Hirschsprung's disease (HSCR, OMIM 142623), also known as intestinal ganglion cell disease, is a rare congenital developmental disorder of intestinal malformation. It has been observed other organ abnormalities except for obstruction of the bowels in an infant, such as gastrointestinal malformations, cleft palate, renal dysfunction, cardiac malformations, craniofacial anomalies, and polydactyly, occurred in 18% of patients with HSCR in previous studies[1]. The average incidence of HSCR in live births is about 1/5000. There are significant racial differences, with the highest morbidity in Asia, especially in China. The incidence of HSCR in men is 2–4 times that of women. Pathologically, HSCR is characterized by congenital intestinal blockage caused by the absence or dysfunction of ganglion cells in the submucosal plexus and intermuscular plexus of the intestinal wall. The etiology of HSCR mainly focuses on the abnormal proliferation, differentiation and migration of intestinal nerve trunk [2, 3]. Intestinal neural crest cell (NCC) migrate and implant into the whole intestine at 5 to 12 weeks of gestation. HSCR is the most common digestive tract malformation in children, and it is a typical developmental disorder of enteric nervous system (ENS)[3]. Most cases of HSCR are sporadic, but there exists the inheritance mode of autosomal dominant, recessive inheritance, with incomplete dominance and diversity phenotypes[4, 5]. The main clinical manifestation is complete or incomplete intestinal obstruction. Severe cases are manifested as the failure of passing the first stool within 48 h after birth. Abdominal distention, vomiting, or neonatal enterocolitis, which seriously affects the quality of life of children and even endangers their lives. In recent years, with the development of high-throughput sequencing and the increasing incidence of HSCR, domestic and foreign scholars attach great importance to it. Therefore, the research on the pathogenesis of HSCR has become a hot topic.
Genetic studies have shown that HSCR-related susceptibility genes are mainly derived from two major signaling pathways and one related transcription factors during ENS development[6]. One is the RET/GDNF/GFRA1 signaling pathway. The RET gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related molecules, neurturin, artemin and persephin, these molecules are linked to glycosylphosphatidylinositol-anchored coreceptors (GFRalpha1/2/2/4), activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations[7, 8]. RET knockout mice exhibited intestinal neuron deletion, superior cervical ganglion deletion, renal hypoplasia or dysgenesis[9, 10]. The other is Endothelin 3-Endothelin Receptor B(EDNRB) signaling Pathway and transcriptional factor SOX10.
Guanylyl cyclase C (GUCY2C) is a transmembrane receptor protein whose expressed mainly in intestinal epithelial cells[11]. Activated GUCY2C can convert guanosine-5'-triphosphate (GTP) into cyclic Guanosine monophosphate (cGMP) and increases the amount of cGMP in cells. Increased cGMP will result in activation of a series of downstream signals, such as including cGMP-dependent protein kinases (PKGs), cyclic nucleotide-gated (CNG) channels and phosphodiesterases(PDEs). These functions are essential for the balance of electrolytes and fluids and tight junctional barrier function of the intestinal epithelium[12]. Abnormal function of GUCY2C gene may lead to autosomal dominant hereditary diarrhea and are predisposed to inflammatory bowel disease[13]. GUCY2C gene is rarely reported as a direct cause of HSCR.
In this study, we collected a trio pedigree with HSCR. The patient showed typical HSCR symptoms. Through gene sequencing, we identified the pathogenic genes of the family. Scientific guidance was made for future fertility and prenatal screening of the family, so as to provide a richer basis for the pathogenic gene spectrum of HSCR.