Rodolphe Soret and his colleagues in Canada and France recently published what I consider a landmark paper in pediatric pathology. It provides new insights into the origins of a highly prevalent childhood disease. Hirschsprung disease (HSCR) is a congenital form of megacolon that occurs when the ganglion cells of the digestive tract fail to develop, impairing or eliminating function. The disease occurs in approximately one of every 5,000 live births, making it a very common disorder in the pediatric population – and therefore one worthy of extensive investigation. The paper I chose is extremely important because it describes a new mechanism to explain the pathogenesis of HSCR. The researchers began by generating a mouse model of HSCR, named Holstein. The model was created to carry a mutation that results in increased secretion of collagen VI, which the authors determined renders the extracellular matrix unwelcoming to neural crest cell migration in the embryonic bowel. Why is this mutation relevant? The absence of ganglion cells in HSCR arises from a lack of neural crest migration into the large intestine during prenatal development. In the mouse model, this defect is further complicated through interaction with other extracellular matrix proteins like fibronectin, interfering with the development of the enteric nervous system. The authors also examined cross-sections of muscle strips from a human HSCR cohort of 16 children (12 with isolated short-segment disease and four with combined HSCR and Down syndrome). They observed that the myenteric ganglia from a ganglionated region of the patients’ intestines were surrounded by abundant collagen VI microfibrils, lending strength to this conclusion. In the children with Down syndrome, the effect was accentuated – and since the human collagen VI genes (COL6A1 and COL6A2) are located on chromosome 21, this finding establishes a connection that could potentially explain the frequent association of HSCR with Down syndrome. The strengths of the paper include its use of powerful methodology and well-designed experiments. The potential weakness, however, is that the experimental work was done in an animal model. It will be interesting to see the reproducibility of these initial findings across other species, particularly when the research reaches its human stage. After that occurs, I anticipate that future research will focus on the genes involved in collagen synthesis in patients with HSCR and other forms of constipation. It’s likely that analysis of HSCR specimens for variations in collagen VI (and possibly other collagen genes) at the histopathological level will start to appear more frequently in the literature. This paper may eventually have a significant impact on our understanding of HSCR, our ways of classifying it, and our methods of diagnosis. Although several genes have been linked to the pathogenesis of HSCR, including RET, GDNF, NRTN, EDNRB, EDN3, ECE1 and others, there’s still a case of “missing heritability.” We still don’t have a plausible explanation for the many forms of HSCR that are not related to these mutations – and, in time, it may emerge that collagen gene upregulation holds the key.
Variations on a Drop by James Nichols
A Paper to Circulate by Ian Cree
Hyperspectral Disease Diagnosis by Peter Griffiths
Diagnosis: Digital by Liron Pantanowitz
Collagen and the Colon by Miguel Reyes-Múgica
Newsletters
Receive the latest pathology news, personalities, education, and career development – weekly to your inbox.
