HISTOLOGY AND HISTOPATHOLOGY

Cellular and Molecular Biology

 

Review

Hirschsprung’s disease as a model of complex genetic etiology

Salud Borrego1,2, Macarena Ruiz-Ferrer1,2, Raquel M. Fernández1,2 and Guillermo Antiñolo1,2

1Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain and 2Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.

Offprint requests to: Salud Borrego, MD, Phd, Department of Genetics, Reproduction and Fetal Medicine, University Hospital Virgen del Rocío, Avda. Manuel Siurot s/n, 41013 Sevilla, Spain. e-mail: salud.borrego.sspa@juntadeandalucia.es


Summary. Hirschsprung disease (HSCR), or aganglionic megacolon, is a developmental disorder characterised by the absence of ganglion cells along variable length of the distal gastrointestinal tract, leading to the most common form of functional intestinal obstruction in neonates and children. Aganglionosis is attributed to a failure of neural crest cells to migrate, proliferate, differentiate or survive during enteric nervous system (ENS) development in the embryonic stage. The incidence of HSCR is estimated at 1/5000 live births and most commonly presents sporadically with reduced penetrance and male predominance, although it can be familial and may be inherited as autosomal dominant or autosomal recessive. In 70% of cases, HSCR occurs as an isolated trait and in the other 30% HSCR is associated with other congenital malformation syndromes. HSCR has a complex genetic etiology with several genes and loci being described as associated with either isolated or syndromic forms. These genes encode for receptors, ligands (especially those participating in the RET and EDNRB signaling transduction pathways), transcriptional factors or other cell elements that are usually involved in the neural crest cell development and migration that give rise to ENS. Nevertheless, the RET proto-oncogene is considered the major disease causing gene in HSCR. A common RET variant within the conserved transcriptional enhancer sequence in intron 1 has been shown to be associated with a great proportion of sporadic cases and could act as a modifier by modulating the penetrance of mutations in other genes and possibly of those mutations in the RET proto-oncogene itself
. Histol Histopathol 28, 1117-1136 (2013)

Key words: Hirschsprung’s disease, Enteric nervous system, RET proto-oncogen, Molecular genetics

DOI: 10.14670/HH-28.1117