Chapter 2 - Phenotype/genotype correlations in epidermal nevus syndrome as a neurocristopathy

Abstract

Epidermal nevus syndrome (ENS) is a term that encompasses several phenotypes defined by the association of an epidermal nevus with one or more congenital systemic anomalies, mainly ocular, osseous and cerebral. The two most frequent, keratinocytic nevus syndrome and linear sebaceous nevus syndrome, also correspond to the neurological phenotypes. They both exhibit overlapping and distinctive features but same etiology: post-zygotic mosaic mutations in RAS genes. Their pathogenesis is due to defective neural crest, further confirming that they are the same basic entity contradicting the concept that they are a group of heterogeneous syndromes with different etiologies. Both have been reported for more than a century. The sebaceous nevus, hallmark of linear sebaceous nevus syndrome, was defined by Jadassohn in 1895; the large number of subsequent contributors in defining this syndrome precludes the introduction of eponyms. Three other distinctive phenotypes within the spectrum of ENS with CNS involvement are CLOVES, SCALP and Heide's syndromes. Recognition of neurological phenotypes with multisystemic involvement should invoke multidisciplinary investigation and management. In some ENS phenotypes the association of melanocytic nevi with keratinocytic and sebaceous nevi, all sharing RAS mutations, predicts multisystemic involvement, in particular severe rickets and osseous anomalies. Phenotype is, therefore, the starting point for clinicians to guide genetic, neurological and other systemic investigations for patient management. The most frequent brain malformation in neurological phenotypes of ENS is hemimegalencephaly (HME). Epilepsy is the most frequent neurological symptom, in particular infantile spasms, with or without HME. The impact of neurological and systemic manifestations is related to onset and extent of the mutations. Timing of the mutation determines phenotype and severity. Proteus syndrome is a neurological phenotype of epidermal keratinocytic nevus syndrome not an independent, separate syndrome.