45,X/46,X,r(Y) karyotype transmitted by father to son after intracytoplasmic sperm injection for oligospermia. A case report.

BACKGROUND: The advent of assisted reproductive techniques, such as intracytoplasmic sperm injection (ICSI), has permitted conception and successful pregnancy for an increasing population of infertile men. Approximately 13.7% of infertile men with aspermia and 4.6% with oligospermia have a coexistent chromosome abnormality. Although the ICSI procedure appears safe thus far, early studies are in progress to evaluate outcomes of such pregnancies. For men whose infertility is linked to genetic conditions, it is an unprecedented challenge to predict the potential effects on their offspring. CASE: At 18 weeks' gestation, a 45,X/46,X,r(Y) karyotype was found on genetic amniocentesis performed for advanced maternal age. The pregnancy was achieved by ICSI using sperm from the husband, who was infertile due to severe oligospermia. Subsequently the same karyotype was found in the father. To our knowledge, this is the first reported case of familial transmission of ring Y chromosome. CONCLUSION: It is strongly recommended that ICSI and other new assisted reproductive techniques be preceded by genetic screening for male infertility as well as other indications warranted by the family history since traditional risk assessment may require revision and outcomes may be uncertain in some cases.     

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.     

1例嵌合型45,X/46,X,r(Y)患者的遗传学分析

目的:应用细胞遗传学和分子生物学技术分析1例嵌合型45,X/46,X,r(Y)患者的核型。方法:应用常规染色体标本制备方法进行G-显带和C-显带;并应用CEPX(DXZ1,Xp11.1-q11.1,Spectrum Green,Vysis)探针、LSI SRY(Yp11.3,Spectrum Orange,Vysis)探针和CEP18(D18Z1,18p11.1-q11.1,Spectrum Aqua,Vysis)与患者的中期分裂相进行荧光原位杂交(fluorescence in situ hybridization,FISH);同时应用PCR技术对患者进行Y染色体微缺失检测。结果:结合G-显带、C-显带、FISH检测结果和Y染色体微缺失的检测结果,确定该患者核型为46,X,r(Y)(p11.3q12)[85]/45,X[15]。Yq11区生精基因微缺失检测未显示该患者存在缺失。结论:细胞遗传学检测结合FISH可以诊断复杂的染色体异常,为患者提供正确的遗传咨询和生育指导。     

High-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis in a pregnancy with a favorable outcome and postnatal progressive decrease of the 45,X cell line

ObjectiveWe present prenatal diagnosis of high-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis in a pregnancy with a favorable outcome and postnatal progressive decrease of the 45,X cell line.Case reportA 36-year-old, gravida 4, para 3, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 45,X[22]/46,X,idic(Y)(q11.2)[4]. Prenatal ultrasound was unremarkable, and the fetus had normal male external genitalia. Repeat amniocentesis was performed at 20 weeks of gestation, and the second amniocentesis revealed a karyotype of 45,X[24]/46,X,idic(Y)(q11.2)[3]. Simultaneous interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed that 60% (62/103 cells) were Y-deleted cells. After genetic counseling, the parents decided to continue the pregnancy, and a 3020-g male baby was delivered with a body length of 52 cm, normal male genital organs and no phenotypic abnormalities. The karyotypes of cord blood, umbilical cord and placenta were 45,X[20]/46,X,idic(Y)(q11.2)[20], 45,X[31]/46,X,idic(Y)(q11.2)[9] and 45,X[40], respectively. At age one month, FISH analysis on urinary cells and buccal mucosal cells revealed 11.5% (7/61 cells) and 13.6% (16/118 cells), respectively for mosaicism for the Y-deleted cells. At age five month, the karyotype of peripheral blood was 45,X[9]/46,X,idic(Y)(q11.2)[31]. FISH analysis on buccal mucosal cells showed no abnormal Y-deleted cell (0/101 cells). At age 11 month, the karyotype of peripheral blood was 45,X[5]/46,X,idic(Y)(q11.2)[35]. FISH analysis on 102 buccal mucosal cells showed no abnormal signals. The infant was doing well with normal physical and psychomotor development.ConclusionHigh-level mosaicism for 45,X in 45,X/46,X,idic(Y)(q11.2) at amniocentesis can be associated with a favorable outcome and progressive decrease of the 45,X cell line.     

Prenatal investigation of a 45,X/46,X,r(?) karyotype in amniocytes using fluorescence in situ hybridization with an X-centromeric probe.

The karyotype of cultured amniotic fluid cells obtained on the indication of advanced maternal age was shown to be a mosaic 45,X/46,X,r(?). The small size and banding pattern made it difficult to determine whether the ring was derived from and X or a Y chromosome, or even from an autosome. By using an X-centromeric probe and fluorescence in situ hybridization (FISH), we demonstrated the ring to have an X centromere. Thus, a more complete genetic counselling was possible. This confirms the usefulness of FISH in identifying and characterizing this and other chromosome rearrangements in prenatal diagnosis.     

45,X/46,X,del(Yq) sex chromosome mosaicism--analysis of the phenotypic expression

Three female patients with Turner-syndrome (sexual infantilism, short stature and somatic Turner-stigmata) have been analysed cytogenetically by means of different banding techniques. A deletion of the distal heterochromatic band Yq12 of the Y chromosome was observed in a mosaic with a 45,X-cell line, i.e. the karyotype is 45,X/46,X,del(Y)(q12). In order to get information about the phenotypic expression of the 45,X/46,X,del(Yq) mosaicism all previously published cases have been reviewed. Comparing the phenotypes of all 45,X/46,X,del(Yq) mosaic cases three different phenotype categories of sexual development can be distinguished: female individuals with sexual infantilism and Turner-stigmata, individuals with ambiguous genitals, ranging from clitoris hypertrophy of female genitals to hypospadia of males, male individuals, who are infertile (azoospermic). A comparison of the appearance of external genitals with the status of gonads of all patients revealed an unequivocal relationship between the gonad status and the resulting phenotype category. Furthermore, the role of Y-chromosomal loci determining testicular differentiation (biological function of H-Y antigen) for male development has been emphasized. The effect of the 45,X-cell line on the expression of short stature and somatic Turner-stigmata is independent of sexual development. Considering the great phenotypic variability of the 45,X/46,X,del(Yq) mosaicism it seems impossible to deduce a definitive phenotype. This problem is acute in prenatal diagnosis especially.     

Delineation of an isodicentric Y chromosome in a mosaic 45,X/46,X,idic(Y)(qter-p11.3::p11.3-qter) fetus by SRY sequencing, G-banding, FISH, SKY and study of distribution in different tissues.

Many factors such as genetic, developmental and hormonal are involved in mammalian sex determination. The relative importance and the mutual interactions among those factors are obscure. Study of cytogenetic mosaicism involving sex chromosomes may help to further unravel the mysterious process. We report a fetus with a mosaic karyotype, 45,X/46,X,idic(Y)(qter-p11.3::p11.3-qter), with unambiguous male external genitalia and a defect in the interventricular septum of the heart. Genotype of this fetus was extensively studied by technologies including sequencing of SRY (sex-determining region on the Y chromosome) gene, G-banding, FISH (fluorescence in situ hybridization) and SKY (spectral karyotyping). A markedly higher percentage of Y-containing cells was observed in the gonads (55%) than in the amniotic fluid (17%) and placental villi (11%), which was considered to be the major reason why the fetus did not have ambiguous genitalia.     

Pure yolk sac tumor of the ovary with mosaic 45X/46X+mar Turner's syndrome with a Y-chromosomal fragment

A pure yolk sac tumor (endodermal sinus tumor) of the dysgenetic gonad developed in a 23-year-old woman whose karyotype was mosaic 45 X/46X+mar Turner's syndrome is reported. Molecular biological studies showed that the patient's DNA contained a fragment of Y chromosome. This case seems to be extremely rare case of developing a pure yolk sac tumor in a patient with mosaic Turner syndrome with a Y-chromosomal fragment. Received: 5 September 1997 / Accepted: 9 December 1997     

Discrepancy between cytogenetic and FISH results on an amniotic fluid sample of 45,X/46,X,idic(Y)(p11)

The presence of abnormal ultrasound markers showing a thick nuchal fold with short middle phalanx of the fifth finger in an otherwise normal-appearing female fetus led to the sampling of amniotic fluid at 16 weeks gestation. Cytogenetic analysis with routine G-banding showed a 45,X karyotype in all 20 cells analysed from two flasks. However, fluorescent in situ hybridization on uncultured cells showed presence of a Y signal in 9 cells, 11 cells showing a single signal for the X. A cytogenetic analysis of the fetal blood at 23 weeks confirmed the presence of two cell lines, 45,X and 46,X, idic(Y)(p11). The couple opted to have the pregnancy terminated. However, the fetus was not available to carry out confirmatory tests.     

Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization

OBJECTIVE: To explore the utility of comparative genomic hybridization to BAC arrays (array CGH) for prenatal diagnosis of microphthalmia and linear skin defects syndrome. METHODS: We used karyotype analysis, FISH and array CGH to investigate an X;Y translocation. Replication studies were done on cultured amniocytes and lymphoblasts. RESULTS: We describe a severe case of MLS syndrome that presented prenatally with multiple anomalies including cystic hygroma, microphthalmia, intrauterine growth restriction and a complex congenital heart defect. Cytogenetic analysis of amniocytes revealed an unbalanced de novo translocation between chromosomes X and Y [karyotype 46,X,der(X)t(X;Y)(p22.3;q11.2).ish der(X)(DXZ1+,DMD+,KAL-,STS-,SRY-),22q11.2 (Tuple1 x 2)]. MLS diagnosis was made at birth and the prenatal karyotype was confirmed. Replication studies showed the derivative X chromosome was the inactive X. Array CGH confirmed the X and Y imbalances seen in the karyotype and also showed twelve BACs in the MLS region were deleted as a result of the translocation. FISH with BAC clones verified the array findings and placed the X breakpoint in Xp22.2, resulting in the amended karyotype, 46,X,der(X)t(X;Y)(p22.2;q11.2).ish der(X)(DXZ1+,DMD+,KAL-,STS-,SRY-),22q11.2(Tuple1 x 2) arr cgh Xp22.33p22.2(LLNOYCO3M15D10 -->GS1-590J6)x 1,Yq11.222q23(RP11-20H21-->RP11-79J10)x 1. CONCLUSION: The sensitivity of array CGH was valuable in detecting monosomy of the MLS critical region. Array CGH should be considered for the prenatal diagnosis of this syndrome.     

Prenatal diagnosis of a 45,X male with a SRY-bearing chromosome 21

Male phenotype associated with a 45,X karyotype is an infrequent finding. We present a case diagnosed prenatally on amniocentesis performed for maternal age. The male phenotype was associated with a translocation of a distal part of Yp including the pseudoautosomal SHOX gene and SRY gene on the short arm of a chromosome 21. By DNA analysis we could show that the X chromosome was of maternal origin and that the breakpoint was in interval 3 of the Y chromosome. Mechanisms and genetic counselling are discussed based on a review of published cases of 45,X and XX males.     

Ring X and other structural X chromosome abnormalities: X inactivation and phenotype

Patients who carry a structural abnormality of the X chromosome are a fascinating group who have provided opportunities to evaluate genotype/phenotype correlation in relation to X chromosome content and inactivation. Turner syndrome (TS) is most commonly associated with a 45,X karyotype and presents with an array of phenotypes, the main ones being poor viability in utero, ovarian failure and infertility, short stature, lymphedema, and other congenital malformations but usually not mental retardation. In some TS patients the karyotype shows both a normal X and a structurally rearranged X chromosome. These structural abnormalities, which include deletions, duplications, inversions, translocations, and rings, are associated with chromosome breaks and significant imbalance of gene content of the X chromosome. However, such abnormalities are generally well tolerated because of the preferential inactivation of the abnormal X, which can restore, at least in part, a balanced genetic makeup. This beneficial effect of X inactivation results in a mild phenotype in most patients with structural abnormalities of the X, similar to that found in TS patients with a 45,X karyotype. However, in cases of ring X chromosomes and of X/autosome translocations the incidence of mental retardation and other congenital abnormalities can be significantly higher than in TS. These abnormal phenotypes can be ascribed to failed or partial X inactivation and/or incomplete selection in favor of cells with normal balance of gene expression. In this article, we present phenotype/genotype correlation in female patients with structural abnormalities of the X and address the role of X inactivation and cell selection in the phenotypic findings. Our review emphasizes a subset of rare patients with ring X chromosomes who have provided evidence of a direct role for X inactivation in determining phenotypes.     

Two pregnancies and the loss of the 46,XX cell line in a 45,X/46,XX Turner mosaic patient

Two successful pregnancies in a patient with a 45,X karyotype are reported. Twelve pregnancies have been reported in 9 monosomy X patients and 57 pregnancies in 24 patients with both a 45,X and a 46,XX cell line. The patient reported here was diagnosed at 10 years of age as a Turner mosaic (45,X/46,XX), but showed no evidence of a normal cell line in any of the four tissues analyzed 15 years later. The difficulty in detecting mosaicism as well as the stability of autosomal and sex chromosomal mosaicism are discussed. An argument is made for early cytogenetic evaluation, utilizing multiple tissues, and analyzing an adequate number of cells.     

Progressive increase of the mosaic level for 45,X in 45,X/46, XX at different amniocenteses and postnatal progressive decrease of the 45,X cell line in a mosaic 45,X/46, XX fetus with a favorable outcome

ObjectiveWe present progressive increase of the mosaic level for 45,X in 45,X/46, XX at different amniocenteses and postnatal progressive decrease of the 45,X cell line in a mosaic 45,X/46, XX fetus with a favorable outcome.Case reportA 35-year-old, primigravid woman underwent amniocentesis at 16 weeks of gestation because of the advanced maternal age. Amniocentesis revealed a karyotype of 45,X [6]/46,XX [14]. Among 20 colonies of cultured amniocytes, six colonies had a karyotype of 45,X, whereas the other 14 colonies had a karyotype of 46,XX. Simultaneous array comparative genomic hybridization (aCGH) on uncultured amniocytes revealed the result of arr [GRCh37] (X) × 1 [0.42] (1–22) × 2. Prenatal ultrasound findings were unremarkable. Repeat amniocentesis at 33 weeks of gestation revealed a karyotype of 45,X [13]/46,XX [7]. Among 20 colonies of cultured amniocytes, 13 colonies had a karyotype of 45,X, whereas the other seven colonies had a karyotype of 46,XX. Simultaneous interphase fluorescence in situ hybridization (FISH) analysis on 100 uncultured amniocytes revealed that 44 cells had monosomy X consistent with 44% mosaicism for 45,X, whereas the rest cells had disomy X. At 38 weeks of gestation, a 2675-g phenotypically normal female baby was delivered. The karyotypes of cord blood, umbilical cord and placenta were 45,X [12]/46,XX [28], 45,X [12]/46,XX [28] and 46,XX [40/40], respectively. When follow-up at age three months, the neonate was normal in development. The karyotypes of peripheral blood was 45,X [4]/46,XX [36], and interphase FISH analysis on 100 buccal mucosal cells showed monosomy X in 11 cells consistent with 11% mosaicism for 45,X, whereas the rest cells had disomy X.ConclusionProgressive increase of the mosaic level for 45,X in 45,X/46, XX at different amniocenteses can be associated with a favorable outcome and postnatal progressive decrease of the 45,X cell line.     

A nonmosaic 45,X karyotype in a mother with Turner's syndrome and in her daughter

OBJECTIVE: To describe a woman with a nonmosaic (45,X) form of Turner's syndrome who gave birth to a girl with 45,X Turner syndrome. DESIGN: Patient report. SETTING: Outpatient clinic of a university hospital. PATIENT(S): A woman with typical phenotypic features of Turner syndrome and a 45,X karyotype and her daughter with the same karyotype. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Routine karyotype analysis on 200 white blood cells on two different occasions, on skin fibroblasts (1,000 mitoses) and on ovarian fibroblasts. Translocation of X-chromosome material was investigated by a complete X paint and fluorescent in situ hybridization analysis. RESULT(S): The patient had a spontaneous puberty and became pregnant on three occasions. Her first daughter has a normal karyotype, the second pregnancy ended in spontaneous abortion, and after the third pregnancy, a girl was born with a 45,X karyotype. Karyotype analysis of a large number of mitoses in three different cell types failed to demonstrate any mosaicism. Translocation of X-chromosome material was ruled out by fluorescent in situ hybridization analysis with an X paint. CONCLUSION(S): This is a rare case of pregnancy in a nonmosaic Turner syndrome patient and, to our knowledge, is the only one that resulted in a live-born baby with the same karyotype. Cryptic mosaicism could not be found despite thorough investigations. Some hypotheses are presented that may explain this unique event.     

45,XO/46,X,dic(Yq) mosaicism in Turner's phenotype with endodermal sinus tumor of the ovary

A case of a endodermal sinus tumor of the ovary in a patient with 45,XO/46,X,dic(Y) mosaicism is reported because of the rarity of the karyotype and condition. A 15-year-old girl was admitted to Yamagata University Hospital because of constipation for several days. Physical examination showed webbing of the neck, cubitus valgus and short stature. Her abdomen was bulging. Chromosomal analysis showed 45,XO/46,X,dic(Yq) mosaicism in karyotype. alpha-Fetoprotein and CA-125 in the serum were high. A left ovarian tumor was found by laparotomy; however, the right ovary was a streak gonad and the uterus was hypoplastic. An endodermal sinus tumor was diagnosed by a pathologist. After operation, cisplatin-vinblastin-bleomycin chemotherapy was instituted and the tumor marker went down. This patient is still healthy and under observation at the outpatient clinic.     

Detection of mosaicism for 46,X,i(Y) (q10) in the blood lymphocytes in a phenotypically normal male neonate with prenatally detected 45,X/46, XY at amniocentesis and cytogenetic discrepancy in various tissues

ObjectiveWe present detection of mosaicism for 46,X,i(Y) (q10) in the blood lymphocytes in a phenotypically normal male neonate with prenatally detected 45,X/46, XY at amniocentesis and cytogenetic discrepancy in various tissues.Case reportA 35-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 45,X [8]/46,XY [15]. Simultaneous array comparative genomic hybridization (aCGH) on uncultured amniocytes revealed the result of arr (Y) × 0–1 with 25.493-Mb mosaic deletion of chromosome Yp11.31-q11.23. Prenatal ultrasound findings were unremarkable. The fetus had normal male external genitalia on fetal ultrasound. Following genetic counseling, the pregnancy was carried to 38 weeks of gestation, and a phenotypically normal male baby was delivered without any abnormalities of the male external genitalia. The cord blood had a karyotypes of 46,X,i(Y) (q10)[8]/45,X[3]/46,XY [29], and placenta had a karyotypes of 45,X [25]/46,X,i(Y) (q10)[7]/46,XY [8]. When follow-up at age two months, the neonate was normal in development. The peripheral blood had a karyotypes of 46,X,i(Y) (q10)[8]/45,X[5]/46,XY [27]. Interphase fluorescence in situ hybridization (FISH) analysis on 101 buccal mucosal cells showed normal X and Y signals in 101/101 cells.ConclusionFetuses with 45,X/46, XY at amniocentesis can be associated with mosaicism for 46,X,i(Y) (q10) in the blood lymphocytes, cytogenetic discrepancy in various tissues and a favorable outcome.     

47,XXY female with testicular feminization and positive SRY: a case report

BACKGROUND: Males with a 47,XXY karyotype have the clinical phenotype of Klinefelter syndrome. A few 47,XXY cases with a female phenotype have been reported. These individuals have positive SRY (testis-determining factor). The genetic explanation of this phenomenon is unclear. CASE: A 34-year-old woman presented with testicular feminization and a 47,XXY karyotype. Cytogenetic analysis and fluorescence in situ hybridization suggested that the Y chromosome had a normal structure; the polymerase chain reaction was positive for SRY. CONCLUSION: This is the third reported case of 47,XXY with afemale phenotype in spite of the presence of a Y chromosome and the normal SRY. This suggests that the phenotypic sex in these patients might be due to the involvement of other sex-determining genes.