Unusual morphology of isolated male epispadia: A rare case report.

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.

Identification of a novel homozygous NR5A1 variant in a patient with a 46,XY disorders of sex development.

OBJECTIVES: 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). CASE REPORT: 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. CONCLUSIONS: 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.

A Case of de la Chapelle Syndrome.

A rare disorder of sex development (DSD) linked to a 46,XX karyotype is characterized by male external genitalia, which can range from typical to atypical, often accompanied by testosterone deficiency. A 3-year-old child who appeared phenotypically male was brought to the hospital by his parents due to concerns about ambiguous genitalia. A comprehensive series of pathological tests and radiological imaging studies were conducted to ascertain the underlying cause of his presentation. Karyotyping revealed a 46,XX genotype, while magnetic resonance imaging (MRI) results indicated the presence of both testes and a Müllerian remnant. Consequently, the diagnosis was established as the de la Chapelle syndrome. This case report aims to highlight various imaging findings associated with this syndrome.

Ambiguous Genitalia: An Unexpected Diagnosis in a Newborn.

Alterations in gonad formation or function can lead to congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. These conditions are referred to as disorders of sex development (DSD) and have a heterogeneous etiology. The assessment of these children by a multidisciplinary team is crucial for an accurate diagnosis and should be initiated promptly due to the potentially life-threatening nature of congenital adrenal hyperplasia, a common cause of DSD. We present a neonate born at 39 weeks with a weak cry, slight hypotonia, poor suction reflex, peculiar facies, and ambiguous genitalia. From the study carried out, the abdominopelvic ultrasound revealed a nodular structure compatible with the left gonad. Aneuploidy screening confirmed the presence of the Y chromosome. Additionally, normal endocrinological studies and the karyotype showed a genotype compatible with cri-du-chat syndrome with partial trisomy of chromosome 3. Children with cri-du-chat syndrome characteristically exhibit a cat-like cry and distinctive facial features, along with developmental delay and intellectual disability. Duplication of 3p is a rare genetic disorder, usually associated with other chromosomal anomalies and congenital malformations, namely, of the genitals.

Bladder Agenesis: A Systematic Review.

Bladder agenesis is a rare congenital deformity characterized by the absence of the bladder. It is primarily observed in postmortem dissections of stillbirths rather than live births. The condition is often associated with other congenital anomalies, leading to the hypothesis that most affected fetuses do not survive to term. However, the exact cause and specific associated anomalies remain unclear and poorly described in the literature. The limited mention of bladder agenesis in textbooks and literature underscores the importance of creating a comprehensive source for future research in this field. Therefore, our objective is to collect and analyze data on bladder agenesis, focusing on associated anomalies and potential causes, to enhance our understanding of the condition. We conducted a thorough review of reports collected from three databases, Google Scholar, PubMed, and Science Direct, last searched on July 30, 2023, starting with 327 reports. Excluding duplicates and records written in languages other than English, veterinary studies, irrelevant reports, or stillbirths. Inclusion criteria were the following: cases must have proven bladder agenesis, not hypoplasia, and must have most of the information, including the age of diagnosis, presenting symptoms, gender, associated anomalies, and management or outcome of the patient. A quality assessment was conducted according to the Joanna Briggs Institute checklist for case reports. A total of 65 case reports from 56 articles were included in the review. Through our manual analysis, we documented a wild array of malformations associated with bladder agenesis. Among the reports reviewed, 93% exhibited urinary system malformations beside bladder agenesis, 77% were found to have reproductive malformations, 44% had gastrointestinal anomalies, 38% showed musculoskeletal malformations, 28% had cardiac malformations, and another 28% had vascular anomalies. The overall mortality rate was 38%, with a higher rate of 74% for males compared to 20% for females. By collating and analyzing those case reports, we aim to contribute to a better understanding of bladder agenesis and its associated anomalies, facilitating further investigations and advancements in the field.

When to address form and when to address function: Timing of surgical reconstruction for a patient with 46 XY DSD.

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.

A Novel Variant in NR5A1 Presenting as 46,XY Difference of Sex Development.

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.

Total Vaginectomy in a True Hermaphrodite: A Case Report.

A case is reported herein of a true hermaphrodite (TH) with an ovotestis, a uterus, a vagina, and an underdeveloped phallus. The patient was raised by his parents as a male, based on the presence of a phallus with ambiguous genitalia. He started experiencing breast enlargement at the age of 14 and menarche by the age of 17. He was reviewed using ultrasound, magnetic resonance imaging of the abdomen, and karyotyping, and the reports showed evidence of Mullerian structures and 46 XX karyotyping. Based on the preferences of the patient and his parents and their psychological outlook toward the male gender, a total mastectomy, hysterectomy, bilateral gonadectomy, and total vaginectomy were performed. This was followed by reconstruction of the male genitalia and supplemented with male hormone replacement therapy. Accordingly, a TH was assigned a male gender.

A Case Report on Ambiguous Genitalia: A Diagnostic, Therapeutic, and Cosmetic Challenge.

Ambiguous genitalia is a matter of concern and needs thorough evaluation and treatment. Gonadectomy becomes a potentially lifesaving procedure in patients with partial androgen insensitivity due to the increased risk of malignancy if left undiagnosed. We present a case report of two patients in their late 20s and 30s, raised as girls, who came with complaints of primary amenorrhea with ambiguous genitalia. Both patients had features of masculinization. Her MRI revealed an absent uterus, cervix, upper 2/3 of the vagina, and ovaries, with the presence of bilateral testicles. She was diagnosed with partial androgen insensitivity syndrome. The first patient underwent bilateral gonadectomy with hernia repair and nerve-sparing reduction clitoroplasty with labioplasty. She is under close follow-up with a further plan for augmentation mammoplasty. The second patient, however, refused clitoroplasty and underwent bilateral gonadectomy. Androgen insensitivity syndrome is an X-linked inheritance with a mutation in the AR gene. It consists of a spectrum of conditions ranging from complete insensitivity to less insensitivity towards testosterone, which results in a complete, partial, and mild form of androgen insensitivity syndrome. Studies have been done on cosmetic outcomes after genitoplasty in children with genital atypicalities, which showed significant improvement (p<0.001) and no difference in ratings by parents and surgeons. Surgeries done on patients with partial androgen insensitivity syndrome are not only lifesaving procedures, but with reasonable reassurance, these aesthetic surgeries help people live a life that otherwise would have been genetically compromised.

The clinical characteristics and quality of life of 248 pediatric and adult patients with Congenital Adrenal Hyperplasia.

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 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). 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, pre-marital screening, and the implementation of awareness programs for people diagnosed with CAH in communities with high consanguineous mating.

Ambiguous genitalia, giant congenital melanocytic nevus and subpulmonic outlet ventricular septal defect in an African child with Neurofibromatosis 1.

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.

Desarrollo genital prenatal. Clasificación, diagnóstico y manejo de las anomalías de la diferenciación sexual / Prenatal genital development. Classification, diagnosis, and management of abnormalities of sexual differentiation

Revisión de la etiopatogenia y clasificación de las anomalías de la diferenciación sexual, así como del desarrollo genital prenatal, para que resulte de utilidad en la evaluación y manejo diagnóstico, mediante una búsqueda bibliográfica de la literatura más actual publicada a través de las bases de datos PubMed, MedLine, Embase, BioMed Central y SciELO. Las anomalías de la diferenciación sexual comprenden un amplio espectro de enfermedades que pueden desarrollarse en diferentes etapas de la vida. Estas anomalías requieren un manejo y evaluación compleja multidisciplinar en la que el obstetra desarrolla un papel fundamental, siendo referente en el diagnóstico prenatal de estas. La discordancia entre el sexo genético determinado por el test prenatal no invasivo y el fenotípico observado por medio de la ecografía es un hallazgo cada vez más frecuente, con una incidencia de 1 por cada 1.500-2.000 embarazos. La detección temprana de esta discordancia puede orientar la sospecha clínica y mejorar el manejo de las anomalías del desarrollo sexual desde la etapa prenatal.(AU)

To review the most current literature on the aetiopathogenesis and classification of abnormalities of sexual differentiation, as well as prenatal genital development. A literature search through PubMed, MedLine, Embase, BioMed Central, and SciELO databases was conducted. Abnormalities of sexual differentiation comprise a wide spectrum of diseases that can develop at different stages of life. These anomalies require complex evaluation by a multidisciplinary team in which the obstetrician plays a fundamental role in prenatal diagnosis. Discrepancy between the genetic sex determined by non-invasive prenatal testing and the phenotypic sex observed by ultrasound is an increasingly frequent finding, with an incidence of 1 in 1,500-2,000 pregnancies. Early detection of this discrepancy can guide clinical suspicion and improve the management of different sexual developmental anomalies from the prenatal period.(AU)

"Exogenous" 5 Alpha Reductase Deficiency: A Case Report.

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.

Disorder of sexual development, urinary bladder duplication, pancake kidney and neural tube defect.

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.

Supernumerary Kidneys Associated with Disorders of Sexual Development and Cloacal Anomaly: A Case Report.

Introduction: 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.

Imaging in fetal genital anomalies.

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.

Whole-Exome Sequencing Identified Rare Genetic Variants Associated with Undervirilized Genitalia in Taiwanese Pediatric Patients.

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.

Babies born with ambiguous genitalia: Developing an educational resource for Australian midwives.

PROBLEM AND BACKGROUND: 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. AIM: 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. METHODS: 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. 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. DISCUSSION: 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. CONCLUSION: 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.

The Development of Normal Fetal External Genitalia Throughout Gestation.

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.