Neurocutaneous Syndromes as Embryonic Neurocristopathies

Abstract

Most neurocutaneous syndromes are somatic genetic mutations involving neural crest derivatives, hence are neurocristopathies. Neural crest is best understood in the context of ontogenetic and phylogenetic development and of the history of the evolution of the concepts surrounding its discovery and interpretation. The neural crest is an embryonic layer of cells at the margins of the neural plate, first distinguished at gastrulation. As the embryonic neural folds close dorsally to form the neural tube, these neural crest cells delaminate by losing their adhesion to neighboring cells, enabling them to migrate peripherally along genetically programmed pathways in the extracellular matrix, where they not only form ectodermal neural structures such as dorsal root ganglia and the autonomic nervous system but also exhibit differentiation into many tissues derived from mesoderm and endoderm. Neural crest cells migrate in distinctive patterns from prosencephalic, mesencephalic, and rhombencephalic sites of the neural tube, but terminal differentiation occurs only after cellular migration is completed. The broad spectrum of tissues differentiated from neural crest and the fact that developmental genes are expressed in all three traditional germ layers has led some to conclude that the germ layer theory is obsolete, but its usefulness in embryology can be retained if neural crest is regarded as a fourth and equal germ layer, as proposed by Hall. Phylogenetic analyses reveal that neural crest tissue is present in all vertebrates. Presumptive neural crest probably exists in pre-vertebrate chordates such as amphioxus and tunicates, but is not evident in any phylum of invertebrates. Vertebrate neural crest is responsible for most of craniofacial development and contributes to development of intestine, as well as to numerous other visceral organs, thymus, meninges, the eye, the heart, and other tissues. Disorders of neural crest tissue are known as neurocristopathies and include all primary neurocutaneous syndromes. The genetic profile of neural crest development is complex with many genes contributing and interacting; many also function as tumor suppressor genes. Epileptogenesis of the brain malformations associated with many neurocutaneous syndromes, such as cortical tubers in tuberous sclerosis complex and hemimegalencephaly in epidermal nevus syndrome, can be explained by several factors: dysplastic neurons function abnormally; primary cortical dysplasias are surrounded by adjacent zones of focal cortical dysplasias of a different histopathological nature; synaptic circuitry is abnormal, including the integration of subcortical heterotopia; inflammation may be associated in the fetus with hamartomatous cerebral lesions; and abnormal microvascular networks can produce focal ischemia.