RASopathies and the skin

Abstract

Patients with complex health problems present to various consultants, including dermatologists, who may be unaware of other clinical features or their potential links. Those who do suspect an association will usually refer to a clinical geneticist, traditionally the go-to specialists for syndromes. The RASopathies are particularly complex and beyond the diagnostic repertoire of many dermatologists. Cardiofaciocutaneous (CFCS), Noonan (NS) and Costello (CS) syndromes can affect the heart, nervous system, skeleton and skin, sometimes with cancer susceptibility and dysmorphic features that may be subtle. Furthermore, the RASopathies overlap both phenotypically and genetically: features of CFCS are found in NS and CS, while CFCS can be caused by mutations in genes responsible for NS and CS. To make things more difficult, the skin manifestations of the RASopathies are generally nonspecific and poorly defined. Dermatologists confidently attach genetic significance to ashleaf macules, axillary freckles and multiple basal cell carcinomas. However, curly hair, eczema and keratosis pilaris are far too common to suggest a genetic diagnosis and even if suspicions are raised, the literature on RASopathies proves unhelpful. Most is written by nondermatologists and lacks clear descriptions of the cutaneous manifestations. For example, geneticists unfamiliar with ulerythema ophryogenes might record ‘sparse eyebrows’ or ‘erythema’. The only way to establish whether common or nonspecific skin disorders are part of a syndrome is to examine as many patients with the syndrome as possible and to record their dermatological manifestations in a precise way. Bessis et al. did exactly this, reporting 45 patients with mutation-positive CFCS. They found that patients with CFCS were significantly more likely than healthy individuals to have keratosis pilaris, multiple melanocytic naevi, palmoplantar keratoderma, ulerythema ophryogenes, curly hair or lax skin. These authors also confirmed a dearth of precise dermatological descriptions in the RASopathy literature, the cutaneous components of CFCS being particularly unclear. There is increasing awareness of the importance of precise phenotypic descriptions. Dermatologists should be aware of the system adopted by geneticists generally, by the UK Hundred Thousand Genomes Project, and indeed by the European Reference Network for Rare Skin Diseases (ERN-Skin, http://skin.ern-net. eu/), namely the Human Phenotype Ontology (https://hpo.ja x.org/app/). The unanswered question here is how useful common cutaneous features can be diagnostically. Of course, we are not going to suspect a genetic disorder in all patients with keratosis pilaris or curly hair, but it is worth considering if the skin condition is unusually marked, absent in close family members or associated with other abnormalities. Some features are more helpful than others: ulerythema ophryogenes and lax skin are stronger pointers to genetic disease than are acne or eczema. Beyond the clinic, such genetic associations may provide insights into the pathogenesis of common dermatoses. This study underlines the need for dermatologists and geneticists to work together. Clinical geneticists cannot be familiar with all conditions in all organ systems and are increasingly devolving responsibility for genetic testing to other specialists. Dermatologists should welcome opportunities to participate with geneticists in multidisciplinary meetings and should encourage the use of correct dermatological terminology. The traditional referral pathway is changing direction.