Cardiac Manifestations and Associations with Gene Mutations in Patients Diagnosed with RASopathies

Abstract

RASopathies are a group of syndromes caused by germline mutations of the RAS/MAPK pathway. They include Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, and Noonan syndrome with multiple lentigines, which share many characteristic features including cardiac abnormalities. Here, we retrospectively reviewed the clinical manifestations and evaluated the genotype-phenotype associations with special focus on cardiac lesions of the patients with RASopathies. Cardiac symptoms were the most common initial presentation (27 %), except for admission to neonatal intensive care. Although there was a significant gap between the first visit to the hospital and the diagnosis of the genetic syndrome (19.9 ± 39.1 months), the age at the clinical diagnosis of the genetic syndrome was significantly lower in patients with CHD than in patients without CHD (47.26 ± 67.42 vs. 86.17 ± 85.66 months, p = 0.005). A wide spectrum of cardiac lesions was detected in 76.1 % (118/155) of included patients. The most common lesion was pulmonary stenosis, followed by atrial septal defect and hypertrophic cardiomyopathy (HCMP). About half of the pulmonary stenosis and HCMP patients progressed during the median follow-up period of 109.9 (range 9.7-315.4) months. Early rapid aggravation of cardiac lesions was linked to poor prognosis. MEK1, KRAS, and SOS1 mutations tend to be highly associated with pulmonary stenosis. Cardiologists may play important roles in early detection and diagnosis of RASopathies as well as associated CHDs. Due to the variety of clinical presentations and their progression of severity, proper management with regular long-term follow-up of these patients is essential.

Pediatric Cardiomyopathies

“…24–27 Genetic variants causing cardiomyopathy in children can also have systemic features affecting noncardiac organs. 28, 29 The RASopathies, including Noonan syndrome, are the most well-known syndromic causes of pediatric cardiomyopathy. 29 Inborn errors of metabolism ( CPT2 deficiency in DCM) and storage disorders (Pompe disease with HCM) are associated with childhood-onset cardiomyopathy.…”

“…28, 29 The RASopathies, including Noonan syndrome, are the most well-known syndromic causes of pediatric cardiomyopathy. 29 Inborn errors of metabolism ( CPT2 deficiency in DCM) and storage disorders (Pompe disease with HCM) are associated with childhood-onset cardiomyopathy. Congenital myopathies can present during childhood with both skeletal and heart muscle involvement; Duchenne muscular dystrophy is a classic example.…”

Diagnosis of Cardiomyopathies: Tips and Tricks for Internists and General Practitioners

“…In these last some typical features are present: a rapid upstroke and downstroke to the arterial pulse; an ejection systolic murmur due to LVOT obstruction (LVOTO) or to systolic anterior movement of the mitral valve (SAM). 23 Other non-cardiovascular signs and symptoms that may suggest a specific cause of HCM are (Table 1): dysmorphorphic face in genetic syndrome such as Danon disease; 3,21,[24][25][26][27] visual impairment in mitochondriopathies; 3,28 palpebral ptosis in mitochondriopathies and myotonic dystrophy; 3,28 sensorineural deafness in mitochondriopathies and Fabry disease; 3,28,29 angiokeratomata in Fabry; 3,29 sensory abnormality and bilateral carpal tunnel syndrome in amyloidosis. 3 The electrocardiogram is typically abnormal in patients with HCM and is often the earliest manifestation, warranting further diagnostic evaluation and having a prognostic role.…”

Co‐occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death

“…Pulmonary stenosis (PS) (57%) is the most common type of CHD in individuals with NS, followed by atrial septal defect (ASD; 32%), and HCM (16%) 10, 1110, 11, 12, 13.…”

“…Pulmonary stenosis (PS) (57%) is the most common type of CHD in individuals with NS, followed by atrial septal defect (ASD; 32%), and HCM (16%). 10,11 PTPN11 mutations are predominantly associated with PS and ASD, while HCM is less prevalent. [10][11][12][13] HCM is associated with mutations in exons 7 and 12 of PTPN11.…”