Publications by authors named "Siddharth K Prakash"

56 Publications

Aortic root dilatation and dilated cardiomyopathy in an adult with Tatton-Brown-Rahman syndrome.

Am J Med Genet A 2021 Oct 13. Epub 2021 Oct 13.

Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Texas, USA.

Tatton-Brown-Rahman syndrome is an autosomal dominant overgrowth syndrome caused by pathogenic DNMT3A variants in the germline. Clinical findings of tall stature due to postnatal overgrowth, intellectual disability, and characteristic facial features, are the most consistent findings observed in patients with Tatton-Brown-Rahman syndrome (TBRS). Since the syndrome was first described in 2014, an expanding spectrum of neuropsychiatric, musculoskeletal, neurological, and cardiovascular manifestations have been reported. However, most TBRS cases described in the literature are children with de novo DNMT3A variants, signaling a need to better characterize the phenotypes in adults. In this report, we describe a 34 year old referred to genetics for possible Marfan syndrome with aortic root dilatation, mitral valve prolapse, and dilated cardiomyopathy, who was diagnosed with TBRS due to a heterozygous de novo DNMT3A variant. This represents the third reported TBRS case with aortic root dilation and the second with cardiomyopathy. Collectively, these data provide evidence for an association with aortic disease and cardiomyopathy, highlight the clinical overlap with Marfan syndrome, and suggest that cardiovascular surveillance into adulthood is indicated.
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http://dx.doi.org/10.1002/ajmg.a.62541DOI Listing
October 2021

International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Radiol Cardiothorac Imaging 2021 Aug 22;3(4):e200496. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes. ©  2021 Jointly between the RSNA, the European Association for Cardio-Thoracic Surgery, The Society of Thoracic Surgeons, and the American Association for Thoracic Surgery. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. All rights reserved. Bicuspid Aortic Valve, Aortopathy, Nomenclature, Classification.
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http://dx.doi.org/10.1148/ryct.2021200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424700PMC
August 2021

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.

PLoS Genet 2021 07 29;17(7):e1009679. Epub 2021 Jul 29.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.
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http://dx.doi.org/10.1371/journal.pgen.1009679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354477PMC
July 2021

International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

J Thorac Cardiovasc Surg 2021 Sep 22;162(3):e383-e414. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1016/j.jtcvs.2021.06.019DOI Listing
September 2021

Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional, and research purposes.

J Thorac Cardiovasc Surg 2021 09 22;162(3):781-797. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada; aeCedars Sinai Heart Institute, Los Angeles, Calif; afDivision of Cardiology, Columbia University Irving Medical Center/NY Presbyterian Hospital, New York, NY.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1016/j.jtcvs.2021.05.008DOI Listing
September 2021

Summary: International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Ann Thorac Surg 2021 09 22;112(3):1005-1022. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1016/j.athoracsur.2021.05.001DOI Listing
September 2021

International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Ann Thorac Surg 2021 09 22;112(3):e203-e235. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.119DOI Listing
September 2021

International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

Eur J Cardiothorac Surg 2021 09;60(3):448-476

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1093/ejcts/ezab038DOI Listing
September 2021

Summary: international consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

Eur J Cardiothorac Surg 2021 09;60(3):481-496

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1093/ejcts/ezab039DOI Listing
September 2021

In-hospital outcomes and long-term survival of women of childbearing age with aortic dissection.

J Vasc Surg 2021 Oct 20;74(4):1135-1142.e1. Epub 2021 Apr 20.

Department of Cardiothoracic and Vascular Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, Tex. Electronic address:

Objective: In the present study, we defined the outcomes and effects of pregnancy in a cohort of women of childbearing age with acute aortic dissection (AAD).

Methods: We reviewed our database of AAD to identify all eligible female patients. Women aged <45 years were included. Data on pregnancy timing with respect to the occurrence of dissection, the demographic data, dissection extent, dissection treatment, dissection-related outcomes, overall maternal and fetal mortality, and genetic testing results were analyzed.

Results: A total of 62 women aged <45 years had presented to us with AAD from 1999 to 2017. Of the 62 women, 37 (60%) had had a history of pregnancy at AAD. Of these 37 patients, 10 (27%) had had a peripartum aortic dissection, defined as dissection during pregnancy or within 12 months postpartum. Of the 10 AADs, 5 were type A and 5 were type B. Three patients had presented with AAD during pregnancy (one in the second and two in the third trimester). Five patients (50%) had developed AAD in the immediate postpartum period (within 3 months) and two (20%) in the late postpartum period. For the immediate postpartum AADs (<3 months), four of the five patients delivered via cesarean section. Of these 10 peripartum AADs, 3 (30%) had occurred in patients with known Marfan syndrome. In-hospital mortality for those with peripartum AAD was 10% (1 of 10). Fetal mortality was 20% (2 of 10).

Conclusions: The frequency of aortic dissection in women of childbearing age at our institution was low. However, pregnancy might increase the risk of those young women genetically predisposed to dissection events. From these data, this risk appears to be greatest in the immediate postpartum period, even for those who undergo cesarean section. Close clinical and radiographic surveillance is required for all women with suspected aortopathy, especially in the third trimester and early postpartum period.
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http://dx.doi.org/10.1016/j.jvs.2021.03.028DOI Listing
October 2021

An unusual cause of acute pericarditis: a case report.

Eur Heart J Case Rep 2021 Feb 4;5(2):ytaa535. Epub 2021 Jan 4.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 6.106, Houston, TX 77030, USA.

Background: Inflammation of the pericardium, or pericarditis, is a frequent cause of acute chest pain in young patients. Pericarditis is typically associated with viral infections, but other potential causes may have distinct prognostic and therapeutic implications.

Case Summary: A 26-year-old man presented with typical signs and symptoms of acute pericarditis. However, imaging disclosed an anterior mediastinal mass that compressed the right ventricular outflow tract. The coarse outflow murmur convincingly mimicked a pericardial friction rub on auscultation.

Conclusion: Clinicians should be aware of alternative aetiologies to pericarditis in patients who present with prolonged or refractory symptoms.
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http://dx.doi.org/10.1093/ehjcr/ytaa535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954249PMC
February 2021

Rare deleterious variants of NOTCH1, GATA4, SMAD6, and ROBO4 are enriched in BAV with early onset complications but not in BAV with heritable thoracic aortic disease.

Mol Genet Genomic Med 2020 10 3;8(10):e1406. Epub 2020 Aug 3.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Bicuspid aortic valve (BAV) is the most common cardiovascular malformation in adults, with a prevalence of 0.5%-2%. The prevalence of BAV in cohorts who were ascertained due to thoracic aortic aneurysms or acute aortic dissections (TAD) is as high as 20%. However, the contribution of causal BAV genes to TAD is not known. Therefore, we evaluated rare deleterious variants of GATA4, NOTCH1, SMAD6, or ROBO4 in patients with BAV who presented with TAD.

Methods: Our cohort consisted of 487 probands with Heritable Thoracic Aortic Aneurysms or Dissections (HTAD, 12% BAV, 29% female) and 63 probands with Early onset complications of Bicuspid Aortic Valve disease (EBAV, 63% TAD, 34% female). After whole exome sequencing, we functionally annotated GATA4, NOTCH1, SMAD6, and ROBO4 variants and compared the prevalence of rare variants in these genes to controls without HTAD.

Results: We identified 11 rare deleterious variants of GATA4, SMAD6, or ROBO4 in 12 (18%) EBAV cases. The burden of rare SMAD6 and GATA4 variants was significantly enriched in EBAV but not in HTAD cases, even among HTAD cases with BAV (p < .003).

Conclusion: Rare variants of NOTCH1, ROBO4, SMAD6, or GATA4 do not significantly contribute to BAV in cohorts with HTAD. We conclude that BAV patients who present with HTAD are a genetically distinct subgroup with implications for genetic testing and prognosis.
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http://dx.doi.org/10.1002/mgg3.1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549564PMC
October 2020

Nosology Spectrum of the Bicuspid Aortic Valve Condition: Complex-Presentation Valvulo-Aortopathy.

Circulation 2020 07 20;142(3):294-299. Epub 2020 Jul 20.

Divisions of Cardiovascular Medicine and Medical Genetics, Department of Internal Medicine, University of Texas Health Science Center at Houston (S.K.P.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046892DOI Listing
July 2020

Genetics in bicuspid aortic valve disease: Where are we?

Prog Cardiovasc Dis 2020 Jul - Aug;63(4):398-406. Epub 2020 Jun 27.

Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address:

Bicuspid aortic valve (BAV) is the most common congenital heart defect, found in up to 2% of the population and associated with a 30% lifetime risk of complications. BAV is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity due to a complex genetic architecture that involves many interacting genes. In this review, we highlight the current state of knowledge about BAV genetics, principles and methods for BAV gene discovery, clinical applications of BAV genetics, and important future directions.
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http://dx.doi.org/10.1016/j.pcad.2020.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530017PMC
October 2020

TGFBR1 Rare Variant Associated With Thoracic Aortic Aneurysm, Double Chamber Left Ventricle, Coronary Anomaly, and Inducible Ventricular Tachycardia.

Circ Cardiovasc Imaging 2020 06;13(6):e010084

Division of Cardiology (K.B.-J., N.B.M., D.R., S.N., I.A.E., D.K., R.W.S., S.K.P.), Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston.

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http://dx.doi.org/10.1161/CIRCIMAGING.119.010084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285880PMC
June 2020

Ulnar Artery Aneurysm as a Late Sequela of Marfan Syndrome.

J Hand Surg Am 2020 Nov 22;45(11):1090.e1-1090.e5. Epub 2020 Mar 22.

Department of Surgery, Division of Plastic Surgery, University of Texas Health Sciences Center at Houston, Houston, TX.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations of the FBN1 gene encoding fibrillin-1, which leads to overexpression of transforming growth factor-β, increased hyaluronan deposition, and matrix metalloproteinase activity in the media of the aorta and other muscular arteries. Marfan syndrome patients present with connective tissue laxity and aneurysmal changes to muscular arteries. Successful medical and surgical intervention has prolonged the life expectancy of MFS patients, which can allow atypical presentations of the syndrome to manifest. We present a case of a 49-year-old man with MFS who developed an ulnar artery aneurysm that was treated by excision and vein grafting.
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http://dx.doi.org/10.1016/j.jhsa.2020.01.010DOI Listing
November 2020

Clinical Characteristics and Long-Term Outcomes of Midaortic Syndrome.

Ann Vasc Surg 2020 Jul 7;66:318-325. Epub 2020 Jan 7.

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Texas Health Science Center Houston, McGovern Medical School, Memorial Hermann Hospital - Heart and Vascular Institute, Houston, TX. Electronic address:

Background: Midaortic syndrome (MAS) is a rare congenital or acquired condition marked by segmental or diffuse stenosis of the distal thoracic and/or abdominal aorta and its branches. The optimal approach to medical or interventional management of MAS and long-term outcomes in adults are not well defined. We reviewed MAS cases to characterize the natural history of aortic disease, identify prognostic factors, and evaluate the durability of invasive interventions.

Methods: We conducted a retrospective review of patients with MAS who presented to Memorial Hermann Hospital and Baylor College of Medicine between 1997 and 2018. We categorized cases according to demographic and clinical manifestations, etiologies, the extent of aortic involvement, interventions, and vascular outcomes.

Results: We identified a cohort of 13 patients with MAS. The etiology of MAS was identified in 6 cases, including genetic syndromes (neurofibromatosis type 1 (2/13), Williams syndrome (1/13), fibromuscular dysplasia (2/13), and Takayasu arteritis (1/13)). Mean age at first documented clinical event was 25.2 (2-67) years, but cases with genetic etiologies presented significantly younger (18.2 years). The most common primary anatomic site was the suprarenal and infrarenal aorta (zones 5-8). Extra-aortic locations involved the renal (4/13), celiac (3/13), and superior mesenteric (3/13) arteries. Clinical manifestations included hypertension (13/13), claudication (9/13), and postprandial abdominal pain (5/13). All patients with available follow-up data underwent at least one surgical or endovascular intervention (range: 1-8). Postoperative complications included renal failure requiring postdischarge hemodialysis and respiratory failure. There were no deaths in long-term follow-up.

Conclusions: MAS is a complex vasculopathy with substantial variability in clinical presentation and anatomic distribution. Extensive disease frequently requires multiple invasive interventions and results in refractory hypertension, which may predict subsequent clinical events. A multidisciplinary approach with long-term monitoring is essential for preservation of end-organ function and quality of life in this debilitating disease.
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http://dx.doi.org/10.1016/j.avsg.2019.12.039DOI Listing
July 2020

Surgical repair of bicuspid aortopathy at small diameters: Clinical and institutional factors.

J Thorac Cardiovasc Surg 2020 06 22;159(6):2216-2226.e2. Epub 2019 Aug 22.

Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Tex. Electronic address:

Objective: Bicuspid aortic valve is a common risk factor for thoracic aortic aneurysm and dissection. Guidelines for elective ascending aortic intervention (AAI) in bicuspid aortic valve are derived from limited evidence, and the extent of practice variation due to patient and provider characteristics is unknown. Using data from 2 large cardiovascular registries, we investigated factors that influence decisions for AAI.

Methods: All bicuspid aortic valve cases with known aortic diameters and surgical status were included. We used multivariable logistic regression to profile predictors of isolated aortic valve replacement (AVR) or AVR+AAI, stratified by patient characteristics, surgical indications, and institution.

Results: We studied 2861 subjects at 18 institutions from 1996 to 2015. The median aortic diameter of patients who underwent AVR+AAI varied widely across institutions (39-52 mm). Aortic diameters were <45 mm in 38% of patients undergoing AVR+AAI. Patients who underwent AAI at <45 mm, compared with those managed nonoperatively, were younger (54 ± 13 vs 61 ± 15 years; P < .001) with more frequent aortic stenosis (53% vs 28%; P < .001) and regurgitation (52% vs 18%; P < .001).

Conclusions: Clinical and institutional factors influence the timing of AAI and are associated with significant variability in ascending aortic diameter at AAI across institutions. More than one third of patients with a bicuspid aortic valve undergo AAI at aortic diameters <45 mm. Long-term outcomes of this subgroup of patients, who may manifest earlier and more severe disease, are needed to determine the risk-benefit ratio of routine aortic interventions at smaller diameters.
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http://dx.doi.org/10.1016/j.jtcvs.2019.06.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035185PMC
June 2020

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years.

Am J Med Genet A 2019 10 16;179(10):1987-2033. Epub 2019 Aug 16.

Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.

Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review.
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http://dx.doi.org/10.1002/ajmg.a.61310DOI Listing
October 2019

Prevalence and clinical characteristics of inappropriate myocardial perfusion imaging tests at a community hospital.

BMJ Open Qual 2019 10;8(3):e000487. Epub 2019 Jul 10.

Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.

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http://dx.doi.org/10.1136/bmjoq-2018-000487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629399PMC
July 2019

Misclassification of bicuspid aortic valves is common and varies by imaging modality and patient characteristics.

Echocardiography 2019 04 4;36(4):761-765. Epub 2019 Mar 4.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas.

Background: Bicuspid aortic valve (BAV) is the most prevalent adult congenital heart defect. BAV causes lifelong progressive disease that can be prevented by early diagnosis and long-term surveillance, but may be compromised by misclassification of valve morphology.

Methods: The study population was derived from the UTHealth Bicuspid Aortic Valve Registry, which includes serial images on more than 200 participants over a mean follow-up interval of 2.8 years. We abstracted descriptions of aortic valve morphology from transthoracic or transesophageal echocardiography, computed tomography angiography, and magnetic resonance angiography reports. We used chi-square and t tests to determine associations between reported valve morphologies (definitely bicuspid, possibly bicuspid, tricuspid, or uncertain) and clinical characteristics and assessed image quality using a validated tool.

Results: About 40% of participants were misclassified in at least one imaging report. The mean interval between misclassification and correct diagnosis was 22 months. TEE, MR and CT were more sensitive than TTE and successfully reclassified 20% of participants, but were only used in 14% of patients. Misclassification was associated with age, the extent of valve calcification and image quality, but was not significantly associated with aortic regurgitation, gender, or cusp configuration.

Conclusion: Misclassification of BAV is prevalent, frequently leads to delayed diagnosis, and is more likely to occur in the most severely affected cases. TEE, CT and MR may increase diagnostic accuracy in up to half of BAV cases but are underutilized. Additional studies are needed to determine if misclassification of BAV patients leads to increased long-term morbidity and mortality.
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http://dx.doi.org/10.1111/echo.14295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532050PMC
April 2019

The impact of somatic mosaicism on bicuspid aortic valve and aortic dissection in Turner Syndrome.

Am J Med Genet C Semin Med Genet 2019 03 27;181(1):7-12. Epub 2019 Feb 27.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 6.106, Houston, Texas.

Somatic mosaicism is a major modifier of turner syndrome (TS) features and may be more prevalent than once thought, as new molecular techniques enable detection of tissue-specific mosaicism. This review explores the causes of mosaicism, discusses how mosaicism may impact congenital aortic defects in TS, and summarizes molecular methods to detect mosaicism in different contexts.
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http://dx.doi.org/10.1002/ajmg.c.31691DOI Listing
March 2019

The Turner syndrome research registry: Creating equipoise between investigators and participants.

Am J Med Genet C Semin Med Genet 2019 03 13;181(1):135-140. Epub 2019 Feb 13.

Division of Pediatric Cardiology, Department of Pediatrics, Oregon Health & Science University, Oregon, Portland.

To address knowledge gaps about Turner syndrome (TS) associated disease mechanisms, the Turner Syndrome Society of the United States created the Turner Syndrome Research Registry (TSRR), a patient-powered registry for girls and women with TS. More than 600 participants, parents or guardians completed a 33-item foundational survey that included questions about demographics, medical conditions, psychological conditions, sexuality, hormonal therapy, patient and provider knowledge about TS, and patient satisfaction. The TSRR platform is engineered to allow individuals living with rare conditions and investigators to work side-by-side. The purpose of this article is to introduce the concept, architecture, and currently available content of the TSRR, in anticipation of inviting proposals to utilize registry resources.
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http://dx.doi.org/10.1002/ajmg.c.31689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425061PMC
March 2019

"Donating our bodies to science": A discussion about autopsy and organ donation in Turner syndrome.

Am J Med Genet C Semin Med Genet 2019 03 11;181(1):36-42. Epub 2019 Jan 11.

Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts.

At the Third Turner Resource Network Symposium, a working group presented the results of collaborative discussions about the importance of autopsy in Turner syndrome (TS). Considerable gaps in understanding the causes of death in TS can only be closed by more frequent death investigations and autopsies. The presentation included an overview of autopsy methods, strategies for utilizing autopsy, and biobanking to address research questions about TS, and the role of palliative care in the context of autopsy. This review highlights strategies to promote autopsy and tissue donation, culminating with an action plan to increase autopsy rates in the TS community.
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http://dx.doi.org/10.1002/ajmg.c.31671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414237PMC
March 2019

45,X mosaicism in a population-based biobank: implications for Turner syndrome.

Genet Med 2019 08 21;21(8):1882-1883. Epub 2018 Dec 21.

Medical Genetics Unit, Department of Pediatrics, MassGeneral Hospital for Children, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41436-018-0411-zDOI Listing
August 2019

Aortic arch tortuosity, a novel biomarker for thoracic aortic disease, is increased in adults with bicuspid aortic valve.

Int J Cardiol 2019 06 17;284:84-89. Epub 2018 Oct 17.

Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 1.150, Houston, TX 77030, USA. Electronic address:

Introduction: Arterial tortuosity has emerged as a predictor of adverse outcomes in congenital aortopathies using 3D reconstructed images. We validated a new method to estimate aortic arch tortuosity on 2D CT. We hypothesize that arch tortuosity may identify bicuspid aortic valve (BAV) patients at high risk to develop thoracic aortic aneurysms or aortic dissections (TAD).

Methods: BAV subjects with chest CT scans were retrospectively identified in our clinical records and matched to tricuspid aortic valve (TAV) controls by age, gender, and presentation with TAD. Subjects with prior ascending aortic intervention were excluded. Measurements included aortic arch tortuosity, length, angle, width and height. Total aortic tortuosity was estimated in subjects with available abdominal images.

Results: 120 BAV and 234 TAV subjects were included. Our 2D measurements were highly correlated with 3D midline arch measurements and had high inter- and intra-observer reliability. Compared to TAV, BAV subjects had increased arch tortuosity (median 1.76 [Q1-Q3: 1.62-1.95] vs. 1.63 [1.53-1.78], P < 0.01), length (149 [136-160] vs. 135 [122-152] mm, P < 0.01), height (46 [41-53] vs. 39 [34-47] mm, P < 0.01), and vertex acuity (70 [61-77] vs. 75 [68-81] degree, P < 0.01). In a multivariable analysis, arch tortuosity remained independently associated with BAV after adjusting for aortic diameter and other clinical characteristics.

Conclusions: We found that aortic arch tortuosity is significantly increased in BAV and may identify BAV patients who are at increased risk for TAD. Further studies to evaluate the association between tortuosity and clinical outcomes are in progress.
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http://dx.doi.org/10.1016/j.ijcard.2018.10.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436988PMC
June 2019

Cardiovascular Health in Turner Syndrome: A Scientific Statement From the American Heart Association.

Circ Genom Precis Med 2018 10;11(10):e000048

Girls and women with Turner syndrome face a lifelong struggle with both congenital heart disease and acquired cardiovascular conditions. Bicuspid aortic valve is common, and many have left-sided heart obstructive disease of varying severity, from hypoplastic left-sided heart syndrome to minimal aortic stenosis or coarctation of the aorta. Significant enlargement of the thoracic aorta may progress to catastrophic aortic dissection and rupture. It is becoming increasingly apparent that a variety of other cardiovascular conditions, including early-onset hypertension, ischemic heart disease, and stroke, are the major factors reducing the life span of those with Turner syndrome. The presentations and management of cardiovascular conditions in Turner syndrome differ significantly from the general population. Therefore, an international working group reviewed the available evidence regarding the diagnosis and treatment of cardiovascular diseases in Turner syndrome. It is recognized that the suggestions for clinical practice stated here are only the beginning of a process that must also involve the establishment of quality indicators, structures and processes for implementation, and outcome studies.
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http://dx.doi.org/10.1161/HCG.0000000000000048DOI Listing
October 2018

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.

Am J Hum Genet 2018 04;102(4):706-712

Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA. Electronic address:

The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs25 and p.Glu750) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.
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http://dx.doi.org/10.1016/j.ajhg.2018.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985335PMC
April 2018

X Marks the Spot: The Profound Impact of Sex on Aortic Disease.

Arterioscler Thromb Vasc Biol 2018 01;38(1):9-11

From the Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston.

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http://dx.doi.org/10.1161/ATVBAHA.117.310433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751955PMC
January 2018
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