Disorders of sexual differentiation: Report of two rare cases.

Gonadal dysgenesis is a distinct variety of Disorders of Sexual Differentiation (DSD) characterised by incomplete or defective formation of the gonads due to either structural or numerical anomalies of the sex chromosomes or mutations in the genes involved in the development of the gland. Here we present two such rare cases that presented during childhood. Both patients presented with ambiguous genitalia with a 45XO/46XY mosaic chromosome pattern. First case, an infant underwent laparoscopic excision of streak gonad, and a single stage hypospadias repair later. Second case, an adolescent who underwent gonadectomy as a child, presented with a mass which was excised and found to contain uterine and ovarian tissue; second stage hypospadias repair is being planned. Mixed gonadal dysgenesis usually presents with a unilateral testis, a streak gonad on the contralateral side and persistent mullerian structures. The most common karyotype noted is 45XO/46XY. These cases are known to have ambiguous external genitalia. The streak gonads have an increased malignant potential and thus, these patients should be carefully screened and followed up for gonadoblastoma.

45,X/46,XY mosaicism: phenotypic characteristics, growth, and reproductive function--a retrospective longitudinal study.

CONTEXT: Most previous studies of 45,X/46,XY mosaicism are case reports or have described single aspects of the disease. OBJECTIVE: The objective was to provide longitudinal data of patients with 45,X/46,XY mosaicism. DESIGN: This was a retrospective, longitudinal study conducted from June 1990 to January 2012. SETTING: The study took place at a tertiary pediatric and andrological referral center. PATIENTS OR OTHER PARTICIPANTS: Twenty-five patients (18 boys, seven girls) with 45,X/46,XY mosaicism and its variants were included and were compared to healthy controls. INTERVENTION(S): No interventions were included in the study. MAIN OUTCOME MEASURE(S): Phenotypes were scored using external masculinization scores. Serum LH, FSH, testosterone, estradiol, and inhibin B levels were reported in male patients. IGF-I levels and height were reported in all patients. Available biopsies/gonadectomies were histologically examined. RESULTS: Fourteen of 18 males had external masculinization scores consistent with normal virilization. Ten of 11 male patients experienced spontaneous puberty. Median height sd score was -2.0 (range, -3 to 0.3) for males and -2.2 (range, -2.5 to -1.4) for females, both considerably below genetic potential. Median 1-yr height gain after GH treatment in seven patients was 0.5 sd (0.1 to 1.2). All tissue samples from 15 patients (eight males, seven females) revealed abnormal gonadal histology. Four patients had carcinoma in situ (CIS); two had tissue samples available from early childhood, one showing CIS. CONCLUSIONS: Gonadal function in most 45,X/46,XY males, even those with genital ambiguity, seems sufficient for spontaneous puberty. Short stature and 45,X/46,XY mosaicism seem associated, but patients appear to benefit from GH treatment. Histology from two patients with biopsies from early childhood indicates that CIS originates before puberty.

Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys.

CONTEXT: Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys. OBJECTIVE: The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys. METHODS: This is a multicenter retrospective study. RESULTS: Mean age at study was 25.6±2.4 years. Eighty-five percent of the patients presented a 'classical' mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of <80 mm. Mean adult height is 156.9±2 cm, regardless of GH treatment. CONCLUSIONS: In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.

A healthy, female chimera with 46,XX/46,XY karyotype.

We report a healthy and unambiguously female newborn, whose phenotypic sex contradicted the expected male sex based on previously performed prenatal cytogenetic analysis. Both 46,XX and 46,XY cells were detected in a villus sample, the former having been attributed to maternal cell contamination. Postnatal karyotyping in peripheral lymphocytes confirmed the presence of two cell lines, one 46,XX (70%) and one 46,XY (30%). After exclusion of alternative explanations for the observed genotype, a diagnosis of chimerism was made. Chimeras containing cell lines of opposite sex usually feature ovotesticular development with associated genital ambiguity. To account for the normal female appearance of our patient, we postulate the exclusive involvement of 46,XX cells in gonad formation.

Phenotypic spectrum of 45,X/46,XY males with a ring Y chromosome and bilaterally descended testes.

OBJECTIVE: To characterize the phenotypic spectrum of males with bilaterally descended testes and a 45,X/46,X,(r)Y karyotype. DESIGN: Retrospective review of patient records; cytogenetic and molecular analysis. SETTING: Tertiary medical center setting. PARTICIPANT(S): Five males, two prepubertal and three postpubertal, with a 45,X/46,X(r)Y karyotype and bilaterally descended testes. INTERVENTION(S): Linear growth evaluation, testicular endocrine and exocrine studies, cytogenetic and molecular analysis on each patient. MAIN OUTCOME MEASURE(S): Clinical phenotype versus genotype. RESULT(S): Both prepubertal males had short stature and low testosterone. All three adults had normal puberty and normal testosterone levels. Two of the adults (one with short stature and one with normal stature) had elevated gonadotropins and azoospermia. The third adult had normal stature, severe oligospermia, normal gonadotropins, and normal serum testosterone. CONCLUSION(S): The phenotypic spectrum of males with a 45,X/46,X(r)Y karyotype and bilaterally descended testes varies greatly from males with short stature and spermatogenic failure to males without short stature and less severely affected spermatogenesis. This broad spectrum of phenotypic findings needs to be taken into account when the clinical geneticist encounters a prenatal diagnosis of a 45,X/46,X(r)Y karyotype. This information will also be helpful for pediatric and reproductive endocrinologists in counseling males with bilaterally descended testes and a 45,X/46,X(r)Y karyotype.

Pregnancy in a hermaphrodite with a male-predominant mosaic karyotype.

OBJECTIVE: To report a pregnancy in a hermaphrodite and review of the literature. DESIGN: Case report and literature review. SETTING: Clinical. PATIENT(S): A patient with male-predominant mosaic karyotype 96% 46XY. INTERVENTION(S): Removal of left ovotestis in combination with a supracervical hysterectomy and bilateral salpingo-oophorectomy. MAIN OUTCOME MEASURE(S): Identification of published cases of pregnancy and hermaphroditism. RESULT(S): The current patient had previous pregnancy and a wedge biopsy of her left gonad, which demonstrated an ovotestis and an area suspicious for a gonadoblastoma. After delivery of her second pregnancy, the patient underwent a hysterectomy and bilateral salpingo-oophorectomy. The histopathologic evaluation following bilateral oophorectomy demonstrated a residual ovotestis without further evidence of a gonadoblastoma. Review of the literature identified 10 other cases of pregnancy in a hermaphrodite patient. CONCLUSION(S): This is the 11th reported case of fertility in a true hermaphrodite and only the second report of a mosaic true hermaphrodite to demonstrate fertility. This is the only case of a pregnancy involving a male-predominant mosaic 96% 46XY and the only case to confirm the genetics of the offspring.

Monozygotic twins of opposite sex.

Although discordant karyotypes are known in identical twins, cases involving differences in sex phenotype are rare. We studied identical twins with the 46,XY karyotype - a male with mixed gonadal dysgenesis and a female with "pure" gonadal dysgenesis. The testis-determining SRY gene was present in DNA from both twins but no mutations were detected in the SRY conserved motif. Monozygosity was indicated by short tandem repeat polymorphism analysis. These observations could be attributed to (i) mutation and mosaicism involving "downstream" sex-determining loci, (ii) variable penetrance of genes such as DSS/NR0B1, duplication of which can disrupt the male-determining pathway, or (iii) occurrence of cryptic 45,X gonadal cell lines.

Gonadoblastoma y disgenesia gonadal mixta / Gonadoblastoma and mixed gonadal dysgenesis

Introducción. El gonadoblastoma se describió por primera vez en 1953 por Scully, se sabe que ocurre casi exclusivamente en gónadas disgenéticas y primordialmente en las primeras 2 décadas de la vida, se asocia a la presencia de material genético del cromosoma Y. Aproximadamente el 30 por ciento de los pacientes con disgenesia gonadal desarrollan gonadoblastoma, 40 por ciento bilateral, por si mismo se podría considerar una neoplasia in situ; sin embargo, del 25 al 30 por ciento se asocia a germinomas que se deben tratar de manera específica. Caso clínico. Se presenta el caso de una paciente educada en el rol femenino de 15 años de edad con ambigüedad de genitales y cariotipo 45XO/46XY. Se le realizó genitoplastia en 2 tiempos con laparotomía exploradora y extirpación de la gónadas disgenéticas, en ambas presentó gonadoblastoma y en una de ellas un germinoma; recibió quimioterapia con cisplatino y ciclosfosfamida por 6 ciclos y durante su seguimiento no hubo evidencia de metástasis o tumor residual. conclusión. El gonadoblastoma es el tumor germinal más frecuente en los pacientes con disgenesia gonadal mixta; por si mismo tiene un comportamiento neoplásico, pero no se han reportado metástasis. Sin embargo, predispone a la presentación de otros tumores germinales como: germinoma, coriocarcinoma, tumor de senos endodérmicos, etc. Por lo tanto, se recomienda extirpación temprana de las gónadas disgéneticas y el manejo específico de la neoplasia germinal de encontrarse otro tumor además del gonadoblastoma

Profile of intersex children in south India.

Thirty five children with ambiguous genitalia admitted to our centre between January 1986 to December 1991, were followed up and their clinical, laboratory and management strategies were analyzed. Most of them presented between 1 month and 2 years of age and only 2 presented in the newborn period. Sixteen were female pseudohermaphrodites. Eighteen out of 31 children were assigned female sex. One genetic female with congenital adrenal hyperplasia was assigned male sex. We practised more than one type of clitoroplasty in our centre. Parents prefer the intersex children to be reared as male possibly because of the less social stigma attached to an impotent male than to sterile female, and because males are socially independent.

Mixed gonadal dysgenesis: endogenous hormonal effects in the endometrium and histogenesis of germinoma.

The clinicopathologic features of two patients with mixed gonadal dysgenesis are presented, with specific reference to the relationship between endogenous sex hormones and the endometrium and the development of neoplastic disease. One patient, whose immature gonad contained granulosa cells and theca cells, had elevated serum estrogen levels and an endometrium with frequent ciliated metaplasia and squamous metaplasia. Another patient had elevated serum testosterone levels and atrophic endometrium. Both had gonadal tumors, more specifically, germinomas, which contained many calcified nodules within the tumor. These findings suggest that these germinomas arose from a gonadoblastoma.

Mixed gonadal dysgenesis: clinical, cytogenetic, endocrinological, and histopathological findings in 16 patients.

We describe clinical, cytogenetic, endocrine, and histopathological findings in 16 patients with mixed gonadal dysgenesis (MGD). All patients except 1 presented genital ambiguity and 10 of them had Ullrich-Turner manifestations. The 45,X/46,XY karyotype was the most frequent with a predominance of 45,X cells in both peripheral lymphocytes and gonads. In all cases Müllerian and Wolffian remnants and/or derivatives were found and in some patients both Wolffian- and Müllerian-derived structures were identified on the streak or testicular side. Postpubertal patients exhibited variable degrees of virilization and all of them had hypergonadotropism coexisting with low to normal baseline serum levels of testosterone; their testicular response to human chorionic gonadotropin (HCG) in terms of testosterone secretion was also variable, ranging from minimal to almost a normal response. All prepubertal patients but 1 had normal baseline levels of pituitary gonadotropins and testosterone and their gonadal response to the HCG challenge was highly variable. With the exception of 1 case, who had a 45,X/46,XY(p-) karyotype, no correlation between the cytogenetic data and degree of external genital ambiguity and the hormonal findings was observed. Additional information on the specific structural abnormalities involving the testis-determining gene of the Y chromosome in patients with MGD is needed in order to further understand the mechanisms responsible for the wide variability characteristic of this disorder.

Partial androgen receptor deficiency and mixed gonadal dysgenesis in Drash syndrome.

Drash syndrome associates a nephropathy characterized by a diffuse mesangial sclerosis of early onset, Wilms tumor, and male pseudohermaphroditism (MPH). A patient with Drash syndrome is reported with the following: karyotype 46,XY, external genitalia near normal female, mixed gonadal dysgenesis, severe androgen receptor deficiency demonstrated for the first time in this syndrome. The possibility of a common genetic denominator with the del 11p13 WAGR complex is suggested. MPH/nephroblastoma association is common. Androgen receptor deficiency has been observed in one case of each syndrome, respectively.

[Mixed gonadal dysgenesis. Apropos of a series of 21 cases]. / La dysgénésie gonadique asymétrique. A propos d'une série de 21 observations.

Twenty-one cases of mixed gonadal dysgenesis referred at age 1 to 16 years are studied. External genitalia were in most cases of types III-IV, with a small penis and posterior hypospadias, asymmetrical genital folds containing an externalized testis on one side. The internal genitalia varied according to the degree of dysgenesis of the gonads, and included an uterus and/or a vagina in 18 among the 21 cases. A chromosomal mosaicism XO/XY or XX/XY was found in 11 patients, the other 10 having a normal 46 XY caryotype. Pubertal follow-up was obtained in 10 cases, and showed always a male sexual development, without possibility to exactly evaluate the function of the testis. Choosing the sex assignment is relatively easy in newborns or infants with mixed gonadal dysgenesis. It relies more on anatomy (size of corpora cavernosa, feasibility of urethroplasty or vaginoplasty) than on the results of hormonal measurements. The presence of an Y chromosome is not by itself an argument to choose the male sex. In most cases, the choice of the female sex is the easiest and relies on strong clinical arguments, but it leads unavoidably to suppress both the testis and the dysgenetic gonad.