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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]

Background: Turner Syndrome (TS) is due to X chromosome monosomy and affects ∼1 per 2500 females at birth. The major features are short stature and primary ovarian failure. Short stature and monosomy for a maternal X chromosome have been implicated in impaired functionality in adult life; however, data on adult outcomes in TS are limited. In this study we evaluated the influence of adult height and parental origin of the single X chromosome on education, employment, and marital outcomes among women with TS. Methods: This was a cross-sectional study of 240 women (25-67 years old) with TS participating in an intramural National Institutes of Health (NIH) study. Parental origin of the single X chromosome was determined by genotyping proband and parental genomic DNA. Information on education, employment, and family status was self reported. Normative data was obtained from the U.S. Bureaus of Census and Labor and Statistics. Results: Seventy percent of the TS group had a baccalaureate degree or higher, compared with 30% of U.S. women ( p<0.0001). Eighty percent of the TS group was employed compared with 70% of the U.S. female population. Approximately 50% of the TS group had ever married, compared with 78% of the general female population ( p<0.0001). Height and parental origin of the single normal X chromosome had no association with education, employment, or marital status. Conclusion: Women with TS currently achieve education and employment levels higher than the female U.S. population but are less likely to marry. Neither adult height nor parental origin of the single X chromosome influenced outcomes in education, employment, or marriage. [ABSTRACT FROM AUTHOR]

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]

Abstract: Apparent demineralization of the skeleton has been noted in females with Turner syndrome (TS) since the first descriptions of the disorder. Studies, using quantitative methods to measure areal bone mineral density (BMD) in TS, have often been confounded by small skeletal size and variable exposure to estrogen. Recent studies taking bone size into account suggest that BMD at skeletal sites of predominantly trabecular bone, e.g., the lumbar spine and ultra distal radius, is normal in women that have used estrogen consistently. However, these women have significantly lower than normal BMD at skeletal sites with predominantly cortical bone, e.g., the radial shaft and femoral neck. It is unknown whether the reduction in cortical BMD is an intrinsic feature of TS perhaps related to haploinsufficiency for SHOX or another X-linked gene, or due to deficient estrogen exposure during childhood and adolescence, and whether this cortical bone deficit increases fracture risk. Current recommendations to begin low dose estrogen treatment in the early teens may clarify these issues. Wide use of bisphosphonates to treat low BMD in young women with TS is not warranted since these agents have little if any effect on cortical bone while trabecular bone has excellent response to estrogens. [Copyright &y& Elsevier]

Objective: To assess the association between serum adrenal cortex autoantibodies and histologically confirmed autoimmune lymphocytic oophoritis. Design: Controlled, prospective. Setting: Tertiary research center. Patient(s): Two hundred sixty-six women with 46,XX spontaneous premature ovarian failure. Intervention(s): Ovarian biopsy in 10 women. Main Outcome Measure(s): Serum adrenal cortex autoantibodies assessed by indirect immunofluorescence and autoimmune oophoritis assessed by immunohistochemical lymphocyte markers. Result(s): We obtained a histologic diagnosis of autoimmune oophoritis in four women who tested positive for adrenal cortex autoantibodies and excluded this diagnosis in ovarian biopsies from six women who tested negative for adrenal cortex autoantibodies (4/4 vs. 0/6). Women with histologically confirmed autoimmune oophoritis had a greater total ovarian volume as assessed by transvaginal sonography (11.4 ± 5.6 mL vs. 1.5 ± 0.4 mL) (mean ± SEM). They were also more likely to have subclinical adrenal insufficiency and clinical signs of androgen deficiency (3/4 vs. 0/6). Overall, 10/266 women tested positive for adrenal cortex autoantibodies (3.8%, 95% confidence interval: 1.8%–6.5%). Conclusion(s): In women who present with 46,XX spontaneous premature ovarian failure as their primary concern there is a clear association between serum adrenal cortex autoantibodies and the presence of histologically confirmed autoimmune oophoritis. [Copyright &y& Elsevier]

: PurposeTo determine whether women with Turner syndrome who were treated with estrogen were more likely to have osteoporosis and fractures.: MethodsAreal bone density at the lumbar spine and femoral neck was measured in 40 adult women with Turner syndrome and 43 age-matched healthy women using dual-energy X-ray absorptiometry. Histories of estrogen treatment and fractures were obtained by structured personal interviews.: ResultsMean (± SD) areal bone density was significantly lower at the lumbar spine (0.87 ± 0.11 g/cm2 vs. 0.98 ± 0.10 g/cm2, P <0.001) and femoral neck (0.68 ± 0.07 g/ cm2 vs. 0.83 ± 0.08 g/cm2, P <0.001) in women with Turner syndrome than in controls. The diagnostic criterion for osteoporosis (T-score <−2.5) was met by 8 women with Turner syndrome (20%) with scores at the lumbar spine and by 3 (8%) with scores at the femoral neck. All women diagnosed with osteoporosis were less than 150 cm in height. Areal bone density correlated significantly with height (lumbar spine: R2 = 0.3, P <0.001; femoral neck: R2 = 0.4, P <0.001). Adjustments for skeletal size reduced the differences between the groups as well as the number of women diagnosed with osteoporosis (e.g., from 8 to 2 women based on lumbar spine scores). The prevalence and type of fractures were similar in the two groups.: ConclusionThe prevalence of osteoporosis and bone fractures is not increased significantly in women with Turner syndrome who are treated with standard estrogen therapy. Women less than 150 cm in height are likely to be misdiagnosed with osteoporosis when areal bone density is measured, unless adjustments for body size are made. [Copyright &y& Elsevier]

A letter to the editor is presented on Turner syndrome in adults.

This article presents a letter to the editor concerning maternal x chromosome, visceral adiposity, and lipid profiles.

Presents a letter to the editor concerning a study of lipid profiles in women with primary ovarian failure.

The article focuses on the findings of a study that aims to determine whether the Turner syndrome (TS) is due to impaired glucose sensing or to a more fundamental cell defect. It notes that type 2 diabetes (T2DM) and impaired glucose tolerance (IGT) are common in TS. The researchers compared insulin responses to glucose and arginine in TS and age-matched control women.

The article discusses a study on the effect of growth hormone (GH) treatment on glucose tolerance in girls with Turner Syndrome (TS). It states that since GH is known to promote insulin resistance, it is expected to increase the propensity for impaired glucose tolerance. The glucose tolerance and insulin secretion were investigated by means of an oral glucose tolerance test (OGTT). The reason for the improvement of glucose tolerance in girls with TS is given.

Presents the authors' reply to a reader's letter to the editor about a study of lipid metabolism in women and offers criticism of the research methods.

Background: Most girls with Turner syndrome (TS) need estrogen replacement treatment (ERT) to induce and maintain feminization and prevent osteoporosis. There is abundant information on ERT use in postmenopausal women, but there is little information on this issue in women with TS. We aimed to determine the level of ERT use in women with TS living in the United States and assess the effects of ERT adherence vs. nonadherence on bone mineral density (BMD). Methods: Fifty women with TS aged 30-59 years had ERT history obtained by structured interviews and BMD assessed at the lumbar spine by dual x-ray absorptiometry (DXA) and quantitative computed tomography (QCT). Results: Thirty-four of the 50 women with TS had received ERT according to current recommendations, and the rest did not either because of physician failure to prescribe (5 of 50) or because of nonadherence to prescribed ERT (11 of 50). The mean duration of ERT was 25 ± 2 years for the standard of care group vs. 8 ± 2 years for the others (p < 0.0001). The major factor promoting adherence to ERT was education on the importance of ERT for bone health (p < 0.001). As expected, lumbar spine BMD was significantly reduced in women not taking ERT according to current guidelines (e.g., a reduction of 20% by QCT, p < 0.001) with 6 of 16 of these women having osteoporosis and 3 of 16 having vertebral compression fractures compared with 0 of 34 in the ERT adherent group. Conclusions: Approximately 70% of women with TS in this sample of highly educated women in the United States are taking ERT as currently recommended and appear to be protected from osteoporosis of the spine, whereas those women using ERT less than 75% of the time are at grave risk for osteoporosis. In a time of new reservations about postmenopausal ERT, it is important to emphasize to young women with TS and their caregivers that ERT is critical for bone health. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To identify and characterize otolaryngologic markers for the early diagnosis of Turner syndrome (TS). Study design: Prospective cohort survey. Methods: Setting: Clinical Center of the National Institutes of Health (NIH). Patients: Ninety-one females, 7–61 years old (average=28.7 y), enrolled in a multidisciplinary study of karyotype–phenotype correlations in TS. Main outcome measures: Age at diagnosis, X chromosome karyotype, history of chronic or recurrent otitis media (OM), sensorineural hearing loss (SNHL), palate dysmorphism, pinna deformity, pterygium colli, low posterior hairline, low-set ears, and micrognathia. Results: Sixty-nine (76%) patients had a history of chronic or recurrent OM, 62 (68%) had a dysmorphic palate, 57 (63%) had SNHL, and 90 (99%) had one or more of these findings. 83 (91%; average age at diagnosis=9.4 y) had one or more external craniofacial signs: pinna abnormalities, pterygium colli, low-set ears, micrognathia or a low posterior hairline. Eight patients (average age at diagnosis=13.2 y) had no external craniofacial signs, although seven (88%) of these eight patients had a history of chronic or recurrent OM, dysmorphic palate or SNHL. The age at diagnosis was not significantly different between groups with or without external craniofacial signs (P =0.126). Conclusions: Patients with mild or incompletely penetrant TS phenotypes often present with otitis media, hearing loss, or both before the diagnosis of TS is established. Palatal dysmorphism, including ogival morphology, is another otolaryngologic marker for TS. Prompt recognition of these manifestations of TS could hasten its diagnosis and appropriate medical care. [Copyright &y& Elsevier]

Certain behavioral and metabolic aspects of Turner syndrome (TS) are attributed to X-chromosome genomic imprinting. To investigate the possible contribution of imprinting to the physical features of the TS phenotype in live-born individuals, we genotyped the single normal X-chromosome in subjects with TS who all underwent a comprehensive evaluation as part of the NIH genotype–phenotype protocol. All had physical examinations, auxological measurements and imaging of the renal and cardiovascular systems. Absolute height and height as a percent of predicted height was the same in XM ( n = 56) and XP ( n = 23) subjects that had reached final height and were not growth hormone treated. Interestingly, adult height was significantly correlated with maternal but not paternal heights in both XM and XP groups. Neck webbing was found in 35% of the XM ( n = 133) and 22% of the XP ( n = 50) groups ( P = 0.11). Renal anomalies were present in 24% of XM and 25% of XP groups ( P = 0.9). Bicuspid aortic valve was found in 26% of XM and 24% of XP groups ( P = 0.83), and any cardiovascular anomaly (abnormal aortic valve, aortic coarctation, elongated transverse aortic arch, anomalous pulmonary venous connection, left superior vena cava) affected 55% of XM and 52% of XP groups. Thus, we found no evidence for X-linked genomic imprinting effects on stature or lymphatic, renal or cardiovascular development in TS. Our sample size was sufficient to exclude such effects within 95% confidence limits. We did demonstrate a selective maternal effect on final stature that was independent of X-chromosome origin, suggesting potential autosomal imprinting effects on growth revealed by X monosomy. [ABSTRACT FROM AUTHOR]

Objective: To determine whether women with 46,XX spontaneous premature ovarian failure have lower serum free-T levels than do control women. Design: Cross-sectional. Setting: National Institutes of Health Clinical Research Center. Patient(s): Women with 46,XX spontaneous premature ovarian failure (n = 130). Intervention(s): Evaluation while off any estrogen therapy and then again after receiving a standardized hormone regimen. Regularly menstruating control women (n = 65) were sampled during the midfollicular phase. Main Outcome Measure(s): Serum total T by RIA after extraction and column chromatography, free T by equilibrium dialysis, and sex hormone–binding globulin by immunoradiometric assay. Result(s): While off estrogen therapy patients had a median serum free-T concentration that was statistically significantly lower than controls (2.2 vs. 3.3 pg/mL). This dropped significantly lower to 1.9 pg/mL while the patients were on physiologic transdermal E2 therapy. This is despite the fact that sex hormone–binding globulin levels did not change. While on E2 therapy, 13% of women (95% confidence interval, 7.9%–20.3%) had serum free-T levels below the lower limit of normal (<1.1 pg/mL). Conclusion(s): As a group, young women with 46,XX spontaneous premature ovarian failure have reduced circulating free-T levels, both during an interval off of estrogen therapy and while on physiologic transdermal E2 therapy. [Copyright &y& Elsevier]

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 ( x² = 10) and COARC (X² = 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. [ABSTRACT FROM AUTHOR]

Background: Premature Ovarian Failure (POF), defined as the development of hypergonadotropic amenorrhea before the age of 40 years, occurs in about 1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. Recently, in seven patients who presented with POF and white matter abnormalities on MRI (ovarioleukodystrophy) eight mutationswere found in EIF2B2, 4 and 5. Methods: To further test the involvement of known mutations of EIF2B genes in POF, we screened 93 patients with POF who did not have identified leukodystrophy or neurological symptoms. We evaluated these eight mutations and two additional mutations that had been found in patients with milder forms of eIF2B-related disorders. We used restriction enzymes and direct sequencing. Results: None of the known mutations in EIF2B genes, either homozygous or heterozygous, were identified in our 93 patients with pure 46,XX POF. The upper 95 % confidence limit of the proportion 0/93 is 3.2%. Conclusions: We conclude that eIF2B mutations, already described in cases of POF associated with white matter abnormalities, are an uncommon cause of pure spontaneous premature ovarian failure. [ABSTRACT FROM AUTHOR]

An asymptomatic young woman was discovered to have life-threatening aneurysms and dissection of the thoracic aorta during routine evaluation in a Turner syndrome (TS) study. The presence of a heart murmur and hypertension had led to diagnosis and surgical repair of an atrial septal defect at age 5 and of aortic coarctation at age 12. The diagnosis of TS was made at 16 years of age due to short stature and delayed pubertal development. She was treated with growth hormone from age 16 to 18 and with atenolol, thyroid hormone, and estrogen. She discontinued her medications and was lost to medical follow-up at age 20. Upon presenting here at age 26, she reported a very active lifestyle, including vigorous exercise and an acting career, with no symptoms of chest or back pain or shortness of breath. Cardiovascular imaging revealed aortic regurgitation, an unsuspected dissection of a severely dilated ascending aorta, and a large descending aortic aneurysm. She required surgical replacement of her aortic valve and ascending aorta, followed by endovascular repair of the descending aortic aneurysm. This patient illustrates the importance of considering the diagnosis of TS in girls with congenital aortic defects and the absolute necessity for close, expert follow-up of these patients who are at high risk for complications after surgical repair due to an underlying aortopathy, hypertension, and metabolic disorders. This patient also emphasizes the need to publicize and follow screening guidelines as there is an increasing number of patients with congenital defects who need transition to adult care. [ABSTRACT FROM AUTHOR]

An abstract of the article " Shunt and right ventricular structural findings in isolated anomalous pulmonary venous return in Turner syndrome," by Laura Olivieri, Anjali Chelliah, Li-Yueh Hsu, Richard B. Thompson, Vladimir Bakalov, Douglas Rosing, Carolyn Bondy, and Andrew E. Arai is presented.

A letter to the editor is presented in response to the article "Declining Estrogen Use in Young Women With Turner Syndrome."