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Nuclear receptor subfamily 5 group A member 1 (NR5A1) is a transcription factor critical for the development of various organs. Pathogenic variants in NR5A1 are associated with a spectrum of disorders of sex development (DSD). A 15-month-old baby, raised as a girl, was referred for genital swelling and ambiguous genitalia. Born to healthy consanguineous parents, the baby had a phallus, perineal hypospadias, labial fusion, and a hypoplastic scrotum. Hormonal evaluation showed normal levels, and ultrasonography revealed small gonads and absence of Müllerian derivatives. Post-human chorionic gonadotropin (hCG) testing indicated an adequate testosterone response. The karyotype was 46,XY, and in it was found a homozygous NR5A1 variant (c.307 C>T, p.Arg103Trp) in a custom 46 XY DSD gene panel. Notably, the patient exhibited complete sex reversal, hyposplenia, and no adrenal insufficiency. Previously, NR5A1 pathogenic variants were considered to be dominantly inherited, and homozygous cases were thought to be associated with adrenal insufficiency. Despite the homozygous pathogenic variant, our patient showed hyposplenism with normal adrenal function; this highlights the complexity of NR5A1 genotype–phenotype correlations. These patients should be monitored for adrenal insufficiency and DSD as well as splenic function. [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]

Diagnosing, managing and assigning gender for different causes of ambiguous genitalia in children can be challenging. This article will discuss about the types, diagnosis and treatment of disorders of sex development including congenital adrenal hyperplasia, 46 XY mixed gonadal dysgenesis and 46XY ovotesticular disorder of sex development. This article reports about 3 cases of disorders of sex development. The first case is about a three-year-old girl who was diagnosed with congenital adrenal hyperplasia, genital examination revealed clitoromegaly and a single urogenital sinus; she was managed medically and surgically. The second case is about a one-month-old child with 46XY karyotype, genital examination revealed penoscrotal hypospadias with right palpable and left impalpable gonads. The patient underwent diagnostic laparoscopy in which both female and male internal organs were found; based on these results a diagnosis of 46XY ovotesticular disorder of sex development was made. The third case is about a 3-month-old child with 46XY karyotype, genital examination revealed hypospadias with bilateral impalpable gonads. Diagnostic laparoscopy showed a uterus with a bilateral ovary-looking gonad; histopathology of the bilateral ovary-looking gonads was consistent with testicular tissue. Based on the above, a diagnosis of 46XY mixed gonadal dysgenesis was made. Disorders of sex development are classified into three main categories based on the karyotype, XX, XY and sex chromosome other than XX and XY. Laboratory investigations, karyotype, genetic analysis, imaging, surgery and tissue biopsy, all aid in diagnosing, deciding gender identity and managing different types of disorders of sex development. [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]

Neurofibromatosis type 1 is an autosomal dominant multisystemic disease caused by mutation of the neurofibromin (NF1) gene located on chromosome 17q11. We report a case of Neurofibromatosis 1 with ambiguous genitalia, giant congenital melanocytic nevus, and associated subpulmonic outlet ventricular septal defect, hitherto unreported in sub‐Saharan Africa. In addition, a literature review of congenital heart diseases associated with Neurofibromatosis 1 is presented. [ABSTRACT FROM AUTHOR]

Testosterone and dihydrotestosterone are significant drivers of male external genital development, and therefore teratogens that alter these hormone profiles have been hypothesized to cause aberrations in development. Here, we present the first case report of genitalia anomalies after prenatal exposure to spironolactone and dutasteride through 8-weeks of gestation. The patient was born with abnormal male external genitalia which was surgically managed. Long-term outcomes such as gender identity, sexual function, hormonal maturation through puberty, and fertility remain unknown. These numerous considerations necessitate multi-disciplinary management with close follow-up to address sexual, psychological, and anatomic concerns. [ABSTRACT FROM AUTHOR]

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.

Introduction: The aim of this retrospective study was to verify the association between the time of diagnosis and initial and final sex assignment in a disorder of sex development (DSD) diagnostic group, looking at the age of the patients at first visit, severity of genital ambiguity, and karyotype. Methods: The time of diagnosis was divided into 3 groups: before 2000, between 2000 and 2006, and after 2006. Data were categorized and analyzed using the χ2 test with α < 0.05. Results: A total of 567 cases were analyzed; 307 were assigned as male, 135 as female, and 125 remained undefined at the first visit. After clinical and laboratory evaluations, 369 patients were male and 198 were female. Neither initial nor final sex assignment proportions changed over time, but there were significant differences in the age at first visit, with referral occurring at an earlier age, as well as more severe genital ambiguity presentations, a higher proportion of sex chromosome aberrations, and a lower frequency of 46,XX DSD cases. This occurred both in the sample as a whole (567 cases) and in the group of 125 patients without definitive sex assignment at the first visit. The results were similar when only 284 patients aged less than 12 months at the first visit were analyzed. Discussion/Conclusion: Over time, there were no changes in sex assignment proportions, but there was an increased awareness of the need for early referral and changes in clinical, cytogenetic, and diagnostic aspects. [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

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]

Disorders of sexual development are a heterogeneous group of disorders in which chromosomal, gonadal or anatomical sex development is atypical. The majority of these children are recognized at birth by ambiguous genitalia. Legal and societal pressures require the physician and parents to assign sex rapidly. Though sex assignment is undebated in several disorders of sexual development, many others need an individualized approach to gender-related concerns. Gender dysphoria is prevalent in disorders of sexual development, and early gender-defining surgeries have potentially lifelong consequences. We use two cases, one of partial androgen insensitivity and another of simple virilizing congenital adrenal hyperplasia to illustrate that in disorders of sexual development, the ethical management principles remain the same at their core despite the vast differences in phenotypes. Sex assignment should maximize functional, psychological and sexual needs. Sex assigned should coincide with gender identity. We propose that we manage such children with the mutual participation of the physician, parents and the child. Though the parents and the physician have the child's best interests when making a decision, the child's developing autonomy should be protected. The communication of the health provider to the parent must be honest if early sex assignment is difficult. [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]

Genital anomalies are a heterogeneous group of congenital pathologies that have become increasingly relevant since the Chicago Consensus of 2005. Their postnatal diagnosis has developed significantly in the last two decades, while prenatal diagnosis seems to be underdeveloped, with few protocols available, fragmented scientific literature, and low diagnostic rates. This review aims to examine the current status of this subspecialty from the perspective of prenatal imaging. Indications for the evaluation of fetal genitalia can be divided into medical and non-medical reasons. Medical reasons include sex-linked disorders, detection of other anomalies, relevant family history, or multiple pregnancy. Non-medical reasons include parental request for sex disclosure. Disclosure of fetal sex may be associated with ethical, legal, and medical issues. The main imaging technology used is 2D ultrasound, although there are other complementary techniques such as 3D, MRI, or Color Doppler. Regarding working methodology, several authors have drawn attention to the lack of standardized protocols and guidelines. Most guidelines tend to limit their recommendations to study indications and ethical issues. Technical proposals, measurements, or working methods have not yet been standardized. Fetal sex determination is usually divided into early and late gestation. Early gestation is based on the sagittal sign. Late gestation is based on direct visualization. There are several measurements to describe male and female genitalia, such as penile length, bilabial diameter, or scrotal diameter. Prenatal diagnosis of genital pathologies presents some particularities such as the wide spectrum of phenotypes, the high frequency of associated deformities, or the time of diagnosis. Some of the most frequent pathologies are ambiguous genitalia, fetal sex discordance, hypospadias, micropenis, clitoromegaly, ovarian cysts, hydro(metro)colpos, and cloacal anomalies. Higher-quality studies and direction from scientific societies through the implementation of clinical guidelines are needed. [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.

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).

Congenital adrenal hyperplasia 'CAH' is a group of autosomal recessive disorders, resulting from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. The most frequent is steroid 21-hydroxylase deficiency, accounting for more than 90% of cases and can have diverse manifestations: from the salt wasting to the non-classical form due to a highly variable genetic mutation. We report a female infant aged two months, from Nag Hammadi, Upper Egypt, whose presentation and laboratory abnormalities were consistent with CAH, the classic 21-hydroxylase deficiency (salt-wasting type). The patient presented with ambiguous genitalia and salt wasting. The karyotyping was that of a normal female. There were elevated levels of serum 17-hydroxy progesterone, adrenocorticotropic hormone, rennin, and rostenedione and testosterone. Also, there were hyperkalaemia and hyponatremia. We conclude that CAH to be keep in mind in the differential diagnosis of any newborn female with ambiguous genitalia with normal karyotyping and we call for dried blood spot 17-hydroxyprogesterone assay to be included in the newborn screening program in Egypt. [ABSTRACT FROM AUTHOR]

Urorectal septum malformation sequence (URSMS) is characterized by a spectrum of anomalies of the urogenital system, hindgut and perineum. It is presumed to be a constellation of an embryonic defect. Herein, we analyzed the clinically diverse syndromes associated with URSMS in our perinatal evaluation unit. We reviewed fetuses with URSMS in referrals for perinatal autopsy over a period of 3 years. Chromosomal microarray and genome sequencing were performed whenever feasible. Literature was reviewed for syndromes or malformations with URSMS. We ascertained URSMS in 12 of the 215 (5%) fetuses. Nine fetuses (75%) had complete URSMS and remainder had partial/intermediate URSMS. Eleven fetuses had malformations of other systems that included: cerebral ventriculomegaly; right aortic arch with double outlet right ventricle; microcephaly with fetal akinesia deformation sequence; ventricular septal defect and radial ray anomaly; thoraco‐abdominoschisis and limb defects; myelomeningocele; spina bifida and fused iliac bones; omphalocele; occipital encephalocele; lower limb amelia and cleft foot. We report on six fetuses with recurrent and five fetuses with unique malformations/patterns where URSMS is a component. Exome sequencing (one family) and genome sequencing (eight families) were performed and were nondiagnostic. Additionally, we review the literature for genetic basis of this condition. URMS is a clinically heterogeneous condition and is a component of several multiple malformation syndromes. We describe several unique and recurrent malformations associated with URSMS. [ABSTRACT FROM AUTHOR]

The birth of a baby with ambiguous genitalia is rare and usually unexpected. Parents often receive inconsistent language from health-professionals after the birth. Initial interaction with the birth team has long-term consequences for families with babies born with ambiguous genitalia. Understand the current practices on the day of birth and explore knowledge gaps for midwives regarding babies born with ambiguous genitalia. Develop educational content that can enable midwives to respond appropriately when the sex of a baby is unclear. This study included two phases, utilising qualitative descriptive research design with semi-structured interviews to understand the experiences of midwives caring for babies with ambiguous genitalia and their families. The findings informed the development a midwifery educational resource using these qualitative findings. Our analysis of 14 interviews with Australian midwives identified that they had no formal education to support families with a baby with ambiguous genitalia. Emotional support, advocacy and medical information translation were areas midwives perceived as essential skills to support these families. Midwives provide a unique role in parental birth experiences. Themes that arose emphasised their psychosocial support role but lacked formal education and guidance on this topic. Midwives had learnt from the media about babies born with ambiguous genitalia and wanted evidence-based education to support parents. Midwife education focusing on both psychosocial and clinical care for parents and their baby with ambiguous genitalia is crucial. Midwives can play a pivotal role in supporting parents with a baby with ambiguous genitalia. Themes from this qualitative study informed the development of a midwifery education digital resource. [ABSTRACT FROM AUTHOR]

In this review, we describe normal development of fetal genitalia throughout gestation as well as the identification of normal male and female genitalia on ultrasound. We use abnormal and ambiguous genitalia as illustrative tools to assist with the identification of normal genitalia and recognition of some of the most common abnormalities in external genitalia development. [ABSTRACT FROM AUTHOR]

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]

46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases. [ABSTRACT FROM AUTHOR]

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]

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disease caused by a mutation in the 7-dehydrocholesterol reductase gene (DHCR7) on chromosome 11, which leads to 7-dehydrocholesterol reductase enzyme defects. This results in the building up of toxic by-products of cholesterol production in the blood and the nervous system. All this affects the growth and development of human body systems. We presented a case of a fetus of a pregnant woman with a high-risk pregnancy after IVF. The patient was referred for a fetal karyotype test, which showed a male sex (46, XY). This woman was referred to our centre for fetal heart evaluation. Based on our protocol established at the Department of Prenatal Cardiology of the Institute of the Polish Mother's Health Centre in Lodz, our examination starts with obstetrical screening, including ultrasound fetal gender evaluation. At this point of examination, the fetus presented ambiguous genitalia and fetal polydactyly. The fetal echocardiographic examination revealed atrioventricular septal defect. The presence of ambiguous genitalia and atrioventricular septal defect allowed us to suspect SLOS. As a result, further diagnostic steps were suggested, and the diagnosis was confirmed. The family chose comfort care with no postnatal intervention and planned the next pregnancy with another donor. We would like to underline the importance of a detailed ultrasound protocol before fetal echocardiographic examination for its proper interpretation. [ABSTRACT FROM AUTHOR]

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

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.

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]

Testes were associated with maleness from antiquity, and ancient societies had fanciful myths about the origins of the sexes and about fetal sexual development. 17th century anatomists developed the concept that mammals developed from eggs and discovered sperm in semen; in 1878, Hertwig observed sperm entering eggs (of sea urchins), establishing the cellular basis of sex development. Individuals with atypical genitalia were known clinically in the 17th century, with much debate about their origins, but by the late 19th century it was generally accepted that gonads determined sex, and that sex determined gender role. Testosterone was isolated in 1935, and Alfred Jost showed that both circulating testosterone and diffusible anti-Mullerian hormone were needed for male development. Patients with apparent androgen insensitivity were reported in 1937 and shown to be unresponsive to exogenous androgen by Lawson Wilkins in 1957; androgen receptor mutations were reported in 1989. Steroidogenic errors were associated with differences in sex development (DSDs) starting in the 1940s, and finding mutations in the responsible enzymes explained many forms of hyper- and hypo-androgenism in both sexes. Sex chromosomes were identified in the early 20th century; Y was associated with maleness, and the responsible SRY gene was identified in 1991. Early efforts to manage patients with DSDs were confounded by philosophical perspectives on the relative roles of prenatal biology versus postnatal environment. Approaches to natal sex assignment evolved in the later 20th century and now emphasize a team approach based on data, not guessing, parental involvement, cultural considerations, and the acknowledgement of uncertainty. [ABSTRACT FROM AUTHOR]

Less-invasive diagnostic approaches for low-birthweight preterm neonates with suspected differences of sex development have not been established. Herein, we describe our diagnostic approaches for a 297-g neonate with ambiguous genitalia. Using a fiberscope, the external genitalia were inspected in an incubator to minimize the risk of hypothermia and infection. Endotracheal aspirate, collected during routine care, was used for genetic testing to avoid anemia and vital signs fluctuations caused by peripheral blood sampling. Array comparative genomic hybridization indicated a 46,XY karyotype. No pathogenic variants of AR and SRD5A2 were found. Endocrinological data could not be evaluated owing to the absence of reference data. Identification and structural evaluation of the internal genitalia and gonads were difficult. On postnatal day 42, the parents assigned their baby's sex as male. Our less-invasive diagnostic approaches of inspection and genetic testing are useful for management, including sex assignment in extremely low-birthweight preterm neonates with ambiguous genitalia. [ABSTRACT FROM AUTHOR]

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.

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.