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This trial randomly assigned girls 5 to 12.5 years of age with Turner's syndrome to receive growth hormone, low-dose estrogen, neither, or both. Growth hormone increased adult height. Combining ultra-low-dose estrogen with growth hormone during childhood may optimize growth. Turner's syndrome, which results from partial or complete X-chromosome monosomy, occurs in about 1 in 2000 live female births 1 and encompasses diverse clinical features, including short stature, ovarian dysgenesis, and neurocognitive problems. 2 The marked short stature in Turner's syndrome (an average, untreated adult height 20 cm below that of the general female population 3 , 4 ) can be ameliorated by treatment with recombinant human growth hormone. Although there is substantial evidence that growth hormone treatment increases adult stature in patients with Turner's syndrome, 5 – 13 data from randomized, double-blind, placebo-controlled studies have been lacking. 13 Ovarian failure, the second major problem associated with . . .

Background/Aims: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m 2 BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS). Methods: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies. Results: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m 2 equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m 2 BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m 2 BSA. Conclusion: Dosing GH per m 2 BSA is at least as efficacious as dosing per kg BW, and is more cost-effective.

Background: A UK study showed final height in Turner syndrome (TS) girls receiving growth hormone is affected by age at pubertal induction and oxandrolone (Ox). Using data from that study, we analysed the effect of timing of oral ethinylestradiol (EE 2 ) and Ox on height velocity (HV), bone maturation and pubertal progression, and compared growth response in EE 2 -treated versus spontaneous puberty. Methods: Analysis of HV, bone age and pubertal stage in 92 TS girls (7-13 years) randomised to Ox (0.05 mg/kg/day; max: 2.5 mg/day) or placebo from 9 years, and EE 2 (year 1: 2 µg/day; year 2: 4 µg/day; year 3: 6/8/10 µg/day × 4 months) or placebo at 12 years with EE 2 at 14 years. Girls enrolled at >12.25 years received EE 2 at 14 years (‘late group'). Results: Fifty-six girls were randomised to EE 2 at 12 years (n = 28, 11 Ox) or 14 years (n = 28, 13 Ox); there were 19 girls in the late group (9 Ox) and 17 girls with spontaneous puberty (10 Ox). Girls receiving EE 2 at 12 versus 14 years had faster bone maturation, but neither group showed acceleration. Ox increased HV without altering bone maturation or pubertal progression. Girls with spontaneous puberty had greater pubertal growth (mean PHV 8.5 cm/year; p < 0.001) and height gain (p < 0.001) than EE 2 -treated girls despite similar mean enrolment height SD and dysmorphology scores. Conclusion: Pubertal induction with EE 2 does not replicate the acceleration observed in unaffected girls or TS girls with spontaneous puberty.

Significance In the human brain, from early in development through to adulthood, the superior temporal sulcus is deeper in the right than the left cerebral hemisphere in the area ventral of Heschl’s gyrus. Irrespective of gender, handedness, and language lateralization, and present in several pathologies, this asymmetry is widely shared among the human population. Its appearance early in life suggests strong genetic control over this part of the brain. In contrast, the asymmetry is barely visible in chimpanzees. Thus this asymmetry probably is a key locus to look for variations in gene expression among the primate lineage that have favored the evolution of crucial cognitive abilities sustained by this sulcus in our species, namely communication and social cognition. Identifying potentially unique features of the human cerebral cortex is a first step to understanding how evolution has shaped the brain in our species. By analyzing MR images obtained from 177 humans and 73 chimpanzees, we observed a human-specific asymmetry in the superior temporal sulcus at the heart of the communication regions and which we have named the “superior temporal asymmetrical pit” (STAP). This 45-mm-long segment ventral to Heschl’s gyrus is deeper in the right hemisphere than in the left in 95% of typical human subjects, from infanthood till adulthood, and is present, irrespective of handedness, language lateralization, and sex although it is greater in males than in females. The STAP also is seen in several groups of atypical subjects including persons with situs inversus, autistic spectrum disorder, Turner syndrome, and corpus callosum agenesis. It is explained in part by the larger number of sulcal interruptions in the left than in the right hemisphere. Its early presence in the infants of this study as well as in fetuses and premature infants suggests a strong genetic influence. Because this asymmetry is barely visible in chimpanzees, we recommend the STAP region during midgestation as an important phenotype to investigate asymmetrical variations of gene expression among the primate lineage. This genetic target may provide important insights regarding the evolution of the crucial cognitive abilities sustained by this sulcus in our species, namely communication and social cognition.

To investigate whether long-term growth hormone (GH) treatment influenced blood pressure (BP), body proportions and BMI in young Turner syndrome (TS) women several years after GH discontinuation. A follow-up study of a randomized GH dose-response trial with 3 GH dosages (1.3, 2.0, and 2.7 mg/m(2)/day). 39 TS patients (20.0 +/- 2.1 years) participated 4.8 (1.9) years after GH discontinuation. Mean GH duration was 8.7 (2.0) years. BP, BMI and body proportions. During GH treatment, DBP had decreased. At the long-term follow-up study, DBP had increased and was similar to pretreatment levels. DBP was negatively influenced by GH dose. SBP was not influenced by GH dose or duration. The BMI increased gradually during and after GH therapy. During GH therapy, shape values of sitting height had decreased to normal values, of foot had increased, and both remained constant after GH discontinuation. GH therapy in girls with TS has, besides height, additional beneficial effects on BP and body proportions, except foot length. Nearly 5 years after ending GH, the favorable effect of GH on BP was still noticeable. The BMI increased gradually over the years, not influenced by GH.

BACKGROUNDEstrogen deficiency and progressive hearing loss (HL) are significant concerns in individuals with Turner syndrome (TS). However, whether childhood estrogen deficiency increases HL risk and whether estrogen replacement therapy (ERT) prevents hearing deterioration are still unclear.METHODSThis prospective cohort study recruited children with TS from a tertiary referral center between 2016 and 2024. All participants received standardized recombinant human growth hormone therapy. Longitudinal monitoring data of hormone levels, metabolic parameters, and annual audiological examinations were recorded. The primary analysis used a multivariate Cox model to estimate the adjusted hazard ratio (HR) of hearing loss between estrogen-deficient and estrogen-normal TS patients without prior exogenous estrogen exposure. The secondary analysis compared annual pure tone average (PTA) and its changes between the ERT and non-ERT groups in a substudy.RESULTSAmong 87 prepubertal pediatric patients with TS, 48 (55.2%) were estrogen deficient, and 38 HL events occurred over a 35-month median follow-up. The estrogen-deficient group had higher HL incidence (27 cases, 56.3%; 20.6 per 100 person-years [PY]) versus estrogen-normal (11 cases, 28.2%; 8.6 per 100 PY), with estrogen deficiency independently increasing HL risk (HR 2.93, 95% CI 1.21-7.12). Notably, estrogen deficiency also independently predicted abnormal distortion product otoacoustic emissions with an even higher effect size (HR 3.98, 95% CI 1.35-11.76). The substudy found that initiating ERT at the age of 12 significantly preserve auditory function, with the ERT group showing markedly lower PTA and slower hearing deterioration (-1.24 dB/year vs. 1.13 dB/year right ear; -1.85 dB/year vs. 1.04 dB/year left ear, P = 0.001).CONCLUSIONChildhood estrogen deficiency is a modifiable risk factor. Initiating ERT around early adolescence may help hearing preservation.TRIAL REGISTRATIONChinese Clinical Trial Registry: ChiCTR2300068063.FUNDINGNational Natural Science Foundation of China (grants 82173154 and 82471155), Fundamental Research Funds for the Central Universities Clinical Research 5010 Program (Sun Yat-sen University, no. 2024004).

Morbidity and mortality from congenital and acquired cardiovascular (CV) disease is increased in Turner syndrome (TS), where traditional indices of CV risk are widely present but the single most common feature remains estrogen deficiency. To investigate CV risk in TS as expressed by the widely available ambulatory arterial stiffness index (AASI) and the impact of female sex hormone replacement therapy (HRT) hereon. TS women (n = 26) were examined following HRT washout and again during 6 months of HRT. Age-matched healthy female controls (n = 24) were examined once. 24-Hour ambulatory blood pressures, AASI in addition to metabolic and anthropometric indices of CV risk were measured. The relatively tachycardic TS women had higher systolic and diastolic blood pressures. HRT reduced diastolic blood pressures with an increase in physical fitness, worsening of glucose tolerance, and a reduction in high-density lipoprotein. AASI was significantly elevated in TS when compared to controls (0.36 (0.02) vs. 0.26 (0.03), p = 0.01) but unaffected by HRT. Major explanatory variables to AASI were status (being TS or not), age, and diurnal pulse variability. AASI was elevated in TS, possibly indicating elevated CV risk with no impact of short-term HRT.

Girls and women with Turner syndrome (TS) suffer from increased risk of cardiovascular diseases. We hypothesized that left ventricular (LV) myocardial strain and aortic elasticity will be impaired in girls with TS. Cardiac MRI of 45 girls with TS and 14 healthy control girls was performed. Tissue tracking was used to assess LV Global Longitudinal (GLS), circumferential (GCS), radial short and long axes (GRS SAX and GRS LAX) in patients compared to controls. Maximal and minimal aortic areas were measured in ascending aorta, proximal descending, and aorta at diaphragm. Regional strain and distensibility were calculated using previously validated formulas. Comparisons were made between patients with and without bicuspid aortic valve (BAV). Inter-observer agreement was assessed for myocardial strain and aortic strain and distensibility. Results of the study showed GLS was significantly impaired in TS patients − 15.6 ± 1.8% compared to the control group − 17.2 ± 1%, p value = 0.013. No significant differences were observed in other strain parameters. Aortic diameter was similar in patients and control groups. Ascending aorta strain and distensibility were significantly lower in TS patients (33 ± 19% and 9.1 ± 5.5 mm Hg − 1 ) compared to control group (55 ± 17% and 13.9 ± 4.9 10 − 3 mm Hg − 1 ), p values 0.004 and 0.013. No significant differences were found in aortic strain and distensibility in the other 2 regions. No significant differences were observed between TS patients with and without BAV in myocardial strain and aortic strain and distensibility. Substantial to perfect inter-observer agreement was found for myocardial strain and aortic strain and distensibility. Cardiac MRI measurements of LV deformation and aortic function carry potential value as markers for early detection of myocardial and aortic disease in TS patients. Validation of the clinical impact and prognostic role require further longitudinal studies.

Abstract Context Turner syndrome (TS) is a genetic condition that is reported to be associated with a prolonged rate-corrected QT (QTc) interval. Objectives To evaluate the prevalence of QTc prolongation in patients with TS, to compare their QTc intervals with healthy controls, and to investigate whether QTc prolongation is associated with a monosomy 45,X karyotype. Method Girls (n = 101) and women (n = 251) with TS visiting our center from 2004–2018 were included in this cross-sectional study. QT intervals of 12-leaded electrocardiograms were measured manually, using Bazett’s and Hodges formulas to correct for heart rate. A QTc interval of >450 ms for girls and >460 ms for women was considered prolonged. Corrected QT (QTc) intervals of patients with TS were compared to the QTc intervals of healthy girls and women from the same age groups derived from the literature. Results In total, 5% of the population with TS had a prolonged QTc interval using Bazett’s formula and 0% using Hodges formula. Mean QTc intervals of these patients were not prolonged compared with the QTc interval of healthy individuals from the literature. Girls showed shorter mean QTc intervals compared with women. We found no association between monosomy 45,X and prolongation of the QTc interval. Conclusions This study shows that the QTc interval in girls and women with TS is not prolonged compared with the general population derived from the literature, using both Bazett’s and Hodges formulas. Furthermore, girls show shorter QTc intervals compared with women, and a monosomy 45,X karyotype is not associated with QTc prolongation.

•Patients with Turner syndrome have a longer corrected QT interval compared with matched controls.•Patients with Turner syndrome are commonly prescribed QTc prolonging medications.•Patients with Turner syndrome are not at greater risk for ventricular arrhythmias. Patients with the Turner syndrome (TS) often have longer QT intervals compared with age-matched peers although the significance of this remains unknown. We sought to determine the degree, frequency and impact of QTc prolongation in patients with TS. A chart review of all patients with an electrocardiogram (ECG) and genetically proven TS was performed. Medications at the time of the ECG were reviewed and QTc calculated. Medications were classified according to QTc risk using www.crediblemeds.com. ECG parameters were compared with an age, gender, and cardiac lesion-matched control group. Over the 10-year period of review, 112 TS patients with a mean age of 34 ± 25 years underwent 226 ECGs. At least 1 QTc prolonging medication was prescribed in 81 (74%) patients. Longer QTc interval correlated with absence of y chromosomal material (p = 0.01), older age (p <0.0001), increased number of QTc prolonging and nonprolonging medications (p <0.0001 each). During the 7.0 ± 5.1 years of follow-up, no patient had ventricular arrhythmia or unexplained sudden death. QTc was significantly shorter in matched controls using either Bazett or Hodges formula (424 ± 16 ms vs 448 ± 28 ms, p <0.0001; and 414.8 ± 16 ms vs 424.2 ± 20 ms; p = 0.0002, respectively). However, there was no difference in the frequency of QTc prolongation >460 msec (2.8% vs 2.6%, p = 0.9). In conclusion, despite frequent use of QT-prolonging medications, ventricular arrhythmias are rare in TS.