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Introduction: Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder requiring treatment with steroids. Both over and under-treatment can have an impact on growth outcomes. Aims: The aim of this study was to study the clinical and hormonal profile of a cohort of individuals with classical 21-hydroxylase CAH and to assess the factors influencing growth outcomes in these individuals. Methods: In this cross-sectional study, individuals with classical CAH were included. Baseline data were obtained from electronic medical records. Anthropometric measurements and hormonal profiles were assessed. Quantitative variables were expressed as mean ± standard deviation or median (interquartile range) and qualitative variables as percentages. To measure the correlation between variables, Spearman’s rank correlation was used. Results: Of the 27 patients with classical 21-hydroxylase CAH, 13 had salt wasting and 14 had simple virilizing phenotype. The median height standard deviation score (SDS) of the cohort was -1 SDS (-2.00 to 0.2) with 24% having short stature (height < -2 SDS). There was no significant difference in height SDS depending on the age, gender, type of CAH or onset of central precocious puberty. There was no significant correlation between glucocorticoid dose and height SDS (r = 0.104). Obesity was a common finding (40% adults, 41.1% children). However, there was no significant correlation between BMI and glucocorticoid dose (r = 0.419). Conclusions: Short stature was a significant finding as noted in earlier studies. However, the high prevalence of obesity was a new finding that could not be explained by the dose of steroids alone.

Introduction: Differences of sex development (DSD) also known as disorders of sex development encompass a wide spectrum of conditions with varying clinical presentations across different age groups. This study aims to analyse various aetiologies of DSD in Assam and the variability of sex assignment at birth. Methods: This retrospective study included the records of people with DSD presenting to a tertiary centre over 10 years. The age at presentation, sex assignment, gender identity, degree of ambiguity, pertinent hormonal and radiological investigations were noted. Descriptive statistics were used for analysis. Results: The age of presentation varied widely, with peaks during infancy and puberty. The most prevalent DSD type was 46, XY DSD (61.2%), followed by 46, XX DSD (19.7%) and sex chromosome DSD (19.1%). Among people with 46, XY DSD, androgen biosynthesis disorders were dominant, particularly 5-a reductase 2 deficiency (46.7%). Among 46, XX DSDs, the most common subtype was androgen excess disorders (51.7%) comprising 21a-hydroxylase deficiency (48,3%) and 11β-hydroxylase deficiency (3.4%). Turner syndrome was most prevalent among sex chromosome DSD (71.4%) with others being Klinefelter syndrome, 45, XO/46, XY mixed gonadal dysgenesis and 46, XX/46, XY chimerism. The degree of ambiguity was variable depending on the type of DSD and similarly, sex assignment at birth was influenced by the level of ambiguity. Conclusion: The study underscores the significance of comprehensive approaches for DSD diagnosis and management, especially in regions with limited resources. The insights gained from this clinical study offer valuable understanding and aid in addressing the complexities associated with these conditions.

Objective: Mixed gonadal dysgenesis (MGD) is an uncommon chromosomal Disorder of Sexual Development (DSD). There is insufficient information regarding clinical findings and growth patterns. This study aimed to provide more information about mixed gonadal dysgenesis, which has not yet been sufficiently defined. Materials and Methods: Data from 10 patients diagnosed with mixed gonadal dysgenesis were retrospectively reviewed. Clinical presentations, complaints at admission, imaging, genetic results, and treatments received by the patients were examined. Gonadal status and the gender of the patients were reared and evaluated by a multidisciplinary council decision. If received, growth hormone treatment doses and height gains were examined. Results: The patients’ ages at admission range from 6 months to 17.5 years. The median height SDS of the patients was −0.75 (2.73), the mean body weight SDS was −0.49 (±1.46), and the mean body mass index (BMI) SDS was 0.26 (±0.97). The complaints at admission varied, including ambiguous genitalia, short stature, and absence of menstruation. Some patients are completely in the female phenotype, while some are inadequately virilized male phenotype. External Masculinization Score (EMS) ranges from 1 to 6.5. The decision to raise 6 patients as female and 4 patients as male was made by a multidisciplinary council. Growth hormone treatment was administered to patients raised as female and diagnosed with short stature. The height SDS gain in treated patients was 0.42 (±0.49). Conclusion: Due to its rarity and varied clinical presentation, our knowledge about mixed gonadal dysgenesis is limited. Therefore, early diagnosis and individualized treatment plans are crucial for this patient group. [ABSTRACT FROM AUTHOR]

Introduction: Differences of sex development (DSD) also known as disorders of sex development encompass a wide spectrum of conditions with varying clinical presentations across different age groups. This study aims to analyse various aetiologies of DSD in Assam and the variability of sex assignment at birth. Methods: This retrospective study included the records of people with DSD presenting to a tertiary centre over 10 years. The age at presentation, sex assignment, gender identity, degree of ambiguity, pertinent hormonal and radiological investigations were noted. Descriptive statistics were used for analysis. Results: The age of presentation varied widely, with peaks during infancy and puberty. The most prevalent DSD type was 46, XY DSD (61.2%), followed by 46, XX DSD (19.7%) and sex chromosome DSD (19.1%). Among people with 46, XY DSD, androgen biosynthesis disorders were dominant, particularly 5-a reductase 2 deficiency (46.7%). Among 46, XX DSDs, the most common subtype was androgen excess disorders (51.7%) comprising 21a-hydroxylase deficiency (48,3%) and 11β-hydroxylase deficiency (3.4%). Turner syndrome was most prevalent among sex chromosome DSD (71.4%) with others being Klinefelter syndrome, 45, XO/46, XY mixed gonadal dysgenesis and 46, XX/46, XY chimerism. The degree of ambiguity was variable depending on the type of DSD and similarly, sex assignment at birth was influenced by the level of ambiguity. Conclusion: The study underscores the significance of comprehensive approaches for DSD diagnosis and management, especially in regions with limited resources. The insights gained from this clinical study offer valuable understanding and aid in addressing the complexities associated with these conditions. [ABSTRACT FROM AUTHOR]

Introduction: Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder requiring treatment with steroids. Both over and under-treatment can have an impact on growth outcomes. Aims: The aim of this study was to study the clinical and hormonal profile of a cohort of individuals with classical 21-hydroxylase CAH and to assess the factors influencing growth outcomes in these individuals. Methods: In this cross-sectional study, individuals with classical CAH were included. Baseline data were obtained from electronic medical records. Anthropometric measurements and hormonal profiles were assessed. Quantitative variables were expressed as mean ± standard deviation or median (interquartile range) and qualitative variables as percentages. To measure the correlation between variables, Spearman's rank correlation was used. Results: Of the 27 patients with classical 21-hydroxylase CAH, 13 had salt wasting and 14 had simple virilizing phenotype. The median height standard deviation score (SDS) of the cohort was -1 SDS (-2.00 to 0.2) with 24% having short stature (height < -2 SDS). There was no significant difference in height SDS depending on the age, gender, type of CAH or onset of central precocious puberty. There was no significant correlation between glucocorticoid dose and height SDS (r = 0.104). Obesity was a common finding (40% adults, 41.1% children). However, there was no significant correlation between BMI and glucocorticoid dose (r = 0.419). Conclusions: Short stature was a significant finding as noted in earlier studies. However, the high prevalence of obesity was a new finding that could not be explained by the dose of steroids alone. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed at integrating the clinical and phenotypic characteristics, hormonal profile and genetic diagnosis of children with malformation syndromes associated with XY disorders of sex development (DSD) in a single-center in Egypt. Methods: This retrospective study included patients with syndromic XY DSD recruited from the Pediatric Endocrinology and Surgery units at Alexandria University Children's Hospital (AUCH), Alexandria, Egypt, between 2018 and 2023. All patients included in the study underwent a detailed clinical and laboratory evaluation, ultrasonography (and laparoscopy if needed). Results: The study included 30 children with syndromic XY DSD; most of these children were diagnosed at birth. The most common extragenital malformations included skeletal anomalies (70%), facial dysmorphism (46.7%), cerebral malformations (30%) and congenital heart disease (23.3%). Ventricular septal defect was the most common congenital heart disease. Conclusion: Integration between clinical, laboratory and genetic data is the cornerstone in the management of XY DSD patients for appropriate decision making of surgical intervention and sex assignment, in addition to screening for other associated features of each mutation. [ABSTRACT FROM AUTHOR]

In less than 10% of cases, males may have isolated epispadias, which is caused by failure in the urethral tubularization process, leading to dorsal urethral defect. This case report presents a unique instance where epispadias was associated with ambiguous genitalia. A 5-year-old boy diagnosed with epispadias. The penis resembled external female genitalia, with scrotal skin covering it. He underwent a two-stage operation without complications. The aim of the surgical techniques is to correct these anomalies and restore urinary continence and sexual function. Long-term outcomes of the surgery can vary, which highlights the need for further research.

Background: A mismatch between chromosomal, gonadal, and phenotypic sexes in individuals with androgen insensitivity syndrome (AIS) creates problems in sex assignment and psychosexual identification. Objective: To identify psychosexual and sex assignment peculiarities of individuals with different forms of AIS. Materials and Methods: In this qualitative study, 41 individuals with AIS aged between 15 and 31 yr who referred to the Universe Center for Reproductive Medicine Tbilisi, Georgia between 2016 and 2021 were studied. All individuals underwent clinical, genealogical, hormonal, ultrasonographic, and cytogenetic examinations. In-depth interviews and medical records assessed psychosexual profiles and sex assignment histories. Results: 32 cases were diagnosed with the complete form of AIS (CAIS), 8 individuals with the partial form (PAIS), and one with a mild form (MAIS). Individuals with CAIS and PAIS were assessed at birth and raised as girls. Individuals with CAIS and female psychosexual disposition were referred to us due to amenorrhea. Adolescent individuals with PAIS assessed as girls referred to us due to masculinization detected in puberty. An individual with MAIS was assessed at birth and raised as a boy with male genitalia. All individuals with AIS had typical hormonal data and sex chromosome complex for men. 20 sexually active individuals with CAIS had penile-vaginal contact with the man. None of the individuals with CAIS and PAIS thought about gender reassignment after being diagnosed, only the individual with MAIS aimed for male-to-female transition. Conclusion: Psychosexual identification remains a significant challenge in AIS management. Detection of female psychosexual disposition in one participant that is unusual to MAIS may be associated with somatic mosaicism of the androgen receptor gene. [ABSTRACT FROM AUTHOR]

Congenital malformations of the urogenital system with fully developed duplications, such as urinary bladder, are sporadic. They are often present in the setting of endogenous molecular disbalance, such as steroid metabolism disturbances. Other rare manifestations of hormonal disbalance present as intersex conditions in which the individual has karyotype-specific internal genital organs with opposite-sex signs of the external genitalia, known as ambiguous genitalia. Congenital variations and malformations are often fully recognized and understood during radiological exams. Herein we present a unique case of a 2-month-old baby with female chromosomal sex and ambiguous genitalia together with the manifestation of several anatomical malformations: urinary bladder duplication in the coronal plane, pancake kidney with supernumerary renal arteries, 2 ureters and neural tube defect.Despite their low incidence rate, knowledge of such malformations is paramount for correct diagnosis and treatment in such cases.

Abstract Background Y-type urethral duplication is a term frequently used to describe a rare condition in the male associated with double urinary stream: a weak interrupted urinary stream through a hypoplastic penile urethra, while the main urine flow is through the anus/perineum via accessory posterior channel. Fortunately, the advent of MRI has provided a powerful tool to study these anomalies in depth and on multiple planes. The study included boys presenting with abnormal micturition through the anus beside weak interrupted urine stream through the penis. Investigations included pelviabdominal ultrasound to screen for possible associated upper urinary tract anomalies, conventional contrast X-ray studies, and pelvic MRI. Results During the period between 2016 through 2021, the study included two newly diagnosed cases with abnormal communication between the lower urinary tract and the anus (the so-called Y-type urethral duplication), in addition to one previously reported case whose preoperative imaging studies (including pelvic MRI) were available for analysis. Different surgical solutions have been applied for each case. Hypoplasia was not only restricted to the penile urethra but also affected the corporeal bodies of the penis with variable degrees. In two cases, only a single corporeal body could be identified. In another case, the three corporeal bodies were present but appeared distorted (irregularities and interruption of corporeal bodies). Conclusion In our present study, pelvic MRI examination clearly unveiled significant degrees of corporeal dysgenesis among cases diagnosed as Y-type urethral duplication that would strongly suggest these cases to belong to the same disease spectrum of penile dysgenesis/agenesis.

Differences of sexual development (DSD) refers to congenital conditions characterized by discordant appearances of external genitalia with respect to sex chromosomes. We present a case of a 46 XY DSD adolescent with bilateral undescended testes and severe scrotolabial anomalies who was lost to follow-up for several years who recently presented with “recurrent UTIs.” Although the patient desired immediate reconstruction to void while standing, shared-decision making was used to first address his bilateral cryptorchidism, with plans to delay other reconstruction until the patient is older. Pediatric patients with DSD have complicated medical and surgical problems and require a collaborative multidisciplinary team.

Differences of sex development (DSDs) are a spectrum of congenital clinical conditions involving the development of gonadal, chromosomal, and anatomical sex. The physical presentation provides incomplete clues because underlying etiologies may present with similar findings. We describe an 8-year-old boy from the Dominican Republic originally diagnosed with congenital adrenal hyperplasia (CAH). He was prescribed oral hydrocortisone and fludrocortisone, with irregular adherence. During infancy, he had human chorionic gonadotropin injections to stimulate phallic growth. After migrating to the United States, medications became depleted but without adrenal crisis. Laboratory testing with high-dose adrenocorticotropin stimulation study ruled out CAH. Careful examination noted an underdeveloped bifid scrotum, bilaterally undescended testicles, a 2-cm phallus, severe penoscrotal hypospadias, and chordee. Subsequently, he had a 2-stage bilateral orchiopexy and surgical repair of penoscrotal hypospadias and chordee. Genetic testing for 46,XY DSD revealed a novel, dominant, heterozygous, likely pathogenic variant (c.102 + 1G > C) in the NR5A1 gene associated with severe phenotype of undervirilized male. This case illustrates the crucial role of molecular genetic testing for the diagnosis of 46,XY DSDs and a novel NR5A1 gene variant. [ABSTRACT FROM AUTHOR]

Telila Mesfin,1 Nuri Haji,1 Fikadu Seyoume,2 Kenbon Seyoum,3 Eshetu Mesfin,4 Tsegaye Erdachew,5 Daniel Ayane,5 Gadisa Badasa,5 Moisan Soboka5 1Department of Medicine, Madda Walabu University Goba General Hospital, Goba, Ethiopia; 2Department of Pediatrics, Madda Walabu University Goba General Hospital, Goba, Ethiopia; 3Department of Midwifery, Madda Walabu University Goba General Hospital, Goba, Ethiopia; 4Department of Public Health, ICAP, Finfine, Oromia, Ethiopia; 5Department of Nursing, Madda Walabu University Goba General Hospital, Goba, EthiopiaCorrespondence: Telila Mesfin, Email telilamesfintadesse@gmail.comIntroduction: The term “disorders of sexual differentiation” refers to a variety of issues that result in the baby’s genitalia being underdeveloped or showing characteristics shared by both sexes. Normal sexual development in utero requires a precise and coordinated spatiotemporal sequence of numerous activating and suppressing factors. Inadequate development of the bipotential gonad into an ovary or a testis is one of the most frequent causes of genital ambiguity (partial gonadal dysgenesis). One in every 50,000 babies suffers from cloacal anomalies, which makes it one of the rarest congenital malformations. The supernumerary kidney is an extremely uncommon congenital abnormality with less than 100 cases reported in the literature.Case: We present five days old neonate admitted to the neonatal intensive care unit with a complaint of absence of anal orifice. The baby had not passed meconium within 48 hours after delivery, but the families later realized that meconium had been passing through the urethral orifice along with urine. The child was born to a 32-year-old para-four woman who claims to have been amenorrheic for the past nine months but could not recall her last regular period. On physical examination, the abdomen was grossly distended, and there was no anal opening other than just a dimple on the sacrococcygeal area, and the external genitalia appears female on inspection with labia majora well developed and no fusion.Conclusion: Disorder of sexual differentiation is a clinically diverse set of diseases that interferes with the proper differentiation and determination of sex in the embryo and fetus. One in 50,000 live births results in cloacal abnormalities, which are extremely uncommon. Less than 100 examples of the supernumerary kidney have been documented in the literature, making it an exceptionally rare congenital anomaly.Keywords: supernumerary kidneys, neonate, cloacal anomaly, ambiguous genitalia

The 45,X/47,XYY mosaicism is an extremely rare genetic disorder with highly phenotypic manifestations such as ovotesticular disorders of sexual development, mixed gonadal dysgenesis and Turner syndrome. Herein, we report two cases with very distinctive phenotypes despite having the same sex chromosome mosaicism of 45,X/47,XYY. It should be kept in mind that the rare type of sex chromosome mosaicism of 45,X/47,XYY may present with genital phenotypes ranging from normal female to male characteristics.

A 19-year-old girl was referred with delayed puberty and ambiguous genitalia. She had short stature with high blood pressure and Turner’s stigmata with external genitalia Prader Score 4. Ultrasound revealed hypoplastic uterus with no gonad. Follicle stimulating hormone, luteinizing hormone and testosterone level were increased (51.29 mIU/mL, 23.66 mIU/mL and 742 ng/dl). Karyotyping revealed 46 XY with Fluorescence in situ hybridization cytogenetic study based on 300 cells showed mosaic chromosome, monosomy X (17%) and XY (83%). Laparascopic gonadectomy was done and showed that testes were only in the right inguinal canal. Then patient had external genitalia reconstruction and received estrogen replacement therapy.

Background: Congenital Adrenal Hyperplasia (CAH) is a chronic disease that requires lifelong treatment. Patients may face stigmatization, which may affect their quality of life (QoL). Therefore, we assessed the clinical characteristics and QoL of patients with CAH in the Middle East. Methods: This case-control study included patients with CAH aged >5 years from two tertiary centers (2020-2021). The patients were matched to a healthy control group and were then divided into pediatric and adult groups. Data were collected fromtheir electronicmedical records. Additionally, the EQ-5D-5L QoL questionnaire was completed by both the patients and control group to assess five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Results: The study included 248 patients with CAH (females: 58.8%), with a family history of the condition (57.3%) and/or parental consanguinity (68.1%). The most frequently reported gene defect was CYP21A2, while the most commonly reported symptoms/signs were ambiguous genitalia and obesity. Almost all female patients had received corrective surgery. The questionnaire response rate was 86.3% (n=214/248). The CAH patient group's mean total QoL score was 85.2 compared with 99.8 in the control. Further, CAH patients had lower QoL scores in all domains compared to those in the control group (p = 0.0001-0.0023). The pain/discomfort and anxiety/depression domains were affected significantly more than the other domains were, with 47.7% and 44.4% participants, respectively, p<0.0001. Additionally, obesity was found to be a predictor of reduced mobility following a logistic regression analysis (p = 0.04, OR (0.18-0.98)). Conclusion: Patients with CAH reported lower QoL overall, particularly in the pain/discomfort and anxiety/depression domains. Based on this, we recommend the early involvement of psychologists in a multidisciplinary team approach, premarital screening, and the implementation of awareness programs for people diagnosed with CAH in communities with high consanguineous mating. [ABSTRACT FROM AUTHOR]

Background: Y-type urethral duplication is a term frequently used to describe a rare condition in the male associated with double urinary stream: a weak interrupted urinary stream through a hypoplastic penile urethra, while the main urine flow is through the anus/perineum via accessory posterior channel. Fortunately, the advent of MRI has provided a powerful tool to study these anomalies in depth and on multiple planes. The study included boys presenting with abnormal micturition through the anus beside weak interrupted urine stream through the penis. Investigations included pelviabdominal ultrasound to screen for possible associated upper urinary tract anomalies, conventional contrast X-ray studies, and pelvic MRI. Results: During the period between 2016 through 2021, the study included two newly diagnosed cases with abnormal communication between the lower urinary tract and the anus (the so-called Y-type urethral duplication), in addition to one previously reported case whose preoperative imaging studies (including pelvic MRI) were available for analysis. Different surgical solutions have been applied for each case. Hypoplasia was not only restricted to the penile urethra but also affected the corporeal bodies of the penis with variable degrees. In two cases, only a single corporeal body could be identified. In another case, the three corporeal bodies were present but appeared distorted (irregularities and interruption of corporeal bodies). Conclusion: In our present study, pelvic MRI examination clearly unveiled significant degrees of corporeal dysgenesis among cases diagnosed as Y-type urethral duplication that would strongly suggest these cases to belong to the same disease spectrum of penile dysgenesis/agenesis. [ABSTRACT FROM AUTHOR]

Introductions: Ambiguous genitalia is a congenital disorder defined by atypical development at the chromosomal, gonadal, or anatomical levels of the sex organ. The incidence of ambiguous genitalia is estimated to be 1 in 4500-5500 births. The management of ambiguous genitalia takes an extended time. This can lead to psychiatric manifestations such as depression, anxiety, suicidal ideation, and substances. Objectives: The study aimed to describe the management of ambiguous genitalia in the scope of psychiatry to optimize the comprehensive treatment of the disorder and achieve a good quality of life for a person with ambiguous genitalia in Indonesia. Methods: This study is a literature review that collects from various sources of scientific journals related to the psychiatric management of the disorder. Results: Ambiguous genitalia should be treated by a multidisciplinary approach, with a mental health professional and other essential expertise of the team. Improper application of parenting in childhood can create a problem in adolescence and adulthood. Certain aspects of the management need a psychiatrist's assistance. Psychological management should focus on giving reliable information that is not confusing and preparing children and adolescents to encounter general and sexual life problems. The family and the child should always be involved during the process. Conclusions: The purpose of the entire ambiguous genitalia treatment is to strengthen the patient and family's adaptive coping to the stressors correlated with ambiguous genitalia and the management to promote good quality of life for children and adolescents. [ABSTRACT FROM AUTHOR]

Background: The approach to management of patients with disorders of sex development (DSD) has been refined over the past two decades. We sought to review DSD cases at our hospital and hypothesized that age at presentation would decline over time. Methods: A retrospective review of patients presenting to our hospital between January 1, 2005 and July 31, 2018, with findings of ambiguous genitalia was performed. Results: A total of 44 patients were identified, 3 with cloacal exstrophy. Of the 41 remaining patients, the majority (n = 24) had ovotesticular DSD. Three time periods in the evolution to a multidisciplinary team (MDT) approach were identified: Period 1 (2003–2009), Period 2 (2010–2013), and Period 3 (2014–present). Median presenting age in Periods 1, 2, and 3 were 7 years (95% CI: 0.5–15), 6.5 years (95% CI: 1–19), and 11 years (95% CI: 2–17), respectively, and were not statistically different. Conclusion: Management of patients with DSD poses a challenge to healthcare providers across the globe. The gradual evolution of patient management with incorporation of MDTs and progression toward delayed surgery is seen in this study. There is indeed a need to set up regional centers of excellence, public awareness programs, and healthcare personnel training programs for optimal management of these patients in low- and middle-income countries (LMICs).

BackgroundCongenital Adrenal Hyperplasia (CAH) is a chronic disease that requires lifelong treatment. Patients may face stigmatization, which may affect their quality of life (QoL). Therefore, we assessed the clinical characteristics and QoL of patients with CAH in the Middle East.MethodsThis case-control study included patients with CAH aged >5 years from two tertiary centers (2020–2021). The patients were matched to a healthy control group and were then divided into pediatric and adult groups. Data were collected from their electronic medical records. Additionally, the EQ-5D-5L QoL questionnaire was completed by both the patients and control group to assess five domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).ResultsThe study included 248 patients with CAH (females: 58.8%), with a family history of the condition (57.3%) and/or parental consanguinity (68.1%). The most frequently reported gene defect was CYP21A2, while the most commonly reported symptoms/signs were ambiguous genitalia and obesity. Almost all female patients had received corrective surgery. The questionnaire response rate was 86.3% (n=214/248). The CAH patient group’s mean total QoL score was 85.2 compared with 99.8 in the control. Further, CAH patients had lower QoL scores in all domains compared to those in the control group (p ≤ 0.0001–0.0023). The pain/discomfort and anxiety/depression domains were affected significantly more than the other domains were, with 47.7% and 44.4% participants, respectively, p

Disorders/differences of sex development (DSDs) are a group of rare and phenotypically variable diseases. The underlying genetic causes of most cases of 46XY DSDs remains unknown. Despite the advent of genetic testing, current investigations of the causes of DSDs allow genetic-mechanism identification in about 20–35% of cases. This study aimed primarily to establish a rapid and high-throughput genetic test for undervirilized males with and without additional dysmorphic features. Routine chromosomal and endocrinological investigations were performed as part of DSD evaluation. We applied whole-exome sequencing (WES) complemented with multiplex ligation-dependent probe amplification to seek explainable genetic causes. Integrated computing programs were used to call and predict the functions of genetic variants. We recruited 20 patients and identified the genetic etiologies for 14 (70%) patients. A total of seven of the patients who presented isolated DSD phenotypes were found to have causative variants in the AR, MAP3K1, and FLNA genes. Moreover, the other seven patients presented additional phenotypes beyond undervirilized genitalia. Among them, two patients were compatible with CHARGE syndrome, one with Robinow syndrome, and another three with hypogonadotropic hypogonadism. One patient, who carried a heterozygous FLNA mutation, also harbored a heterozygous PTPN11 mutation and thus presented some phenotypes of Noonan syndrome. We identified several genetic variants (12 nonsense mutations and one microdeletion) that account for syndromic and nonsyndromic DSDs in the Taiwanese population. The identification of these causative genes extended our current understanding of sex development and related congenital disorders. [ABSTRACT FROM AUTHOR]

Abstract Background The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female. Case presentation We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene. Conclusions Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families’ pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions.

Abstract Background The aim of this article is to review the essential concepts, current terminologies and classification, management guidelines and the rationale of gender assignment in different types of differences/disorders of sexual development. Main body The basics of the present understanding of normal sexual differentiation and psychosexual development were reviewed. The current guidelines, consensus statements along with recommendations in management of DSD were critically analyzed to formulate the review. The classification of DSD that is presently in vogue is presented in detail, with reference to old nomenclature. The individual DSD has been tabulated based on various differential characteristics. Two schemes for analysis of DSD types, based on clinical presentation, karyotype and endocrine profile has been proposed here. The risk of gonadal malignancy in different types of DSD is analyzed. The rationale of gender assignment, therapeutic options, and ethical dimension of treatment in DSD is reviewed in detail. Conclusion The optimal management of different types of DSD in the present era requires the following considerations: (1) establishment of a precise diagnosis, employing the advances in genetic and endocrine evaluation. (2) A multidisciplinary team is required for the diagnosis, evaluation, gender assignment and follow-up of these children, and during their transition to adulthood. (3) Deeper understanding of the issues in psychosexual development in DSD is vital for therapy. (4) The patients and their families should be an integral part of the decision-making process. (5) Recommendations for gender assignment should be based upon the specific outcome data. (6) The relative rarity of DSD should prompt constitution of DSD registers, to record and share information, on national/international basis. (7) The formation of peer support groups is equally important. The recognition that each subject with DSD is unique and requires individualized therapy remains the most paramount.

Context Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important. Objective We aimed to better understand the presentation and prevalence of pediatric DSD. Methods A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood. Conclusion DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care. [ABSTRACT FROM AUTHOR]

The 45,X/47,XYY mosaicism is an extremely rare genetic disorder with highly phenotypic manifestations such as ovotesticular disorders of sexual development, mixed gonadal dysgenesis and Turner syndrome. Herein, we report two cases with very distinctive phenotypes despite having the same sex chromosome mosaicism of 45,X/47,XYY. It should be kept in mind that the rare type of sex chromosome mosaicism of 45,X/47,XYY may present with genital phenotypes ranging from normal female to male characteristics. [ABSTRACT FROM AUTHOR]

Biallelic pathogenic variants in DYNC2H1 are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the DYNC2H1 gene. However, therewas no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in DYNC2H1 was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited DYNC2H1 deep-intronic variant c.10606-14A >Gpredicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense- mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of DYNCH2H1 mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy. [ABSTRACT FROM AUTHOR]

Turner syndrome (gonadal dysgenesis with short stature and sterility) is characterized by chromosomal karyotype 45,X in 50% of cases or by mosaicism (45,X/46,XX and 45,X/46,XY) in 30–40% or X structural defects (deletions, long arm isochromosome, ring chromosome). When mosaic Turner syndrome (TS) occurs with a Y chromosome, there may be ambiguous genitalia. Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disease with an X-Linked recessive pattern of inheritance that predominantly affects males, while females are usually asymptomatic. DMD has also been observed in groups of females affected by TS, not homozygous for the mutation. Here, we report a case of an Indian neonate born with ambiguous genitalia diagnosed prenatally by ultrasound who had a karyotype of 45,X/46,XY and who also had Duchenne muscular dystrophy caused by a de novo mutation in the DMD gene. Physical examination was normal without the typical dysmorphic features of TS with the exception of the genitourinary system showing ambiguous genitalia. Gender was assigned as female. At the age of three years, she had increasing difficulty walking, running, jumping and climbing stairs, proximal upper and lower extremity muscle weakness and a positive Gowers' sign. In addition, the serum creatine kinase (CK) value was over 30X the upper limit of normal. This study shows that DMD can occur in females with TS having 45,X/46,XY mosaicism and that this coexistence should be considered in women affected by TS who start to develop potential typical symptoms such as motor or developmental delay. [ABSTRACT FROM AUTHOR]

46,XY sex reversal 11 (SRXY11) is a rare and recently identified form of 46,XY difference in sexual development (DSD), caused by variants in the DEAH-Box Helicase 37 gene ( DHX37 ). DHX37 is crucial for ribosome biogenesis, but its specific role in gonadal development remains unclear. The genital phenotype varies widely, ranging from typical female to typical male. We present a 46,XY infant with prenatal ultrasound findings of atypical genitalia. Amniotic fluid gene analysis revealed a known heterozygous pathogenic variant in DHX37 , p.R308Q (c.923G>A), confirmed postnatally. The patient was born with markedly undervirilized genitalia with posteriorly fused labioscrotal folds, a single introitus, no clitoromegaly, and nonpalpable gonads. Laboratory evaluation at multiple points showed undetectable anti-Müllerian hormone (AMH) and inhibin B levels, elevated gonadotropin levels, and negligible testosterone levels. Clinical course was complicated by urine retention in the vagina and uterus and hydronephrosis requiring catheterization. Endoscopy revealed a urogenital sinus with separate urethral and vaginal openings and 2 cervices leading into 2 separate uteri suggestive of a bicornuate bicollis uterus. Laparoscopy revealed 2 intra-abdominal gonads adjacent to the fallopian tubes. Evidence for inheritance, penetrance, genotype-phenotype correlation, and risk of malignancy in SRXY11 is limited to case reports., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Ambiguous genitalia is a rare disorder where it is unclear whether an infant's external genitals are male or female. This can be attributed to various internal and external etiologies, such as androgen receptor abnormalities, gonadal abnormalities (such as gonadal dysgenesis or Klinefelter syndrome where a male has an extra X chromosome), enzymatic defects, etc. Correction of such atypical genitalia requires a multidisciplinary approach, including but not limited to surgeons and therapists. It is important to keep in mind that the treatment plan is tailored according to the specific etiology that is causative of the patient's condition, along with the anticipated perioperative and postoperative complications. Islamically speaking, this topic has been addressed in various Islamic literature and disciplines, including guidelines for dealing with this medical condition. Moreover, follow-up of the patient must be done to allow smooth integration into society., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mohammed et al.)

Objective: To determine the magnitude and classification of cases of ambiguous genitalia presenting to our setup. Study Design: Cross-sectional study. Place and Duration of Study: Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi Pakistan, from Aug 2018 to Feb 2019. Methodology: All the patients with ambiguous genitalia referred for cytogenetic analysis, were included in the study. The patients were subjected to a detailed history and physical examination. The record of radiological investigations was were obtained. Cytogenetic analysis was performed using the conventional G-banding technique. Hormonal testing included 17- hydroxyprogesterone (17-OHP) levels was also performed. Results: Fifty-one cases of ambiguous genitalia were studied. The median age was 15 months. Thirty-three patients (64.7%) had a 46XY karyotype, 17 (33.3%) had a 46XX karyotype while 1 (1.9%) had 45X/46, XY mosaic karyotype. Thirty patients (58.8%) were products of consanguineous marriage. Congenital adrenal hyperplasia was diagnosed in 12 cases (70.5%) of 46 XX karyotype and in 3 cases (9%) of 46XY karyotype. Conclusion: Ambiguous genitalia, currently categorized as disorders of sex development, are not uncommon in our populartion. Increased awareness and early diagnosis are crucial to prevent life threatening complications of congenital adrenal hyperplasia, to determine sex of rearing, and to counsel the parents or patients.

This study aimed to widen the knowledge of a recently identified, autosomal‐recessive, multiple congenital anomalies syndrome to date observed in only other three children. This is the second report of biallelic mutations in MAPKAPK5 whose impairment during human development has been associated with neurological, cardiac, and facial anomalies combined with fingers and toes malformations. Through the affected patients' genetic and phenotypic features overlap, this report confirms MAPKAPK5 as causative gene and adds unique neurodevelopmental characterization. Moreover, based on the complex congenital genitourinary anomalies reported and MAPKAPK5 literature review, we also propose kidney and external genitalia involvement as a key syndromic feature whose expressivity may be more severe in males. [ABSTRACT FROM AUTHOR]

Abstract Background 46XY partial gonadal dysgenesis (PGD) is a rare subtype of disorder of sex development (DSD). 46YY PGD is a congenital disease with atypical chromosomal, gonadal, or anatomical sex development. The patient in this case report had male and female genitalia simultaneously. We created a flowchart of the differential diagnosis for clinicians. Case presentation A 41-year-old male was admitted to the hospital complaining of lower quadrant abdominal pain for 1 day. Physical examination revealed that his penis size was normal, but a urethral orifice was located in the perineum area between the scrotum and anus. One small testicle was in the left scrotum, but no testicle was present on the right. The patient’s abdomen was bulging, and he had lower abdominal pain. According to the emergency CT scan, a lesion (74*65 mm) was found in the right pelvis between the bladder and rectum. The lesion showed an unclear boundary and hematocele appearance. The lesion was removed by emergency surgery, and the pathology report indicated a mixed germ cell tumor with a seminoma and yolk sac tumors. Conclusion This article is a case report of germ cell tumors in 46XY PGD patients. The literature review summarizes the clinical diagnosis, and a flowchart is provided for physicians in future practice. The importance of this report is that it will help acquaint physicians with this rare disease and make the right initial clinical decision quickly through the use of this flowchart. However, the variants of special subtypes of 46XY DSD are myriad, and all the diagnoses could not be covered in one flowchart.

Abstract Background Disorders of sex development are anomalies in which the development of urogenital ridge is undifferentiated for the male and female child. Imaging plays a vital role in investigating the gross anatomy and associated anomalies. Ultrasonography, such as genitography and magnetic resonance, is the primary modality for demonstrating internal gonads and genitalia. Early multidisciplinary approach in the management of ambiguous genitalia including early surgical intervention is the predominant practice, with few current considerations on deferral of genital reconstruction until adolescent age. Case presentation We report the rare case of a 24-year-old adult female from a majority ethnic group of the Volta region, Ghana who was diagnosed and raised as male, now requiring surgical restoration to the female gender. The surgical team decided to assign external genitalia to correspond with the already intact internal organs, thus constructing the vulva. Consent was given by the client and her family members for management and surgical intervention. The surgery was scheduled and duly performed with a successful outcome. Understanding and consent was sought from the patient for the purpose of using her images for teaching, scientific publication, and demonstrations. Conclusion The advantages of deferring surgical reconstruction with psychological counseling after early assessment need to be considered to prevent inappropriate gender assignment.

Urogenital sinus (UGS) and cloacal malformations are the spectra of disease affecting mainly females, resulting in an unusual confluence of the genital and urinary tract with or without the involvement of the gastrointestinal tract. Successful reconstruction of these anomalies depends on the accurate preoperative delineation of abnormal anatomy with the help of cross-sectional and other contrast studies like genitourogram along with cystourethroscopy wherever indicated. We hereby report a case of a 14-year-old female who presented with irregular cyclical hematuria and was diagnosed with persistent UGS with urethral duplication. After a thorough evaluation, the patient was successfully managed with surgical reconstruction, described in this study. Persistent UGS is a complex developmental anomaly. Complete characterization of anomaly requires a thorough evaluation such as hormonal assessment, endoscopy, cross-sectional, and radiological contrast study. Surgical reconstruction needs individualization and may need clitoroplasty, labioplasty, and urethral and vaginal mobilization. Morphological and functional outcome is satisfactory in a well-planned surgical reconstruction.

Mutations in the nuclear receptor subfamily 5 group A member 1 (NR5A1) are the underlying cause of 10-20% of 46,XY disorders of sex development (DSDs). We describe a young girl with 46,XY DSD due to a unique novel mutation of the NR5A1 gene. An 11-year-old subject, raised as a female, was noticed to have clitromegly. She looked otherwise normal. However, her evaluation revealed a 46,XY karyotype, moderate clitromegly but otherwise normal female external genitalia, undescended atrophied testes, rudimentary uterus, no ovaries, and lack of breast development. Serum testosterone and estradiol were low, and gonadotropins were elevated. Adrenocortical function was normal. DNA was isolated from the peripheral leucocytes and used for whole exome sequencing. The results were confirmed by Sanger sequencing. We identified a novel mutation in NR5A1 changing the second nucleotide of the translation initiation codon (ATG>ACG) and resulting in a change of the first amino acid, methionine to threonine (p.Met1The). This led to severe gonadal dysgenesis with deficiency of testosterone and anti-Müllerian hormone (AMH) secretion. Lack of the former led to the development of female external genitalia, and lack of the latter allowed the Müllerian duct to develop into the uterus and the upper vagina. The patient has a female gender identity. Bilateral orchidectomy was performed and showed severely atrophic testes. Estrogen/progesterone therapy was initiated with excellent breast development and normal cyclical menses. In summary, we describe a severely affected case of 46,XY DSD due to a novel NR5A1 mutation involving the initiation codon that fully explains the clinical phenotype in this subject. [ABSTRACT FROM AUTHOR]

Background: The Congenital Adrenal Hyperplasia due to 21 hydroxylase deficiency is the most common cause of genital ambiguity in persons with XX sexual chromosomes. Genital ambiguity among persons with XY sexual chromosomes comprises diverse and rare etiologies. The deficiency of 17-beta-hydroxysteroid dehydrogenase type 3 enzyme (HSD17B3) is a rare autosomal recessive disorder due to functionally altered variants of the HSD17B3 gene. In this disorder/difference of sex development, the conversion of androstenedione into testosterone is impaired. The appearance of external genitalia of 46,XY individuals varies from typically male to almost female. Case presentation: We report on a child presenting severe ambiguous genitalia. Due to access constraints, specialized care did not start until the child was 10 months old. Parents are consanguineous and were born in an area of high isonymy that is a cluster for rare recessive diseases. A new homozygous missense variant c.785G > T was found in exon 10 of the HSD17B3 gene. Conclusions: Researchers-clinicians and researchers-researchers collaborative efforts to elucidate the genetic basis of this disease were critical since this etiologic investigation is not available through the public health system. This case exemplifies the families' pilgrimage in cases of genital ambiguity due to a rare genetic condition. Recognizing the etiology was the baseline to provide information on prognosis and treatment options, and to shelter family and child doubts and hopes in order to better support their decisions. [ABSTRACT FROM AUTHOR]

Abstract Background 49XXXXY syndrome is the rarest X chromosome aneuploidy, with approximate incidence of 1:85,000–100,000 male births. Worldwide, around 100 cases have been reported. In this report, we describe one such case seen in Sri Lanka. Case presentation A 10-day-old Sri Lankan neonate born in a tertiary care center was referred to the pediatric endocrinology unit of Lady Ridgeway Hospital due to detection of ambiguous genitalia at birth. He was the first child born to nonconsanguineous healthy parents following an uncomplicated antenatal period. He was born at term via normal vaginal delivery, with a birth weight of 2.385 kg. The baby was active, and there was no documented hypoglycemia or alteration in basic biochemical investigations. On examination, the child had hypertelorism, upslanting palpebral fissures, flat occiput, and mild webbing of the neck. System examination was normal. Genitalia examination revealed bifid scrotum, perineal urethra, 2 cm phallus, and bilateral testis in situ. Hormonal analysis, including dehydroepiandrosterone sulfate, testosterone, and 17-OH progesterone levels, was normal except for an elevated level of follicle-stimulating hormone, indicating gonadal dysgenesis. Ultrasound of the abdomen detected testis located at bilateral inguinal canal, and no Müllerian structures were visible. Echocardiography showed a small patent foramen ovale with otherwise normal heart. Chromosome analysis revealed 49XXXXY syndrome. Conclusion 49XXXXY syndrome should be entertained as a rare possibility for ambiguous genitalia, and karyotyping is an essential investigation for evaluation of such patients.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder commonly caused by mutation of the CYP21A2 gene, resulting in deficiency of an enzyme required for cortisol synthesis in the adrenal cortex. In 90-95% of cases, the deficient enzyme is 21-hydroxylase (21-OH), with an incidence ranging from 1 in 5,000 to 15,000 live births across various ethnic and racial backgrounds. In classical 21-OH deficiency (21-OHD) CAH, excessive androgen exposure in the fetus results in virilization at birth.1 The management of ambiguous genitalia in children with CAH presents a unique and ethically challenging decision-making dilemma for the medical team. Insensitive and poorly informed statements made in the delivery room may cause long-term psychological problems for the families. It is important to refrain from assigning gender until sufficient diagnostic information can be gathered. Parents, as guardians, and the supporting medical team must make decisions on behalf of the child, with the goal of enabling the child to grow into a healthy and happy adult with his or her assigned gender.2,3 We report a case of a child with CAH, focusing on the ethical challenges in management of ambiguous genitalia.

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic syndrome that occurs as result of an androgen receptor mutation; it affects the normal masculinization process in chromosomal male patients. More than 900 androgen receptor mutations that can lead to AIS have been identified. The complete androgen insensitivity is characterized by a total lack of response to androgens, usually in patients with 46XY karyotype but with feminine phenotype. Primary amenorrhoea and inguinal swellings in female patients are the main signs that could raise suspicion for this syndrome. Patients with partial androgen insensitivity have ambiguous genitalia at birth and gynecomastia during puberty, whereas those with mild androgen insensitivity present a normal male phenotype but altered spermatogenesis during adulthood and pubertal gynecomastia. The diagnosis of AIS often proves to be a challenge; its management is complex and requires a multidisciplinary approach to meet decision-making challenges in sex assignment, fertility and timing of gonadectomy, psychological outcomes and genetic counselling.

Mutations in the nuclear receptor subfamily 5 group A member 1 (NR5A1) are the underlying cause of 10–20% of 46,XY disorders of sex development (DSDs). We describe a young girl with 46,XY DSD due to a unique novel mutation of the NR5A1 gene. An 11-year-old subject, raised as a female, was noticed to have clitromegly. She looked otherwise normal. However, her evaluation revealed a 46,XY karyotype, moderate clitromegly but otherwise normal female external genitalia, undescended atrophied testes, rudimentary uterus, no ovaries, and lack of breast development. Serum testosterone and estradiol were low, and gonadotropins were elevated. Adrenocortical function was normal. DNA was isolated from the peripheral leucocytes and used for whole exome sequencing. The results were confirmed by Sanger sequencing. We identified a novel mutation in NR5A1 changing the second nucleotide of the translation initiation codon (ATG>ACG) and resulting in a change of the first amino acid, methionine to threonine (p.Met1The). This led to severe gonadal dysgenesis with deficiency of testosterone and anti-Müllerian hormone (AMH) secretion. Lack of the former led to the development of female external genitalia, and lack of the latter allowed the Müllerian duct to develop into the uterus and the upper vagina. The patient has a female gender identity. Bilateral orchidectomy was performed and showed severely atrophic testes. Estrogen/progesterone therapy was initiated with excellent breast development and normal cyclical menses. In summary, we describe a severely affected case of 46,XY DSD due to a novel NR5A1 mutation involving the initiation codon that fully explains the clinical phenotype in this subject.

Aim: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder of the adrenal steroidogenic pathway. The most common form of CAH is due to 21-hydroxylase deficiency resulting from mutations in CYP21A2 gene. The present study aimed to identify CYP21A2 common gene mutations, phenotype correlation, and to analyze the segregation pattern in CAH patients, parents, and siblings. Materials and Methods: Sixteen families having at least one classic CAH child in each family, a total of 58 subjects were recruited. The presence of six most common gene mutations, namely, Intron 2 (c.293-13A/C>G), c.844G>T (p.Val282Leu), c.1019G>A (p.Arg340His), c.92C>T (p.Pro31Leu), c.955C>T (p.Gln319*), and c.518T>A (p.Ile173Asn) in CYP21A2 gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using specific primers. Results: Out of 16 classic CAH females analyzed, salt-wasting (SW) form was present in 12 (75%) and simple virilizing form in four (25%) children. Isolated clitoromegaly was the most common clinical presentation followed by ambiguous genitalia. The most common mutation observed in CAH patient population was Intron 2 (c.293-13A/C>G) (100%) followed by p.Pro31Leu (98%), p.Gln319* (93%), p.Val282Leu (91.4%), and p.Ile173Asn (19%). Although p.Arg340His mutation was not observed in this study. Interestingly, Intron 2 (c.293-13A/C>G) homozygous was observed in 31.3% of the entire study cohort and p.Ile173Asn mutation was found to be associated with SW form. Conclusions: Our results suggested a high prevalence of CYP21A2 gene mutations among CAH patients and heterogeneous mutation spectrum in their families of south Indian cohort. The outcomes afford valuable evidence for premarital and prenatal screening as well as planning suitable programs to prevent the development of CAH in Indian population.

Objectives Accurate delineation of anatomy in children with ambiguous genitalia early in life is important. This commonly involves conventional fluoroscopic genitogram (traumatic to the child) and magnetic resonance imaging (MRI) examination (involves sedation). In this study, our objectives were twofold: (1) to describe the findings on transperineal ultrasound (TPUS) in normal children and (2) to describe the findings on TPUS in children with ambiguous genitalia and correlate them with conventional genitogram. Materials and Methods TPUS was prospectively performed in 10 children without genital ambiguity (5 girls and 5 boys). Subsequently, 15 consecutive children having disorders of sex differentiation (DSDs) with genital ambiguity underwent TPUS. The presence or absence of müllerian structures was documented. Of these patients, 14 also underwent conventional genitogram as a part of routine evaluation. The gold standard was established either by comparison with surgical findings (in patients who underwent surgery) or by comparison with a combination of findings on genitogram and transabdominal ultrasound in patients who did not undergo surgery. Results In all normal children, lower urogenital tracts could be clearly delineated on TPUS. Out of the 15 children with ambiguous genitalia, TPUS could establish the presence/absence of müllerian structures in 14. This was concordant with findings on conventional genitogram/surgery. In one patient, müllerian structure was missed on TPUS but demonstrated on genitogram. In two children, TPUS showed the müllerian structure, which was not seen on genitogram. When both the controls and the cases were combined, TPUS had an accuracy of 95% and specificity of 100% in the detection of müllerian structures. Conclusion TPUS is feasible and accurate in demonstration of lower urogenital tract anatomy in children with DSDs having ambiguous genitalia. It can be performed without sedation, and is suitable for use as a screening modality in children with ambiguous genitalia.

Abstract Background Generalized glucocorticoid resistance syndrome has a tremendously heterogenous and very broad clinical spectrum. This syndrome is caused by loss of glucocorticoid receptor (GR) function due to mutation leading impairment in GR signalling. It presents with hypercortisolism, hypertension, enlarged adrenal glands but no Cushingoid features. Extensive endocrinologic investigations and genetic analysis can determine this disease and help in managing the sequalae of this syndrome. We report this case after looking into its rarity and presentation which would give an insight about this disease. Case presentation A 26-year-old female presented with, hirsutism, acne, deep voice (which was patients main concern), hypercortisolism, raised testosterone, without features of Cushing’s. On examination she was normotensive, hirsutism and poorly developed breast with ambiguous genitalia. On investigation, she was found to have left adrenal mass, hypercortisolism and had resistance to dexamethasone suppression test. She underwent left open adrenalectomy followed by continued medication with dexamethasone. Conclusion This syndrome should be considered as a differential diagnosis in patients with hypercortisolism but without any features of Cushing’s syndrome. It is a difficult diagnosis for a urologist, endocrinologist help should be sought for better outcomes and adherence on long-term hormonal treatment.

Disorders of Sexual Development (DSD) are rare syndromes, which show congenital discordance between chromosomal, gonadal and phenotypic sex. A retrospective analysis was performed to analyse the histopathological profile and spectrum of a large number of cases of DSD received at a tertiary care center. There were 45 cases of DSD encountered over a period of eight years, from January 2012 to December 2020. Detailed evaluation of each case with respect to demographic details, clinical features, imaging and pathology was done. All cases were classified as per Chicago Consensus Classification (2006) modified in 2010. The 46, XY DSD were the most common 26 (57.78%) cases, followed by sex chromosomal DSD 14 (31.1%) and 46,XX, DSD 5 (11.1%). Among 46, XY DSD, Complete Gonadal Dysgenesis (CGD) (Swyer syndrome) and Complete Androgen Insensitivity Syndrome (CAIS) had the highest number of cases, with 30.77% cases of each. Among 46XX, DSD, cases of ovotesticular DSD amounted to 80%. In sex chromosomal DSD, cases of Mixed Gonadal Dysgenesis (MGD) amounted to 78.57%. Out of 45 cases studied in this series, 20% cases showed neoplasms, of which 8.89% were malignancies. Nine out of 45 (20%) patients had neoplasms, out of which 5 (55.6%) had benign tumours while 4 (44.4%) had malignant tumours. Five patients had gonadoblastoma and three of these had coexistent dysgerminoma. Two patients had sertoli cell adenomas, one seminoma and one serous cystadenoma. Frequent clinical features noted were primary amenorrhea seen in 25 (55.5%) cases and ambiguous genitalia seen in 18 (40%) cases, while the most common location of gonad was intra-abdominal in 30 (66.6%) cases. Streak gonads were seen in CGD, MGD and Turner's syndrome. Malignant germ cell tumours were seen in CGD and CAIS. Early diagnosis, good histopathology and follow-up are essential in the management of DSDs. [ABSTRACT FROM AUTHOR]

Background: The aim of this article is to review the essential concepts, current terminologies and classification, management guidelines and the rationale of gender assignment in different types of differences/disorders of sexual development. Main body: The basics of the present understanding of normal sexual differentiation and psychosexual development were reviewed. The current guidelines, consensus statements along with recommendations in management of DSD were critically analyzed to formulate the review. The classification of DSD that is presently in vogue is presented in detail, with reference to old nomenclature. The individual DSD has been tabulated based on various differential characteristics. Two schemes for analysis of DSD types, based on clinical presentation, karyotype and endocrine profile has been proposed here. The risk of gonadal malignancy in different types of DSD is analyzed. The rationale of gender assignment, therapeutic options, and ethical dimension of treatment in DSD is reviewed in detail. Conclusion: The optimal management of different types of DSD in the present era requires the following considerations: (1) establishment of a precise diagnosis, employing the advances in genetic and endocrine evaluation. (2) A multidisciplinary team is required for the diagnosis, evaluation, gender assignment and follow-up of these children, and during their transition to adulthood. (3) Deeper understanding of the issues in psychosexual development in DSD is vital for therapy. (4) The patients and their families should be an integral part of the decision-making process. (5) Recommendations for gender assignment should be based upon the specific outcome data. (6) The relative rarity of DSD should prompt constitution of DSD registers, to record and share information, on national/international basis. (7) The formation of peer support groups is equally important. The recognition that each subject with DSD is unique and requires individualized therapy remains the most paramount. [ABSTRACT FROM AUTHOR]

Background: The sex determination process requires distinct signaling pathways to generate either testis or ovaries from the same precursor structures, the primordial gonad. Deviations of this signaling mechanism may result in disorders/differences of sex development (DSD). The 46, XX testicular DSD is a rare genetic condition identified by a discrepancy between genetic and phenotypic sex caused sex reversal syndrome. Case Presentation: We describe the case of a 5 years-old 46, XX boy with ambiguous genitalia. On physical examination he had severe hypospadias, bifid scrotum, micropenis and palpable bilateral testes. Cytogenetic analysis of patient reveals a 46, XX karyotype. Hormonal assay showed low level of FSH, LH and Testosterone and there was no evidence of Mullerian structures based on pelvic imaging. The histopathology of gonadal tissue showed a Leydig cell hyperplasia which gives the impression of Sertoli cell nodule. Polymerase chain reaction (PCR) analysis failed to identify the presence of SRY gene, therefore a diagnosis of 46, XX Testicular DSD with SRY-negative was established. Conclusion: This report presents a rare case of SRY-negative 46, XX Testicular DSD in a boy with ambiguous genitalia. A comprehensive management including clinical, cytogenetic and molecular analyses have indicated that undiscovered genetic or environmental factors needs to be elucidated. It is important to carry out further molecular testing to establish precise diagnosis of DSD and to provide appropriate genetic counseling for patients and their family.

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.

Introduction: Diverse sex development (dsd) is an umbrella term for different congenital conditions with incongruence of chromosomal, gonadal, and phenotypic sex characteristics. These are accompanied by various uncertainties concerning health-related, medical, psychosocial, and legal issues that raise controversial discussion. Aim: The aim of this exploratory study was to investigate 3 questions: What are the most controversial and disputed issues in the context of intersex/dsd? Which issues are associated with the biggest knowledge gaps? Which issues involve the greatest difficulty or uncertainty in decision-making? A further aim was to investigate whether the group of persons concerned, the parents of intersex children, and the group of experts in the field had differing views regarding these questions. Methods: A self-developed questionnaire was distributed among persons concerned, parents of children with intersex/dsd, and experts in the field. It contained open and multiple-choice questions. The answers from 29 participants were entered into data analysis. A mixed-method approach was applied. Quantitative data were analysed descriptively. Qualitative data were analysed according to the principles of qualitative content analysis. Main Outcome Measure: Participants answered questions on the most controversial and disputed issues, issues associated with the biggest knowledge gaps, and issues associated with the most difficulty or uncertainty in decision-making. Results: The findings indicate that controversial issues and uncertainties mainly revolve around surgical interventions but also around the question of how to adequately consider the consent of minors and how to deal with intersex in the family. Significant differences were found between persons concerned and parents vs academic experts in the field regarding the perceptions of procedure of diagnostic investigation and/or treatment in adulthood, on legal questions concerning marriage/registered civil partnerships, and on lack of psychosocial counseling close to place of residence. Conclusion: The necessity of irreversible gonadal and genital surgery in early childhood is still a matter of strong controversy. To ensure the improvement in well-being of intersex persons, including a sexual health perspective, the positive acceptance of bodily variance is an important prerequisite. Psychosocial support regarding one-time decisions as well as ongoing and changing issues of everyday life appears to be an important means in reaching overall quality of life.Lampalzer U, Briken P, Schweizer K. Dealing With Uncertainty and Lack of Knowledge in Diverse Sex Development: Controversies on Early Surgery and Questions of Consent—A Pilot Study. Sex Med 2020;8:472–489.

Abstract BACKGROUND: Because normal male sexual differentiation is more complex than normal female sexual differentiation, there are more cases of disorders of sex development (DSDs) with 46,XY karyotype that have unclear etiology. However, Leydig and Sertoli cell markers are rarely used in distinguishing such individuals. OBJECTIVES: To evaluate the function of Leydig and Sertoli cells in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion. STUDY DESIGN AND SETTING: Case-control study with 77 patients, including eight with partial androgen insensitivity syndrome, eight with 5α-reductase deficiency type 2 (5ARD2) and 19 with idiopathic 46,XY DSD, and 42 healthy controls, from the Interdisciplinary Study Group for Sex Determination and Differentiation (GIEDDS), at the State University of Campinas (UNICAMP), Campinas, Brazil. METHODS: Baseline levels of gonadotropins, anti-Müllerian hormone (AMH), inhibin B, insulin-like 3 (INSL3), testosterone and dihydrotestosterone in cases, and AMH, inhibin B, and INSL3 levels in controls, were assessed. RESULTS: There was no significant difference in age between cases and controls (P = 0.595). AMH and inhibin B levels were significantly lower in cases than in controls (P = 0.031 and P < 0.001, respectively). INSL3 levels were significantly higher in cases than in controls (P = 0.003). Inhibin B levels were lower in 5ARD2 patients (P = 0.045) and idiopathic patients (P = 0.001), in separate comparisons with the controls. CONCLUSION: According to our findings, we can speculate that inhibin B levels may be used to differentiate among DSD cases.