The Non-Enteric Phenotypes of Hirschsprung's Disease in Humans and the Spotting Lethal Rat

Abstract

Hirschsprung's disease (HSCR) is a condition that was once labelled as purely enteric. The problem arises from the lack of nerve cells in the distal portion of the gastrointestinal tract and this non-functioning, aganglionic portion of the gut causes bowel obstruction. With the discovery of increasing numbers of associated genes, phenotypes and syndromes, it is becoming better known as a multisystem disorder. There are 10 known genes causing HSCR, with the RET proto-oncogene being the major one implicated in its pathogenesis. There may be dozens more unknown genes causing minor or modifying effects. Other genes such as EDNRB, EDN3, PHOX2B, and SOX10 are gaining attention as they are involved in syndromic HSCR. In some cases this can translate to a more severe form of disease with longer aganglionosis. Aside from modifying HSCR severity, these genes also have pleomorphic effects particularly on neural crest derived tissues. Subsequently this translates to various effects on the central, peripheral and autonomic nervous systems, endocrine and integumentary systems. This is the central concept behind the term "neurocristopathy". This thesis provides a background on the genetics and phenotypes of HSCR as a neurocristopathy. We also review neural crest dysfunction associated with HSCR disease syndromes. Of particular interest are the autonomic nervous system (ANS) and the adrenal medulla, both of which are neural crest derived. The animal model of HSCR used in these studies is the spotting lethal (sl) rat, which carries an endothelin receptor B (Ednrb) mutation causing HSCR, and a piebald coat. Studies on the sl rat have given us clues on other possible effects of neural crest dysfunction. We found that not only are Ednrb mutant rats smaller than their wild type counterparts, but so are their adrenal glands in proportion to body size. The urinary catecholamines noradrenaline (NA), adrenaline (AD) and dopamine (DA), measured as markers of adrenal medullary function, were also found to be somewhat decreased compared to wild type rats. We asked if this finding was reproducible and relevant to humans. Therefore a similar investigation was conducted in HSCR patients, where we found a decrease in AD, but not NA and DA. We discuss the possible reasons for this discrepancy, with one possibility being that NA is increased in compensation for the lack of NA. Taking the above into account, we propose that all patients, even with non-syndromic HSCR (particularly those genetically susceptible) may be prone to neurologic, endocrine or perhaps integumentary disease as they age. With better post-operative outcomes and increased survival, newborns with HSCR who have had resection operations would have entered into middle to late childhood by now, while other patients treated decades ago would be middle aged. Studying this population of patients may reveal previously undetected ANS dysfunction or other abnormalities, and we suggest that HSCR patients whether syndromic or not, would benefit from targeted long-term follow-up as they survive into adulthood. In effect, our findings give some incentive for studying the effect of EDNRB pathway polymorphisms on normal development and autonomic variability in the normal population.