Challenges in the diagnosis of intestinal neuronal dysplasia type B:A look beyond the number of ganglion cells

Intestinal neuronal dysplasia type B(IND-B)is a controversial condition among gastrointestinal neuromuscular disorders.Constipation is its most common clinical manifestation in patients.Despite intense scientific research,there are still knowledge gaps regarding the diagnostic criteria for IND-B in the histopathological analysis of rectal biopsies.The guidelines published in the past three decades have directed diagnostic criteria for quantifying the number of ganglion cells in the nervous plexus of the enteric nervous system.However,it is very complex to distinguish numerically what is pathological from what is normal,mainly because of the difficulty in determining a reliable control group composed of healthy children without intestinal symptoms.Thus,a series of immunohistochemical markers have been proposed to assist in the histopathological analysis of the enteric nervous system.Several of these markers facilitate the identification of other structures of the enteric nervous system,in addition to ganglion cells.These structures may be related to the etiopathogenesis of IND-B and represent new possibilities for the histopathological diagnosis of this disease,providing a view beyond the number of ganglion cells.This review critically discusses the aspects related to the disease definitions and diagnostic criteria of this organic cause of constipation.

Intestinal neuronal dysplasia type B:A still little known diagnosis for organic causes of intestinal chronic constipation

Intestinal neuronal dysplasia type B(IND-B) is a controversial entity among the gastrointestinal neuromuscular disorders. It may occur alone or associated with other neuropathies, such as Hirschsprung's disease(HD). Chronic constipation is the most common clinical manifestation of patients. IND-B primarily affects young children and mimics HD, but has its own histopathologic features characterized mainly by hyperplasia of the submucosal nerve plexus. Thus, IND-B should be included in the differential diagnoses of organic causes of constipation. In recent years, an increasing number of cases of IND-B in adults have also been described, some presenting severe constipation since childhood and others with the onset of symptoms at adulthood. Despite the intense scientific research in the last decades, there are still knowledge gaps regarding definition, pathogenesis, diagnostic criteria and therapeutic possibilities for IND-B. However, in medical practice, we continue to encounter patients with severe constipation or intestinal obstruction who undergo to diagnostic investigation for HD and their rectal biopsies present hyperganglionosis in the submucosal nerve plexus and other features, consistent with the diagnosis of IND-B. This review critically discusses aspects related to the disease definitions, pathophysiology and genetics, epidemiology distribution, clinical presentation, diagnostic criteria and therapeutic possibilities of this still little-known organic cause of intestinal chronic constipation.

Mutation of RET proto-oncogene in Hirschsprung's disease and intestinal neuronal dysplasia

AIM： To investigate the genetic relationship between Hirschsprung＇s disease （HD） and intestinal neuronal dysplasia （IND） in Chinese population.METHODS： Peripheral blood samples were obtained from 30 HD patients, 20 IND patients, 18 HD/IND combined patients and 20 normal individuals as control. Genomic DNA was extracted according to standard procedure. Exons 11,13,15,i7 of RET proto-oncogene were amplified by polymerase chain reaction （PCR）. The mutations of RET proto-oncogene were analyzed by single strand conformational polymorphism （SSCP） and sequencing of the positive amplified products was performed.RESULTS： Eight germline sequence variants were detected. In HD patients, 2 missense mutations in exon 11 at nucleotide 15165 G→A （G667S）, 2 frameshifc mutations in exon 13 at nucleotide 18974 （18974insG）, 1 missense mutation in exon 13 at nucleotide 18919 A→G （K756E） and 1 silent mutation in exon 15 at nucleotide 20692 G→A（Q916Q） were detected. In HD/IND combined patients, 1 missense mutation in exon 11 at nucleotide 15165 G→A and 1 silent mutation in exon 13 at nucleotide 18888 T→G （L745L） were detected. No mutation was found in IND patients and controls.CONCLUSION： Mutation of RET proto-oncogene is involved in the etiopathogenesis of HD. The frequency of REr proto-oncogene mutation is quite different between IND and HD in Chinese population, IND is a distinct clinical entity genetically different from HD.