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Annals of Pediatric Endocrinology &... Dec 2019Patients with ovotesticular disorder of sex development (DSD) and mixed gonadal dysgenesis (MGD) usually present with asymmetric gonads and have wide phenotypic...
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). Müllerian 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.
PubMed: 31905442
DOI: 10.6065/apem.2019.24.4.231 -
International Journal of Endocrinology 2019The purpose of this study was to describe baseline data on etiological, clinical, laboratory, and management strategies in Kenyan children and adolescents with Disorders...
OBJECTIVE
The purpose of this study was to describe baseline data on etiological, clinical, laboratory, and management strategies in Kenyan children and adolescents with Disorders of Sex Development (DSD).
METHODS
This retrospective study included patients diagnosed with DSD who presented at ages 0-19 years from January 2008 to December 2015 at the Kenyatta National (KNH) and Gertrude's Children's (GCH) Hospitals. After conducting a search in the data registry, a structured data collection sheet was used for collection of demographic and clinical data. Data analysis involved description of the frequency of occurrence of various variables, such as etiologic diagnoses and patient characteristics.
RESULTS
Data from the records of 71 children and adolescents were reviewed at KNH ( = 57, 80.3%) and GCH ( = 14, 19.7%). The mean age at the time of diagnosis was 2.7 years with a median of 3 months. Thirty-nine (54.9%) children had karyotype testing done. The median age (IQR) of children with reported karyotypes and those without was 3.3 years (1.3-8.9) and 8.3 years (3.6-12.1), respectively (=0.021). Based on karyotype analysis, 19 (48.7%) of karyotyped children had 46,XY DSD and 18 (46.2%) had 46,XX DSD. There were two (5.1%) children with sex chromosome DSD. Among the 71 patients, the most common presumed causes of DSD were ovotesticular DSD (14.1%) and CAH (11.3%). Majority (95.7%) of the patients presented with symptoms of DSD at birth. The most common presenting symptom was ambiguous genitalia, which was present in 66 (93.0%) patients either in isolation or in association with other symptoms. An ambiguous genitalia was initially observed by the patient's mother in 51.6% of 62 cases despite the high rate (84.7%) of delivery in hospital. Seventeen (23.9%) of the cases had a gender reassignment at final diagnosis. A psychologist/psychiatrist or counselor was involved in the management of 23.9% of the patients.
CONCLUSION
The commonest presumed cause of DSD was ovotesticular DSD in contrast to western studies, which found CAH to be more common. Investigation of DSD cases is expensive and needs to be supported. We would have liked to do molecular genetic analysis outside the country but financial challenges made it impossible. A network for detailed diagnostics in resource-limited countries would be highly desirable. There is a need to train health care workers and medical students for early diagnosis. Psychological evaluation should be carried out for all patients at diagnosis and support given for families.
PubMed: 31871452
DOI: 10.1155/2019/2985347 -
Genetics Feb 2020XY C57BL/6J (B6) mice harboring a -type Y chromosome (Y ), known as B6.Y mice, commonly undergo gonadal sex reversal and develop as phenotypic females. In a minority...
XY C57BL/6J (B6) mice harboring a -type Y chromosome (Y ), known as B6.Y mice, commonly undergo gonadal sex reversal and develop as phenotypic females. In a minority of cases, B6.Y males are identified and a proportion of these are fertile. This phenotypic variability on a congenic B6 background has puzzled geneticists for decades. Recently, a B6.Y colony was shown to carry a non-B6-derived region of chromosome 11 that protected against B6.Y sex reversal. Here. we show that a B6.Y colony bred and archived at the MRC Harwell Institute lacks the chromosome 11 modifier but instead harbors an ∼37 Mb region containing non-B6-derived segments on chromosome 13. This region, which we call , protects against B6.Y sex reversal in a proportion of heterozygous animals through its positive and negative effects on gene expression during primary sex determination. We discuss 's influence on the testis determination process and its possible origin in light of sequence similarities to that region in other mouse genomes. Our data reveal that the B6.Y sex reversal phenomenon is genetically complex and the explanation of observed phenotypic variability is likely dependent on the breeding history of any local colony.
Topics: Animals; Chromosomes, Human, Pair 13; DNA-Binding Proteins; Disorders of Sex Development; Female; Gene Expression Regulation, Developmental; Genome; Gonadal Dysgenesis, 46,XY; Gonads; Humans; Male; Mice; Mice, Inbred C57BL; Nuclear Proteins; Ovary; Sex Determination Processes; Testis; Transcription Factors; Y Chromosome
PubMed: 31836612
DOI: 10.1534/genetics.119.302786 -
Pediatric Endocrinology Reviews : PER Dec 2019Ovotesticular Differences in Sexual Development (OT-DSD) is a rare subset of DSD with great phenotypic variability characterized by the presence of both testicular and... (Review)
Review
Ovotesticular Differences in Sexual Development (OT-DSD) is a rare subset of DSD with great phenotypic variability characterized by the presence of both testicular and ovarian tissue in the same individual. Here, we describe the case of 46,XX, SRY-negative baby with ambiguous genitalia and ovotestis discovered during laparoscopy. As the family decided on female gender of rearing, the testicular component of the ovotestis was removed while the ovarian component was preserved. Stemming from this case, we review the clinical presentation of OT-DSD throughout ages, the role of genetics and risk for gonadal tumors when making decisions about prophylactic gonadectomy. Finally, we summarize the most recent information of the spontaneous endocrine function, with or without conservative therapy, and fertility potential of people with OT-DSD.
Topics: Female; Humans; Infant; Male; Ovotesticular Disorders of Sex Development; Sexual Development; Testicular Diseases
PubMed: 31763803
DOI: 10.17458/per.vol17.2019.kmv.endocrineovotesticulardsd -
Molecular Medicine Reports Jan 2020Disorders of sex development (DSDs) are congenital conditions in which the external appearance of the individual does not coincide with the chromosomal constitution or... (Clinical Trial)
Clinical Trial
Disorders of sex development (DSDs) are congenital conditions in which the external appearance of the individual does not coincide with the chromosomal constitution or the gonadal sex. In other words, there is an ambiguous or intermediate condition between the male and female phenotypes of the anatomical sex. These atypical conditions are manifested in several ways, ranging from genital ambiguity to phenotypes that are so attenuated that they can go unnoticed or appear normal. Currently, there is a lack of understanding of the factors responsible for these outcomes; however, they are likely to be conditioned by genetic, hormonal and environmental factors during prenatal and postnatal development. The present study determined the genetic etiology of DSDs in Colombian patients by conventional cytogenetic analysis, FISH and MLPA (for SF1, DAX1, SOX9, SRY and WNT4). A cohort of 43 patients with clinical phenotypes of sex development disorder was used in the present study. Using this multistep experimental approach, a diagnostic percentage of 25.58% was obtained: 17 patients (39.53%) were classified as having gonadal development disorders, the majority of which were ovotesticular disorders with numerical and/or structural alterations of the sex chromosomes, 9 patients (20.93%) were classified as having testicular DSD with a 46,XY karyotype, and 3 patients (6.98%) as having ovarian DSD with a 46,XX karyotype. The remaining 14 patients (32.56%) were classified as 'other' since they could not be grouped into a specific class of gonadal development, corresponding to hypospadias and multiple congenital anomalies. These findings highlight the importance of histological and cytogenetic studies in a gonadal biopsy. In 11/43 cases, the multistep experimental protocol presented in the present study yielded etiological or histological findings that could be used to define the medical management of patients with DSDs. In conclusion, for the etiological diagnosis of DSDs, a broad‑spectrum approach that includes endocrinological tests, conventional karyotyping, molecular karyotyping by FISH and, molecular tests is required, in addition to gonadal tissue analyses, to identify genetic alterations.
Topics: Abnormal Karyotype; Adolescent; Adult; Child; Child, Preschool; Chromosomes, Human, X; Chromosomes, Human, Y; Disorders of Sex Development; Female; Humans; Infant; Infant, Newborn; Karyotyping; Male; Middle Aged
PubMed: 31746433
DOI: 10.3892/mmr.2019.10819 -
Journal of the Endocrine Society Nov 2019Gonadal sex determination is a complex genetic process by which an embryonic primordium is driven to form an ovary or a testis, which requires a delicate dosage balance...
Gonadal sex determination is a complex genetic process by which an embryonic primordium is driven to form an ovary or a testis, which requires a delicate dosage balance involving many genes. Disruption in this molecular pathway can lead to differences of sex development (DSD). Although some genetic mechanisms leading to 46,XY DSD have been elucidated, little is known about copy-number variation (CNV) causing testicular or ovotesticular 46,XX DSD. We describe a 20-year natural history of a man with -negative 46,XX who was born with atypical male external genitalia, aortic coarctation, and bilateral blepharophimosis-ptosis. The molecular study identified a heterozygous 3-Mb 15q26.2 deletion, a gene-poor containing , which encodes the nuclear receptor COUP-TFII that is highly expressed in ovary and cardiac arteries. Immunohistochemistry confirmed the low COUP-TFII expression on his ovotestis tissue. Monosomy of 15q26.2, encompassing the gene, may act as a Z-factor regulating the male sex determination negatively. This finding supports a novel type of CNV resulting in DSD in an individual who developed male puberty spontaneously.
PubMed: 31687637
DOI: 10.1210/js.2019-00241 -
Journal of Clinical Imaging Science 2019Disorder of sex development is an inclusive term that refers to any problem where the genital organ is atypical in relation to chromosomes or gonads. Ovotesticular...
Disorder of sex development is an inclusive term that refers to any problem where the genital organ is atypical in relation to chromosomes or gonads. Ovotesticular disorder of sex development, which is formerly known as "true hermaphroditism," is the most rare form among all disorders of sex development in humans. It is characterized by the simultaneous presence of both ovarian and testicular tissues in the same individual and characteristically presents with ambiguous genitalia in neonates or infants. Herein, we present an unusual case of a 19-year-old individual with phenotypically nearly normal male genitalia who presented with the complaint of bilateral breast enlargement.
PubMed: 31538032
DOI: 10.25259/JCIS_45_2019 -
Journal of Clinical Research in... Sep 2020The 46,XX ovotesticular disorder of sex development (DSD) is rarely observed in humans. This disorder is generally described as ambiguous genitalia with the presence of...
The 46,XX ovotesticular disorder of sex development (DSD) is rarely observed in humans. This disorder is generally described as ambiguous genitalia with the presence of ovarian and testicular tissues in different gonads or in the same gonad. Almost no subjects with 46,XX ovotesticular DSD have sex-determining region of the Y chromosome (SRY) gene. It is known that excessive expression of SRY-related high mobility group box 9 (SOX9) is the cause of SRY-negative 46,XX ovotesticular DSD in the absence of SRY. Here, we analyzed our SRY-negative case with 46,XX ovotesticular DSD. In an array comparative genomic hybridization study using a peripheral blood sample from the patient, a duplication of 1114 kb (Hg19 coordinates: chr17:69006280-70120619) in the region of 17q24.3 containing SOX9 was detected. This is the first case reported from Turkey, exhibiting SOX9 duplication in SRY-negative 46,XX ovotesticular DSD.
Topics: 46, XX Disorders of Sex Development; Child, Preschool; Disorders of Sex Development; Female; Gene Deletion; Gene Duplication; Genes, sry; Humans; Male; Ovotesticular Disorders of Sex Development; Promoter Regions, Genetic; SOX9 Transcription Factor; Turkey
PubMed: 31476840
DOI: 10.4274/jcrpe.galenos.2019.2019.0101 -
PloS One 2019Testicular or ovotesticular disorders of sex development (DSD) in individuals with female karyotype (XX) lacking the SRY gene has been observed in several mammalian...
Testicular or ovotesticular disorders of sex development (DSD) in individuals with female karyotype (XX) lacking the SRY gene has been observed in several mammalian species, including dogs. A genetic background for this abnormality has been extensively sought, and the region harboring the SOX9 gene has often been considered key in canine DSD. Three types of polymorphism have been studied in this region to date: a) copy number variation (CNV) in a region about 400 kb upstream of SOX9, named CNVR1; b) duplication of SOX9; and c) insertion of a single G-nucleotide (rs852549625) approximately 2.2 Mb upstream of SOX9. The aim of this study was thus to comprehensively analyze these polymorphisms in a large multibreed case-control cohort containing 45 XX DSD dogs, representing 23 breeds. The control set contained 57 fertile females. Droplet digital PCR (ddPCR) was used to study CNVR1 and the duplication of SOX9. Fluorescent in situ hybridization (FISH) was used to visualize copy numbers on a cellular level. The Sanger sequencing approach was performed to analyze the region harboring the G-insertion. We confirmed that CNVR1 is highly polymorphic and that copy numbers varied between 0 and 7 in the case and control cohorts. Interestingly, the number of copies was significantly higher (P = 0.038) in XX DSD dogs (mean = 2.7) than in the control females (mean = 2.0) but not in all studied breeds. Duplication of the SOX9 gene was noted only in a single XX DSD dog (an American Bully), which had three copies of SOX9. Distribution of the G-nucleotide insertion was similar in the XX DSD (frequency 0.20) and control (frequency 0.14) cohorts. Concluding, our study showed that CNVR1, located upstream of SOX9, is associated with the XX DSD phenotype, though in a breed-specific manner. Duplication of the SOX9 gene is a rare cause of this disorder in dogs. Moreover, we did not observe any association of G-insertion with the DSD phenotype. We assume that the genetic background of XX DSD can be different in certain breeds.
Topics: Animals; Case-Control Studies; DNA Copy Number Variations; Disorders of Sex Development; Dog Diseases; Dogs; Female; SOX9 Transcription Factor; X Chromosome
PubMed: 31220175
DOI: 10.1371/journal.pone.0218565 -
Italian Journal of Pediatrics May 2019The choice of the sex of rearing in patients with ovotesticular differences of sex development (OT-DSD) is difficult. The final decision should be given by the patient...
BACKGROUND
The choice of the sex of rearing in patients with ovotesticular differences of sex development (OT-DSD) is difficult. The final decision should be given by the patient himself or herself, but families' opinion is not to neglect especially when the diagnosis is precocious and the patient can't give the consent to medical or surgical procedures. How should we behave if the parents refuse to raise a child with genital ambiguity?
CASE PRESENTATION
We describe and comment on our multidisciplinary approach in three patients with neonatal diagnosis of OT-DSD. The families expressed a strong desire for that which concerned the sex of rearing of their babies in contrast to the International trend of "wait and see". A specific counselling and a constant psychological support were given.
CONCLUSIONS
Recent trends suggest of postponing surgery to involve the patient in the decision. Child's well-being is the goal of therapy. When medical and psychological support is not able to force parents to accept a child suffering from genital ambiguity, we think that it is better to opt for reversible medical/surgical treatments rather than allowing patients to grow up within a family that does not accept them.
Topics: Decision Making; Disorders of Sex Development; Female; Humans; Infant, Newborn; Italy; Male; Parents
PubMed: 31146767
DOI: 10.1186/s13052-019-0660-8