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

Background: Cutaneous epidermal nevi are genotypically diverse mosaic disorders. Pathogenic hotspot variants in , , and less frequently and may cause isolated keratinocytic epidermal nevi and sebaceous nevi or several different syndromes when associated with extracutaneous anomalies. Therefore, some authors suggest the concept of mosaic RASopathies to group these different disorders.

Methods: In this paper, we describe three new cases of syndromic epidermal nevi caused by mosaic variants: one associating an extensive keratinocytic epidermal nevus with hypomastia, another with extensive mucosal involvement and a third combining a small sebaceous nevus with seizures and intellectual deficiency. Moreover, we performed extensive literature of all cases of syndromic epidermal nevi and related disorders with confirmed pathogenic postzygotic variants in or .

Results: Most patients presented with bone, ophthalmological or neurological anomalies. Rhabdomyosarcoma, urothelial cell carcinoma and pubertas praecox are also repeatedly reported. pathogenic variants are involved in 50% of the cases, especially in sebaceous nevi, oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. They are frequently associated with eye and brain anomalies. Pathogenic variants in are rather present in syndromic keratinocytic epidermal nevi and phacomatosis pigmentokeratotica.

Conclusion: This review delineates genotype/phenotype correlations of syndromic epidermal nevi with somatic and pathogenic variants and may help improve their follow-up.