Y chromosome sequences in Turner's syndrome: association with virilization and gonadoblastoma

The presence of Y chromosome fragments in patients with Turner's syndrome is known to increase the risk of gonadoblastoma and virilization. Y chromosome material is detected in up to 6% of patients with Turner's syndrome by karyotype. By DNA analysis, Y chromosome sequences have been reported in 0-60% of patients. The putative gonadoblastoma gene has been mapped to the pericentromeric region of the Y chromosome increasing the interest in studying these sequences. AIMS: 1. To determine the frequency of occult Y chromosome sequences in patients with Turner's syndrome. 2. To analyze the clinical implications of Y sequences detected by karyotype and occult Y sequences. STUDY DESIGN: Cross-sectional study of 58 patients with Turner's syndrome (30 45,X; two with structural anomalies; 26 mosaic [two of whom were 45,X/46,XY]). SRY, TSPY and DYZ3 sequences were amplified by PCR using genomic DNA from peripheral blood. RESULTS: All three Y chromosome sequences were found in one out of 56 patients whose karyotype was not suggestive of having Y chromosome material and in one patient with 45,X/46,Xr(X) karyotype. The patients with the ring chromosome and 45,X/46,XY karyotype underwent surgery and were found to have a gonadoblastoma and dysgerminoma. The four patients with Y chromosome material had non-virilized female genitalia. CONCLUSIONS: Analysis by PCR was more sensitive in detecting Y chromosome sequences than conventional karyotype. The presence of Y material was not associated with virilization. We confirmed the association of Y fragments and gonadoblastoma at an early age.     

Absence of Y specific DNA sequences in two siblings with 46XX hermaphroditism.

We report two siblings with 46XX hermaphroditism in whom we were unable to show the presence of Y specific DNA sequences using the DNA probes Y-190, GMGY-7, pHY2.1, pDP34, and 27a. We conclude that an autosomal or X chromosome gene mutation is the most likely mechanism of inheritance in this family with 46XX hermaphroditism.     

YqTER deletion causes arrest of spermatogenesis in early puberty

We report a 12-7/12 year-old male with obesity, eunuchoid proportions, genetic stigmata of Turner's syndrome and mild developmental delay. We investigated whether cytogenetic alterations could be responsible for his phenotype. Conventional karyotype in 70 peripheral blood cells was 45,X(15%)/46,XYqh-(85%). Dual FISH on 1,000 nuclei revealed 8% of X0 cells (DXZ1 X-centromeric probe) and 92% of XY cells (DYZ3 Y-centromeric probe). We studied Y chromosome microdeletions by PCR. The patient showed a terminal Yq deletion from the 5I interval including the AZFb and AZFc regions. FSH, LH and testosterone (468 ng/dl) were within the normal range for his age. At Tanner IV pubertal development the spermiogram showed azoospermia and the testicular aspirate spermatic arrest. The present report suggests that Y chromosome deletions including AZFb and AZFc regions may cause spermatogenic arrest in early puberty.     

45，X/46，X，+mar男性患儿临床及遗传学分析

目的分析45,X/46,X,+mar男性患儿的临床及遗传学特征。方法回顾分析2例确诊45,X/46,X,+mar男性患儿的临床资料,并复习相关文献。结果2例男性患儿,年龄分别为10岁7个月和3岁1个月,均有矮小表现,且伴有性腺发育落后。例1合并精索静脉曲张,头颅磁共振成像示部分空蝶鞍,外周血染色体核型分析为45,X[31]/46,X,+mar[69],二代测序检测提示Y染色体短臂SRY基因拷贝数重复,长臂USP9Y基因整体缺失。例2外周血染色体核型分析也为45,X[5]/46,X,+mar[75],全基因组CNV检测提示染色体核型为46,XY,Y染色体AZFb+AZFc区域完全缺失。结论矮小症患儿应密切关注其外生殖器的形态及功能,必要时进行遗传学分析。     

Mixed gonadal dysgenesis in a patient with de novo tas(Y;19)(p11.3;q13.4) and 45,X mosaicism

We report a patient with a de novo telomeric association between chromosomes 19 and Y in conjunction with mixed gonadal dysgenesis. The patient was first admitted to the clinic because of abnormal external genitalia. Laparoscopic evaluation revealed (1) a rudimentary uterus, one fallopian tube, and a small gonad resembling an ovary on the right side, and (2) an immature fallopian tube, a vas deferens, and a gonad resembling a testis on the left side. Conventional cytogenetic analysis performed on cultivated peripheral blood cells, and tissue obtained from the phallus and a gonadal structure which resembled a testis revealed two different cell lines with the 46,X,tas (Y;19)(p11.3;q13.4) and 45,X karyotype. Y chromosome microdeletion analysis showed that the patient did not have any genomic deletions in the AZFa, b, c, or SRY regions on the long arm of the Y chromosome. This is the first report of a patient with mixed gonadal dysgenesis that is accompanied by a telomeric association between chromosomes 19 and Y with 45,X mosaicism.     

Presence of Turner stigmata in a case of dysgenetic male pseudohermaphroditism with 45,X/46,X+mar karyotype

A case is reported of dysgenetic male pseudohermaphroditism (DMPH) having Turner stigmata and 45,X/46,X+mar karyotype. The marker chromosome of this patient consisted of most if not all of the short arm, including the sex determining region of the Y chromosome. Although this karyotype is relatively common in Turner's syndrome and occasionally observed in mixed gonadal dysgenesis, DMPH is usually exemplified by a 46,XY karyotype except for one patient reported with 45,X/46,XY mosaicism. Turner stigmata have not previously been reported in DMPH. The present patient is an intermediate case between mixed gonodal dysgenesis and typical DMPH, and this indicates that 45,X/ 46,X +mar karyotype abnormality can result in a wide range of phenotype such as DMPH, mixed gonodal dysgenesis and Turner's syndrome.     

Presence of Turner stigmata in a case of dysgenetic male pseudohermaphroditism with 45,X/46,X+mar karyotype

Accepted 19 November 1996
A case is reported of dysgenetic male pseudohermaphroditism (DMPH) having Turner stigmata and 45,X/46,X+mar karyotype. The marker chromosome of this patient consisted of most if not all of the short arm, including the sex determining region of the Y chromosome. Although this karyotype is relatively common in Turner''s syndrome and occasionally observed in mixed gonadal dysgenesis, DMPH is usually exemplified by a 46,XY karyotype except for one patient reported with 45,X/46,XY mosaicism. Turner stigmata have not previously been reported in DMPH. The present patient is an intermediate case between mixed gonodal dysgenesis and typical DMPH, and this indicates that 45,X/46,X+mar karyotype abnormality can result in a wide range of phenotype such as DMPH, mixed gonodal dysgenesis and Turner''s syndrome.

     

A 45,X/46,XY DSD (Disorder of Sexual Development) case with an extremely uneven distribution of 46,XY cells between lymphocytes and gonads

In 45,X/46,XY DSDs, the proportion of the two cell lineages is uneven in different organs and tissues, and 45,X and 46,XY cells can be found throughout the body. The gonadal development of 45,X/46,XY patients depends on the population of 46,XY cells in the gonads and the clinical features are variable. We had a 45,X/46,XY DSD patient whose 46,XY population in peripheral blood was extremely low, less than 0.2%, and was not detected by FISH analysis. However, the patient showed bilateral testicular development and more than 50% of the cells in the gonads had the 46,XY karyotype. This case suggests that a drastically imbalanced distribution could occur in 45,X/46,XY DSD cases.     

Risk of gonadoblastoma in female patients with Y chromosome abnormalities and dysgenetic gonads

We report two female patients with gonadal dysgenesis and sex chromosome mosaicism involving the Y chromosome. Conventional karyotyping was supplemented with fluorescent in situ hybridisation techniques in order to confirm the presence of Y chromosomes. One patient is a phenotypic female with karyotype 45,X/46,X,idic(Y)(q11.2). She underwent a laparoscopic gonadectomy at which streak ovaries without evidence of gonadoblastoma were removed. The second patient presented as a virilised female with karyotype 45,X/47,XYY. At laparoscopy, she was found to have mixed gonadal dysgenesis with a gonadoblastoma in situ. We recommend early gonadectomy in female children presenting with gonadal dysgenesis and the presence of a Y chromosome although once the gonadoblastoma locus on Y chromosome gene has been cloned it may be possible to identify those patients who have a low risk of developing gonadoblastoma.     

Association of Turner's syndrome and Swyer's syndrome in the same family

We report two phenotypically and genetically different diseases in the same family. One patient presented with Turner phenotype as a result of chromosomal mosaicism 45,X/46,X, inv(X)(q21;q24) (30%/70%). Her father's sister showed 46,XY female gonadal dysgenesis (Swyer's syndrome) as a result of a point mutation in the SRY gene on her Y chromosome. DNA sequencing revealed a G-->C transversion (nucleotide position 693) resulting in a change from glycine95 to arginine (G95R). Here we report for the first time an association of Turner's syndrome and Swyer's syndrome in the same family.     

Molecular analysis in Turner syndrome

OBJECTIVE: The frequency of Y-chromosome material is high in Turner syndrome (TS), but the ocurrence of gonadoblastoma seems to be low. We performed a study to evaluate whether DNA analysis might be a useful tool in the evaluation of patients with TS. SUBJECTS: Unrelated patients with TS (n = 52) of Venezuelan mestizo ethnic origin were diagnosed by cytogenetic analysis as having TS. METHODS: Clinical assessment, karyotyping, endocrine evaluation, fluorescence in situ hybridization, and polymerase reaction chain analysis of the Y-chromosome loci. RESULTS: We found that 7.69% (4 of 52) patients with TS had Y-chromosome material. A low occurrence of gonadoblastoma was also found (2 of 52 [3.85%]). Two patients showed a 45,X/46,XY karyotype, and gonadoblastoma in the gonadal biopsy specimen was not found. Two patients had no Y chromosome on initial karyotype; they were positive on lymphocyte DNA to Y-sequences specific. Both patients (45,X) had bilateral gonadoblastoma. The four patients with Y-chromosome material in peripheral blood lymphocytes had Y-chromosome sequences on gonadal DNA. Fluorescence in situ hybridization confirmed their Y-chromosome origin. CONCLUSIONS: Our results suggest that the detection of Y-chromosome material should be carried out in all patients with TS and not be limited to patients with TS with cytogenetically identifiable Y chromosome and/or virilization.     

Short stature as the only presenting feature in a patient with an isodicentric (Y)(q11.23) and gonadoblastoma. A clinical and molecular cytogenetic study

A 13-year-old phenotypically female patient presented with short stature (height SDS –2.6), but without any Turner stigmata or other dysmorphic features. Chromosome analysis showed mosaicism for an isodicentric (idic) (Y)(q11.23) containing cell line and a 45,X cell line. Subsequent gonadectomy revealed a left streak ovary and a right ovary of abnormal appearance, which on histological examination appeared to contain a gonadoblastoma. DNA analysis showed that the proposed critical region of the gonadoblastoma locus on the Y chromosome was contained within the patient's idic (Y). Conclusion The case described here shows that patients with 45,X/46,X, isodicentric (Yp) mosaicism and a female phenotype (1) can lack external virilisation but still have a gonadoblastoma and (2) do not necessarily have Turner stigmata but can present with only short stature. This case also underlines the importance of karyotyping patients with unexplained short stature to enable gonadectomy if Y-derived material is detected. Received: 12 July 2000 / Accepted: 20 September 2000     

Germ cell tumor showing partial trisomy 1 in a gonadectomized intersex child with monosomy X and double Y mosaicism

High incidence of germ cell tumors arising from dysgenetic gonads in patients with sexual chromosome abnormalities has been described, especially in patients with a Y chromosome bearing cell line. Here we report a 14-year-old patient with ambiguous genitalia. Constitutional karyotype showed 45,X/46,X,derY [?t(Yp;Yq)] mosaicism. The patient developed an abdominally located mixed malignant germ cell tumor 5 years after the removal of the dysgenetic gonads. Tumor karyotype showed partial trisomy 1q, a derivative 8q, and a hyperdiploidy with +X, +7, +12, +15, +19, +21, and an unidentified marker.     

Detection of hidden Y mosaicism in Turner's syndrome: importance in the prevention of gonadoblastoma

The presence of Y chromosome fragments in patients with Turner's syndrome (TS) is known to increase the risk of gonadoblastoma. The investigation of Y sequences is usually performed only in the presence of marker chromosomes and therefore does not rule out the presence of hidden mosaicism in patients with 45,X TS without any marker. Aims: 1. To investigate the presence of hidden Y mosaicism in non-mosaic 45,X patients with TS, using samples from different tissues, and its association with the development of gonadoblastoma. Study design: Twenty patients with a 45,X karyotype were studied. The SRY and DYZ3 sequences were amplified by PCR, using genomic DNA from peripheral blood, oral epithelial cells and hair roots. Prophylactic gonadectomy was offered to the Y-positive patients. Results: The analysis of the different tissues revealed that seven (35%) out of the 20 patients studied presented hidden chromosome Y mosaicism. Four of these patients underwent prophylactic gonadectomy, and bilateral gonadoblastoma was found in one of them. Conclusions: A systematic search for hidden Y chromosome mosaicism in patients with TS and 45,X karyotype is justified by the possibility of developing gonadoblastoma.     

Normal growth and normalization of hypergonadotropic hypogonadism in atypical Turner syndrome (45,X/46,XX/47,XXX)

A comparison has been made of a case with 45,X/46,XX/47,XXX mosaicism with some 50 cases in the literature. A significant positive correlation was found between height standard deviation scores of mosaic patients from the literature and the frequency of cells with a normal chromosome constitution (n=21,r _s =0.552,P<0.01). In contrast, a significant negative correlation was seen between body height and the frequency of cells with a 45,X constitution (n=21,r _s =–0.594,P<0.01). There was no significant correlation of height standard deviation score with the 47,XXX cell line (n=21,r _s =–0.353). A patient with a rare chromosomal mosaicism (45,X/46,XX/47,XXX) is described. The diagnosis was first made by chromosome analysis in amniotic cells. The patient showed no symptoms suggestive of Turner syndrome and growth followed the 75th height percentile. Basal and gonadotropin-releasing hormone stimulated gonadotropin levels normalized after age 4.8 years and did not subsequently return to hypergonadotropic levels. In blood lymphocytes, there was an increase in the frequency of cells with a normal chromosome constitution over 9 years. This in vivo cell selection is discussed. Chromosome analysis in skin fibroblasts showed the same triple mosaicism with a similar distribution of cell lines as in blood lymphocytes. In conclusion, statistical evidence was demonstrated that the severity of short stature is correlated with the distribution of cell lines in 45,X/46,XX/47,XXX mosaicism. This finding is of importance for the genetic counselling in cases of prenatal diagnosis of mosaic Turner syndrome.     

45,X/47,XY,+13 mosaicism and Crohn's disease

The unusual karyotype 45,X/47,XY,+13 in an 8.5-year-old girl with the Turner phenotype is described. She displayed none of the phenotypic manifestations of trisomy 13. The patient suffered from Crohn's disease, which is known to be associated with the Turner syndrome. To our knowledge this is the first reported case of Crohn's disease in a patient with 45,X and Y chromosome mosaicism.     

Sex chromosome fragment in a phenotypically normal female. Significance of occult Y-related material

The authors report a 15-year-old short, nonvirilized, prepubertal female whose peripheral karyotype revealed a mosaicism in which 62 percent of the cells had a karyotype of 45X, and the other 38 percent had a karyotype of 46X plus a small unidentified marker chromosome. Since the authors were unable to determine from the karyotype whether this marker was derived from an X or a Y chromosome and because of the high risk for neoplasia in abnormal gonads containing Y material, she underwent surgical exploration, with removal of gonadal tissue. Microscopic examination of the streak gonads revealed a mixture of dysgenetic ovarian and testicular type tissues. The presence of testicular-like tubules strongly implied the presence of Y material in the genotype. Review of the literature reveals at least 19 similar cases in which presumed sex chromosomal markers or fragments were found in phenotypically normal females. Because of the risk of gonadal neoplasia in patients with occult Y chromosomal material, gonadectomy is indicated when the origin of the marker chromosome is uncertain.     

A 45 X/46 X dic (Yq) puberal male without genital ambiguity. Critical study of the peculiarities of his phenotype]

A boy with a chromosomal mosaic 45 X/46 X dic Yq is described. The unusual features were a Turner phenotype with normal genitalia and he was in puberty. It is apparent that it is not possible to blame alterations in the Y chromosome when this mosaic is associated with ambiguous genitalia or the stigmata of Turner's syndrome.     

Carcinoma in situ of the testis in children with 45,X/46,XY gonadal dysgenesis

The frequency of gonadal tumors in intersex patients with a karyotype including a Y chromosome is very high. In other at-risk groups, testicular germ cell tumors have been shown to be preceded by carcinoma in situ (CIS) changes. We investigated gonadal tissue from four children, aged 1 month to 18 years, with 45,X/46,XY gonadal dysgenesis, and with male or ambiguous genitalia, for the presence of CIS germ cells. Twelve gonadal biopsies and gonadectomy specimens were analyzed by means of conventional histology and densitometric DNA measurements. CIS changes were detected in specimens from all four patients, and aneuploid DNA distributions of the CIS germ cells confirmed the malignant potential of these cells. In one case, electron microscopic analysis revealed the same ultrastructural features of the CIS germ cells as previously described in seminoma cells. These observations indicate that in all patients with 45,X/46XY gonadal dysgenesis and a male phenotype, gonadal biopsies should be considered as soon as the syndrome is diagnosed. We believe that the finding of CIS warrants gonadectomy.     

Two XX males diagnosed in childhood. Endocrine, renal, and laboratory findings.

Two prepubertal boys with bilateral cryptorchidism were identified as 46,XX after nuclear sexing studies in several tissues. Gonadal histology and chromosome studies suggested that true hermaphroditism or mosaicism were unlikely. Xg blood grouping was informative in one patient. Accepting paternity, this suggested either that both Xs were maternal, with loss, for example, of the male determining Y chromosome, or that the paternal X chromosome did not express, probably because of a deletion, the allele for the positive Xg blood group. The patients had normal thyroid stimulating hormone reserves but subnormal responses to human chorionic gonadotrophin stimulation, and may need hormonal replacement at puberty. Both had renal anomalies. We suggest that chromosome analysis is essential when cryptorchidism, hypospadias, or microgenitalia are found and that an intravenous pyelogram is desirable.