Mosaic RASopathies: comprehensive genetic and clinicopathological analysis for diagnosis and management

Abstract

Mosaic RASopathies are rare conditions caused by postzygotic mutations arising during embryonic development in genes of the RAS/MAPK signaling pathway. They are mainly characterized by a combination of epidermal nevi and extracutaneous manifestations. Distinguishing between different entities can be challenging because of their substantial clinical and genetic overlap. Our aim was to demonstrate the importance of genetic background for accurate diagnosis and further prognostic assessment of disease progression by analyzing genotype–phenotype correlations within this clinical group. The study enrolled 18 patients (10 male and 8 female patients) ranging in age from 1 month to 21 years with congenital craniofacial nevi and variable extracutaneous abnormalities. DNA isolated from peripheral blood leukocytes and affected tissues (nevus and tumor) was analyzed using a targeted next-generation sequencing (NGS) panel covering RAS/MAPK pathway genes, followed by Sanger sequencing. Eight patients were diagnosed with Schimmelpenning–Feuerstein–Mims syndrome caused by postzygotic pathogenic/likely pathogenic variants in the HRAS (n = 4) or KRAS (n = 4) genes. Seven patients were clinically diagnosed with phacomatosis pigmentokeratotica (PPK), and mosaic genetic variants were identified in the HRAS (n = 4), KRAS (n = 2), or BRAF (n = 1) genes. In two additional patients with similar phenotypes, somatic mutations in PIK3CA (n = 1) and FGFR2 (n = 1) were identified in affected skin, while in one further case, no clinically significant variant was detected. We compared the spectrum of extracutaneous anomalies according to the affected gene by combining our data with data from other clinical cases of mosaic RASopathies described in the literature. In summary, 53 cases with HRAS postzygotic variants and 41 cases with KRAS variants were included in the analysis of genotype–phenotype correlations. Hypophosphatemic rickets (HR) and malignant tumors were associated with pathogenic/likely pathogenic variants in the HRAS gene, while ophthalmological, neurological, cardiovascular, and renal disorders were more common in KRAS -mutant patients. Thus, genetic testing of affected tissue in comparison to normal tissue (peripheral blood) is essential for accurate diagnosis of these mosaic disorders. Consideration of clinical manifestations and the identified genotype–phenotype correlations may further assist in determining prognosis and guiding patient management.