Buccal cell FISH and blood PCR-Y detect high rates of X chromosomal mosaicism and Y chromosomal derivatives in patients with Turner syndrome

Turner syndrome (TS) is the result of (partial) X chromosome monosomy. In general, the diagnosis is based on karyotyping of 30 blood lymphocytes. This technique, however, does not rule out tissue mosaicism or low grade mosaicism in the blood. Because of the associated risk of gonadoblastoma, mosaicism is especially important in case this involves a Y chromosome. We investigated different approaches to improve the detection of mosaicisms in 162 adult women with TS (mean age 29.9 ± 10.3). Standard karyotyping identified 75 patients (46.3%) with a non-mosaic monosomy 45,X. Of these 75 patients, 63 underwent additional investigations including FISH on buccal cells with X- and Y-specific probes and PCR-Y on blood. FISH analysis of buccal cells revealed a mosaicism in 19 of the 63 patients (30.2%). In five patients the additional cell lines contained a (derivative) Y chromosome. With sensitive real-time PCR we confirmed the presence of this Y chromosome in blood in three of the five cases. Although Y chromosome material was established in ovarian tissue in two patients, no gonadoblastoma was found. Our results confirm the notion that TS patients with 45,X on conventional karyotyping often have tissue specific mosaicisms, some of which include a Y chromosome. Although further investigations are needed to estimate the risk of gonadoblastoma in patients with Y chromosome material in buccal cells, we conclude that FISH or real-time PCR on buccal cells should be considered in TS patients with 45,X on standard karyotyping.     

Utility of Ultrasound and Magnetic Resonance Imaging in Patients with Disorders of Sex Development Who Undergo Prophylactic Gonadectomy

Study ObjectiveTo evaluate ultrasonography and magnetic resonance imaging (MRI) in identifying gonads in patients with disorders of sex development (DSD) who undergo prophylactic gonadectomy, and to assess the capacity of preoperative imaging to detect premalignant and malignant transformation.Design, Setting, and ParticipantsRetrospective cohort at a tertiary referral center of 39 patients with DSD who underwent MRI and/or ultrasonography before prophylactic gonadectomy.InterventionsNone.Main Outcome MeasuresIdentification of gonads on preoperative imaging.ResultsThirty-three patients underwent ultrasonography, which identified 54% (35/65) of gonads and 14 patients had MRI, which identified 41% (11/27) of gonads. There was no significant difference between imaging modalities in the proportion of gonads identified (P = .25). The proportion of pathology-confirmed dysgenetic gonads identified was higher on ultrasound compared with MRI (51% vs 8%; P = .02). There was no difference in the proportion of pathology-confirmed testes identified on ultrasound and MRI (54% vs 71%; P = .33). Eleven out of 39 patients (28%) were diagnosed with a premalignant lesion, and there were no distinguishing characteristics documented on imaging reports to suggest transformation. The only diagnosed malignancy in this series had imaging describing a “normal-sized ovary.”ConclusionUltrasonography and MRI identified 40%-50% of gonads in patients with DSD who underwent prophylactic gonadectomy, with no significant difference between the 2 modalities. Clinicians should, therefore, consider ultrasonography as a first-line imaging modality. Premalignant lesions were not detected on either imaging modality. The only malignancy was described as a “normal-sized ovary” which should raise concern in a patient with complete gonadal dysgenesis expected to have streak gonads.     

A Case of 45,X/46,XY Mosaicism Presenting as Swyer Syndrome

BackgroundSwyer syndrome is a difference of sex development that is typically associated with mutations in genes responsible for testicular development. It is speculated that some cases may result from cryptic 45,X/46,XY mosaicism leading to abnormal gonadal development. The presence or absence of a 45,X lineage is important for prognosis and management.CaseWe present a case of apparent Swyer syndrome associated with a 46,XY chromosomal complement in lymphocytes and 45,X/46,XY mosaicism on analysis of her noncancerous gonad. Gonadal histology was consistent with a 45,X phenotype.Summary and ConclusionThis case demonstrates the clinical variability in the presentation of 45,X/46,XY mosaicism and highlights the importance of thorough genetic testing that includes consideration of chromosomal mosaicism. We will discuss the implications of this diagnosis for management.     

Breast cancer,ovarian gonadoblastoma and cervical cancer in a patient with Peutz-Jeghers Syndrome

BACKGROUND: Peutz-Jeghers Syndrome (PJS) is a rare autosomal dominant disorder characterized by gastrointestinal hamartomatous polyps and mucocutaneous pigmentation. Patients with PJS have increased risk for gastrointestinal, breast, and female genital tract cancers. CASE: Multiple genital tract cancers in a 34-year-old woman with PJS are described. The patient, who was admitted to our department with severe vaginal bleeding, was performed right salpingo-oophorectomy because of pure gonadoblastoma in 1996. In 2003, concomitant to cervical carcinoma, breast cancer was diagnosed. Patient underwent left modified radical mastectomy due to the invasive papillary carcinoma. The patient received six cycles combination chemotherapy and radiation therapy because of stage IIIB cervical cancer. CONCLUSION(S): This is the first case report presenting PJS associated with multiple genital tract tumors including ovarian gonadoblastoma in literature. The clinical significance of these tumors in PJS patients has been reviewed.     

Y Chromosome Specific DNA Probe in the Diagnosis of a Patient with mos 45, X/46, XYnf

In a patient with mos 45,X/46,XYnf, the diagnosis was confirmed with a Y chromosome-specific DNA probe, Y-190. The patient was a phenotypic female without Turner syndrome stigmata other than short stature. She showed some evidence of virilization and high serum testosterone. Her peripheral blood karyotype was mos 45,X/46X, +mar. Although this marker chromosome resembled a Y chromosome, there was no quinacrine bright region on its long arm. Southern blot analysis of her peripheral blood mononuclear cell DNA with Y-190 as a probe showed strong hybridization with this probe. Gonadectomy was performed, and bilateral gonadoblastomas were found.     

Gonadoblastoma-Associated Mixed Gonadal Germ Cell Tumor with Dysgerminoma and Hepatoid Yolk Sac Tumor Components in 46XY Gonadal Dysgenesis

BackgroundDisorders of sex development are congenital conditions with atypical chromosomal, gonadal, or anatomical sex development. Gonadal dysgenesis in patients containing a Y chromosome have a high risk of developing germ cell tumors with potential for malignant transformation.CaseWe present the case of a 17-year-old phenotypic female with primary amenorrhea and 46,XY complete gonadal dysgenesis. Pelvic ultrasound showed a solid cystic lesion in the right gonad. Pathology showed a gonadoblastoma-associated mixed gonadal germ cell tumor with dysgerminoma and hepatoid yolk sac tumor.Summary and ConclusionTo our knowledge, this mixed neoplasm association has not been previously reported and this case illustrates the challenges for the diagnosis of gonadal dysgenesis-associated tumors, emphasizing its recognition and prognostic implications.     

Pathological conditions predisposing to infertility and gynaecological neoplasia

Some of the conditions long blamed for female factor infertility are now acknowledged as well established risk factors of gynecological neoplasia. This realization has lead to the proposition that infertility might be a risk factor for the development of several types of gynecological neoplasms. This review addresses different conditions that play a role in both infertility and gynaecological neoplasia. An intricate interplay between growth factors and hormonal factors (estrogens and progestins, androgens and gonadotropins) is said to link the state of infertility to some gynecological tumors. The relation between endometriosis -as one of the well established causes of female infertility - and ovarian cancer is well known. Endometriosis has been particularly related to endometrioid and clear-cell ovarian carcinomas. Another evidence for this association is embodied in finding endometriotic lesions adjacent to ovarian cancers. The polycystic ovary syndrome (PCOS), one of the most prevalent endocrine disorders and a long studied cause of female infertility increases the risk of endometrial carcinoma. The link between PCOS and endometrial carcinoma seems to be endometrial hyperplasia. PCOS-associated endometrial carcinoma tends to present at a younger age and early stage, with lower grade and lower risk of metastasis. Turner’s syndrome and other types of ovarian dysgenesis constitute a rare cause of infertility and are known to confer a definite risk of germ cell tumors. There seems to be a link between infertility and an increased risk of gynecological neoplasia. Hence, it is important to assess the risk of malignancy in each category of infertile patients so as to provide optimal and timely intervention.