Congenital Aganglionic Megacolon Research Articles

Hirschsprung's Disease - Review of Clinical Features, Diagnosis and Treatment

Introduction and purpose: Hirschsprung's disease, also known as congenital aganglionic megacolon, is a rare congenital disorder that affects the large intestine. Due to the absence of ganglion cells, the affected segment of the colon becomes narrow and unable to relax. The disease is present from birth but may not always be immediately apparent. In this paper, we will attempt to present the current state of knowledge regarding the diagnosis and treatment of Hirschsprung's disease, based on the analysis of literature available on the PubMed platform.
 Description of the state of knowledge: Hirschsprung's disease (HSCR), also known as congenital aganglionosis of the colon, involves abnormal migration, proliferation, and differentiation of neural crest cells, leading to the absence of autonomic nerve ganglia within the colon. HSCR is associated with mutations in several genes, with RET, GDNF, EDNRB and SOX10 being identified as the main causes of the disease. Mutations in the RET gene are associated with the hereditary form of Hirschsprung's disease. Symptoms of HSCR appear in newborns and may include bilious vomiting, diarrhea associated with enterocolitis, failure to pass meconium within the first 24 hours of life, impaired peristalsis, jaundice, feeding difficulties, and progressive abdominal distension.
 Summary: Diagnosis is typically made based on clinical presentation, imaging studies, and biopsy. Treatment usually involves surgery to remove the affected segment of the colon and reconnect the healthy portions. Although postoperative complications are relatively common, long-term studies suggest that the majority of children with Hirschsprung's disease function well in society.

Overview of Hirschsprung Disease: A Narrative Literature Review

Hirschsprung disease is a congenital malformation resulting from the failure of neural crest cells to migrate into the gastrointestinal tract. The exact cause of this disorder is unknown, but it is suspected that there is an interaction of several factors, including gene mutations and epigenetic mechanisms. This literature review aimed to describe the pathophysiology, clinical symptoms, and treatment of Hirschprung disease. Mild to severe constipation is a common manifestation of Hirschsprung's disease with poor diet, poor weight gain, and progressive abdominal distention. However, diarrhea may be the first sign, as only water can flow around the affected stool. The most serious complication in the neonatal period is Hirschsprung-associated enterocolitis (HAEC), which can occur both preoperatively and postoperatively. Surgery is the definitive treatment in all cases of Hirschsprung's disease, with resection of the aganglionic segment and anastomosis of the bowel proximal to the anus, known as a pull-through procedure. In conclusion, Hirschsprung disease is a congenital aganglionic megacolon or functional obstruction of the large intestine and is caused by multifactorial factors, especially the role of genetic aspects.

A Case Report on 2 years Child: Hirschprung’s Disease

Introduction: Hirschsprung's disease is the most common cause of large intestinal obstructing in neonates. Hirschsprung's disease is a congenital anomaly caused by migratory failure of neural crest cells leading to abnormal innervations of the bowel .The defect begins in the internal and sphincter and extends proximally for a variable length of gut. Hirschprung's disease is a disorder of the gut caused due to congenital absence of ganglion cells in the sub-mucosal and myenteric plexus of intestine. This disease is also known as megacolon or congenital Aganglionic megacolon. Case presentation: A 2 years old male child, known case of Hirschprung’s disease, was brought to AVBRH for further management. As narrated by the mother, the child was not passing stool since birth. There was no history of abdominal distention, vomiting or fever. The child pass the stool with the help of enema which was given to the child in the morning and evening. Mast. Devansh has past history of NICU stay. In View of not passing stools, USG of abdomen and pelvis done. Endorectal pull through surgery was done on 4/02/2021 under general anesthesia. No any past surgical history. There is a past history of rectal biopsy done in 1 1/2 month of age. Conclusion:The patient was admitted in AVBRH for further management. Then the report mainly focused on surgical management and quality nursing care due to which patient was discharged without any further complication and satisfaction.

Abdominal compartment syndrome in a 10-year-old boy with delayed presentation of congenital aganglionic megacolon

Abdominal compartment syndrome (ACS) involves adverse physiologic consequences arising from the increased intra-abdominal pressure, leading to high mortality. However, this syndrome has been scarcely reported in pediatric emergency settings. We describe a 10-year-old boy with ACS presenting with painful abdominal distension, oliguria, and dyspnea. Despite the absence of known congenital anomalies, he had undergone frequent episodes of constipation since 5 years of age, and had not defecated for recent 2 months. With computed tomography scans showing the entire colorectal distension, his manifestations were considered to have stemmed from congenital aganglionic megacolon, which had gone undetected. This case underlines the needs for considering ACS and consequent surgical decompression in a child with severe abdominal distension.

Hirschsprung's Diseases Complicated by Sigmoid Volvulus: A Systematic Review

Hirschsprung's disease and sigmoid volvulus can sometimes be seen in the same patient. To investigate the presence of Hirschsprung's disease in patients with sigmoid volvulus and to discuss the diagnosis and treatment methods. Systematic review. This systematic review has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the methodological quality of systematic reviews guidelines. The PubMed and Scopus databases were scanned using the keywords "Hirschsprung* volvulus*" and "congenital aganglionic megacolon volvulus*". The reference list of the selected studies was reviewed for cross-checking. Two reviewers independently screened the available literature. Only the Hirschsprung's disease cases involving sigmoid volvulus were included, and cases of patients with volvulus in other sites was excluded. There was no restriction with respect to the publication language and type of writing. The primary outcome was morbidity and mortality. A total of 31 cases were analyzed in 22 articles; 97% of the patients were under the age of 40, 90% were male. There was a statistically significant difference in the necessity for relaparotomy between patients who were scheduled for sigmoid volvulus therapy with the suspicion of Hirschsprung's disease and patients who were treated without suspicion of Hirschsprung's disease (0% vs 37.5%, p=0.02). While there was no postoperative death in cases with suspected Hirschsprung disease, this mortality rate was 25% in cases without suspicion (p = 0.08). Hirschsprung's disease should be excluded with rectal biopsy if a patient with sigmoid volvulus is under 40 years of age and has complaints of constipation from childhood.

Gfra1 Underexpression Causes Hirschsprung's Disease and Associated Enterocolitis in Mice.

Background & AimsRET, the receptor for the glial cell line–derived neurotrophic factor (GDNF) family ligands, is the most frequently mutated gene in congenital aganglionic megacolon or Hirschsprung’s disease (HSCR). The leading cause of mortality in HSCR is HSCR-associated enterocolitis (HAEC), which is characterized by altered mucin composition, mucin retention, bacterial adhesion to enterocytes, and epithelial damage, although the order of these events is obscure. In mice, loss of GDNF signaling leads to a severely underdeveloped enteric nervous system and neonatally fatal kidney agenesis, thereby precluding the use of these mice for modeling postnatal HSCR and HAEC. Our aim was to generate a postnatally viable mouse model for HSCR/HAEC and analyze HAEC etiology.MethodsGDNF family receptor alpha-1 (GFRa1) hypomorphic mice were generated by placing a selectable marker gene in the sixth intron of the Gfra1 locus using gene targeting in mouse embryonic stem cells.ResultsWe report that 70%–80% reduction in GDNF co-receptor GFRa1 expression levels in mice results in HSCR and HAEC, leading to death within the first 25 postnatal days. These mice mirror the disease progression and histopathologic findings in children with untreated HSCR/HAEC.ConclusionsIn GFRa1 hypomorphic mice, HAEC proceeds from goblet cell dysplasia, with abnormal mucin production and retention, to epithelial damage. Microbial enterocyte adherence and tissue invasion are late events and therefore unlikely to be the primary cause of HAEC. These results suggest that goblet cells may be a potential target for preventative treatment and that reduced expression of GFRa1 may contribute to HSCR susceptibility.

Diagnostic value of the preoperatively detected radiological transition zone in Hirschsprung's disease.

The cardinal diagnostic sign of congenital aganglionic megacolon, or Hirschsprung's disease (HD), is an aganglionic segment of the distal colon or rectum. To determine the surgical planning of a radiological transition zone (TZ) in HD, this study investigated the association between a radiological TZ and the bowel resection length. A prospective observational study was conducted in children (n = 192) with suspected HD determined by radiological TZ on contrast barium enema, and who underwent pull-through operations. The bowel resection length was ≥10cm above the proximal radiological TZ levels and confirmed by intraoperative frozen sections. In the contrast enema, the presence and level of a radiological TZ were recorded. Correlation of the TZ features with ganglion cells assessed by immunostaining of neuronal nuclei (NeuN) and the odds ratio were calculated. The sensitivity and specificity for diagnosing HD by the presence of a radiological TZ were 86.9 and 92.1%, respectively; Youden's index was 79.0%. The positive and negative predictive values were 91.7 and 87.6%. The kappa value indicating an association between TZ and HD was 0.776 (P < 0.05). The correlation rate between a radiological TZ and the pathological results was 88.5% in the rectosigmoid colon and 44.4% in the descending colon, and was higher in children older than 3 months (85.3%) than in infants (69.0%). A preoperatively determined radiological TZ has potential value to identify the length of resected bowel in patients with HD, and it also has a high predictive value for diagnosis of HD.

Hirschsprung's disease

Hirschsprung's disease (HD) or congenital aganglionic megacolon is characterized by an absence of ganglion cells in the myenteric Auerbach's plexus, the deep submucosal Henle's plexus, and the submucosal Meissner's plexus in the distal colon. The usual presentation of Hirschsprung's disease can be demonstrated by the following clinical scenario. A 3-day-old male presented with failure to pass meconium within 48 h of birth and progressive abdominal distension. Barium study showed dilated colon with no specific zone of transition. The newborn was delivered at 40 weeks gestation after an otherwise normal pregnancy. Transanal rectal biopsy demonstrated the absence of ganglion cells on multiple sections and special staining. The patient underwent an exploratory laparotomy, upon which he was found to have markedly dilated small bowel and colon up to the area of sigmoid. A transverse loop colostomy was performed. The patient recovered well from the initial surgery and underwent definitive surgical therapy of the HD at a later time. The following core competencies are addressed in this article: Medical knowledge, Patient care. Republished with permission from: Prabhakaran S. Absite corner: Hirschsprung's disease. OPUS 12 Scientist 2009; 3(3):44-46.

Hirschsprung’s Disease in Adult Treated by Coloprotectomy and Colo-Anal Anastomosis

Hirschsprung’s disease or congenital aganglionic megacolon, occurs in approximately 1 in every 5000 live births and is about 4 times more frequent in males than in females. Hirschsprung disease is the most frequent aetiology of intestinal occlusion in child. This disease is characterized by lack of ganglionical cells in the submucous membrane and in the myenterical plexuses of the digestive tract in its distal part. Hirschsprung’s disease is a rare pathology Most cases become manifest during the neonatal period, but in rare instances, the disease is initially diagnosed in adult patients.

Severe hyponatremia and repeated intestinal resections for intestinal dysmotility mimicking congenital aganglionic megacolon due to delay in the diagnosis of congenital hypothyroidism.

Congenital hypothyroidism (CH) may present with nonspecific signs and symptoms, though, majority of infants can be asymptomatic. Therefore, understimation and delay in diagnosis may result in severe complications. A 5-month-old female admitted to our clinic with the history of repeated surgical operations due to the diagnosis of congenital aganglionic megacolon. Investigations performed in our clinic revealed the diagnosis of congenital (primary) hypothyroidism due to thyroid agenesis. Histopathologic evaluation of previously resected colon sample revealed normal ganglionic cell included colon. During follow-up she developed severe hyponatremia with a plasma sodium level of 106 mEq/L. Eunatremia was maintained following achievement of euthyroid state. In conclusion, since presenting symptoms can be variable and nonspecific, hypotyhroidism should be kept in mind in the differential diagnosis of patients with persistent abdominal distention mimicking aganglionic megacolon and severe hyponatremia of unknown origin.

Severe birth defects in children perinatal exposed to HIV from a "real-world" setting: Infectious Diseases National Institute, Bucharest, Romania.

IntroductionThe shift in epidemic trends in recent years in Romania shows new problems in regard of HIV vertical transmission, firstly in intravenous drug user's mothers co-infected with hepatitis viruses and with social problems, and secondly the children of young mothers with an old HIV infection and long antiretroviral therapy history.Materials and MethodsWe studied all HIV perinatal exposed children routinely followed up in the Paediatric Department of the National Institute of Infectious Diseases, since January 1st 2006 till December 31st 2012. The analyses consisted of describing the birth defects and association with certain risk factors: gender, mother's age at birth and exposure to antiretrovirals in the first trimester of pregnancy.ResultsWe analyzed 244 children born to HIV-infected mothers. The incidence of HIV infection was 16.39%. The rate of birth defects was 39.34% (96/244 cases). The most frequent findings were cardiac malformations (47/96), followed by musculoskeletal defects (24/96), neurologic defects (20/96), urogenital malformations (13/96), digestive tract defects (3/93), metabolic disorders (2/96) and genetic disorders (2/96). We found nine cases of severe congenital anomalies: complex heart defect, total congenital aganglionic megacolon, anal imperforation, Dandy-Walker syndrome, gangliosidosis, Niemann-Pick syndrome, Down syndrome, true hermaphroditism and cleft palate. Two children died during first year of life due to severe malformations. 9% of cases had associated malformations. The gender rate was in favour of males in group with birth defects (58/38) and with no birth defects (82/66). The median age at birth in mothers was 22 years, similar in both groups. The highest mean age at birth was in offspring's mothers with neurologic congenital defects 25, 15 years old, but is not statistically significant (p=0.1). In the studied period the highest number of birth defects were found in 2012, 37 children, compared with less than 15 in previous years (not statistically significant, p=0.07). In our studied patients the risk of birth defects was not statistically associated with HIV transmission or with exposure to antiretrovirals before and in first trimester of pregnancy (p=0.88).ConclusionThe rate of birth defects among HIV-exposed children was not significantly associated with antiretroviral exposure, but we identify very rare and severe congenital conditions. We have noticed also a trend to increasing number of birth defects in 2012 among studied patients compared to previous years.

Index of Suspicion

* ALT: : alanine aminotransferase AST: : aspartate aminotransferase BUN: : blood urea nitrogen CBC: : complete blood count CNS: : central nervous system CSF: : cerebrospinal fluid CT: : computed tomography ECG: : electrocardiography ED: : emergency department EEG: : electroencephalography ESR: : erythrocyte sedimentation rate GI: : gastrointestinal GU: : genitourinary Hct: : hematocrit Hgb: : hemoglobin MRI: : magnetic resonance imaging WBC: : white blood cell An 11-year-old boy presents to the emergency department with a 1-week history of frequent episodes of nonbloody, nonbilious emesis associated with diarrhea and abdominal cramping. He has urgency and fecal incontinence. He has been afebrile and denies any rashes, joint pain, sick contacts, headaches, or other symptoms. On further questioning, his mother reveals that he has had 2 similar episodes of abdominal distension and diarrhea during the past 6 to 7 years. Between these episodes, she states that he normally has nonbloody, hard stools accompanied by straining and chronic abdominal pain and pain with defecation. When asked specifically, his mother does not remember when he passed his first stool after he was born. On physical examination, his temperature is 37.6°C, pulse is 100 beats per minute, respiratory rate is 16 breaths per minute, blood pressure is 113/62 mm Hg, oxygen saturation is 100% on room air, height is 63 inches (95%), and weight is 36.7 kg (25%). He has abdominal distention and diffuse abdominal tenderness with voluntary guarding. There is palpable stool in the left quadrant. There is no perianal erythema or skin tag, and rectal examination reveals a low anal tone. A CT scan of the abdomen (Figure 1) reveals a markedly distended rectosigmoid colon with circumferential, confluent, and contiguous mural thickening. Basic metabolic profile, CBC, and urinalysis results are unremarkable, but the C-reactive protein level is elevated at 131 mg/L (1248 nmol/L). Because of the concern for enterocolitis, he is empirically given broad-spectrum intravenous antibiotics and transferred to a children’s hospital for further evaluation. Figure 1. A CT scan of the abdomen shows a markedly distended rectosigmoid colon with circumferential mural thickening. A 4-year-old boy presents for evaluation of intermittent fevers of 4 weeks’ duration after 2 separate antibiotic courses prescribed for acute otitis media. He has experienced clear rhinorrhea and …

A Triple Threat: Down Syndrome, Congenital Central Hypoventilation Syndrome, and Hirschsprung Disease

Down syndrome (DS) is recognized by characteristic facial features, intellectual disability, and an increased risk for cardiac malformations and duodenal atresia. Recently, Hirschsprung disease (HSCR), or congenital aganglionic megacolon, has been seen more often among patients with DS. Given the systemic nature of DS-related features, it is natural to attribute neonatal complications to the chromosomal aberration. We describe a biracial male infant with DS who had significantly delayed defecation and required continuous ventilator support, but had no primary cardiac or lung disease. Subsequent evaluations confirmed total colonic aganglionosis. Because we were unable to safely extubate the infant, a diagnosis of congenital central hypoventilation syndrome (CCHS) was considered and confirmed by molecular analysis of the PHOX2B gene, revealing a heterozygous polyalanine repeat-expansion mutation containing 27 repeats (normal gene contains 20 repeats). HSCR coexisting with CCHS is known as Haddad syndrome. This is the first reported case with co-occurrence of DS, CCHS, and HSCR.

Congenital aganglionic megacolon in Nigerian adults: Two case reports and review of the literature

Congenital aganglionic mega colon (Hirschsprung's disease) is a motor disorder in the gut, due to a defect in the craniocaudal migration of the neuroblast originating from the neural crest that occurs during the first twelve weeks of gestation, causing a functional intestinal obstruction, with its attendant complications, in infants. Despite modern pediatric practice, with emphasis on early diagnosis, Hirschsprung's disease is seen in adults in regions where perinatal care is limited. We report two cases of Nigerian adults with longstanding, recurrent constipation, getting relieved by laxatives and herbal enemata, and then presented to our Emergency Department with a history of progressive abdominal distention, colicky pain, occasional vomiting, and weight loss. Per rectal examination revealed a gripping sensation in the rectum, 10 cm from the anal verge, with rectal fecal load. Barium enema showed a grossly distended proximal large colon, with high fecal retention, with the transition zone at the middle one-third of the rectum. Due to difficulty in bowel preparation of these patients, emergency laparotomy was done. The first case had a diverting sigmoid colostomy and later had a low anterior resection. The second case had a one-stage procedure. Histology of both the cases showed aganglionosis of the stenotic segment and a normal distal rectum. Both patients had complete resolution of the symptoms, without complications, in a three-year follow-up. The related literatures were reviewed. Hirschsprung's disease should be considered in adults patient presenting with chronic constipation. Low anterior resection of the rectum would be a surgical option for the treatment of short and zonal segment of adult Hirschsprung's disease.

Placement of a Port Catheter Through Collateral Veins in a Patient with Central Venous Occlusion

Long-term utilization of central venous catheters (CVCs) for parenteral nutrition has a high incidence of central venous complications including infections, occlusions, and stenosis. We report the case of a 31-year-old woman presenting with a malabsorption caused by short gut syndrome due to congenital aganglionic megacolon. The patient developed a chronic occlusion of all central neck and femoral veins due to long-term use of multiple CVCs over more than 20 years. In patients with central venous occlusion and venous transformation, the implantation of a totally implanted port system by accessing collateral veins is an option to continue long-term parenteral nutrition when required. A 0.014-in. Whisper guidewire (Terumo, Tokyo) with high flexibility and steerability was chosen to maneuver and pass through the collateral veins. We suggest this approach to avoid unfavorable translumbar or transhepatic central venous access and to conserve the anatomically limited number of percutaneous access sites.

Megacolon en gatos: tratamiento con acupuntura

Clinical experience in veterinary medicine shows that acupuncture is useful in megacolon, including idiopathic megacolon in felines. This disease is very similar to Hirschsprung's disease or congenital aganglionic megacolon in humans. Objective Traditionally, resolution of this chronic disease has required the use of enemas or laxatives through-out the cat's life, colectomy, which involves complicated postoperative care, and, in some cases, euthanasia. Acupuncture can constitute a non-aggressive and satisfactory treatment both for cats and their owners. Method We studied megacolon from the perspective of traditional Chinese medicine and present two practical examples. Results In all cases, treatment response was positive. Because routine treatment could not be applied in some aggressive animals, homeosiniatry (injection of homeopathic or homotoxicologic remedies in acupuncture points) was used. Conclusions The satisfactory results in cats, even when acupuncture was not feasible, indicate that acupuncture and homeosiniatry can be considered as a good alternative to treat megacolon, as well as other similar diseases in other types of animal and in humans.

C620R mutation of the murine ret proto‐oncogene: Loss of function effect in homozygotes and possible gain of function effect in heterozygotes

Germline RET mutations are responsible for different inherited disorders: Hirschsprung disease (congenital aganglionic megacolon), caused by loss of function mutations, familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2, caused by gain of function mutations. Intriguingly, some RET mutations, including C620R, are associated with both types of diseases. To investigate the dual role of such RET mutations, a mouse model with a targeted mutation ret(C620R) was generated. ret(C620R/C620R) offspring die during the first postnatal day, and show kidney agenesis and intestinal aganglionosis. Decreased outgrowth of the Ret-positive cells was observed in ret(C620R/C620R) neuronal cell cultures, which is suggestive of an impaired migration, proliferation or survival of the Ret-expressing cells. Electronmicroscopy revealed the absence of membrane-bound Ret in ret(C620R/C620R) cells as compared to ret(+/+) and ret(+/C620R) cells. On the other hand, aged ret(+/C620R) mice develop precancerous lesions in the adrenal gland or in the thyroid. Our results suggest that the ret(C620R) mutation has a loss of function effect in homozygotes and exhibits a dominant gain of function effect with low penetrance causing hyperplasia in heterozygotes.

Haddad Syndrome: A Case Study

Hirschsprung's disease (HD), also known as congenital aganglionic megacolon, is a relatively common cause of congenital obstruction of the colon. Congenital central hypoventilation syndrome (CCHS), also known as Ondine's curse, is a rare condition involving failed autonomic respiration in the absence of cardiorespiratory disease resulting in inadequate alveolar ventilation. Both conditions typically present in the newborn period and belong to a group of disorders referred to as neurocristopathies. HD and CCHS most commonly exist as discrete entities, but the coexistence of them is now called Haddad syndrome. Although few documented cases of Haddad syndrome exist in the literature, the association of CCHS and HD suggests a common etiology involving neural crest development.

Genomic structure of the gene for the SH2 and pleckstrin homology domain-containing protein GRB10 and evaluation of its role in Hirschsprung disease.

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most frequent cause of congenital bowel obstruction. Germline mutations in the RET receptor tyrosine kinase have been shown to cause HSCR. Mice that carry null alleles for RET or for its ligand, glial cell line-derived neurotrophic factor (GDNF), both exhibit complete intestinal aganglionosis and renal defects. Recently, the Src homology 2 (SH2) domain-containing protein Grb10 has been shown to interact with RET in vitro and in vivo, early in development. We have confirmed the map location of GRB10 on human chromosome 7, isolated human BACs containing the gene, elucidated its genomic structure, isolated a highly polymorphic microsatellite marker adjacent to exon 14 and scanned the gene for mutations in a large panel of HSCR patients. No evidence of linkage was detected in HSCR kindreds and no mutations were found in patients. These data suggest that while GRB10 may be important for signal transduction in developing embryos, it does not play an obvious role in HSCR.

HumanGFRA1: Cloning, Mapping, Genomic Structure, and Evaluation as a Candidate Gene for Hirschsprung Disease Susceptibility

Congenital aganglionic megacolon, commonly known as Hirschsprung disease (HSCR), is the most frequent cause of congenital bowel obstruction. Germline mutations in theRETreceptor tyrosine kinase have been shown to cause HSCR. Knockout mice forRETand for its ligand, glial cell line-derived neurotrophic factor (GDNF), exhibit both complete intestinal aganglionosis and renal defects. Recently, GDNF and GFRA1 (GDNF family receptor, also known as GDNFR-α), its GPI-linked coreceptor, were demonstrated to be components of a functional ligand for RET. Moreover,GDNFhas been implicated in rare cases of HSCR. We have mappedGFRA1to human chromosome 10q25, isolated human and mouse genomic clones, determined the gene's intron–exon boundaries, isolated a highly polymorphic microsatellite marker adjacent to exon 7, and scanned forGFRA1mutations in a large panel of HSCR patients. No evidence of linkage was detected in HSCR kindreds, and no sequence variants were found to be in significant excess in patients. These data suggest thatGFRA1's role in enteric neurogenesis in humans remains to be elucidated and that RET signaling in the gut may take place via alternate pathways, such as the recently described GDNF-related molecule neurturin and its GFRA1-like coreceptor, GFRA2.