Gender determination and long-time follow-up analysis of mixed gonadal dysgenesis.

INTRODUCTION: Mixed gonadal dysgenesis (MGD) is a rare disorder of sexual development. The management of MGD is challenging since the disease significantly impacts a patient's growth, hormone balance, and gonadal development. This article used a large population and a long follow-up period for its analysis. OBJECTIVES: This study aims to summarize the gender determination basis and analyze the long-term follow-up of mixed gonadal dysgenesis. METHODS: A total of 45 patients' clinical data were summarized and analyzed. Patients were divided by gender. Next, we followed up regarding the occurrence of complications after surgery, the patients' satisfaction with external genitalia appearance, the growth of the patients, counting the surgical pattern the incidence of surgical complications and the development of the patients' growth. All patients included in this study underwent chromosomal karyotype analysis, abdomen exploration, and pathological biopsy. After sex determination, 7 patients who were raised as female underwent clitoroplasty, and bilateral gonadectomy. 38 male patients underwent urethroplasty + one-sided gonadectomy. RESULTS: Patient follow-up started in the third month after surgery. Female patients reported no surgery-related complications, while 14 male patients showed surgery-related complications. Additionally, 20 male patients (60.6 %) had a lower height compared to normal peers, 12 of which (36.4 %) were lower than the second standard deviation of the height of normal peers. CONCLUSION: The clinical manifestations of mixed gonadal dysgenesis are variable, and the management is complicated. Children's gonadal function, external genital conditions, psychological evaluation, and parents' wishes should be considered before sex determination. In China, most patients are raised as males with a high incidence of postoperative complications. We found that short stature is a common feature in male patients, thus their height and growth should be carefully supervised. Patients should pay attention to their sexual function and sexual potential during adulthood.

Early development of a gonadal tumor in a patient with mixed gonadal dysgenesis

SUMMARY A gonadal tumor was diagnosed in the first months of life in a patient with genital ambiguity, a 45,X/46,XY karyotype, and mixed gonadal dysgenesis. Gonadal biopsies at the age of 3 months revealed dysgenetic testes and a gonadoblastoma on the right testis. Even though gonadal tumors are rare in childhood, this case indicates that prophylactic removal of dysgenetic gonads should be performed as early as possible, especially when the female sex is assigned to a patient with a Y-chromosome sequence.

The Evaluation of Cases with Y-Chromosome Gonadal Dysgenesis: Clinical Experience over 18 Years.

OBJECTIVE: Y-chromosome gonadal dysgenesis (GD) is a rare subgroup of disorders of sexual development (DSD) which results from underdeveloped testis and may exhibit heterogenous symptoms. These patients are phenotypically classified into two groups - complete and partial, and their karyotypic description is either 46,XY GD or 45,X/46,XY GD. In this study; we aimed to evaluate the characteristics of cases with Y-chromosome GD. METHODS: Thirty eight cases were followed-up between 1998 and 2016. The age of admission ranged between 0 and 17 years. Clinical and laboratory findings as well as follow-up characteristics of the cases were evaluated retrospectively from the patient files. RESULTS: There were 26 cases (four complete, 22 partial) in the 46,XY GD group, and 12 cases (four complete, 8 patients with complete GD in the 45,X/46,XY. Mean age at admission was 6.2±4.6 years for all cases. Patients with complete GD in the 45,X/46,XY GD group were diagnosed earlier that the patients with complete GD in the 46,XY group [11 years vs. 14.31 years of age (p<0.01)]. There were no additional findings in 55% of all patients. In the remaining 45% additional clinical findings, mainly short stature, were detected in 75% of the patients in the 45,X/46,XY GD and 30% of the patients in the 46,XY GD groups. All patients with complete 46,XY and 45,X/46,XY GD were raised as females. There was no gender dysphoria in patients that were raised as females, except for one case. Gonadectomy was performed in 14 patients, at a mean age of 8.75±2.3 years and pathological assessment of the gonads was reported as normal in all cases. CONCLUSION: Y-chromosome GD is a very heterogenous clinical and genetic disorder and requires a multifaceted approach to management. Whether including syndromic features or not, associated clinical features may lead to earlier diagnosis, especially in complete forms of GD. Due to difficulties encountered in the long-term follow-up of these patients, evaluation of appropriateness of sex of rearing decision is not truly possible. Performance of gonadectomy during the first decade appears be a preventive factor for tumor development since these tumors are usually seen during the second decade.

Early development of a gonadal tumor in a patient with mixed gonadal dysgenesis.

A gonadal tumor was diagnosed in the first months of life in a patient with genital ambiguity, a 45,X/46,XY karyotype, and mixed gonadal dysgenesis. Gonadal biopsies at the age of 3 months revealed dysgenetic testes and a gonadoblastoma on the right testis. Even though gonadal tumors are rare in childhood, this case indicates that prophylactic removal of dysgenetic gonads should be performed as early as possible, especially when the female sex is assigned to a patient with a Y-chromosome sequence.

Mixed gonadal dysgenesis in Yaoundé: A preliminary experience about three cases.

UNLABELLED: Mixed gonadal dysgenesis is characterised by unilateral chromosomal abnormality, which is probably the result of anaphase lag during mitosis. The 45, XO/46, XY karyotype is the most common form of mosaicism involving the Y chromosome. It is a rare clinical entity with a worldwide incidence of 1.5/10,000 live births. Its epidemiology in Sub-Saharan Africa is not known. This study reports experience in the management of 3 cases at the Yaounde Gynecologic-Obstetric and Paediatric Hospital. From November 2009 to November 2014, 3 cases were successfully managed at our institution. RESULTS: All patients presented with asymmetrical gonadal differentiation. On one side of the body, a poorly-developed testicular gonad and on the other side a gonadal streak. A persistent Mόllerian remnant was equally found in the 3 cases. Management of mixed gonadal dysgenesis should be done in tertiary health care centres. A multidisciplinary team approach is recommended.

Disgenesia gonadal mixta como forma de presentación de un desorden de la diferenciación sexual de causa cromosómica / Mixed gonadal dysgenesis as a form of presentation of sex differentiation disorder of chromosomal origin

La diferenciación sexual es un proceso genéticamente determinado y controlado, que puede ser alterado por diferentes tipos de mutaciones genéticas, o por el efecto de hormonas u otros disruptores ambientales que actúan sobre el embrión, resultando en la formación de genitales externos que no se corresponden con el sexo genético y con los genitales internos. La disgenesia gonadal mixta clasifica en los desórdenes de la diferenciación sexual de causa cromosómica. Se describe un paciente de un año de edad que es atendido en el Hospital Pediátrico Juan Manuel Márquez, por presentar genitales externos atípicos. El diagnóstico del paciente fue de disgenesia gonadal mixta, y se realizó con los complementarios siguientes: ecografía ginecológica, estudios hormonales y cariotipo. El tratamiento instaurado inicialmente, fue quirúrgico en dos tiempos operatorios, y el seguimiento hormonal hasta la pubertad (14 años), cuando se inició terapia de reemplazo hormonal según lo establecido por la edad de la paciente(AU)

Sex differentiation is a genetically determined and controlled process that may be altered by various types of genetic mutations or by the effect of hormones or other environmental disruptors acting upon the embryo. The result is the formation of external genitalia that does not match with the genetic sex and the internal genitalia. Mixed gonadal dysgenesis is classified into the sexual differentiation disorders of chromosomal cause. Here is a one-year old child, who was seen at Juan Manuel Marquez pediatric hospital since he presented with atypical external genitalia. The diagnosis was mixed gonadal dysgenesis, based on supplementary tests like gynecological echography, hormone studies and karyotype. The initial treatment was surgical in two surgical times, and the hormonal follow-up lasted till puberty (14 years) when the hormone replacement therapy started according to the indications for the patient's age(AU)

Disgenesia gonadal mixta como forma de presentación de un desorden de la diferenciación sexual de causa cromosómica / Mixed gonadal dysgenesis as a form of presentation of sex differentiation disorder of chromosomal origin

La diferenciación sexual es un proceso genéticamente determinado y controlado, que puede ser alterado por diferentes tipos de mutaciones genéticas, o por el efecto de hormonas u otros disruptores ambientales que actúan sobre el embrión, resultando en la formación de genitales externos que no se corresponden con el sexo genético y con los genitales internos. La disgenesia gonadal mixta clasifica en los desórdenes de la diferenciación sexual de causa cromosómica. Se describe un paciente de un año de edad que es atendido en el Hospital Pediátrico “Juan Manuel Márquez”, por presentar genitales externos atípicos. El diagnóstico del paciente fue de disgenesia gonadal mixta, y se realizó con los complementarios siguientes: ecografía ginecológica, estudios hormonales y cariotipo. El tratamiento instaurado inicialmente, fue quirúrgico en dos tiempos operatorios, y el seguimiento hormonal hasta la pubertad (14 años), cuando se inició terapia de reemplazo hormonal según lo establecido por la edad de la paciente.

Sex differentiation is a genetically determined and controlled process that may be altered by various types of genetic mutations or by the effect of hormones or other environmental disruptors acting upon the embryo. The result is the formation of external genitalia that does not match with the genetic sex and the internal genitalia. Mixed gonadal dysgenesis is classified into the sexual differentiation disorders of chromosomal cause. Here is a one-year old child, who was seen at “Juan Manuel Marquez” pediatric hospital since he presented with atypical external genitalia. The diagnosis was mixed gonadal dysgenesis, based on supplementary tests like gynecological echography, hormone studies and karyotype. The initial treatment was surgical in two surgical times, and the hormonal follow-up lasted till puberty (14 years) when the hormone replacement therapy started according to the indications for the patient's age.

45,X/46,X,psu dic(Y) gonadal dysgenesis: influence of the two cell lines on the clinical phenotype, including gonadal histology.

A child born with ambiguous genitalia (Prader III) was found to have a 45,X[92.2%]/46,X,psu dic(Y)(p12)[7.8%] karyotype in peripheral blood lymphocytes. The testosterone level was consistent with that of a normal male; however, gonadotropins were elevated. Ultrasound and endoscopy of the urogenital sinus revealed well-developed Müllerian structures. At 3.5 months, the child was operated for right-sided incarcerated hernia, and the gonad situated at the inguinal region was biopsied and classified as primitive testis. Based on the presence of Müllerian structures, anatomy of external genitalia and wish of the parents, the child was assigned female gender. She underwent removal of the left gonad at 4 months during another acute surgery; histology was similar to the right gonad. The rest of the right gonad was removed at 16 months, and feminizing genitoplasty took place at 3 years. The right and left gonad contained 28 and 22% of cells with a Y chromosome, respectively. During further histological examination, dysgenetic features of the gonads were discovered. Some germ cells displayed abnormal development based on the specific expression of immunohistochemical markers (OCT3/4, TSPY, KITLG), indicating a possible risk for future malignant germ cell tumor development. Contribution of the 45,X cell line to the phenotype was also observed: the patient developed celiac disease, and her growth pattern resembled that of Turner syndrome responding to growth hormone treatment.

Mixed gonadal dysgenesis: whole life follow-up of a rare case.

There are two forms of gonadal dysgenesis - mixed and pure. In the mixed form, some differentiated gonads as well as some either ovarian or testicular rudiments are present. This form results in a number of phenotypes with a possibility of malignant transformation. In the pure form occurring in female gender, also some rudimental gonads are bilaterally present. In the case of simultaneous presence of Y chromosome, also some malignant transformation may appear (Siklar et al. 2007). Chromosomal aberrations are present in 2-7 % adult pairs with fertility disorders and in 0.6 % of newborns. However, only few cases with similar chromosomal aberrations were described so far (Roubin et al. 1977; Alexander et al. 1978; Teyssier et al. 1982; Caglayan et al. 2009). Mixed gonadal dysgenesis presents as a unilateral testis, usually intraabdominal, also with a streak gonad on contralateral side, and persistent mullerian structures. 45X/45XY karyotype is the most frequent in such cases with predominance of 45X cells in both peripheral lymphocytes and gonads. We present a rare case of a left undescended testis, normally descended right testis, with penoscrotal hypospadias, who had a normal karyotype and whose histopathological findings were endometrial tissue and fallopian tube in left testicular biopsy. Gonadal dysgenesis should always be kept in mind because of a possibility of undescended testis and proximal hypospadias. If karyotype reveals a 46XY gonadal dysgenesis, these patients need the careful follow-up to screen for gonadoblastoma in remaining normal testis. Subjecting the patients to prophylactic orchidectomy with hormone replacement can be an additional option in such patients.

45,X/46,XY mosaicisme: report of five cases and clinical review.

INTRODUCTION: The mosaicism 45, X/46, XY is a gonosomal abnormality characterized by a broad phenotypic spectrum, ranging from women with or without Turner syndrome stigmata, to men apparently normal, passing by the ambiguous phenotypes with variable virilisation of external genitalia. From the histological point of view, several situations may arise. PATIENTS AND METHODS: We analyzed the clinical, hormonal, sonographic, and genitographics data, as well as peroperative and histological findings for five cases of mosaicism 45, X/46, XY, and we discussed treatment performed. RESULTS: The mean age of patients was 6.6 years, two had a female phenotype with clitoral hypertrophy (one of them had Turner syndrome stigmata), one had a normal male phenotype with bilateral cryptorchidism and two had an ambiguity of external genitalia assigned to male. Short stature was noted for four patients. Surgical exploration concluded to the diagnosis of mixed gonadal dysgenesis for four of our patients. No cases of gonadoblastoma have been reported, for girls a prophylactic gonadectomy was performed, for boys the streak gonad was resected and the dysgenetic testis biopsied and preserved, subject for constant monitoring. CONCLUSION: This heterogeneity indicate the importance of an accurate clinical and histological evaluation of any patient presenting with 45, X/46,XY mosaicism.

Desafíos quirúrgicos de las anomalías del desarrollo sexual / The surgical challenges of disorders of sex development (DSD)

Las Anomalías del Desarrollo Sexual (ADS) siguen siendo un desafío fascinante para los pediatras, endocrinos, biólogos, psiquiatras, genetistas, radiólogos, cirujanos y para toda la sociedad. Este artículo busca destacar las controversias y cuestiones actuales de la reconstrucción genital en niños nacidos con genitales anormales. Se revisan las principales técnicas actuales de masculinización y feminización junto con sus progresos y sus problemas. Se discuten las herramientas de decisión utilizadas para asignar un género en algunos recién nacidos con ADS complejas mostrando que en el amanecer del tercer milenio, uno todavía no conoce por qué un niño es un niño y una niña es una niña(AU)

Disorders of Sex Development (DSD) remain a fascinating challenge for the paediatricians, endocrinologists, biologists, psychiatrists, geneticists, radiologists, surgeons and for the whole society. This article aims at highlighting the current controversies and questions met with genital reconstruction in children born with abnormal genitalia. The main current techniques of masculinization and feminization are reviewed with their progress and their problems. The tools of decision used to assign a gender in some newborns with complex DSD are discussed showing that at the dawn of the third mille-nium, one still does not know why a boy is a boy, and a girl is a girl(AU)

Surgical options in disorders of sex development (dsd) with ambiguous genitalia.

Disorders of sexual development (DSD) include three main groups of patients: (1) The virilised 46,XX DSD essentially represented by congenital adrenal hyperplasia (CAH) ; (2) The undervirilised 46,XY DSD essentially represented by hypospadias; and (3) the chromosomic jigsaws essentially represented by mixed gonadal dysgenesis. It is in this last group that gender assignment remains a difficult decision involving various indicators, which can be split into four categories: (1) the inside sex (i.e., genes, hormones and target tissues); (2) the outside sex (i.e., anatomy of genitalia including size of the genital tubercle, mullerian cavity and potential adult height of the patient); (3) the functional sex (i.e., potential sexuality and fertility); and (4) and the social sex (i.e., the cultural medium in which the child is brought up). The challenge is to outline the future individual identity of the child in the postnatal period using these indicators. Current evolutions of surgical techniques of 'feminisation' and 'masculinisation' are described as well as their outcomes.

Laparoscopic diagnosis and treatment of a phenotypic girl with mosaic 45,XO/46,X,idic(Y) mixed gonadal dysgenesis.

We report our experience with laparoscopic gonadal biopsy and gonadectomy for a girl with a dicentric Y chromosome in mixed gonadal dysgenesis (MGD). A 4-year-old phenotypic girl was referred to our hospital because of slight enlargement of the clitoris. Fluorescence in situ hybridization analysis with Y chromosome-specific probes showed a karyotype with 45,XO/46,X,+idic(Y)(p11.32) and presence of the sex-determining region Y sequence. The pathologic finding by frozen section technique using laparoscopic biopsy specimens during the operation demonstrated a left streak gonad and right testis, and she was diagnosed with MGD. Finally, we performed laparoscopic bilateral gonadectomy. Laparoscopic management is a good approach for patients with sexual development disorders, including MGD because it provides minimally invasive surgery for children and enables all necessary procedures, including evaluation, biopsy, and gonadectomy, for diagnosis and treatment.

Gender dysphoria and gender change in an adolescent with 45,X/46,XY mixed gonadal dysgenesis.

This is a report of a 13-year-old 45,X/46,XY patient who was assigned as female gender and had feminizing surgery during infancy. Psychological problems became progressively more severe from childhood to incapitation by age 13 years. Gender identity reversal was performed after extensive physiological testing. Because he wanted to have corrective surgery, his external genitalia sex reassignment was made male from female. There were surgical problems with his phalloplasty; after surgery at infancy there was reduction of the phallus with recession of the glans to the typical clitoral location. Genital response during sexual activity and satisfaction after reconstructive surgery for male genitalia are as yet unknown. This patient is a typical example for medical, psychological and surgical dilemmas of sex reassignment and the problems of early corrective surgery. Sufficient brain virilisation associated with undervirilised external genitalia is an important problem for assignment of gender identity.

[Mixed gonadal dysgenesis combined with gonadoblastoma].

Gonadal dysgenesis is defined by incomplete or defect forming of gonads, a result of disturbed process of migration of germ cells or and their correct organization in gonadal ridge. The combination of dysgenetic gonads and Y chromosome is a prerequisite for developing ovarian neoplasma--most frequent gonadoblastoma. We present a case of mixed gonadal dysgenesis at a patient with caryotype 46XY in combination with gonadoblastoma.

Scrotal hysterectomy in a male patient with mixed gonadal dysgenesis 46,XY(75%)/45,X(25%).

We report on a 20-year-old man in whom endocrinological investigation owing to dysmorphic signs characteristic for Turner syndrome revealed mixed gonadal dysgenesis. The patient was referred to us for further diagnostic investigations on a right intrascrotal tumour. Both testes were intrascrotal and hypotrophic with normal testosterone production. Surgical investigation showed a circumscribed tumor that proved to be a rudimentary uterus without evidence of malignancy at histological examination. Biopsies from both tested showed no signs of malignant disease. After removal of the tumor, we decided not to remove the testes prophylactically because of the male phenotype and the sufficient testosterone production.

Laparoscopic excision of Mullerian structures in a neonate with mixed gonadal dysgenesis: a case report.

Excision of Mullerian structures in children with disorders of sexual differentiation is an operative challenge. We report our experience with laparoscopic excision of Mullerian structures in a neonate with mixed gonadal dysgenesis. The salient features of the procedure were excellent visualisation and ease of dissection.

The use of laparoscopy in intersex patients.

The management of intersex patients is a challenge. Although in the majority of patients the diagnosis may be made on the basis of cytogenetic and biochemical tests, there is a selective group of patients with difficulties in the establishment of final diagnosis and gender assignment. Since laparoscopy has been used in the management of impalpable gonads in the normal male population, it may be an alternative method for the diagnosis and surgical management of intersex patients. Thus we have evaluated our experience with laparoscopy in intersex population. Over the last 10 years (1995-2005) more than 80 intersex patients underwent surgical correction at our department. Out of those, 14 patients with a median age of 3 years (range 2-18 years) underwent laparoscopic surgery. Laparoscopic gonadectomy with subsequent estrogen replacement was performed following gonadal biopsy in five patients with androgen insensitivity syndrome (AIS). In three patients with mixed gonadal dysgenesis (MGD) gonadal biopsy was performed. In two of those the initial diagnosis was changed to true hermaphroditism, and they underwent removal of ovotestis from one side and orchidopexy of the normal testis on the other. In one patient with MGD, timed gonadectomy following laparoscopic biopsy was performed due to malignant potential of the streak gonads. In two patients with persistent müllerian duct syndrome (PMDS), laparoscopic orchidopexy was performed following gonadal biopsy. Three patients with total gonadal dysgenesis (TGD) underwent laparoscopic gonadectomy and one with true hermaphroditism underwent laparoscopic biopsy followed by bilateral inguinal orchiectomy with preservation of the ovarian tissue. Our data show that the laparoscopic gonadal biopsy remains the only way to obtain morphologic gonadal structure and to establish a final diagnosis in doubtful cases. Magnification and easy access to the pelvic cavity allow removal of gonads or ductal structures with the advantages of minimally invasive procedure.

Urinary continence is well preserved after total urogenital mobilization.

PURPOSE: Total urogenital sinus mobilization (TUM) has been advocated as a successful technique in the repair of common urogenital sinus anomalies. To our knowledge the long-term effects on continence, voiding pattern and bowel control have not been published. We present our experience and assessment regarding these issues. MATERIALS AND METHODS: We retrospectively reviewed our experience with TUM. Medical records were reviewed for each patient along with long-term followup by telephone questionnaire and clinical visits. Uroflowmetry was performed in recent patients who were old enough to cooperate in the study. RESULTS: A total of 13 females underwent TUM. Medical records were reviewed for all patients. Patients were divided into 2 groups. Group 1 consisted of 7 patients who underwent surgery before the age of achieving continence, and group 2 consisted of 6 patients who were incontinent before surgery. One patient in group 2 was lost to long-term followup. Two children in group 1 have enuresis, a 27-month-old with day and nighttime enuresis and a 3-year-old with only nocturnal enuresis. All patients in group 2 were continent immediately postoperatively. CONCLUSIONS: TUM preserves urinary continence immediately postoperatively among patients who are continent before surgery. Furthermore, it does not appear to delay the natural development of continence among patients undergoing surgery before the age of toilet training.

Feminizing surgical management of intersex patients.

The study's objective was to evaluate the results of surgical modalities for children with ambiguous genitalia. The records of 55 patients who were reared as females between 1985 and 2001 were reviewed regarding diagnosis, age at surgery, operative procedures, and outcome. The mean age at surgery was 3.5 years, and the follow-up period averaged 4.1 years with a range of 2 months-17 years. The types of reconstructive surgical techniques were clitorovaginoplasty in 29, staging clitoral surgery and vaginoplasty in seven, clitoroplasty in five, total urogenital mobilization (TUM) in three, vaginal bowel substitution in two, clitoridectomy in one, and gonadectomy in six, and two are waiting for vaginal substitution surgery after gonadectomy. The main complications were vaginal stenosis in four patients. All of the TUM patients had good appearances of their urethral orifice and vagina, all of them were continent, and none of them had urinary tract infections. With our limited experience with the TUM procedure, we feel that it is possible to obtain a better cosmetic and functional result with an easier technique. Among the 10 patients of postpubertal age, none of them had had sexual experience. Eight of the postpubertal patients asked questions about their reproductive status. Patients with an intersex disorder should be informed about their problems, especially about their reproductivity.