RASopathies: Dermatologists’ viewpoints

Abstract

Ras/mitogen-activated protein kinase pathway dysregulation results in a group of disorders, collectively termed as RASopathies. Neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome/loose anagen hair, Legius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome and capillary malformation-arteriovenous malformation are the well-recognized RASopathies. These are characterized by multi-organ tumours and hamartomas. Some other features in common are facial dysmorphism, skeletal abnormalities, congenital heart disease, neurocognitive abnormalities and risk of various solid-organ and haematological malignancies. Some of the RASopathies are heterogeneous, caused by several gene mutations resulting in variations in phenotypes and severity ranging from mild to fatal. Significant phenotypic overlaps among different disorders, often makes it difficult to pinpoint a clinical diagnosis. Specific cutaneous manifestations are present in some of the RASopathies and are often the earliest clinical signs/symptoms. Hence, dermatologists contribute significantly as primary care physicians by identifying disorder-specific cutaneous lesions. However, diagnostic work-up and management of these disorders are often multidisciplinary. Confirmation of diagnosis is possible only by genetic mapping in each case. Genetic counseling of the patients and the affected families is an important component of the management. The aim of this review is description of cutaneous manifestations of RASopathies in the background of multi-system involvement to enable dermatologists a comprehensive and logical approach to work up and diagnose such patients in the absence of facility for specific molecular testing.

Paternally Inherited Noonan Syndrome Caused by a PTPN11 Variant May Exhibit Mild Symptoms: A Case Report and Literature Review

“…Growth delay leading to short stature is observed in more than 50% of patients, with heights falling below the 25th percentile for their age. Other clinical characteristics include sensorineural hearing loss (approximately 20%), ID (around 30%, typically in mild forms), and abnormal electrocardiography (seen in approximately 25% of cases) [25,26]. A literature review of NS patients with PTPN11 p.Arg498Trp found that eight cases were genetically confirmed by genetic test [3,12,13,[16][17][18].…”

Dermatological manifestations, management, and care in RASopathies

“…Pathogenic variants in more than 10 genes may result in NS phenotype, with variants on PTPN11, SOS1, RAF1, RIT 1 and KRAS being identified in 90% of cases. Clinical 1) (Bessis, Miquel, et al, 2019;Palit & Inamadar, 2020;Quaio et al, 2013). Lymphatic anomalies are common in NS, lymphedema of lower limbs, sometimes accompanied by lymphedema of genitals has been described in 15 cases and is the most common lymphatic postnatal anomaly (Sleutjes et al, 2022).…”

“…Patients with classical NS may have subtle to moderate cutaneous and related manifestations, including low posterior hairline, palmoplantar hyperkeratosis, café‐au‐lait spots, lentigines and pigmented nevi. Multiple lentigines, >3 café‐au‐lait spots, keratosis pilaris, ulerythema ophryogenes, sparse scalp hair and sparse or absent eyelashes and brows are more consistently associated with PTPN11 pathogenic variants (Table 1) (Bessis, Miquel, et al, 2019; Palit & Inamadar, 2020; Quaio et al, 2013). Lymphatic anomalies are common in NS, lymphedema of lower limbs, sometimes accompanied by lymphedema of genitals has been described in 15 cases and is the most common lymphatic postnatal anomaly (Sleutjes et al, 2022).…”

RASopathies: Evolving Concepts in Pathogenetics, Clinical Features, and Management

“…Cutaneous features and other manifestations are dynamic in these syndromes and manifestations vary according to age. [ 6 ] Cutaneous,[ 1 2 7 18 19 20 ] extracutaneous manifestations,[ 1 2 7 18 19 20 ] and diagnostic criteria[ 21 22 23 ] for various RASopathies are summarized in Table 2 , Table 3 , and Table 4 , respectively. More studies are required for phenotype and genotype correlation.…”

“…[ 26 ] NS due to KRAS mutations shares features with CS and CFCS. Mutations in RAF1 are characterized by hypertrophic cardiomyopathy (HOCM), significant intellectual disability,[ 27 ] laryngomalacia, hoarse cry,[ 7 ] and pigmented lesions, while patients with mutations in BRAF have melanocytic nevi and lentigines. Patients having mutations in CBL have a higher risk of myeloproliferative disorders.…”