Dermatological manifestations in Costello syndrome: A prospective multicentric study of 31 HRAS‐positive variant patients

Abstract

AbstractBackgroundData on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description.ObjectivesTo describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype–genotype correlations.MethodsWe performed a 10‐year, large, prospective, multicentric, collaborative dermatological and genetic study.ResultsThirty‐one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and ‘cobblestone’ papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype–genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S).Conclusions and RelevanceThis validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.