Prevalence, distribution, and risk markers for the development of gonadal germ cell tumors in patients with certain types of disorders of sexual differentiation with Y chromosome - A retrospective study.

PURPOSE: To study the prevalence, subtypes, and risk markers for the development of gonadal germ cell tumors (GCT's) among disorders of sexual differentiation (DSD) patients with the Y chromosome. MATERIALS AND METHOD: Design: A retrospective review of the patient's case records from 2010 to 2020 in Government Medical College, Thiruvananthapuram, India was studied. The study participants included 54 subjects with DSD containing the Y chromosome. Demographic data, external masculinization scoring, associated congenital anomalies, karyotyping, intraoperative findings such as gonadal location and internal genital ducts, histopathology of the resected gonads, and its immunohistochemistry were collected. The prevalence of gonadal GCT's was estimated from paraffin-embedded gonadectomy samples (S = 82). RESULTS: The median age of occurrence of gonadal GCT's was 18 years. The prevalence of malignant gonadal GCT's was highest among the PAIS group (19.2%) followed by gonadal dysgenesis (15.8% each in MGD and CGD) and least among CAIS (7.7%) (p < 0.01). The most common type of malignant gonadal GCT's in the descending order of frequency was dysgerminoma, seminoma, mixed GCT, and yolk sac tumor. Multivariance logistic analysis showed post-puberty and the presence of congenital anomalies were associated with the occurrence of gonadal GCT's ( P < 0.01). CONCLUSION: The overall prevalence of gonadal GCT's (malignant and premalignant) among DSD with Y chromosomes is nearly 25%. Dysgerminoma is the most common malignant gonadal GCT's. Age at or above 18 years and the presence of congenital anomalies like renal agenesis, retroperitoneal vascular defects, and congenital diaphragmatic hernia were independent risk markers for the development of gonadal GCT's.

DDX3Y is likely the key spermatogenic factor in the AZFa region that contributes to human non-obstructive azoospermia.

Non-obstructive azoospermia, the absence of sperm in the ejaculate due to disturbed spermatogenesis, represents the most severe form of male infertility. De novo microdeletions of the Y-chromosomal AZFa region are one of few well-established genetic causes for NOA and are routinely analysed in the diagnostic workup of affected men. So far, it is unclear which of the three genes located in the AZFa chromosomal region is indispensible for germ cell maturation. Here we present four different likely pathogenic loss-of-function variants in the AZFa gene DDX3Y identified by analysing exome sequencing data of more than 1,600 infertile men. Three of the patients underwent testicular sperm extraction and revealed the typical AZFa testicular Sertoli cell-only phenotype. One of the variants was proven to be de novo. Consequently, DDX3Y represents the AZFa key spermatogenic factor and screening for variants in DDX3Y should be included in the diagnostic workflow.

Gonadal tumor and malignancy in 118 patients with disorders of sex development with Y chromosome.

OBJECTIVE: To provide more information about tumor prevalence and malignant transformation among patients with disorders of sex development (DSD) for further guidance in prophylactic gonadectomies and surveillance. METHODS: SPSS software (version 20.0) was used for all statistical analyses. RESULTS: Phenotypically female DSD patients with a Y chromosome have a higher risk of gonadal malignancy. CONCLUSION: Bilateral gonadal resection is recommended as soon as diagnosis is made for phenotypically female patients with disorders of sex development with a Y chromosome.

Rats exhibit age-related mosaic loss of chromosome Y.

Mosaic loss of the Y chromosome (LOY) is the most frequent chromosomal aberration in aging men and is strongly correlated with mortality and disease. To date, studies of LOY have only been performed in humans, and so it is unclear whether LOY is a natural consequence of our relatively long lifespan or due to exposure to human-specific external stressors. Here, we explored whether LOY could be detected in rats. We applied a locus-specific PCR and target sequencing approach that we used as a proxy to estimate LOY in 339 samples covering eleven tissues from young and old individuals. We detected LOY in four tissues of older rats. To confirm the results from the PCR screening, we re-sequenced 60 full genomes from old rats, which revealed that the Y chromosome is the sole chromosome with low copy numbers. Finally, our results suggest that LOY is associated with other structural aberrations on the Y chromosome and possibly linked to the mosaic loss of the X chromosome. This is the first report, to our knowledge, demonstrating that the patterns of LOY observed in aging men are also present in a rodent, and conclude that LOY may be a natural process in placental mammals.

A reinvestigation of non-disjunction resulting in 47, XXY males of paternal origin.

We have used polymorphisms within the Xp/Yp pseudoautosomal region (PAR 1) to determine the frequency and location of recombination in 80 paternally derived 47, XXY males. Of 64 informative results, there were 10 single cross-overs, one double cross-over and 53 without a cross-over. Therefore 2/3 of 47, XXY males of paternal origin result from meiosis in which the X and Y chromosomes fail to recombine. This failure was not associated with the presence of an increase in recombination in the smaller Xq/Yq pseudoautosomal region (PAR 2) or with the presence of microdeletions within PAR 1.

Phenotype/karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases.

Over 600 cases with a Y aneuploidy (other than non-mosaic 47,XYY) were reviewed for phenotype/karyotype correlations. Except for 93 prenatally diagnosed cases of mosaicism 45,X/46,XY (79 cases), 45,X/47,XYY (8 cases), and 45,X/46,XY/47,XYY (6 cases), all other cases were ascertained postnatally. Special emphasis was placed on structural abnormalities. This review includes 11 cases of 46,XYp-; 90 cases of 46,XYq- (52 cases non-mosaic; 38 cases 45,X mosaic); 34 cases of 46,X,r(Y) (9 cases non-mosaic and 25 cases 45,X mosaic); 8 cases of 46,X,i(Yp) (4 non-mosaic and 4 mosaic with 45,X); 12 cases of 46,X,i(Yq) (7 non-mosaic and 5 mosaic); 44 cases of 46,X,idic(Yq); 80 cases of 46,X, idic(Yp) (74 cases had breakpoints at Yq11 and 6 cases had breakpoints at Yq12); 130 cases of Y/autosome translocations (50 cases with a Y/A reciprocal translocation, 20 cases of Y/A translocation in 45,X males, 60 cases of Y/DP or Y/Gp translocations); 52 cases of Y/X translocations [47 cases with der(X); 4 cases with der(Y), and 1 case with 45,X with a der(X)], 7 cases of Y/Y translocations; 151 postnatally diagnosed cases of 45,X/46,XY; 14 postnatally diagnosed cases of 45,X/47,XYY; 18 cases of 45,X/46,XY/47,XYY; and 93 aforementioned prenatally diagnosed cases with a 45,X cell line. It is clear that in the absence of a 45,X cell line, the presence of an entire Yp or a region of it including SRY would lead to a male phenotype in an individual with a Y aneuploidy, whereas the lack of Yp invariably leads to a female phenotype with typical or atypical Ullrich-Turner syndrome (UTS). Once there is a 45,X cell line, regardless of whether there is Yp, Yq, or both Yp and Yq, or even a free Y chromosome in other cell line, there is an increased chance for that individual to be a phenotypic female with UTS manifestations or to have ambiguous external genitalia. This review once again shows a major difference in reported phenotypes between postnatally and prenatally diagnosed cases of 45,X/46,XY, 45,X/47,XYY, and 45,X/46,XY/47,XYY mosaicism. It appears that ascertainment bias can explain the fact that all known patients with postnatal diagnosis are phenotypically abnormal, while over 90% of prenatally diagnosed cases are reported to have a normal male phenotype. Further elucidation of major Y genes and their clinical significance can be expected in the rapidly expanding gene mapping projects. More, consequently better, phenotype/karyotype correlations can be anticipated at both the cytogenetic and the molecular level.

Genotypic analysis of primary head and neck squamous carcinoma by combined fluorescence in situ hybridization and DNA flow cytometry.

Concurrent DNA flow cytometric (FCM) and fluorescence in situ hybridization (FISH) analyses were prospectively performed on 24 primary untreated head and neck squamous carcinomas for characterization of the genotypic and phenotypic DNA aberrations of these neoplasms. Eleven tumors (42.0%) manifested DNA diploidy (DI = 1.00) and 15 (58.0%) had DNA aneuploidy (DI < or > 1.00) by FCM. Fluorescence in situ hybridization results showed aneusomy in the majority of DNA diploid and in all DNA aneuploid tumors. The extent of the abnormalities for individual chromosomes and the number of involved chromosomes in a given DNA diploid or aneuploid tumor were significantly different. Overall, a statistical correlation between the FCM DNA index (DI) and the magnitude of the chromosomal aberration by FISH was found. Our results also show a significant association between the DI and histologic differentiation and stage of disease in these neoplasms. In conclusion, (1) chromosomal aneusomy characterizes most DNA diploid (DI = 1.00) and all DNA aneuploid (DI < or > 1.00) head and neck squamous carcinomas; (2) polysomy is the most prevalent finding; (3) loss of the Y chromosome in tumors from male patients is a consistent feature; (4) the FCM DI reflects net chromosomal gains or losses in these neoplasms; and (5) DNA aneuploidy is associated with tumor aggressiveness.

Gonadoblastomas in 45,X/46,XY mosaicism: analysis of Y chromosome distribution by fluorescence in situ hybridization.

Gonadoblastomas are composed of nests of neoplastic germ cells and sex cord derivatives surrounded by ovarian-type stroma. These tumors are found almost exclusively in persons with gonadal dysgenesis associated with a Y chromosome or Y chromosome fragment, and accordingly, the Y chromosome has been implicated in gonadoblastoma oncogenesis. To evaluate this association, we used two-color fluorescence in situ hybridization with chromosome-specific probes to determine the distribution of the X and Y chromosomes in the tumor nests and surrounding stromal cells in paraffin tissue sections of three gonadoblastomas in two patients with gonadal dysgenesis and 45,X/46,XY mosaicism. Statistical analysis of the data from the fluorescence in situ hybridization demonstrated that in all three gonadoblastomas, the proportion of nuclei with a Y chromosome signal was significantly higher in the tumor cells than in the nontumoral cells of the surrounding stroma (P<.001). These results suggest that Y chromosome material participates in gonadoblastoma tumorigenesis.

Ambiguous genitalia in an elderly woman with a mosaic 45,X/46,X,dic(Y)(Q11.2) karyotype.

A 66-year-old woman presented with clitoromegaly since childhood, primary amenorrhea, no breast development, and a large right inguinal hernia. A mosaic karyotype was identified containing a predominant 45,X cell line and a cell line with 46 chromosomes, one X chromosome, and a small dicentric Y chromosome with a breakpoint in band qII.2. The patient underwent hysterectomy, bilateral gonadectomy, inguinal hernia repair, clitoral recession, and formation of a neointroitus. A dysgerminoma was identified in the right dysgenetic gonad. This report demonstrates the natural history of untreated mixed gonadal dysgenesis and the importance of early evaluation and treatment, as well as the molecular characterization of a dicentric Y chromosome.

[Characteristics of the morphology and mitotic condensation of human Y chromosomes with structural rearrangements]. / Osobennosti morfologii i mitoticheskoi kondensatsii Y-khromosom cheloveka so strukturnymi perestroikami.

Parameters of the length and mitotic condensation were investigated in the following cases of Y-chromosome aberrations: isodicentric Y(q), Y-chromosome without heterochromatic block, and Y-chromosome with satellites. In the Ydic we revealed some differences between f-block, that is located near the inactive kinetochore, and the block near the active centromere. Satellites exert no influence on the mitotic function of Y chromosome, presumably owing to the presence of C-heterochromatic material. With the absence of heterochromatic region, a decline in condensation of the non-fluorescent segment was observed in addition to a simultaneous increase in its length. The mechanism of functioning of the structural heterochromatin is discussed.

[Clinical examinations, chromosomal and molecular DNA in patients with Swyer syndrome]. / Badanie kliniczne, chromosomowe i molekularne DNA u pacjentek z zespolem swyera.

Two girls with Swyer syndrome (SS) were described. Diagnosis was established according to clinical data and ultrasound, laparoscope, histopathological, hormonal and cytogenetical examinations. One presents diagnostic possibilities followed advanced methods in genetics. The GTG and RBG high resolution bounding technique and replication analysis of short arms (Xp and Yp) were employed. Normal structure of end segments of X and Y chromosomes was mentioned. Molecular DNA analysis by polymerase chain reaction (PCR) did not find any mutation in SRY gene. Normal structure of this gene does not exclude possibility of SS existence. Our data implicates on the other mechanism of these disturbances.

[Sex chromatin in oncomorphology]. / Polovoi khromatin v onkomorfologii.

SCr body is a label of repression of one of the sex chromosomes (X chromosome in women or Y chromosome in men) in the interphase nucleus. By the end of the synthesis period these chromosomes undergo derepression since DNA replication occurs. Thus, by the end of the synthetic and in premitotic periods of the cellular cycle the SCr body disappears. In tumors of various locations, a clear-cut inverse proportional dependence between a decrease in the number of nuclei with SCr bodies and an increase in the mitotic index was demonstrated. Therefore, the CSr test is an index of the growth rate (proliferative activity) of the examined tumor. By this test it is possible to determine the degree of the tumor progression, to assess the mitotic activity in small pieces of biopsy materials. The SCr test may be an additional method for differential diagnosis of malignant tumors.

Prevalencia de microdeleciones del cromosoma Y en hombres chilenos infértiles / Y chromosome microdeletion prevalence in infertile Chilean men

Objetivo. El objetivo de este estudio es determinar la prevalencia de microdeleciones del cromosomaY en hombres chilenos infértiles. Material y métodos. Se incluyeron 102 hombres con diagnóstico de azoospermia u oligozoospermia severa que consultaron en la Unidad de Andrología por infertilidad. Se llevó a cabo análisis de microdeleciones de la región del factor de azoospermia (AZF) del cromosomaY a través de reacción en cadena de la polimerasa, utilizando ADN genómico extraído de leucocitos de sangre periférica. Cada paciente fue analizado utilizando sequence tagged sites para las regiones AZFa, AZFb y AZFc. Resultados. Sesenta y siete pacientes presentaron azoospermia y 35 oligozoospermia severa. Se encontraron microdeleciones del cromosomaY en el 9,8% de los pacientes. La mutación más prevalente fue AZFc, afectando al 3,9% de la muestra, seguida por AZFbc (2,9%), AZFa (2,0%) y AZFb (1,0%). Solo los hombres azoospérmicos presentaron las mutaciones. Conclusiones. La prevalencia de microdeleciones del cromosomaY en hombres chilenos infértiles es similar a la presentada en estudios internacionales. Estas mutaciones deben ser buscadas cuando se enfrenta a un paciente infértil con alteraciones cuantitativas severas del seminograma, ya que AZFa y AZFb están asociados con ausencia completa de gametos viables, y la portación de AZFc tiene importantes consecuencias en el potencial de fertilidad de la descendencia masculina (AU)

Objective. The aim of this study is to determine the prevalence of Ychromosome microdeletions in infertile Chilean men. Material and methods. A group of 102 infertile men with azoospermia or severe oligozoospermia were screened while attending a fertility clinic for microdeletions in the azoospermia factor (AZF) region of Ychromosome by multiplex polymerase chain reaction. Genomic DNA was extracted from peripheral blood samples. Each patient was analysed for the presence of sequence tagged sites in the AZFa, AZFb, and AZFc regions. Results. Azoospermia and severe oligozoospermia was found in 67 and 35 patients, respectively. Microdeletions were found in 9.8% of patients. The most prevalent mutation was AZFc, affecting 3.9% of the sample. This was followed by AZFbc with 2.9%, AZFa with 2.0%, and AZFb with 1.0%. Only azoospermic men were found to have these genetic alterations. Conclusions. Prevalence of Ychromosome microdeletions in infertile Chilean men is similar to the prevalence presented in international studies. As AZFa and AZFb mutations are associated with complete absence of viable gametes, and AZFc has important consequences in the fertility potential of the offspring, these mutations have to be searched when presented with an infertile patient with severe sperm alterations (AU)

[A satellited Y chromosome]. / Propos sur un chromosome Y à satellites.

A previous report in 1967 on the observation of a satellited Y chromosome found in a French Canadian family line is confirmed by the use of the ammoniacal silver procedure which stains selectively the nucleolus organizer regions (NORs) in acrocentric human chromosomes. There is evidence that this peculiar chromosome results from the translocation to the distal end of the Y chromosome long arms of a satellited segment from a D or G autosome.

Turner syndrome resulting from partial deletion of Y chromosome short arm: localization of male determinants.

Chromosome studies performed because of the possibility of Turner syndrome in an infant girl with pedal edema and mild neck webbing revealed an XY karyotype. Subsequent exploratory laparotomy showed dysplastic ovaries with nests of germ cells with the morphologic features of gonadoblastoma. Repeat chromosome studies from peripheral blood using high-resolution techniques, and also from skin and ovarian fibroblasts, showed an XY karyotype but with a partial deletion of the Y short arm, which was not detected with standard techniques. These findings indicate that testis determining factors are located in this deleted region of the Y chromosome but that other gene(s) remain that induce gonadoblastoma.

[Chromosomal rearrangements and sterility in the lemur]. / Remaniements chromosomiques et stérilité chez les lémuriens.

Autosomal rearrangements are one of the causes of human sterility, particularly in males, where they result in a considerable diminution of gametogenesis. The relationships between multivalents and trivalents, and problems of gametogenesis observed in certain lemur hybrids, make these animals a good model for the study of human male sterility of chromosomal origin.

[Undescended testis and hypospadia in sex chromosomal aberrations]. / Maldescensus testis und Hypospadie bei Aberration der Geschlechtschromosomen.

If hermaphrodite genitals are present in the patient or a higher degree of hypospadia is shown with maldescensus testis, a chromosomal disorder must be considered as one potential cause of the anomaly. The case report of a child with cryptorchidism on the right, inguinal testis on the left and penoscrotal hypospadia is presented as an example. A mosaic karyotype 45, X/46, X, idic (Yp) was diagnosed in this patient after chromosomal analysis. The cell line with the isodicentric Y chromosome could be demonstrated in about 90% of the lymphocytes, but only in 7% of the fibroblasts of the preputium. A derivative Y could not be detected in interphase nuclei in the buccal mucosa, i.e. only the cell line with monosomy X was presented. There was thus chromosomal mosaicism with unequal tissue involvement and a high potential for malignant transformation. Guidelines of pediatric urological, cytogenetic and endocrinological investigations and the diagnostic procedures are described and discussed. A prevention protocol for patients with comparable gonosomal mosaicism is presented.

Phenotype of two males with abnormal Y chromosomes.

Two infertile males with sex chromosomal abnormalities and mosaic karyotype, 45,X/46,X,dic(Yq) and 45,X/46,X,ring(Y), had considerably changed physical findings, including tooth sizes and craniofacial dimensions. Spermatogenesis was preserved with abnormal meiotic chromosomal behaviour. Mosaic karyotype and structurally changed Y chromosome in both cases had an influence on physical parameters. Tests were normally developed and spermatogenesis was preserved but depressed in later stages.

XX/XY chimerism encountered during prenatal diagnosis.

46,XX/46,XY chimerism has previously been reported in patients with abnormal sexual development, and rarely in otherwise normal individuals. We report the first postnatally documented prenatal diagnosis of whole-body 46,XX/46,XY chimerism in humans, discovered by maternal age amniocentesis. The normal male phenotype in this child creates a dilemma in prenatal counselling, since genotypic male/female chimerism cannot be assumed to imply an abnormal sexual phenotype.