Cause Of Disorders Of Sex Development Research Articles

Unveiling the Significance of the Androgen Receptor Gene in Disorders of Sex Development

Abstract Disorders of sex development (DSD) encompass a range of congenital conditions where the development of chromosomal, gonadal or anatomical sex is atypical. There are many genes associated with DSD, and one of them is the androgen receptor (AR) gene, which plays a pivotal role in normal sex development. Studies reported numerous genetic variations in the AR gene that lead to 46, XY DSD, including androgen insensitivity syndrome and hypospadias. Identifying and understanding the genetic causes of DSD will aid the healthcare providers design a tailored-made management for DSD patients and optimise patients’ quality of life. This narrative review will explore the significance of the AR gene in DSD while discussing DSD in general.

Disorders of sex development (DSD) 46.XY due to type 2 5-α reductase deficiency in three siblings: Case report from a low-resource setting

Introduction and ImportanceDisorders of Sexual Development (DSD) is a rare autosomal recessive genetic condition significantly affecting patients' lives in various aspects, particularly psychosocially. Type 2 5-α reductase is a cause of DSD 46,XY. It is rare to find multiple DSDs in the same family. Patients may present with amenorrhea and ambiguous genitalia. This case report is aimed to highlight the genetic aspects of the disease, the challenges to diagnostics and the various management options for the patients. MethodsCase series of three siblings with DSD 46, XY with relevant discussion. OutcomesThree sisters, aged nineteen, seventeen, and fifteen years old came with an identical complaint of late menarche. Their physical examinations revealed elementary breast development and little axillary hair. The external genitals consisted of vulva, major and minor labia. Clitoromegaly was present with short (<5 cm) vagina. No female internal genital was found but undescended testes were palpable. Presences of testes was confirmed via ultrasound. Laboratory results showed reduced estradiol, highly increased follicle stimulating hormone (FSH), normal male testosterone levels and increased testosterone-dihydrotestosterone ratio (T/DHT >20). Karyotype was 46,XY. Diagnoses of DSD 46, XY due to type 2 5-α reductase deficiency were established. Patient 1 chose female as the gender of choice whilst patients 2 and 3 chose male. All patients are due for corrective surgery along with psychotherapy and psychoeducation. ConclusionDSD 46, XY due to type 2 5-α reductase deficiency is a rare autosomal recessive genetic disorder requiring comprehensive diagnostics and holistic management to improve patient quality of life.

Disorders of Sex Development.

Disorders of Sex Development.

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.

Molecular genetics of disorders of sex development in a highly consanguineous population

Consanguinity increases the risk of hereditary diseases including disorders of sex development (DSD). There are minimal data on DSD in the highly consanguineous population of Saudi Arabia. This study reports the molecular genetics of a series of patients with different types of DSD. MethodsWe enrolled 77 patients from 47 families with DSD. DNA was isolated from peripheral leucocytes. Genes of interest were amplified by polymerase chain reaction and subsequently sequenced. ResultsOverall, 77 patients from 47 families (44 of them are consanguineous) had a total of 29 mutations; 16 of them were described before and 13 were novel mutations. The most common condition was 5-α reductase (SRD5A2) deficiency (25 patients from 18 families) and the most common mutation was a splice site mutation in intron 1 (c.282-2A>G). The next most common condition was 11-β hydroxylase (CYP11B1) deficiency where 19 patients from 10 families had 8 mutations (7 of them are novel). Other mutations affected CYP17A1 with 2 novel and 2 known mutations in 7 patients; HSD3B2 with 2 known mutations in 11 patients of 4 families; StAR with 1 novel and 1 known mutations in 4 patients; NR0B1 with 1 novel mutation in 2 siblings; HSD17B3 with 1 known mutation in 3 siblings; LHCGR with 1 novel mutation in 2 siblings; and AR with 1 novel and 3 known mutations in 4 unrelated patients. ConclusionIn the highly consanguineous and homogeneous population of Saudi Arabia, SRD5A2 and CYP11B1 deficiencies are common causes of DSDs. Other DSDs occur less frequently but often with novel mutations.

Efficacy of intelligent diagnosis with a dynamic uncertain causality graph model for rare disorders of sex development.

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 DSD-related diseases.

Novel NR5A1 Pathogenic Variants Cause Phenotypic Heterogeneity in 46,XY Disorders of Sex Development

Steroidogenic factor 1 (NR5A1/SF1) is a key transcription factor that is known to regulate the development of adrenal glands and gonads and is also involved in steroidogenesis. Several pathogenic NR5A1 variants have been reported to cause 46,XY disorders of sex development (DSD), with varying clinical phenotypes ranging from hypospadias to complete gonadal dysgenesis. Most often, the primary cause of DSD is due to variants in gene(s) related to gonadal development or the steroidogenic pathway. In the present study, we have analyzed 64 cases of 46,XY DSD for pathogenic NR5A1 variants. We report a total of 3 pathogenic variants of which 2 were novel (p.Gly22Ser and p.Ser143Asn) and 1 was already known (p.Ser32Asn). Functional studies have revealed that the 2 mutations p.Gly22Ser and p.Ser32Asn could significantly affect DNA binding and transactivation abilities. Further, these mutant proteins showed nuclear localization with aggregate formation. The third mutation, p.Ser143Asn, showed unspeckled nuclear localization and normal DNA binding, but the ability of transcriptional activation was significantly reduced. In conclusion, we recommend screening for NR5A1 pathogenic variants in individuals with features of 46,XY DSD for better diagnosis and management.

Genetic spectrum of disorders of sex development in children in Ukraine

Disorders of sex development (DSD) is a group of pathological conditions where there is a discrepancy between the chromosomal, gonadal and phenotypic sex. Objective — to investigate the clinical and molecular genetic characteristics of DSD in children in Ukraine. Materials and methods. We carried out a retrospecti­­ve analysis of 106 medical records of patients with DSD during period from 2000 to 2019 and analyzed the results of clinical data, medical history, hormonal, genetic, functional and instrumental investigations. All patients (from birth to 18 years old) underwent cytogenetic (karyotyping according to the standard methods) and, if necessary, molecular genetic studies (FISH method). Molecular genetic testing was performed in a selected group of patients with 46,XY and 46,XX DSD (n = 49) using whole exome sequencing (WES). Results and discussion. Among the examined 106 patients with DSD, chromosomal DSD was diagnosed in 17.0 % (n = 18) of patients, 46,XY DSD — in 68.9 % (n = 73) and 46,XX DSD — in 14.1 % (n = 15) cases. The majority of children (60 %) out of 46,XY DSD cohort are brought up in a female civilian sex, and 57.1 % of patients out of 46,XX DSD cohort — as males. Among children with 46,XY, and 46,XX DSD genetic testing (WES) found pathogenic mu­­tations in 46.9 % of cases, variants of unknown significan­­ce — in 30.6 % of cases, in 6.1 % of patients the identified mutations were not the cause of DSD, and in 16.3 % of patients WES didn’t find the genetic cause of their disease. According to the data of the Registry, the largest group of DSD in Ukrainian children (68.9 %) is 46,XY DSD, and the most common genetic cause of DSD in them (26 %) are mutations in the androgen receptor gene. Conclusions. All patients with 46,XY and 46,ХХ DSD require genetic testing (in particular WES) to verify the clinical diagnosis, justify treatment tactics and further observation.

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

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

Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9

Disorders of sex development (DSDs) are conditions affecting development of the gonads or genitalia. Variants in two key genes, SRY and its target SOX9, are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated SOX9 upregulation in the early gonad is crucial for testis development, yet the regulatory elements underlying this have not been identified in humans. Here, we identified four DSD patients with overlapping duplications or deletions upstream of SOX9. Bioinformatic analysis identified three putative enhancers for SOX9 that responded to different combinations of testis-specific regulators. All three enhancers showed synergistic activity and together drive SOX9 in the testis. This is the first study to identify SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively. These enhancers provide a hitherto missing link by which SRY activates SOX9 in humans, and establish SOX9 enhancer mutations as a significant cause of DSD.

Disorder Of Sex Development : Ambiguous Genitalia, Partial Androgen Insensitivity Syndrome

Disorders of sex development (DSDs) also known as “intersex” are congenital condition by mismatch in which chromosomal, gonadal and anatomical. One in 4.500 infants is born with abnormalities of External genitalia, and mostly unexplained in molecular term. Androgen Insensitivity Syndrome (AIS) is a common cause of DSDs. Partial Androgen Insensitivity Syndrome (PAIS) is one of three broad subdivided phenotypes of AIS. Typically, characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype. In males characterized, Pais is common to observe a micropenis, hypospadias, and cryptorchidism. Individuals with PAIS that are characterized as women have been observe to have clitoromegaly and a fused labia during puberity . We reported a 13 year old child, with chief complaint primer amenorrhea. The patient admit as a girl but not yet got her menstruation. Patient was referred by Endocrinology Fertility and Reproductive Consultant of OBGYN, that has done Cromosomal and Hormonal analysis. We perform a laparascopy Exploratif and we get no uterus, fallopian tubal and ovarium that are exist. But, we found testis in inguinal canal. Decision regarding gender assignment are still confronted between patient”s Family and medical staff. The prognosis is depends on the ambiguity of genital, Physical, and Physicosocial adjustment for sex assignment.

A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations.

Disorders of sex development (DSD) are a heterogeneous group of conditions affecting the differentiation and development of the internal and external genitalia. Here, we aimed at identifying the genetic cause of DSD in two 46,XY sisters from a consanguineous family. We performed a whole-exome sequencing of two 46,XY female individuals. Sanger sequencing was used to validate the most likely candidate variant, affecting the desert hedgehog (DHH) gene. Molecular dynamics simulations were performed to get insights into the impact of the variant on protein structure and on its interaction with the protein partner BOC (brother of CDO/cell adhesion molecule, downregulated by oncogenes). The index patient presented with a female phenotype, primary amenorrhoea (low oestradiol and testosterone and high FSH and LH). She also had an apparent absence of intra-abdominal gonads and uterus, facial dysmorphy, psychomotor retardation and neuropathy. Her sister displayed a similar gonadal and endocrinological picture, without dysmorphy or psychomotor retardation. Whole-exome sequencing revealed a homozygous variant in DHH leading to the p.Trp173Cys substitution. The relevant Trp residue is conserved, and its alteration was predicted to be deleterious. Molecular dynamics simulations showed that the mutation increases the conformational flexibility of the protein and potentially alters its interaction with BOC, a positive regulator of Hedgehog signalling. We do not exclude an interference of the mutation with DHH-intein-mediated auto-processing. This report increases the number of described homozygous DHH variants and highlights the importance of advanced bioinformatic tools to better understand the pathogenicity of human variants.

Recent findings on the genetics of disorders of sex development.

Disorders of sex development (DSD) are a diverse group of conditions affecting gonadal development, sexual differentiation, or chromosomal sex. In this review, we will discuss recent literature on the genetic causes of DSD, with a focus on novel genetic sequencing technologies, new phenotypes associated with known DSD genes, and increasing recognition of the role of genetic regulatory elements in DSD. We performed a comprehensive search of PubMed through August 2016 to identify important peer-reviewed publications from 2015 to 2016 on the topic of DSD genetics. Whole-exome sequencing was used to successfully identify genetic causes of DSD in 35% of a cohort of 46,XY patients who had not previously received a genetic diagnosis. A novel mutation in NR5A1 has been identified as a cause of 46,XX testicular and ovotesticular DSD, demonstrating a previously unappreciated role of NR5A1 in preventing testicular differentiation in 46,XX individuals. Genetic regulatory elements of SOX9 have been identified as causes of 46,XX and 46,XY DSD.

Genetic evaluation of children with ambiguous genitalia

Objectives The aim of the study was to conduct a clinical assessment of pediatric patients with ambiguous genitalia, perform molecular genetic studies for SRY and SOX9 genes, and provide genetic counseling for patients and their families. Background Ambiguous genitalia, currently known as disorders of sex development (DSDs), are associated with atypical development of chromosomal, gonadal, or anatomical sexual characteristics, with an incidence of one in 4500 live births. Their early management is crucial for preventing complications, especially psychiatric impacts on the patient and the family, and should be decided after careful consideration of the child's welfare. Materials and methods Sixteen patients aged 1 day to 6 years were selected from the Genetic and Endocrinology Unit, Pediatric Department, Faculty of Medicine, Menoufia University, Egypt. All patients were subjected to detailed history taking, a thorough clinical examination, routine and hormonal investigations, imaging studies, and cytogenetic and molecular studies for SRY and SOX9 genes. Results History revealed seven patients (43.75%) with positive consanguinity and five patients with similar conditions in their families. Hormonal study revealed five patients (31.25%) above normal ranges for serum 17-OH progesterone levels and two patients (12.5%) below normal ranges. Karyotyping revealed six patients with 46, XX DSD, eight with 46, XY DSD, one with 45, X, and another with 45, X/46, XY. On the basis of molecular studies, the SRY gene was positive for six patients with a normal male 46, XY karyotype and for one patient with 45, X karyotype (translocated SRY). SRY was negative for five patients with a normal female 46, XX karyotype and for one patient with 45, X/46, XY karyotype (deleted SRY). All patients were positive for the SOX9 gene and no deletions were detected. Conclusion Early identification of the genetic cause of DSD will in many cases streamline and direct clinical management of the patient with more focused endocrine and imaging studies and better surgical decision.

Disorders of sex development: effect of molecular diagnostics.

Disorders of sex development (DSDs) are a diverse group of conditions that can be challenging to diagnose accurately using standard phenotypic and biochemical approaches. Obtaining a specific diagnosis can be important for identifying potentially life-threatening associated disorders, as well as providing information to guide parents in deciding on the most appropriate management for their child. Within the past 5 years, advances in molecular methodologies have helped to identify several novel causes of DSDs; molecular tests to aid diagnosis and genetic counselling have now been adopted into clinical practice. Occasionally, genetic profiling of embryos prior to implantation as an adjunct to assisted reproduction, prenatal diagnosis of at-risk pregnancies and confirmatory testing of positive results found during newborn biochemical screening are performed. Of the available genetic tests, the candidate gene approach is the most popular. New high-throughput DNA analysis could enable a genetic diagnosis to be made when the aetiology is unknown or many differential diagnoses are possible. Nonetheless, concerns exist about the use of genetic tests. For instance, a diagnosis is not always possible even using new molecular approaches (which can be worrying for the parents) and incidental information obtained during the test might cause anxiety. Careful selection of the genetic test indicated for each condition remains important for good clinical practice. The purpose of this Review is to describe advances in molecular biological techniques for diagnosing DSDs.

Characteristic of patients with disorders of sex development (DSD) in Cipto Mangunkusumo Hospital, Jakarta

Disorder of Sex Development (DSD) is a congenital condition in which development of chromosomal, gonadal or anatomical sex is atypical. They are complex condition related to social stigma, cultural and beliefs in Indonesian population. In Indonesia, there is only a few study regarding characteristic of DSD patients. The aims of our study was to evaluate the characteristic of patients with DSD in Cipto Mangunkusumo Hospital, Jakarta, Indonesia. We retrospectively reviewed the medical records of patients followed up over the period from 2010 to 2012 in Endocrinology Pediatric Clinic, Cipto Mangunkusumo Hospital, Jakarta, Indonesia. We found 74 patients with DSD. In this paper we excluded 29 patients confirmed as Congenital Adrenal Hyperplasia and 3 patients with Turner syndrome. Of 42 patients, 23 (54.8%) patients had 46,XY DSD; 11 (26.2%) patients had sex chromosome DSD; 3 (7.1%) patients had 46,XY DSD, and 5 patients have not done chromosomal analysis. The age when first diagnosed was ranging from newborn to 14 years old. Most cases referred by pediatrician (33.3%) and urologist (23.8%) with frequent complaint were ambiguous genitalia (52.4%) and severe hypospadia (14.3%). The most frequent of phenotype was hypospadia (66.7%). Twenty five (59.5%) of patients have been raised as boy prior to diagnosis. Twelve patients were raised as girls have 46, XY karyotype and 2 patients raised as boys have 46, XX karyotype. Definite diagnosis of 23 patients with 46, XY DSD was found only in 4 (17.4%) patients. The problem regarding lack of definitife diagnosis was related with the high cost of laboratory examination and socioeconomic problem in Indonesia. Our study suggest that the most common cause of DSD in our clinic was 46, XY DSD. Karyotype and clinical phenotype may help in establishing the diagnosis.

A Newborn with Genital Ambiguity, 45,X/46,XY Mosaicism, a Jumping Chromosome Y, and Congenital Adrenal Hyperplasia

Disorders of sex development (DSD), formerly termed “intersex” conditions, arise from numerous causes. CAH secondary to 21-hydroxylase deficiency is the most common cause of DSD. Sex chromosome disorders, including sex chromosome mosaicism, are the second most common cause of DSD. We discuss a medically complex neonate with DSD presenting with ambiguous genitalia. Hormone levels suggested 21-hydroxylase deficiency. Molecular analysis revealed compound heterozygous mutations in the 21-hydroxylase gene (CYP21A2), confirming the diagnosis of CAH. Chromosome analysis revealed sex chromosome mosaicism with three cell lines: 45,X[8]/45,X,tas(Y;16)(p11.32;p13.3)[8]/45,X,t(Y;8)(p11.32;p23.3)[4] with the Y chromosome in telomere association with chromosomes 8p and 16p in different cell lines, a “jumping translocation.” Histologically, the right gonad had irregular, distended seminiferous tubules with hyperplastic germ cells contiguous with ovarian stroma and primordial follicles. The left gonad had scant ovarian stroma and embryonic remnants. Chromosome analyses showed mosaicism in both gonads: 45,X[17]/45,X,tas(Y;8)(p11.32;p23.3)[3]. This is the first case of coexisting CAH and 45,X/46,XY mosaicism reported in the English literature and the third case of a constitutional chromosome Y “jumping translocation.” Our report documents the medical and genetic complexity of children such as this one with ambiguous genitalia and discusses the need for a multidisciplinary team approach.

Disorders of sex development: new genes, new concepts

Formerly known as 'intersex' conditions, disorders of sex development (DSDs) are congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. A complete revision of the nomenclature and classification of DSDs has been undertaken, which emphasizes the genetic aetiology of these disorders and discards pejorative terms. Uptake of the new terminology is widespread. DSDs affecting gonadal development are perhaps the least well understood. Unravelling the molecular mechanisms underlying gonadal development has revealed new causes of DSDs, although a specific molecular diagnosis is made in only ∼20% of patients. Conversely, identification of the molecular causes of DSDs has provided insight into the mechanisms of gonadal development. Studies of N-ethyl-N-nitrosourea mutagenesis in the mouse, and multigene diagnostic screening and genome-wide approaches, such as array-comparative genomic hybridization and next-generation sequencing, in patients with DSDs are accelerating the discovery of genes involved in gonadal development and DSDs. Furthermore, long-range gene regulatory mutations and multiple gene mutations are emerging as new causes of DSDs. Patients with DSDs, their parents and medical staff are confronted with challenging decisions regarding gender assignment, genital surgery and lifelong care. These advances are refining prognostic prediction and systematically improving the diagnosis and long-term management of children with DSDs.

Gender dysphoria associated with disorders of sex development

Disorders of sex development (DSDs) are estimated to be prevalent in 0.1-2% of the global population, although these figures are unlikely to adequately represent non-white patients as they are largely based on studies performed in Europe and the USA. Possible causes of DSDs include disruptions to gene expression and regulation-processes that are considered essential for the development of testes and ovaries in the embryo. Gender dysphoria generally affects between 8.5-20% of individuals with DSDs, depending on the type of DSD. Patients with simple virilizing congenital adrenal hyperplasia (CAH), as well as those with CAH and severe virilization, are less likely to have psychosexual disorders than patients with other types of DSD. Early surgery seems to be a safe option for most of these patients. Male sex assignment is an appropriate alternative in patients with Prader IV or V DSDs. Patients with 5α-reductase 2 (5α-RD2) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) deficiencies exhibit the highest rates of gender dysphoria (incidence of up to 63%). Disorders such as ovotesticular DSD and mixed gonadal dysgenesis are relatively rare and it can be difficult to conclusively evaluate patients with these conditions. For all DSDs, it is important that investigators and authors conform to the same nomenclature and definitions to ensure that data can be reliably analysed.

Etiological Classification and Clinical Assessment of Children and Adolescents with Disorders of Sex Development - Original Article

Objective: In 2006, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology (ESPE) published a consensus statement on management of intersex disorders. The aim of our study was to determine the etiological distribution of disorders of sex development (DSD) according to the new DSD classification system and to evaluate the clinical features of DSDs in our patient cohort. Methods: We retrospectively reviewed the records of patients followed up during the past three years. The subjects were divided into three etiologic groups according to their karyotypes. The definite diagnosesin each subgroup were established by clinical and laboratory investigations including abdominopelvic imaging as well as basal and stimulated hormone measurements. Molecular genetic testing, except for CYP21A2 gene, could not be performed. Results: Out of a total of 95 patients, 26 had sex chromosome DSD, 45 had 46,XY DSD and 24 had 46,XX DSD. The most common causes of DSDs were Turner’s syndrome (TS), congenital adrenal hyperplasia (CAH) and androgen insensitivity syndrome (AIS). There was a wide variation in age of presentation ranging from 1 day to 17.5 years with a mean of 6.5±6.5 years. The most frequent complaints at presentation were ambiguous genitalia, isolated perineal hypospadias and short stature. Conclusion: The results of our study demonstrate that the new DSD classification system leads to a major change in the distribution of etiological diagnoses of DSDs, which is exemplified by the significant frequencies of TS and vanishing testes syndrome. This alteration expands the clinical spectrum and increases the mean age at diagnosis. However, the most common causes of ambiguous genitalia, such as CAH and AIS, remain unchanged. Further studies using molecular genetic analyses are needed to give a more precise distribution of etiologies of DSDs, especially in 46,XY patients.Conflict of interest:None declared.