Cardiac publications

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Cardiac publications

Cardiac imaging in RASopathies/mitogen activated protein kinase syndromes

Rita Gravino, Giuseppe Pacileo UOSD Cardiologia Riabilitativa Intensiva e Scompenso, Seconda Università di Napoli, Ospedale Monaldi, Napoli, Italy 

Abstract

RASopathies include a spectrum of disorders due to dysregulation of RAS/mitogen activated protein kinase pathway that plays an essential role in the control of the cell cycle and differentiation. As a consequence, its dysregulation has profound developmental consequences, in particular cardiac malformations. RASopathies with cardiac features are: Noonan syndrome, multiple lentigines syndrome, cardio-faciocutaneous syndrome, Costello syndrome, neurofibromatosis-1, Legius syndrome, neurofibromatosis- Noonan syndrome.

The former syndromes are associated with a high rate of cardiac involvement (60-85%) and 12 genes: PTPN11, SOS1, RAF1, KRAS, HRAS, BRAF, MEK1/MAP2K1, MEK2/MAP2K2, NRAS, SHOC2, CBL and SPRED1. Although the majority of these diseases are readily distinguishable in clinical terms, an integrated imaging study of the cardiac condition associated to RASopathies helps to better define risk assessment, surveillance, and management of these patients.

Introduction

RASopathies include a spectrum of disorders due to dysregulation of RAS/mitogen activated protein kinase (MAPK) pathway that plays an essential role in the control of the cell cycle and differentiation. As a consequence, its dysregulation has profound developmental consequences. Although each condition may exhibit unique phenotypic features, many share characteristic overlapping features may occur, including craniofacial dysmorphology, cardiac malformations and cutaneous, musculoskeletal and ocular abnormalities, varying degrees of neurocognitive impairment and, in some syndromes, an increased risk of developing cancer.1 RASopathies (or  neurocardiofaciocutaneous syndromes) with cardiac features are Noonan syndrome, multiple lentigines syndrome (LEOPARD), cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, neurofibromatosis- 1 (NF1), Legius syndrome (NF1-like), neurofibromatosis-Noonan syndrome (NFNS). The former syndromes are associated with a high rate of cardiac involvement (60- 85%) whereas cardiac abnormalities are infrequent in Legius and NF1. To date, 12 genes are associated with these spectrum of disease: PTPN11, SOS1, RAF1, KRAS, HRAS, BRAF, MEK1/MAP2K1, MEK2/MAP2K2, NRAS, SHOC2, CBL and SPRED1 (Table 1).2 These gene encode for Ras proteins, small guanosine nucleotide-bound GTPases which comprise a critical signaling hub within the cell.3 This high-gene heterogeneity account for variety of phenotypic features, leading to different syndromes. Although the majority of these diseases are readily distinguishable in clinical terms, with or without diagnostic criteria, none of them have any pathognomonic signs. Thus an integrated imaging study of the cardiac condition associated to RASopathies helps to better define risk assessment, surveillance, and management of these patients.

Clinical, Pathological, and Molecular Analyses of Cardiovascular Abnormalities in Costello Syndrome: A Ras/MAPK Pathway Syndrome

Angela E. Lin,1* Mark E. Alexander,2 Steven D. Colan,2 Bronwyn Kerr,3 Katherine A. Rauen,4,5 Jacqueline Noonan,6 Jeanne Baffa,7 Elizabeth Hopkins,8 Katia Sol-Church,9 Giuseppe Limongelli,10 Maria Christina Digilio,11 Bruno Marino,12 A. Micheil Innes,13 Yoko Aoki,14 Michael Silberbach,15 Marie-Ange Delrue,16 Susan M. White,17 Robert M. Hamilton,18 William O’Connor,19 Paul D. Grossfeld,20 Leslie B. Smoot,2 Robert F. Padera,21 and Karen W. ripp8

1Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts

2Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts

3Genetic Medicine, Academic Health Science Centre, Central Manchester Foundation Trust Manchester, UK

4Comprehensive Cancer Center, San Francisco, California

5Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, California

6Department of Pediatrics, University of Kentucky Medical Center, Lexington, Kentucky

7Nemours Cardiac Center, Wilmington, Delaware

8Division of Medical Genetics, Wilmington, Delaware

9Department of Biomedical Research, A.I. duPont Hospital for Children, Wilmington, Delaware

10Cardiology, Second University of Naples, Monaldi Hospital, Naples, Italy

11Medical Genetics, Bambino Gesu` Pediatric Hospital, Rome, Italy

12Department of Pediatrics, Pediatric Cardiology, La Sapienza University, Rome, Italy

13Department of Medical Genetics, University of Calgary, Calgary, Canada

14Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan

15Department of Pediatrics, Division of Cardiology, Doernbecher Children’s Hospital, Portland, Oregon

16Service de Genetique Medicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

17Genetic Health Services Victoria, Royal Children’s Hospital, Victoria, Australia

18Division of Cardiology, Hospital for Sick Children, Toronto, Canada

19Department of Pathology, University of Kentucky Medical Center, Lexington, Kentucky

20Department of Pediatrics, University of California, San Diego, California

21Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts

Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes (‘‘RASopathies’’). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients(44%), usually non-progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%),and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow-up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction.Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one-fourth of those with arrhythmia, but is generally self-limited in the remaining three-fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated.