Download PDF
Journal of Pediatric Epilepsy 2016; 05(02): 070-081
DOI: 10.1055/s-0035-1570069
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Neurocutaneous Syndromes as Embryonic Neurocristopathies

Harvey B. Sarnat
1   Department of Paediatrics, University of Calgary Faculty of Medicine and Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
2   Department of Clinical Neurosciences, University of Calgary Faculty of Medicine and Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
3   Department of Pathology (Neuropathology), University of Calgary Faculty of Medicine and Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
,
Laura Flores-Sarnat
1   Department of Paediatrics, University of Calgary Faculty of Medicine and Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
2   Department of Clinical Neurosciences, University of Calgary Faculty of Medicine and Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
› Author Affiliations
Further Information

Publication History

24 June 2014

26 June 2014

Publication Date:
11 January 2016 (online)

    Permissions and Reprints

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.

Keywords

neural crest - autonomic nervous system - craniofacial development - cardiac neural crest - neurocristopathy
 

  • References

  • 1 Hall BK. The neural crest and neural crest cells: discovery and significance for theories of embryonic organization. J Biosci 2008; 33 (5) 781-793
    CrossrefPubMedGoogle Scholar
  • 2 Hall BK. The Neural Crest and Neural Crest Cells in Vertebrate Development and Evolution. 2nd ed. New York, NY: Springer; 2009
    CrossrefGoogle Scholar
  • 3 Le Douarin NM, Kalcheim C. The Neural Crest. 2nd ed. Cambridge, UK: Cambridge University Press; 1999
    CrossrefGoogle Scholar
  • 4 Bronner-Fraser M. Origins and developmental potential of the neural crest. Exp Cell Res 1995; 218 (2) 405-417
    CrossrefPubMedGoogle Scholar
  • 5 Bronner-Fraser M, Fraser SE. Differentiation of the vertebrate neural tube. Curr Opin Cell Biol 1997; 9 (6) 885-891
    CrossrefPubMedGoogle Scholar
  • 6 Tessier P. Anatomical classification facial, cranio-facial and latero-facial clefts. J Maxillofac Surg 1976; 4 (2) 69-92
    CrossrefPubMedGoogle Scholar
  • 7 Tessier P. Plastic Surgery of the Orbit and Eyelids. 1st ed. Philadelphia, PA: Mosby (Masson); 1981
    Google Scholar
  • 8 Carstens MH. Development of the facial midline. J Craniofac Surg 2002; 13 (1) 129-187 , discussion 188–190
    CrossrefPubMedGoogle Scholar
  • 9 Carstens MH. Neural tube programming and craniofacial cleft formation. I. The neuromeric organization of the head and neck. Eur J Paediatr Neurol 2004; 8 (4) 181-210 , discussion 179–180
    CrossrefPubMedGoogle Scholar
  • 10 Carstens MH. Neural tube programming and the pathogenesis of craniofacial clefts, part 1: the neuromeric organization of the head and neck; part 2: mesenchyme, pharyngeal arches, developmental fields, and the assembly of the human face. In: Sarnat HB, Curatolo P, eds. Malformations of the Nervous System, vol. 87. Edinburgh, NY, Toronto: Elsevier; 2008: 247-276 , 277–339
    Google Scholar
  • 11 Pander CH. Dissertatio inauguralis, sistens historiam metamorphoseos quam ovum incubatum prioribus quinque diebus subit. Würzburg, Germany: HL Brünner; 1817
    CrossrefGoogle Scholar
  • 12 Allman GJ. On the anatomy and physiology of Cordylophora, a contribution to our knowledge of the Tubularian zoophytes. Phil Trans Roy Soc Lond 1843; 143: 367-384
    PubMedGoogle Scholar
  • 13 Remak R. Untersuchungen über die Entwickelung der Wirbelthiere. Berlin, Germany: G Reimer; 1850-1855
    Google Scholar
  • 14 Huxley TH. A Manual of the Anatomy of Vertebrated Animals. 1st ed. London, UK: 1871
    CrossrefGoogle Scholar
  • 15 Von Baer KE. Über Entwickelungsgeschichte der Tiere. Beobachtung und Reflexion, vol. 1. Konigsberg: Gebrudern Borntrager; 1828– 1837: 157
    Google Scholar
  • 16 Huxley TH. On the anatomy and the affinities of the family of the Medusae. Phil Trans Roy Soc 1849; 139: 413-434
    PubMedGoogle Scholar
  • 17 Haeckel E. Die Gastrula und die Entfurchung der Thiere. Jena Z Naturwiss 1874; 9: 402-508
    PubMedGoogle Scholar
  • 18 Sedgwick A. On the inadequacy of the cellular theory and on the early development of nerves, particularly of the third nerve and of the sympathetic in Elasmobranchii. J Cell Sci 1894; 37: 87-101
    PubMedGoogle Scholar
  • 19 Hertwig O, Hertwig R. Die Entwicklung des mittleren Keimblattes der Wirbelthiere. Jen Zeit Naturwiss 1882; 15: 286-340
    PubMedGoogle Scholar
  • 20 Oppenheimer JM. The non-specificity of the germ layers. Q Rev Biol 1940; 15: 1-27
    PubMedGoogle Scholar
  • 21 Hall BK. Germ layers and the germ-layer theory revisited: primary and secondary germ layers, neural crest as a fourth germ layer, homology, demise of the germ-layer theory. Evol Biol 1997; 30: 121-186
    PubMedGoogle Scholar
  • 22 De Beer GR. The differentiation of neural crest cells into visceral cartilages and odontoblasts in Amblystoma, and a re-examination of the germ-layer theory. Proc R Soc Lond B Biol Sci 1947; 134 (876) 377-398
    CrossrefPubMedGoogle Scholar
  • 23 Holmdahl DE. Die Enstehung und weitere Entwicklung der Neuralleiste (Ganglienleiste) bei Vögeln und Säugetieren. Z Mikrosk Anat Forsch 1928; 14: 99-298
    PubMedGoogle Scholar
  • 24 Reid RGB. Biologicale: Evolution by Natural Experiment. A Bradford Book. Cambridge, MA: MIT Press; 2007
    Google Scholar
  • 25 Martinez-Morales JR, Henrich T, Ramialison M, Wittbrodt J. New genes in the evolution of the neural crest differentiation program. Genome Biol 2007; 8 (3) R36
    CrossrefPubMedGoogle Scholar
  • 26 His W. Untersuchungen über die erste Anlage des Wirbeltierleibes. Die erste Entwicklung des Hühnchens im Ei. Leipzig, Germany: FCW Vogel; 1868
    CrossrefGoogle Scholar
  • 27 His W. Unserer Körperform und das Physiologische Problem ihrer Entstehung. Leipzig, Germany: Engelmann; 1874
    Google Scholar
  • 28 Ramón y Cajal S. Histology of the Nervous System of Man and Vertebrates. NY, Oxford: Oxford University Press; 1995
    Google Scholar
  • 29 Marshall AM. The morphology of the vertebrate olfactory organ. Q J Microsc Sci 1879; 19: 300-340
    PubMedGoogle Scholar
  • 30 Platt JB. Ectodermal origin of the cartilages of the head. Anat Anz 1893; 8: 506-509
    PubMedGoogle Scholar
  • 31 Platt JB. The development of the cartilaginous skull and of the branchial and hypoglossal musculature in Necturus. Morphol Jb 1897; 25: 377-464
    PubMedGoogle Scholar
  • 32 Hörstadius S. The Neural Crest: Its Properties and Derivatives in the Light of Experimental Research. Oxford, UK: Oxford University Press; 1950
    Google Scholar
  • 33 Sarnat HB, Menkes JH. How to construct a neural tube. J Child Neurol 2000; 15 (2) 110-124
    CrossrefPubMedGoogle Scholar
  • 34 Sarnat HB. Molecular genetic classification of central nervous system malformations. J Child Neurol 2000; 15 (10) 675-687
    CrossrefPubMedGoogle Scholar
  • 35 Sarnat HB, Flores-Sarnat L. Integrative classification of morphology and molecular genetics in central nervous system malformations. Am J Med Genet A 2004; 126A (4) 386-392
    CrossrefPubMedGoogle Scholar
  • 36 Flores-Sarnat L, Sarnat HB. Axes and gradients of the neural tube and other criteria for an integrated morphological and molecular genetic classification of nervous system malformations. In: Sarnat HB, Curatolo P, eds. Malformations of the Nervous System, vol. 87. Edinburgh, NY, Toronto: Elsevier; 2008: 3-11
    Google Scholar
  • 37 Basch ML, Bronner-Fraser M, García-Castro MI. Specification of the neural crest occurs during gastrulation and requires Pax7. Nature 2006; 441 (7090) 218-222
    CrossrefPubMedGoogle Scholar
  • 38 von Kölliker A. Die Embryonalen Keimblätter und die Gewebe. Zeit wiss Zool 1884; 40: 179-213
    PubMedGoogle Scholar
  • 39 Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 2009; 119 (6) 1438-1449
    CrossrefPubMedGoogle Scholar
  • 40 Nichols DH. Formation and distribution of neural crest mesenchyme to the first pharyngeal arch region of the mouse embryo. Am J Anat 1986; 176 (2) 221-231
    CrossrefPubMedGoogle Scholar
  • 41 Nichols DH. Ultrastructure of neural crest formation in the midbrain/rostral hindbrain and preotic hindbrain regions of the mouse embryo. Am J Anat 1987; 179 (2) 143-154
    CrossrefPubMedGoogle Scholar
  • 42 Evans DJ, Noden DM. Spatial relations between avian craniofacial neural crest and paraxial mesoderm cells. Dev Dyn 2006; 235 (5) 1310-1325
    CrossrefPubMedGoogle Scholar
  • 43 Sarnat HB. Clinical neuropathology practice guide 5-2013: markers of neuronal maturation. Clin Neuropathol 2013; 32 (5) 340-369
    CrossrefPubMedGoogle Scholar
  • 44 Abzhanov A, Tzahor E, Lassar AB, Tabin CJ. Dissimilar regulation of cell differentiation in mesencephalic (cranial) and sacral (trunk) neural crest cells in vitro. Development 2003; 130 (19) 4567-4579
    CrossrefPubMedGoogle Scholar
  • 45 Lemos DR, Paylor B, Chang C, Sampaio A, Underhill TM, Rossi FM. Functionally convergent white adipogenic progenitors of different lineages participate in a diffused system supporting tissue regeneration. Stem Cells 2012; 30 (6) 1152-1162
    CrossrefPubMedGoogle Scholar
  • 46 Billon N, Iannarelli P, Monteiro MC , et al. The generation of adipocytes by the neural crest. Development 2007; 134 (12) 2283-2292
    CrossrefPubMedGoogle Scholar
  • 47 Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by β3-adrenoceptor activation and high-fat feeding. Cell Metab 2012; 15 (4) 480-491
    CrossrefPubMedGoogle Scholar
  • 48 Carobbio S, Rosen B, Vidal-Puig A. Adipogenesis: new insights into brown adipose tissue differentiation. J Mol Endocrinol 2013; 51 (3) T75-T85
    CrossrefPubMedGoogle Scholar
  • 49 Liu W, Shan T, Yang X , et al. A heterogeneous lineage origin underlies the phenotypic and molecular differences of white and beige adipocytes. J Cell Sci 2013; 126 (Pt 16) 3527-3532
    CrossrefPubMedGoogle Scholar
  • 50 Peirce V, Carobbio S, Vidal-Puig A. The different shades of fat. Nature 2014; 510 (7503) 76-83
    CrossrefPubMedGoogle Scholar
  • 51 Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol 2010; 12 (2) 143-152
    CrossrefPubMedGoogle Scholar
  • 52 Orr H. Contribution to the morphology of the lizard. J Morphol 1887; 1: 311-372
    CrossrefPubMedGoogle Scholar
  • 53 Sarnat HB, Netsky MG. Evolution of the Nervous System. 2nd ed. New York, NY: Oxford University Press; 1981
    Google Scholar
  • 54 Sarnat HB. Cerebral Dysgenesis. Embryology and Clinical Expression. New York, NY: Oxford University Press; 1992: 357-378
    Google Scholar
  • 55 Hall BK. Consideration of the neural crest and its skeletal derivatives in the context of novelty/innovation. J Exp Zoolog B Mol Dev Evol 2005; 304 (6) 548-557
    PubMedGoogle Scholar
  • 56 Newth DR. Fate of the neural crest in lampreys. Nature 1950; 165 (4190) 284
    PubMedGoogle Scholar
  • 57 Newth DR. On the neural crest of the lamprey embryo. J Embryol Exp Morphol 1956; 4: 358-375
    PubMedGoogle Scholar
  • 58 Holland LZ, Holland ND. Evolution of neural crest and placodes: amphioxus as a model for the ancestral vertebrate?. J Anat 2001; 199 (Pt 1–2) 85-98
    CrossrefPubMedGoogle Scholar
  • 59 Baker CV, Bronner-Fraser M. Vertebrate cranial placodes I. Embryonic induction. Dev Biol 2001; 232 (1) 1-61
    CrossrefPubMedGoogle Scholar
  • 60 Kourakis MJ, Smith WC. A conserved role for FGF signaling in chordate otic/atrial placode formation. Dev Biol 2007; 312 (1) 245-257
    CrossrefPubMedGoogle Scholar
  • 61 Holland LZ, Albalat R, Azumi K , et al. The amphioxus genome illuminates vertebrate origins and cephalochordate biology. Genome Res 2008; 18 (7) 1100-1111
    CrossrefPubMedGoogle Scholar
  • 62 Manni L, Lane NJ, Joly JS , et al. Neurogenic and non-neurogenic placodes in ascidians. J Exp Zoolog B Mol Dev Evol 2004; 302 (5) 483-504
    PubMedGoogle Scholar
  • 63 Jeffery WR, Strickler AG, Yamamoto Y. Migratory neural crest-like cells form body pigmentation in a urochordate embryo. Nature 2004; 431 (7009) 696-699
    CrossrefPubMedGoogle Scholar
  • 64 Meulemans D, Bronner-Fraser M. Amphioxus and lamprey AP-2 genes: implications for neural crest evolution and migration patterns. Development 2002; 129 (21) 4953-4962
    PubMedGoogle Scholar
  • 65 Meulemans D, Bronner-Fraser M. Gene-regulatory interactions in neural crest evolution and development. Dev Cell 2004; 7 (3) 291-299
    CrossrefPubMedGoogle Scholar
  • 66 Schober A, Unsicker K. Growth and neurotrophic factors regulating development and maintenance of sympathetic preganglionic neurons. Int Rev Cytol 2001; 205: 37-76
    PubMedGoogle Scholar
  • 67 Huber K. Segregation of neuronal and neuroendocrine differentiation in the sympathoadrenal lineage. Cell Tissue Res 2015; 359 (1) 333-341
    CrossrefPubMedGoogle Scholar
  • 68 Escriva H, Holland ND, Gronemeyer H, Laudet V, Holland LZ. The retinoic acid signaling pathway regulates anterior/posterior patterning in the nerve cord and pharynx of amphioxus, a chordate lacking neural crest. Development 2002; 129 (12) 2905-2916
    PubMedGoogle Scholar
  • 69 Putnam NH, Butts T, Ferrier DE , et al. The amphioxus genome and the evolution of the chordate karyotype. Nature 2008; 453 (7198) 1064-1071
    CrossrefPubMedGoogle Scholar
  • 70 Habeck JO. Islands of cartilage and bone at the margin of the carotid bodies of rats. Anat Anz 1990; 171 (4) 277-279
    PubMedGoogle Scholar
  • 71 Arda HE, Benitez CM, Kim SK. Gene regulatory networks governing pancreas development. Dev Cell 2013; 25 (1) 5-13
    CrossrefPubMedGoogle Scholar
  • 72 Zhu X, Gleiberman AS, Rosenfeld MG. Molecular physiology of pituitary development: signaling and transcriptional networks. Physiol Rev 2007; 87 (3) 933-963
    CrossrefPubMedGoogle Scholar
  • 73 Ito T, Udaka N, Ikeda M, Yazawa T, Kageyama R, Kitamura H. Significance of proneural basic helix-loop-helix transcription factors in neuroendocrine differentiation of fetal lung epithelial cells and lung carcinoma cells. Histol Histopathol 2001; 16 (1) 335-343
    PubMedGoogle Scholar
  • 74 Kameda Y, Saitoh T, Nemoto N, Katoh T, Iseki S. Hes1 is required for the development of the superior cervical ganglion of sympathetic trunk and the carotid body. Dev Dyn 2012; 241 (8) 1289-1300
    CrossrefPubMedGoogle Scholar
  • 75 Ernsberger U. Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia. Cell Tissue Res 2009; 336 (3) 349-384
    CrossrefPubMedGoogle Scholar
  • 76 Ernsberger U. The role of GDNF family ligand signalling in the differentiation of sympathetic and dorsal root ganglion neurons. Cell Tissue Res 2008; 333 (3) 353-371
    CrossrefPubMedGoogle Scholar
  • 77 Kirby ML, Gale TF, Stewart DE. Neural crest cells contribute to normal aorticopulmonary septation. Science 1983; 220 (4601) 1059-1061
    CrossrefPubMedGoogle Scholar
  • 78 Nakamura T, Colbert MC, Robbins J. Neural crest cells retain multipotential characteristics in the developing valves and label the cardiac conduction system. Circ Res 2006; 98 (12) 1547-1554
    CrossrefPubMedGoogle Scholar
  • 79 Snider P, Olaopa M, Firulli AB, Conway SJ. Cardiovascular development and the colonizing cardiac neural crest lineage. ScientificWorldJournal 2007; 7: 1090-1113
    CrossrefPubMedGoogle Scholar
  • 80 Kirby ML, Hutson MR. Factors controlling cardiac neural crest cell migration. Cell Adhes Migr 2010; 4 (4) 609-621
    CrossrefPubMedGoogle Scholar
  • 81 Flores-Sarnat L. Epidermal nevus syndrome. In: Dulac O, Lassonde M, Sarnat HB, eds. Pediatric Neurology. Edinburgh, NY, Toronto: Elsevier; 2013: 348-368
    Google Scholar
  • 82 Hutson MR, Kirby ML. Neural crest and cardiovascular development: a 20-year perspective. Birth Defects Res C Embryo Today 2003; 69 (1) 2-13
    CrossrefPubMedGoogle Scholar
  • 83 Hong CS, Saint-Jeannet JP. Sox proteins and neural crest development. Semin Cell Dev Biol 2005; 16 (6) 694-703
    CrossrefPubMedGoogle Scholar
  • 84 Sarnat HB, Flores-Sarnat L. Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. J Child Neurol 2005; 20 (8) 637-643
    CrossrefPubMedGoogle Scholar
  • 85 Etchevers HC, Amiel J, Lyonnet S. Molecular bases of human neurocristopathies. Adv Exp Med Biol 2006; 589: 213-234
    PubMedGoogle Scholar
  • 86 Knecht AK, Bronner-Fraser M. Induction of the neural crest: a multigene process. Nat Rev Genet 2002; 3 (6) 453-461
    CrossrefPubMedGoogle Scholar
  • 87 Sarnat HB, Flores-Sarnat L. Genetics of neural crest and neurocutaneous syndromes. In: Dulac O, Lassonde M, Sarnat HB, eds. Elsevier Handbook of Clinical Neurology: Paediatric Neurology, vol. 111. Edinburgh, London, NY, Toronto: Elsevier; 2013: 309-314
    Google Scholar
  • 88 Lacosta AM, Canudas J, Gonzalez C, Muniesa P, Sarasa M, Dominguez L. Pax7 identifies neural crest, chromatophore lineages and pigment stem cells during zebrafish development. Int J Dev Biol 2007; 51 (4) 327-331
    CrossrefPubMedGoogle Scholar
  • 89 Hong CS, Saint-Jeannet JP. The activity of Pax3 and Zic1 regulates three distinct cell fates at the neural plate border. Mol Biol Cell 2007; 18 (6) 2192-2202
    CrossrefPubMedGoogle Scholar
  • 90 García-Castro MI, Marcelle C, Bronner-Fraser M. Ectodermal Wnt function as a neural crest inducer. Science 2002; 297 (5582) 848-851
    PubMedGoogle Scholar
  • 91 Hayward P, Kalmar T, Arias AM. Wnt/Notch signalling and information processing during development. Development 2008; 135 (3) 411-424
    CrossrefPubMedGoogle Scholar
  • 92 Lumsden A, Sprawson N, Graham A. Segmental origin and migration of neural crest cells in the hindbrain region of the chick embryo. Development 1991; 113 (4) 1281-1291
    PubMedGoogle Scholar
  • 93 Lumsden A, Krumlauf R. Patterning the vertebrate neuraxis. Science 1996; 274 (5290) 1109-1115
    CrossrefPubMedGoogle Scholar
  • 94 Zehir A, Hua LL, Maska EL, Morikawa Y, Cserjesi P. Dicer is required for survival of differentiating neural crest cells. Dev Biol 2010; 340 (2) 459-467
    CrossrefPubMedGoogle Scholar
  • 95 Stubbusch J, Narasimhan P, Huber K, Unsicker K, Rohrer H, Ernsberger U. Synaptic protein and pan-neuronal gene expression and their regulation by Dicer-dependent mechanisms differ between neurons and neuroendocrine cells. Neural Dev 2013; 8: 16
    CrossrefPubMedGoogle Scholar
  • 96 Bolande RP. The neurocristopathies: A unifying concept of disease arising in neural crest maldevelopment. Hum Pathol 1974; 5: 409-429
    CrossrefPubMedGoogle Scholar
  • 97 Bolande RP. Neurocristopathy: its growth and development in 20 years. Pediatr Pathol Lab Med 1997; 17 (1) 1-25
    CrossrefPubMedGoogle Scholar
  • 98 Flores-Sarnat L. Epilepsy in neurological phenotypes of epidermal nevus syndrome. J Pediatr Epilepsy 2016; 5 (2) 97-110
    Article in Thieme ConnectPubMedGoogle Scholar
  • 99 Sarnat HB, Flores-Sarnat L. Neuropathologic research strategies in holoprosencephaly. J Child Neurol 2001; 16 (12) 918-931
    CrossrefPubMedGoogle Scholar
  • 100 Sarnat HB, Benjamin DR, Siebert JR, Kletter GB, Cheyette SR. Agenesis of the mesencephalon and metencephalon with cerebellar hypoplasia: putative mutation in the EN2 gene—report of 2 cases in early infancy. Pediatr Dev Pathol 2002; 5 (1) 54-68
    CrossrefPubMedGoogle Scholar
  • 101 Flores-Sarnat L. Congenital infiltrating lipomatosis of the face: recognition and pathogenesis. Neuropediatrics 2012; 43 (6) 346-348
    Article in Thieme ConnectPubMedGoogle Scholar
  • 102 Bodemer C. Incontinentia pigmenti and hypomelanosis of Ito. In: Dulac O, Lassonde M, Sarnat HB, eds. Pediatric Neurology. Edinburgh, NY, Toronto: Elsevier; 2013: 341-347
    Google Scholar
  • 103 Molho-Pessach V, Schaffer JV. Blaschko lines and other patterns of cutaneous mosaicism. Clin Dermatol 2011; 29 (2) 205-225
    CrossrefPubMedGoogle Scholar
  • 104 Blaschko A. Der Nervenverteilung in her Haut in ihrer Beziehung zu der Erkrankungen der Haut. Wien, Leipzig: Braumüller. Supplement to the Proceedings of the German Dermatological Society, 7th Congress in Breslau in May 1901. 1901
    PubMedGoogle Scholar
  • 105 Fischel L, Blaschko A. Ein weitere Beitrag zu den strichförmigen Hauterkrankungen [in German]. Archiv für Dermatologie und Syphilis 1906; 82 (2) 209-226
    PubMedGoogle Scholar
  • 106 Jackson R. The lines of Blaschko: a review and reconsideration: observations of the cause of certain unusual linear conditions of the skin. Br J Dermatol 1976; 95 (4) 349-360
    CrossrefPubMedGoogle Scholar
  • 107 Findlay G. The genetic mosaic. J R Soc Med 1993; 86 (4) 212-216
    PubMedGoogle Scholar
  • 108 Schulz Y, Wehner P, Opitz L , et al. CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance. Hum Genet 2014; 133 (8) 997-1009
    CrossrefPubMedGoogle Scholar
  • 109 Bergman JE, de Ronde W, Jongmans MC , et al. The results of CHD7 analysis in clinically well-characterized patients with Kallmann syndrome. J Clin Endocrinol Metab 2012; 97 (5) E858-E862
    CrossrefPubMedGoogle Scholar
  • 110 Layman WS, McEwen DP, Beyer LA , et al. Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome. Hum Mol Genet 2009; 18 (11) 1909-1923
    CrossrefPubMedGoogle Scholar
  • 111 Kim HG, Layman LC. The role of CHD7 and the newly identified WDR11 gene in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Mol Cell Endocrinol 2011; 346 (1–2) 74-83
    CrossrefPubMedGoogle Scholar
  • 112 Flores-Sarnat L. Neurocutaneous melanocytosis. In: Dulac O, Lassonde M, Sarnat HB, eds. Handbook of Clinical Neurology: Pediatric Neurology, vol. 111. Edinburgh, NY, Toronto: Elsevier; 2013: 369-388
    Google Scholar
  • 113 Newth DR. A remarkable embryonic tissue. Br Med J 1951; 2 (4723) 96-99
    CrossrefPubMedGoogle Scholar
  • 114 Fox H, Emery JL, Goodbody RA, Yates PO. Neuro-cutaneous melanosis. Arch Dis Child 1964; 39: 508-516
    CrossrefPubMedGoogle Scholar
  • 115 Poduri A, Evrony GD, Cai X , et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 2012; 74 (1) 41-48
    CrossrefPubMedGoogle Scholar
  • 116 Lee JH, Huynh M, Silhavy JL , et al. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat Genet 2012; 44 (8) 941-945
    Google Scholar
  • 117 Poduri A, Evrony GD, Cai X, Walsh CA. Somatic mutation, genomic variation, and neurological disease. Science 2013; 341 (6141) 1237758
    CrossrefPubMedGoogle Scholar
  • 118 Najm IM, Tassi L, Sarnat HB, Holthausen H, Russo GL. Epilepsies associated with focal cortical dysplasias (FCDs). Acta Neuropathol 2014; 128 (1) 5-19
    CrossrefPubMedGoogle Scholar
  • 119 Blümcke I, Thom M, Aronica E , et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011; 52 (1) 158-174
    CrossrefPubMedGoogle Scholar
  • 120 Sarnat HB, Flores-Sarnat L, Trevenen CL. Synaptophysin immunoreactivity in the human hippocampus and neocortex from 6 to 41 weeks of gestation. J Neuropathol Exp Neurol 2010; 69 (3) 234-245
    CrossrefPubMedGoogle Scholar
  • 121 Sarnat HB, Flores-Sarnat L, Hader W, Bello-Espinosa L. Mitochondrial “hypermetabolic” neurons in paediatric epileptic foci. Can J Neurol Sci 2011; 38 (6) 909-917
    CrossrefPubMedGoogle Scholar
  • 122 Prabowo AS, Anink JJ, Lammens M , et al. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol 2013; 23 (1) 45-59
    CrossrefPubMedGoogle Scholar