Neural Crest System - Abnormalities

Embryology - 11 Dec 2023        Expand to Translate
Google Translate - select your language from the list shown below (this will open a new external page)
العربية | català | 中文 | 中國傳統的 | français | Deutsche | עִברִית | हिंदी | bahasa Indonesia | italiano | 日本語 | 한국어 | မြန်မာ | Pilipino | Polskie | português | ਪੰਜਾਬੀ ਦੇ | Română | русский | Español | Swahili | Svensk | ไทย | Türkçe | اردو | ייִדיש | Tiếng Việt    These external translations are automated and may not be accurate. (More? About Translations)

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.

System Abnormalities

Abnormality Links: abnormal development | abnormal genetic | abnormal environmental | Unknown | teratogens | ectopic pregnancy | cardiovascular abnormalities | coelom abnormalities | endocrine abnormalities | gastrointestinal abnormalities | genital abnormalities | head abnormalities | integumentary abnormalities | musculoskeletal abnormalities | limb abnormalities | neural abnormalities | neural crest abnormalities | placenta abnormalities | renal abnormalities | respiratory abnormalities | hearing abnormalities | vision abnormalities | twinning | Developmental Origins of Health and Disease |  ICD-11 Historic Embryology   1915 Congenital Cardiac Disease | 1917 Frequency of Anomalies in Human Embryos | 1920 Hydatiform Degeneration Tubal Pregnancy | 1921 Anencephalic Embryo | 1921 Rat and Man | 1966 Congenital Malformations

Some Recent Findings

Review - Hirschsprung disease - Insights on genes, penetrance, and prenatal diagnosis "The objective of this mini-review is to provide insights on the advances in the understanding of the genetic variants associated with different manifestations of Hirschsprung disease, which may present with a range of denervation from a short segment of colon to total colonic and small bowel or extensive aganglionosis. A recent article in this journal documented potential gene variants involved in long-segment Hirschsprung disease in 23 patients. Gene variants were identified using a 31-gene panel of genes related to Hirschsprung disease or enteric neural crest cell development, as previously reported in the literature. The study identified potentially harmful variants in eight genes across 13 patients, with a detection rate of 56.5% (13/23 patients). Five patients had pathologic variants in RET, NRG1, and L1CAM, and the remainder were considered variants of unknown significance. The authors attempted prenatal diagnosis of Hirschsprung disease utilizing an amniocentesis sample obtained for advanced maternal age in a family with a known deleterious RET mutation, manifested in the father (long-segment Hirschsprung disease) and older daughter (total colonic aganglionosis). The fetus had the same RET variant but, after several years of follow-up, has not developed any symptoms of Hirschsprung disease, supporting the conclusion that this RET mutation is an autosomal dominant gene with incomplete penetrance. This experience suggests that genetic counseling is appropriate to carefully assess the justification of prenatal testing, especially, when the phenotype of long-segment Hirschsprung disease is so variable and the disease is potentially curable with surgery." Prenatal Ascertainment of a Fetus With Homozygous Loss of the SOX10 Gene and Phenotypic Correlation by Autopsy Examination "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 "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. The developmental biology of melanocytes and its application to understanding human congenital disorders of pigmentation.

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on 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. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Neural Crest Abnormalities <pubmed limit=5>Neural Crest Abnormalities</pubmed>

Neuroblastoma

This childhood cancer can arise initially from the adrenal or other tissues. 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%). The disease development is classified by the International Neuroblastoma Staging System.

Neuroblastoma (Image: NZ Crown copyright)

Changes in Childhood Survival Rates

Childhood Cancer Study (1999) - Survival Rates

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)
Table data modified from: Childhood Cancer Survivor Study   Links: neural crest abnormalities

See also data from and another Italian study 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."

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

Links: OMIM - Neuroblastoma

Neurofibromatosis

Neurofibromatosis type 1 (NF1, von Recklinghausen's disease) is an autosomal dominant disease caused by a germ-line-inactivating mutation in the NF1 gene on chromosome 17.

Links: StatPearls

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.

Molecularly, the transcription factor Tbx1 and its downstream targets SDF1/CXCR4 appear critical for events of neural crest cell migration and survival. While generally described as a neural crest abnormality, there are indications of pharyngeal endoderm and mesoderm involvement through other signaling pathways (Wnt11r and Fgf8a). A mouse study 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.
• 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.

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). 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)

Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease is a hereditary demyelinating disease of the peripheral nervous system.

Subtype 1A has duplication mutation of peripheral myelin protein 22 gene on chromosome {{Chr17)).

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

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

Reviews

Vega-Lopez GA, Cerrizuela S, Tribulo C & Aybar MJ. (2018). Neurocristopathies: New insights 150 years after the neural crest discovery. Dev. Biol. , , . PMID: 29802835 DOI.

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.

Search PubMed

Search April 2010 "Neural Crest Development" - All (4354) Review (843) Free Full Text (1621)

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

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

• Children's Neuroblastoma Cancer Foundation CNCF
• Childhood Cancer Survivor Study CCSS
• AIHW Cancer compendium: information and trends by cancer type

Glossary Links

Glossary: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols | Term Link

---

Cite this page: Hill, M.A. (2023, December 11) Embryology Neural Crest System - Abnormalities. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Neural_Crest_System_-_Abnormalities

What Links Here?

© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G