Normal pelvic ultrasound or MRI does not rule out neoplasm in patients with gonadal dysgenesis and Y chromosome material.

INTRODUCTION: Patients with gonadal dysgenesis (GD) with a Y chromosome have an increased risk of gonadal neoplasm. Few data exist on the ability of imaging to detect malignancy in intra-abdominal gonads in these patients. OBJECTIVE: We aimed to determine the correlation between preoperative imaging findings and gonadal pathology in GD patients with Y chromosome material. METHODS: A retrospective review was performed of patients with XY or XO/XY GD who underwent gonadectomy at our institution from 2003 to 2017. Patients were assessed preoperatively with ultrasonography; some additionally underwent MRI. RESULTS: The series consisted of 10 patients, all with female gender and non-palpable gonads. Median age was 13.1 years (range 2.4-18.3 years). Overall, four of the ten patients (40%) had a tumor (gonadoblastoma or dysgerminoma) on final pathology. Four patients had a gonad or gonads that were definitively seen on ultrasonography. All visualized gonads were described as "normal" or "small" with the exception of one patient, who had a normal MRI. Three of the four patients in this group had a tumor on final pathology. The remaining six patients had a gonad or gonads that were not definitively visualized on ultrasound; one patient in this group had a tumor on final pathology. Overall, five of seven gonads (71%) definitively visualized on ultrasound had tumor on final pathology, and two of thirteen gonads (15%) not visualized on ultrasound had tumor on final pathology; this difference was statistically significant (p = 0.012). Three patients were imaged with MRI. Of the gonads that could be visualized on MRI, no definitive abnormalities were seen. All patients imaged with MRI had tumors on final pathology. DISCUSSION: Both ultrasound and MRI are relatively poor at identifying and characterizing intra-abdominal gonads in GD patients. The majority of patients who had a neoplasm had normal imaging findings. Gonads that were definitively visualized on ultrasound were more likely to contain neoplasms that could not be visualized, which perhaps because of tumor growth. No other consistent imaging findings of malignancy were found. Our study included ultrasound evaluations that were completed over 10 years ago and not performed by pediatric ultrasonographers, which may have biased the results. However, results suggest that when discussing gonadectomy with GD patients, one should not be reassured by "normal" imaging findings. Neither ultrasound nor MRI should be relied on for surveillance in GD patients who decide against gonadectomy. CONCLUSION: A normal ultrasound or MRI does not rule out neoplasm in GD patients with intra-abdominal gonads.

Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management.

Recent studies on gonadal histology have improved the understanding of germ cell malignancy risk in patients with disorders of sex development (DSD), and evidence-based gonadal management strategies are gradually emerging. Especially in 46,XY DSD and 45,X/46,XY DSD, which are characterized by gonadal dysgenesis, the risk of germ cell malignancy is significantly increased. This paper summarized the progress over the past 10 years in malignancy risk assessment in patients with DSD, and its implications for optimal surgical handling of the involved gonads.

[Congenital disorders of gonadal differentiation: clinico-morphological variants and surgical treatment].

The article presents the results of examination and surgical treatment of 25 patients with congenital disorders of gonadal differentiation. Survey plan included an assessment of the external genitalia, karyotyping and molecular analysis of Y-chromosome, determination of serum gonadotropins and testosterone levels, visualization of the gonads using ultrasound and laparoscopy methods, and intraoperative morphological examination of the material. Based on the results of a comprehensive survey, mixed testicular dysgenesis was identified in 25% of patients, complete testicular dysgenesis--in 16%, partial gonadal dysgenesis--in 44%, ovotesticular violation of sexualization--in 16% of patients. Clinical, macroscopic and morphological characteristics of each of these options are defined. The choice of sexual identity and tactics of surgical treatment are explained.

Mutation of the MIF type II receptor in two brothers.

The Müllerian inhibiting factor (MIF) is responsible for regression of Müllerian ducts during male sexual differentiation. Mutations in MIF or its type II receptor lead to persistence of the uterus and Fallopian tubes in male children--i.e., persistent Müllerian duct syndrome (PMDS). Both are rare autosomal recessive disorders. We report a 7-month-old male infant who underwent inguinal herniorrhaphy. Remnants of vas deferens and gonads with macroscopic characteristics of ovaries, along with Fallopian tubes and a rudimentary uterus, were found. Karyotype confirmed male sex. Molecular genetics revealed the most frequent MIF type II receptor gene mutation--27 bp deletion. Investigation of the older brother presenting bilateral cryptorchidism at 7 years of age led to similar clinical findings and the same mutation. We report here an MIF type II receptor mutation in two brothers, with the particularity that the surgical findings in the younger son initiated the diagnostic process in both children.

Insights into selected genetic diseases affecting the female reproductive tract and their implication for pathologic evaluation of gynecologic specimens.

CONTEXT: Recent advances in the understanding of genetic conditions involving the female genital tract and mechanisms of carcinogenesis in this setting affect patient management and thus necessitate appropriate pathologic evaluation of specimens. In the past, specimens from prophylactic surgery were a rarity; however, they are now more frequently encountered and often require a significant variation from routine processing methods. Pathologists also receive more specimens requiring prospective workup for possible underlying genetic conditions such as microsatellite instability. OBJECTIVE: To summarize the current knowledge of important genetic and hereditary conditions affecting the female reproductive organs while highlighting the resulting practical significance for specimen handling, "grossing," and microscopic evaluation in gynecologic pathology. DATA SOURCES: This update is based on a review of recent peer-reviewed literature and the experience with cases at the parent institutions. CONCLUSIONS: Gynecologic specimens received from patients with certain genetic conditions require specific clinicopathologic knowledge for appropriate pathologic examination. The evaluation of prophylactic resection specimens focuses on the detection of cancer precursors and possible occult disease, which may require a more thorough and detailed examination than an obvious carcinoma. Standardized protocols for handling prophylactic gynecologic resection specimens are available for some, but not all, types of specimens. The prospective evaluation of a gynecologic pathology specimen for potential genetic conditions such as microsatellite instability is a very recent subject. Currently, well-established protocols are not available; however, as clinical and prognostic significance has become more clearly elucidated, familiarity with this evolving field is increasingly important to properly assess these pathologic specimens.

Laparoscopic gonadectomy in a kidney transplant patient with pure gonadal dysgenesis: a case report.

BACKGROUND: Laparoscopy has been successfully used following renal transplantation for many procedures, including native kidney nephrectomy, revision of transplant ureters and cholecystectomy. Laparoscopic surgery has also been used recently to treat pelvic disorders in patients after renal transplantation, such as removal of endometriotic cyst and hysterectomy. In such cases, we must pay special attention to the anatomy of the renal graft transplanted into the pelvic cavity. CASE: A woman received a kidney transplant at 7 years old, with her mother as the donor. At 19 years old, she was diagnosed with pure gonadal dysgenesis and began hormone replacement therapy and monitoring of tumor markers. At 23 years old, laparoscopic gonadectomy was performed under general anesthesia. Bilateral atrophic gonads were removed without any complications. The renal graft in the right hemipelvis did not obstruct the operation. CONCLUSION: To our knowledge, this case is the first published report of laparoscopic castration in a patient with a sexual differentiation disorder and prior renal transplantation.

[Identification of potential neoplastic risk in gonadal development abnormality with Y chromosome of 79 cases].

OBJECTIVE: To identify the potential neoplastic risk in gonadal development abnormality with Y chromosome. METHODS: Inquiries about the illness history were made. Lymphocyte chromosomal karyotype of peripheral blood was analyzed. Sex determining region Y gene and relative steroids and enzymes were detected. Gonadal site was examined through medical imaging. Gonadal excision was performed by laparotomy or laparoscopy. Pathological examinations were done on all of the specimens. RESULTS: Among 41 cases of androgen insensitive syndrome, spermatogenic cell neoplasm occurred in 1 patient, sertoli cell tumor in 2, and interstitial cell hyperplasia in 5. Among 14 cases of 17 alpha-hydroxylase deficiency (XY) syndrome, one was sertoli cell tumor, and one was sertoli cell hyperplasia. In 4 cases of XY pure gonadal dysgenesis, one was gonadoblastoma with dysgerminoma. One of 16 cases of XO/XY gonadal dysgenesis was spermatogenic cell neoplasm with agenda cell tumor. Four cases of testes degeneration were all with dysgenetic testes. All of the gonadoblastoma and germ-cell tumor were located in the pelvis. Tumors occurred mostly during 15 years of age to 32 years. CONCLUSIONS: The gonads of XY pure gonadal dysgenesis has high risks of gonadoblastoma and germ-cell tumor. The older the onset age after puberty, the higher the malignancy risk is. Once diagnosed, bilateral gonads should be excised as soon as possible.

Impact of the Y-containing cell line on histological differentiation patterns in dysgenetic gonads.

OBJECTIVE: Gonadal karyotyping is considered a tool for increasing our knowledge of disturbed gonadal development in patients with gonadal dysgenesis and for estimating more accurately the risk for gonadoblastoma formation. The objective was to gain insight into the role of Y chromosome distribution in the histological heterogeneity of gonads of patients with gonadal dysgenesis. DESIGN: Investigation of the possible relationship between peripheral blood karyotype, gonadal karyotype, morphological differentiation patterns of dysgenetic gonads and tumour formation. PATIENTS: In total 22 gonadal samples from 19 patients with gonadal dysgenesis (45,X/46,XY and variants n = 14; 46,XY: n = 3; 46,XX: n = 2) were examined. MEASUREMENTS: Morphological examination and immunohistochemical staining for testis specific protein, Y encoded (TSPY) and fluorescent and nonfluorescent in situ hybridization directly on gonadal tissue. RESULTS: No correlation was observed between peripheral blood karyotype and gonadal karyotype or between gonadal karyotype and the corresponding differentiation pattern. A Y-containing cell line in Sertoli cells was encountered no more frequently than were other cell types. CONCLUSIONS: The distribution of the Y-containing cell line in peripheral blood is not a suitable indicator for predicting the histological differentiation pattern found in the gonads of patients with gonadal dysgenesis. The analysis of Y-containing cell lines in the gonads of such patients could be informative with regard to the specific characteristics of gonadal development in humans as compared to chimeric mouse models. Moreover, it is essential to understand the mechanisms underlying disturbed gonadogenesis in these patients. As the gonadal karyotype is not related to the encountered gonadal differentiation pattern, it does not allow prediction of the risk for gonadoblastoma formation.

Persistent mullerian duct syndrome with transverse testicular ectopia.

A 15-month-old boy was discovered to have internal female genitalia during an operation for bilateral inguinal hernia. The biopsies showed normal testicular tissue and the karyotyping result was 46XY, so the diagnosis of persistent mullerian duct syndrome (PMDS) was made. At the second operation, the uterine fundus and fallopian tubes were excised. Then, he underwent bilateral orchiopexy. We discuss a rare presentation of this disorder, its management, and genetic implications together with a review of the literature.

Surgical, medical and psychological dilemmas of sex reassignment: report of a 46,XY patient assigned female at birth.

This is a report of a 16 year-old 46,XY male who was reassigned female and had feminizing surgery during infancy because of what was judged to be inadequate genital masculinization. This patient had a dysgenetic testis that was shown to be producing testosterone during infancy. Although initially the reassignment appeared to be successful, psychological problems became progressively more severe during childhood to incapacitation by age 10 years. After it was verified that he had a male sexual identity, reassignment as male began, initially by living as a boy, then with testosterone therapy. Staged phalloplasty surgery was begun at age 16 years. Currently he has an adult-sized penis, although its function is not yet clear. Sadly, none of the steps to align his sex assignment to his perception as male has significantly alleviated his psychological issues and he continues to be severely impaired and socially compromised. Major issues include the crippling psychiatric disease that is resistant to psychotherapy and surgical problems with phalloplasty after surgery at infancy that involved reduction of the phallus with recession of the glans to the typical clitoral location. The glans was left intact at the anterior base of the phallus. Genital responsiveness during sexual activity and satisfaction are as yet unknown.

[Diagnostic principles of gonadal dysgenesis in adolescents].

103 patients aged 11-20 with short stature and/or with delayed puberty were studied. Among all patients classical form of gonadal dysgenesis was diagnosed in 31 patients (karyotype 45,X- 17 patients, 45,X/46,XX- 14), "mixed" gonadal dysgenesis in one patient (karyotype 45,X/46,XY)-, "pure" gonadal dysgenesis- in 5 cases (karyotype 46,XY-in 4 , 45,X -- in one). The majority of cases (66) were diagnosed as ovarian dysgenesis with the mosaic karyotype- 46,XX/45,X. In the clinical diagnostics of ovarian dysgenesis some difficulties were aroused because of slight reduction of height and delayed sexual development, mild appearance absence or somatic anomalies. The main diagnostic criteria for the various forms of gonadal dysgenesis are detection of characteristic karyotype and hypogonadotropic hypogonadism. Characteristic phenotype is more informative in the cases of classical and "mixed" forms of gonadal dysgenesis. Early diagnosis of gonadal dysgenesis is very important for effective correction of height and sexual development. Timely begin hormonal therapy may avoid complications induced bihypoestrogenia, such are: osteoporosis, cardiovascular diseases and etc. Karyotype investigation and in the cases of revealing Y chromosome material, and therefore gonadectomy must precede the beginning of hormonal therapy.

The laparoscopic management of intersex patients: the preferred approach.

UNLABELLED: In the world's largest series of patients with intersex treated by laparoscopy, authors from Sao Paulo found that this technique allowed easy identification and removal of gonads. They also found that other organs could be removed and genitoplasty performed. OBJECTIVE: To present possibly the largest series of the use of laparoscopy for treating intersex patients. PATIENTS AND METHODS: Fifty intersex patients (34 with male and two with female pseudohermaphroditism, nine with gonadal dysgenesis, four with true hermaphroditism, and one with complex hypospadias), aged 0.5-46 years (mean 18.3), underwent laparoscopy to remove gonads and/or ductal structures incompatible with the social gender, or for gonadal tumour or a potential risk for malignancy. When necessary, genitoplasty was performed concomitantly. RESULTS: At the laparoscopic evaluation, 10 gonads of six patients were absent, while four were identified as 'vanishing'; 72 gonads (46 dysgenetic, 17 normal testes, one normal ovary, one ovotestis, seven gonadoblastomas or dysgerminomas) were removed; two ovotestes were replaced in the scrotum after removing the ovarian segment, as was one normal testis. Twelve patients with a urogenital sinus had its vaginal component removed, 11 including a hysterectomy. Three of these patients had a combined perineal approach to complete its removal, together with masculinizing genitoplasty. There were no intraoperative complications or conversions; two patients had complications after surgery. CONCLUSIONS: Laparoscopy allows the straightforward identification and removal of gonads. All abnormal ductal structures must be removed, as this increases the chance of resecting unidentified gonads. Removing the uterus and vaginal component of the urogenital sinus in patients with male social sex is feasible, with low morbidity. Genitoplasty, according to the social sex, can be performed in the same procedure.

Genital ambiguity with a Y chromosome: does gender assignment matter?

Recommendations for sex of rearing in newborns with genital ambiguity, testicular differentiation and a Y chromosome continue to be challenging. Complaints from former patients have forced those providing the medical, surgical and psychological care for these individuals to reassess evaluation and treatment strategies. In this paper, the histories of six patients born with genital ambiguity and at least partial testicular differentiation with a karyotype containing a Y chromosome are presented. Three of these patients were assigned as males and three as females. The factors involved in these individuals' adaptation to the assigned gender and their subsequent quality of life are discussed. Factors needing further study, including the parents' ability to accept and support the sex of rearing, the child's temperament, associated psychological disorders, and other influences, such as masculinization of the central nervous system, are highlighted.

[Modern concepts in the treatment of intersexuality]. / Zum aktuellen Stand der Intersextherapie.

Treatment of intersexuality is demanding and requires experience and interdisciplinary cooperation. Preconditions for normal development and clear gender identification are correct (not emergency) diagnosis and gender assignment and adequate hormonal and surgical treatment. Surgery should be done early (6th to 15th month) as atraumatically as possible with cosmetically and functionally satisfying results. These preconditions are not met consistently, resulting in a 20-25% rate of mistakes in diagnosis and treatment. In experienced centers, feminizing genitoplasty, even of the severest forms, is carried out through a perineal one-stage approach. Masculinization corresponds to surgery for severe hypospadias. The high risk of malignant degeneration requires removal of all inadequate structures such as streak gonads, uterus, and tubes. In 5-alpha deficiency, early gonadectomy and feminization are not recommended since gyneophile behavior can be expected. Late or non-correction is rejected by the majority of psychiatrists. Many problems remain unclear and controversial due to lack of knowledge. In the future they can only be solved through cooperation, documentation, and observation of these individuals over their lifetime.

Erroneous genetic sex determination of a newborn twin girl due to chimerism caused by foetal blood transfusion. A case report.

OBJECTIVE: We present a case of erroneous sex determination in a newborn twin girl (twin A) due to chimerism. CASE REPORT: Amniocentesis and ultrasound examination had pointed towards male sex of both twins. At birth, twin A presented as a phenotypically normal female with 46,XY karyotype, and 46,XY gonadal dysgenesis was suspected. Twin B was a normal male. RESULTS: In our department, further examinations of twin A included undetectable testosterone and inhibin-B and elevated FSH. Ultrasound suspected an infantile uterus, and sequencing of the SRY gene was normal. After gonadectomy, a 46,XX karyotype was demonstrated in both normal infantile ovaries and in the fibroblasts from a skin biopsy. Analysis of X-linked markers in DNA from blood lymphocytes in both twins was identical, consistent with 46,XY karyotypes. CONCLUSION: Twin A is a 46,XX female with a chimeric 46,XY blood cell line due to intrauterine transfusion from her twin brother.

[Congenital genital anomalies. Aspects of diagnostics and treatment]. / Igimtos lytiniu organu anomalijos. Diagnostikos ir gydymo aspektai.

Congenital genital anomalies are a very complex pathology. In order to clarify its causes it is important to revert to the genetic conditions and regularities of embriological development. The genital disturbances are mostly determined by chromosomal or endocrinic disorders or by impaired biochemical processes. Clinical problems arise when the genetical sex is in discrepancy with ambiguous genitalia. True hermaphroditism, congenital adrenal hyperplasia, testicular feminization and gonadal dysgenesis are the most common syndromes. Diagnostic criteria applied are similar for all (establishment of karyotype, investigation of hormones and their derivates, genital ultrasound and endoscopy, if needed - radiological examination), but medical and surgical treatment is applied to each patient individually.