Comprehensive characterization of the genetic landscape of familial Hirschsprung’s disease

Abstract

Background Hirschsprung’s disease (HSCR) is one of the most common congenital digestive tract malformations and can cause stubborn constipation or gastrointestinal obstruction after birth, causing great physical and mental pain to patients and their families. Studies have shown that more than 20 genes are involved in HSCR, and most cases of HSCR are sporadic. However, the overall rate of familial recurrence in 4331 cases of HSCR is about 7.6%. Furthermore, familial HSCR patients show incomplete dominance. We still do not know the penetrance and genetic characteristics of these known risk genes due to the rarity of HSCR families. Methods To find published references, we used the title/abstract terms “Hirschsprung” and “familial” in the PubMed database and the MeSH terms “Hirschsprung” and “familial” in Web of Science. Finally, we summarized 129 HSCR families over the last 40 years. Results The male-to-female ratio and the percentage of short segment-HSCR in familial HSCR are much lower than in sporadic HSCR. The primary gene factors in the syndromic families are ret proto-oncogene (RET) and endothelin B receptor gene (EDNRB). Most families show incomplete dominance and are relevant to RET, and the RET mutation has 56% penetrance in familial HSCR. When one of the parents is a RET mutation carrier in an HSCR family, the offspring’s recurrence risk is 28%, and the incidence of the offspring does not depend on whether the parent suffers from HSCR. Conclusion Our findings will help HSCR patients obtain better genetic counseling, calculate the risk of recurrence, and provide new insights for future pedigree studies.

Diagnostic accuracy of barium enema versus full‐thickness rectal biopsy in children with clinically suspected Hirschsprung's disease: A comparative cross‐sectional study

“…21 Inverted rectosigmoid ratio and TZ were the most sensitive radiologic signs in our study, which was in agreement with previous studies. 2,7,24 Our study shows a high PPV of 0.92 (0.82-0.97) and a relatively lower NPV of 0.80 (0.50-0.94) for the totality of BE findings for the diagnosis of HSD. This finding suggests that a positive BE can be used to determine whether definitive surgical intervention is necessary.…”

“…4 HSD is more common in boys than girls, albeit in familial forms where fair sex distribution is expected. 2,3,6 The cause is thought to be multifactorial, with familial cases associated with a range of genetic mutations identified to date, in addition to sporadic cases. 2 The aganglionic segment in HSD usually begins at the rectum, extends cranially and is associated with the severity of the manifestations.…”

“…2,3,6 The cause is thought to be multifactorial, with familial cases associated with a range of genetic mutations identified to date, in addition to sporadic cases. 2 The aganglionic segment in HSD usually begins at the rectum, extends cranially and is associated with the severity of the manifestations. 1 In about 80% of cases, there is short segment disease that is limited to the rectosigmoid region of the colon; while in 3%-10% of cases, long segment disease that can affect the entire colon is observed.…”

“…HSD is more common in boys than girls, albeit in familial forms where fair sex distribution is expected 2,3,6 . The cause is thought to be multifactorial, with familial cases associated with a range of genetic mutations identified to date, in addition to sporadic cases 2 .…”

“…Hirschsprung's disease (HSD), a common cause of functional intestinal obstruction in children, is caused by congenital absence of ganglion cells in the distal bowel wall 1–4 . HSD is most commonly diagnosed in newborns with delayed passage of meconium or other signs of intestinal obstruction 1,5 .…”