MicroRNA-126-3p/5p and Aortic Stiffness in Patients with Turner Syndrome.

Background: Turner Syndrome (TS) is a relatively rare X-chromosomal disease with increased cardiovascular morbidity and mortality. This study aimed to identify whether the circulating miR-126-3p/5p are involved in the pathophysiology of vascular dysfunction in TS. Methods: Using the RT-qPCR, the abundance levels of miR-126-3p and miR-126-5p were determined in 33 TS patients and 33 age-matched healthy volunteers (HVs). Vascular screening, including the assessment of blood pressure, pulse wave velocity, augmentation index, aortic deformation, arterial distensibility, and arterial elastance, was conducted in TS patients and HVs. Results: The abundance levels of miR-126-3p and miR-126-5p were significantly higher in TS patients compared to HVs (p < 0.0001). Within the TS cohort, miR-126-3p/5p correlated significantly with aortic deformation (r = 0.47, p = 0.01; r = 0.48, p < 0.01) and arterial distensibility (r = 0.55, p < 0.01; r = 0.48, p < 0.01). In addition, a significant negative correlation was demonstrated between miR-126-3p and arterial elastance (r = −0.48, p = 0.01). The receiver operating characteristic analysis showed that miR-126-3p and miR-126-5p separated the tested groups with high sensitivity and specificity. Conclusions: The abundance levels of miR-126-3p and miR-126-5p were significantly higher in TS patients compared to HVs. Within the TS cohort, a lower abundance level of miR-126-3p and miR-126-5p was linked with a significantly higher aortic stiffness.

Cross-sectional seroprevalence surveys of SARS-CoV-2 antibodies in children in Germany, June 2020 to May 2021.

The rate of SARS-CoV-2 infections in children remains unclear due to many asymptomatic cases. We present a study of cross-sectional seroprevalence surveys of anti-SARS-CoV-2 IgG in 10,358 children recruited in paediatric hospitals across Germany from June 2020 to May 2021. Seropositivity increased from 2.0% (95% CI 1.6, 2.5) to 10.8% (95% CI 8.7, 12.9) in March 2021 with little change up to May 2021. Rates increased by migrant background (2.8%, 4.4% and 7.8% for no, one and two parents born outside Germany). Children under three were initially 3.6 (95% CI 2.3, 5.7) times more likely to be seropositive with levels equalising later. The ratio of seropositive cases per recalled infection decreased from 8.6 to 2.8. Since seropositivity exceeds the rate of recalled infections considerably, serologic testing may provide a more valid estimate of infections, which is required to assess both the spread and the risk for severe outcomes of SARS-CoV-2 infections.

Left atrial remodelling among Turner syndrome patients: novel insights from non-invasive 3D echocardiography.

Background: To assess (I) the left atrial (LA) size, function and (II) the impact of excess weight on the LA and left ventricular (LV) performance in Turner syndrome (TS) patients. Methods: Twenty-five TS patients without congenital heart disease (CHD) and 19 healthy, age-matched controls underwent three-dimensional echocardiography (3DE) for LA volume measurements and two-dimensional speckle tracking echocardiography (2DSTE) for LA strain measurements. LV performance was measured through LV Tei-index, indexed isovolumetric contraction (ICT/√RR interval), indexed relaxation (IVRT/√RR interval) and indexed filling time (FT/√RR interval). Results: Compared to healthy controls, normal-weight TS patients (n=16) displayed significantly increased heart rate (92.88±16.66 vs. 76.53±15.65 bpm; P=0.005), reduced indexed LV filling time (11.67±2.55 vs. 15.16±5.07; P=0.018), reduced 3D maximum LA volume at LV end systole/BSA (16.74±5.00 vs. 19.89±4.32 mL/m2; P=0.05), reduced 3D LA total emptying volume/BSA [10.04 (5.05/18.46) vs. 13.11 (7.69/18.46) mL/m2; P=0.001] and reduced 3D LA active emptying volume/BSA [2.61 (0.1/3.82) vs. 3.44 (1.64/6.37) mL/m2; P=0.006]. Compared to normal-weight TS patients, overweight/obese TS patients (n=9) showed impaired LV Tei-index [0.38 (0.26/0.55) vs. 0.27 (0.07/0.41); P=0.009], prolonged indexed IVRT (2.04±0.72 vs. 1.30±0.64; P=0.015), prolonged indexed ICT [1.96 (1.57/2.73) vs. 1.29 (0.35/2.69); P=0.009] and increased 3D LA active emptying volume/BSA (3.38±1.21 vs. 2.29±1.07 mL/m2; P=0.032). Conclusions: Normal-weight TS patients with increased heart rate and reduced LV filling time display subtle LV diastolic dysfunction in the form of reduced LA reservoir and pump function. Manifested systolic and diastolic LV dysfunction among overweight TS patients is partially compensated through an increase in LA active pump function.

Insights from circulating microRNAs in cardiovascular entities in turner syndrome patients.

BACKGROUND: Turner syndrome (TS) is a chromosomal disorder, in which a female is partially or entirely missing one of the two X chromosomes, with a prevalence of 1:2500 live female births. The present study aims to identify a circulating microRNA (miRNA) signature for TS patients with and without congenital heart disease (CHD). METHODS: Microarray platform interrogating 2549 miRNAs were used to detect the miRNA abundance levels in the blood of 33 TS patients and 14 age-matched healthy volunteer controls (HVs). The differentially abundant miRNAs between the two groups were further validated by RT-qPCR. RESULTS: We identified 60 differentially abundant miRNA in the blood of TS patients compared to HVs, from which, 41 and 19 miRNAs showed a higher and a lower abundance levels in TS patients compared to HVs, respectively. RT-qPCR confirmed the significantly higher abundance levels of eight miRNAs namely miR-374b-5p, miR-199a-5p, miR-340-3p, miR-125b-5p, miR-30e-3p, miR-126-3p, miR-5695, and miR-26b-5p in TS patients as compared with the HVs. The abundance level of miR-5695 was higher in TS patients displaying CHD as compared to TS patients without CHD (p = 0.0265; log2-fold change 1.99); whereas, the abundance level of miR-126-3p was lower in TS patients with congenital aortic valve disease (AVD) compared to TS patients without BAV (p = 0.0139, log2-fold change 1.52). The clinical feature statistics revealed that miR-126-3p had a significant correlation with sinotubular junction Z-score (r = 0.42; p = 0.0154). CONCLUSION: The identified circulating miRNAs signature for TS patients with manifestations associated with cardiovascular diseases provide new insights into the molecular mechanism of TS that may guide the development of novel diagnostic approaches.

Assessment of left ventricular myocardial work in Turner syndrome patients: insights from the novel non-invasive pressure-strain loop analysis method.

BACKGROUND: Turner syndrome (TS), a relatively rare chromosomal disease, is associated with multiple cardiovascular risk factors that possibly lead to increased left ventricular afterload and functional impairment. The aim of this study was to investigate whether alterations in myocardial work and work efficiency can be found in TS patients through left ventricular pressure-strain loop analysis (PSL). METHODS: Thirty-eight patients with TS and 19 healthy, age-matched controls were recruited for this study. Global peak systolic strain (GLPS) and PSL of the left ventricle was assessed in study participants. TS patients whose history included coarctation of the aorta or prior cardiac surgery were excluded from GLPS and PSL analyses (n=5). RESULTS: Median age was 16.00 years in the TS group and 16.35 years in the control group (P=0.236). GLPS did not show significant differences between both groups (P=0.524). TS patients demonstrated, compared to controls, a significantly higher global myocardial work index (BSA) (mean ± SD: 1,497±505 vs. 1,214±245 mmHg*%/m2; P=0.027). Heart rate was significantly increased in TS patients, compared to controls (mean ± SD: 90.08±14.79 vs. 73.95±15.05 bpm; P<0.001), and correlated significantly with global myocardial work index [body surface area (BSA)] within the TS cohort (r=0.558, P=0.001). CONCLUSIONS: TS patients showed signs of increased myocardial workload that were only detectable through the novel PSL analysis method and not through GLPS. Moreover, elevated resting heart rate was linked with increased myocardial workload in TS patients. Further studies will have to investigate whether TS patients may develop advanced left ventricular systolic dysfunction later in life.

Left ventricular remodelling among Turner syndrome patients: insights from non-invasive 3D echocardiography-derived pressure-volume loop analysis.

BACKGROUND: Turner syndrome (TS) is a X-chromosomal disease affecting one in 2500-3000 female newborns. TS individuals are at high cardiovascular risk and more likely to be overweight or obese. The aim of this study was to assess left ventricular performance in TS patients through three-dimensional speckle tracking echocardiography (3DSTE) and non-invasive left ventricular pressure-volume loop (PVL) analysis. Moreover, this study focused on the impact of excess weight on the left ventricular efficiency in TS patients. METHODS: Thirty-six TS patients and 19 healthy age-matched controls were included in this study. 3DSTE and non-invasive left ventricular PVL analysis were performed and left ventricular efficiency parameters were calculated. RESULTS: TS patients had significantly lower values than controls in longitudinal strain (- 16.67 ± 3.23% vs. - 18.47 ± 1.87%; p = 0.029), but significantly higher values for arterial elastance (BSA) (3.31, 1.87-5.88 mmHg/mL vs. 2.99, 2.31-4.61 mmHg/mL; p = 0.011) and cardiac work (BSA) (292,070 ± 71,348 mmHg*mL*HR vs. 248,595 ± 70,510 mmHg*mL*HR; p = 0.036). Compared with normal weight patients, overweight and obese TS subjects demonstrated worse left ventricular efficiency (175.08 ± 17.73 mmHg vs. 157.24 ± 26.75 mmHg; p = 0.037). Even after excluding TS patients with cardiovascular morbidity, arterial elastance (BSA) was compared to healthy peers, significantly increased in TS patients. CONCLUSIONS: 3DSTE and non-invasive left ventricular PVL analysis might be useful tools to detect early cardiac changes in TS. Arterial elastance seems to be significantly increased in TS patients, independent of cardiovascular morbidity. Compared with normal weight TS patients, overweight/obese TS patients displayed lower left ventricular efficiency.

Two-dimensional speckle tracking of the abdominal aorta: a novel approach to evaluate arterial stiffness in patients with Turner syndrome.

BACKGROUND: Turner syndrome (TS) is an X-chromosomal disease affecting one in 2,500-3,000 female newborns. Girls and women with TS show multiple cardiovascular risk factors that all have an impact on arteriosclerosis and thus arterial stiffness. An accurate and non-invasive screening of arterial stiffness is essential to improve the overall outcome in these patients. METHODS: Thirty-five TS patients and 19 healthy, age-matched controls were prospectively recruited for this study. Arterial stiffness was measured at the abdominal aorta in subxiphoid view using two-dimensional speckle tracking (2DST). Acquisition was performed at a frame rate of 60-90 fps. Mean peak circumferential strain (AAO-S, %) was measured offline for respective layers (inner layer = AAO-SENDO, %; middle layer = AAO-SMESO, %; outer layer = AAO-SEPI, %). RESULTS: Compared with the control group, patients with TS showed significantly lower peak circumferential strain values in each layer [AAO-SENDO (mean ± SD): 10.98%±4.73% vs. 15.32%±4.78%, P=0.002; AAO-SMESO (mean ± SD): 6.36%±2.22% vs. 9.18%±2.83%, P<0.001; AAO-SEPI (mean ± SD): 4.49%±1.76% vs. 6.31%±2.53%, P=0.003]. Abdominal aortic strain values correlated significantly with left ventricular diastolic function assessed by mitral early (E) and late (A) flow ratio (AAO-SENDO and E/A: r=0.475, P<0.001; AAO-SMESO and E/A: r=0.504, P<0.001; AAO-SEPI and E/A: r=0.393, P=0.003). Heart rate correlated significantly negative with 2DST assessed arterial distensibility (r=-0.366; P=0.007). Relative intra- and interobserver variability ranged between 8.67% and 21.03% for 2DST of the abdominal aorta. CONCLUSIONS: 2DST of the abdominal aorta might provide additional diagnostic value to detect possible functional vascular impairments in patients with TS. Left ventricular diastolic function is coupled with increased arterial stiffness in TS patients. The relatively high intra- and interobserver variability of 2DST of the abdominal aorta requires further improvement of the speckle tracking algorithm.

Dermatologische Aspekte aus der S2k-Leitlinie zum Down-Syndrom im Kindes- und Jugendalter.

Das Down-Syndrom (DS) ist mit einer Inzidenz von 1 : 700 aller Geburten nicht selten und mit diversen Erkrankungen unterschiedlicher Organsysteme assoziiert. Zu den schwerwiegenden Erkrankungen zählen Herzfehler und Leukämie. Letztere zeigt sich im Neugeborenenalter und geht nicht immer in eine klassische myeloische Leukämie über (transiente myeloproliferative Erkrankung). Dermatologisch bilden die Neugeborenen Pusteln/Vesikulopusteln, die bei DS nicht nur an typische Neugeborenenexantheme und Infektionen, sondern auch an die transiente myeloproliferative Erkrankung denken lassen sollten. Die meisten Dermatosen jedoch sind benigner Natur und umfassen im Wesentlichen Verhornungsstörungen, die sich als Xerosis, Keratosis pilaris, Lichenifikation und Ichthyosis vulgaris zeigen. Typisch, aber nicht spezifisch, ist auch die palmare Vierfingerfurche. Die Patienten neigen häufig zu Follikulitiden, die aufgrund einer Elastolyse in eine Anetodermie übergehen. Die bekannte Immundysbalance erklärt das Auftreten von Autoimmunerkrankungen, die sich an der Haut als Alopecia areata und Vitiligo manifestieren. Als typische Hautveränderungen bei DS zählen zudem Elastosis perforans serpiginosa, Syringome, Milien-ähnliche Calcinosis cutis (Milia-like calcinosis cutis) und Multiple eruptive Dermatofibrome.

Dermatological aspects of the S2k guidelines on Down syndrome in childhood and adolescence.

With an incidence of 1 in 700 births, Down syndrome (DS) is not an uncommon condition. It is associated with various disorders of different organ systems. Serious disorders include cardiac defects and leukemia. With an onset during the newborn period, the latter does not always progress to classic myeloid leukemia (transient myeloproliferative disorder). Skin manifestations in newborns include pustules/vesiculopustules. In individuals with DS, such lesions should not only prompt suspicion for typical neonatal rashes and infections but also for transient myeloproliferative disorder. However, most dermatoses are benign. They essentially comprise disorders of keratinization that present as xerosis, keratosis pilaris, lichenification, and ichthyosis vulgaris. Also typical but not specific is the four-finger palmar crease (simian crease). Patients frequently develop folliculitides, which - due to elastolysis - subsequently progress to anetoderma. The known immune disturbance in DS patients explains the occurrence of autoimmune diseases such as alopecia areata and vitiligo. Typical skin conditions associated with DS include elastosis perforans serpiginosa, syringomas, milia-like calcinosis cutis, and multiple eruptive dermatofibromas.

Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature.

Short stature is a common pediatric disorder affecting 3% of the population. However, the clinical variability and genetic heterogeneity prevents the identification of the underlying cause in about 80% of the patients. Recently, heterozygous mutations in the ACAN gene coding for the proteoglycan aggrecan, a main component of the cartilage matrix, were associated with idiopathic short stature. To ascertain the prevalence of ACAN mutations and broaden the phenotypic spectrum in patients with idiopathic short stature we performed sequence analyses in 428 families. We identified heterozygous nonsense mutations in four and potentially disease-causing missense variants in two families (1.4%). These patients presented with a mean of -3.2 SDS and some suggestive clinical characteristics. The results suggest heterozygous mutations in ACAN as a common cause of isolated as well as inherited idiopathic short stature.

Genetic Polymorphisms as Predictive Markers of Response to Growth Hormone Therapy in Children with Growth Hormone Deficiency.

Objective Growth hormone (GH) deficiency (GHD) is commonly treated with recombinant human GH (rhGH). Individual response to rhGH therapy varies widely and there is evidence that variations in growth-related genes, e. g. the GH receptor (GHR) gene, may impact treatment response. We aimed to identify genetic polymorphisms which could serve as predictive markers of response to rhGH therapy. Methods We conducted a genetic analysis of single nucleotide polymorphisms (SNPs) and the GHR exon 3 deletion in 101 paediatric GHD patients receiving rhGH. Patients were analysed for 13 known SNPs in 11 genes of the GH axis (SOS1, IGFR1, GAB1, LHX4, IGFBP3, GRB10, GHRHR, GHSR), growth plate (VDR, ESR1) and cell cycle (CDK4). Individual index of responsiveness (IoR) values were compared by genotype. We also analysed the potential association between the IoR and the GHR exon 3 deletion. IoRs were analysed by genotype by one-way analysis of variance and unpaired t-test. Results Variations in two SNPs, rs2888586 (SOS1) and rs2069502 (CDK4), and the GHR exon 3 deletion were significantly associated with response to rhGH treatment. Conclusions Genetic variations are potentially suitable as predictive markers of rhGH treatment response in GHD. Genetic analysis provides a starting point for individualised treatment of GHD.

Down Syndrome: Gestational Age-Related Neonatal Anthropometrics for Germany.

BACKGROUND: Neonates with Down syndrome (DS) weigh less, are smaller and have increased first-year mortality, especially if born small for gestational age (GA). DS-specific GA-related neonatal anthropometrics for Germany are lacking. OBJECTIVES: To construct reference tables and centile curves for birth weight (g), crown-heel length (cm) and head circumference (cm) by sex and GA for German DS neonates. METHODS: Retrospective anthropometric data from live-born singleton DS neonates born in Germany from January 1966 to June 2010 were collected using standardized questionnaires and patient records. Reference tables were created based on means and standard deviations. The 3rd, 10th, 25th, 50th, 75th, 90th and 97th centile curves were constructed and smoothed using running medians and Cole's LMS method. RESULTS: Anthropometric measurements were obtained for 1,304 DS neonates [males/females: 713/591 (54.7%/45.3%)]. Reference tables and centile charts were constructed from 3,542 (males/females: 1,932/1,610) observations for GA 32-41 weeks. Compared with general-population newborns, prematurity was increased (21.1 vs. 6.3%) at GA 32-36 weeks. Term-born (GA 40 weeks) male and female DS neonates were 352.5 and 223.5 g lighter and 1.5 and 1.4 cm smaller than general-population neonates, and head circumference was also 1.4 and 1.5 cm smaller, respectively. CONCLUSION: This is the first study to report GA-related, sex-specific reference tables and centile charts of birth weight, length and head circumference for DS neonates born in Germany. Compared with the general German population, DS newborns are more frequently born prematurely, weigh less, are smaller and have a smaller head circumference at birth.