XX Ovotesticular Disorder Research Articles

68. Inguinal Hernia Containing the Uterus in a Case of 46 XX Ovotesticular Disorder of Sex Development

68. Inguinal Hernia Containing the Uterus in a Case of 46 XX Ovotesticular Disorder of Sex Development

High-Throughput Splicing Assays Identify Known and Novel WT1 Exon 9 Variants in Nephrotic Syndrome

Frasier syndrome (FS) is a rare Mendelian form of nephrotic syndrome (NS) caused by variants which disrupt the proper splicing of WT1. This key transcription factor gene is alternatively spliced at exon 9 to produce 2 isoforms ("KTS+" and "KTS-"), which are normally expressed in the kidney at a ∼2:1 (KTS+:KTS-) ratio. FS results from variants that reduce this ratio by disrupting the splice donor of the KTS+ isoform. FS is extremely rare, and it is unclear whether any variants beyond the 8 already known could cause FS. To prospectively identify other splicing-disruptive variants, we leveraged a massively parallel splicing assay. We tested every possible single nucleotide variant (n= 519) in and around WT1 exon 9 for effects upon exon inclusion and KTS+/- ratio. Splice disruptive variants (SDVs) made up 11% of the tested point variants overall and were tightly concentrated near the canonical acceptor and the KTS+/- alternate donors. Our map successfully identified all 8 known FS or focal segmental glomerulosclerosis (FSGS) variants and 16 additional novel variants which were comparably disruptive to these known pathogenic variants. We also identified 19 variants that, conversely, increased the KTS+/KTS- ratio, of which 2 are observed in unrelated individuals with 46,XX ovotesticular disorder of sex development (46,XX OTDSD). This splicing effect map can serve as functional evidence to guide the clinical interpretation of newly observed variants in and around WT1 exon9.

An approach to the management and care of an individual with 46, XX ovotesticular disorder of sexual differentiation

Ovotesticular disorder of sexual differentiation (OT-DSD) is a rare condition defined by the presence of both testicular and ovarian elements in the same individual. Definitive diagnosis is made based on histological assessment of the gonad/s confirming both ovarian and testicular components. In this paper, we describe how a diagnosis of 46XX, OT-DSD was made in a 20-year-old individual with enlarged breasts and ambiguous genitalia. The initial impression was congenital adrenal hyperplasia (CAH) based on 46, XX karyotype and absence of testes on physical examination and imaging. However, biochemical tests were inconsistent with CAH, hence a more probable diagnosis of 46, XX OT-DSD was considered. The patient suffered from gender dysphoria and after extensive counseling, he decided to undergo gender-affirming surgery: laparoscopic excision of the left gonad, subtotal hysterectomy, bilateral mastectomy, and a masculinizing genitoplasty. Histopathology of the left gonad revealed an ovotestes which confirmed the diagnosis of 46, XX OT-DSD.

Duplication of SOX9 associated with 46,XX ovotesticular disorder of sex development.

The purpose of the present study was to investigate whether ten unrelated SRY-negative individuals with this sex differentiation disorder presented a double dose of SOX9 as the cause of their disease. Ten unrelated SRY-negative 46,XX ovotesticular disorder of sexual development (DSD) subjects were molecularly studied. Multiplex-ligation dependent probe amplification (MLPA) and quantitative real-time PCR analysis (qRT-PCR) for SOX9 were performed. The MLPA analysis demonstrated that one patient presented a heterozygous duplication of the entire SOX9 coding region (above 1.3 value of peak ratio), as well as at least a ~ 483 kb upstream duplication. Moreover, no duplication of other SOX9 probes was observed corresponding to the region between -1007 and -1500 kb upstream. A qRT-PCR analysis showed a duplication of at least -581 kb upstream and ~1.63 kb of the coding region that encompasses exon 3. The limits of the duplication were mapped approximately from ~71539762 to 72122741 of Chr17. No molecular abnormalities were found in the remaining nine patients. This study is thought to be the first report regarding a duplication of SOX9 that is associated with the presence of 46,XX ovotesticular DSD, encompassing at least -581 kb upstream, and the almost entire coding region of the gene.

Clinical Spectrum of Disorders of Sex Development: A Cross-sectional Observational Study.

Objective:Disorders of sex development (DSD) constitutes a small but difficult and equally important area of endocrinology. It is often a social emergency as the decision regarding sex assignment in these cases is extremely disturbing and difficult to both families and healthcare professionals. Our study was devised to assess the clinical and chromosomal profile of patients with suspected DSD and classify them according to the new DSD consensus document.Subjects and Methods:This study was a cross-sectional observational study carried out in the department of pediatrics of a tertiary care hospital from August 2012 to August 2014. All patients with suspected DSD in the age group of 0–19 years were included. After detailed history and examination, karyotyping, abdominal sonography, and hormonal analysis were done. Additional studies like gonadal biopsy, laparoscopy, and hormone stimulation tests were done in selected cases.Results:About 41 patients were included in the study. The mean age of presentation was 87 months (1 day to 16 years). Only seven (13.7%) patients presented in neonatal period. In total, 25 patients had ambiguous genitalia; 46, XX DSD were diagnosed in 24 (58.5%) patients, 46, XY DSD in 10 (24.4%) patients, and sex chromosome DSD in 7 (17.1%). Congenital adrenal hyperplasia (CAH) was the commonest disease diagnosed in 21 (51.2%) patients. Turner syndrome, Klinefelter syndrome, androgen insensitivity syndrome, 46, XX ovotesticular disorder, and 46, XY gonadal dysgenesis were diagnosed in 3, 3, 4, 3, and 5 patients, respectively. Eleven patients with CAH presented in shock and six had history of sib deaths.Conclusion:46, XX DSD were the commonest etiological group in our study and CAH was the commonest individual disease. There is a need for educating general public and practitioners regarding DSD to allow early intervention. Moreover, there is a need to introduce routine neonatal screening for CAH in our country.

A case report: 46,XX ovotesticular DSD

Ovotesticular disorder of sex development (ovotesticular DSD) is a very raredisorder in which an infant is born with the internal reproductive organs (gonads) of both sexes (female ovaries and male testes). The gonads can be any combination of ovary, testes or combined ovary and testes (ovotestes). This article aim to present a rare case of 46,XX ovotesticular disorder of sexual development (DSD) in a 14-year-old child.

46, XXovotesticular disorder of sex development with serous cystadenomas of the ovary

Ovotesticular disorder of sex development (DSD) is an extremely rare condition and is defined as presence of both ovarian and testicular tissue in the same individual, regardless of the karyotype and the status of the external or internal genitalia. This disorder was formerly called True hermaphroditism and 400-500 cases have been reported in literature till date. Various chromosomal abnormalities have been described but 46XX is the commonest. Both Mullerian and Wolffian duct derivatives are present in the same individual and the external as well as internal genitalia display a spectrum of phenotypes. The external genitalia are ambiguous and a uterus and a phallus areoften present. The gonads may be ovotestis or a combination of ovary on one side and testes or ovotestis on the other side. These gonads are prone to develop both benign and malignant neoplasms. Tumors like dysgerminoms, seminomas, gonadoblastoma, and mucinous cystadenomas have been described. Serous cystadenomas however, have not been described.

Coexistence of Trisomy 13 and SRY (−) XX Ovotesticular Disorder of Sex Development

ABSTRACTIntroduction: Ovotesticular disorder of sex development (OT-DSD) is a rare disorder of sexual differentiation characterized by the presence of both testicular and ovarian tissue in an individual and the majority of cases have been reported with 46,XX karyotype. In 46,XX cases, testicular differentiation may occur due to the translocation of SRY to the X chromosome or to an autosome. Case report: Herein, we present a female newborn with a combination of trisomy 13 and SRY (-) XX OT-DSD. Conclusion: Trisomy 13 is a relatively common and well-known chromosomal disorder in which disorders of sexual differentiation are not frequent. In the absence of SRY, overexpression of pro-testis genes, or decreased expression of pro-ovarian/anti-testis genes have been suggested as underlying mechanisms of testicular formation. The findings in this patient were suggestive of an underlying genomic disorder associated with FGF9 and/or SPRY2.

46 XX Ovotesticular Disorder of Sexual Development with Detected SRY (Sexdetermining Region Y) Gene: A Case Report

Ovotesticular disorder or true hermaphroditism is a condition in which an individual has both ovary and testis. The ovary is usually located on the left side, whereas the testis is on the opposite side. The SRY gene is detected in one third of cases of 46 XX ovotesticular DSD. The most common karyotype of ovotesticular DSD is 46 XX. Here, we report the case of a girl with SRY positive 46 XX karyotype diagnosed as ovotesticular DSD by gonadal biopsy. The patient presented with female phenotype and ambiguous genital since birth. The external genital showed an accessoria penile without OUE with rough right labia majora that looked like scrotum. Testicle was felt on the right side of scrotum. USG revealed no appearance of normal uterus, right testicle was visualized but no visualization of left testicle. Right and left ovaries were not clearly visualized. Karyotyping-46 XX and SRY gene was detected on 472 bp fragment on multiplex PCR of AZF/SRY gene analysis. Diagnostic laparoscopy showed left hemiuterus with fallopian tube and unilateral left side ovary. The shape and size of left fallopian tube was normal. Histopathologic examination report revealed left gonad was ovarium with primary follicle and right gonad was testicle with leydig cell and seminiferous tubules. This patient was decided as a girl. The operation was initiated and divided into 2 phases. The first phase was orchidectomy of the right side testicle and the second phase was genital reconstruction (clitoroplasty and labioplasty).

46,XX ovotesticular disorder in a Mexican patient with Beckwith–Wiedemann syndrome: a case report

IntroductionBeckwith–Wiedemann syndrome is an overgrowth syndrome that is characterized by hypoglycemia at birth, coarse face, hemihypertrophy and an increased risk to develop embryonal tumors. In approximately 15% of patients, the inheritance is autosomal dominant with variable expressivity and incomplete penetrance, whereas the remainder of Beckwith–Wiedemann syndrome cases are sporadic. Beckwith–Wiedemann syndrome molecular etiologies are complex and involve the two imprinting centers 1 (IC1) and 2 (IC2) of 11p15 region. This case report describes, for the first time, the unusual association of ovotesticular disorder in a patient from Morelia, Mexico with Wiedemann-Beckwith syndrome.Case presentationWe report the case of a Mexican six-year-old girl with Beckwith–Wiedemann Syndrome, ambiguous genitalia, and bilateral ovotestes. She has a 46,XX karyotype without evidence of Y-chromosome sequences detected by fluorescence in situ hybridization with both SRY and wcp-Y probes.ConclusionAlthough a random association between these two conditions cannot be excluded, future analysis of this patient with Beckwith–Wiedemann syndrome and 46,XX ovotesticular disorder may lead to new insights into these complex pathologies. We speculate that a possible misregulation in the imprinted genes network has a fundamental role in the coexistence of these two disorders.