1. Hirschsprung’s Disease and Other Neurocristopathies
Virginie Achim
Swedish Medical Center
April 19, 2012

2. Neural Crest Cell Development
Neurulation is the process of the neural tube formation. It begins with appearance of the neural plate, which invaginates along its central axis to form the neural groove, with neural folds on each side. Gradually, the neural folds approach each other in the midline and fuse there, thus converting the neural groove into a neural tube. Formation of the neural tube begins in the region of the future neck (the 4th somite) and proceeds in the cranial and caudal directions. The tube remains temporarily open by way of the cranial (anterior) and caudal (posterior) neuropores. Closure of the anterior neuropore occurs on the 25th day, whereas the posterior neuropore closes on the 27th day. As the neural tube separates from the surface ectoderm, the neural crest cells migrate to the sides of the neural tube. The neural crest separates into the right and left part, and migrate to dorsolateral aspects of the neural tube, giving rise to the sensory ganglia of the spinal and cranial nerves.
Important genes for differentation: Slug/Snail, FoxD3, Sox10, Sox9, AP-2 and c-Myc

3. Neural Crest Derivatives

4. Neural Crest Development

5. CS
Born at 39 weeks gestation by C-section for frank breech position Apgar scores 8 and 9 at 1 and 5 minutes, respectively Developed grunting, abdominal distention, and bilious drainage from OG tube at 12 hours of life Transferred to SCH where he was found to have malrotation and underwent a Ladd’s procedure

6. CS
Post-operatively, he was found to have difficulty with feedings initially both by mouth and with an NG tube
He was also found to have axial hypotonia, decreased levels of wakefulness, and infrequent stool

7. Contrast Enema 4/9/2012

8. Contrast Enema 4/9/2012

9. Contrast Enema 4/9/2012
Narrow in rectum with perhaps longer segment involvement

10. Biopsy Suction biopsy – not diagnostic
Partial thickness biopsy – lack of ganglion cells, scattered enlarged nerve trunks, calretinin staining negative for fibrils
Calretinin immunoreactivity is normally present in small intrinsic nerves located in the muscularis mucosae and lamina propria. In the mucosa of aganglionic bowel, expression is completely absent.

11. Neurocristopathy Term coined by Bolande in 1974
Refers to a diverse group of disorders resulting from impaired growth, along with defective differentiation and migration of the neural crest cells

12. Neurocristopathy
Hirschsprung’s disease could be defined as a neurocristopathy, characterized by absence of intrinsic parasympathetic ganglion cells in the submucosal and myenteric plexuses, which results from premature migratory arrest of neural crest cells.

13. Neurocristopathies Dysgenetic Neoplastic
Consists of congenital malformations resulting from derangement of neural crest cell migration and colonization
Examples include Hirschsprung’s disease, albinism
Neoplastic
Consists of true neoplasms such as hamartomas, pre-neoplastic hyperplasia
Examples include MCT, neuroblastoma, pheochromocytoma

14. Hirschsprung’s Disease
Incidence approximately 1 in 5000 live births
4:1 male to female ratio
Can be sporadic or syndromic

15. Genetics of Hirschsprung’s Disease
Isolated HSCR
RET proto-oncogene mutation most common
Present in 15% of patients
Other genetic mutations involve EDNRB, EDN3, TTF-1

16. Syndromic Hirschsprung’s Disease
Syndrome
Gene
% with HSCR
Phenotypic features
MEN 2A
RET
<1%
MCT, Pheochromocytoma, Parathyroid hyperplasia
Smith-Lemli-Opitz
DHCR7
16%
Growth retardation, facial dysmorphism
Down
Trisomy 21
2-9%
Prominent epicanthal folds, hypotonia, MR
Waardenburg-Shah
SOX10, EDN3, EDNRB
100%
Deafness, piebaldism, neurologic defects
Mowat-Wilson
ZHFX1B
62%
Abnormal facies, MR, cardiac defects, GU defects
Haddad
PHOX2B
Congenital central hypoventilation, neuroblastoma
Goldberg-Shprintzen
KIAA1279
Microcephaly, cleft palate, absent corpus callosum
Kauffman-McKusik
MKKS
Not established
Polydactyly, congenital heart defects
Syndromic Hirschsprung’s disease is associated with longer segment of aganglionosis.
Kapur, RP.

17. Syndromic Hirschsprung’s Disease
Syndrome
Gene
% with HSCR
Phenotypic features
MEN 2A
RET
<1%
MCT, Pheochromocytoma, Parathyroid hyperplasia
Smith-Lemli-Opitz
DHCR7
16%
Growth retardation, facial dysmorphism
Down
Trisomy 21
2-9%
Prominent epicanthal folds, hypotonia, MR
Waardenburg-Shah
SOX10, EDN3, EDNRB
100%
Deafness, piebaldism, neurologic defects
Mowat-Wilson
ZHFX1B
62%
Abnormal facies, MR, cardiac defects, GU defects
Haddad
PHOX2B
Congenital central hypoventilation, neuroblastoma
Goldberg-Shprintzen
KIAA1279
Microcephaly, cleft palate, absent corpus callosum
Kauffman-McKusik
MKKS
Not established
Polydactyly, congenital heart defects
Talk about the importance of genetic testing for mutations that may have future implications in malignancy such as RET an PHOX2B.

18. Waardenburg-Shah Syndrome
Sensorineural deafness
Piebaldism, Heterochromic irides
Hirschsprung’s disease
Can also be a component of developmental delay
Due to mutation in EDN3, EDNRB, and SOX10
SOX-10: SRY (sex-determining region Y-box10)

19. Waardenburg-Shah Syndrome

20. Haddad Syndrome
Triad of congenital central hypoventilation (Ondine’s curse), Hirschsprung’s disease, and neuroblastoma
Due to mutation in PHOX2B gene
Recognition is important for early detection of malignancy
Paired-like homeobox 2b (PHOX2B), also known as neuroblastoma Phox (NBPhox), is a protein that in humans is encoded by the PHOX2B gene located on chromosome 4.[1]
It codes for a homeodomain transcription factor. It is expressed exclusively in the nervous system, in most neurons that control the viscera (cardiovascular, digestive and respiratory systems). It is also required for their differentiation.

21. Goldberg-Shprintzen Syndrome
Facial dysmorphic features include sloping forehead, depressed nasal bridge, high arched palate, hypertelorism, pointed chin, large distorted ears
Congenital absence of the corpus callosum can result in intractable seizures
Hirschsprung’s disease

22. Goldberg-Shprintzen Syndrome
Figure 1. Patient 1 with distinct facial dysmorphic features of the Goldberg-Shprintzen syndrome: sloping forehead, depressed nasal bridge, mild hypertelorism, pointed chin, and large distorted ears.
Shinawi, M. et al

23. CS Genetics and Neurology consulted Plan for pull through tomorrow
Cranial US : Normal
Brain MRI: Normal
Karyotype: no evidence of Trisomy 21
Metabolic workup: Negative
Plan for pull through tomorrow
UGI with SBFT today

24. Conclusions
Hirschsprung’s disease may be far more a generalized autonomic neuropathy than an isolated entity and should be treated as such.

25. References
Ahola, JA., Koivusalo, A., et al. “Increased incidence of Hirschsprung’s disease in patients with hypoplastic left heart syndrome– a common neural crest-derived etiology?” Journal of Pediatric Surgery 44: (2009), Kapur, RP. “Practical pathology and genetics of Hirschsprung’s Disease.” Seminars in Pediatric Surgery 18 (2009), Larsen’s Human Embryology, 4th edition, 2008, Ch2. Parisi, MA. “Hirschsprung Disease Overview.” GeneReviews. Seattle: Shahar, E., Shinawi, M. “Neurocristopathies Presenting with Neurologic Abnormalities Associated with Hirschsprung’s Disease.” Pediatric Neurology, 28:5 (2003), Shimotake, T., Iwai, N., Yanagiahara, J., et al. “Impaired Proliferative Activity of Mesenchymal Cells Affects the Migratory Pathway for Neural Crest Cells in the Developing Gut of Mutant Murine Embryos.” Journal of Pediatric Surgery, 30: 3 (1995), Stovroff, M., Dykes, F., Teague, GW. “The Complete Spectrum of Neurocristopathy in an Infant With Congenital Hypoventilaion, Hirschsprung’s Disease and Neuroblastoma.” Journal of Pediatric Surgery, 30:8 (1995), Turkdogan-Sozuer, D., Ozed, MM., et al. “Hemimegalencephaly and Hirschsprung’s Disease: A Unique Association.” Pediatric Neurology 18:5 (1998),