What are RASopathies?

What are RASopathies?

RASopathies are a group of genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway [1]. Some RASopathies are quite familiar to us by their names already known to us! Of course it has nothing to do with the renin-angiotensin-system.  Names of RASopathies very  familiar to us are type 1 neurofibromatosis, Noonan syndrome and Noonan syndrome with multiple lentigines (formerly called LEOPARD Syndrome). Other less familiar ones are capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome and Legius syndrome.

RASopathies are one of the largest known groups of malformation syndromes, affecting almost one in a thousand individuals. Though the RASopathies have varying clinical presentations, they have several common features due to the Ras/MAPK pathway dysregulation. Cardiac malformations are one of them. This discussion will be focused only on cardiac malformations as other possible malformations are numerous.

Noonan syndrome is associated with a dysplastic pulmonary valve producing pulmonary stenosis. Hypertrophic cardiomyopathy is often associated [2]. The combination of hypertrophic cardiomyopathy right ventricular outflow tract obstruction should make one suspect underlying RASopathy. Other congenital cardiac lesions like atrial septal defect, atrioventricular septal defect, tetralogy of Fallot and patent ductus arteriosus have also been described. Noonan syndrome is an autosomal dominant disorder [1].

A study of cardiac manifestations in neurofibromatosis type 1 found cardiac abnormalities in 11 of the 65 patients. Five had mitral regurgitation, 2 had secundum atrial septal defect, one patient each had valvar pulmonary stenosis, ventricular septal defect, tricuspid regurgitation and aortic regurgitation [3].

Capillary malformation-arteriovenous malformation is caused by RASA1 mutations [4]. It is characterised by capillary malformations, arteriovenous malformation and arteriovenous fistula. Arteriovenous malformations cause overgrowth of the extremity (Parkes Weber syndrome).

Costello syndrome is a RASopathy caused by mutations in HRAS [5]. Associated cardiovascular abnormalities are pulmonary stenosis, hypertrophic cardiomyopathy, septal defects and aortic dilatation. Atrial arrhythmias may be seen in half of the patients. They are non-reentrant atrial tachycardias namely, ectopic atrial tachycardia and multifocal atrial tachycardia (MAT) or chaotic atrial tachycardia [6].

Cardio-facio-cutaneous syndrome is also associated with pulmonary stenosis, hypertrophic cardiomyopathy and septal defects [7]. Cardiovascular involvement is seen in three fourth of the cases of Cardio-facio-cutaneous syndrome. Among the septal defects, atrial septal defect is more common.

Legius syndrome resembles neurofibromatosis type 1 in that café-au-lait macules can be seen, but lack the risk of cancer [8]. It is caused by heterozygous mutations in SPRED1 gene. Mitral valve prolapse and paroxysmal atrial tachycardia have been reported rarely in Legius syndrome [9].

References

1. Rauen KA. The RASopathies. Annu Rev Genomics Hum Genet. 2013;14:355-69. doi: 10.1146/annurev-genom-091212-153523. Epub 2013 Jul 15. PMID: 23875798; PMCID: PMC4115674.
2. Digilio M, Marino B. Clinical manifestations of Noonan syndrome. Images Paediatr Cardiol. 2001 Apr;3(2):19-30. PMID: 22368597; PMCID: PMC3232501.
3. İncecik F, Hergüner ÖM, Alınç Erdem S, Altunbaşak Ş. Neurofibromatosis type 1 and cardiac manifestations. Turk Kardiyol Dern Ars. 2015 Dec;43(8):714-6. doi: 10.5543/tkda.2015.27557. PMID: 26717333.
4. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, Vanwijck R, Vikkula M. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003 Dec;73(6):1240-9. doi: 10.1086/379793. Epub 2003 Nov 24. PMID: 14639529; PMCID: PMC1180390.
5. Gripp KW, Morse LA, Axelrad M, Chatfield KC, Chidekel A, Dobyns W, Doyle D, Kerr B, Lin AE, Schwartz DD, Sibbles BJ, Siegel D, Shankar SP, Stevenson DA, Thacker MM, Weaver KN, White SM, Rauen KA. Costello syndrome: Clinical phenotype, genotype, and management guidelines. Am J Med Genet A. 2019 Sep;179(9):1725-1744. doi: 10.1002/ajmg.a.61270. Epub 2019 Jun 20. PMID: 31222966; PMCID: PMC8238015.
6. Levin MD, Saitta SC, Gripp KW, Wenger TL, Ganesh J, Kalish JM, Epstein MR, Smith R, Czosek RJ, Ware SM, Goldenberg P, Myers A, Chatfield KC, Gillespie MJ, Zackai EH, Lin AE. Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients. Am J Med Genet A. 2018 Aug;176(8):1711-1722. doi: 10.1002/ajmg.a.38854. Epub 2018 Jul 28. PMID: 30055033; PMCID: PMC6107379.
7. Pierpont ME, Magoulas PL, Adi S, Kavamura MI, Neri G, Noonan J, Pierpont EI, Reinker K, Roberts AE, Shankar S, Sullivan J, Wolford M, Conger B, Santa Cruz M, Rauen KA. Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2014 Oct;134(4):e1149-62. doi: 10.1542/peds.2013-3189. Epub 2014 Sep 1. PMID: 25180280; PMCID: PMC4179092.
8. Denayer E, Legius E. Legius Syndrome and its Relationship with Neurofibromatosis Type 1. Acta Derm Venereol. 2020 Mar 25;100(7):adv00093. doi: 10.2340/00015555-3429. PMID: 32147744.
9. Legius E, Stevenson D. Legius Syndrome. GeneReviews® [Internet]. Adam MP, Ardinger HH, Pagon RA, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2022.