Intersex Research Articles

Management of the child with ambiguous genitalia

Management of the child with ambiguous genitalia

Laterality of amygdalavolume of brain in different genders help predict individuals with ambiguous genitalia of disorders of sexual development

Laterality of amygdalavolume of brain in different genders help predict individuals with ambiguous genitalia of disorders of sexual development

Ambiguous genitalia in newborn.

Ambiguous genitalia in newborn.

Phenotypic spectrum and long-term outcomes of patients with 46,XX disorders of sex development.

46,XX disorders of sex development (DSD) involve atypical genitalia accompanied by a normal female karyotype. This study was performed to investigate the clinical characteristics and long-term outcomes of patients with 46,XX DSD. The study included 34 patients with 46,XX DSD who presented with ambiguous genitalia or delayed puberty. Patients with congenital adrenal hyperplasia were excluded. Clinical phenotypes and overall outcomes were analyzed retrospectively. Age at presentation ranged from birth to 40 years (median, 0.6 years), and the follow-up period ranged from 0.3 to 29.7 years (median, 8.8 years). Twenty patients were assigned female (58.8%). Etiologies included disorders of gonadal development (n=22), exogenous androgen exposure during pregnancy (n=5), association with syndromic disorders or genital anomalies (n=2), and unclassified causes (n=5). Ovotestis was the most frequent gonadal pathology (41.7%). Müllerian duct remnants were usually underdeveloped (52.9%) or absent (23.5%). Spontaneous puberty occurred in 17 of the 21 patients of pubertal age, while 9 patients required sex hormone replacement therapy. Gonadal complications were observed in 4 patients (gonadal tumors [n=3], and spontaneous gonadal rupture [n=1]), and gender dysphoria occurred in 1 patient who was assigned male. This study described the wide phenotypic spectrum and pubertal outcome of patients with 46,XX DSD. Long-term multidisciplinary monitoring for pubertal development, fertility, gender identity, and gonadal complications is recommended.

Aarskog Syndrome: Deep Phenotyping and Genomic Landscape of a New Cohort Including Adult Patients.

Aarskog-Scott syndrome (AAS, MIM#305400) is an X-linked disorder characterized by recognizable facial features, short stature, and genitourinary and skeletal malformations. AAS is attributed to pathogenic variants in FGD1, and ~60 patients with a genetic diagnosis have been reported to date. We hereby present a molecularly confirmed cohort of 14 male AAS patients from 13 families. Among 14 patients, 12 were referred during childhood, while two were referred at adulthood due to infertility. Six out of 11 patients with available records had antenatal manifestations, comprising shortened tubular bones, growth restriction, polyhydramnios, pes equinovarus, increased nuchal translucency, fetal hypokinesia, echogenic intracardiac focus, and ambiguous genitalia. In addition to well-described AAS findings, distinctive features observed in multiple patients included variable skin findings (n = 5), renal malformations (n = 2), muscular build (n = 2), and infertility (n = 2). Cardiac (n = 4) and ocular manifestations (n = 6) were identified at significantly higher rates than previously reported. This cohort also presents new patients with osteochondritis dissecans and oligo/azoospermia, providing further evidence to acknowledge these once-reported findings as part of the disease spectrum. Eleven different FGD1 variants, including seven novel ones, were identified through targeted FGD1 sequencing. Two variants were found to be recurrent, detected in two independent families. Our study provides additional insights into the clinical and genotypic landscape of AAS through the largest molecularly confirmed cohort, including two adult patients.

The epidemiology of disorders of sex development.

The epidemiology of disorders of sex development.

The prevalence of congenital anomalies in Basrah maternity hospital in the last 3 years

Background. Congenital anomalies (CAs) are structural or functional birth defects, including metabolic disorders, resulting from intrinsic developmental abnormalities or poor embryogenesis. They represent a significant cause of neonatal morbidity and mortality. Aim. To determine the prevalence of congenital anomalies in Basrah Maternity Hospital over the past three years. Method. A cross-sectional study was conducted at Basrah Maternity and Children Hospital from 2021 to 2023. Data were collected from official hospital records, including both vaginal and cesarean deliveries. Ethical approval was obtained from the Department of Obstetrics and Gynecology at Basrah Medical College and the Basrah Ministry of Health. Results and discussion. The study analyzed 127 cases of congenital anomalies. Gender distribution included 38.6% males, 46.5% females, and 15% with ambiguous genitalia. Birth weight varied, with 6.3% weighing <1500g and 7.1% >3500g. The most common anomalies were musculoskeletal (33.9%), anencephaly (15.7%), and congenital hydrocephalus (10.2%). The mean maternal age was 25.61 years, with 51.2% of mothers aged 20-29 years, while the mean paternal age was 32.82 years, with 47.2% aged 30-40 years. A consanguinity rate of 7.1% was reported. Mortality rates varied depending on the type of anomaly. Conclusion. The study highlights the complexity of congenital anomalies and the need for targeted interventions. Factors such as gender, parental age, and consanguinity influence anomaly patterns. Addressing mortality disparities requires improved healthcare strategies and interdisciplinary collaboration. Further research is essential to identify underlying causes and improve neonatal outcomes.

Infertility Work-up Reveals Adult Female Hypospadias Diagnosed via Pelvic MRI: A Rare Case Report

Female hypospadias (FH) is an extremely rare congenital anomaly characterized by an abnormally located urethral meatus on the anterior vaginal wall. Unlike male hypospadias, FH is seldom observed and is often overlooked, typically coexisting with other urogenital anomalies. The primary treatment is surgical urethral reconstruction. We present the case of a 26-year-old woman with a history of congenital adrenal hyperplasia and female pseudohermaphroditism. During an infertility work-up, a pelvic MRI revealed a urethro-vaginal communication concurrent with FH.

Urban intensity and runoff effects on oxidative stress and pathological severity in the testes and ovaries of blue crabs, Callinectes amnicola within a tropical lagoon system (Nigeria).

S. The spread of impermeable surfaces in urban coastal areas increases runoff, carrying pollutants that degrade surface water quality and impact the stress responses of coastal fauna. This study investigated oxidative stress and gonad health in male and female Callinectes amnicola (blue crabs) from urban and suburban regions of Lagos Lagoon. Gonadal damage in the crabs was linked to estrogenic metals (Cu, Zn, Pb, Cd) and antioxidant responses (MDA, GSH, GPx, CAT, and SOD). Urban male crabs showed higher oxidative stress, with elevated MDA and lower GSH and CAT levels, alongside regressive gonadal changes due to increased Pb, Cd, and Zn exposure. Suburban crabs, however, displayed more intersex conditions (ovotestes) correlated with elevated Cu levels in lagoon sediment. These results highlight severe testicular disruption in urban males and ovarian dysgerminomas in suburban females, indicating a sex-specific impact of pollution on reproductive health. The study identifies two primary reproductive toxicity risks: (1) male testicular damage and regressive lesions in urban crabs, caused by increased lipid peroxidation and oxidative stress, and (2) female endocrine disruption, with ovotestes in suburban populations potentially leading to nonviable follicles. These findings emphasize that urban blue crabs face significant risks across both sexes, while suburban populations are more affected by female-specific risks. The study underscores the need for targeted environmental management to address the different stressors impacting these populations.

Novel non-synonymous and synonymous gene variants of SRD5A2 in patients with 46,XY-DSD and DSD-free subjects.

SRD5A2 gene variants are associated with deficiency of steroid 5α-reductase type 2, which is an autosomal recessive disorder of sex development (DSD) present in 46,XY males with ambiguous genitalia. To determine the causality of the disorder, this study involved genetic screening of SRD5A2 in six unrelated patients with this condition. Polymerase chain reaction (PCR) assays excluded large duplications, insertions, or deletions, while bidirectional Sanger sequencing identified 15 single-nucleotide variants (SNVs), six patients with 46,XY-DSD carrying pathogenic non-synonymous SNVs (nsSNVs), and three subjects who were DSD-free with novel synonymous SNVs (sSNVs). Genomic outcomes showed that 9 non-synonymous coding SNVs are linked to patients with SRD5A2-associated steroid 5α-reductase type 2 deficiency (c.169G > C: p.E57Q; c.145G > A: p.A49T/c.686T > C: p.F229S; c.100G > A: p.G34R/c.344G > A: p.G115D; c.591G > T: p.E197D; c.92C > T: p.S31F/c.481A > C: p.I161L (a novel missense variant; Km,app = 1.19 ± 0.1 μM, Vmax,app = 688 ± 145.8 pmol/mg P/min); c.686T > C: p.F229S). This analysis also highlighted 2 non-disease-causing sSNVs in three DSD-free subjects (c.243G > T: p.T81 = ; c.594C > T: p.I198=). These silent mutations or sSNVs in the SRD5A2 gene have no functional consequences and might not be involved in steroid 5α-reductase 2 deficiency. The identification of these sSNVs in both healthy controls and patients might suggest natural genetic variability with a very low allele frequency in the Mexican population. Furthermore, these findings indicated that nsSNVs in the SRD5A2 gene altered normal development of external male genitalia, supporting their pathogenicity.

A Newborn With Ambiguous Genitalia and Persistent Hypoglycemia.

A Newborn With Ambiguous Genitalia and Persistent Hypoglycemia.

Human Sexuality: Logical Fallacies and the Shotgun Aim of Arguments from Nature

Observations from nature employed to challenge a traditional model of binary human sex, fixed at conception, typically draw on the diversity of sex expression and plasticity in the animal kingdom, variable fetal developmental pathways in humans that result in intersex conditions, or purported minor sexual dimorphism in humans. This article draws attention to logical fallacies unconsciously employed when projecting observations of biological phenomena to what should be affirmed, or what is possible, for humans. A recent publication by three Christian researchers, encapsulating multiple aspects of arguments from nature, serves as an expedient example for critique.

A Clinical Case of Ambiguous Genitalia in A New Born

Introduction: Ambiguous genitalia, also called as atypical genitalia is a rare condition where a child is born with outer genitals that do not clearly look either male or female. Lack of production of certain hormones can cause the embryo to develop with a female body type, regardless of genetic sex. Methodology: a 20 days old baby came in OPD with persistent vomiting and dehydration. She had hypernatremia, hypokalemia, cardiac arrhythmia. Genital examination showed ambiguous genitalia. Karyotyping report XY genotype. With conservative management she recovered and went home but returned back in emergency within few days in poor condition. There was severe depletion of serum potassium level and persistent arrhythmia for which the baby was transferred to NICU and put on ventilator. The baby finally died due to persistant arrythmia Result: on first admission the baby had hypokalemia (2.6 mmol/L), hypernatremia (168 mEq/L), moderate dehydration and metabolic acidisis (pH 7.31, Bicarbonate 18 mmol/L). Baby managed conservatively and Discharged. On 2nd admission the baby had poor general condition, persistant metabolic acidosis (pH 7.28 and Bicorbonate 12 mmol/L) and persistant hypokalemia Conclusion: with all the above findings we can conclude that the baby was suffering from congenital adrenal hyperplasia probably due to 17 alpha hydroxylase deficiency.

Can Individuals with 47,XYY Karyotypes Exist without Male Phenotype? A Narrative Literature Review and Case Report.

The 47,XYY syndrome is a genetic condition found in about 1 in 1000 male children. The expected phenotype is male but could vary greatly. Those with genitourinary abnormalities may also present with microphallus, hypoplastic scrotum, cryptorchidism, hypospadias and macroorchidism. This study reports a child with sex ambiguity who possesses an initial 47,XYY karyotype. We also conducted a narrative literature review of 47,XYY individuals and their respective genital phenotype and/or gender identity. The narrative literature review was performed by searching for "47,XYY" in the PubMed database. All studies published in English, Spanish or Portuguese from January 1960 to January 2024 that contained the term "47,XYY" in the title or abstract were included. Studies that did not describe the genital phenotype and/or gender identity of cases were excluded. We also described the case of a 2-month-old patient with the 47,XYY karyotype and sex ambiguity. Our patient underwent additional karyotype testing, resulting in 47,XYY [30] and another 45,X [2]/47,XYY [98] with mosaicism being confirmed by fluorescent in situ hybridization (FISH) on buccal smears (nuc ish (DXZ1 × 1, DYZ3 × 2)[64/100]/(DXZ1 × 1, DYZ3 × 0)[36/100]. A gonadal biopsy revealed an atrophic testis on the left and a streak gonad on the right, with a final diagnosis of mixed gonadal dysgenesis determined. The narrative review revealed 643 articles, of which 350 met the inclusion criteria. However, we excluded 132 articles because they presented no new cases. We included 138 articles, which presented a series containing less than 10 new cases with the 47,XYY karyotype (total of 327 cases), 58 articles presented 4001 cases and 22 articles presented 75 patients with the 47,XYY karyotype in mosaic with 45,X. For all 4403 analyzed cases, 4354 (98.90%) presented a male phenotype, of which 4322 had the 47,XYY karyotype and 32 had mosaicism with 45,X lineage. A further 23 (0.52%) presented a female phenotype, of which four had the 47,XYY karyotype and 19 had mosaicism with 45,X lineage. In addition, 23 (0.52%) cases presented ambiguous genitalia, of which two had the 47,XYY karyotype and 21 had mosaicism with 45,X lineage. Finally, three (0.06%) cases had undefined phenotypes, all with mosaicism with 45,X lineage. Of the six cases with the 47,XYY karyotype and no male phenotype, one had complete androgen insensitivity syndrome (CAIS), one had lipoid congenital adrenal hyperplasia, two had probable CAIS, and two presented an incomplete diagnostic investigation. A female or ambiguous genital phenotype in an individual with 47,XYY karyotype is uncommon and should alert to the presence of the 45,X lineage or association with other causes of disorder/difference of sex development.

P-06 WHEN IS GENDER SELECTION IN CONGENITAL ADRENAL HYPERPLASIA?

Abstract Introduction Congenital adrenal hyperplasia (CAH) is one of the most common (classical type; nonclassical type) genetic diseases and is inherited in an autosomal recessive manner. This disease can lead to adrenal insufficiency, fluid-electrolyte disorder, and ambiguous genitalia as a result of axis dysfunction in cortisol biosynthesis. The optimal time for gender identity formation is between the ages of 18 and 36 months. The gender assignment of patients with CAH should be done as soon as possible before people around them know about it. Clinical Case A 23-year-old patient with known CAH due to 21-hydroxylase deficiency was referred to our clinic by a psychiatrist 1 year ago with the diagnosis of gender dysphoria. In his history, the patient was admitted first to the hospital with complaints of nausea and vomiting only one month after birth by his family. During examination at that time, BP was 70/40mmHg, and genital examination revealed ambiguous genitalia. In laboratory tests, Na:128mEq/l, K:5.1 mEq/l, DHEA-SO4: 4mcg/dl, basal cortisol: 1.18 mcg/dl and 17-OH progesterone: 6.8 ng/ml were found, and Karyotype analysis was reported as 46 XX. According to these results, the patient was diagnosed with CAH. Genetic analysis revealed CYP21A2 IVS2-13 C>G homozygous mutation. The patient who has classical type CAH was accepted as a phenotypically and genetically female child by her family and had undergone 2 correction operations since the age of 1 due to ambiguous genitalia. Between 2003 and 2013, he continued his follow-up in the pediatric endocrinology department and used Hydrocortisone + Fludrocortisone treatment in varying doses. He expressed that he did not go for regular check-ups and did not use his medications until 2018. Due to being untreated for a long time, his testosterone levels were high as male normal ranges, and his phenotype was male. The Ferriman-Gallwey score was determined as 22, and reconstruction scars and narrow vaginal opening were observed in the genital examination. In the laboratory test without any treatment were 17-OH-progesterone > 20ng/ml, basal cortisol: 7.8 mcg/dl, ACTH: 570 pg/ml, total testosterone: 524 ng/L, estradiol: 42 ng/L, DHEAS:252 mcg/dl, FSH:4.5 IU/L, LH: 0.76 IU/L, Na:136 mEq/L, K:4.3 mEq/L. The patient, who had simple virilizing CAH and gender dysphoria together, was first planned to start steroid replacement therapy in terms of CAH treatment. According to his clinical course, a decision was made to re-evaluate him in terms of identity change and testosterone replacement therapy. Conclusion The majority of CAH patients were raised as chromosomally female-identifying and living as female despite masculinized gender behaviors. Only 5.2% of these patients experienced gender dissatisfaction. Recent studies have shown that rather than intrauterine hormone exposure, regular treatment during the growth period and gender orientation during follow-up are more accurate and important regarding psychosocial satisfaction.Figure 1Possesses a masculine phenotype without using any testosterone

P-05 17Β-HYDROXYSTEROID DEHYDROGENASE 3 DEFICIENCY: TWO CASE REPORTS

Abstract Introduction 17-β-hydroxysteroid dehydrogenase type3 (17β-HSD3) is an enzyme that produces testosterone from androstenedione, encoded by the HSD17B3 gene. Its deficiency causes 46 XY disorder of sex development (DSD) with autosomal recessive inheritance. 46 XY individuals with this enzyme deficiency can exhibit a wide range of phenotypes, ranging from normal female external genitalia to ambiguous genitalia. In early childhood, the diagnosis might be clinically indistinguishable from other causes of 46 XY DSD such as partial androgen insensitivity syndrome (AIS) and 5α-reductase type 2 deficiency. Laboratory diagnosis is based on a low testosterone/androstenedione ratio. The diagnosis is confirmed by molecular genetic testing. If the diagnosis is missed in early infancy, patients present with severe virilization symptoms and amenorrhea during puberty. We present two siblings followed and managed with a presumed diagnosis of AIS until the genetic testing was performed. Clinical Case 1 A 4-month-old patient with female external genitalia was operated on with suspicion of bilateral inguinal hernia, and pathologic investigation revealed immature testicular tissue. No uterus and ovaries could be detected by pelvic ultrasound. The karyotype analysis was consistent with 46 XY, and the patient was followed up with the diagnosis of AIS. The patient’s parents were first cousins. The patient was started on estradiol replacement when she was 13 years old. At the age of 21, she underwent vaginoplasty due to a 2 cm long vaginal canal. A genetic analysis was available when the patient was 21 years old. Next generation sequencing revealed a previously reported homozygous c.277+5g>A mutation in exon 3 of HSD17B3 gene. The diagnosis was established as 17β-HSD3 deficiency. Clinical Case 2 After the index case was diagnosed with AIS karyotype analyses were performed on three other siblings at the time. The patient’s 7 years old sibling, who had a complete female-appearing genitalia, had a karyotype of 46XY. As the presumed diagnosis was AIS, bilateral orchiectomy was performed after counselling. Estradiol replacement was started at the age of 14 and complete breast development was achieved. Vaginal length was reported as 8 cm. Further genetic analysis was performed at the age of 27 and it revealed that the two siblings shared the same genetic mutation. Both preferred to retain the female gender identity during adulthood. Two other female siblings with a karyotype of 46XX and both parents had a heterozygous c.277+5g>A mutation in the HSD17B3 gene. Conclusion Although clinical evaluation and laboratory test results might point out to 17-β-HSD3 deficiency, the definite diagnosis is established with genetic testing. As these patients might develop male gender identity, awareness of the disease and early genetic testing is of importance for the prevention of misdiagnoses, counselling for gender identity, deciding on surgical interventions, and management of these patients.

Nationwide carrier screening for congenital adrenal hyperplasia: integrated approach of CYP21A2 pathogenic variant genotyping and comprehensive large gene deletion analysis

BackgroundCongenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD CAH) is an autosomal recessive disorder resulting from pathogenic variants in the CYP21A2 gene. The disorder exhibits variable clinical severity, with the classical form manifesting as salt-wasting crisis in neonates, while inducing ambiguous genitalia in females and precocious puberty in males through simple virilization. Identifying at-risk couples during the preconception stage holds significance for optimizing reproductive choices. Methods: This study included 204 unrelated preconception individuals undergoing carrier screening. A robust molecular approach was devised for rapid detection of nine prevalent CYP21A2 pathogenic variants, utilizing Amplification-Refractory Mutation System (ARMS) PCR and mass spectrometry (MS) genotyping. Complementary quantitative real-time PCR (qPCR) and PCR-based Restriction Fragment Length Polymorphism (PCR-based RFLP) assays were employed for comprehensive gene deletion analysis. The concordance of pathogenic variant detection between ARMS-PCR and MS, as well as the consistency observed in molecular insights from qPCR and PCR-based RFLP, fortified the accuracy of our methodologies. Results: Our combined method could detect common pathogenic variants and large gene deletions with high concordance between ARMS-PCR, MS genotyping, qPCR, and PCR-based RFLP assays. Remarkably, two carriers exhibited significant large-scale deletions, while another manifested a carrier state due to minor-scale gene conversion. The estimated carrier frequency in our cohort using these methods was approximately 1 in 65 individuals. Conclusions: The methods used for 21-OHD CAH carrier screening offer a reliable, swift, and cost-effective approach for detecting common pathogenic variants and large deletions. Despite some limitations, such as the inability to detect all rare mutations, the techniques provide a practical solution for carrier screening, with an estimated carrier frequency of 1 in 65 in our study population. These findings support the potential adoption of these methods in national carrier screening programs, offering a practical balance between efficiency and affordability.

Genital Ambiguity in a 46, XY individual : a Rare Case

Introduction: Ambiguous genitalia/disorders of sexual development (DSD) is a disorder of sexual development that is atypical chromosomally, gonadally and anatomically, which is generally characterized by the presence of unclear external genitalia, which can cause biological, social and psychological problems in the patient. as well as family. Objective: To report a rare case of 46 XY disorders of sexual development. Case Report: A 20 years old patient was reported with complaints of primary amenorrhea, breasts that had not yet grown and genitals resembling male genitals. Through physical examination, fine hair appeared above the lips, acne, prominent thyroid cartilage, mammary tanner stage M1, and a structure resembling a penis on the genitalia. The patient was examined according to the algorithm for patients with DSD, namely an ultrasound examination with the result that no gonads were found, then the patient underwent a karyotyping examination with results of 46 XY. In the investigation, it revealed LH: 58.45 mIU/ml, FSH: 57.74 mIU/ml, testosterone: 228 ng/dl. Next, the patient is planned for further imaging examinations. Conclusions: DSD is genetically heterogeneous and careful assessment by a multidisciplinary team is essential to accurately diagnose DSD. Many forms of DSD go undiagnosed. It is important for physicians to have a clear decision-making pathway in evaluating patients with DSD Keywords: Disorders of Sexual Development, Ambiguous Genitalia, 46 XY

Congenital omphalocele with ectopic liver and hepatic cyst and unilateral kidney: A rare combination

Omphalocele is a rare congenital abdominal wall defect in which internal organs protrude through an abdominal wall defect covered by the peritoneum. There is paucity of literature on rare co-occurrence of ectopic liver in omphalocele content with congenital hepatic cysts. Here, we aim to report a case of a 33-week-old fetus with ambiguous genitalia and omphalocele. While performing an autopsy, we discovered that omphalocele contained an ectopic liver. In addition, we identified two hepatic cysts in the main liver and evidence of cholestasis on microscopy. Furthermore, a single kidney was identified in the sac. The condition was so clinically significant that it causes retardation of fetal growth and perinatal death of the fetus.

Robotic-assisted neovaginal creation: stepwise approach to the Davydov technique in a patient with Mayer-Rokitansky-Küster-Hauser syndrome.

Robotic-assisted neovaginal creation: stepwise approach to the Davydov technique in a patient with Mayer-Rokitansky-Küster-Hauser syndrome.