Laparoscopic gonadectomy in a case of a dicentric fluorescent Y-chromosome mosaicism with Turner-like phenotype and virilized external genitalia

In few cases of Turner syndrome the karyotype reveals the presence of an additional Y-bearing cell line, which is referred to as a borderline case of mixed gonadal dysgenesis. We report a 20-year-old woman with primary amenorrhea, virilization and a few Turner stigmata, who revealed rare mosaicism of 45,X/46,X dic (Y; 5)(q12; q11), +5/46,X, der (Y), which was detected by conventional G-banding and multicolor spectral karyotyping. She underwent laparoscopic gonadectomy in which mixed gonadal dysgenesis was found and both gonads were removed. No evidence of gonadoblastoma was noted on the gonads. Virilization improved postoperatively. We recommend gonadectomy via laparoscope in women presenting with Turner-like phenotype, virilization and the presence of a Y chromosome. This report describes the role of cytogenetic and molecular genetic investigations in the definition of mosaicism in Turner syndrome.     

Gonadendysgenesie

In gonadal dysgenesis, differentiation of the primitive gonad to mature gonads is missing. The main symptoms include primary amenorrhea and missing secondary sexual development. To the gynecologist, pure gonadal dysgenesis 46,XX and 46,XY, mixed gonadal dysgenesis, and Turner’s syndrome are clinically important. In all patients with gonadal dysgenesis containing Y chromosome material (e.g. Swyer’s syndrome), removal of the gonads is highly recommended in order to prevent malignancy. The risk of malignancy in these organs is about 25%. Estrogen and progestogen replacement therapy is advocated at the onset of puberty for the induction of female sexual characteristics and prevention of the sequelae of chronic estrogen deficiency. Turner’s syndrome shows typical additional symptoms requiring an interdisciplinary approach, including pediatricians and internists.     

Cytogenetic studies in primary amenorrhea]

Cytogenetic analysis in 125 women with primary amenorrhea consisting of determinations of sex chromatin and karyotype, and in some cases of autoradiography were performed. On the basis of clinical, endocrinologic and cytogenetic criteria, the women were divided into ten clinical groups. In Turner's syndrome 45,X monosomie was observed only in 9 patients and in the remaining 12 cases varies types of mosaicism or of structural aberrations of the X chromosome. In pure gonadal dysgenesis, the patients exhibited 46,XY karyotype have the tendency to malign tumors of the gonads. In all cases with male pseudohermaphroditism the karyotypes 46,XY were observed. The remaining patients with primary amenorrhea exhibited 46,XX karyotype and belonged to the cases with Mayer-Rokitansky-Kustner syndrome, with adrenogenital syndrome, with hypoplasia of the ovaries, with primary amenorrhea of uterine or pituitary origin or at last with pubertas tarda.     

Adnexal Torsion Due to Borderline Mucinous Tumor of the Gonad in a Prepubertal Girl with Mixed Gonadal Dysgenesis (45,X/46,XY) and a Turner Phenotype

BackgroundTurner syndrome (TS) is a sex chromosome condition characterized by complete or partial loss of the X chromosome. Patients with mixed gonadal dysgenesis (45,X/46,XY) and a Turner phenotype are predisposed to gonadoblastoma with malignant transformation.CaseWe present the case of a TS patient with 45,X/46,XY with 2 episodes of left adnexal torsion (AT). Biopsies during detorsion showed benign mucinous cystadenoma. Pathology following bilateral gonadectomy revealed a left gonad with mucinous borderline tumor and right gonad with gonadoblastoma, both of which have malignant potential.Summary and ConclusionGonadectomy is recommended in XY gonadal dysgenesis to decrease risk of malignant transformation from gonadoblastoma. Although rare in pediatric patients, ovarian malignancies have been identified among AT cases. To our knowledge, we present the first case of AT due to borderline ovarian mucinous tumor of the ovary and contralateral gonadoblastoma in a patient with mixed gonadal dysgenesis (45,X/46,XY) and a Turner phenotype.     

Clinical picture in patients with 46,X,i(Xq) karyotype. Are there differences from Turner syndrome?

Clinical presentation in 2 patients with 46,X,i(Xq)-Karyotype are described. In both cases no mosaicism could be detected. The two patients show the classical features of gonadal dysgenesis: short stature, sexual infantilism and primary amenorrhea due to streak ovaries. Other characteristic somatic manifestations of the Turner syndrome such as webbing of the neck, however, were missing. In one of the two cases a Hashimoto's thyroiditis was present, which has been repeatedly reported before in the literature in cases with 46,X,i(Xq)-karyotype.     

Morphology of the genitals in gonadal dysgenesis

The entity includes the Turner syndrome, the pure gonadal dysgenesis (Swyer syndrome), the asymmetrical gonadal differentiation, and gonadal dysgenesis of some forms of trisomy. The necessity of prophylactic gonadectomy in all patients with Y chromosome is stressed because of a close association with the arising of tumors in the dysgenetic gonads. The requirements are described of a successful substitution with steroids.     

Anomalies de structure du chromosome Y et syndrome de Turner

Although specifically male, the human Y chromosome may be observed in female karyotypes, mostly in women with Turner syndrome stigmata. In women with isolated gonadal dysgenesis but otherwise normal stature, the testis determining factor or SRY gene may have been removed from the Y chromosome or may be mutated. In other women with Turner syndrome, the karyotype is usually abnormal and shows a frequent 45,X/46,XY mosaicism. In these cases, the phenotype depends on the ratio between Y positive and 45,X cell lines in the body. When in mosaicism, Y chromosomes are likely to carry structural abnormalities which explain mitotic instability, such as the existence of two centromeres. Dicentric Y isochromosomes for the short arm (idic[Yp]) or ring Y chromosomes (r[Y]) are the most frequent abnormal Y chromosomes found in infertile patients and in Turner syndrome in mosaic with 45,X cells. Although monocentric, deleted Y chromosomes for the long arm and those carrying microdeletions in the AZF region are also instable and are frequently associated with a 45,X cell line. Management of infertile patients carrying such abnormal Y chromosomes must take into account the risk and the consequences of a mosaicism in the offspring.     

Spontaneous Sexual Development and Heavy Menstrual Bleeding in 45,X Monosomy and 45,X/47,XXX Mosaic Turner Syndrome and a Review of the Literature

Turner syndrome (TS) is one of the most common sex chromosome disorders and is characterized by short stature and gonadal dysgenesis. A few patients with TS achieve normal sexual development, menarche, and even pregnancy. We encountered two cases of Turner syndrome with spontaneous sexual development and menstruation. The patients had different karyotypes, 45,X monosomy and 45,X/47,XXX mosaic TS, and presented with severe anemia due to excessive menstrual bleeding. Abnormal uterine bleeding patterns are expected in patients with primary ovarian insufficiency; however, the menstrual patterns of patients with TS have not been well described in the literature. Here, we describe these cases along with a brief review of the relevant literature.     

Hormonal and cytogenetic studies in phenotypically female patients with gonadal dysgenesis

In 4 cases of gonadal dysgenesis the clinical, hormonal, cytogenetic, and histological findings were correlated. There were 2 patients with 46,XY karyotype, one patient with 45,X Turner's syndrome and one patient with a 46,XX chromosome complement. All patients had streak gonads with ovarian stroma. In one phenotypically female 46,XY individual an involuted gonadoblastoma was found. Her testosterone was four-fold higher in gonadal vein blood compared to peripheral blood. Cytogenetic analysis of multiple tissues in both cases with the 46,XY karyotype greatly reduced the probability of mosaicism. In the patient with 45,X Turner's syndrome and in the one with 46,XX gonadal dysgenesis only peripheral blood cells were karyotyped and mosaicism was not further excluded by analysis of other tissues. The concentrations of steroid hormones in gonadal vein blood were low. The levels ranged as follows: estrone 41-98 pg/ml, estradiol 18-90 pg/ml, testosterone 37-294 ng/100 ml, dihydrotestosterone 13-22 ng/100 ml, and progesterone 0.3-1.5 ng/ml. It was concluded that gonadal streaks were similarly deficient in biosynthesis of steroid hormones despite different chromosomal complements.     

Gonadal malignancy in 202 female patients with disorders of sex development containing Y-chromosome material

The objective of this study was to examine risks for gonadal malignancy in a large sample of adult female patients with disorders of sex development (DSD). A retrospective-observational study was conducted from July 1992 to March 2015 and 202 women with DSD were enrolled. Tumor risks for different types of DSD were measured. We found that the patients’ total gonadal-malignancy risk was 18.3% (37/202). Tumors included gonadoblastoma (n?=?11), seminoma (n?=?8), dysgerminoma (n?=?5), choriocarcinoma (n?=?1), sertoli cell tumors (n?=?11), and leydig cell tumors (n?=?1). The incidence of gonadal malignancy in patients with complete androgen insensitivity syndrome (CAIS), pure 46, XY gonadal dysgenesis, 45 X/46 XY mixed gonadal dysgenesis, 17α-hydroxylase/17, 20-lyase deficiency and partial androgen insensitivity syndrome (PAIS) were 27.1% (13/48), 22.4% (15/67), 10.9% (5/46), 10% (2/20) and 9.5% (2/21), respectively. Our results suggest that the incidence of gonadal malignancy increases with age for female patients with Y-chromosome material. Upon diagnoses, immediate, prophylactic gonadectomies should be considered for adult female patients with DSD containing Y chromosome material if they cannot receive regular follow-ups.     

Premature Ovarian Failure and Ovarian Dysgenesis Associated with Balanced and Unbalanced X-6 Translocations, Respectively: Implications for the Investigation of Ovarian Failure

Summary: This study reports the effect of an inherited (X;6) translocation which has not previously been described. The proband was intellectually delayed and had ovarian dysgenesis. Karyotyping revealed an unbalanced karyotype: 46, X, der(X)t{X;6)(q22; p11.2). Her mother was shown to be a carrier of an apparently balanced translocation between the X chromosome and chromosome 6: 46, X, t(X;6)(q22;p11.2). This finding in the mother raises to 7 the number of cases reported which involve a break within the X chromosome 'critical region', at band Xq22, without causing ovarian dysgenesis, although it was associated with premature ovarian failure. These cases aim to highlight to clinical specialists the range of gonadal and other phenotypic anomalies (apart from those associated with Turner syndrome) which can occur due to partial deletions of the X chromosome. These findings have implications for the investigation of both ovarian dysgenesis and premature ovarian failure.     

Familial Swyer syndrome: a rare genetic entity

Swyer syndrome is a pure gonadal dysgenesis associated with a 46 XY karyotype and primary amenorrhea in a phenotypic female. Individuals in this syndrome are at an increased risk for development of gonadal malignancies. Swyer syndrome (gonadal dysgenesis) running in families is rare event and few such scenarios were reported in the literature. Here we are presenting this rare entity involving three affected siblings born to a non-consanguineous couple. Index case - A 23-year-old female with primary amenorrhea is presented with a mass per abdomen. The clinical findings and laboratory investigations revealed hypergonadotropic hypogonadism picture and, imaging revealed a left ovarian tumor. Primary surgical debulking of ovarian cancer was done, histopathology of which revealed a dysgerminoma FIGO stage IIIC. The family history of the patient revealed a similar pattern as the elder sister had primary amenorrhea and had succumbed to ovarian cancer and the younger sister also has primary amenorrhea. Karyotype of all the three patients revealed a male genotype with a female phenotype. The early diagnosis of the patients with Swyer syndrome is very important because of the increased risk for the development of malignancy. This is a rare event to have two sisters with ovarian cancers in three siblings affected with familial gonadal dysgenesis syndrome each of them having a different genotype and first of its kind to ever be reported in literature.     

Gonadal dysgenesis and somatic stigmata in patients with 45,X/46,Xr(X) ring chromosome

Two cases of gonadal dysgenesis and stigmata of Turner's syndrome with ring chromosome X are described. Their features support the idea that ring chromosome X should be considered as a deletion in the genetic sense, affecting both the gonadal and statural determinants. Without knowing the cytogenetic findings, these patients are usually labeled as having Turner's syndrome. Furthermore, endocrine data and histologic examination of the gonads are indistinguishable from those of individuals with 45,X or 46XX gonadal dysgenesis.     

Spontaneous menstruation in patients with Turner syndrome in our observations

OBJECTIVES: Patients with Turner syndrome (TS) may present a wide spectrum of gonadal function including spontaneous menstruation and fertility. DESIGN: The aim of our study was to present the patients with Turner syndrome (TS) with spontaneous menstruations considering specific karyotype and X-inactivation processes. MATERIALS AND METHODS: 5 women from group of 55 patients in age from 15 to 38 years with diagnosis of TS and gonadal function were found. Clinical analysis included the evaluation of spontaneous pubertal development and hormones levels. Cytogenetic analysis was performed on peripheral blood samples using GTG banding technique. X inactivation studies were done by dynamic RBG technique. RESULTS: In two patients with mosaic karyotype and predominant 46,XX line two pregnancies were observed. They had regular menses and normal sexual development. In one patient (karyotype: 45,X[2]/46,XX[98]) spontaneous abortions and premature birth were present. Second patient was (46,XX[245]/46,X,r(X)(p22q26)[5]) in pregnancy in this time. Another three patients menstruated irregularly. The menarche appeared later. The karyotypes were: 46,X,del(X)(p11.3) in two patients and 45,X[64]46,X,r(X) (p22q26)[18]/46,XX[4] in one. CONCLUSIONS: We conclude that spontaneous menstruations and possibility of pregnancy depend on specific karyotype in patients with TS.     

Hypogonadism and Sex Steroid Replacement Therapy in Girls with Turner Syndrome

Turner syndrome is the most common example of hypergonadotropic hypogonadism resulting from gonadal dysgenesis. Most patients present delayed, or even absent, puberty. Premature ovarian failure can be expected even if spontaneous menarche occurs. Laboratory markers of gonadal dysgenesis are well known. The choice of optimal hormone replacement therapy in children and adolescents remains controversial, particularly regarding the age at which therapy should be initiated, and the dose and route of estrogen administration. On the basis of a review of the literature, we present the most acceptable schedule of sex steroid replacement therapy in younger patients with Turner syndrome.     

Serum immunoglobulin levels,autoimmunity and cell-mediated immunity in primary ovarian failure

Serum immunoglobulin levels and autoantibodies to thyroid and ovary were estimated in patients with primary ovarian failure. IgG and IgM levels in 29 patients with 45X0 karyotype, 9 with pure gonadal dysgenesis with 46XX karyotype, 2 with 46XY karyotype, and 4 others with chromosomal mosaicism were significantly lower (P < 0.001) than those in a control group of 45 age-matched normal females in the follicular phase of the menstrual cycle. IgA and IgE levels were comparable in patients and controls. However, for patients in the 45X0 group, both IgE and testosterone levels were lower than for those with the 46XX karyotype. The 45X0 group also had significantly higher titers of anti-thyroid antibodies than either normals or pure gonadal dysgenetics (46XX). Both patient groups (45X0 and 46XX) had higher titers of anti-ovarian antibodies (mainly against follicles, as determined by immunofluorescence) than did normals. Patients with other karyotypes did not show evidence of autoimmunity to thyroid or ovary. In seven patients tested for total and active T-cell populations and lymphocyte responses to concanavalin A, these parameters of cell-mediated immunity were lower than in age-matched normals, whereas their responses to phytohemagglutinin were within the normal range.     

Factors associated with the reduction of bone density in patients with gonadal dysgenesis

OBJECTIVE: To correlate bone mineral density (BMD) in women with primary hypoestrogenism caused by 46,XX pure gonadal dysgenesis or Turner's syndrome with age, age at estrogen therapy initiation, length of estrogen use, and body mass index (BMI). DESIGN: Cross-sectional study. SETTING: Academic tertiary-care hospital. PATIENT(S): Thirty-eight women, aged 16 to 35 years (mean, 24.6 years), affected by these genetic disorders. INTERVENTION(S): Measurement of lumbar spine and femoral neck BMD using double x-ray absorptiometry. The results were correlated with the control variables by using Pearson's coefficient of correlation. Variables associated with BMD were evaluated by multiple linear regression analysis. MAIN OUTCOME MEASURE(S): Bone mineral density. RESULT(S): Bone mineral density of the lumbar spine showed that 90% of the women presented osteopenia or osteoporosis. The femoral neck was affected in 55% of these women. The length of estrogen therapy and the BMI showed a positive association with BMD at the lumbar spine and femoral neck, respectively. CONCLUSION(S): Women affected by pure gonadal dysgenesis or Turner's syndrome presented a marked decrease in BMD of the lumbar spine and femoral neck. Medical attention for their diagnosis and early hormone replacement therapy are advised.     

79例XY性腺发育异常患者性腺肿瘤发生情况分析

目的 探讨表型为女性、染色体含有Y或Y成分的性腺发育异常患者的性腺肿瘤发生情况.方法 1989年10月至2005年12月间于北京协和医院妇产科因性腺发育异常手术切除双侧性腺的患者共79例,所有患者均取外周血进行淋巴细胞染色体核型分析、Y基因性决定区检测以及相关激素和酶检测,影像学检查了解性腺位置.行经腹或腹腔镜下性腺切除术,所有手术标本均行病理检查.结果 79例患者中,雄激素不敏感综合征患者41例,其中发生精原细胞瘤1例、支持细胞腺瘤2例,占7%;170r羟化酶缺乏症患者14例,其中发生支持细胞腺瘤1例,占7%;XY单纯性腺发育不全患者4例,其中发生性腺母细胞瘤及无性细胞瘤1例,占1/4;XO/XY性腺发育不全患者16例,其中发生精原细胞瘤及性腺母细胞瘤1例,占6%;睾丸退化患者4例中无肿瘤发生.发生肿瘤的性腺多位于盆腔内,发生肿瘤的年龄集中于15～23岁.结论 表型为女性、染色体含有Y或Y成分的性腺发育异常患者易发生性腺母细胞瘤和生殖细胞肿瘤,一旦确诊宜及早切除双侧性腺.     

Swyer Syndrome: A Case of Dysgerminoma Solely within the Fallopian Tube

Background46XY pure gonadal dysgenesis (Swyer syndrome) is a rare disorder of sexual development. Patients have a 46XY karyotype, though phenotypically they appear female with normal external genitalia and vagina. Although patients exhibit normal Müllerian structures (uterus, fallopian tubes, and vagina), they possess a pair of bilateral undifferentiated gonad streaks. Delayed puberty and primary amenorrhea are the common presentations. There is an increased risk of developing tumors in the gonads and therefore a bilateral gonadectomy is recommended.CaseA 16-year-old girl who presented with primary amenorrhea was diagnosed with Swyer syndrome. She underwent prophylactic bilateral gonadectomy and salpingectomies. She was discovered to have no gonadal malignancy, conversely dysgerminoma solely within the fallopian tube.Summary and ConclusionBoth bilateral salpingectomies and bilateral gonadectomies should be recommended as the operation of choice in patients with Swyer Syndrome.     

Coexistence of Mayer-Rokitansky-Küster-Hauser Syndrome and Turner Syndrome: A Case Report

BackgroundTurner syndrome is a common chromosomal disorder, with an incidence of 1 in 2000 live-born female infants. Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) affects 1 in 4500 female births and, rarely, it might be associated with gonadal dysgenesis.CaseA 17-year-old girl was referred to our clinic with short stature and primary amenorrhea. The patient was diagnosed with Turner syndrome and underwent estrogen therapy. At the age of 24 years, just after the patient's sexual initiation, the first complete gynecological examination was performed. A blind-ending vagina was revealed and the patient was diagnosed with MRKH.Summary and ConclusionEarly diagnosis of coexistence of MRKH and Turner syndrome, although very difficult, might prevent patients from developing serious complications.