Dermatological manifestations, management, and care in RASopathies

Abstract

RASopathies are rare genetic disorders caused by germline pathogenic variants in genes belonging to the RAS/MAPK pathway, which signals cell proliferation, differentiation, survival and death. The dysfunction of such signaling pathway causes syndromes with overlapping clinical manifestations. Skin and adnexal lesions are the cardinal clinical signs of RASopathies, such as cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, Costello syndrome, neurofibromatosis (NF1), Legius syndrome, Noonan-like syndrome with loose anagen hair (NSLH) and Noonan syndrome. As NF1, one of the most common RASopathies, described in 1882, has its clinical features well delineated, we will focus on the dermatological diagnosis, management and care of non-NF1 RASopathies, which are less known and more recently described. Dermatological manifestations are important clinical diagnostic elements that can aid differential diagnosis among RASopathies. They can affect dermis and epidermis, causing pigmented lesions (melanocytic nevi, café-au-lait spots, and lentigines), hyperkeratosis (keratosis pilaris, ulerythema ophryogenes, and palmoplantar keratosis) or hyperplasia. To date there are rare known links to malignancy, but oftentimes skin lesions require close attention because they can highly affect quality of life.

The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic–Therapeutic Implications

“…The most common manifestations are sparse, curly, fine, brittle slow-growing hair; sparse to absent eyebrows with ulerythema ophryogenes; sparse to absent eyelashes; dystrophic rapid-growing nails; skin abnormalities such as keratosis pilaris, hyperkeratosis, ichthyosis, eczemas, xerosis, hemangiomas and numerous pigmented naevi (more common in patients with BRAF mutations) [33][34][35][36]. Some skin anomalies evolve with age: xerosis and follicular hyperkeratosis can improve [37], palmoplantar hyperkeratosis tends to worsen, especially in pressure areas, lymphedema may become more severe, and pigmented naevi [38,39] tend to grow in number [40].…”