Advances in understanding functional variations in the Hirschsprung disease spectrum (variant Hirschsprung disease)

Abstract

Hirschsprung disease (HSCR) is a fairly well understood congenital, genetically based functional obstruction due to the congenital absence of ganglion cells in the distal bowel. However, although over 90% of Hirschsprung cases conform to the normally accepted histological diagnostic criteria, it has become increasingly clear that in addition to HSCR, there is a group of functional disturbances relating to a number of other congenital neurodysplastic conditions causing some degree of gastrointestinal tract malfunction. Although these represent a variety of possibly separate conditions of the enteric nervous system, this spectrum it would appear to be also influenced by similar developmental processes. The term "variant Hirschsprung" is commonly used to describe these conditions, but ganglion cells are mostly present if abnormal in number and distribution. These conditions are a problem group being amongst the most difficult to diagnose and treat with possible practical and legal consequences. The problem appears to be possibly one of definition which has proven difficult in the relative paucity of normal values, especially when correlated to age and gestation. It is the purpose of this paper to review the current position on these conditions and to explore possible shared common pathogenetic and genetic mechanisms. This article explores those conditions where a similar pathogenetic mechanisms to HSCR can be demonstrated (e.g. hypoganglionosis) as well as other neural features, which appear to represent separate conditions possibly linked to certain syndromes.

Cell therapy for GI motility disorders: comparison of cell sources and proposed steps for treating Hirschsprung disease

“…The resulting ENS is a complex interconnected network containing~500 million neurons in humans; more than the spinal cord (24,26). Gut motility disorders can arise from the loss of subtypes of enteric neurons as occurs in some forms of diabetic gastroparesis, achalasia, and Chagas disease (28,42,50,58) or the congenital absence of the ENS, which occurs in Hirschsprung disease (6,12,31,44,49,54). GI motility disorders caused by enteric neuropathies are some of the most clinically challenging GI conditions to manage (18 -20, 42) and thus there has been considerable interest in the potential of cell therapy to treat such disorders (9,11,28).…”

Waardenburg Syndrome with Isolated Deficiency of Myenteric Ganglion Cells at the Sigmoid Colon and Rectum

“… 19 , 20 Regarding one of the previously reported cases, 6 Moore suggested that the isolated deficiency of myenteric ganglion cells seen therein could represent a secondary mechanism or apoptosis of the ganglia due to an immune reaction. 4 We suggest that myenteric ganglion cells that had already migrated were eliminated by an eosinophil-mediated mechanism in these three cases.…”

“…HD is defined as a functional intestinal obstruction due to the congenital absence of ganglion cells in both Meissner and Auerbach plexuses in the distal colon. 4 , 10 As is common in HD, the distal edges of myenteric and submucosal ganglion cells are aligned. 4 However, Kapur reported that the distal edge of submucosal ganglion cells was significantly more proximal than the distal edge of myenteric ganglion cells in 19/59 cases.…”

“… 4 , 10 As is common in HD, the distal edges of myenteric and submucosal ganglion cells are aligned. 4 However, Kapur reported that the distal edge of submucosal ganglion cells was significantly more proximal than the distal edge of myenteric ganglion cells in 19/59 cases. 11 The reverse was rare (1/59 cases) and the gap was small.…”

Diagnostic Algorithm in Hirschsprung's Disease: Focus on Immunohistochemistry Markers

“…Hirschsprung disease (HD) is a congenital, genetically-based functional obstruction due to the congenital absence of ganglion cells in the distal bowel (aganglionosis) (1,2). The absence of ganglion cells along with an analysis of hypertrophy and hyperplasia of nerves in the nerve plexus of submucosa and muscularis mucosae in rectal biopsy specimens (RB) are regarded as potential hallmarks for its diagnosis (3).…”