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Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies.

ABSTRACT: The RASopathies are a group of similar genetic syndromes with cardiovascular abnormalities, characteristic facial features, short stature, abnormalities of the skin and musculoskeletal system, and variable neurodevelopmental challenges. The most common cardiovascular abnormalities include pulmonary valvular stenosis and hypertrophic cardiomyopathy. Congenital polyvalvular disease (CPVD) refers to congenital dysplasia of two or more cardiac valves. We diagnosed a RASopathy in two individuals with CPVD and noted that CPVD in RASopathies has rarely been reported in the literature. Thus, we performed a retrospective chart review and literature review to investigate the association and characterize the phenotype of CPVD in the RASopathies. CPVD was present in 2.5% (n = 6/243) of individuals in our RASopathy cohort. Involvement of two cardiac valves, commonly the aortic and pulmonic valves, was seen in the majority of individuals (6/8; 75%) in our cohort, but only 27% (3/11) of reported CPVD and RASopathy cases in the literature. CPVD should be considered an associated cardiovascular phenotype of the RASopathies, which has implications for diagnosis and management.

SUBMITTER: Matalon DR

PROVIDER: S-EPMC8711298 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies.

Matalon Dena R DR Stevenson David A DA Bhoj Elizabeth J EJ Santani Avni B AB Keena Beth B Cohen Meryl S MS Lin Angela E AE Sheppard Sarah E SE Zackai Elaine H EH

American journal of medical genetics. Part A 20210308 5

The RASopathies are a group of similar genetic syndromes with cardiovascular abnormalities, characteristic facial features, short stature, abnormalities of the skin and musculoskeletal system, and variable neurodevelopmental challenges. The most common cardiovascular abnormalities include pulmonary valvular stenosis and hypertrophic cardiomyopathy. Congenital polyvalvular disease (CPVD) refers to congenital dysplasia of two or more cardiac valves. We diagnosed a RASopathy in two individuals with ...[more]

PMID: 33683002

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Project description:As binary switches, RAS proteins switch to an ON/OFF state during signaling and are on a leash under normal conditions. However, in RAS-related diseases such as cancer and RASopathies, mutations in the genes that regulate RAS signaling or the RAS itself permanently activate the RAS protein. The structural basis of this switch is well understood; however, the exact mechanisms by which RAS proteins are regulated are less clear. RAS/MAPK syndromes are multisystem developmental disorders caused by germline mutations in genes associated with the RAS/mitogen-activated protein kinase pathway, impacting 1 in 1,000-2,500 children. These include a variety of disorders such as Noonan syndrome (NS) and NS-related disorders (NSRD), such as cardio facio cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML, also known as LEOPARD syndrome). A frequent manifestation of cardiomyopathy (CM) and hypertrophic cardiomyopathy associated with RASopathies suggest that RASopathies could be a potential causative factor for CM. However, the current supporting evidence is sporadic and unclear. RASopathy-patients also display a broad spectrum of congenital heart disease (CHD). More than 15 genes encode components of the RAS/MAPK signaling pathway that are essential for the cell cycle and play regulatory roles in proliferation, differentiation, growth, and metabolism. These genes are linked to the molecular genetic pathogenesis of these syndromes. However, genetic heterogeneity for a given syndrome on the one hand and alleles for multiple syndromes on the other make classification difficult in diagnosing RAS/MAPK-related diseases. Although there is some genetic homogeneity in most RASopathies, several RASopathies are allelic diseases. This allelism points to the role of critical signaling nodes and sheds light on the overlap between these related syndromes. Even though considerable progress has been made in understanding the pathophysiology of RASopathy with the identification of causal mutations and the functional analysis of their pathophysiological consequences, there are still unidentified causal genes for many patients diagnosed with RASopathies.

Project description:Background and objectiveAs more children with congenital heart disease survive to adulthood, adult congenital heart disease (ACHD) prevalence will increase (currently ~1 million US patients). Heart failure (HF) accounts for 26-42% of ACHD deaths. The rate of ACHD heart transplantations (ACHD HTx) is also increasing. We describe the ACHD HTx recipient/candidate cohort, analyze ACHD HTx outcomes, identify ACHD HTx specific challenges, and discuss opportunities to better serve more patients with ACHD HF.MethodsPubMed literature search including articles published from 2010-2023. Reviewed 89 studies, 67 included. Our search focused on the challenges of ACHD HTx and potential solutions.Key content and findingsACHD HTx recipients are young [median age 35 years, interquartile range (IQR): 24-46 years]. 87-95% of ACHD HTx recipients had prior cardiac surgery. The most common underlying diagnoses include transposition of the great arteries (31%) and Fontan/Glenn circulation (28%). 63% of listed ACHD HTx candidates received a transplant within one year of listing. Post-transplant 1-year survival is 80%, 5-year survival 74%, and 10-year survival 59%. There are 4 unique ACHD HTx challenges: (I) difficulty in assessing pulmonary hypertension, resulting in some centers selecting oversized donor hearts. However, selecting oversized hearts does not improve post-operative mortality and could prolong waitlist time. (II) Increased immunologic sensitization, increasing rejection risk. Desensitization therapy has enabled sensitized HTx recipients to enjoy outcomes similar to non-sensitized recipients. (III) Procedural complexity with ~30% of cases requiring additional surgical reconstruction. Detailed multidisciplinary planning, extensive imaging, and transferring the patient into the operating room early can help manage the complexities and reduce organ ischemic time. (IV) Increased intraoperative bleeding due to patients' surgical histories and circulatory collaterals. Preoperative collateral coil embolization and select utilization of hypothermic circulatory arrest can help reduce bleeding. Additional Fontan specific challenges include extensive great artery repair, liver failure, plastic bronchitis, and protein loss enteropathy. Finally, given limited donor heart availability, mechanical circulatory support is a promising technology for patients with ACHD HF.ConclusionsThe prevalence of ACHD HTx is slowly but steadily increasing. The operational complexity of ACHD HTx can be managed, and the majority of recipients have excellent outcomes (59% 10-year survival).

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Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies.

Publications

Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies.

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