Hirschsprung disease: Insights on genes, penetrance, and prenatal diagnosis

Abstract

The objective of this mini‐review is to provide insights on the advances in the understanding of the genetic variants associated with different manifestations of Hirschsprung disease, which may present with a range of denervation from a short segment of colon to total colonic and small bowel or extensive aganglionosis. A recent article in this journal documented potential gene variants involved in long‐segment Hirschsprung disease in 23 patients. Gene variants were identified using a 31‐gene panel of genes related to Hirschsprung disease or enteric neural crest cell development, as previously reported in the literature. The study identified potentially harmful variants in eight genes across 13 patients, with a detection rate of 56.5% (13/23 patients). Five patients had pathologic variants in RET, NRG1, and L1CAM, and the remainder were considered variants of unknown significance. The authors attempted prenatal diagnosis of Hirschsprung disease utilizing an amniocentesis sample obtained for advanced maternal age in a family with a known deleterious RET mutation, manifested in the father (long‐segment Hirschsprung disease) and older daughter (total colonic aganglionosis). The fetus had the same RET variant but, after several years of follow‐up, has not developed any symptoms of Hirschsprung disease, supporting the conclusion that this RET mutation is an autosomal dominant gene with incomplete penetrance. This experience suggests that genetic counseling is appropriate to carefully assess the justification of prenatal testing, especially, when the phenotype of long‐segment Hirschsprung disease is so variable and the disease is potentially curable with surgery.

Effect of Transumbilical Single-Port Laparoscopic-Assisted Duhamel Operation on Serum CRP and IL-6 Levels in Children with Hirschsprung’s Disease

“…The clinical manifestations of children with HD are mainly refractory constipation, abdominal distension, malnutrition, and stunted growth or Hirschsprung's disease with enterocolitis. In recent years, the improvement of diagnosis and treatment technology has enabled 70–90% of cases to be diagnosed in the neonatal period, and only a few children with milder clinical symptoms are not diagnosed until adolescence or adulthood [ 4 , 5 ]. Since the long-term development of this disease will cause the expansion of the proximal colon to continue to increase, the patient's constipation symptoms will continue to increase or even develop into acute intestinal obstruction, and it is recommended to carry out early active surgical treatment for such children [ 6 ].…”

The Role of Autophagy in Tumor Immune Infiltration in Colorectal Cancer

“…DAPK1 expression induced autophagy and apoptotic activity in various cancers [47] by causing autophagic cell death via reducing the interaction between Beclin-1, Bcl-2, and Bcl-X L [48]. NRG1 gene was considered as an important signature of Hirschsprung disease [49][50][51]. It can be speculated that NRG1 participate in a series of colon disease; in the tumor microenvironment, NRG1 could promote antiandrogen resistance in prostate cancer [52].…”

Performance of Chromosomal Microarray Analysis for Detection of Copy Number Variations in Fetal Echogenic Bowel

“…Loss-of-function mutations in the Ret gene (MIM# 164761) may cause autosomal dominant familial and sporadic Hirschsprung's disease (MIM# 142623), 25 and the Ret gene mutation is detected in more than 50% of patients with familial Hirschsprung's disease. 26 Infants with Hirschsprung's disease may frequently develop symptoms of impaired bowel peristalsis within 2 months after birth, including failure of meconium passage within 48 hours of birth, constipation, vomiting, abnormal pain or distension, and diarrhea, and patients may manifest mental retardation and hypotonia. 27 Besides, the Ret gene was found to show a haploinsufficiency (score of 3).…”