Hirschsprung disease: associated syndromes and genetics

Jeanne Amiel ^1*, Eileen Sproat-Emison ², Merce Garcia-Barcelo ³, Francesca Lantieri ⁴, Gregor Burzynski ⁵, Salud Borrego ⁶, Anna Pelet ¹, Stacy Arnold ², Xiaoping Miao ³, Paola Griseri ⁷, Alice S Brooks ⁸, Guillermo Antinolo ⁶, Loïc De Pontual ¹, Mathieu Clement-Ziza ¹, Arnold Munnich ¹, Carl Kashuk ², Kristen West ², Kenneth Kak-Yuen Wong ³, Stanislas Lyonnet ¹, Aravinda Chakravarti ², Paul Kwong-Hang Tam ³, Isabella Ceccherini ⁷, Robert MW Hofstra ⁵ and Raquel Fernandez ⁶

¹ Universite Paris 5-Descartes, France
² Johns Hopkins University School Of Medicine, United States
³ The University Of Hong Kong, China
⁴ Universita Degli Studi Di Genova, Italy
⁵ University Of Groningen, Netherlands
⁶ Biomédica en Red de Enfermedades Raras, Spain
⁷ Istituto G. Gaslini, Italy
⁸ Erasmus Mc, Rotterdam, Netherlands

^* To whom correspondence should be addressed. E-mail: amiel{at}necker.fr.

Accepted 27 August 2007

Abstract

Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5,000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-mendelian malformation with low, sex-dependant penetrance, variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and 5 loci have been found to be involved in HSCR development.