Clinical application of noninvasive prenatal screening for sex chromosome aneuploidies in 50,301 pregnancies: initial experience in a Chinese hospital.

To evaluate the clinical performance of noninvasive prenatal screening (NIPS) for fetal sex chromosome aneuploidies (SCAs), pregnant women were recruited in this retrospective observational study. The NIPS test was undertaken using high-throughput gene sequencing. In total,50,301 pregnant women were analysed for demographic characteristics and medical history. Of them, 308 women (0.61%) had high risk for fetal SCAs, including 138 for 45,X, 111 for 47,XXY, 42 for 47,XXX, and 17 for 47,XYY. After the pre-test counselling, 182 participants chose to undergo invasive prenatal diagnosis, confirming 59 positive cases. The combined positive predictive value of NIPS was 32.42% (59/182), 18.39% (16/87), 44.4% (12/27), 39.29% (22/56), and 75% (9/12) for detecting SCAs, 45,X, 47,XXX, 47,XXY, and 47,XYY, respectively. NIPS can be a useful method to detect the fetal SCAs using high-throughput gene sequencing, though accuracy can still be improved, especially for 45,X. Although the value of NIPS compare favorably with those seen in traditional screening approaches for SCAs, it is important to highlight the limitations of NIPS while educating clinicians and patients.

Guía de actuación en las anomalías de la diferenciación sexual (ADS) / desarrollo sexual diferente (DSD) / Management guidelines for disorders / different sex development (DSD)

Las anomalías de la diferenciación sexual (ADS) engloban un amplio espectro de discordancias entre los criterios cromosómico, gonadal y fenotípico (genital) que definen la diferenciación sexual; actualmente, se aboga por la denominación de «desarrollo sexual diferente» (DSD). Su origen es congénito; se clasifican en función de los cromosomas sexuales presentes en el cariotipo; las causas genéticas conocidas son muy diversas y heterogéneas, aunque algunos casos pueden ser secundarios a factores maternos o medioambientales. Su diagnóstico y tratamiento requieren siempre una atención médica y psicosocial multidisciplinar. El diagnóstico etiológico precisa la interacción entre las exploraciones clínicas, bioquímicas (hormonales), genéticas, de imagen y, eventualmente, quirúrgicas. El tratamiento debe abordar la asignación de género, la posible necesidad de tratamiento hormonal substitutivo (suprarrenal si hay insuficiencia suprarrenal y con esteroides sexuales si hay insuficiencia gonadal a partir de la edad puberal), la necesidad de intervenciones quirúrgicas sobre las estructuras genitales (actualmente se tiende a diferirlas) y/o sobre las gónadas (en función de los riesgos de malignización), la necesidad de apoyo psicosocial y, finalmente, una adecuada programación de la transición a la atención médica en las especialidades de adultos. Las asociaciones de personas afectadas tienen un papel fundamental en el apoyo a familias y la interacción con los medios profesionales y sociales. La utilización de Registros y la colaboración entre profesionales en Grupos de Trabajo de sociedades médicas nacionales e internacionales es fundamental para avanzar en mejorar los medios diagnósticos y terapéuticos que precisan los DSD

Disorders of Sex Development (DSD) include a wide range of anomalies among the chromosomal, gonadal, and phenotypic (genital) characteristics that define sexual differentiation. At present, a definition as Different Sexual Development (DSD) is currently preferred. They originate in the pre-natal stage, are classified according to the sex chromosomes present in the karyotype. The known genetic causes are numerous and heterogeneous, although, in some cases, they may be secondary to maternal factors and/or exposure to endocrine-disrupting chemicals (EDCs). The diagnosis and treatment of DSD always requires multidisciplinary medical and psychosocial care. An aetiological diagnosis needs the interaction of clinical, biochemical (hormonal), genetic, imaging and, sometimes, surgical examinations. The treatment should deal with sex assignment, the possible need for hormone replacement therapy (adrenal if adrenal function is impaired, and with sex steroids from pubertal age if gonadal function is impaired), as well as the need for surgery on genital structures (currently deferred when possible) and/or on gonads (depending on the risk of malignancy), the need of psychosocial support and, finally, an adequate organisation of the transition to adult medical specialties. Patient Support Groups have a fundamental role in the support of families, as well as the interaction with professional and social media. The use of Registries and the collaboration between professionals in Working Groups of national and international medical societies are crucial for improving the diagnostic and therapeutic tools required for the care of patients with DSD

Turner syndrome isochromosome karyotype correlates with decreased dental crown width.

The aim of this project was to study possible influences of Turner syndrome (TS) karyotype and the number of X chromosomes with intact short arm (p-arm) on dental crown width. Primary and permanent mesio-distal crown width was measured on plaster casts from 112 TS females. The influence on crown width of four karyotypes: 1. monosomy (45,X), 2. mosaic (45,X/46,XX), 3. isochromosome, and 4. other, and the number of intact X chromosomal p-arms were investigated. In comparisons between karyotypes, statistically significant differences were found for isochromosome karyotype maxillary second premolars, canines, laterals, mandibular first premolars, and canines, indicating that this karyotype was the most divergent as shown by the most reduced crown width. When each karyotype group were compared versus controls, all teeth in the isochromosome group were significantly smaller than controls (P < 0.01-0.001). The 45,X/46,XX karyotype expressed fewer and smaller differences from controls, while 45,X individuals seemed to display an intermediate tooth width compared with 45,X/46,XX and isochromosomes. No significant difference in crown width was found comparing the groups with one or two intact X chromosomal p-arms. Both primary and permanent teeth proved to have a significantly smaller crown width in the entire group of TS females compared to healthy females. We conclude that the isochromosome group deviates most from other karyotypes and controls, exhibiting the smallest dental crown width, while individuals with 45,X/46,XX mosaicism seemed to have a less affected crown width. An influence of the number of intact p-arms on crown width could not be demonstrated in this study.

Kabuki syndrome in a girl with mosaic 45,X/47,XXX and aortic coarctation.

OBJECTIVE: To describe the clinical findings of a patient with mosaic 45,X/47,XXX and aortic coarctation. DESIGN: Descriptive case study. SETTING: Tertiary medical center. PATIENT(S): A 6-year-old girl with stigmata of Turner syndrome, aortic coarctation, patent ductus arteriosus, and a peculiar facial appearance. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cytogenetic analysis. RESULT(S): The patient manifested a characteristic Kabuki syndrome facial appearance with long palpebral fissures, everted lateral third of lower eyelids, arched eyebrows, a depressed nasal tip, large dysplastic ears and epicanthic folds. She had undergone cardiac surgery for treatment of aortic coarctation and patent ductus arteriosus. Cytogenetic analysis of the blood lymphocytes revealed a karyotype of mos 45,X,9ph [35 cells]/47,XXX,9ph [5 cells]. CONCLUSION(S): This is the first report of mosaic 45,X/47,XXX associated with Kabuki syndrome. We emphasize that Kabuki syndrome, a peculiar facial appearance and aortic coarctation, should be considered in girls with sex chromosome abnormalities.

Endocrine function in a 48,XXYY adult with type 2 diabetes: case report with a review of the literature.

We present the clinical, biological, endocrinal and psychological characteristics of a 48,XXYY adult. The 43-year-old male examined is the first reported case of this XY polysomy concomitant with type 2 diabetes. Endocrine investigations suggested dysfunction of Leydig and Sertoli cells whereas the pituitary function appeared normal. We compare the phenotypic, behavioral and pathological features of the syndrome in our patient with other reports in the literature.

[Dicentric Y chromosome]. / Les chromosomes Y dicentriques.

Dicentric Y chromosomes are the most common Y structural abnormalities and their influence on gonadal and somatic development is extremely variable. Here, we report the third comprehensive review of the literature concerning dicentric Y chromosomes reported since 1994. We find 78 new cases for which molecular studies (PCR or FISH) have been widely applied to investigate SRY (68% of cases), GBY, ZFY, RFS4Y, GCY and different genes at AZF region. For dic(Yq), all cases (n = 20) were mosaic for 45,X and 4 of them were also mosaic for a 46,XY cell line. When breakpoints were available (15/20 cases), they were in Yp11. 50% of cases were phenotypic female and 20% phenotypic male while 20% of cases were reported with gonadal dysgenesis. Gonadal histology was defined in 8 cases but only in one case, gonadal tissu was genetically investigated because of gonadoblastoma. For dic(Yp) (n = 55), mosaicism concerned only 45,X cell line and was found in 50 cases while the remainder five cases were homogeneous. When breakpoints were available, it was at Yq11 in 50 cases and at Yq12 in two cases. 54% of cases were phenotypic female, 26% were phenotypic male and 18% were associated with genitalia ambiguous. SRY was analyzed in 33 cases, sequenced in 9 cases and was muted in only one case. Gonads were histologically explored in 34 cases and genetically investigated in 8 cases. Gonadoblastoma was found in only two cases. Through this review, it seems that phenotype-genotype correlations are still not possible and that homogeneous studies of dic(Y) in more patients using molecular tools for structural characterization of the rearranged Y chromosome and assessment of mosaicism in many organs are necessary to clarify the basis of the phenotypic heterogeneity of dicentric Y chromosomes and then to help phenotypic prediction of such chromosome rearrangement.

Asociación de síndrome de Down y de Klinefelter / A case of association between Down's and Klinefelter's syndromes

El primer caso de doble aneuploidía (48,XXY,+21) fue diagnosticado por Ford, et al en 1959. Actualmente, la frecuencia de la asociación del síndrome de Down y Klinefelter se estima en 0,7 3 100.000 recién nacidos. La apariencia clínica es de fenotipo Down. La vida media de los pacientes con síndrome de Down varía dependiendo de la existencia de complicaciones asociadas; asimismo, no está descrito que la asociación de ambos síndromes implique un acortamiento del pronóstico vital de estos pacientes

The first case of double aneuploidy was reported in 1959 by Ford and associates, who examined a patient with an XXY and trisomy 21 karyotype. The incidence of combined Klinefelter's and Down's syndromes is estimated to be 0.7 per 100 000 newborns. The phenotype is invariably that of Down's syndrome, and the life expectancy of individuals with this syndrome varies depending on the existence of associated complications. There is no evidence to date that the association of the two syndromes implies a shorter life expectancy

Chromosome aberrations in a schizophrenia population.

Cytogenetic abnormalities with schizophrenia may provide a valuable clue to the identification of target loci and successful search for major genes. We have performed chromosomal examinations by using the GTG banding technique on 134 schizophrenics. In 43 patients (32%), random numerical and structural aberrations were detected. Structural aberrations predominated and usually consisted of deletions and inversion of various chromosomes. Numerical changes were present in one or two cells in 14 cases including trizomy 21, marker and acentric chromosomes, and 47,XXY. The seven cases with pericentric inversion and enlargement of the heterochromatin region of chromosome 9 (inv(9); 9qh+) were observed in the study. The incidence (5.2%) of inv(9) and 9qh+ in our schizophrenic patients were found higher than the general population, suggesting that a susceptibility locus for schizophrenia may be located at pericentromeric region of chromosome 9. Our study have detected 1q21, 7q23, inv(9), 9qh+, 11q23, 21q22, 22q11-13 and Xp11-q13 suggested that these chromosomal lesions are prevalent in schizophrenics. The reason for this might be that these anomalies increase risk for schizophrenia in a relatively nonspecific way, such as contributing to disruption of normal embryogenesis of the nervous system.

Chromosomal anomalies in cryptorchidism and hypospadias.

PURPOSE: We studied the incidence of chromosomal anomalies in patients with cryptorchidism and hypospadias to determine the value of routine karyotyping in this population. MATERIALS AND METHODS: Blood samples from 984 patients with cryptorchidism and/or hypospadias were studied for chromosome analysis. RESULTS: Chromosomal anomalies were detected in 27 of the 916 patients (2.94%) with cryptorchidism and in 7 of the 100 (7%) with hypospadias. There were chromosomal aberrations in 13 of the 706 patients (1.84%) with isolated cryptorchidism (no additional congenital abnormalities) and in 14 of the 210 (6.67%) with cryptorchidism with associated anomalies. We identified normal karyotypes in 26 patients with isolated hypospadias, although 7 of the 74 (9.46%) with hypospadias and additional abnormalities had chromosomal aberrations. CONCLUSIONS: It is important to perform karyotyping in these patients, mainly when they show associated abnormalities other than cryptorchidism or hypospadias. However, cost-benefit analysis must be done in each case.

Understanding new genetics of male infertility.

PURPOSE: Greater than 10% of couples are unable to achieve pregnancy. In at least 30% to 50% of these infertility cases a male factor abnormality is involved. Genetic defects are believed to be the cause of a significant percent of these abnormalities. In fact, defects causing infertility, such as chromosomal disorders and congenital hypothalamic-pituitary-gonadal axis syndromes, have long been recognized. With the development of gene targeting technologies in animal models many genes required for male fertility in animals are known, contributing to our understanding of the etiology of this important health problem. We present not only recognized genetic disorders associated with male infertility, but also its emerging and previously unrecognized genetic etiologies. MATERIALS AND METHODS: This review is organized to enable the reader to recognize promptly the major types of genetic defects associated with male infertility, their clinical characteristics and appropriate therapeutic approaches. Due to the explosion of current knowledge in this field and to length restrictions the discussion of genetic defects is concise, referencing predominantly review articles relevant to the topic. RESULTS: Assisted reproductive technologies for overcoming sterility resulting from unrecognized etiologies may have important potential consequences for infertile couples and their offspring. CONCLUSIONS: Familiarity with the genes associated with male infertility is essential for the urologist to better understand, diagnose and treat the male factor couple.

Exploring the complex relationship between adolescent sexual offending and sex chromosome abnormality.

The nature and importance of the relationship between sex chromosome abnormalities (SCAs) and sexual maladaptive behaviour is uncertain. When considering the aetiology of sexual offending behaviour, the importance of sex chromosome disorder lies in its biopsychological manifestations and in its complex interactions with external influences. At the Adolescent Forensic Service, in keeping with previous research in institutional settings, we found a higher pick-up rate of SCAs among sexual offenders (5/121) than would be expected in an unbiased community sample (1.2/1000 male livebirths; Jacobs et al. (1992)). We present descriptive data on five patients with SCAs out of a total of 121 sexual offenders who presented to the Adolescent Forensic Service over a 6-year period. We discuss the biopsychosocial features of these five patients and compare them with the remainder of the sexual offenders in the series. We discuss the advantages of early diagnosis and the need for professional vigilance by adolescent forensic psychiatrists, child and adolescent psychiatrists, paediatricians and clinical geneticists.

Lack of correlation between human y-positive spermatozoa and acrosomal abnormalities and variations in intensity of fluorescence of sperm stained with quinacrine compounds.

Seminal fluid from 170 men was examined for acrosomal abnormalities of sperm (Papanicolaou procedure X 1000) and for y-positive cells (quinacrine-stained smears). No correlation was found between these parameters, suggesting that acrosomal abnormalities are similarly distributed among x- and y-bearing spermatozoa. The proportion of y-positive sperm was found to be low (23.6 + 10.7% (SD) for the oligozoospermic specimens and 23.7 +/- 9.8% for specimens with sperm counts above 40 million/ml). Three degrees of fluorescence intensity were observed--weak, moderate, and strong--the strong fluorescence being associated with the highest percentage of y-bodies (30.6 +/- 12.7%, 36.6 +/- 5.7%) and the weak fluorescence with the lowest (16.7 +/- 7.0%, 15.0 +/- 9.5%). It is suggested that structural abnormalities and/or metabolic alterations in either the DNA molecule or the chromosomal proteins may be responsible for variability in the ability to bind quinacrine compounds.

Male pseudohermaphroditism: genetics and clinical delineation.

The genetics and clinical delineation of male pseudohermaphroditism are reviewed. These disorders are categorized initially by their genetic etiology--cytogenetic, Mendelian, or teratogenic. It is especially important to distinguish cytogenetic forms, usually associated with 45,X/46,XY mosaicism, from Mendelian (genetic) forms because in the former the prevalence of gonadoblastomas or dysgerminomas is about 15--20%. Genetic forms include (1) those associated with a multiple malformation pattern, (2) those due to an error in adrenal or testicular hormonal biosynthesis, (3) complete testicular feminization, (4) incomplete testicular feminization, (5) Reifenstein syndrome, (6) pseudovaginal perineoscrotal hypospadias, and (7) agondia, and possibly other conditions. Incomplete testicular feminization and the Reifenstein syndrome may or may not represent varied expressivity of the same trait. The designation pseudovaginal perineoscrotal hypospadias is appropriate only if constellations of clinical features are present and if no metabolic abnormalities are demonstrable. Etiology and available genetic data are reviewed for each of these disorders.