Mosaic RASopathies concept: different skin lesions, same systemic manifestations?

Area of Science:

• Genetics
• Dermatology
• Oncology

Background:

• Cutaneous epidermal nevi represent a spectrum of genotypically diverse mosaic disorders.
• Pathogenic variants in RAS (HRAS, KRAS, NRAS) and BRAF genes are implicated.
• These variants can lead to isolated nevi or syndromic conditions with extracutaneous manifestations, prompting the concept of mosaic RASopathies.

Purpose of the Study:

• To describe three new cases of syndromic epidermal nevi caused by mosaic HRAS variants.
• To conduct a comprehensive literature review of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in HRAS, KRAS, NRAS, or BRAF.

Main Methods:

• Case reporting of three new patients with syndromic epidermal nevi and mosaic HRAS variants.
• Extensive literature review and analysis of previously reported cases with pathogenic somatic variants in RAS or BRAF genes.

Main Results:

• Syndromic epidermal nevi frequently present with bone, ophthalmological, or neurological anomalies.
• KRAS variants (50% of cases) are associated with sebaceous nevi, oculoectodermal syndrome, and encephalocraniocutaneous lipomatosis, often with eye and brain anomalies.
• HRAS variants are more commonly found in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica.

Conclusions:

• This review establishes genotype/phenotype correlations for syndromic epidermal nevi associated with somatic RAS and BRAF variants.
• Improved understanding can enhance patient follow-up and management strategies for these mosaic disorders.