1. RASopathies

Numerous genetic syndromes have been identified under the term RASopathies.1 These include Noonan syndrome, LEOPARD syndrome (Noonan with multiple lentigines syndrome), Costello syndrome, cardiofaciocutaneous syndrome, and neurofibromatosis-1. A common feature among these syndromes is mutations in the rat sarcoma-mitogen-activated protein kinase (Ras-MAPK) signal transduction pathway. Cardiac manifestations associated with RASopathies often include atrial septal defects (ASD), pulmonary valve stenosis, and hypertrophic cardiomyopathy.

a. Noonan syndrome

It is an autosomal dominant disorder characterised by facial dysmorphism, postnatal growth retardation, and a range of cardiac defects including atrial septal defects (ASD), pulmonary valve stenosis, hypertrophic cardiomyopathy, and tetralogy of Fallot. Approximately 50% to 80% of individuals with Noonan syndrome develop congenital heart disease.2 Cutaneous manifestations such as cutis verticis gyrate and lymphedema are also observed.. Several genes have been implicated in the causation of Noonan syndrome, including PTPN11 (found in 50% of cases), RAF1, KRAS, SOS1, MEK1 (MAP2K1), and BRAF. All of these genetic mutations lead to a gain of function in the Ras/MAPK signalling pathway.3

b. Noonan with multiple lentigines syndrome (LEOPARD syndrome)

It is an autosomal dominant genetic disorder which was previously known by the acronym LEOPARD syndrome (Lentigenes, ECG abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness). It occurs due to a missense mutation in the PTPN11 gene, which disrupt the neuroectodermal layers.4 Cutaneous findings include multiple lentigines involving the face, neck, and upper trunk with sparing of mucosal surfaces.5 Cardiac abnormalities associated with the syndrome can include pulmonic stenosis, hypertrophic cardiomyopathy, and, less commonly atrial septal defects (ASD), subaortic stenosis, mitral valve defects, and atrial myxoma. Additionally, patients may present with abnormal ECG findings.

c. Costello syndrome

This is an autosomal dominant genetic disorder caused by mutations in the Ras oncogenes HRAS or KRAS. It is characterised by short stature, feeding difficulties in infancy, failure to thrive, developmental delays, hypotonia, and joint laxity.6 Key cutaneous findings include periorificial papillomas, sparse curly hair, lax skin on the hands and feet, deep palmoplantar creases, and acanthosis nigricans. Cardiac manifestations in Costello syndrome often involve hypertrophic cardiomyopathy, pulmonary valve stenosis, supraventricular tachycardia, and arrhythmias.7

d. Cardiofaciocutaneous (CFC) syndrome

This is an autosomal dominant disorder caused by mutations in the Ras/MAPK pathway. The most common mutations occur in genes such as BRAF, MEK1, MEK2 and KRAS.8 Some of the cutaneous findings include sparse, curly, friable hair with the absence of eyebrows and eyelashes. Patients also experience keratosis pilaris, generalised ichthyosis-like scales, palmoplantar hyperkeratosis, ulerythema ophryogenes, melanocytic naevi, and eczema. In terms of cardiac manifestations, patients may have hypertrophic cardiomyopathy, atrial septal defects (ASD), patent ductus arteriosus (PDA), pulmonary valve stenosis, other valvular dysplasia, arrhythmias, and tetralogy of Fallot.9

e. Neurofibromatosis 1

This is a multisystem autosomal dominant disorder that occurs due to a mutation in the tumour suppressor gene, NF-1, located on the chromosome 17q encoding for neurofibromin.10 Cutaneous findings include café au lait macules, neurofibromas, axillary freckling, neurofibromas, and dysmorphic facial features.11 Cardiac manifestations such as hypertension secondary to aortic coarctation, pulmonic stenosis, and aortic valve stenosis have also been described.

2. Carney complex

Carney complex was previously known as LAMB (Lentigenes, Atrial myxoma, Mucocutaneous myxoma and Blue naevi) and NAME (Naevi, Atrial myxoma, Myxoid neurofibromas, and Ephelides). It is an either an autosomal dominant or X-linked disorder caused by mutations in the PRKAR1A gene.12 This condition is characterised by cutaneous features of lentigines similar to Noonan syndrome but also involves mucosal features. A key manifestation of the Carney complex is the presence of cardiac myxomas.

3. H syndrome

It is an autosomal recessive genodermatosis with progressive sclerodermoid cutaneous changes with overlying hypertrichosis and hyperpigmentation on thighs, limbs, and lower trunk.13 It is caused by a mutation in the SLC29A3 gene, which encodes the hENT3 nucleoside transporter.14 The H syndrome also includes Heart abnormalities, Hepatomegaly, Hypogonadism, Hallux valgus, Hyperglycemia, and decreased Height. Cardiac manifestations include mitral valve prolapse, atrial and ventricular septal defects (ASD, VSD) and cardiomegaly.