Intestinal neuronal dysplasia

Intestinal neuronal dysplasia (IND) or hypergan-glionosis, a condition that clinically resembles Hirschsprung's disease, was first described by Meier-Ruge in 1971.7 It is often associated with Hirschsprung's disease and may cause failure of clinical improvement after resectional pull-through surgery. In 1983, Fadda et al classified IND into two clinically and histologically distinguished subtypes, called types A and B. Type A occurs in less than 5% of cases and is characterized by congenital aplasia or hypoplasia of the sympathetic innervation, presenting acutely in the neonatal period with episodes of intestinal obstruction, diarrhea and bloody stools. Type B is clinically indistinguishable from Hirschsprung's disease: it is characterized by a malformation of the parasympathetic submucous plexus, and accounts for more than 95% of cases of isolated IND.35

The incidence of isolated IND varies from 0.3 to 40% of all suction rectal biopsies.36 The incidence varies considerably among different countries; some investigators have reported that 25-35% of patients with Hirschsprung's disease have associ ated IND.35,37 However, others have rarely encountered IND in association with Hirschsprung's disease.38 Part of this discrepancy may be due to the persisting confusion over the essential diagnostic criteria.

For a long time, IND has been diagnosed on the basis of four histological criteria applied to acetyl-cholinesterase-stained suction rectal biopsies. In 1991, on the recommendations of a working party (the Consensus of German Pathologists), Borchard et al published diagnostic criteria for IND using a suction rectal biopsy specimen. These comprised two obligatory criteria: hyperplasia of the submu-cosal plexus and an increase in acetyl-cholinesterase-positive nerve fibers in the adventi-tia around submucosal blood vessels. Two additional criteria might be used: neuronal hetero-topia and increased acetylcholinesterase-positive nerve fibers in the lamina propria.39 However, concern has been expressed about whether intestinal neuronal dysplasia can be safely diagnosed by mucosal and submucosal alterations alone, without myenteric plexus abnormalities. Submucosal hyperganglionosis may reflect a normal age-related phenomenon due to immaturity, with clinical and histochemical normalization after the first year of life. Furthermore, it has been reported that most of the patients with submucosal IND have a spontaneous clinical improvement, which is sometimes associated with histological normalization.40,41

To date, submucosal intestinal neuronal dysplasia has been reported in several disorders such as intestinal malformations, meconium plug syndrome, cystic fibrosis, gastroschisis, pyloric stenosis and inflammatory processes involving the gut. The high frequency of histological 'abnormalities' in young infants may represent a normal variant of postnatal development rather than a pathological process. Investigations using more refined and morphometric methods in rectal specimens from infants and children without bowel disease are needed to define the normal range for different ages.41

Patients with IND have been subjected to multiple types of treatment; however, the majority of patients with IND can be treated conservatively. If bowel symptoms persist after at least 6 months of conservative treatment, internal sphincter myec-tomy should be considered. The rapid acetyl-

Genetic aspects 265

cholinesterase technique has been found to be of great value in determining the extent of IND intra-operatively.42

Genetic aspects Hirschsprung's disease

HSCR occurs as an isolated trait in 70% of patients, and is associated with chromosomal abnormality in 12% of cases, trisomy 21 being by far the most frequent (> 90%). Additional congenital anomalies are found in 18% of cases, and include gastrointestinal malformation, cleft palate, polydactyly, cardiac septal defects and craniofacial anomalies. The higher rate of associated anomalies in familial cases than in isolated cases (39% vs. 21%) strongly suggests syndromes with Mendelian inheritance.43 Isolated HSCR appears to be a multi-factorial malformation with low, sex-dependent penetrance, variable expression according to the length of the aganglionic segment, and a suggestion of involvement of one or more gene(s) with low penetrance.44 These parameters must be taken into account for accurate evaluation of the recurrence risk in relatives. Segregation analyses suggested an oligogenic mode of inheritance in isolated HSCR. With a relative risk as high as 200, HSCR is an excellent model for the approach to common multifactorial diseases.

A large number of chromosomal anomalies have been described in HSCR patients. Free trisomy 21 (Down's syndrome) is by far the most frequent, involving 2-10% of ascertained HSCR cases. Syndromes associated with HSCR can be classified as: pleiotropic neurocristopathies; syndromes with HSCR as a mandatory feature; and occasional association with recognizable syndromes. The neural crest is a transient and multipotent embryonic structure that gives rise to neuronal, endocrine and paraendocrine, craniofacial, conotruncal heart and pigmentary tissues. Neurocristopathies encompass tumors, malformations and single or multifocal abnormalities of the tissues mentioned above in various combinations. Multiple endocrine neoplasia type 2 (MEN 2) and Waardenburg syndrome are the most frequent neurocristopathies associated with HSCR.45

Waardenburg syndrome, an autosomal dominant condition, is by far the most frequent condition combining pigmentary anomalies and sensori-neural deafness, resulting from the absence of melanocytes of the skin and the stria vascularis of the cochlea. The combination of HSCR with Waardenburg syndrome defines the WS4 type (Shah-Waardenburg syndrome). Indeed, homozy-gous mutations of the endothelin pathway and heterozygous SOX10 mutations have been identified in WS4 patients with central nervous system involvement including seizures, ataxia and demyelinating peripheral and central neuro-pathies.46

A wide spectrum of additional isolated anomalies have been described among HSCR cases with an incidence of sporadic types varying from 5 to 30%.47,48 No constant pattern is observed. These anomalies include distal limb, sensorineural, skin, gastrointestinal, central nervous system, genital, kidney and cardiac malformations, and facial dysmorphic features.

These data highlight the importance of a careful assessment by a clinician trained in dysmorphol-ogy for all newborns diagnosed with HSCR. Skeletal X-ray and cardiac and urogenital echographic survey should be systematically performed. The observation of one additional anomaly to HSCR should prompt chromosomal studies.

Molecular genetics

Eight genes are known to be involved in HSCR in humans, namely the proto-oncogene RET (RET), glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN), endothelin B receptor (EDNRB), endothelin 3 (EDN3), endothelin converting enzyme 1 (ECE1), SOX10 and SIP1 genes. RET and EDNRB signaling pathways were considered biochemically independent. However, an HSCR patient heterozygous for weak hypomorphic mutations in both RET and EDNRB has recently been reported.49 Each mutation was inherited from a healthy parent. Sox10, otherwise, is involved in cell lineage determination and could be responsible of the reduced expression of EDNRB in the dom mouse.

The RET signaling pathway

The first observation was about an interstitial deletion of chromosome 10q11.2 in patients with TCA

and mental retardation.50 The proto-oncogene RET, identified as disease-causing in MEN 2 and mapping to 10q11.2, was regarded as a good candidate gene, owing to the concurrence of MEN 2A and HSCR in some families and the expression in neural crest-derived cells. Consequently, RET gene mutations were identified in HSCR patients.51 Expression and penetrance of a RET mutation is variable and sex dependent within HSCR families (72% males and 51% females). Over 80 mutations have been identified including large deletions encompassing the RET gene, microdeletions and insertions, nonsense, missense and splicing muta-tions.52,53 Haploinsufficiency is the most likely mechanism for HSCR mutations. Biochemical studies showed variable consequences of some HSCR mutations (misfolding, failure to transport the protein to the cell surface, abolished biological activity).

Despite extensive mutation screening, a RET mutation is identified in only 50% of familial and 15-20% of sporadic HSCR cases.54 However, most families, with a few exceptions, are compatible with linkage at the RET locus.55

Mutations in the RET ligand, such as GDNF, GFRA1-4, NTN, persephin (PSPN) and artemin (ARTN), may occur, but are not sufficient to lead to HSCR.

The endothelin signaling pathway

A susceptibility locus for HSCR in 13q22 was suggested for three main reasons: a significant lod score at 13q22 in a large inbred Old Order Mennonite community with multiple cases of HSCR; de novo interstitial deletion of 13q22 in several patients with HSCR; and synteny between the murine locus for piebald-lethal, a model of aganglionosis, and 13q22 in humans. Subsequently, an EDNRB missense mutation was identified in the Mennonite kindred.56'57 Both EDNRB and EDN3 were screened in a large series of isolated HSCR patients, and EDNRB mutations were identified in approximately 5% of the patients. It is worth mentioning that the penetrance of EDN3 and EDNRB heterozygous mutations was incomplete in those HSCR patients, de novo mutations have not hitherto been observed and short HSCR (S-HSCR) is largely predominant.58


The last de novo mouse model for WS4 in humans is dominant megalon (Dom). The Dom gene is SOX10, a member of the sex-determining factor (SRY)-like, high mobility group (HMG) DNA binding proteins. Subsequently, heterozygous SOX10 mutations have been identified in familial and isolated patients with WS4 (including de novo mutation) with high penetrance.59

Intestinal neuronal dysplasia

Studies have been performed to investigate the potential role of HSCR-associated RET, GDNF, EDNRB and EDN3 genes in the development of IND. They demonstrated that only three RET mutation were detected in patients with HSCR, no mutation in this gene was observed in IND and mixed HSCR/IND patients, HSCR and HSCR/IND patients showed over-representation of a specific RET polymorphism in exon 2, while IND patients exhibited a significantly lower frequency of the same polymorphism comparable with that of controls. These findings may suggest that IND is genetically different from HSCR.

A homozygous mutation of the EDNRB gene in spotting lethal (sl/sl) rats leads to the HSCR phenotype with long segmented aganglionosis. The heterozygous (+/sl) EDNRB-deficient rats revealed more subtle abnormalities of the enteric nervous system: the submucous plexus was characterized by a significantly increased ganglionic size and density, and the presence of hypertrophied nerve fiber strands, resembling the histopathological criteria for IND. Other animal models, such as Ncx/HoxllL.l-defi-cient mice, suggest that many other genes could be involved in the pathogenesis of IND.60


  1. Taviras S, Pachinis V. Development of the mammalian enteric system. Curr Opin Genet Dev 1999; 9: 321.
  2. Lyonnet S, Bolino A, Pelet A et al. A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nat Genet 1993; 4: 346-350.
  3. Gershon MD, Chalazonitis A, Rothman TP. From neural crest to bowel: development of the enteric nervous system. J Neurobiol 1993; 24: 199-214.
  4. Badner JA, Sieber Wk, Garver KL et al. A genetic study of Hirschsprung's disease. Am J Hum Genet 1990; 46: 568-580.
  5. Staiano A, Corazziari E, Andreotti MR, Clouse RE. Esophageal motility in children with Hirschsprung's disease. Am J Dis Child 1991; 145: 310-313.
  6. Larsson LT, Shen Z, Ekbland E et al. Lack of neuronal nitric oxide synthase in nerve fibers of aganglionic intestine: a clue to Hirschsprung's disease. J Pediatr Gastroenterol Nutr 1995; 20: 49-53.
  7. Meier-Ruge W. Uber Ein Erkrankungsbild des colon mit Hirschsprung-Symptomatik. Vehr Dtsch Ges Pathol 1971; 55: 506-510.
  8. Lake BD, Puri P, Nixon HH, Claireaux AE. Hirschsprung's disease. An appraisal of histochemically demonstrated acetylcholinesterase activity in suction rectal biopsy specimens as an aid to diagnosis. Arch Path Lab Med 1978; 26: 288-291.
  9. Romanska HM, Bishop AE, Brereton RJ et al. Increased expression of muscular neural cell adhesion molecule in congenital aganglionosis. Gastroenterology 1993; 105: 1104-1109.
  10. Vanderwinden JM, De Laet MH, Schiffmann SN et al. Nitric oxide synthase distribution in the enteric nervous system of Hirschsprung's disease. Gastroenterology 1993; 105: 969-973.
  11. Vanderwinden JM, Rumessen JJ, Liu H et al. Interstitial cells of cajal in human colon and in Hirschsprung's disease. Gastroenterology 1996; 111: 901-910.
  12. Coran AG, Teitelbaum DH. Recent advances in management of Hirschsprung's disease. Am J Surg 2000; 180: 382-387.
  13. Bill JAH, Chapman ND. The enterocolitis of Hirschsprung's disease: its natural history and treatment. Am J Surg 1962; 103: 70-74.
  14. Elhalaby EA, Coran AG, Blane CE et al. Enterocolitis associated with Hirschsprung's disease: a clinical-radiological characterization based on 168 patients. J Pediatr Surg 1995; 30: 1023-1027.
  15. Swenson O, Fisher JH. Hirschsprung's disease during infancy. Surg Clin North Am 1956; 36: 115-122.
  16. Marty TL, Matlak ME, Hendrickson M et al. Unexpected death from enterocolitis after surgery for Hirschsprung's disease. Pediatrics 1995; 96: 118-121.
  17. Loening-Baucke V. Modulation of abnormal defecation dynamics by biofeedback treatment in chronically constipated children with encopresis. J Pediatr 1990; 116: 214-222.
  18. Taxman TI, Yulish BS, Rothstein FC. How useful is barium enema in diagnosis of infantile Hirschsprung's disease? Am J Dis Child 1986; 140: 881-884.
  19. Aldridge RT, Campbell PE. Ganglion cells distribution in the normal rectum and anal canal: a basis for diagnosis of Hirschsprung's disease by anorectal biopsy. J Pediatr Surg 1968; 3: 475-489.
  20. Milla PJ. Regulatory gut peptides in intestinal neuronal dysplasia and Hirschsprung's disease. In Hadziselimovic F, Herzog B, eds. Falk Symposium 65.

Inflammatory Bowel Disease and Morbus Hirschsprung. Dordrecht: Kluwer Academic Publishers, 1992: 239-250.

  1. Hellstrom PM, Lundberg JM, Holfelt T, Goldstein M. Neuropeptide Y, peptide YY and sympathetic control of rectal tone and anal canal pressure in the cat. Scand J Gastroenterol 1989; 24: 231-243.
  2. Langer JC, Fitzgerald PG, Winthrop AL et al. One vs two stage Soave pull-through for Hirschsprung's disease in the first year of life. J Pediatr Surg 1996; 31: 33-37.
  3. Pierro A, Fasoli L, Kiely EM et al. Staged pull-through for rectosigmoid Hirschsprung's disease is not safer than primary pull-through. J Pediatr Surg 1997; 32: 505-509.
  4. Hackam DJ, Superina RA, Pearl RH. Single stage repair of Hirschsprung's disease: a comparison of 109 patients over 5 years. J Pediatr Surg 1997; 32: 1028-1031.
  5. Jona JZ, Cohen RD, Georgeson KE et al. Laparoscopic pull-through procedure for Hirschsprung's disease. Semin Pediatr Surg 1998; 7: 228-231.
  6. Smith BM, Stainer RB, Lobe TE. Laparoscopic Duhamel pull-through procedure for Hirschsprung's disease in Childhood. J Laparoendosc Surg 1994; 4: 273-276.
  7. Curran TJ, Raffensperger JG. Laparoscopic Swenson pull-through: a comparison with the open procedure. J Pediatr Surg 1996; 31: 1155-1156.
  8. De La Torre- Mondragon L, Ortega-Salgado JA. Transanal endorectal pull-through for Hirschsprung's disease. J Pediatr Surg 1998; 33: 1283-1286.
  9. Langer JC, Minkes RK, Mazziotti MV et al. Transanal one-stage Soave procedure for infants with Hirschsprung's disease. J Pediatr Surg 1999; 34: 148-152.
  10. Albanese CT, Jennings RW, Smith B et al. Perineal one-stage pull-through for Hirschsprung's disease. J Pediatr Surg 1999; 34: 377-380.
  11. Langer JC, Scifert M, Mikes RK. One stage Soave pull-through for Hirschsprung's disease. A comparison of the transanal and open approach. J Pediatr Surg 2000; 35: 820-822.
  12. Teeraratkul S. Transanal one stage endorectal pull-through for Hirschsprung's disease in infants and children. J Pediatr Surg 2003; 38: 184-187.
  13. Miele E, Tozzi A, Staiano A et al. Persistence of abnormal gastrointestinal motility operation for Hirschsprung's disease. Am J Gastroenterol 2000; 95: 1226-1230.
  14. Di Lorenzo C, Flores AF, Reddy SN et al. Small bowel neuropathy in symptomatic children after surgery for Hirschsprung's disease. Gastroenterology 1997; 112: 783A.
  15. Fadda B, Meier WA, Meier-Ruge W et al. Neuronale intestinale Dysplasie: Eine Kritische 10-Jahres-Analyse Klinischer und Bioptischer Diagnostik. Z Kinderchir 1983; 38: 305-311.
  16. Smith VV. Isolated intestinal neuronal dysplasia: a descriptive pattern or a distinct clinicopathological entity? In Hadziselimomic F, Herzog B, eds. Inflammatory Bowel Disease and Morbus Hirschsprung. Dordrecht, The Netherlands: Kluwer Academic, 1992: 203-214.
  17. Kobayashi H, Hirakawa H, Surana R et al. Intestinal neuronal dysplasia is a possible cause of persistant bowel symptoms after pull-through operation for Hirschsprung's disease. J Pediatr Surg 1995; 30: 253-259.
  18. Fadda B, Pistor G, Meier-Ruge W et al. Symptoms, diagnosis and therapy of neuronal intestinal dysplasia masked by Hirschsprung's disease. J Pediatr Surg 1987; 2: 76-80.
  19. Borchard F, Meier-Ruge W, Wiebecke B et al. Innervationsstrunger des Dickdarms - Klassifikation und Diagnostik. Pathologe 1991; 12: 171-174.
  20. Cord-Udy CL, Smith VV, Ahmed S et al. An evaluation of the role of suction rectal biopsy in the diagnosis of intestinal neuronal dysplasia. J Pediatr Gastroenterol Nutr 1997; 24: 1-6.
  21. Koletzko S, Jesh I, Faus- Kebler T et al. Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: a prospective study on interobserver variation and clinical outcome. Gut 1999; 44: 856-861.
  22. Kobayashi H, O'Briain S, Hirakawa H et al. A rapid tecnique for acetylcholinesterase staining. Arch Pathol Lab Med 1994; 118: 1127-1129.
  23. Brooks AS, Breuning MH, Meijers C. Spectrum of phenotypes associated with Hirschsprung disease: an evaluation of 239 patients from a single institution. The Third International Meeting: Hirschsprung Disease and the Correlated Neurocristopathies. France: Evian, 1998
  24. Puffenberger EG, Kauffman ER, Bolk S et al. Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet 1994; 3: 1217-1225.
  25. Decker RA, Peacock ML, Watson P. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-

phenotype correlation. Hum Mol Genet 1998; 7: 129-134.

  1. Edery P, Attie T, Amiel J et al. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nat Genet 1996; 12: 442-444.
  2. Sarioglu A, Tanyel FC, Buyukpamukcu N, Hicsonmez A. Hirschsprung-associated congenital anomalies. Eur J Pediatr Surg 1997; 7: 331-337.

48 Auricchio A, Griseri P, Carpentieri ML et al. Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. Am J Hum Genet 1999; 64: 1216-1221.

  1. Martucciello G, Biocchini M, Dodero P et al. Total colonic aganglionosis associated with interstitial deletion of the long arm of chromosome 10. Pediatr Surg Int 1992; 7: 308.
  2. Edery P, Lyonnet S, Mulligan LM et al. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature 1994; 367: 378-380.
  3. Angrist M, Bolk S, Thiel B et al. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet 1995; 4: 821-830.
  4. Seri M, Yin L, Barone V et al. Frequency of RET mutations in long- and short-segment Hirschsprung disease. Hum Mutat 1997; 9: 243-249.
  5. Attie T, Pelet A, Edery P et al. Diversity of RET protooncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet 1995; 4: 1381-1386.
  6. Bolk S, Pelet A, Hofstra RM et al. A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. Proc Natl Acad Sci USA 2000; 97: 268-273.
  7. Borrego S, Ruiz A, Saez ME et al. RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease. J Med Genet 2000; 37: 572-578.
  8. Kiss P, Orsztovics M. Association of 13q deletion and Hirschsprung's disease. J Med Genet 1989; 26: 793-794.
  9. Puffenberger EG, Hosoda K, Washington SS et al. A missense mutation of endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 1994; 30: 1257-1266.
  10. Auricchio A, Casari G, Staiano A, Ballabio A. Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. Hum Mol Genet 1996; 5: 351-354.
  11. Southard-Smith EM, Angrist M, Eleison JS et al. The Sox10 (Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genom Res 1999; 9: 215-225.
  12. Yamataka A, Datano M, Kobayashi H et al. Intestinal neuronal displasia-like pathology in Ncx/Hox11L.1 deficient mice. J Pediatr Surg 2001; 36: 1293-1296.

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