Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, ...including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10(-7)), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91-178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57-99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.
Background
The risk of aortic complications associated with pregnancy in women with Marfan syndrome (MFS) is not fully understood.
Methods and Results
MFS women participating in the large National ...Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) were evaluated. Among 184 women with MFS in whom pregnancy information was available, 94 (51%) had a total of 227 pregnancies. Among the women with pregnancies, 10 (10.6%) experienced a pregnancy‐related aortic complication (4 type A and 3 type B dissections, 1 coronary artery dissection, and 2 with significant ≥3 mm aortic growth). Five of 7 aortic dissections, including all 3 type B, and the coronary dissection (75% of all dissections) occurred in the postpartum period. Only 5 of 8 women with pregnancy‐associated dissection were aware of their MFS diagnosis. The rate of aortic dissection was higher during the pregnancy and postpartum period (5.4 per 100 person‐years vs 0.6 per 100 person‐years of nonpregnancy; rate ratio, 8.4 95% CI=3.9, 18.4; P<0.0001).
Conclusions
Pregnancy in MFS is associated with an increased risk of aortic dissection, both types A and B, particularly in the immediate postpartum period. Lack of knowledge of underlying MFS diagnosis before aortic dissection is a major contributing factor. These findings underscore the need for early diagnosis, prepregnancy risk counseling, and multidisciplinary peripartum management.
Anatomically Oriented Right Ventricular Volume Measurements With Dynamic Three-Dimensional Echocardiography Validated by 3-Tesla Magnetic Resonance Imaging Petra S. Niemann, Luiz Pinho, Thomas ...Balbach, Christian Galuschky, Michael Blankenhagen, Michael Silberbach, Craig Broberg, Michael Jerosch-Herold, David J. Sahn The right ventricle (RV) is anatomically complex, and although magnetic resonance imaging (MRI) has been used to evaluate its anatomy and function, the accuracy of 3-dimensional/4-dimensional (4D) echocardiography (echo) for evaluating the RV has not been clearly established. We studied normal subjects and others with congenital heart disease both by 4D echo and with a multiplanar set of cine magnetic resonance images. Results from both studies could be analyzed with the same anatomically oriented new RV analysis software method. The method was easily and reproducibly used for evaluation of the RV both by MRI and 4D echo, documenting the accuracy of 4D echo for RV volume determination when compared with multiplanar MRI.
Abstract Marfan Syndrome (MFS) is an autosomal dominant connective tissue disease associated with acute aortic dissection (AAD). We used two large registries that include MFS patients to investigate ...possible trends in the chronobiology of AAD in MFS. We queried the International Registry of Acute Aortic Dissection (IRAD) and the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) registry to extract data on all patients with MFS who had suffered an AAD. The group included 257 patients with MFS who suffered an AAD between 1980 and 2012. Chi-square tests were used for statistical testing. Mean subject age at time of AAD was 38 years and 61% of subjects were male. AAD was more likely in the winter/spring season (Nov-Apr) than the other half of the year (57% vs. 43%, p=0.05). Dissections were significantly more likely to occur during the daytime hours, with 65% of dissections occurring from 6AM to 6PM (p=0.001). Males were more likely to dissect during the daytime hours (6AM-6PM) than females (74% vs. 51%, p=0.01). These insights offer a glimpse of the times of greatest vulnerability for MFS patients who suffer from this catastrophic event. In conclusion, the chronobiology of AAD in MFS reflects that of AAD in the general population.
Turner syndrome (TS), a genetic condition affecting roughly 1 in 2,000 females, is caused by a complete or partial loss of the second sex chromosome. This special issue of the American Journal of ...Medical Genetics Part C is a collection of research and clinical care reviews in TS from an international group of physician and scientist leaders who attended the 2018 "Turner Network Resource Symposium: Turner Science in the 21st Century", held in Arlington Virginia, July 15th-17th, 2018. Both this special issue and the 2018 Symposium are fueled by two rationales. First, inadequate attention has been given to health and psychosocial problems in girls and women with TS; and second, that an understanding of TS might shed light on the role of sex chromosome dosage in common conditions such as heart disease and autoimmune disease. These seminars interweave multiple themes: the fundamental partnership between participants with rare diseases and researchers, new knowledge regarding clinical care in TS, and an understanding of the "molecular phenotype" of TS-associated conditions.
Cardiac malformations occur commonly in Turner syndrome (TS), but the outcomes of cardiac operations and catheter-based procedures are unknown. The Pediatric Cardiac Care Consortium database was ...queried for individuals with TS and other female subjects without genetic abnormalities or syndromes (non-TS NTS). Procedures for left-sided heart lesions represented most TS procedures (95.2%). Three hundred ninety-eight patients with TS who underwent 637 of these procedures of interest were compared with 25,913 female NTS subjects who underwent 56,625 procedures. The numbers of procedures per admission (1.47 vs 1.61, p = 0.01) and per patient (1.85 vs 2.16, p <0.0001) were significantly lower in patients with TS. Procedures for cyanotic heart disease other than hypoplastic left heart (HLH) were performed 4.5-fold less frequently in patients with TS. Patients with TS and NTS subjects had equivalent hospital lengths of stay, except for patients with TS who underwent hypoplastic aortic arch operations, patent ductus arteriosus ligation, pulmonary artery balloon dilation, balloon atrial septostomy, and catheter closure of atrial septal defects. There were 34 deaths among patients with TS and 1,795 among NTS subjects (8.6% vs 7.2%, p = 0.30). When HLH was excluded, mortality was lower in the TS group (3.9% vs 6.5%, p = 0.05). Operations for partial anomalous pulmonary venous connection (14.3% vs 1.9%, p = 0.03) and HLH (90.4% vs 70.5%, p = 0.08) were more likely to result in death in patients with TS. In conclusion, given generally comparable lengths of stay and numbers of procedures as well as uniformly excellent results, these data suggest that the diagnosis of TS does not increase the utilization of limited health care resources. Operations for HLH and partial anomalous pulmonary vein connection carry additional risk for those with TS. These results will permit risk stratification, prognostication, and counseling of individuals with TS and their families.
Girls and women with Turner syndrome are at risk for aortic dissection and rupture. However, the size of the aorta and the clinical characteristics among those with Turner syndrome and dissection ...have received little attention.
We obtained medical records from 20 individuals who voluntarily participated in the International Turner Syndrome Aortic Dissection Registry. Type A dissections occurred in 17 of 20 (85%) cases, and type B occurred in 3 cases of which 1 occurred after coarctation stent placement. Of those with spontaneous aortic dissections, 18 of 19 (95%) had an associated cardiac malformation that included a bicuspid aortic valve. In 1 individual there was no predisposing finding other than the presence of Turner syndrome. Associated pregnancy was documented in 1 of 19 (5%). More than half (13/19, 68%) came to medical attention >24 hours after the onset of symptoms. For those with type A dissections, the mean ascending aortic size index was 2.7±0.6 cm/m(2) (n=9).
Aortic dissection in Turner syndrome occurs in young individuals at smaller aortic diameters than in the general population or other forms of genetically triggered aortopathy. The absence of aortic valve or other cardiac malformations appears to markedly reduce the risk of aortic dissection However, aortic dissection can occur in Turner syndrome without cardiac malformations or hypertension. Individuals with Turner syndrome who are >18 years of age with an ascending aortic size index >2.5 cm/m(2) should be considered for an aortic operation to prevent aortic dissection.
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