3K1, an analysis of the significance of our own data, and a short analysis of the current scientific literature on this issue.

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

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

Disorders of sex development -A complex puzzle for the doctor and the patient-A rare case report

Disorders of Sex Development (DSD) are referred to a group of disorders in which at least two out of gonadal sex, genetic sex, phenotypic sex and genital tract sex show discordance between them. Among the three main categories of DSD, 46XY DSD is a rarer type which we encountered in our case. A 14 year old female presented with abdominal pain and lump since 10 days. On clinical examination she had external sexual characters of a female. Karyotyping revealed a 46XY type. Intra-operatively, there was a normal uterus with a tumor mass in the location of the right gonad which was removed, along with a biopsy taken from the contralateral gonad, both intra-abdominal in location. Histopathologic examination of the tumor mass revealed a malignant mixed germ cell tumour (GCT) comprising of dysgerminoma and yolk sac tumour and the contralateral gonad was found to be testis, with evidence of intratubular germ cell neoplasm unclassified (IGCNU). Patient underwent 4 cycles of chemotherapy after the histopathologic diagnosis but was later lost to follow-up. The relative ambiguity of these disorders with their propensity to develop into type II GCTs makes these cases unique, perplexing and of utmost importance. Keywords: 46XY DSD, Mixed GCT, IGCNU.

Gender Identity and Assignment Recommendations in Disorders of Sex Development Patients: 20 Years’ Experience and Challenges

Objective:Gender assignment in infants and children with disorders of sex development (DSD) is a stressful situation for both patient/families and medical professionals.Methods:The purpose of this study was to investigate the results of gender assignment recommendations in children with DSD in our clinic from 1999 through 2019.Results:The mean age of the 226 patients with DSD at the time of first admission were 3.05±4.70 years. 50.9% of patients were 46,XY DSD, 42.9% were 46,XX DSD and 6.2% were sex chromosome DSD. Congenital adrenal hyperplasia (majority of patients had 21-hydroxylase deficiency) was the most common etiological cause of 46,XX DSD. In 46,XX patients, 87 of 99 (89.7%) were recommended to be supported as a female, 6 as a male, and 4 were followed up. In 46,XY patients, 40 of 115 (34.8%) were recommended to be supported as a female, and 70 as male (60.9%), and 5 were followed up. In sex chromosome DSD patients, 3 of 14 were recommended to be supported as a female, 9 as a male. The greatest difficulty in making gender assignment recommendations were in the 46,XY DSD group.Conclusion:In DSD gender assignment recommendations, the etiologic diagnosis, psychiatric gender orientation, expectation of the family, phallus length and Prader stage were effective in the gender assignment in DSD cases, especially the first two criteria. It is important to share these experiences among the medical professionals who are routinely charged with this difficult task in multidisciplinary councils.

MYRF haploinsufficiency causes 46,XY and 46,XX disorders of sex development: Bioinformatics consideration

Disorders of sex development (DSDs) are defined as congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In many DSD cases, genetic causes remain to be elucidated. Here, we performed a case-control exome sequencing study comparing gene-based burdens of rare damaging variants between 26 DSD cases and 2625 controls. We found exome-wide significant enrichment of rare heterozygous truncating variants in the MYRF gene encoding myelin regulatory factor, a transcription factor essential for oligodendrocyte development. All three variants occurred de novo. We identified an additional 46,XY DSD case of a de novo damaging missense variant in an independent cohort. The clinical symptoms included hypoplasia of Mullerian derivatives and ovaries in 46,XX DSD patients, defective development of Sertoli and Leydig cells in 46,XY DSD patients and congenital diaphragmatic hernia in one 46,XY DSD patient. As all of these cells and tissues are or partly consist of coelomic epithelium (CE)-derived cells (CEDC) and CEDC developed from CE via proliferaiton and migration, MYRF might be related to these processes. Consistent with this hypothesis, single-cell RNA sequencing of foetal gonads revealed high expression of MYRF in CE and CEDC. Reanalysis of public chromatin immunoprecipitation sequencing data for rat Myrf showed that genes regulating proliferation and migration were enriched among putative target genes of Myrf. These results suggested that MYRF is a novel causative gene of 46,XY and 46,XX DSD and MYRF is a transcription factor regulating CD and/or CEDC proliferation and migration, which is essential for development of multiple organs.

Screening for structural variants of four candidate genes in dogs with disorders of sex development revealed the first case of a large deletion in NR5A1

Disorders of sex development (DSD) are important causes of infertility and sterility, and are risk factors for gonadal carcinogenesis. Many DSDs are caused by genetic factors, mainly sex chromosome abnormalities or mutations of genes involved in sexual development, as well as structural variants (SVs) - large deletions, duplications, and insertions, if these overlap genes involved in sex development. The aim of this study was to determine if there were SVs in four candidate genes - NR0B1 (DAX1), NR5A1, RSPO1, and SOX3 - using droplet digital PCR (ddPCR). There was study of two cohorts of dogs with DSD, including 55 animals with XX DSD and 15 with XY DSD. In addition, 40 control females and 10 control males were included in the study. Among cases, for which there were evaluations, a large deletion consisting of four exons of the NR5A1 gene was identified in a Yorkshire Terrier with a rudimentary penis, hypospadias, bilateral cryptorchidism, and spermatogenesis inactive testes. This is the first mutation in the NR5A1 gene leading to XY DSD phenotype to be reported in domestic animals. There were no SVs in the genes evaluated in the present study in the cohort of dogs with XX DSD. The results from this study provide evidence that the large structural variants of these genes are rarely associated with the DSD phenotype in dogs.

Nonsense-associated altered splicing of MAP3K1 in two siblings with 46,XY disorders of sex development

Although splicing errors due to single nucleotide variants represent a common cause of monogenic disorders, only a few variants have been shown to create new splice sites in exons. Here, we report an MAP3K1 splice variant identified in two siblings with 46,XY disorder of sex development. The patients carried a maternally derived c.2254C>T variant. The variant was initially recognized as a nonsense substitution leading to nonsense-mediated mRNA decay (p.Gln752Ter); however, RT-PCR for lymphoblastoid cell lines showed that this variant created a new splice donor site and caused 39 amino acid deletion (p.Gln752_Arg790del). All transcripts from the variant allele appeared to undergo altered splicing. The two patients exhibited undermasculinized genitalia with and without hypergonadotropism. Testosterone enanthate injections and dihydrotestosterone ointment applications yielded only slight increase in their penile length. Dihydrotestosterone-induced APOD transactivation was less significant in patients’ genital skin fibroblasts compared with that in control samples. This study provides an example of nonsense-associated altered splicing, in which a highly potent exonic splice site was created. Furthermore, our data, in conjunction with the previous data indicating the association between MAP3K1 and androgen receptor signaling, imply that the combination of testicular dysgenesis and androgen insensitivity may be a unique phenotype of MAP3K1 abnormalities.

Down syndrome with Disorder of Sex development (DSD): A Rare Presentation

Down syndrome is the most common genetic disorder among live born infants, which is associated with a number of congenital malformations and requires a huge medical and social cost. Here, we report a very rare association in an infant with Down syndrome and XY disorder of sex development (DSD).&#x0D; Bangladesh J Child Health 2020; VOL 44 (1) :48-51

Androgens by immunoassay and mass spectrometry in children with 46,XY disorder of sex development.

ObjectiveSteroid measurement is a challenge in pediatric endocrinology. Currently, liquid chromatography with tandem mass spectrometry (LC-MS/MS) is considered a gold standard for this purpose. The aim of this study was to compare both LC-MS/MS and immunoassay (IA) for androgens before and after human recombinant chorionic gonadotropin (rhCG) stimulus in children with 46,XY disorders of sex development (DSD).Methods Nineteen patients with 46,XY DSD were evaluated; all of them were prepubertal and non-gonadectomized. Testosterone, dihydrotestosterone (DHT), DHEA and androstenedione were measured by IA and LC-MS/MS before and 7 days after rhCG injection. The correlation between IA and LC-MS/MS was analyzed by the intraclass correlation coefficient (ICC) and Spearman’s rank correlation coefficient (SCC). For concordance analysis the Passing and Bablok (PB) regression and the Bland and Altman (BA) method were used.ResultsTestosterone showed excellent correlation (ICC = 0.960 and SCC = 0.964); DHT showed insignificant and moderate correlations as indicated by ICC (0.222) and SCC (0.631), respectively; DHEA showed moderate correlation (ICC = 0.585 and SCC = 0.716); and androstenedione had poor and moderate correlations in ICC (0.363) and SCC (0.735), respectively. Using the PB method, all hormones showed a linear correlation, but proportional and systematic concordance errors were detected for androstenedione, systematic errors for testosterone and no errors for DHEA and DHT. By the BA method, there was a trend of IA to overestimate testosterone and androstenedione and underestimate DHEA and DHT when compared to LC-MS/MS.ConclusionTraditional IA should be replaced by LC-MS/MS for the androgens measurement in prepubertal children whenever is possible.

Molecular Characteristics of Sequence Variants in GATA4 in Patients with 46,XY Disorders of Sex Development without Cardiac Defects

A GATA4 haploinsufficiency has been well described in patients with congenital heart defects (CHDs), whilst only a few studies have reported mutations related to a 46,XY disorder of sex development (DSD) phenotype. This study investigated the clinical phenotypes and molecular characteristics of two 46,XY DSD patients harboring GATA4 variants. Mutation analysis was performed using a targeted gene panel or whole-exome sequencing. The transactivation activity of each variant protein was examined by in vitro luciferase reporter assay using the AMH and SRY promoters. Subject 1 presented with a micropenis and hypospadias. Subject 2 showed complete female external genitalia with a 46,XY karyotype. Both patients were responsive to hCG stimulation tests and did not manifest CHD. A novel heterozygous variant, c.643A>G (p.R215G), in GATA4 was identified in Subject 1, whereas Subject 2 harbored a previously reported variant, c.1220C>A (p.P407Q), in GATA4 and a previously known pathogenic mutation, i.e., c.226C>T (p.Q76*) in the AR gene. The reporter assays using the SRY and AMH promoters revealed decreased transcriptional activity of both p.P407Q and p.R215G. However, the GATA4 p.P407Q variant was classified as likely benign. In conclusion, it is essential to integrate clinical features and endocrine findings when interpreting sequence variants.

Demetylation of the sex-determining region Y gene promoter and incidence of disorder of sex development in cloned dog males.

Canine cloning is occasionally accompanied by abnormal sexual development. Some male donor cells produce cloned pups with female external genitalia and complete male gonadal dysgenesis, which is classified as an XY disorder of sex development (XY DSD). In this study, we examine the potential of 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, to reduce the phenotypic abnormality XY DSD in somatic cell nuclear transfer (SCNT)- derived pups. We used a 9-year-old normal male German Shepherd dog as a cell donor. Donor cells were treated with 10 nM 5-aza-dC for 4 days before being used for SCNT. At the same stage of cell development, significantly lower levels of DNA methylation of the sex-determining region Y (SRY) promoter was observed in the treated donor cells compared to that in the untreated cells (95.2% versus 53.3% on day 4 for the control and treated groups, respectively). No significant differences were observed in the control or treatment groups concerning fusion rate, pregnancy rate (30 days or entire period), the number of pups, or the incidence of XY DSD. However, more XY DSD dogs were observed in the control group (31.25%) than in the treatment group (14.29%). Hypermethylation of the SRY promoter was observed in the XY DSD cloned pups in both the treatment (84.8%) and control groups (91.1 ± 1.4%) compared to the methylation level in the phenotypically normal male pups of the treatment (23.2 ± 20.9%) and control groups (39.1 ± 20.1%). These results suggest that 5-aza-dC treatment of donor cells can reduce the methylation level of the SRY promoter in donor cells, and thus, 5-aza-dC is advantageous for reducing the incidence of XY DSD in canine cloning.

Prevalence of gene mutations in a Chinese 46,XY disorders of sex development cohort detected by targeted next-generation sequencing.

46,XY disorders of sex development (DSD) is characterized by incomplete masculinization genitalia, with gonadal dysplasia and with/without the presence of Müllerian 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 next-generation 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.

Clinical and molecular characteristics of patients with 46,XY DSD due to NR5A1 gene mutations

Steroidogenic factor 1 (SF1, NR5A1) is a nuclear receptor that regulates multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Human mutations in SF1 were initially found in patients with severe gonadal dysgenesis and primary adrenal failure. However, more recent case reports have suggested that heterozygous mutations in SF1 may also be found in patients with 46,XY partial gonadal dysgenesis and underandrogenization but normal adrenal function. We have analyzed the gene encoding SF1 (NR5A1) in a cohort of 310 Russian patients with 46,XY disorders of sex development (DSD). Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described. We have not found any phenotype-genotype correlations and any clinical and laboratory markers that would allow to suspect this type of before conducting molecular genetic analysis.

What Does AMH Tell Us in Pediatric Disorders of Sex Development?

Disorders of sex development (DSD) are conditions where genetic, gonadal, and/or internal/external genital sexes are discordant. In many cases, serum testosterone determination is insufficient for the differential diagnosis. Anti-Müllerian hormone (AMH), a glycoprotein hormone produced in large amounts by immature testicular Sertoli cells, may be an extremely helpful parameter. In undervirilized 46,XY DSD, AMH is low in gonadal dysgenesis while it is normal or high in androgen insensitivity and androgen synthesis defects. Virilization of a 46,XX newborn indicates androgen action during fetal development, either from testicular tissue or from the adrenals or placenta. Recognizing congenital adrenal hyperplasia is usually quite easy, but other conditions may be more difficult to identify. In 46,XX newborns, serum AMH measurement can easily detect the existence of testicular tissue, leading to the diagnosis of ovotesticular DSD. In sex chromosomal DSD, where the gonads are more or less dysgenetic, AMH levels are indicative of the amount of functioning testicular tissue. Finally, in boys with a persistent Müllerian duct syndrome, undetectable or very low serum AMH suggests a mutation of the AMH gene, whereas normal AMH levels orient toward a mutation of the AMH receptor.

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

The aim of this study was to assess the prevalence of pathogenic variants in the SRD5A2 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 SRD5A2, and the genotype-phenotype correlation was studied. As a result, 10 pathogenic or likely pathogenic biallelic variants in SRD5A2, 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 SRD5A2 and in nearly 90% of those without pathogenic variants in SRD5A2 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 SRD5A2 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.