Chapter 36 - Genetics of neural crest and neurocutaneous syndromes

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Abstract

Neural crest progenitor cells are identified at the lateral margins of the neural placode at the time of gastrulation. With folding of the placode, these precursors are brought to the dorsal midline of the neural tube at the site of closure, become committed to neural crest lineage and almost immediately migrate peripherally to various predetermined sites in the body and then differentiate as a variety of cellular types in all three of the traditional “germ layers.” All of these processes of migration and differentiation of neural crest are precisely genetically programed, temporally and spatially, by a variety of genes. Primary neurocutaneous syndromes are all very different diseases with different genetic mutations, but the unifying factor amongst them is that all are neurocristopathies and can be explained as such, including the tumor-suppressor function of several of these genes, especially those of neurofibromatosis 1 and 2 and tuberous sclerosis. This chapter reviews the principal genes that program neural crest development and also are documented, implicated, or suspected in the pathogenesis of neurocutaneous syndromes. Recent genetic discoveries are noted in epidermal nevus syndrome, including Proteus syndrome and their association with hemimegalencephaly and congenital infiltrating lipomatosis of the face.

Introduction

With the exception of tuberous sclerosis and neurofibromatosis 1 and 2, the genetic defects in most of the neurocutaneous syndromes remain unknown or merely speculative. The pathogenesis of these syndromes is mediated by the neural crest tissue, hence to approach an understanding of the mechanism and, ultimately, the etiology, one must first be cognizant of the considerable data on the genetic regulation of neural crest formation, migration, and terminal differentiation, including its inductive role on peripheral non-neural tissues that involves craniofacial development (Sarnat and Flores-Sarnat, 2005, Flores-Sarnat and Sarnat, 2008).

Section snippets

Neural crest

The neural crest is a population of transitory embryonic cells of neuroectodermal derivation defined by its peripheral migratory behavior outside the neural tube and ability to differentiate into numerous cellular types. It is not yet sufficiently developed to constitute an anatomical structure. Neural crest cells first appear in primordial form at the lateral margins of the neural placode at the time of, or very shortly after, gastrulation. They are not yet committed to neural crest lineage

Craniofacial development

Neural crest forms nearly all of the face and most of the cranium except for the posterior third of the parietal bones, occipital bones, and the endochondral bone of the base of the skull, which are derived from paraxial mesoderm. Neural crest is the origin of the cartilage and membranous bone of the face and calvarium, connective tissues, the globe of the eye except for the retina and choroid, cranial nerve sheaths, and blood vessels including the stria vascularis that covers the hair cells of

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