True Hermaphroditism Research Articles

Perspectives in Pediatric Pathology, Chapter 7. Ovotesticular DSD (True Hermaphroditism).

Perspectives in Pediatric Pathology, Chapter 7. Ovotesticular DSD (True Hermaphroditism).

Ovotesticular Disorder of Sex Development: A Single-Center Experience

Ovotesticular disorder of sex development (OT DSD) is a rare disorder of sex development characterized by the presence in the same individual of both histologically proven testis and ovary. There are scant data from the Indian subcontinent regarding this disorder. The aim of this study was to describe the clinical, biochemical, imaging, cytogenetic, surgical, and histopathologic findings and outcomes of patients with OT DSD from Western India. The records of patients referred to our center for disorders of sex development between 2005 and 2013 were reviewed, and 7 patients were found to have histologically proven OT DSD. The median age at presentation was 8 years (range, 2 months to 25 years). Clinical presentation varied from genital ambiguity and inguinal swelling at birth to gynecomastia and cyclical hematuria after puberty. Karyotype was 46, XX in 6 patients and 46, XY in 1 patient. All patients underwent pelvic ultrasonography, laparoscopy, and surgery for removal of gonads not congruous with the chosen sex of rearing. Gender assignment for all the patients was done by the parents at birth, which was mainly influenced by the external genitalia and sociocultural influences, with 5 out of the 7 patients being reared as males. There was no evidence of gonadal tumors in our study. OT DSD should be considered as one of the differential diagnoses in cases of ambiguous genitalia with nonpalpable or asymmetrical gonads, pubertal gynecomastia, and cyclical hematuria, irrespective of the karyotype or internal genitalia.

"Normalizing" Intersex Didn't Feel Normal or Honest to Me.

“Normalizing” Intersex Didn’t Feel Normal or Honest to Me. Karen A. Walsh I am an intersex woman with Complete Androgen Insensitivity Syndrome (CAIS). My 57–year history with this has its own trajectory—mostly driven by medical events, and how I and my parents reacted. Most of my treatment by physicians has not been positive. It didn’t make me “normal” at all. I was born normal and didn’t require medical interventions. And by the way, I’ve never been confused about who or what I am. Truthful disclosure didn’t come to me about my biology and what was done to me as an infant until I was 33, when I forced the issue by removing my medical records from my endocrinologist’s office. I learned that there was never full disclosure to my [End Page 119] parents either, and therefore there was no informed consent for the “corrective” surgeries performed on me as an infant. My parents were only told that their little girl would get cancer and would not have a normal development as a girl unless her “deformed ovaries” were removed, and that they should never discuss these problems with me. Thus, after having presented with an inguinal hernia and having exploratory surgery at age 16 months, my intra–abdominal testes were removed in a second surgery two months later. I was pronounced a “male pseudohermaphrodite,” a diagnosis that was shared neither with my parents nor with me. Years later, I discovered an article my surgeon published in 1960 in the Delaware Medical Journal about me and another intersex person he operated on (whom he labeled a “true hermaphrodite”). The article gives a very detailed pathology report of my gonads, but only two sentences regarding my welfare and the rationale for performing those surgeries. Dr. J. F. Kustrup wrote in this article, “These [two cases] emphasize the need for early diagnosis and treatment in order to avoid the possibility of malignant change and to permit these individuals to follow a normal psychosexual pattern.” And: “Hermaphroditism and pseudohermaphroditism are conditions in which early diagnosis and treatment are essential to avoid malignant degeneration and to allow the child some chance toward normal pyschic [sic] development.” I was grateful to find this article because it revealed the unfounded assumptions underpinning the recommendations for treatment, much of which continues today. Worse even than the sort of social prejudice that shapes treatment is the absence of evidence for what doctors treat as “necessary” interventions. For my syndrome, CAIS, there never was—and still is not—data to support the cancer scare, or the opinion that I’d be confused and not have a normal life. From about the age of four, I can remember being different and being stonewalled by my doctor and prevented by my parents from talking about it. The feelings and fears I tried to express were shushed away, and I could tell that my questions were upsetting everyone. Even if I had wanted to be complicit with their lame diversions and nonsensical explanations, the massive abdominal scars were there as a daily reminder and hinted at a very different story. The Road to Hell is Paved with Good Intentions Growing up, I was treated like a fascinoma and a lab rat at a major teaching hospital on the East Coast. All I learned from those doctors as a young kid was what it feels like to be ogled, photographed and probed by a roomful of white–coated male doctors. Dissociation made itself my friend, and helped me to cope through the annual genital and anal exams and probing. I thought I was a freak and I felt completely powerless to protect myself from them and their “care”. At my annual appointment at age 12, with my mom present, three doctors told me I was infertile. Learning that I couldn’t have kids really saddened and shocked me, but there was no opportunity to talk about my feelings—either that day, or any time afterward. I was told to stop crying. I remember them telling me that there was no one else like me and that this was a random genetic anomaly, thereby reinforcing the freakishness...

Refining the regulatory region upstream of SOX9 associated with 46,XX testicular disorders of Sex Development (DSD).

Disorders of Sex Development (DSD) are a heterogeneous group of disorders affecting gonad and/or genito-urinary tract development and usually the endocrine-reproductive system. A genetic diagnosis is made in only around 20% of these cases. The genetic causes of 46,XX-SRY negative testicular DSD as well as ovotesticular DSD are poorly defined. Duplications involving a region located ∼600 kb upstream of SOX9, a key gene in testis development, were reported in several cases of 46,XX DSD. Recent studies have narrowed this region down to a 78 kb interval that is duplicated or deleted respectively in 46,XX or 46,XY DSD. We identified three phenotypically normal patients presenting with azoospermia and 46,XX testicular DSD. Two brothers carried a 83.8 kb duplication located ∼600 kb upstream of SOX9 that overlapped with the previously reported rearrangements. This duplication refines the minimal region associated with 46,XX-SRY negative DSD to a 40.7-41.9 kb element located ∼600 kb upstream of SOX9. Predicted enhancer elements and evolutionary-conserved binding sites for proteins known to be involved in testis determination are located within this region.

A Case of Ovotesticular Disorder of Sex Development: An Evolving Diagnosis

A Case of Ovotesticular Disorder of Sex Development: An Evolving Diagnosis

Polymorphism of the CTNNB1 and FOXL2 Genes is not Associated with Canine XX Testicular/Ovotesticular Disorder of Sex Development.

78,XX testicular or ovotesticular disorder of sex development (DSD) is the most common sex anomaly in dogs, but its molecular background remains unknown. It was hypothesized that the causative mutation may reside in canine chromosome 23 (CFA23), where two genes playing a pivotal role in ovarian development (CTNNB1 and FOXL2) are located. The aim of our study was to search for polymorphism in both candidate genes in 15 DSD dogs (78,XX and a lack of the SRYgene) and 29 normal females. Altogether, 7 novel polymorphic variants were identified: 5 SNPs in CTNNB1 and 2 indels in the FOXL2 gene. The distribution of the identified variants was similar in the DSD and control dogs. Therefore, we concluded that the conducted research did not prove an association between these polymorphisms and canine testicular or ovotesticular XX DSD.

Identidad sexual y genitales ambiguos en la infancia: reporte de dos casos

Se presentan dos casos evaluados en la ciudad de Barranquilla, Colombia que llegan a la consulta de Psiquiatría Infantil del Hospital Cari-Mental, pacientes con trastorno en la diferenciación sexual. El primer caso corresponde a una paciente de 6 años de edad que nace con genitales ambiguos, pero con diagnóstico y manejo tardío, el segundo caso un paciente de 1 año de edad con características fenotípicas y comportamiento masculino con genitales ambiguos que actualmente se encuentra en estudio para confirmar sospecha diagnostica de hermafroditismo verdadero. Se realiza una búsqueda sistemática en la base de datos de la Universidad Libre obteniéndose una serie de artículos científicos actualizados, con los cuales se sustentará y respaldará la importancia de conocer y actuar oportunamente frente a esta condición, estableciéndose que su valoración debe ser integral, interdisciplinaria y que el impacto emocional que se genera no solo afecta al paciente sino también a su entorno familiar.

The disturbed gonadal differentiation: dysgenesis and ovotesticular disorder of sex formation

The objective of the present study was differential diagnostics between ovotestis and gonadal dysgenesis, the choice of the gender and the surgical strategy for the treatment of abnormal sexual glands. Diagnostics of the disturbances of gonadal differentiation (DGD) requires morphological verification. The ovotesticular gonad is characterized by the presence of a mature ovarian tissue and a dysgenetic testicular component. The authors describe the surgical separation of the ovotestis with preservation of the segments represented by the mature ovarian tissue. The presence of immature ovarian elements in the testicular gonad is one of the signs of its dysgenesis. Such cases need to be treated by the surgical removal of dysgenetic gonads.

Clinical, Cytogenetic, and Molecular characterization of Disorders of Sexual Development (DSD) in Sudan

Abstract Sex determination is defined as a genetic events that lead to male or female gonadal-development, whereas sexual differentiation is the subsequent steps leading to functional sexuality and secondary sexual characteristics. DSD have an estimated incidence of 0.1 to 0.5% of live births. It presents in several forms e.g., male and female pseudohermaphroditism, gonadaldysgenesis, and true hermaphroditism. Aims The present study aimed to explore and characterize cytogenetics, molecular alterations, hormonal profile, and clinical aspects of different types of DSD in Sudan for the first time. Methods The study comprised 70 patients, of which 18 raised as males, and 52 as females. Medical history, physical examination, culturing of lymphocytes, chromosomal analysis, PCR analysis for SRY gene, hormonal profile, pelvic ultrasound, laparoscopic examination (when required), histopathology, and psychological assessment were done. Results The vast majority of patients (40%) were adults ≥17-year-old, followed by patients ≤ 2 year-old (33%). Although, 50% of the patients were referred due to genital ambiguity, other cause including primary amenorrhea, failure to thrive, and short stature were reported. Of the 70 patients only 13 patients (19%) were satisfied with their sex of rearing, 5 patients (6%) were not satisfied, 16 patients (23%) could not decide, and 36 patients (51%) were children. Female genital mutilation was performed in almost all adult patients raised as female including those diagnosed as Male pseudohermaphrodites. The analysis showed 23 patients were diagnosed as male pseudohermaphrodites, 2 as testicular feminization syndrome, 14 as complete gonadal dysgenesis, 8 as female pseudohermaphrodites, 6 as true hermaphrodites, 1 as Smith-Lemli-Opitz syndrome, one case of Down syndrome, and 15 patients were under controversial till the end of the study. Conclusion Based on the study conclusion one may concludes that multidisciplinary approach remains the best strategy for diagnosis and management of such cases. Labor-attending staff should be well trained to avoid sex assignment errors`. Female genital mutation, if performed in DSD, ends the chance of prepuberty diagnosis and complicates the sex-reassignment constructive surgery.

Ontogenic and morphological study of gonadal formation in genetically-modified sex reversal XY(POS) mice.

Mammalian sexual fate is determined by the presence or absence of sex determining region of the Y chromosome (Sry) in the “bipotential” gonads. Recent studies have demonstrated that both male and female sexual development are induced by distinct and active genetic pathways. Breeding the Y chromosome from Mus m. domesticus poschiavinus (POS) strains into C57BL/6J (B6J) mice (B6J-XYPOS) has been shown to induce sex reversal (75%: bilateral ovary, 25%: true hermaphrodites). However, our B6N-XYPOS mice, which were generated by backcrossing of B6J-XYPOS on an inbred B6N-XX, develop as males (36%: bilateral testis with fertility as well as bilateral ovary (34%), and the remainder develop as true hermaphrodites. Here, we investigated in detail the expressions of essential sex-related genes and histological features in B6N-XYPOS mice from the fetal period to adulthood. The onsets of both Sry and SRY-box 9 (Sox9) expressions as determined spatiotemporally by whole-mount immunohistochemistry in the B6N-XYPOS gonads occurred 2–3 tail somites later than those in B6N-XYB6 gonads, but earlier than those in B6J-XYPOS, respectively. It is possible that such a small difference in timing of the Sry expression underlies testicular development in our B6N-XYPOS. Our study is the first to histologically show the expression and ectopic localization of a female-related gene in the XYPOS testes and a male-related gene in the XYPOS ovaries. The results from these and previous experiments indicate that the interplay between genome variants, epigenetics and developmental gene regulation is crucial for testis development.

A case of true hermaphroditism presenting as a testicular tumour.

True hermaphroditism represents only 5% cases of all of disorders of sexual differentiation (DSD) and usually present in early childhood with ambiguous genitalia. Occasionally, cases might present later on in adolescence with problems of sexual maturation. Our case report presents a true hermaphrodite with normal male phenotype that presented as a left testicular mass, two years after being diagnosed with Sertoli cell only syndrome in the contralateral testis. Histological examination of the left testis showed ovarian, fallopian tube, myometrial, endometrial, and epididymal tissue. This combination of findings is found in approximately one-third of true hermaphrodites, but it is very rare to present clinically as an inguinoscrotal mass.

Medical audit of children with ambiguous genitalia-review of children treated over 18 years

Introduction: The survival of a newborn or a child presenting with ambiguous genitalia depends upon the timely diagnosis and institution of appropriate medical care. We undertook this study with the aim to determine if appropriate clinical and confirmatory diagnosis was arrived on time and if the treatment instituted was relevant and satisfactory. Methods: All children who were evaluated for ambiguous genitalia under the Department of Pediatric Endocrinology over the preceding 18 years were invited for a review. Data including time taken to make a clinical diagnosis, time taken to confirm the diagnosis, reasons for delay if any, and appropriateness of the sex assigned for rearing and treatment instituted were collected from the charts. Patients were evaluated for adequacy of response to treatment, compliance, problems encountered if any and subjective parental satisfaction. Results: A total of 165 children were diagnosed to have conditions with ambiguous genitalia and were called for a review. 33 children attended the review. 15 were being raised as boys and 18 as girls. 12 children had virilising congenital adrenal hyperplasia (CAH), 6 had cryptorchidism, 6 had hypospadias, 3 had complete and 1 had partial testicular feminisation, 2 had mixed gonadal dysgenesis (MGD), 2 had hypogonadism and 1 was a true hermaphrodite. An appropriate clinical diagnosis was made in 30childrenon the day one and a final confirmatory diagnosis was made within a month in 23. Conclusion: In most conditions presenting with ambiguous genitalia, a clinical and confirmatory diagnosis can be made in a short duration. Initiation of appropriate treatment results in favourable outcomes in terms of growth sexual identity and adaptation.

Clinical Review of 95 Patients with 46,XX Disorders of Sex Development Based on the New Chicago Classification

Study ObjectiveThe aim of our study was to determine the etiologic distribution of 46,XX disorder of sexual development (DSD) according to the new DSD classification system and to evaluate the clinical features of this DSD subgroup in our patient cohort. ParticipantsThe evaluation criteria and clinical findings of 95 46,XX patients were described by clinical presentation, gonadal morphology, genital anatomy, associated dysmorphic features, presence during prenatal period with/without postnatal virilization, hormonal characteristics, and presence or absence of steroidogenic defects among 319 patients with DSD. ResultsTypes and ratios of each presentation of our 95 patients with 46,XX DSD were as follows: 82 had androgen excess (86.3%): (74 had classical congenital adrenal hyperplasia, 2 had CAH variant possibility of P450-oxidoreductase gene defect), 6 had disorders of ovarian development (6.3%): (1 patient had gonadal dysgenesis with virilization at birth with bilateral streak gonad, 4 patients had complete gonadal dysgenesis, and 1 patient had ovotesticular DSD) and 7 had other 46,XX DSD. Two sisters, who had 46,XX complete gonadal dysgenesis,were diagnosed with Perrault Syndrome with ovarian failure due to streak gonads and associated with sensorineural deafness. Conclusion46,XX DSD are usually derived from intrauterine virilization and CAH is the most common cause of 46,XX DSD due to fetal androgen exposure.

Severe birth defects in children perinatal exposed to HIV from a "real-world" setting: Infectious Diseases National Institute, Bucharest, Romania.

IntroductionThe shift in epidemic trends in recent years in Romania shows new problems in regard of HIV vertical transmission, firstly in intravenous drug user's mothers co-infected with hepatitis viruses and with social problems, and secondly the children of young mothers with an old HIV infection and long antiretroviral therapy history.Materials and MethodsWe studied all HIV perinatal exposed children routinely followed up in the Paediatric Department of the National Institute of Infectious Diseases, since January 1st 2006 till December 31st 2012. The analyses consisted of describing the birth defects and association with certain risk factors: gender, mother's age at birth and exposure to antiretrovirals in the first trimester of pregnancy.ResultsWe analyzed 244 children born to HIV-infected mothers. The incidence of HIV infection was 16.39%. The rate of birth defects was 39.34% (96/244 cases). The most frequent findings were cardiac malformations (47/96), followed by musculoskeletal defects (24/96), neurologic defects (20/96), urogenital malformations (13/96), digestive tract defects (3/93), metabolic disorders (2/96) and genetic disorders (2/96). We found nine cases of severe congenital anomalies: complex heart defect, total congenital aganglionic megacolon, anal imperforation, Dandy-Walker syndrome, gangliosidosis, Niemann-Pick syndrome, Down syndrome, true hermaphroditism and cleft palate. Two children died during first year of life due to severe malformations. 9% of cases had associated malformations. The gender rate was in favour of males in group with birth defects (58/38) and with no birth defects (82/66). The median age at birth in mothers was 22 years, similar in both groups. The highest mean age at birth was in offspring's mothers with neurologic congenital defects 25, 15 years old, but is not statistically significant (p=0.1). In the studied period the highest number of birth defects were found in 2012, 37 children, compared with less than 15 in previous years (not statistically significant, p=0.07). In our studied patients the risk of birth defects was not statistically associated with HIV transmission or with exposure to antiretrovirals before and in first trimester of pregnancy (p=0.88).ConclusionThe rate of birth defects among HIV-exposed children was not significantly associated with antiretroviral exposure, but we identify very rare and severe congenital conditions. We have noticed also a trend to increasing number of birth defects in 2012 among studied patients compared to previous years.

Disorders of sex development in a developing country: perspectives and outcome of surgical management of 39 cases.

Improvements in diagnostic testing and genital repair have significantly advanced the management of disorders of sex development (DSD). Challenges however, still exist in the management of DSD. This study evaluated the types, challenges of surgical management, and outcome of DSD in south-east Nigeria. Retrospective analysis of 39 children with DSD managed from January 2005 to December 2013 at the University of Nigeria Teaching Hospital, Enugu, Nigeria. Types of DSD were: 46, XX DSD in 17 (43.6 %) cases; 46, XY DSD 16 (41 %); Ovotesticular DSD 5 (12.8 %); and one (2.6 %) 46, XY Ovotesticular DSD. Median age at definitive gender assignment was 3 years (range 2 months-14 years). Gender assignment was female for 20 (51.3 %; all 46, XX DSD, one each of 46, XY DSD, Ovotesticular DSD and 46, XY Ovotesticular DSD), and male for 19 (48.7 %; 15 of 46, XY DSD, 4 of Ovotesticular DSD). Eight cases reared as male before presentation required gender reassignment after evaluation and counselling. Genital repair was undertaken at mean age of 4.1 years (range 6 months-14 years). After average follow-up of 22.5 months (range 1 month-7 years), a total of eleven (28.2 %) developed procedure-related complications. Challenges were delayed diagnosis, inadequate diagnostic facilities, and need for gender reassignment. There is a wide spectrum of DSD in our setting. Time to diagnosis, evaluation, and outcome may be improved by public enlightenment initiative, focused education of healthcare personnel and provision of relevant diagnostic facilities through enhanced funding and collaboration.

Etiological diagnosis of undervirilized male/XY disorder of sex development.

To do clinical, hormonal and chromosomal analysis in undervirilized male / XY disorder of sex development and to make presumptive etiological diagnosis according to the new Disorder of Sex Development (DSD) classification system. Case series. Endocrine Unit at National Institute of Child Health, Karachi, Pakistan, from January 2007 to December 2012. Patients of suspected XY DSD / undervirilized male visiting endocrine clinic were enrolled in the study. Criteria suggested XY DSD include overt genital ambiguity, apparent female/male genitalia with inguinal/labial mass, apparent male genitalia with unilateral or bilateral non-palpable testes, micropenis and isolated hypospadias or with undescended testis. The older children who had delayed puberty were also evaluated with respect to DSD. As a part of evaluation of XY DSD, abdominopelvic ultrasound, karyotype, hormone measurement (testosterone, FSH, LH), FISH analysis with SRY probing, genitogram, laparoscopy, gonadal biopsy and HCG stimulation test were performed. Frequencies and percentages applied on categorical data whereas mean, median, standard deviation were calculated for continuous data. A total of 187 patients met the criteria of XY DSD. Age ranged from 1 month to 15 years, 55 (29.4%) presented in infancy, 104 (55.6%) between 1 and 10 years and 28 (15%) older than 10 years. Twenty five (13.4%) were raised as female and 162 as (86.6%) male. The main complaints were ambiguous genitalia, unilateral cryptorchidism, bilateral cryptorchidism, micropenis, delayed puberty, hypospadias, female like genitalia with gonads, inguinal mass. The karyotype was 46 XY in 183 (97.9%), 46 XX in 2 (1.1%), 47 XXY in 1 (0.5%), 45 X/46 XY in 1 (0.5%) patient. HCG stimulation test showed low testosterone response in 43 (23 %), high testosterone response in 62 (33.2%), partial testosterone response in 32 (17.1%) and normal testosterone response in 50 (26.7%). Genitogram was carried out in 86 (45.98%) patients. Presumptive etiological diagnosis of androgen sensitivity syndrome/ 5-alpha reductase deficiency, testicular biosynthetic defect/ leydig cell hypoplasia, partial gonadal dysgenesis, ovotesticular DSD, XX testicular DSD, mixed gonadal dysgenesis, testicular vanishing syndrome, klinefelter syndrome, hypogonadotropic hypogonadism, isolated hypospadias and isolated micropenis was made. Clinical, chromosomal and hormonal assessment may help in making the presumptive etiological diagnosis. Further molecular genetics analysis are needed in differentiating these abnormalities and to make a final diagnosis.

Embryology and adult urology - Not always mutually exclusive: A case report on true hermaphroditism at an adult urology clinic.

True hermaphrodite (TH) is one of the rarest varieties of disorders of sexual differentiation. Most patients present early in the life and are managed by pediatricians. We present a rare case of an adult TH which was first diagnosed by a urologist. We discuss the pathology of TH and its clinical relevance. Knowledge and awareness of embryology are vital to all specialties.

Occurrence of bilateral dysgerminoma in a true hermaphroditism goat

Ovarian dysgerminoma is a neoplasm that originates from primordial germ cells of the ovary. In human, this tumor may be associated with gonadal dysgenesis. In animal species, occurrence of dysgerminoma is uncommon. The present study described occurrence of bilateral dysgerminoma in a true hermaphroditism goat in Iran. Morphologically, a uterus, two uterine horns, and two gonadal structures at the end of the uterine horns were observed. The cervix was opened into a much distended vagina. Histopathologically, two gonads were composed of inactive seminiferous tubules with a row of Sertoli cells and rete testis, but the ovarian tissues including ovarian stroma and a few graafian follicles were seen only in the right gonad. On the left side, epididymis and fallopian tubes were located adjacent to the each other. Vasa deferentia were parallel with two uterine horns and located in the uterine mesentery on each side. Base on the histology findings of two gonads, true hermaphroditism was confirmed in this goat. In addition, both of the gonads showed characteristics of dysgerminoma tumor. Tumor cells arranged as sheet or nest pattern and were separated by delicate connective tissue septa. Neoplastic cells were large, round to polygonal with finely granular to eosinophilic cytoplasm and distinct cell border. Nuclei of tumor cells were spherical and had vesicular chromatin and often multiple nucleoli. Mitotic figures were frequent. Lymphocytic cells infiltrated in the stromal tumor.

Gonadoblastoma and selected other aspects of gonadal pathology in young patients with disorders of sex development.

Some patients with disorders of sex development (DSDs), previously known as intersex disorders, have abnormal gonadal development and an increased risk of germ cell tumors. Because of their relative rarity, however, many pathologists are unfamiliar with the morphological findings in the gonads of DSD patients and their clinical significance. This review concentrates on some of the most common DSDs where gonadal specimens may come to the attention of pathologists. It highlights the findings in gonadal dysgenesis, a DSD with a spectrum of clinical, pathologic, and molecular features but with the shared attributes of having both Y chromosomal material (even if in very limited amounts) in the gonad and also having mutations or deletions in genes necessary for normal gonadal development, mostly in those upstream of the SOX9 gene. This situation results in testicular tissue lacking normal Sertoli cells, which are now considered an essential element for the normal maturation of the primordial germ cells that migrate to the gonad from the embryonic yolk sac. Germ cells with delayed maturation mimic neoplastic germ cells, but there are both morphological and immunohistochemical differences. If the gonad having germ cells with delayed maturation also harbors the TSPY gene on the GBY locus of the Y chromosome, the cells may undergo neoplastic transformation and result in the distinctive gonadoblastoma, whose pathologic features are explored at length herein, including its potential for variant morphologies, such as a "dissecting" pattern. Another important DSD, the androgen insensitivity syndrome (AIS), is discussed at length, including the varied appearances of the testis and its distinctive lesions-hamartomas and Sertoli cell adenomas. The potential for germ cell neoplasia in the partial AIS is also discussed and contrasted with that of the complete AIS. A third major topic is ovotesticular DSD (true hermaphroditism). The clinical features and morphology of this condition are reviewed, including the arrangements of the tissue components in an ovotestis. Several other DSDs with distinctive gonadal findings are also considered, including Klinefelter syndrome, 5α-reductase deficiency, 17β-hydroxysteroid dehydrogenase deficiency, and female adrenogenital syndrome.

A Down-Klinefelter syndrome case: Maybe a fortuitous association, certainly a hard therapeutic decision

1.1. A unified theory is presented to explain the origin of certain congenital gonadal defects on the basis of genetic imbalance involving the sex chromosomes (X,Y) and the autosomes. Non-disjunction of the sex chromosomes, chromosomal aberrations of the sex chromosomes (such as deletion, crossing over or translocation of sex genes between the X and Y chromosomes) and gene mutation have been implicated. (Chart 1.) The clinical characteristics of gonadal defects are reviewed and representative cases are included from the literature to support the theory.1.1. “Pure gonadal dysgenesis”2.2. “Incomplete gonadal dysgenesis”3.o4.a. Seminiferous tubule dysgenesis Klinefelter syndrome Germinal aplasia “Turner's syndrome in males” “Low fertility men” Male pseudohermaphrodite5.b. Congenital anorchia1.2. Non-disjunction of the sex chromosomes, during the development of the mature sperm or ovum, produces the more commonly recognized forms of gonadal dysgenesis (Turner's syndrome-XO) and seminiferous tubule dysgenesis (Klinefelter's syndrome-XXY) as well as the “superfemale” syndrome-XXX. Non-disjunction or loss of a sex chromosome in the zygote may give rise to mosaic patterns of XO-XX, XO-XXX, XX-XXY and XY-XO in a few individuals.2.3. A chromosomal aberration (e.g., deletion of sex genes) is postulated as the basis for congenital defective ovarian development in chromatin-positive females with an XX sex chromosome complement.3.4. Mutation or deletion of X or Y chromosome sex genes is postulated as the cause of certain congenital testicular defects in chromatin-negative individuals (XY) with Klinefelter's syndrome, germinal aplasia, Turner's syndrome in boys and men, low fertility, congenital anorchia or “pure gonadal dysgenesis.” Male pseudohermaphroditism may be due to a hereditary mutation of the maternal X chromosome or a maternal autosome which is capable of modifying the action of the Y chromosome sex genes.4.5. The linkage of sex determining genes located on the Y chromosome to an X chromosome by means of crossing over or by a translocation during spermatogenesis is postulated to be the cause of chromatin-positive true hermaphrodites. Similarly, the linkage of sex determining genes located on the X chromosome to a Y chromosome is postulated to cause chromatin-negative true hermaphrodites. A theory for the unilateral action of separate sex genes in the X and Y chromosome is presented to explain the different gonad on each side of the body in these individuals. A broadened concept of true hermaphroditism to include some instances of gonadal dysgenesis with vestigial ovarian and testicular elements is suggested.5.6. Translocation of female-determining genes from a broken X chromosome to an autosome may influence the production of ovaries in an XO individual. Translocation of male-determining genes from a broken Y chromosome to an autosome may influence the production of testes in an XO male pseudohermaphrodite.6.7. Autosomal mutations may result in hypogonadism in certain individuals with non-sex-linked congenital somatic defects (evidence of the autosomal aberration).7.8. Congenital anomalies associated with gonadal aplasia and dwarfism are known to occur in an XO individual. It is postulated that the varying somatic defects in Turner's syndrome may be related to the presence of recessive genes with deleterious effects on the X chromosome or the influence of genetic imbalance.