Hirschsprung disease, or congenital aganglionic megacolon, is commonly assumed 
to be a sex-modified multifactorial trait. To test this hypothesis, complex 
segregation analysis was performed on data on 487 probands and their families. 
Demographic information on probands and the recurrence risk to relatives of 
probands are presented. An increased sex ratio (3.9 male:female) and an elevated 
risk to sibs (4%), as compared with the population incidence (0.02%), are 
observed, with the sex ratio decreasing and the recurrence risk to sibs 
increasing as the aganglionosis becomes more extensive. Down syndrome was found 
at an increased frequency among affected individuals but not among their 
unaffected sibs, and the increase was not associated with maternal age. Complex 
segregation analysis was performed on these family data. The families were 
classified into separate categories by extent of aganglionosis. For cases with 
aganglionosis beyond the sigmoid colon, the mode of inheritance is compatible 
with a dominant gene with incomplete penetrance, while for cases with 
aganglionosis extending no farther than the sigmoid colon, the inheritance 
pattern is equally likely to be either multifactorial or due to a recessive gene 
with very low penetrance. A model of gene action with random effects during 
morphogenesis is compatible with our observations.