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.     

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.     

Dysgerminoma in a 10-Year Old with 45X/46XY Turner Syndrome Mosaicism

BackgroundTurner syndrome is a genetic disorder resulting from the absence of or structural abnormality of one X chromosome. The presence of Y chromosome material in girls with Turner syndrome confers an increased risk of benign and malignant germ cell tumor and prophylactic bilateral gonadectomy is recommended.CaseA 10-year-old Turner mosaic syndrome (45X/46XY) patient underwent prophylactic gonadectomy after unremarkable preoperative pelvic imaging. Histopathology showed a streak right gonad, and left gonad with gonadoblastoma with limited degree of infiltrating germinoma.Summaryand ConclusionGonadoblastoma and dysgerminoma have been reported in girls with Turner mosaic who carry Y chromosome material. Prophylactic gonadectomy should be considered in these girls without delay.     

Prevalence of chromosomal aberrations in Mexican women with primary amenorrhoea

Primary amenorrhoea refers to the absence of menarche by the age of 16-18 years in the presence of secondary sexual characteristics, and occurs in 1-3% of women of reproductive age. To study the prevalence of chromosomal abnormalities and the different options available for clinical management of women in Mexico with primary amenorrhoea, a cross-sectional study was conducted in 187 women with primary amenorrhoea referred from Department of Reproductive Medicine of Morones Prieto Hospital, IMSS in Monterrey, Mexico during 1995-2003. Peripheral blood lymphocytes were cultured for chromosomal studies by the standard methods. Numerical or structural abnormalities of the sex chromosome were found in 78 women (41.71%). These women were classified into four categories: X-chromosome aneuploidies (22.99%: 12.83% pure line and 10.16% mosaicism association with a 45, X cell line); presence of chromosome Y (10.70%); structural anomalies of the X chromosome (4.28%); and marker chromosomes (3.74%). In conclusion, the prevalence of chromosomal abnormalities in Mexican women with primary amenorrhoea is within the range (24-46%) reported in world literature. Chromosomal analysis is absolutely necessary for appropriate clinical management of these patients.     

Screening of seven putative 45,X subjects with deoxyribonucleic acid probes to detect low-level mosaicism for Y cell lines

The frequency of monosomy X in cytogenetically abnormal abortion material (10% to 15%) suggests that viable 45,X subjects might have covert mosaicism for X or Y cell lines. The deoxyribonucleic acid samples from seven 45,X subjects with Turner syndrome were examined with three Y-specific deoxyribonucleic acid probes. Successive hybridizations with each of these three sensitive deoxyribonucleic acid probes did not reveal any Y-specific band.     

Gonadal dysgenesis in own material]

Eleven patients with Turner syndrome and 6 with pure gonadal dysgenesis were examined. Diagnosis was made on the base of clinical and cytogenetic examination. All patients had primary amenorrhea and underdevelopment of primary, secondary and tertiary sexual features. Hormonal estimations revealed elevated FSH serum concentration in women with Turner syndrome and with pure gonadal dysgenesis (46, XY) vs. to patients with 46, XX. Estradiol and Progesterone levels were low in all cases. All women were treated with estrogens and progestational agents in sequential manner with good results. We did not observe significant phenotypic differences between patients with monosomie X and patients with structural abnormalities within chromosome X and mosaicism.     

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.     

Turner综合征Y染色体物质嵌合分子遗传学研究

摘要：目的　分析Turner综合征（TS）患儿Y染色体物质及衍生物嵌合发生的情况，为TS患儿诊断后的监测提供科学建议，改善国内TS监测和保健管理的现状。方法　选取2006年2月至2007年8月在重庆医科大学附属儿童医院诊断为TS患儿30例，进行基因组DNA 的Y编码睾丸特异性蛋白基因（TSPY）、 Y染色体中心着丝粒DYZ3重复序列（DYZ3 ）和Y性别决定区域（SRY）3个Y染色体特异序列多聚酶链反应（PCR）检测，反应结果阳性的病例补充SRY探针原位荧光杂交（FISH）分析。结果　基因组DNA 的PCR结果显示，3例患儿的TSPY、 DYZ3扩增均为阳性（10.00%），其中只有1例 SRY 扩增阳性（3.33%）；3例Y染色体物质阳性病例进一步进行FISH研究，结果显示3例SRY杂交信号均为阳性。结论　运用3个Y染色体特异序列的分子遗传学研究，证实Y染色体物质嵌合在TS不少见，每一个TS患儿都应在诊断后进行Y染色体物质的分子遗传学监测。     

Prenatal diagnosis of 45,X and 45,X mosaicism: the need for thorough cytogenetic and clinical evaluations

OBJECTIVES: Mosaicism involving a 45,X cell line is relatively common in prenatal diagnosis. In prenatally diagnosed cases, the prognosis of non-mosaic 45,X and 45,X/46,XY mosaicism are different. Therefore, accurate identification of a cell line containing Y chromosome is critical for genetic counseling and postnatal management. METHODS: We investigated the ultrasound findings and outcomes of pregnancies with a 45,X cell line identified during mid-trimester cytogenetic analysis. RESULTS: A total of 105 cases were found to have a 45,X cell line by standard cytogenetic analysis. Seventy-four cases were found to have non-mosaic 45,X at initial diagnosis. Of these 74 cases, 68 had abnormal ultrasound findings that were characteristic of Turner syndrome. Of the six cases with normal ultrasound findings, ultrasound examination was normal with male genitalia identified in three cases. Thorough cytogenetic and fluorescent in situ hybridization (FISH) analysis identified Y chromosome material in all three cases, one with a dicentric Y;14 chromosome and the other two cases with a marker chromosome containing Sex-determining Region (SRY) material in a small portion of the cells. In contrast, in 31 cases with a mosaic 45,X karyotype, ultrasound abnormality was identified only in one case. CONCLUSIONS: The present data suggest the need for follow-up ultrasound examination and thorough cytogenetic and molecular analysis for Y chromosome material in 45,X cases with normal ultrasound findings.     

Maternal XX/X chromosome mosaicism in donor oocyte in vitro fertilization (IVF)

ObjectiveTo evaluate if the degree of maternal X chromosome mosaicism is correlated to the pregnancy loss rate in donor oocyte IVF in women with a Turner syndrome mosaic (TS-Mosaic) diagnosis.DesignProspective trial.Patients and methodsWomen with X chromosome Turner syndrome mosaicism and infertility were enrolled in a clinical trial. The rate of mosaicism was determined through florescence in situ hybridization (FISH) of 500 maternal lymphocytes. Following a detailed medical, including cardiac, evaluation, donor oocyte in vitro fertilization (IFV) was performed and pregnancy and pregnancy loss rates were observed.ResultsThe rates of maternal X chromosome mosaicism noted in the cycles from women with miscarriages (3%, 4%, 4%, and 6%) were not statistically different from cycles in TS-Mosaic women with normal deliveries (3% and 11%). These data suggest that the rate of maternal X chromosome mosaicism does not affect pregnancy loss rates in TS-Mosaic women undergoing donor oocyte IVF.     

Down syndrome: a study of chromosomal mosaicism

Recent data suggest that chromosome mosaicism is a possible mechanism for intrauterine and postnatal survival in cases of trisomy 18 and Turner syndrome (45X). The aim of this study was to evaluate if chromosomal mosaicism is a possible mechanism of survival in Down syndrome (DS) (trisomy 21) individuals. Mosaicism was studied by interphase fluorescence in-situ hybridization (FISH), using a specific probe for chromosome 21 (21q22.13-21q22.2) in 78 cases suspected of DS. To rule out tissue specific mosaicism, buccal cells or amniocytes were analysed in addition to blood in 20 DS cases. Thirty-three per cent of the cases studied by FISH in only peripheral blood were mosaics. In 20 cases of trisomy 21, two tissues were studied and mosaicism was not detected in either of the two tissues in 15 cases. The remaining five cases were mosaics in both the tissues analysed. Clinical comparisons in 17 DS mosaics showed a direct relationship between the percentage of trisomic cells and the degree of phenotypic manifestations. These results suggest that mechanism(s) other than mosaicism may exist for the intrauterine and postnatal survival of DS cases.     

Turner综合征患者标记染色体的鉴定与分析

目的 分析11例携带标记染色体的Turner综合征患者的核型,研究这类染色体的表型效应。方法 选择11例具Turner综合征表型的患者,常规核型分析均显示为携带标记染色体的嵌合体,其中6例标记染色体呈环状。患者G带核型表示为mos．45,X／46,X,＋mar或者mos．45,X／46,X,＋r．以X／Y着丝粒探针,应用荧光原位杂交（FISH）技术分析这些标记染色体起源,对其中2例较大的环状染色体,结合反向染色体涂染确定断裂位点,比较不同断裂位点的标记染色体的遗传学效应。结果11例患者所携带的标记染色体均为环状染色体,r（X）的断裂位点分别位于Xp22、Xq22、Xq24、Xq26等。结论 Turner综合征患者的标记染色体主要来源于X染色体,且表现为r（X）形式。r（X）均以嵌合型的形式存在。     

X-autosome translocations in amenorrhoea: a report of a three way translocation from Indian Population

Chromosomal translocations have been reported in a number of women undergoing cytogenetic studies for amenorrhoea and gonadal dysgenesis. This study was taken up to emphasize the role of X chromosome and to know the frequency of X-autosomal translocations in women with amenorrhoea in Indian population. Cytogenetic analysis was carried out in 1567 subjects referred for amenorrhoea during the period 2002–2012. GTG-banding was performed from peripheral blood lymphocyte cultures to detect the chromosome abnormalities in all the cases. The karyotype results revealed 43.6% cases with chromosomal abnormalities (n?=?683 of 1567 cases). The X-autosomal translocations was found in 2.64% (n?=?18 of 683 cases). The common chromosomes involved with X were chromosomes 2, 4, 14 and 20. The translocations involved both p and q arms of the X chromosome.The break point “q26” of X was observed in the majority of the cases. Two interesting cases are discussed: one with three way translocation and another with two translocations. A high number of primary amenorrhoea (PA) and secondary amenorrhoea (SA) cases were involved in X-auto translocation which clearly reveals that chromosomal analysis plays an important role in the evaluation of amenorrhoea.     

Association of microscopic gonadoblastoma and contralateral ovarian fibroadenoma in patients with gonadal dysgenesis and Turner phenotype

A rare case of microscopic gonadoblastoma associated with gonadal fibroadenoma in a patient with gonadal dysgenesis and Turner phenotype is reported. The higher incidence of tumor pathologies in patients with gonadal dysgenesis presenting a Y chromosome in their karyotype is discussed, and the need for judicious microscopic analysis of the gonadal streaks of these patients for the detection of possible incipient tumors is emphasized.     

Mucinous cystadenoma in a female patient with 45,X/46,XY karyotype

The mosaic karyotype of 45,X/46,XY has a wide phenotypic spectrum and there are substantial differences between prenatally and postnatally diagnosed cases. The phenotype varies between normal male to classical Turner syndrome. There is a high risk of gonadal tumor development in the dysgenetic gonads of patients with sex chromosome mosaicism. We report a case of a 24-year-old patient with a pelvic mass and amenorrhea referred to our laboratory for karyotyping. Peripheral blood chromosome analysis showed a mosaic karyotype of 45,X[17]/46,XY[83]. The tumor originated from the left ovary and the right ovary was found to be a streak gonad. The uterus was intact. Pathologic examination of the tumor revealed mucinous cystadenoma. Physical examination of the patient showed signs of Turner syndrome, as short stature (145 cm), short neck and asymmetric shoulders. Her mental state was normal. Y chromosome microdeletion screening involving SRY and ZFY genes was performed and no deletion was found. The patient was informed about the condition during the genetic counseling session.     

Primary Amenorrhoea

Primary amenorrhoea may be defined as the absence of menses and secondary sexual characteristics by age 14, or the absence of menses regardless of the presence of secondary sexual characteristics by age 16. All patients require investigation. Classification of patients with primary amenorrhoea into four groups based on the presence or absence of breasts and the presence or absence of a uterus simplifies the investigations required to make a diagnosis. These four groups are: 1) breasts present, uterus present, 2) breasts absent, uterus present, 3) breasts present, uterus absent and 4) breasts absent, uterus absent. Patients in group one should be investigated and treated in the same manner as secondary amenorrhoea. Patients in group two have hypogonadotrophic hypogonadism or hypergonadotrophic hypogonadism. Patients in group three have either mullerian agenesis or androgen insensitivity syndrome (testicular feminization). Patients in group four are rare and are always 46 XY karyotype. They require further endocrinological testing and treatment. Aft patients with a Y chromosome and the presence of gonads require a gonadectomy because of the risk of malignancy. Aft patients who do not synthesize endogenous estradiol require estrogen replacement therapy, even at this young age, to prevent osteoporosis and, in many cases, to complete their pubertal development.     

Evaluation of sex chromosome aneuploidies in women with Turner's syndrome by G-banding and FISH. A serial case study

OBJECTIVE: To evaluate sex chromosome aneuploidies in patients with Turner's syndrome using two cytogenetic techniques. STUDY DESIGN: A sample of 35 women with a clinical suspicion of Turner syndrome was examined in the Hospital of Obstetrics and Gynecology, Instituto Mexicano del Seguro Social, Monterrey, Mexico. They were subjected to a conventional cytogenetic technique with G-banding and to fluorescence in situ hybridization (FISH) using a specific alpha satellite X chromosome (DXZ1) and specific alpha satellite Y chromosome (DYZ1). RESULTS: Using both techniques, 17 cases (48.57%) showed the same karyotype. Using FISH: (1) in 8 cases the presence of the Y chromosome was confirmed, (2) in 18 cases (51.43%) a new cell line was identified, (3) in 2 cases (5.71%) the derivative X was clarified, and (4) in 3 cases (8.57%) the origin of the chromosome markers (1 of X chromosome and 2 of Y chromosome) was delineated. FISH highlighted the differences between the initial diagnosis, based on G-banding, and the final diagnosis, determined by specific probes for the X and Y chromosomes. CONCLUSION: FISH is a useful tool in the detection of low-frequency cell lines and identification of the nature and origin of derivative chromosomes and unknown chromosome markers that have important implications for the treatment of patients with Turner's 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.     

Screening for mutations in the SRY gene in patients with mixed gonadal dysgenesis or with Turner syndrome and Y mosaicism

OBJECTIVE: To investigate the presence of mutations in the open reading frame (ORF), as well as on the 5' and 3', flanking regions of the SRY gene in patients with mixed gonadal dysgenesis (MGD) or with Turner syndrome (TS) and Y mosaicism. STUDY DESIGN: We studied 13 patients with MGD and three patients with TS and Y mosaicism. DNA was isolated from blood leukocytes for subsequent polymerase chain reaction (PCR) and direct sequencing were performed in the ORF, as well as from the 5' and 3' flanking regions of the SRY gene. RESULTS: No mutations were present in any of the patients studied. CONCLUSION: The absence of mutations in these regions indicated that mutations were an unlikely cause of MGD or TS with Y mosaicism and suggested that there are others genes playing an important role in sex development.