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Ovotesticular disorder is a rare form of sexual development in which a patient may have one ovary and one testis, or more commonly a gonad or gonads containing both ovarian and testicular tissue. Patients with this condition typically present in infancy with ambiguous genitalia. Delayed presentations of clinically symptomatic, older patients with normal external genitalia are extremely rare. We present a case of a 14-year-old male with normal external genitalia who presented with symptoms and signs consistent with spermatic cord torsion but found to have ovotesticular disorder on evaluation.

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.

When infants are identified with a difference of sex development (DSD), a thoughtful approach to imaging is essential to appropriate clinical management. This review provides a comprehensive guide for radiologists who are tasked with performing this critical assignment. We review the embryologic basis of DSDs, with attention to the imaging findings that can indicate specific diagnoses. We also discuss techniques for optimal imaging, including strategies for identifying the gonads by US, tactics for performing genitograms with fluoroscopy and contrast-enhanced US, and the appropriate utilization of MRI. Finally, we review the clinical data and imaging findings that characterize some of the most common DSDs, including congenital adrenal hyperplasia, complete androgen insensitivity syndrome and gonadal dysgenesis.

Objectives Aromatase deficiency is a rare autosomal recessive disease that results in the absence of aromatase. In females it presents with ambiguous genitalia and lack of secondary sexual characteristics during puberty. Aromatase deficiency is not attributed to any specific population, but it is more commonly seen in consanguineous parents. Herein, we report the first Old Order Mennonite family with that diagnosis. Case presentation Our proband is an Old Order Mennonite female born with ambiguous genitalia who was identified to carry novel homozygous variant in the CYP19A1 gene c.1304G>A (p. Arg435His). Her older brother was later confirmed with the same genetic diagnosis. Conclusions Recognizing the cultural sensitivity, unrecognized affected cases, and late presentation of males affected with aromatase deficiency, this condition may be more prevalent than believed in that population.

The aim of the study is to encourage a critical debate on the use of normality in the medical literature on DSD or intersex. For this purpose, a scoping review was conducted to identify and map the various ways in which “normal” is used in the medical literature on DSD between 2016 and 2020. We identified 75 studies, many of which were case studies highlighting rare cases of DSD, others, mainly retrospective observational studies, focused on improving diagnosis or treatment. The most common use of the adjective normal was in association with phenotypic sex. Overall, appearance was the most commonly cited criteria to evaluate the normality of sex organs. More than 1/3 of the studies included also medical photographs of sex organs. This persistent use of normality in reference to phenotypic sex is worrisome given the long-term medicalization of intersex bodies in the name of a “normal” appearance or leading a “normal” life. Healthcare professionals should be more careful about the ethical implications of using photographs in publications given that many intersex persons describe their experience with medical photography as dehumanizing.

Disorders of sex development (DSD) are a heterogeneous group of pathologies that result in an alteration in sex determination or differentiation. DSD are estimated to affect 1: 4,500 newborns and according to the 2006 Chicago Consensus classification, DSD can be divided into three categories: those with a 46 XX karyotype, those with a 46 XY karyotype and those relating to sex chromosomes. It is crucial to correctly identify the pathology already in the first days of life to direct the patient and his family to the best path of care. For this reason, the role of the pediatrician is fundamental in the correct identification of the clinical picture and in supporting the family during the long process that involves the management of these patients. To make a diagnosis, it is necessary to follow a path led by a multidisciplinary team that includes several steps such as the execution of the genetic analysis, the evaluation with diagnostic imaging methods and laboratory evaluations. The therapeutic management, on the other hand, is still very complex even if in recent years we have moved from an attitude of early gender reassignment to an approach of watchful waiting to let the patient choose when she/he is mature enough to do so, which gender she/he feels to belong. It should not be forgotten that throughout this process the pediatrician must be both supportive and clinically active in the management of the child and his family.

Objective: To determine the etiology of ambiguous genitalia in newborn females with XX karyotype. Study Design: Cross Sectional Observational study. Setting: Children Hospital and Institute of Child Health Multan (CH& ICH). Period: July 2018 to December 2019. Material & Methods: Fifty two patients were enrolled after taking informed consent from parents/guardians. Various causes of ambiguous genitalia like CAH, maternal intake of virilizing drugs during pregnancy and isolated local genital defect were noted. Results: Out of 52 patients, mean gestational age was 38.23 ± 2.36 weeks and 10 (20.2 %) had gestational age up to 36 weeks while 42 (80.8%) had gestational age more than 36 weeks. Mean age was 12.37 ± 4.21 days. Mean weight was 2965.43 ± 412.23 grams while 24 (46.1%) had weight up to 2500 grams and 28 (53.9%) had weight more than 2500 grams. Congenital adrenal hyperplasia in our study cases was noted in 45 (86.5%). Congenital local genital defects in our study cases were noted in 6 (11.5%) while maternal ingestion of virilizing drugs during pregnancy was noted in 1 (2%). CAH was not associated with gestational age or weight of newborn with p value 0.680 and 0.595 respectively. Conclusion: Congenital adrenal hyperplasia in our study cases was the commonest reason of ambiguous genitalia in newborn females with XX karyotype followed by congenital local defects and maternal use of virilizing drugs. High index of suspicion is required for the diagnosis of potential life threatening disorder like CAH.

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.

Neonates with ambiguous genitalia have various clinical presentations, etiologies, and outcomes, ranging from benign to life-threatening. This review provides a summary of these findings. Some diagnoses may lead to delayed sex assignment. A systematic approach to the evaluation of disorders of sex development can allow for timely treatment and family counseling.

After 20 years of debate on intersex care, there has been a slight movement away from the paradigm of 'optimal gender' including early genital modification to conform to predicted gender identity towards a paradigm of 'full consent' including the provision of full information about the risks, benefits and alternatives to interventions and the postponement of irreversible interventions on minors too young to give informed consent. However, controversy continues. Against this background, the aim of this study was to analyse core aspects of current debates in intersex care. Focus was placed on controversies about surgery on external genitalia; gonadectomies; the expressed wishes of patients under the age of consent; and how to deal with intersex within the family. Eight guideline-based interviews were conducted with two people with intersex/diverse sex development conditions who had been subjected to surgery, two parents of children with an intersex/dsd condition, two medical doctors, and two psychologists. Data were analysed thematically. Findings indicate that while 'full consent' influenced actions and debate, the persons involved held differing opinions about how this policy can or should be achieved. In addition, the data illustrated how concepts such as normalcy, identity and sexuality are relevant when dealing with intersex issues.

The clinical case of a rare variant of disorder of sex development (DSD) is described. This disorder was diagnosed with an emergency operation for the traumatic rupture of the gonad. A patient (14 years old) with a male phenotype and lack of muller duct derivatives had a female SRY negative karyotype (46,XX) and an ovotesticular gonad structure as a result of duplication in the regulatory zone of the SOX9 gene. Ovotesticular disorders of sex development with karyotype 46,XX, as a rule, are accompanied by an ambiguous genitalia and derivatives of the muller structures. Early diagnosis of the described variant of DSD was difficult due to the development of male type genitalia. Timely identification of DSD including the presented option of DSD, is possible during routine examinations of the urologist with mandatory ultrasound examination of the scrotum and pelvis.

Background: Ovotesticular disorder of sexual development (OT-DSD) is a rare condition characterized by abnormal gonadal development. Although most OT-DSD is diagnosed during infancy, diagnosis is o...

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

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.

Akbulut, Sami/0000-0002-6864-7711; TUNCALI, TIMUR/0000-0003-3600-8701 WOS:000531194300001 PubMed: 32388791 Purpose Congenital adrenal hyperplasia (CAH) is rare autosomal recessive disease. CAH due to 21-hydroxylase deficiency accounts for 95% of cases. We aimed to share the first case of coexistence of simple virilizing-type congenital adrenal hyperplasia [I172N mutation in the CYP21A], triple translocation [t(9;11;12)], and ovarian granulose cell tumor. Methods A 59-year-old female patient was presented to our clinic, complaining with abdominal pain and distension. Physical examination revealed palpable abdominal mass, virilism, ambiguous genitalia, clitoramegaly, and hyperpigmentation. Contrast-enhanced abdominal computed tomography showed a giant mass originating from the right tubo-ovarian structure. Results The patient was operated in the light of the clinico-radiological features mentioned above. A giant mass weighing 3500 g was detected on the right tubo-ovarian structure during laparotomy, and mass was excised with right tubo-ovarian structure. Immunohistochemical examination revealed ovarian granulosa cell tumor. The high serum concentration of 17-OH progesterone was measured at baseline and after 250-mu g bolus of synthetic ACTH. In genetic analysis, we screened for six-point mutations, large deletions, and non-common mutations using restriction fragment length polymorphism (RFLP) methods, PCR, and sequencing of CYP21 gene respectively. The patient was detected to be homozygous for the I172N mutation. In addition, 50% of the metaphases examined had triple translocation [t(9;11;12)]. Conclusion The coexistence of congenital adrenal hyperplasia, triple chromosomal translocations, and ovarian granulosa cell tumor has not been described previously. This coexistence may be a sign of a new syndrome.

BackgroundThe 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 bodyThe 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.ConclusionThe 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.

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.

Disorders of sex development (DSD) are a group of congenital conditions associated with anomalous development of internal and external genital organs. Ovotesticular disorder of sex development (OT-DSD) is a condition in which a child is born with both testicular tissue (that possesses variable fertility potential within seminiferous tubules) and ovarian tissue (with primordial follicles). These tissues may be co-existent in the same gonad (ovotestis) or independently in separate gonads. Here, we report the clinical case of a 21-month-old boy that we met during a humanitarian surgical mission performed at Hospital Dr. Francisco Moscoso Puello, Santo Domingo, Dominican Republic. The child was referred for management of hypospadias, cryptorchidism, and symptomatic right inguinal and umbilical hernias. With further chromosomal evaluation, the diagnosis of SRY-negative OT-DSD was made, and shared decision-making was used to determine the timing of gender assignment, reconstruction, and the child’s long-term care team. OT-DSD is an uncommon condition with unclear causes. Once a DSD condition is suspected at birth, a complete investigation should be performed, encompassing a descriptive examination, a basic electrolyte and hormonal profile, genetic assessment, and pelvic ultrasound. Consultation with a multidisciplinary team is warranted, including pediatric urology or pediatric surgery with urologic training, endocrinology, genetics, psychology, pathology, and the patient’s pediatrician at minimum before surgical reconstruction. It is crucial to involve the patient and their family with shared decision-making before surgery or gender assignment.

Hydrocephalus is a clinical condition that consists of an accumulation of cerebrospinal fluid around the brain; Dandy- Walker syndrome is a rare cause of it. We present the case of a newborn with prenatal diagnose of hydrocephalus due to a Dandy-Walker malformation, as well as ambiguous genitalia. After birth, diagnosis of Dandy-Walker malformation associated with uncommon extracranial manifestations is confirmed. Specifically, the baby presents interscrotal hypospadias and coronary sinus dilatation due to the persistence of the left superior vena cava. With the exposition of this case, we bring Malformacion de Dandy-Walker asociada a malformaciones extracraneales en un neonato Dandy-Walker malformation associated with extracranial abnormalities in a newborn out the complexity of the Dandy-Walker syndrome due to the malformations associated with it; the ones that will determine the prognosis and the need of a multidisciplinary treatment.

INTRODUCTION AND OBJECTIVE:9p24.3 is a chromosome hotspot for human GU anomalies with micro-deletions or -duplications associated with ambiguous genitalia and gonadal dysgenesis. One gene in 9p24.3...

Sex differentiation disorders (SDD) is the discrepancy between the genetic, gonadal and phenotypic sex of the child. Treatment of children with this pathology is a multidisciplinary problem relating to the different aspects of pediatric urology-andrology. The pediatric urologist-andrologist, who, in addition to the pediatric endocrinologist and genetics, examines newborns with sex differentiation disorders in perinatal centers and outpatient department, should be informed about proper diagnostic evaluation of children with such pathology. The presence of ambiguous genitalia requires such measures, as an exclusion of life-threatening conditions associated with virializing congenital adrenal hyperplasia in girls; determination of the chromosomal gender as a basis when choosing a legal gender for a child, the study of the hormonal status at an early age of 3-6 months to determine a prognosis of the gonadal hormonal function, an identification of exact variant of the SDD. Following the diagnostic algorithm at an early age with a proper sequence, patient referring determines the success of diagnostic and therapeutic procedures.

Purpose Patients with ovotesticular disorder of sex development (DSD) and mixed gonadal dysgenesis (MGD) usually present with asymmetric gonads and have wide phenotypic variations in internal and external genitalia. The differential diagnosis of these conditions is based on karyotype and pathological findings of the gonads. This study investigated the clinical features at presentation, karyotype, sex of rearing, and pubertal outcomes of patients with ovotesticular DSD and MGD. Methods The study comprised 23 patients with DSD who presented with asymmetric gonads. The presenting features, karyotype, sex of rearing, and pubertal outcomes were reviewed retrospectively. Results All 23 patients presented with ambiguous genitalia at a median age of 1 month (range, 1 day-1.6 years). Mullerian duct remnants were identified in 15 of 23 patients (65.2%). Fourteen patients were diagnosed with ovotesticular DSD, whereas the other 9 were diagnosed with MGD. Eight of 14 patients (57.1%) with ovotesticular DSD were raised as males, while 7 of 9 patients with MGD (77.8%) were assigned as males. One male-assigned patient with ovotesticular DSD changed to female sex at age 20 years. Conclusion Patients with ovotesticular DSD and MGD manifest overlapping clinical presentations and hormonal profiles. It is difficult to determine the sex of rearing and predict long-term pubertal outcomes. Therefore, long-term follow-up is required to monitor spontaneous puberty, sex outcome, and urological and gynecological complications.

This is an interview study with 32 British and Swedish health professionals who worked in multidisciplinary teams (MDTs) that delivered care for children and adults with intersex variations, otherw...

Context: Limited data are available on the exact incidence of disorders of sex development (DSD) with genital ambiguity at birth. Objective: To determine frequency of ambiguous genitalia in newborns. Design: Prospective multicenter study. Setting: Three tertiary care hospitals. Patients or Other Participants: All 14,177 babies born during the study period were included. Main Outcome Measures: All newborns were examined at birth; data on weeks of gestation, birth weight, and length were collected. A structured questionnaire was used for data collection. Quigley and Prader scales were used for phenotypic grading. Clinical and genetic investigations were performed. Results: Eighteen babies with ambiguous genitalia were found among 14,177 newborns (1.3/1000). Fifteen newborns had 46, XY DSD, one had 46, XX congenital adrenal hyperplasia, and one had 45, X/46, XY mixed gonadal dysgenesis. Karyotype analysis was not done in one baby who died in the neonatal period. The ratio of prematurity was higher in the DSD group (44% vs 11%; P < 0.001) and the ratio of small for gestational age was also higher in the DSD group (22% vs 5%; P = 0.007). Eight babies with DSD had mothers who had additional medical conditions, such as preeclampsia, depression, insulin resistance, and gestational diabetes mellitus. Conclusion: The frequency of ambiguous genitalia was higher than in previous studies, but, as with any experiment, the finding should be met with caution because this study was conducted in tertiary care hospitals. In addition, lower birth weight in the DSD group supports the hypothesis that early placental dysfunction might be important in the etiology of male genital anomalies. Copyright (C) 2019 Endocrine Society

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.

Individuals with an incongruence of their chromosomal sex and genital appearance are classified as having a disorder of sexual development (DSD), and they often present with ambiguous genitalia. The diagnosis and management of DSD patients are usually challenging and require a multidisciplinary approach. Gender assignment should not be based solely on physical exam and imaging but also on the genotype and hormonal function of the gonads. We present an infant born with ambiguous genitalia; the parents were told they were having a male infant during the prenatal ultrasound but at birth, the infant was found to have female-appearing external genitalia with no palpable gonads. MRI of the abdomen was inconclusive, but further workup, including karyotype, hormonal function, and intraoperative evaluation, was consistent with a male infant. He was, therefore, subsequently assigned to the male sex.

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.

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.

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.

The birth of a child with genital ambiguity, now more appropriately termed “disordered sexual development” or “DSD” is not a medical emergency. Such infants are perfectly healthy, at least initially, with normal cardiopulmonary function, normal electrolytes, and normal glucose concentrations. Even among infants with adrenal failure, the signs of mineralocorticoid deficiency (hyperkalemia, hyponatremia, acidosis) are not typically seen until 5–10 days of age, and hypoglycemia is quite rare. Instead, the emergency is social. The standard birth announcement declares “It’s a boy!” or “It’s a girl!” rather than the more appropriate “We had a healthy baby!”, and reflects society’s intransigently dichotomous, Manichean obsession with defining people by their sex. Thus, following the physical exam and review of the pregnancy history, the first step in the evaluation of the child with DSD is to speak to the family, congratulate them on the birth, and reassure them about all the good news about the baby. It is critical not to offer guesses or presumptive diagnoses; instead, tell the parents that, as embryos, boys and girls start out looking the same, that the processes of genital development are complex, and that a definitive diagnosis will be available within a few days to a week (depending on the available laboratory infrastructure). Parents are typically quite gratified when the doctor says, “We don’t know if your baby is a boy or a girl, but we know how to find out, we know how to deal with the various potential problems, and everything is going to be OK.” The next step is to call the best pediatric endocrinologist available.

A disorder of sexual development (DSD) can be defined as “…any problem noted at birth where the genitalia are atypical in relation to the chromosomes or gonads.” “Ambiguous genitalia” is a common term that is used to describe “atypical” internal or external genitalia. However, there are DSDs without ambiguity of the external genitalia that are not noted until later in life (e.g., pubertal failure). The definition of DSDs is not always hard and fast, or straightforward. For example, individuals with Turner syndrome are “female” yet Turner syndrome is a form of a DSD.

Congenital adrenal hyperplasia is a group of inherited disorders associated with decreased cortisol production and usually excessive adrenal sex steroid secretion. 21-Hydroxylase deficiency (21-OHd) is the most common cause. Depending on the functional residual enzymatic activity, clinical phenotypes are classified as classical 21-OHd CAH with prenatal onset, presentation of ambiguous genitalia at birth in females and with or without salt-wasting in both sexes. In prepubertal children, insufficient therapy causing exposure to elevated androgens is associated with decreased reproductive capability, specifically gonadal dysfunction in both sexes.

Objective: To describe the mode of presentation and frequency of external genital anomalies in disorder of sex development (DSD) Methods: This cross-sectional study was conducted at Children Hospital & Institute of Child Health, Lahore from January to December, 2016 on Children with DSD above 10 years of age. A detailed history and physical examination were done. Positive findings were recorded on a predesigned proforma and analyzed by SPSS 21. Karyotyping on blood samples was done to determine their genetic sex. Results: Out of 83 DSD children, 67% (n=56) were assigned a female sex at birth of which 9% (n=5) had ambiguous genitalia. Male sex at birth was given to 33% (n=27) of which 96% (n=26) had genital ambiguity. Mode of presentation other than ambiguous genitalia were delayed puberty, amenorrhea, hirsuitism, gynaecomastia, cyclic hematuria etc. Clitoromegaly was the main finding in 62.5% (n=5) and micropenis in 45% (n=9). Karyotypic sex of 56 female sex of rearing was 46XX 80% (n=45), 45X0 13% (n=7), XXX 2% (n=1) and 46 XY in 5% (n=3). Karyotypic sex of 27 male sex of rearing was 46XY in 78% (n=21), 46XX in 15% (n=4) and 47XXY in 7% (n=2). Conclusion: Disorders of sex development presented with a wide spectrum of external genital anomalies ranging from clitoromegaly in females to micropenis and hypospadias in males. There was also an extreme diversity in mode of presentation of these cases including pubertal delay, amenorrhea in females and gender confusion disorders. doi: https://doi.org/10.12669/pjms.37.1.2991 How to cite this:Khan S, Tafweez R, Haider A, Yaqoob M. Spectrum of external genital anomalies in disorders of Sex Development at Children Hospital & Institute of Child Health, Lahore, Pakistan. Pak J Med Sci. 2021;37(1):244-249. doi: https://doi.org/10.12669/pjms.37.1.2991 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Summary The diagnosis and management of children born with ambiguous genitalia is challenging for clinicians. Such differences of sex development (DSDs) are congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. The aetiology of DSDs is very heterogenous and a precise diagnosis is essential for management of genetic, endocrine, surgical, reproductive, and psychosocial issues. In this Review, we outline a step-by-step approach, compiled in a diagnostic algorithm, for the clinical assessment and molecular diagnosis of a patient with ambiguity of the external genitalia on initial presentation. We appraise established and emerging technologies and their effect on diagnosis, and discuss current controversies.

Disorders of sex development (DSDs) are characterized by discordance between phenotypic, gonadal, and genetic sex. DSDs can be classified into three categories based on karyotype: 46,XX, 46,XY, and sex chromosome DSDs. While many of the underlying genetic etiologies of DSDs are known, many remain elusive. DSDs are often diagnosed in the newborn period due to the presence of ambiguous genitalia on physical exam. The expanding use of noninvasive prenatal testing has increased the number of DSDs diagnosed prenatally. Some DSDs are also diagnosed in childhood or adulthood. Working together with a dedicated, multidisciplinary team, the primary care physician can be instrumental in the diagnosis, medical management, and general support of patients with DSDs. This chapter provides background on DSDs and highlights emergent situations and special considerations for individuals with DSDs.

Purpose Little is known about the phenotypes, diagnoses, and sex of rearing of infants with atypical genital development in the United States. As part of a multicenter study of these infants, we have provided a baseline report from US difference/disorder of sex development clinics describing the diagnoses, anatomic features, and sex of rearing. We also determined whether consensus guidelines are followed for sex designation in the United States. Methods Eligible participants had moderate-to-severe genital atypia, were aged

Queer Bioethics and the inventory of its potential populations include a wide range of queer subjects: lesbian parents, HIV-positive gay and bisexuals, transgender youth, and non-cisgendered individuals, to name a few. With the ethical dilemmas and ethical duties couched inside of a Queer Bioethics in mind, this article will consider one of the field’s most enduring citizens: the intersex child. More specifically, the figure of the intersex child with ovotesticular non-normativity will be scrutinized on ethical and clinical planes – a major aspect of queer bioethics is, after all, clinical ethics for queer populations. Ovotesticular conditions will be covered at length; we discuss different variations in addition to narrowing the topic to those with 46,XX and ambiguous genitalia, specifically those 75% diagnosed under the age of 20, and speak on issues related to this population. We will also briefly discuss the population of the 20% diagnosed under the age of 5 years old. Interventions will be discussed in all realms of intersex conditions – specifically ovotestes. We will conclude with a principalist approach to ethical topics such as autonomy, beneficence, and non-maleficence, weighing these principles equally and ultimately erring on the side of autonomy within pediatric ethics where possible.

Misdiagnosing a cloaca as a disorder of sex development may lead to inappropriate testing, treatment, and negative emotional consequences to families. We were impressed by the fact that a significant number of patients suffering from a cloaca were referred to us with the diagnosis of a “disorder of sex development” previously referred as “ambiguous genitalia” or “intersex”. On re-evaluation, none of them truly had a disorder of sex differentiation. This prompted us to conduct the following retrospective review to try to find the cause of the misdiagnosis and the way to prevent it. A retrospective review of our colorectal database was performed to identify the total number of patients with cloacas and the number initially diagnosed as “ambiguous genitalia, intersex”/disorder of sex development. The external appearance of their genitalia and unnecessary testing or treatment received were recorded. A total of 605 patients with cloacas were identified. Of these, 77 (12.7%) were referred to us with the diagnosis of “ambiguous genitalia” and 13 of them (17%) went on to receive an intervention that was not indicated: karyotyping (10), steroids (3), and ovarian biopsy (1). The karyotype result in all patients was XX. The misdiagnosis was triggered by the external appearance of the perineum, simulating a case of virilization with a hypertrophic clitoris, but was simply prominent labial skin. Careful examination of the perineal structure allowed us to determine that it consisted of folded skin with no evidence of corpora. Patients born with a cloaca are at risk for mismanagement from being erroneously labeled as disorders of sex development. The diagnosis of a cloacal anomaly is a clinical one. The practitioner must distinguish between phallus-like clitoral hypertrophy and a normal clitoris with prominent labial skin.

Highlights • Physical examination: Enlarged clitoris/micropenis, Bifid scrotum/labioscrotal fold, Separate urethral and vaginal orifices. • USG: A rudimentary uterus with no ovary, the rt. testis in the mid inguinal canal, and lt. testis in the deep inguinal ring. • Inj. Testosterone was given for consecutive 3 months followed by multiple surgeries at different settings. • 1st & 2nd stage of surgery: Seperation and closure of vaginal orifice, correction of chordee, and urethral plate was shaped. • 3rd stage of surgery: Urethroplasty, left orchiopexy and scrotal reconstruction were performed., Introduction Ambiguous Genitalia is a form of birth defect in which sex of the newborn cannot be readily distinguishable because of atypical appearance of the external genitalia. Case report–clinical findings The patient, an 8 months old baby, was identified as a female baby since birth; but, some senior members of their neighborhood raised confusion regarding sex differentiation of the child. On examination, there was enlarged clitoris or micropenis, bifid scrotum or labioscrotal fold, and separate presence of urethral and vaginal orifices. Right testis was found in the middle of right inguinal canal and left testis was found near the deep inguinal ring. Case report–diagnosis, therapeutic intervention and outcome The ultrasonogram showed a rudimentary uterus measuring 26.7 × 7.27 mm with no ovary and the right testis was found in the mid inguinal canal while the left testis was in the deep inguinal ring. Diagnostic endoscopic procedure showed normal appearing testes in deep inguinal ring, about 2 cm vaginal remnant with normal urethra and bladder. Hormonal study revealed low serum testosterone with normal DHT and high oestradiol while the karyotyping revealed 46XY. After 3 months of hormonal treatment, multiple surgical interventions were taken to correctly determine the sex of the child. Later on the patient was discharged with follow up advices. Conclusion ‘Ambiguous genitalia’ is considered as a taboo in Bangladesh; hence, the social awareness regarding this curable disorder is a timely need in Bangladesh.

We report a case of ambiguous genitalia in a 15-year-old patient to demonstrate input of medical imaging in the diagnosis and care of this rare congenital deformation. Disorders of sexual differentiation (DSD) have been defined as congenital conditions in which development of chromosome, gonad, or anatomic sex is atypical and that raise an issue in the sex assignment. In lower socioeconomic countries where antenatal diagnosis is almost non-existent, due to lack of technical facilities, their medical and surgical management is hard. The case which we report was investigated by ultrasonography and genitography, which remains primary indications in our context.

Background/Aims: Parents of children born with disorders of sex development (DSD) often experience anxiety, but risk factors, including parental perception of the severity of their child’s DSD, have not been examined. We hypothesized that severity of illness (SOI) ratings would relate to parental anxiety, and would be higher for parents of children with a potentially life-threatening DSD (e.g., 21-hydroxylase deficiency). Methods: Eighty-nine parents (Mage = 33.0, 56.2% mothers) of 51 children (Mage in months = 8.7) with a DSD including ambiguous genitalia were recruited from 12 specialized DSD clinics. Parents completed questionnaires prior to genitoplasty, 6 months post-genitoplasty, and 12 months post-genitoplasty (if completed). Data were analyzed with linear mixed modeling. Results: Parental anxiety decreased over time, χ2(1) = 10.14, p < 0.01. A positive relationship between SOI and anxiety was found, with SOI being a strong predictor of anxiety (b = 0.53, p < 0.01; χ2[1] = 5.33, p < 0.05). An SOI by time interaction indicated SOI had an increasing effect on anxiety over time, b = 0.06, p < 0.05; χ2(1) = 6.30, p < 0.05. There was no diagnosis by SOI interaction. Conclusion: Parental anxiety decreased over time, but those with higher SOI ratings reported greater initial anxiety followed by slower resolution over time. Underlying etiology of DSD had no effect on the relationship between SOI and anxiety.

The clitoris is a highly complex organ whose structure has only been clarified in recent years through the use of modern imaging techniques. Clitoromegaly is an abnormal enlargement of this organ. It may be congenital or acquired and is usually due to an excess of androgens in fetal life, infancy, or adolescence. Obvious clitoromegaly in individuals with ambiguous genitalia is easily identifiable, whereas borderline conditions can pass unnoticed. Case reports of clitoromegaly with or without clinical or biochemical hyperandrogenism are quite numerous. In these subjects, a comprehensive physical examination and an accurate personal and family history are needed to investigate the enlargement. We reviewed the literature on the conditions that may be involved in the development of clitoromegaly in childhood and adolescence.

Despite being the hidden sex in society, intersex people with ambiguous genitalia are visible in a number of circus and sideshow novels. These characters are often used as plot devices, performing a stable gender identity whilst concealing their intersex status for the sake of the plot. They are portrayed as deceptive and licentious, their identities placing them outside of the sex and gender binaries and leaving them dehumanised. It is only in Pantomime by Laura Lam that the possibility of an alternative portrayal is glimpsed, although questions regarding the sex and gender binaries and non-normative sexuality remain.

Congenital midline facial anomalies are a rare group of disorders that are often accompanied by a constellation of other clinical anomalies, many of which have been recognized as syndromes. The index case is a child with midline facial defect with cleft palate associated with ambiguous genitalia and an umbilical defect. Differential diagnoses including Holoprocencephaly (HPE), Midline facial Plane defect, Oral-facial Digital syndrome, and Kallmanns syndrome are discussed. Although the most probable diagnosis is HPE, ambiguous genitalia and umbilical deformity are atypical findings which merit special mention.

The baby with atypical or ambiguous genitalia is usually born in secondary care. For most clinicians, this is an unfamiliar and challenging scenario with the potential for life-long ramifications arising from a consultation led by an unprepared clinician. Language needs to be used carefully with particular clarity when liaising with parents, local health professionals and the specialist multidisciplinary team. Confidence in the recognition and assessment of atypical or ambiguous genitalia in a newborn will guide the local clinician when deciding on the initial investigations required and is a foundation for subsequent management. The local team have key roles in the initial support for parents as well as managing expectations at a time of great uncertainty. There are numerous different diagnoses that can result in atypical or ambiguous genitalia. The clinical findings should guide the initial investigations, and there are many pitfalls when it comes to interpreting the results. The aim of this article is to provide an initial approach to the management of a baby born with atypical or ambiguous genitalia.