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.
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.
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
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
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.
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