Disorder of Sex Development, Mosaic Genetic Disorder 45x, 46xy: A Case Report

Background. Disorder of sex development (DSD) is a congenital disorder associated with interference in chromosomes, gonads, or sexes anatomically. Individual affected with DSD can be recognized since birth due to external genital ambiguity. Sexual chromosome DSD occurred because sexual chromosome numeric or structural disorder. Mosaic karyotype 45X/46XY is among the rare sexual chromosome DSD with incidence less than 1:15,000 live births. DSD individuals are susceptible to stigmatization. This can cause stress, negative emotion, and social isolation. Therefore, DSD individual management should be done as optimal as possible. Case Presentation: Twelve years old girl complaining a bump arose from anterior side of her genital resembles male genital since 4 years prior to admission without micturition and defecation complains. Patient has not experienced menarche. On external genital examination, we found the normal female external genital such as mons pubis, pubic hair, labia majora, labia minora, hymen, perineum, but without clitoris which in this case it is replaced by a glans of penis, arising from anterior commissure of labia majora area, with an urethral estuary. Before the management is done, patient underwent multidiscipline consultations and further examinations. Subsequently, it was approved that the joint conference formation consisting obstetric and gynecology, urologist, and pediatric endocrinologist to determine the optimal management for the patient. Conclusion: In this case, diagnosis was made with history taking, clinical examination, and supporting investigation such as ultrasound imaging and could be followed by biochemistry test, voiding cystourethrography or genitogram to determine next management. Counseling should be done in detail towards the family to know what action is best for the patient. Multidiscipline team was required to get the optimum result either in medical, ethical, or religious point of view. Surgery in this case was considered followed by long term therapy afterwards.

3β-Hydroxysteroid Dehydrogenase Type 2 (3βHSD2) Deficiency due to a Novel Compound Heterozygosity of a Missense Mutation (p.Thr259Met) and Frameshift Deletion (p.Lys273ArgFs*7) in an Undervirilized Infant Male with Salt Wasting

Deficiency of 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) is a rare type of congenital adrenal hyperplasia (CAH), causing impaired steroid hormone production in both adrenals and gonads. Phenotype ranges, according to the genetic defect, from the salt-wasting form in both sexes to undervirilization in males and virilization in females. We present a 13-month-old male infant who was admitted to the hospital with signs of adrenocortical insufficiency and genital ambiguity. Clinical presentation, hormonal profile, laboratory evaluation, and karyotype were suggestive of the salt-wasting form of CAH due to 3βHSD2 deficiency. Mutational analysis revealed a missense mutation c.776C>T (p.Thr259Met), inherited by the mother, and a frameshift deletion c.818-819delAA (p.Lys273ArgFs*7), inherited by the father. Both mutations are considered pathogenic. To our knowledge this is the first case of an undervirilized male infant with salt wasting bearing this pathogenic frameshift deletion p.Lys273ArgFs*7 in compound heterozygosity with the missense mutation p.Thr259Met.

Steroidogenic electron-transfer factors and their diseases

Most steroidogenesis disorders are caused by mutations in genes encoding the steroidogenic enzymes, but work in the past 20 years has identified related disorders caused by mutations in the genes encoding the cofactors that transport electrons from NADPH to P450 enzymes. Most P450s are microsomal and require electron donation by P450 oxidoreductase (POR); by contrast, mitochondrial P450s require electron donation via ferredoxin reductase (FdxR) and ferredoxin (Fdx). POR deficiency is the most common and best-described of these new forms of congenital adrenal hyperplasia. Severe POR deficiency is characterized by the Antley-Bixler skeletal malformation syndrome and genital ambiguity in both sexes, and hence is easily recognized, but mild forms may present only with infertility and subtle disorders of steroidogenesis. The common POR polymorphism A503V reduces catalysis by P450c17 (17-hydroxylase/17,20-lyase) and the principal drugmetabolizing P450 enzymes. The 17,20-lyase activity of P450c17 requires the allosteric action of cytochrome b5, which promotes interaction of P450c17 with POR, with consequent electron transfer. Rare b5 mutations are one of several causes of 17,20-lyase deficiency. In addition to their roles with steroidogenic mitochondrial P450s, Fdx and FdxR participate in the synthesis of iron-sulfur clusters used by many enzymes. Disruptions in the assembly of Fe-S clusters is associated with Friedreich ataxia and Parkinson disease. Recent work has identified mutations in FdxR in patients with neuropathic hearing loss and visual impairment, somewhat resembling the global neurologic disorders seen with mitochondrial diseases. Impaired steroidogenesis is to be expected in such individuals, but this has not yet been studied.

Cytogenetic and molecular characterization of an SRY-negative 46, XX ovotesticular DSD

Introduction: Ovotesticular disorder of sex development is a rare condition by the concomitant presence of testicular and ovarian tissue, and usually presents genital ambiguity. Are chromosomally heterogeneous, and cytogenetic analyses is relevant. Objective: report on a patient from Manaus, Amazonas state with ovotesticular disorder of sex differentiation 46, XX and SRY-negative. Case report: Patient of 19 years, first child of non-consanguineous parents. At birth, the patient was diagnosed with genital ambiguity and, without early diagnosis, he was registered as being of the male sex. The patient underwent surgery to correct bilateral cryptorchidism, orchiopexy and colpectomy. During puberty, he developed female and male sexual characteristics. Endocrinological (normal total testosterone and estradiol as high follicle-stimulating hormone and luteinizing hormone), histopathological (right gonad, ovarian follicles and left gonads, atrophic testicles), karyotype (46, XX) and molecular (SRY-negative). Diagnosis of ovotesticular disorder of sex development was established. The patient chose to remain male and underwent bilateral mastectomy, vaginal colpectomy and bilateral gonadectomy. Currently, the patient receives hormonal replacement therapy, follow-up with a multi-professional approach and awaits masculinizing genitoplasty. Discussion: In diagnostic research, cytogenetic and molecular analysis are primary tools. For OT-DSD individuals with 46, XX, the female sex is suggested as the best sex option. Unlike the reported cases, the patient chose the male sex, since the sex at registration of birth was important in his choice. Conclusion: Cytogenetic and molecular analyses allowed us to assist in the etiological diagnosis of the patient with OT-DSD from Manaus. However, molecular analyses are necessary to elucidate the genes involved in the sexual determination of this patient.

So, and if it is not congenital adrenal hyperplasia? Addressing an undiagnosed case of genital ambiguity

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

Clinical profile of patients with 46 XY disorders of sex development: a single centered experience

Background: XY disorders of sex development are a complex entity that needs medical attention from childhood to adolescence and throughout life. The aim of the study was to analyze retrospectively the medical records of subjects with 46 XY disorders of sex development (DSD) and characterize their clinical profile and management course in a tertiary care centre.Methods: 32 subjects with 46 XY DSD attending Endocrinology OPD / Gynecology between 2010 to 2020 were enrolled in the study. Data collected includes age at presentation, symptoms, sex of rearing, phenotype, external masculinisation score (EMS), karyotyping, gonadal features like location and histopathology, psychosexual domain and their management and follow up. Statistical Analysis: The mean and standard deviation was calculated for normally distributed data.Results: The mean (SD) age of all study subjects (n=32) were 15.5 ± 5.32 years. 46 XY DSD included cases of complete gonadal dysgenesis (n=6), mixed gonadal dysgenesis (n=6), complete androgen biosynthetic defects (n=9), partial gonadal dysgenesis (n=2), 5-alpha-reductase type 2 deficiency (n=8) and 17 betahydroxysteroid deficiency (n=1). The most common clinical presentation was for primary amenorrhea followed by genital ambiguity and virilisation in females. Resection of testis at the earliest or a biopsy of the testis if resection is postponed in a female sex assigned 46 XY DSD is favored. Male sex assigned 46 XY DSD needs corrective surgeries and orchidopexy for undescented viable testis with periodic follow up for testicular malignancy.Conclusions: 46 XY DSD’s may shares similarities in their clinical presentation, though age of presentation may be in a wide range. Proper gender assignment, gonadectomy, reconstructive surgeries, hormone replacement and time to time follow up for testicular malignancy in cases where the testes are preserved is the ideal management.

Role of Transperineal Ultrasound (TPUS) in Children with Ambiguous Genitalia

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

Genital ambiguity: a cytogenetic evaluation of gender

Background: Genital ambiguity is a complex genetic disorder of sexual differentiation into male or female. The purpose of the present study is to correlate the sex of rearing with the genetic sex and to find out the prevalence of chromosomal anomalies in patients with ambiguous genitalia. The findings can help in proper diagnosis, genetic counselling, and the reassignment of sex, if necessary. Methods: In this cross-sectional study, 22 patients from north Kerala, ranging in age from 17 days to 17 years, were included. All cases were subjected to the following: a detailed history, physical examination, evaluation of clinical data, and cytogenetic analysis. Based on the standard protocol, peripheral blood lymphocyte culture was done. Chromosomal analysis was carried out with the help of an automated karyotyping system after G-banding of chromosomes.Results: Out of the 22 patients with ambiguous genitalia, 12 patients were genetic females with karyotype 46, XX, and nine patients were genetic males with 46, XY karyotype. One was a rare variant of Klinefelter syndrome with karyotype 49, XXXXY. The most common diagnosis was congenital adrenal hyperplasia, followed by partial androgen insensitivity syndrome. Discrepancies between genetic sex and sex of rearing were noted in 27% of the cases.Conclusions: This study unfolds the variable etiology of ambiguous genitalia and emphasizes the importance of karyotyping in diagnosis, proper assignment of the sex, and appropriate management of patients with genital ambiguity.