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Dosage compensation serves to equalize X chromosome gene expression in mammalian males and females and involves extensive silencing of the 2nd X chromosome in females. If dosage compensation mechanisms completely suppressed the 2nd X chromosome, then actual physical loss of this "eXtra" chromosome should have few consequences. However, X monosomy has major effects upon normal development, fertility and longevity in humans and some other species. This article reviews observations and arguments attempting to explain the phenotypic effects of X monosomy in humans and other mammals in terms of X chromosome gene dosage.

Objectives. Turner syndrome (TS) is associated with congenital cardiovascular defects (CCVDs), most commonly bicuspid aortic valve (BAV) and aortic coarctation (COARC), congenital renal anomalies, and fetal lymphedema. It has been theorized that compressive or obstructive effects of fetal lymphedema may actually cause cardiovascular and renal dysmorphogenesis in TS. The objective of this study was to determine whether there is a specific association between a history of fetal lymphedema and CCVDs in monosomy X, or TS, independent of karyotype or general severity of the phenotype. Methods. This was a prospective study of 134 girls and women who have TS (mean age: 30 years) and were clinically evaluated for evidence of fetal lymphedema, classified as central (signified by the presence of neck webbing) or peripheral (current or perinatal, or dysplastic fingernails). The presence of BAV and/or COARC was detected by magnetic resonance imaging combined with echocardiography, and renal anomalies were determined by ultrasound. Results. There is a strong association between developmental central lymphedema, signified by neck webbing, and the presence of BAV ([chi square] = 10) and COARC ([chi square] = 8). The association between webbed neck and CCVDs was independent of karyotype. There was, in contrast, no significant association between renal anomalies and webbed neck or CCVDs. Conclusions. The strong, statistically significant association between neck webbing and the presence of BAV and COARC in TS suggests a pathogenetic connection between fetal lymphatic obstruction and defective aortic development. The presence of neck webbing in TS should alert the clinician to the possibility of congenital cardiovascular defects. Pediatrics 2005;115:732-735; X-chromosome, aortic coarctation, bicuspid aortic valve, lymphedema., ABBREVIATIONS. CCVD, congenital cardiovascular defect; BAV, bicuspid aortic valve; COARC, coarctation; TS, Turner syndrome. Congenital cardiovascular defects (CCVDs), including most commonly bicuspid aortic valve (BAV) and coarctation of the aorta [...]

Turner Syndrome(TS) is adevelopmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30-50 timesmore frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in nonsyndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS. [ABSTRACT FROM AUTHOR]

Introduction Aortic abnormalities contribute to increased morbidity and mortality of women with Turner syndrome ( TS). Impaired aortic stiffness may prove to have clinical prognostic value in TS as is the case in other diseases such as Marfan syndrome, diabetes and hypertension. Additionally, the parental origin of the X chromosome in TS may influence aortic stiffness. Objective To assess the relation between X chromosome parental origin and aortic stiffness in TS patients. Methods Twenty-four subjects with TS participated in this cross-sectional study at a tertiary care centre. The parental origin of the X chromosome was determined. Cardiac-gated multidetector computerized tomography ( MDCT) was performed and distensibility of the ascending aorta ( AA), a measure of aortic stiffness, was calculated. Results Fourteen women were Xm (maternal origin) and 10 were Xp (paternal origin) for their inheritance of the single X chromosome. Age, body size, blood pressure and AA areas were similar in the two groups. However, the calculated AA distensibility was significantly lower in the Xm group (2·8 ± 1·1 mm/Hg) than in the Xp group (4·1 ± 1·5 mm/Hg); P < 0·05. Conclusion This study demonstrates that TS subjects that inherit their single X chromosome from their mother (Xm) have a significantly stiffer aorta compared with the TS with a paternally originating X chromosome (Xp), consistent with a potentially greater risk for cardiovascular complications. These findings suggest that parental chromosomal analysis and aortic stiffness measurements would be useful for the risk assessment and clinical management of TS patients. [ABSTRACT FROM AUTHOR]

Most women with Turner syndrome (TS) are infertile due to primary ovarian failure. However, approximately 5% experience spontaneous pregnancy, and recently, more women with TS have used assisted reproductive technology with donated oocytes (ART-OD) to become pregnant. The first generation of Turner patients undergoing ART-OD demonstrated a high rate of fatal aortic dissection in late pregnancy or postpartum. More recent observations, particularly from Nordic countries, suggest a lesser risk of dissection, but confirm a high rate of pre-eclampsia in ART-OD pregnancies. This article reviews publications since 2000 concerning maternal outcomes for pregnancies in women with TS to determine if specific risk factors such as type of pregnancy, age, or presence of underlying congenital cardiovascular disease may identify women at special risk. [ABSTRACT FROM AUTHOR]

This article reviews current patterns of ascertainment, clinical characteristics and quality of care for girls with Turner syndrome, based on a cohort of 100 girls (aged 7-17 years) prospectively evaluated at the National Institute of Child Health since 2001. Approximately 25% were diagnosed prenatally or at birth owing to webbed neck and other features typical of fetal lymphedema, few were diagnosed during early childhood, with the majority undiagnosed until age 9 years or older. Major clinical features included thyroid autoimmunity (51%), congenital cardiovascular anomalies (44%), liver abnormalities (36%), hypertension (34%), hearing loss (30%) and renal anomalies (18%). Of the group, 75% were being or had been treated with growth hormone. These girls were an average of 5 cm taller and significantly less obese than the untreated group. We discuss new guidelines for the initiation of puberty and urgent research needed to promote the health and longevity of girls suffering from Turner syndrome as they become adults. [ABSTRACT FROM AUTHOR]

Background: Turner syndrome (TS) (45,X) is associated with premature ovarian failure, usually occurring during childhood. Estrogen treatment is required for the development of secondary sexual characteristics and to maintain feminization. The present study aimed to determine the level of sexual activity in adult women with TS participating as volunteers in the NIH natural history study. Methods: The Derogatis Interview for Sexual Functioning was administered to 98 women, average age 37 ± 10 years (range 18–59) with karyotype-proven TS. Results were compared to gender-based norms, expressed as standardized area T-scores. Results: The average total score was 32 ± 12, approximately at the 10th centile, based on nonpatient community respondents. The survey included independent sections on fantasy, arousal, experience, orgasm, and relationship. Scores on sexual fantasy were in the normal range and were significantly greater than scores on all the other sections ( p < 0.001). Approximately 30% of the study group were involved in a partner relationship, and this group scored within the average range on all sections. We examined factors that might influence sexual function, including age; parental origin of the single normal X chromosome; physical stigmata, such as neck webbing; estrogen use; testosterone levels; age of puberty; and hearing loss, but none of these appeared to contribute. Of all factors investigated, only height and years of education were positively correlated with partnership status and sexual function. In summary, women with TS in a partner relationship report relatively normal overall sexual function, but the majority of unpartnered women reported very low level sexual functioning. Conclusions: Further study is needed to elucidate the nature of psychosocial impediments affecting establishment of partner relations and sexual functioning in women with TS. [ABSTRACT FROM AUTHOR]

New treatments for girls and women with Turner syndrome (monosomy X) have dramatically improved their quality of life and health. Young girls are treated with growth hormone to enhance adult height, and with estrogen to induce and maintain feminization, and prevent osteoporosis. Vigilant screening for otitis, thyroid disease, hypertension, dyslipidemia and diabetes allows for early and effective medical treatment of these common problems. Comprehensive cardiovascular evaluation and regular monitoring of aortic diameter are essential to identify individuals at risk for dissection or rupture. Insights derived from the study of metabolic risk factors in women with Turner syndrome may illuminate gender differences in atherosclerotic heart disease. [ABSTRACT FROM AUTHOR]

Abnormalities in quality of life and cognitive measures have been observed in women with Turner syndrome (TS), and a relationship between these phenomena and chromosomal constitution has been suggested. In contrast, few studies have systematically evaluated the presence of mood and behavioral syndromes in these women. In this study, 100 TS women were administered the Structured Clinical Interview for DSM IV after a two-week period during which their hormone replacement had been discontinued. The majority of women who met criteria for a psychiatric condition had a mood or anxiety disorder. Overall, 52 (52%) of the TS women met criteria for a current or a past depressive or anxiety disorder. Eighteen of the women with TS met criteria for a current Axis I psychiatric disorder [Depression - major ( n  = 5), minor ( n  = 5), dysthymia ( n  = 1); Anxiety ( n  = 9)]. Forty-six of the women with TS met criteria for a past Axis I psychiatric illness [Depression: unipolar ( n  = 41), bipolar ( n  = 3); Anxiety ( n  = 7); eating disorder ( n  = 6); substance dependence ( n  = 3)]. Five women with TS met criteria for an Axis II personality disorder. Women with TS reported a higher rate of lifetime depression compared with rates observed in community-based studies but similar to those obtained from gynecologic clinic samples. [ABSTRACT FROM AUTHOR]

A response from the author of the article " X Chromosome parental origin and aortic stiffness in Turner syndrome" in the 2014 issue is presented.

Abstract: The higher prevalence of autoimmune diseases in women compared to men could be due to effects of ovarian hormones, pregnancy and/or the presence of a second X chromosome. To elucidate the role of these factors, we investigated the prevalence and spectrum of autoimmune diagnoses in women with primary ovarian insufficiency associated with X chromosome monosomy (Turner syndrome, TS, n = 244) and women with karyotypically normal (46,XX) primary ovarian insufficiency (POI, n = 457) in a prospective study, conducted at the National Institutes of Health. We compared the study group prevalence to normative data for the U.S. population of women. Chronic lymphocytic (Hashimoto’s) thyroiditis (HT) occurred in 37% of women with TS vs. 15% with POI (P < 0.0001); HT prevalence in both ovarian insufficiency groups significantly exceeded that in U.S. population of women (5.8%). Inflammatory bowel (IBD, 4%) and celiac disease (CD, 2.7%) were significantly increased in TS, but not in POI. No other autoimmune diagnosis, including Graves’ disease or Type 1 diabetes appears to be significantly increased in either group. Women with TS had higher pro-inflammatory IL6 and TGF β1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF β2 levels (p < 0.005 for both) compared to POI and to normal volunteers. Lifetime estrogen exposure and parity were significantly lower in TS compared to POI, which were in turn lower than the general population of women. The finding that lymphocytic thyroiditis is greatly increased in both women with TS and POI suggests that factors associated with ovarian insufficiency per se promote this form of autoimmunity. The absence of a normal second X-chromosome further contributes to increased autoimmunity in TS. [Copyright &y& Elsevier]