Review Article Clinics in Surgery Published: 11 Oct, 2017 The Evolving Genetic Landscape of Hirschprung Disease: An Update and Review Amit Kumar Yadav* and Gaurav Chopra Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India Abstract Hirschsprung Disease (HD) is a developmental disorder characterized by the complete absence of ganglion cells in the distal gastrointestinal tract. It is the most common cause of functional intestinal obstruction in neonates and children. The aganglionosis is believed to be either due to failure of neural crest cells to migrate, proliferate, differentiate or survive during gut development in the embryonic stage. The incidence of HD is estimated at 1/5000 live births and shows a male predominance. It is usually sporadic, although it can be familial and may be inherited as autosomal dominant or autosomal recessive. In 70% of cases, HD occurs as an isolated trait and in the other 30% it is associated with other congenital malformation syndromes. HD has a complex multifactorial etiology, and genetic factors play a key role in its pathogenesis. Several gene loci appear to be involved. Many of these have been identified by conducting Genome Wide Association (GWAS) studies and recently by Next Generation Sequencing (NGS). These genes encode for receptors, ligands (especially those participating in the RET, EDNRB and Semaphorin signaling pathways), transcriptional factors (PHOX2B & SOX10). These genes are involved in the neural crest cell development and migration that give rise to ganglion cells. Overall, the RET proto-oncogene is considered the major disease causing gene in HD. A greater understanding of the genetic landscape of this disease might pave way for genetic counseling, prenatal and preimplantation diagnosis in the management of HD. Keywords: Hirschprung disease; Genetics; RET; Genome wide association studies (GWAS); Next generation sequencing (NGS); Semaphorins Introduction OPEN ACCESS Hirschsprung Disease (HD), or congenital intestinal aganglionosis, is a pediatric disorder which *Correspondence: is characterized by complete absence of ganglion cells from a part of the intestine. Its incidence is Amit Kumar Yadav, Department of reported to be 1:5000 births [1]. The neuronal ganglion cells are of neural crest origin. Since during Pathology, Vardhman Mahavir Medical development the migration of these cells is from proximal to distal the aganglionic segment typically College and Safdarjung Hospital, includes the distal rectum and proximal extent is variable. The absence of ganglion cells has been New Delhi, 110029, India, Tel: attributable to either failure of migration of these enteric neural crest cells or due to absence of 9101126707281; survival, proliferation or differentiation of these cells [2]. E-mail: [email protected] Received Date: 08 Jul 2016 When the aganglionosis is restricted to the rectosigmoid colon it is known as short-segment disease. These represent the vast majority (80%) of cases of HD. However, in approximately 15% to Accepted Date: 17 Sep 2017 20% patients the aganglionosis extends proximal to the sigmoid colon which is designated as long- Published Date: 11 Oct 2017 segment disease. In about 5% cases the aganglionosis involves the entire colon called total colonic Citation: aganglionosis. In extremely rare situation the aganglionosis is seen extending into small intestine Yadav AK, Chopra G. The Evolving or even more proximally, the so called total intestinal aganglionosis [3]. This condition is invariably Genetic Landscape of Hirschprung fatal [4]. Disease: An Update and Review. Clin Surg. 2017; 2: 1672. The patients typically present with inability to pass meconium within first 48 hours of life. The other modes of presentation include constipation, vomiting along with painful and distended Copyright © 2017 Amit Kumar abdomen. The abdominal distension can be sometimes quite massive due to huge distension of the Yadav. This is an open access colon known as megacolon. However, sometimes it presents in older children or adult. Thus in cases article distributed under the Creative presenting with chronic constipation in these age groups possibility of HD should be kept in mind. Commons Attribution License, which permits unrestricted use, distribution, The diagnosis of HD is established by histopathological examination to show absence of ganglion cells in submucosal plexus. Suction biopsy is the preferred method as it is safe and does and reproduction in any medium, not require general anesthesia. Other findings seen in biopsies include hypertrophic nerve fibers provided the original work is properly [5]. Acetylcholinesterase histochemistry shows abnormally increased nerve fibers in the mucosa cited. Remedy Publications LLC., | http://clinicsinsurgery.com/ 1 2017 | Volume 2 | Article 1672 Amit Kumar Yadav, et al., Clinics in Surgery - Pediatric Surgery Table 1: Chromosomal abnormalities seen in association with HD and their underlying gene loci. Chromosome abnormality Clinical features Chromosome locus (Gene) % of individuals with HD Impaired learning ability, short stature, congenital heart Down syndrome Trisomy 21 0.6%-3% disease, craniofacial features Deletion 10q11 Impaired learning ability, hypotonia del110q11.2(RET) Unknown Deletion 10q23 Mostly isolated HD; one with rectocutaneous fistula del110q.23.1(NRG3) Unknown Impaired learning ability, growth failure, craniofacial Deletion 13q del113q22(EDNRB) Unknown features Impaired learning ability, microcephaly, craniofacial Unknown Deletion 2q22 del 2Qq22(ZEB2) features, seizures Impaired learning ability, short stature, craniofacial Deletion 4p12-p13 del4p12(PHOX2B) Unknown features Deletion/duplication 17q21 Impaired learning ability, multiple congenital anomalies Del17q21/dup17q21-q23 (Unknown) Unknown Table 2: Syndromes associated with HD. Syndrome Features Chromosome locus/gene % with HD Retinal dystrophy, obesity, impaired learning ability, Bardet-Biedel syndrome Atleast 14 loci/genes 2%-10% [9] polydactyly, hypogenitalism, renal abnormalities Cartilage hair hypoplasia anauxetic Short limbed dwarfism, sparse hair, immune defects 9p13.3/RMRP 7%-9% [10] dysplasia spectrum disorder 4p13/PHOX2B 10q11.21/RET Congenital central hypoventilation Hypoxia, reduced ventilator drive, neuroblastoma 5p13.2/GDNF 20% [11] syndrome (CCHS) 20q13.32/EDN3 11p14.1/BDNF Familial dysutonomia (Riley-day Sensory and autonomic dysfunction(including abnormal tear, 9p31.3/ELP1(IKBKAP) Unknown [12] syndrome) sweat and saliva production) Distal digital hypoplasia, diaphragmatic hernia, CHD, Fryns syndrome Unknown Unknown [13] craniofacial, impaired learning ability Craniofacial anomaly, microcephaly, impaired learning ability, 10q22.1/KIFIBP(KIAA1279) Goldberg-Shprintzen syndrome Common [14] polymicrogyria Others Impaired learning ability, hydrocephalus, corpus callosum Llsyndrome Xq28 / L1 CAM Rare [15] agenesis, adducted thumbs Medullary thyroid carcinoma, pheochromocytoma, MEN 2A/FMTC 10q11.21 I RET 1% [16] hyperparathyroidism Medullary thyroid carcinoma, pheochromocytoma, mucosal MEN 2B and intestinal neuromas, skeletal abnormalities, corneal 10q11.21 /RET Rare [17] changes Impaired learning ability, microcephaly, craniofacial Mowat-Wilson syndrome abnormalities,Congenital heart disease, corpus callosum 2q22.3 /ZEB2 41% - 71% [18] agenesis, epilepsy, short stature 13q22.3/EDNRB Waardenburg syndrome type 4 Common [19] Pigmentary abnormalities, deafness 20q13.32/EDN3 (Waardenburg-Shahsyndrome) 22q13.1/SOX10 Almost 100% 17q11.2/NF1, Neurofibromatosis 1 Café-au-lait macules, neurofibroma, Lisch nodules Unknown [20] 5p13.2/GDNF? Craniofacial abnormalities, impaired learning ability, seizures, Pitt-Hopkins syndrome 18q21.2/TCF4 Unknown [21] hyperventilation, hypoventilation, constipation Impaired learning ability, hypospadias, 2/3 syndactyly, Smith-Lemli-Opitz syndrome 11q13.4/DHCR7 Unknown [22] congenital heart disease, craniofacial abnormalities [6]. Other supporting investigations include anorectal manometry, (Trisomy 21) which has been reported to vary from as low as 2% to abdominal radiographs with barium enema. Intraoperative frozen as high as 10% [8]. sections help in planning an accurate surgery. It is however interesting to note that chromosome 21 does not The phenotype of these patients is however highly variable. This contain any gene which is known to be associated with HD. Therefore, can be explained on the basis of the genetic abnormalities and the in addition to trisomy 21 there are other chromosomal abnormalities interactions between the various genes in cases of HD. An overview which specifically involve HD associated genes like EDNRB, RET, of the current understanding of this highly complex genetic landscape NRG3, ZEB2 and PHOX2B. In case of all of these genes both the alleles is presented in this article. need to be functional for normal status. In case even a single allele Genetic Abnormalities in Hirschprung gets inactivated due to mutation there will be clinical manifestation. This loss of single allele is known as haploinsufficiency. The details of Disease the chromosomal abnormalities leading to HD are presented in Table The genetic abnormalities can be broadly classified into 1. It was observed that only some of the patients of HD possessed chromosomal anomalies and single gene abnormalities. some of these chromosomal anomalies that are every patient of HD does not carry all of these anomalies. On further investigation the Chromosomal anomalies causative genes were