X chromosome parental origin and aortic stiffness in turner syndrome.

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.

Spectrum of aortic valve abnormalities associated with aortic dilation across age groups in Turner syndrome.

BACKGROUND: Congenital aortic valve fusion is associated with aortic dilation, aneurysm, and rupture in girls and women with Turner syndrome. Our objective was to characterize aortic valve structure in subjects with Turner syndrome and to determine the prevalence of aortic dilation and valve dysfunction associated with different types of aortic valves. METHODS AND RESULTS: The aortic valve and thoracic aorta were characterized by cardiovascular MRI in 208 subjects with Turner syndrome in an institutional review board-approved natural history study. Echocardiography was used to measure peak velocities across the aortic valve and the degree of aortic regurgitation. Four distinct valve morphologies were identified: tricuspid aortic valve, 64% (n=133); partially fused aortic valve, 12% (n=25); bicuspid aortic valve, 23% (n=47); and unicuspid aortic valve, 1% (n=3). Age and body surface area were similar in the 4 valve morphology groups. There was a significant trend, independent of age, toward larger body surface area-indexed ascending aortic diameters with increasing valve fusion. Ascending aortic diameters were (mean±SD) 16.9±3.3, 18.3±3.3, and 19.8±3.9 mm/m(2) (P<0.0001) for tricuspid aortic valve, partially fused aortic valve, and bicuspid aortic valve+unicuspid aortic valve, respectively. Partially fused aortic valve, bicuspid aortic valve, and unicuspid aortic valve were significantly associated with mild aortic regurgitation and elevated peak velocities across the aortic valve. CONCLUSIONS: Aortic valve abnormalities in Turner syndrome occur with a spectrum of severity and are associated with aortic root dilation across age groups. Partial fusion of the aortic valve, traditionally regarded as an acquired valve problem, had an equal age distribution and was associated with an increased ascending aortic diameters.

Bicuspid aortic valve and aortic coarctation are linked to deletion of the X chromosome short arm in Turner syndrome.

BACKGROUND: Congenital heart disease (CHD) is a cardinal feature of X chromosome monosomy, or Turner syndrome (TS). Haploinsufficiency for gene(s) located on Xp have been implicated in the short stature characteristic of the syndrome, but the chromosomal region related to the CHD phenotype has not been established. DESIGN: We used cardiac MRI to diagnose cardiovascular abnormalities in four non-mosaic karyotype groups based on 50-metaphase analyses: 45,X (n=152); 46,X,del(Xp) (n=15); 46,X,del(Xq) (n=4); and 46,X,i(Xq) (n=14) from peripheral blood cells. RESULTS: Bicuspid aortic valves (BAV) were found in 52/152 (34%) 45,X study subjects and aortic coarctation (COA) in 19/152 (12.5%). Isolated anomalous pulmonary veins (APV) were detected in 15/152 (10%) for the 45,X study group, and this defect was not correlated with the presence of BAV or COA. BAVs were present in 28.6% of subjects with Xp deletions and COA in 6.7%. APV were not found in subjects with Xp deletions. The most distal break associated with the BAV/COA trait was at cytologic band Xp11.4 and ChrX:41,500 000. One of 14 subjects (7%) with the 46,X,i(Xq) karyotype had a BAV and no cases of COA or APV were found in this group. No cardiovascular defects were found among four patients with Xq deletions. CONCLUSIONS: The high prevalence of BAV and COA in subjects missing only the X chromosome short arm indicates that haploinsufficiency for Xp genes contributes to abnormal aortic valve and aortic arch development in TS.

High levels of education and employment among women with Turner syndrome.

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.

Serious aortic complications in a patient with Turner syndrome.

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.

Perturbation of the transforming growth factor ß system in Turner syndrome.

OBJECTIVE: To measure components of the circulating transforming growth factor ß (TGFß) system in patients with Turner syndrome (TS) compared to relevant controls and to ascertain correlation with endocrine and cardiovascular parameters. METHODS: TGFß1, TGFß2 and endoglin (a vascular TGF receptor component) were measured using enzyme-linked immunoassays in the sera of 40 subjects with TS and 40 healthy volunteer women. The cardiovascular phenotype in TS subjects was extensively characterized by cardiac magnetic resonance (MR) and echo. RESULTS: TGFß1 levels were about 3-fold higher in TS while TGFß2 levels were about 3.5-fold higher in controls (P<0.000 1 for both). Soluble endoglin levels were 25% higher in TS (P<0.000 1). Variation in TGFß system components was not explained by age, blood pressure, platelet count, thyroid function, body proportions or cardiovascular phenotype. CONCLUSION: There is profound perturbation of the TGFß system evident in the circulation of individuals with TS.

Trends in GH use in a Turner syndrome natural history study.

The present observations are derived from 273 girls and women aged 7-40 years participating in the National Institutes of Health natural history study of Turner syndrome (TS) in the interval 2001-2011. There was a higher percentage of GH use among individuals in the pediatric age group (7-17, n = 118, 83%) compared to young adult women with prior GH use (18-40, n = 155, 61%). The major factor in this divergence seems to be a trend toward earlier diagnosis of TS in the younger age group. We find a striking association between history of GH use and lower total body and abdominal fat mass in young adults with TS approximately one decade after discontinuation of GH treatment. The interpretation of this observation is limited by the fact that our study subjects were not randomly assigned to GH treatment. There may be a bias involving poor health care, childhood obesity, delayed diagnosis, absent GH treatment and persistent adult obesity. Further studies on the socioeconomic factors implicated in patterns of GH use and non-use for girls with TS are needed to illuminate this important issue.

N-terminal pro-brain natriuretic peptide levels and aortic diameters.

BACKGROUND: Women with X-chromosome monosomy or Turner syndrome (TS) are at increased risk for aortic dilation and dissection. To better understand the pathology and develop tools to monitor the risk of aortic disease, we investigated N-terminal pro-brain natriuretic peptide (BNP) (NT-proBNP) levels in women with TS and healthy female controls. METHODS: We evaluated NT-proBNP levels in women with karyotype-proven TS and healthy female volunteers in relation to ascending aortic diameter and descending aortic diameter measured by cardiovascular magnetic resonance imaging. RESULTS: The NT-proBNP levels were strongly and positively correlated with ascending aortic diameter and descending aortic diameter in both cohorts. The TS group (n = 114, age 37.4 ± 12 yr) had greater body surface area-indexed aortic diameters and higher NT-proBNP levels than the control group (n = 27, age 46.4 ± 11 years): 88.3 ± 62.7 versus 53.5 ± 35 pg/mL, P = .0003. Within the TS group, NT-proBNP levels were higher in those with dilated ascending aorta (n = 42, 112.4 ± 75.7 pg/mL) compared with those with normal aortic dimensions (n = 72, 74.2 ± 49 pg/mL, P = .0014). Abnormally high NT-pro BNP levels were seen in 3 of 4 TS women who presented with previously undetected aortic aneurysm and/or dissection. CONCLUSIONS: The NT-proBNP levels are positively associated with aortic diameters in women with and without TS, suggesting a role for BNP in arterial wall homeostasis. Further study is necessary to determine whether NT-proBNP measurement may be used to monitor aortic diameter and/or detect aortic pathology in individuals at risk for aortic disease.

Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency.

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 ß1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF ß2 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.

Aneurysmal dilatation of medium caliber arteries in Turner syndrome.

Turner syndrome is the most common chromosomal abnormality in female subjects, affecting 1 in 2000 live births. The condition is associated with a generalized vasculopathy as well as congenital cardiac and other defects. We report aneurysmal dilation of medium caliber arteries involving the celiac axis and coronary vessels in two women with Turner syndrome.

Otolaryngologic markers for the early diagnosis of Turner syndrome.

OBJECTIVE: To identify and characterize otolaryngologic markers for the early diagnosis of Turner syndrome (TS). STUDY DESIGN: Prospective cohort survey. 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.

X-chromosome gene dosage and the risk of diabetes in Turner syndrome.

BACKGROUND: Turner syndrome (TS) is caused by the absence or fragmentation of the second sex chromosome. An increased risk of diabetes mellitus (DM) has consistently been noted, but the specific phenotype and genetic etiology of this trait are unknown. METHODS: In a prospective study, we examined the prevalence of DM in adult participants in an intramural National Institutes of Health (NIH) TS study. Results were analyzed with respect to karyotype, age, body mass index (BMI), and autoimmune indices. Insulin sensitivity and secretion were compared in age- and BMI-matched euglycemic women with TS and healthy female controls. We compared gene expression profiles in lymphocytes from differentially affected TS groups. RESULTS: Type 2 DM was present in 56 of 224 (25%) of the women with TS; type 1 DM was found in only one woman (<0.5%). DM was more prevalent among women with an isoXq chromosome compared to X monosomy (40.0 vs. 17.3%; P = 0.004). Euglycemic women with TS (n = 72; age, 33 +/- 12 yr; BMI, 23 +/- 3 kg/m(2)) had significantly higher glycemic and lower insulin responses to OGTT, with insulin sensitivity similar to controls. Gene expression profiles comparing 46,X,i(X)q vs. 45,X groups showed a significant increase in Xq transcripts and in potentially diabetogenic autosomal transcripts in the isoXq group. CONCLUSION: Type 2 DM associated with deficient insulin release is significantly increased among women with monosomy for the X-chromosome but is increased even more among women with monosomy for Xp coupled with trisomy for Xq. These data suggest that haploinsufficiency for unknown Xp genes increases risk for DM and that excess dosage of Xq genes compounds the risk.

Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans?

Immunogenetic mechanisms operating within the immune system are known to influence cytokine profiles and disease susceptibility. Yet the role of the individual's neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary "defect" related to specific neurohormonal immune phenotype(s). We report that in a large subpopulation of healthy humans the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-alpha and IL-12 production but 2-fold lower IL-10 production induced by LPS ex vivo. In alternative settings, we found low baseline levels and profoundly blunted stress-induced epinephrine responses but high TNF-alpha levels in Lewis vs Fischer inbred rats. Additionally, isoproterenol, a beta adrenoreceptor agonist suppressed LPS-induced TNF-alpha production, with more pronounced effect in Lewis than in Fischer rats. In human monocytes, epinephrine and the beta(2) adrenoreceptor agonist fenoterol potently inhibited LPS-induced TNF-alpha and IL-12, but stimulated IL-10 production. The order of potency for hormones able to inhibit IL-12 production ex vivo was: epinephrine > norepinephrine > or = 1,25-(OH)(2) vitamin D(3) > hydrocortisone. This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles. Since Lewis and Fischer rats have opposite susceptibility to experimental immunological diseases, this suggests that the parallel human phenotypes could be linked to differing responsiveness and susceptibility to infections and immune/inflammatory-related conditions.

Fracture risk and bone mineral density in Turner syndrome.

Bone health is a major lifelong concern in caring for women and girls with Turner syndrome (TS). There is an approximately 25% increase in fracture risk most of which is related to medium or high impact trauma. The long bones, especially of the forearm are predominantly affected. This fact may be due to a selective cortical bone deficiency in TS which is unrelated to hypogonadism. In addition, lack of adequate estrogen replacement can lead to trabecular bone deficiency and increase in vertebral compression fractures after age 45. Evaluation of bone density by dual X-ray absorptiometry (DEXA) is important, however, it should be used judiciously in TS in view of its inherent tendency to underestimate the bone density of people with short stature. Bone size-independent methods, such as QCT or volumetric transformation of DEXA data should be used in individuals shorter than 150 cm. Achieving optimal bone density is of critical importance for fracture prevention in TS, and should be pursued by timely introduction of hormone replacement therapy, adequate dose of estrogens during the young adult life, optimal calcium and vitamin D intake and regular physical exercise. In addition, other measures to prevent fall and trauma should be considered, including optimizing hearing and vision, avoiding contact sports and exercise to improve coordination.

Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome.

BACKGROUND: Individuals with Turner syndrome (TS) are at increased risk for impaired glucose tolerance and diabetes mellitus. It is unknown whether pharmacological GH treatment commonly used to treat short stature in TS alters this risk. OBJECTIVE: Our objective was to compare adiposity and glucose tolerance in GH-treated vs. untreated girls with TS. METHODS: In a cross sectional study, GH-treated girls with TS (n = 76; age 13.6 +/- 3.7 yr) were compared to girls with TS that never received GH (n = 26; age 13.8 +/- 3.5 yr). Protocol studies took place in the NIH Clinical Research Center from 2001-2006 and included oral glucose tolerance tests, body composition analysis by dual-energy x-ray absorptiometry, and abdominal fat quantification by magnetic resonance imaging. GH was not given during testing. RESULTS: Total body fat (35 +/- 8 vs. 28 +/- 8%, P < 0.0001), sc abdominal fat (183 vs. 100 ml, P = 0.001), and intraabdominal fat (50 vs. 33 ml, P < 0.0001) were significantly greater in untreated girls. Fasting glucose and insulin were similar, but the response to oral glucose was significantly impaired in the untreated group (28 vs. 7% with impaired glucose tolerance, P = 0.006). A specific excess of visceral fat and insulin resistance was apparent only in postpubertal girls that had never received GH. GH-treated girls demonstrated lower adiposity compared with untreated girls for an average of 2 yr after discontinuation of GH. CONCLUSIONS: Abdominal adiposity is significantly lower and glucose tolerance significantly better in GH-treated vs. untreated girls with TS, suggesting that beneficial effects upon body composition and regional fat deposition outweigh transient insulin antagonism associated with GH administration.

Analysis of auditory phenotype and karyotype in 200 females with Turner syndrome.

OBJECTIVES: Turner syndrome is the most common sex chromosome disorder in females, and is caused by a total or partial deletion of one X chromosome. The purpose of this study was to describe the auditory phenotype in a large group of individuals with Turner Syndrome, with analysis focusing on hearing loss and age, as well as the phenotypic relationship to karyotype variation. DESIGN: Our analysis of auditory function was part of a large-scale, natural history study in which clinical and genetic factors related to Turner syndrome were examined. This ascertainment avoids the bias inherent in studies of patients referred to audiology or otolaryngology specialty clinics. Analysis included data from 200 females with Turner syndrome ranging in age from 7 to 61 yr (mean=27.9 yr). RESULTS: We observed hearing loss in approximately one-half of females with Turner syndrome, and report on a common, previously unlabeled audiometric configuration found in 24% of ears tested. Our cross-sectional design revealed an observable deterioration in hearing loss above the averaged rate of age-related hearing loss seen in an otologically screened, standardized population. Karyotype analysis revealed air conduction thresholds that were significantly poorer in the 46, XdelXp and 46, XiXq groups than in the 46, XdelXq group. CONCLUSIONS: This natural history study provides a more representative description of the auditory phenotype associated with Turner syndrome than previous studies that may have been biased by the method of ascertainment. Correlative analysis of Turner syndrome-specific hearing loss features with karyotype revealed that air conduction threshold elevations are associated with loss of the p arm of chromosome X. Our cross-sectional data indicate a loss of hearing sensitivity at an accelerated rate beyond a normal age-related decline, which warrants continued audiologic monitoring in all females with Turner syndrome regardless of a history of normal hearing.

Uterine development in Turner syndrome.

OBJECTIVE: To evaluate uterine development of women with Turner syndrome (TS) receiving conventional medical care. STUDY DESIGN: In a cross-sectional study we used ultrasonography for uterine evaluation in 86 women with TS 18 to 45 years of age participating in an intramural NIH study, and who had abnormal karyotypes in >70% of white blood cells. Outcomes were uterine dimensions and shape. Information on hormone treatment was obtained by personal interview. RESULTS: Twenty-five percent had a mature in size and shape uterus, and 31% had an immature uterus, with the remainder in a transitional category. Twenty percent of all participants were not taking hormone replacement therapy (HRT) in the preceding year. The majority on treatment were taking conjugated estrogens (CE) or oral contraceptives (OC). Factors associated with uterine maturity were history of spontaneous puberty and duration and type of HRT, with estradiol-based treatment being the most effective. The age at starting HRT was not a critical factor. CONCLUSIONS: Women with TS may develop a normal uterus even at a late start of HRT given adequate duration of treatment and regardless of karyotype.

Growth hormone treatment and left ventricular dimensions in Turner syndrome.

OBJECTIVE: To determine whether cardiac dimensions were different in girls with Turner syndrome (TS) who received growth hormone (GH) compared with those who did not receive GH. STUDY DESIGN: This retrospective, cross-sectional study analyzed echocardiograms in 86 females with TS divided into GH-treated (n = 67) and untreated (n = 19) groups. The subjects all participated in the National Institutes of Health protocol between 2001 and 2006. RESULTS: The average age was 16.2 years (range, 10 to 25 years), and average duration of GH treatment was 4.4 years (range, 1 to 14 years). The GH-treated group was taller by approximately 7 cm (P = .004), but cardiac dimensions normalized to body surface area (BSA), including septal and posterior wall thickness and left ventricular (LV) mass and internal diameters, did not differ significantly between the 2 groups. The fractional shortening index was similar in the 2 groups. Multiple regression analyses indicated that BSA, but not duration of GH treatment, predicted LV dimensions in girls with TS. CONCLUSIONS: GH treatment of girls with TS increases stature but does not disproportionately affect cardiac dimensions.

The physical phenotype of girls and women with Turner syndrome is not X-imprinted.

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 X(M) (n = 56) and X(P) (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 X(M) and X(P) groups. Neck webbing was found in 35% of the X(M) (n = 133) and 22% of the X(P) (n = 50) groups (P = 0.11). Renal anomalies were present in 24% of X(M) and 25% of X(P) groups (P = 0.9). Bicuspid aortic valve was found in 26% of X(M) and 24% of X(P) 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 X(M) and 52% of X(P) 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.