Neural Crest System - Abnormalities

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Introduction

While the cells originate from the ectoderm layer, unlike the neural tube which "pinches off" from the surface ectoderm, the neural crest cells head off on migrations throughout the embryo forming a diverse range of cell types and contributions to many different tissues.

This behaviour also means that failure of correct migration or differentiation can lead to a number of different abnormalities.


Neural Crest Links: neural crest | Lecture - Early Neural | Lecture - Neural Crest Development | Lecture Movie | Schwann cell | adrenal | melanocyte | Peripheral Nervous System | enteric nervous system | cornea | Cranial Nerves | Cardiac | Nicole Le Douarin | Neural Crest Movies | neural crest abnormalities | Category:Neural Crest
Historic Embryology - Neural Crest  
1879 Olfactory Organ | 1905 Cranial and Spinal Nerves | 1908 10 mm Peripheral | 1910 Mammal Sympathetic | 1920 Human Sympathetic | 1939 10 Somite Embryo | 1942 Origin | 1957 Adrenal

Some Recent Findings

  • Prenatal Ascertainment of a Fetus With Homozygous Loss of the SOX10 Gene and Phenotypic Correlation by Autopsy Examination [1] "The SOX10 gene plays a vital role in neural crest cell development and migration. Abnormalities in SOX10 are associated with Waardenburg syndrome Types II and IV, and these patients have recognizable clinical features. This case report highlights the first ever reported homozygous loss of function of the SOX10 gene in a human. This deletion is correlated using family history, prenatal ultrasound, microarray analysis of amniotic fluid, and ultimately, a medical autopsy examination to further elucidate phenotypic effects of this genetic variation." (More? Sox)
  • Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans[2] "Hirschsprung (HSCR) disease is a complex genetic disorder attributed to a failure of the enteric neural crest cells (ENCCs) to form ganglia in the hindgut. Hedgehog and Notch are implicated in mediating proliferation and differentiation of ENCCs. Nevertheless, how these signaling molecules may interact to mediate gut colonization by ENCCs and contribute to a primary etiology for HSCR are not known. Here, we report our pathway-based epistasis analysis of data generated by a genome-wide association study on HSCR disease, which indicates that specific genotype constellations of Patched (PTCH1) (which encodes a receptor for Hedgehog) and delta-like 3 (DLL3) (which encodes a receptor for Notch) SNPs confer higher risk to HSCR. Importantly, deletion of Ptch1 in mouse ENCCs induced robust Dll1 expression and activation of the Notch pathway, leading to premature gliogenesis and reduction of ENCC progenitors in mutant bowels. Dll1 integrated Hedgehog and Notch pathways to coordinate neuronal and glial cell differentiation during enteric nervous system development. In addition, Hedgehog-mediated gliogenesis was found to be highly conserved, such that Hedgehog was consistently able to promote gliogenesis of human neural crest-related precursors. Collectively, we defined PTCH1 and DLL3 as HSCR susceptibility genes and suggest that Hedgehog/Notch-induced premature gliogenesis may represent a new disease mechanism for HSCR."
  • An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation.[3]
  • The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation.[4]
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Neural Crest Abnormalities


Brett T Chiquet, Qiuping Yuan, Eric C Swindell, Lorena Maili, Robert Plant, Jeffrey Dyke, Ryan Boyer, John F Teichgraeber, Matthew R Greives, John B Mulliken, Ariadne Letra, Susan H Blanton, Jacqueline T Hecht Knockdown of Crispld2 in zebrafish identifies a novel network for nonsyndromic cleft lip with or without cleft palate candidate genes. Eur. J. Hum. Genet.: 2018; PubMed 29899370

Guillermo A Vega-Lopez, Santiago Cerrizuela, Celeste Tribulo, Manuel J Aybar Neurocristopathies: New Insights 150 Years After the Neural Crest Discovery. Dev. Biol.: 2018; PubMed 29802835

Ian C Welsh, James Hart, Joel M Brown, Karissa Hansen, Marcelo Rocha Marques, Robert J Aho, Irina Grishina, Romulo Hurtado, Doris Herzlinger, Elisabetta Ferretti, Maria J Garcia-Garcia, Licia Selleri Pbx loss in cranial neural crest, unlike in epithelium, results in cleft palate only and a broader midface. J. Anat.: 2018; PubMed 29797482

Martyn T Cobourne, Sachiko Iseki, Anahid A Birjandi, Hadeel Adel Al-Lami, Christel Thauvin-Robinet, Guilherme M Xavier, Karen J Liu How to make a tongue: Cellular and molecular regulation of muscle and connective tissue formation during mammalian tongue development. Semin. Cell Dev. Biol.: 2018; PubMed 29784581

Salah Boudjadi, Bishwanath Chatterjee, Wenyue Sun, Prasantha Vemu, Frederic G Barr The expression and function of PAX3 in development and disease. Gene: 2018; PubMed 29730428

Neuroblastoma

A smaller recent infant cancer study (Tiwan, Medical Center Cancer Registry, 1995 - 2001) of 82 infants (40 males and 42 females, 12 neonates) showed neuroblastoma as the third most common infant cancer (12 infants 14.6%).

Neuroblastoma (Image: NZ Crown copyright)


Changes in Chilhood Survival Rates - Neuroblastoma

Cancer Infant number (percentage)
acute leukemia 21 infants (25.6%; acute myeloid leukemia in 12, and acute lymphoblastic leukemia in 9)
retinoblastoma 14 (17.1%)
neuroblastoma 12 (14.6%)
brain tumor 9 (11.0%)
germ cell tumor 8 (9.8%)
hepatoblastoma 5 (6.1%)
soft tissue sarcoma 5 (rhabdomyosarcoma 1, fibrosarcoma 3, other sarcoma 1)

Childhood Cancer Survival Rates table modified from: Childhood Cancer Survivor Study


See data from[5] and another Italian study[6] showed: "Age of less than 1 year at time of diagnosis was a favorable prognostic factor for neuroblastoma and ganglioneuroblastoma. The extent of disease at diagnosis was related to prognosis for neuroblastoma and ganglioneuroblastoma and other selected solid tumors."

Database Search: OMIM- Neuroblastoma (2006 - 242 search results)

Links: OMIM - Neuroblastoma

DiGeorge syndrome

DiGeorge chromosome 22

DiGeorge syndrome (velocardiofacial syndrome, third and fourth pharyngeal pouch syndrome, Hypoplasia of thymus and parathyroids) is the most frequent microdeletion syndrome in humans caused by a hemizygous deletion (1.5 to 3.0-Mb) of chromosome 22q11.2.[7]

Molecularly, the transcription factor Tbx1 and its downstream targets SDF1/CXCR4 appear critical for events of neural crest cell migration and survival.[8] While generally described as a neural crest abnormality, there are indications of pharyngeal endoderm and mesoderm involvement through other signaling pathways (Wnt11r and Fgf8a).[9] A mouse study[10] has shown that vitamin B12 treatment can enhances Tbx1 gene expression and improve outcomes.

Table - Human Tbx Family
Approved
Symbol
Approved Name Previous Symbols Synonyms Chromosome
TBX1 T-box 1 VCF CATCH22 22q11.21
Human TBX Family  
Table - Human Tbx Family
Approved
Symbol
Approved Name Previous Symbols Synonyms Chromosome
TBX1 T-box 1 VCF CATCH22 22q11.21
TBX2 T-box 2 17q23.2
TBX3 T-box 3 UMS "TBX3-ISO, XHL" 12q24.21
TBX4 T-box 4 17q23.2
TBX5 T-box 5 HOS 12q24.21
TBX6 T-box 6 16p11.2
TBX10 T-box 10 TBX7 TBX13 11q13.2
TBX15 T-box 15 TBX14 1p12
TBX18 T-box 18 6q14.3
TBX19 T-box 19 "dj747L4.1, TPIT" 1q24.2
TBX20 T-box 20 7p14.2
TBX21 T-box 21 "TBLYM, T-bet" 17q21.32
TBX22 T-box 22 "CPX, CLPA" Xq21.1
TBX23P T-box 23, pseudogene TBX23 1q25
TBR1 T-box, brain 1 2q24.2
EOMES eomesodermin TBR2 3p24.1
MGA MGA, MAX dimerization protein "KIAA0518, MAD5, MXD5, FLJ12634" 15q15
TBXT T-box transcription factor T T 6q27
    Links: Developmental Signals - Tbx | OMIM Tbx3 | HGNC | Bmp Family | Sox Family | Tbx Family


Abnormalities: cardiovascular, thymic and parathyroid, craniofacial anomalies, renal anomalies, hypocalcemia and immunodeficiency.

Search PubMed: Digeorge Syndrome | Takao syndrome


Links: TBX | Neural Crest Development | Head Development

OMIM: Digeorge Syndrome | T-BOX 1 | CXCR4

Neurofibromatosis Type 1 (NF1)

  • Neurofibromatosis Type 1 (von Recklinghausen) occurs in 1 in 3,000 to 4,000 people with characteristic skin blemishes forming in early childhood.[11]
  • Multiple café-au-lait spots (flat skin patches darker than the surrounding area) appear in early childhood which increase in both size and number with age.
  • tumors can develop along nerves in the skin, brain, and other parts of the body. In the iris of the eye, Lisch nodules (benign growths) also appear
(French, café-au-lait = coffee with milk)

Links: OMIM - Neurofibromatosis Type 1 | Genetics Home Reference - Neurofibromatosis Type 1 | Nemours Foundation - Neurofibromatosis | Neurofibromatosis, Inc. (USA) | Atlas of Genetics and Cytogenetics in Oncology- Neurofibroma

Intestinal Aganglionosis

Intestinal Aganglionosis, also known as Hirschsprung's Disease or Megacolon, is a lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis).

In general, its severity is dependent upon the amount of the GIT that lacks intrinsic ganglia, due to developmental lack of neural crest migration into those segments. (More? Gastrointestinal Tract - Abnormalities)

  • Intestinal Aganglionosis, Hirschsprung's Disease or Megacolon
  • lack of enteric nervous system (neural ganglia) in the intestinal tract responsible for gastric motility (peristalsis).
  • severity is dependent upon the amount of the GIT that lacks intrinsic ganglia, due to developmental lack of neural crest migration into those segments.
  • first indication in newborns is an absence of the first bowel movement, other symptoms include throwing up and intestinal infections.
  • Clinically this is detected by one or more tests (barium enema and x ray, manometry or biopsy) and can currently only be treated by surgery. A temoporary ostomy (Colostomy or Ileostomy) with a stoma is carried out prior to a more permanent pull-through surgery.


Megacolon surgery.gif Megacolon stoma.gif
Short section of the colon without smooth muscle neural ganglia Longer section without ganglia

The first indication in newborns is an absence of the first bowel movement, other symptoms include throwing up and intestinal infections. Clinically this is detected by one or more tests (barium enema and x ray, manometry or biopsy) and can currently only be treated by surgery. A temoporary ostomy (Colostomy or Ileostomy) with a stoma is carried out prior to a more permanent pull-through surgery.

Congenital failure of autonomic control describes the occasional association with congenital central hypoventilation syndrome (CCHS, Ondine's curse or Haddad Syndrome) perhaps correlating with a failure of neural crest associated with the respiratory system. This condition is a decrease in respiration (hypoventilation) usually during sleep and an insensitivity to stimuli which should increase respiration (hypercarbia and hypoxia).[12] Recent CCHS research has also identified Paired-like Homeobox 2B (PHOX2B) gene mutations associated with this disorder.

OMIM: Hirschsprung's Disease | Congenital failure of autonomic control | PHOX2B)

Search PubMed: hirschprung's+disease

Links:NIH - NIDDK - Hirschsprungs | MedlinePlus - Hirschsprung's disease

Tetralogy of Fallot

Cardiac abnormality possibly stemming from abnormal neural crest migration. Named after Etienne-Louis Arthur Fallot (1888) who described it as "la maladie blue".

Links: Cardiovascular System Development | Cardiac Tutorial | Lecture - Heart | Cardiovascular System - Abnormalities

Treacher Collins syndrome

(TCS) A genetic developmental abnormality results from autosomal dominant mutations of the gene TCOF1 encoding the protein Treacle, identified in 2006. The syndrome is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects. These defects may relate to the effects on neural crest migration.

Links: Neural Crest Development | OMIM - TCOF1 | PMID: 8563749)

Melanoma

In Australia each year 8,800 people are diagnosed with melanoma, and almost 1000 people die (Data, Cancer Council Australia).

Two different findings on the reprogramming of melanoma cells, which have a neural crest origin, when transplanted between species into embryos.

Kulesa PM, Kasemeier-Kulesa JC, Teddy JM, Margaryan NV, Seftor EA, Seftor RE, Hendrix MJ. Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment. Proc Natl Acad Sci U S A. 2006 Feb 27; [Epub ahead of print]

Lee LM, Seftor EA, Bonde G, Cornell RA, Hendrix MJ. The fate of human malignant melanoma cells transplanted into zebrafish embryos: assessment of migration and cell division in the absence of tumor formation. Dev Dyn. 2005 Aug;233(4):1560-70.

Links: Medline Plus - Melanoma | Cancer Council Australia - Skin cancer in Australia | American Academy of Dermatology - Melanoma: What It Looks Like | New Zealand Dermatological Society - Melanoma

Self Assessment Questions

OMIM Database

Online Mendelian Inheritence in Man Database. OMIM

Internet Search OMIM database with the keyword "neural crest" or the above abnormality names.

OMIM Sample Entries

Neural Crest disease entries from 74 entries found (1999 search), using "neural crest"

*193500 WAARDENBURG SYNDROME, TYPE I; WS1

*162200 NEUROFIBROMATOSIS, TYPE I; NF1

*188400 DIGEORGE SYNDROME; DGS

#171400 MULTIPLE ENDOCRINE NEOPLASIA, TYPE II; MEN2#277580 WAARDENBURG-SHAH SYNDROME600501 ABCD SYNDROME*256700 NEUROBLASTOMA#142623 HIRSCHSPRUNG DISEASE#162300 MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIB; MEN2B#130650 BECKWITH-WIEDEMANN SYNDROME; BWS164210 OCULOAURICULOVERTEBRAL DYSPLASIA#171300 PHEOCHROMOCYTOMA#176270 PRADER-WILLI SYNDROME; PWS#193510 WAARDENBURG SYNDROME, TYPE IIA; WS2A214800 CHOANAL ATRESIA, POSTERIOR; PCA*600594 DIGEORGE CRITICAL REGION GENE 2249400 MELANOSIS, NEUROCUTANEOUS*155735 MELANOMA ADHESION MOLECULE; MCAM217100 CONSTRICTING BANDS, CONGENITAL#146150 HYPOMELANOSIS OF ITO; HMI#137600 IRIDOGONIODYSGENESIS, TYPE 2; IRID2#188550 THYROID CARCINOMA, PAPILLARY*601499 RIEGER SYNDROME, TYPE 2; RIEG2#601631 IRIDOGONIODYSGENESIS, TYPE 1; IRID1*601654 EYES ABSENT 2; EYA2#118200 CHARCOT-MARIE-TOOTH DISEASE, TYPE 1B; CMT1B#106200 ANIRIDIA; AN1*602942 NEUROBLASTOMA STAGE 4S GENE603807 PETERS ANOMALY WITH CATARACT

References

  1. LeBel DP, Wolff DJ, Batalis NI, Ellingham T, Matics N, Patwardhan SC, Znoyko IY & Schandl CA. (2017). First Report of Prenatal Ascertainment of a Fetus With Homozygous Loss of the SOX10 Gene and Phenotypic Correlation by Autopsy Examination. Pediatr. Dev. Pathol. , , 1093526617744714. PMID: 29216801 DOI.
  2. Ngan ES, Garcia-Barceló MM, Yip BH, Poon HC, Lau ST, Kwok CK, Sat E, Sham MH, Wong KK, Wainwright BJ, Cherny SS, Hui CC, Sham PC, Lui VC & Tam PK. (2011). Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans. J. Clin. Invest. , 121, 3467-78. PMID: 21841314 DOI.
  3. High FA, Zhang M, Proweller A, Tu L, Parmacek MS, Pear WS & Epstein JA. (2007). An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation. J. Clin. Invest. , 117, 353-63. PMID: 17273555 DOI.
  4. Hornyak TJ. (2006). The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation. Adv Dermatol , 22, 201-18. PMID: 17249303
  5. Dama E, Pastore G, Mosso ML, Maule MM, Zuccolo L, Magnani C & Merletti F. (2006). Time trends and prognostic factors for survival from childhood cancer: a report from the Childhood Cancer Registry of Piedmont (Italy). Eur. J. Pediatr. , 165, 240-9. PMID: 16411094 DOI.
  6. Yang CP, Hung IJ, Jaing TH, Shih LY & Chang WH. (2005). Cancer in infants: a review of 82 cases. Pediatr Hematol Oncol , 22, 463-81. PMID: 16169813 DOI.
  7. Wurdak H, Ittner LM & Sommer L. (2006). DiGeorge syndrome and pharyngeal apparatus development. Bioessays , 28, 1078-86. PMID: 17041894 DOI.
  8. Duband JL, Escot S & Fournier-Thibault C. (2016). SDF1-CXCR4 signaling: A new player involved in DiGeorge/22q11-deletion syndrome. Rare Dis , 4, e1195050. PMID: 27500073 DOI.
  9. Choe CP & Crump JG. (2014). Tbx1 controls the morphogenesis of pharyngeal pouch epithelia through mesodermal Wnt11r and Fgf8a. Development , 141, 3583-93. PMID: 25142463 DOI.
  10. Lania G, Bresciani A, Bisbocci M, Francone A, Colonna V, Altamura S & Baldini A. (2017). Vitamin B12 ameliorates the phenotype of a mouse model of DiGeorge syndrome. Hum. Mol. Genet. , 26, 4540. PMID: 29036321 DOI.
  11. De Schepper S, Boucneau J, Lambert J, Messiaen L & Naeyaert JM. (2005). Pigment cell-related manifestations in neurofibromatosis type 1: an overview. Pigment Cell Res. , 18, 13-24. PMID: 15649148 DOI.
  12. Croaker GD, Shi E, Simpson E, Cartmill T & Cass DT. (1998). Congenital central hypoventilation syndrome and Hirschsprung's disease. Arch. Dis. Child. , 78, 316-22. PMID: 9623393

Reviews

Cordero DR, Brugmann S, Chu Y, Bajpai R, Jame M & Helms JA. (2011). Cranial neural crest cells on the move: their roles in craniofacial development. Am. J. Med. Genet. A , 155A, 270-9. PMID: 21271641 DOI.

Trainor PA. (2010). Craniofacial birth defects: The role of neural crest cells in the etiology and pathogenesis of Treacher Collins syndrome and the potential for prevention. Am. J. Med. Genet. A , 152A, 2984-94. PMID: 20734335 DOI.

Kim S & Chung DH. (2006). Pediatric solid malignancies: neuroblastoma and Wilms' tumor. Surg. Clin. North Am. , 86, 469-87, xi. PMID: 16580935 DOI.

Yang CP, Hung IJ, Jaing TH, Shih LY & Chang WH. (2005). Cancer in infants: a review of 82 cases. Pediatr Hematol Oncol , 22, 463-81. PMID: 16169813 DOI.

Croaker GD, Shi E, Simpson E, Cartmill T & Cass DT. (1998). Congenital central hypoventilation syndrome and Hirschsprung's disease. Arch. Dis. Child. , 78, 316-22. PMID: 9623393

Articles

Fernández RM, Bleda M, Luzón-Toro B, García-Alonso L, Arnold S, Sribudiani Y, Besmond C, Lantieri F, Doan B, Ceccherini I, Lyonnet S, Hofstra RM, Chakravarti A, Antiñolo G, Dopazo J & Borrego S. (2013). Pathways systematically associated to Hirschsprung's disease. Orphanet J Rare Dis , 8, 187. PMID: 24289864 DOI.

Dama E, Pastore G, Mosso ML, Maule MM, Zuccolo L, Magnani C & Merletti F. (2006). Time trends and prognostic factors for survival from childhood cancer: a report from the Childhood Cancer Registry of Piedmont (Italy). Eur. J. Pediatr. , 165, 240-9. PMID: 16411094 DOI.

Bajaj R, Smith J, Trochet D, Pitkin J, Ouvrier R, Graf N, Sillence D & Kluckow M. (2005). Congenital central hypoventilation syndrome and Hirschsprung's disease in an extremely preterm infant. Pediatrics , 115, e737-8. PMID: 15930201 DOI.


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Search Pubmed: neural crest abnormalities | neuroblastoma | Neurofibromatosis type 1

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Cite this page: Hill, M.A. (2018, June 18) Embryology Neural Crest System - Abnormalities. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Neural_Crest_System_-_Abnormalities

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