Allometric considerations when assessing aortic aneurysms in Turner syndrome: Implications for activity recommendations and medical decision‐making

Corbitt, Holly; Maslen, Cheryl L.; Prakash, Siddharth K.; Morris, Shaine A.; Silberbach, Michael

doi:10.1002/ajmg.a.38584

Cited by 9 publications

(3 citation statements)

References 17 publications

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“…We tested this hypothesis using a whole exome sequencing study of individuals from the GenTAC registryTurner syndrome cohort, with and without BAV. (Eagle & GenTAC Investigators, 2009;Kroner et al, 2011) We used BAV status and aortic Z-scores as the phenotypic variables for the analysis (Corbitt, Maslen, Prakash, Morris, & Silberbach, 2018;Quezada, Lapidus, Shaughnessy, Chen, & Silberbach, 2015), with aortic enlargement with a Z-score of greater than 2 as a proxy for aortic aneurysm formation. The whole exome sequencing on 188 Turner syndrome samples was done by the NHLBI Resequencing and Genotyping Service at the University of Washington.…”

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confidence: 99%

The genetic basis of Turner syndrome aortopathy

Corbitt

Gutierrez

Silberbach

et al. 2019

American J of Med Genetics Pt C

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Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC registry. A gene-based burden test, SKAT-O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z-scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome-wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13-fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.

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confidence: 99%

The genetic basis of Turner syndrome aortopathy

Corbitt

Gutierrez

Silberbach

et al. 2019

American J of Med Genetics Pt C

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“…Therefore, Quezada et al recently introduced the TSZ-score formula by using healthy girls and women with TS as reference populations (based on 481 individuals with TS aged 3–70 years who underwent echocardiography examinations) [ 13 ]. Since ascending aortic ASI is age-dependent for individuals under 15 years, the TSZ-score may aid decision-making to some extent, leading to its gradual recommendation by guidelines [ 3 , 22 , 23 ]. However, due to racial differences (with East Asians commonly exhibiting lower BSA than Caucasians), the TSZ-score tends to underestimate aortic lesions in the Chinese TS population.…”

Section: Discussionmentioning

confidence: 99%

Assessment of aortic dilatation in Chinese children and adolescents with Turner syndrome: a single center experience

Su,

Sun,

et al. 2024

BMC Pediatr

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Background Patients with Turner syndrome (TS) face an increased risk of developing aortic dilatation (AD), but diagnosing AD in children presents greater complexity compared to adults. This study aimed to investigate the application of various assessment indicators of AD in Chinese children and adolescents with TS. Methods This study included TS patients admitted to Shenzhen Children’s Hospital from 2017 to 2022. Cardiovascular lesions were diagnosed by experienced radiologists. Patients without structural heart disease were divided into different body surface area groups, then the Chinese TS population Z-score (CHTSZ-score) of the ascending aorta was calculated and compared with other indicators such as aortic size index (ASI), ratio of the ascending to descending aortic diameter (A/D ratio), and TSZ-score (Quezada’s method). Results A total of 115 TS patients were included, with an average age of 10.0 ± 3.7 years. The incidences of the three most serious cardiovascular complications were 9.6% (AD), 10.4% (coarctation of the aorta, CoA), and 7.0% (bicuspid aortic valve, BAV), respectively. The proportion of developing AD in TS patients aged ≥ 10 years was higher than that in those < 10 years old (16.6% vs. 1.8%, P = 0.009), and the proportion of patients with CoA or BAV who additionally exhibited AD was higher than those without these conditions (31.6% vs. 5.2%, P < 0.001). The ASI, A/D ratio, TSZ-score, and CHTSZ-score of the 11 patients with AD were 2.27 ± 0.40 cm/m2, 1.90 ± 0.37, 1.28 ± 1.08, and 3.07 ± 2.20, respectively. Among the AD patients, only 3 cases had a TSZ-score ≥ 2, and 2 cases had a TSZ-score ≥ 1. However, based on the assessment using the CHTSZ-score, 6 patients scored ≥ 2, and 5 patients scored ≥ 1. In contrast, the TSZ-score generally underestimated the aortic Z-scores in Chinese children with TS compared to the CHTSZ-score. Conclusions The applicability of ASI and A/D ratio to children with TS is questionable, and racial differences can affect the assessment of TSZ-score in the Chinese population. Therefore, establishing the CHTSZ-score specifically tailored for Chinese children and adolescents is of paramount importance.

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“…Ascending aorta dilatation is clearly impacted by age (Corbitt, Maslen, Prakash, Morris, & Silberbach, 2018; Duijnhouwer et al, 2018; Olsson, Thelin, Ståhle, Ekbom, & Granath, 2006), and the development of dissection generally is not seen until the fourth decade of life. The relatively young age of this cohort at diagnosis and follow‐up time period may not have allowed for significant enough aortic growth to detect a treatment difference.…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and rate of dilatation in Turner syndrome patients treated for aortic dilatation

Pater

Gutmark‐Little

Tretter

et al. 2020

American J of Med Genetics Pt A

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Turner syndrome is associated with an increased risk of aortic aneurysms and dissection. Recent 2017 clinical care guidelines recommend medical therapy to treat aortic dilatation, although whether this slows dilatation is unknown. We aimed to describe a pre‐guideline cohort of Turner syndrome patients with aortic dilatation, the rate of dilatation following diagnosis, and post therapy dilatation rates. We conducted a retrospective review of Turner syndrome patients with a dilated aortic root or ascending aorta by current definitions. In total, 40 patients were included with 22 treated patients. Most patients had 45,X karyotype, were white, non‐Hispanic, and received both growth hormone and estrogen. Except for hypertension, there were no differences in risk factors among treated and untreated groups. Bicuspid aortic valve was very common. Treatment group patients had significantly more dilated ascending aortas by absolute measurements and aortic size index. In an adjusted model, there was minimal change in aortic measures over time and this was not associated with medication use. In conclusion, in this cohort, Turner syndrome patients with aortic dilatation were more likely to be treated if they had hypertension and if they met multiple dilatation criteria. Further study is needed to establish medical therapy efficacy on dilatation progression.

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Allometric considerations when assessing aortic aneurysms in Turner syndrome: Implications for activity recommendations and medical decision‐making

Cited by 9 publications

References 17 publications

The genetic basis of Turner syndrome aortopathy

The genetic basis of Turner syndrome aortopathy

Assessment of aortic dilatation in Chinese children and adolescents with Turner syndrome: a single center experience

Clinical characteristics and rate of dilatation in Turner syndrome patients treated for aortic dilatation

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