Hirschsprung disease is a congenital form of aganglionic megacolon that results 
from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, 
although it may be associated with several inherited conditions, such as 
multiple endocrine neoplasia type 2. The rearranged during transfection (RET) 
proto-oncogene is the major susceptibility gene for Hirschsprung disease, and 
germline mutations in RET have been reported in up to 50% of the inherited forms 
of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease. 
The prevalence of Hirschsprung disease in multiple endocrine neoplasia type 2 
cases was recently determined to be 7.5% and the cooccurrence of Hirschsprung 
disease and multiple endocrine neoplasia type 2 has been reported in at least 22 
families so far. It was initially thought that Hirschsprung disease could be due 
to disturbances in apoptosis or due to a tendency of the mutated RET receptor to 
be retained in the Golgi apparatus. Presently, there is strong evidence favoring 
the hypothesis that specific inactivating haplotypes play a key role in the 
fetal development of congenital megacolon/Hirschsprung disease. In the present 
study, we report the genetic findings in a novel family with multiple endocrine 
neoplasia type 2: a specific RET haplotype was documented in patients with 
Hirschsprung disease associated with medullary thyroid carcinoma, but it was 
absent in patients with only medullary thyroid carcinoma. Despite the limited 
number of cases, the present data favor the hypothesis that specific haplotypes 
not linked to RET germline mutations are the genetic causes of Hirschsprung 
disease.