Generation of functional oocytes from male mice in vitro.

Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes1-5. Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down's syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.

Gonadal dysfunction and beyond: Clinical challenges in children, adolescents, and adults with 47,XXY Klinefelter syndrome.

Klinefelter syndrome (KS) is the most frequent sex chromosomal aneuploidy. The karyotype 47,XXY originates from either paternal or maternal meiotic nondisjunction during gametogenesis. KS males are very likely to exhibit marked gonadal dysfunctions, presenting both in severely attenuated spermatogenesis as well as hypergonadotropic hypogonadism. In addition, neurocognitive and psychosocial impairments, as well as cardiovascular, metabolic and bone disorders are often found in KS and might explain for an increased morbidity/mortality. All conditions in KS are likely to be induced by both gene overdosage effects resulting from supernumerary X-chromosomal genes as well as testosterone deficiency. Notwithstanding, the clinical features are highly variable between KS men. Symptoms can become obvious at infancy, childhood, or adolescence. However, the majority of KS subjects is diagnosed during adulthood. KS adolescents require specific attention regarding pubertal development, in order to exploit their remaining fertility potential and allow for timely and tailored testosterone replacement. The chances for sperm retrieval might decline with age and could be hampered by testosterone replacement; therefore, cryostorage of spermatozoa is an option during adolescence, before the decompensation of endocrine and exocrine testicular functions becomes more overt. Sperm from semen or surgically retrieved, in combination with intracytoplasmic sperm injection enables KS males to become biological fathers of healthy children. The aim of this article is to present the current knowledge on KS, to guide clinical care and to highlight research needs.

Fertile offspring from sterile sex chromosome trisomic mice.

Having the correct number of chromosomes is vital for normal development and health. Sex chromosome trisomy affects 0.1% of the human population and is associated with infertility. We show that during reprogramming to induced pluripotent stem cells (iPSCs), fibroblasts from sterile trisomic XXY and XYY mice lose the extra sex chromosome through a phenomenon we term trisomy-biased chromosome loss (TCL). Resulting euploid XY iPSCs can be differentiated into the male germ cell lineage and functional sperm that can be used in intracytoplasmic sperm injection to produce chromosomally normal, fertile offspring. Sex chromosome loss is comparatively infrequent during mouse XX and XY iPSC generation. TCL also applies to other chromosomes, generating euploid iPSCs from cells of a Down syndrome mouse model. It can also create euploid iPSCs from human trisomic patient fibroblasts. The findings have relevance to overcoming infertility and other trisomic phenotypes.

A Track Record on SHOX: From Basic Research to Complex Models and Therapy.

SHOX deficiency is the most frequent genetic growth disorder associated with isolated and syndromic forms of short stature. Caused by mutations in the homeobox gene SHOX, its varied clinical manifestations include isolated short stature, Léri-Weill dyschondrosteosis, and Langer mesomelic dysplasia. In addition, SHOX deficiency contributes to the skeletal features in Turner syndrome. Causative SHOX mutations have allowed downstream pathology to be linked to defined molecular lesions. Expression levels of SHOX are tightly regulated, and almost half of the pathogenic mutations have affected enhancers. Clinical severity of SHOX deficiency varies between genders and ranges from normal stature to profound mesomelic skeletal dysplasia. Treatment options for children with SHOX deficiency are available. Two decades of research support the concept of SHOX as a transcription factor that integrates diverse aspects of bone development, growth plate biology, and apoptosis. Due to its absence in mouse, the animal models of choice have become chicken and zebrafish. These models, therefore, together with micromass cultures and primary cell lines, have been used to address SHOX function. Pathway and network analyses have identified interactors, target genes, and regulators. Here, we summarize recent data and give insight into the critical molecular and cellular functions of SHOX in the etiopathogenesis of short stature and limb development.

Long-term management of patients with disorders of sex development (DSD).

Differences or disorders of sex development (DSD) describe a biological discrepancy between chromosomal, gonadal, and phenotypical sex, often affecting the morphology of the genito-reproductive organs. DSD is most often due to genetic abnormalities affecting chromosomal composition or single genes. Most children with 46,XX karyotype and DSD have congenital adrenal hyperplasia due to 21-hydroxylase deficiency and should be regarded as unchallenged females. For children with 46,XY DSD, the situation is even much more complicated since indeed an exact genetic diagnosis is still missing. Depending on the phenotype, this may be true for more than 80% of children with severe hypospadias, in contrast in post-pubertal patients with clinical evidence of complete androgen insensitivity, whom 95% show an underlying mutation within the androgen receptor gene. DSD and numerical aberrations of sex chromosomes, especially 45,X/46,XY mosaicism depends essentially on the assessment of the exact clinical morphology with a focus of the external and internal genital structures and of the endocrine and reproductive function of the gonads with the aim for a best prognosis of the child. This assessment should be done in a center of expertise.

Parental decisions regarding prenatally detected fetal sex chromosomal abnormality and the impact of genetic counselling: an analysis of 57 cases in Taiwan.

OBJECTIVE: To analyse parental decisions regarding pregnancies with sex chromosome abnormalities (SCA). METHODS: Collected and reviewed records from our hospital for 1991-2005. Genetic counselling was provided by obstetricians or perinatologists. RESULT: Among 57 fetuses with SCA were 36 non-mosaic cases (four of 36, 45,X; 12 of 36, 47,XXY; seven of 36, 47,XYY, 13 of 36, 47,XXX) and 21 mosaic cases (15 of 21, 45,X mosaicism). Only 20% of 45,X mosaic pregnancies were continued, whereas all other mosaic pregnancies (100%) were continued (P = 0.004). Of 32 SCA cases counselled by a perinatologist, 66% (21 of 32) were continued. In contrast, 36% (nine of 25) of cases counselled by a general obstetrician were continued, a barely significant difference (P = 0.048). More couples chose to continue pregnancies in recent years. CONCLUSION: Genetic counselling by well-trained specialists is valuable, and the trend towards fewer terminations at our centre suggests improved parental knowledge of pathology associated with SCA.

Factors contributing to sex assignment and reassignment decisions in Turkish children with 46,XY disorders of sex development.

BACKGROUND: Sex assignment decisions for children with disorders of sex development (DSD) should be based on integrative assessments of relevant biological and psychosocial characteristics. AIM: To investigate the factors that contributed to sex assignment decisions for children with 46,XY DSD. PATIENTS: Sixty-one children recruited from a clinical sample were evaluated. METHODS: Findings of endocrinological and psychiatric evaluations were entered into a logistic regression analysis. RESULTS: Gender identity was the strongest correlate of assigned sex. External genital under-virilization, sex announced at birth and toy/ activity preferences were predominant predictors. Twelve children, six of whom were prepubertal, were reassigned to male sex. CONCLUSIONS: Psychological factors seem to be as influential on sex reassignment decisions as are endocrinological and social factors, especially if the disorder is diagnosed at an older age. Prepubertal gender conversion is possible, which implies the importance of follow-up during childhood.

49, XXXXY syndrome.

49, XXXXY syndrome is a rare sex chromosomal disorder. A 5-month-old boy had failure to thrive and multiple congenital anomalies including microcephaly, facial dysmorphism (hypertelorism, megacornea, cleft palate, and micrognathia), obvious heart murmur, umbilical hernia, microphallus, and mild clenched hands. Chromosomal studies via techniques of G-banding and fluorescence in situ hybridization showed the constitution to be 47, XXXXY in all cells. Ventriculomegaly and congenital cardiac defects (patent ductus arteriosus, atrial septal defect, and peripheral pulmonary stenosis) were noted. He has severe atopic dermatitis with high IgE levels and psychomotor retardation. After heart surgery and nutritional support, he has better growth and the rehabilitation program is continuing.