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1.
Dvoráková S Dvoráková K Malíková M Skába R Vlcek P Bendlová B 《Journal of pediatric surgery》2005,40(6):e1-e6
Purpose
The RET proto-oncogene is involved in neural crest disorders. Activating germline mutations in the RET proto-oncogene cause the development of familial medullary thyroid carcinoma (FMTC) or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Inactivating germline mutations in the RET proto-oncogene are detected in Hirschsprung's disease (HSCR). Only in a very small number of families are these 2 diseases expressed together.Methods
This study presents a novel Czech kindred with FMTC-HSCR phenotype. Two family members (mother and daughter) were tested for RET germline mutations in exons 10, 11, 13, 14, 15, and 16.Results
Direct fluorescent sequencing of genomic DNA revealed a heterozygous mutation in the RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was reclassified, thanks to genetic screening from the apparently sporadic MTC-HSCR to FMTC-HSCR.Conclusion
The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be added to the small worldwide cohort of families with MEN2A/FMTC-HSCR. 相似文献2.
Background
Multiple endocrine neoplasia 2A (MEN 2A) is a genetic syndrome manifesting as medullary thyroid carcinoma (MTC), hyperparathyroidism, and pheochromocytoma. Multiple endocrine neoplasia 2A results from mutations in the RET proto-oncogene. Hirschsprung disease (HSCR) is a rare manifestation of MEN 2A and has been described in known MEN 2A families.Methods
Here we describe 2 MEN 2A families that were only identified after the diagnosis of HSCR.Results
Kindred 1: A boy presented in infancy with HSCR. Genetic screening revealed a C609Y mutation, which is consistent with MEN 2A. Evaluation of his sister, father, and grandmother revealed the same mutation. All 3 had thyroidectomies demonstrating C-cell hyperplasia. The grandmother had a microscopic focus of MTC.Kindred 2: An infant boy and his sister were diagnosed with HSCR as neonates. Genetic testing demonstrated a C620R gene mutation consistent with MEN 2A. Total thyroidectomies revealed metastatic MTC in the father and C-cell hyperplasia in both children.Conclusions
Hirschsprung disease can be the initial presentation of MEN 2A. We strongly recommend that genetic screening be performed in patients presenting with HSCR, looking for the known RET mutations associated with MEN 2A. If a mutation consistent with MEN 2A is detected, genetic screening of all first-degree relatives in the kindred is recommended. 相似文献3.
Kim JH Yoon KO Kim H Kim JK Kim JW Lee SK Seo JM 《Journal of pediatric surgery》2006,41(10):1708-1712
Background/Purpose
The endothelin receptor B (EDNRB) signaling pathway, which is the second major susceptible gene for Hirschsprung's disease (HSCR), is crucial for the development of the enteric nervous system. The allele frequency of polymorphisms was mostly tested in the American and European population, but the data of an ethnically diverse, non-Caucasian population are unclear. To further investigate the variants and haplotypes of the EDNRB gene, this study examined sequence variations in Korean patients with sporadic HSCR.Methods
All 8 exons and intron/exon boundaries of the EDNRB gene in 18 Korean patients with sporadic HSCR and 84 healthy individuals were screened using PCR amplification and direct sequencing.Results
A total of 8 different nucleotide substitutions were identified. Of these, 4 were new variants (promoter-116C>T; 5′UTR-121G>T; IVS4+62C>A; IVS5+121G>C) and the others were previously described variants. The distribution of variations was even different from that reported for Chinese and Japanese subjects as well as other ethnic groups. This study also analyzed the haplotypes for an association between the variants identified with HSCR.Conclusions
This study identified additional sequence variants of the EDNRB gene, but the estimated EDNRB haplotypes did not show any disease risk. 相似文献4.
Introduction
Hirschsprung disease (HSCR) is associated with the later development of multiple endocrine neoplasia (MEN2), because RET gene variations are associated with both conditions. Specifically, HSCR-MEN2 cosegregation mostly relates to the cysteine-rich area at the RET-620 (the “Janus gene”).Aim
The aim of this study was to explore the clinical and genetic associations of HSCR-MEN2 in a cohort of HSCR patients.Methods
RET gene variation was evaluated by heteroduplex single-strand conformational polymorphism analysis and validated with automated sequencing techniques in HSCR patients (including 18 kindreds). Those with RET C620 variations were subjected to familial evaluation for coexisting HSCR-MEN2.Results
A cohort of 118 patients with HSCR (n = 89) or medullary thyroid carcinoma (n = 29) were studied, including 3 families where a RET-620 point mutation was identified. No C618, C609, or C611 variations were detected. In 1 remarkable 6-generational family (family 3), HSCR in early generations seemed to be later replaced by MEN2A. In the other 2 families with total colonic aganglionosis, a relative with a medullary thyroid carcinoma was identified.Conclusion
Gene mutation in the RET-620 position carries significant risk and may be part of a targeted investigation of high-risk areas in HSCR. We propose an alternative hypothesis of endoplasmic reticulum control to explain the changing phenotypic expression. 相似文献5.
6.
Background
Hirschsprung disease (HSCR, Online Mendelian Inheritance in Man 142623) is a typical developmental disorder of the enteric nervous system in which ganglion cells fail to innervate the lower gastrointestinal tract during embryonic development. SOX10 gene is involved in the normal development of the enteric nervous system. Heterozygous SOX10 mutations have been identified in patients with syndromic HSCR. However, no mutations have been reported to date to be associated to isolated HSCR patient. We thus sought to investigate whether mutations in the SOX10 are associated with isolated HSCR in the Chinese population.Methods
Polymerase chain reaction amplification and direct sequencing were used to screen 4 exons of the SOX10 gene for mutations and polymorphisms in 104 patients with sporadic HSCR and 96 ethnically matched controls in Han Chinese populations.Results
In this study, 4 single nucleotide polymorphisms (SNPs) were identified: SNP1: c.18C>T (GAC→GAT) in exon 2; SNP2: c.122G>T (GGC→GTC) in exon 2; SNP3: IVS2+10 (C→G) in intron 2; and SNP4: c.927T>C (CAT→CAC) in exon 4. SNP1 and SNP2 were novel described polymorphisms in the Chinese population. No SOX10 mutations were found in Han Chinese with isolated HSCR.Conclusions
Our results revealed that there was no association between the 4 SNPs of the SOX10 gene and HSCR. This study showed that the SOX10 gene is unlikely to be a major HSCR gene in the Chinese Han population. 相似文献7.
The ability to predict the risk of MEN2 and medullary thyroid carcinoma (MTC) by genetic RET proto-oncogene analysis has provided an essential tool in identifying patients in whom thyroid cancer can be prevented by prophylactic thyroidectomy but emphasizes the need for clear policy guidelines. Children of families with RET cysteine mutations (exons 10, 11, 13, and 16) may develop early metastatic tumours and require prophylactic thyroidectomy. The 918 mutation associated with MEN2B is associated with early aggressive behaviour and distant metastatic spread. This has led to active screening of affected families underlining the need for specific intervention strategies.
Aim
To evaluate the risk to children of families with MEN2 and to assess the risk and determine the treatment.Methods
Twenty-five patients from 10 families with MEN2 phenotypes were screened for RET mutations. Polymerase chain reaction amplification was performed on all 21 exons of the RET proto-oncogene, followed by heteroduplex single-strand conformation polymorphism (HEX-SSCP) analysis. Polymerase chain reaction products demonstrating variation in the HEX-SSCP gels were subjected to automated DNA sequencing analysis.Results
Eleven significant RET mutations were detected in affected families. Eight index cases received initial thyroidectomy for established MTC (plus 2 advised). In the family members screened, 3 prophylactic thyroidectomies (2 with early MTC) were performed and a further 2 recommended. An exon 10 C620W missense mutation (the “Janus” gene) was detected in a patient with Hirschsprung's disease plus 1 family member.Conclusion
RET analysis of MEN has revolutionized the management of children of families with MEN2 and allowed surgical prediction and prophylaxis to take place. The presence of an exon 10 C620W mutation in association with Hirschsprung's disease was difficult to assess. We suggest possible guidelines for management of families with MTC and the role of genetic testing in their evaluation. 相似文献8.
Maria-Mercè Garcia-Barceló Vincent Chi-Hang Lui Man-ting So Thomas Yuk-yu Leon Elly Sau-wai Ngan Toufique Ehsan Patrick Ho-yu Chung Kenneth Kak-yuen Wong Paul Kwong-hang Tam 《Journal of pediatric surgery》2009,44(10):1892-1898
Purpose
The combination of partial absence of the sacrum, anorectal anomalies, and presacral mass constitutes Currarino syndrome (CS), which is associated with mutations in MNX1 motor neuron and pancreas homeobox 1 (previously HLXB9).Here, we report on the MNX1 mutations found in a family segregating CS and in 3 sporadic CS patients, as well as on the clinical characteristics of the affected individuals.Methods
MNX1 mutations were identified by direct sequencing the coding regions, intron/exon boundaries of MNX1 in 5 CS Japanese family members and 3 Chinese sporadic cases and their parents.Results
There were 2 novel (P18PfsX37, R243W) and 2 previously described (W288G and IVS2 + 1G > A) mutations. These mutations were not found in 198 control individuals and are predicted to impair the functioning of the MNX1 protein.Conclusions
The variability of the CS phenotype among related or unrelated patients bearing the same mutation advocates for differences in the genetic background of each individual and invokes the implication of additional CS susceptibility genes. 相似文献9.
Cui-Ping Liu Jin-Tu Lou Chun-Fen Luo Fei Chen Meng Li 《Journal of pediatric surgery》2009,44(9):1805-1811
Background
Hirschsprung disease (HSCR, OMIM 142623) is a complex congenital disorder characterized by intestinal obstructions caused by the absence of the intestinal ganglion cells of the nerve plexuses in variable lengths of the digestive tract. The PHOX2B gene is involved in neurogenesis and disruption of Phox2b in mice results in a HSCR-like phenotype. The first association study of the PHOX2B gene with HSCR derived from Chinese population in Hong Kong; here, we address the question of whether PHOX2B acts as a predisposing factor in HSCR pathogenesis in Chinese population in mainland.Methods
To investigate the contribution of PHOX2B to the HSCR phenotype, polymerase chain reaction amplification and direct sequencing were used to screen PHOX2B coding regions and intron/exon boundaries for mutations and polymorphisms in 102 patients with HSCR and 96 ethnically matched controls, in Han Chinese populations of Southeastern China.Results
In this study, we genotyped 4 single nucleotide polymorphisms (SNPs) (including 1 novel SNP) located within the PHOX2B gene. Statistically significant differences were found for c.701 A > G and IVS2 + 100 A > G, and the log-additive model was accepted as the best inheritance model (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.11-2.87) for IVS2 + 100 A > G. We also showed that the haplotype-A G A N composed of 4 SNPs exhibited significant association with the disease (P = .03); this haplotype was more frequently observed in cases than in controls (OR, 2.31; 95% CI, 1.11-4.82).Conclusions
Our study provided further evidence that the PHOX2B gene is involved in the susceptibility to HSCR in the Han Chinese population. Our findings are in accordance with the involvement of PHOX2B in the signaling pathways governing the development of enteric neurons. 相似文献10.
Background
Multiple endocrine neoplasia (MEN) 2B is a rare hereditary syndrome that results from an activating mutation of the RET proto-oncogene. The RET gene is involved in the development of the enteric nervous system. Patients with MEN 2B have enlarged enteric ganglia and may be affected by gastrointestinal dysmotility. A deficiency of the neurotransmitter substance P (SP) has been identified in both pediatric and adult patients with chronic constipation.Methods
Three patients, in whom constipation was the presenting symptom and MEN 2B had been provisionally diagnosed, underwent genetic analysis. Seromuscular colonic biopsies were taken for immunofluorescence imaging in all 3 patients. A retrospective review of the patient notes was undertaken.Results
All 3 patients had constipation refractory to conservative treatment. Genetic analyses in the 3 patients confirmed an identical RET mutation (Met918Thr). Immunofluorescence imaging in all 3 patients identified grossly enlarged myenteric plexus ganglia but surprisingly a low density of SP-labeled nerve fibers in the colonic circular muscle. Nitric oxide synthase and vasoactive intestinal peptide labeling were not reduced.Conclusion
The results show an association between MEN 2B and its most common RET mutation, colonic dysmotility, and low density of SP in the colonic circular muscle. Larger numbers of patients need to be studied to investigate whether low SP is primarily associated with the constipation or RET mutation and if it is a common feature of MEN 2B. 相似文献11.
Although apparently the same condition as Hirschsprung's disease (HSCR), total colonic aganglionosis (TCA) patients (2%-14% congenital aganglionosis) display clinical, histopathologic, and genetic differences that may account for altered clinical presentations.
Patients and methods
Clinical, radiologic, and histologic features of 22 TCA patients of 114 HSCR cases (including 16 kindreds) were retrospectively evaluated by chart review. With ethical permission, DNA mutation analysis of the RET and EDNRB genes was carried out. Polymerase Chain Reaction (PCR) products were screened for genetic variation of by Hetroduplex Single Strand conformation polymorphism (HEX/SSCP) analysis and compared with 60 normal population control samples (20/ethnic groups). The SSCP variants were validated with automated sequencing techniques showing conformational variants in acrylamide gel.Results
Of the 22 patients, 12 (55%) presented within the first 28 days of extrauterine life, but 10 presented later with 3 (14%) presenting more than 6 months of age. The TCA patients evaluated differed clinically, radiologically, and histologically, and misdiagnosis occurred in 23% (5/22). Seven patients (32%) were familial—the remainder being nonrelated. Histologic features varied, and difficulties in diagnosis occurred in 5 (24%), with unclear histologic condition delaying diagnosis in one and a mistaken aganglionic level, requiring repeat surgery in two.RET variations were detected in 82% (18/22)of TCA as opposed to 33% short segment (S-HSCR) with multiple genetic RET variations in 5 (28%). Genetic variations included exon 2 SNPs but less than in S-HSCR. One had an isolated RET A4 variation with no other abnormalities. Intronic RET variations occurred in intron 6 (2 patients) (IVS6+56delG) and intron 16 (2 patients) (IVS16-38delG). A cysteine radical mutation (C620R) (2 patients) was related to Multiple Endocrine Neoplasia Type 2 (MEN2) in the family. In contrast to S-HSCR, genetic variations in TCA aggregated to the important tyrosine kinase (intracellular) region in 5 patients suggesting a possible pathogenetic link. EDNRB variations occurred in 7 patients (32%) all within exon 4 of the gene.Conclusions
Total colonic aganglionosis differs clinically from other HSCR phenotypes and may lead to misdiagnosis. Potential disease-related RET gene mutations include exon 17-21 genetic variations that suggest the possibility of disrupted downstream signaling pathways from vital gene recruitment sites as possible TCA contributing factors. 相似文献12.
Background/Purpose
The Currarino's syndrome (CS), which is characterized by sacral bony anomalies, anorectal malformation, and a presacral mass, is associated with mutations of HLXB9 gene. The aim of this study was to clearly define the clinical manifestations and molecular anomalies of CS in China.Methods
We studied the medical history and clinical manifestations of a child with presacral mass. Genomic DNA was extracted from lymphocytes, and mutation analysis of the HLXB9 gene was conducted by using polymerase chain reaction and direct sequencing in the child and her parents.Results
A previously unreported heterozygous missense mutation of HLXB9 gene was detected in the child.Conclusions
The HLXB9 gene mutation could take place in sporadic cases of CS without a typical hemisacrum. 相似文献13.
Fernandez RM Ruiz-Ferrer M Lopez-Alonso M Antiñolo G Borrego S 《Journal of pediatric surgery》2008,43(11):2042-2047
Purpose
Hirschsprung disease (HSCR) is a developmental disorder caused by a failure of neural crest cells to migrate, proliferate, and/or differentiate during the enteric nervous system development. It presents a multifactorial, nonmendelian pattern of inheritance, with several genes playing some role in its pathogenesis. Its major susceptibility gene is the RET protooncogene, which encodes a receptor tyrosine kinase activating several key signaling pathways in the enteric nervous system development. Given the pivotal role of RET in HSCR, the genes encoding their ligands (GDNF, NRTN, ARTN, and PSPN) are also good candidates for the disease.Methods
We have performed a case-control study using Taqman technology to evaluate 10 polymorphisms within these genes, as well as haplotypes comprising them, as susceptibility factors for HSCR.Results
No differences were found in the allelic frequencies of the variants or in the haplotype distribution between patients and controls. In addition, no particular association was detected of the variants/haplotypes to any demographic/clinical parameters within the group of patients.Conclusion
These data would be consistent with the lack of association between these polymorphisms and HSCR, although they do not permit to completely discard a possible role of other variants within these genes in the disease. Moreover, because the gene-by-gene approach does not take into account the polygenic nature of HSCR disease, it would be interesting to investigate sets of variants in many other different susceptibility loci described for HSCR, which may permit to consider possible interactions among susceptibility genes 相似文献14.
15.
Ishihara N Shimada A Kato J Niimi N Tanaka S Miura K Suzuki T Wakamatsu N Nagaya M 《Journal of pediatric surgery》2005,40(9):1411-1419
Background/Purpose
Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS). In this study, we investigated variations in the enteric neural plexus abnormalities in MWS using morphometry-based histopathologic analysis.Methods
Seven patients with MWS (3 with mutations in exon 8 of ZFHX1B and 4 with deletions) who had undergone modified Duhamel's operations for Hirschsprung disease were examined. Surgically resected rectosigmoid specimens were analyzed morphometrically.Results
The length of the aganglionic segment was longer than 3 cm in all the patients with deletions. In 3 patients with mutations, the aganglionic region was not detected in the surgically resected specimens; however, the parameters of the ganglions and plexus were significantly smaller than those of controls (cloaca and aproctia), indicative of a transitional zone. Variation in the severity of pathological changes among the 3 patients with mutations was also noted.Conclusions
The variations in myenteric plexus pathologies in MWS appear to be caused by both variations in ZFHX1B abnormalities and epigenetic factors. 相似文献16.
Bütter A Gagné J Al-Jazaeri A Emran MA Deal C St-Vil D 《Journal of pediatric surgery》2007,42(1):203-206
Purpose
Prophylactic total thyroidectomy is now recommended after having confirmed RET mutations in children of parents with multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. We reviewed our experience to determine the incidence of medullary thyroid carcinoma with respect to age at surgery, the location of the mutation, and its association with Hirschsprung's disease (HD).Methods
A retrospective review from 1996 to 2005 revealed 20 children with genetic screening for multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma who underwent a prophylactic total thyroidectomy with parathyroid gland preservation.Results
The median age of the 20 patients (9 boys and 11 girls) included in this study was 8.2 years (range, 3.7-16.9 years) at the time of their surgery. Final pathology revealed normal thyroid tissue (n = 3; median age, 5.9 years), C-cell hyperplasia (n = 13; median age, 10 years), or medullary thyroid carcinoma (n = 4; median age, 8 years). Four children, all with mutations in C620, had a previous diagnosis of HD. At a median follow-up of 3.7 years (range, 1 month to 8.4 years), all patients were well and cancer free.Conclusions
There is no correlation between histologic findings and median age at surgery. Hirschsprung's disease was found in 50% of the patients with the RET mutation in C620. In children of C620 parents, symptoms of HD should be actively sought, and if such are found, rectal biopsies should be performed even if mutation results are not yet available. Based on the age of the earliest cancer and the safety of total thyroidectomy, children should promptly undergo surgery after genetic screening and before their fifth year of life. 相似文献17.
Solari V Ennis S Yoneda A Wong L Messineo A Höllwarth ME Green A Puri P 《Journal of pediatric surgery》2003,38(3):497-501
Background/Purpose: Total intestinal aganglionosis (TIA) extending from the duodenum to the rectum is the most rare form of Hirschprung's disease (HSCR) and usually is fatal. RET is the major gene associated with HSCR, and germline mutations of this gene account for up 50% of familial and up to 15 to 20% of sporadic cases in HSCR. The aim of this study was to investigate DNA variants in the RET gene in TIA patients using the WAVE DNA Fragment Analysis System. Methods: Genomic DNA was extracted from whole blood samples from 6 patients with TIA. Polymerase chain reaction (PCR) amplification of the 21 exons of RET was performed using published oligonucleotide primers. Heteroduplexes were followed by the WAVE DNA Fragment Analysis System with the DNASep cartridge. Results: WAVE system technology detected 16 variants in the RET gene in the 6 patients with TIA. Three patients had a significant mutation in exon 8, 11, and 15, respectively. Thirteen RET polymorphic variants also were detected in the 6 patients, with L746L variant in exon 13 occurring in 4 patients. Conclusions: WAVE system technology is an efficient method for the detection of DNA sequence variants. Our findings suggest that not only RET mutations but also RET polymorphic variants may contribute to the occurrence of TIA. J Pediatr Surg 38:497-501. 相似文献
18.
Gwen Wendelschafer-Crabb Vishala Neppalli James Hodges Daniel Saltzman William R Kennedy 《Journal of pediatric surgery》2009,44(4):773-782
Purpose
Idiopathic chronic childhood constipation (ICCC) includes children who are severely constipated and who are resistant to behavioral or medical treatments. These children are distinguished from those with Hirschsprung's disease (HSCR) by the presence of enteric ganglia in rectal biopsy specimens. We investigated potential autonomic dysfunction by examining nerves in rectal mucosa.Methods
Immunostaining, confocal microscopy, and nerve analysis were performed on formalin-fixed and on Zamboni-fixed rectal biopsy specimens from children who were severely constipated. A computer-assisted neuron tracing technique was used to determine mucosal nerve density in Zamboni-fixed biopsy sections.Results
Nerves in Zamboni-fixed biopsy specimens were better stained than in formalin-fixed biopsy specimens. Regardless of fixation method, a deficiency of mucosal nerves was observed in ICCC when compared to children who are not constipated. Analysis of autotraced mucosal nerves confirmed the deficiency in ICCC biopsy specimens. Mucosal nerves were also severely deficient in patients with HSCR, even in transitional segments that contained ganglia.Conclusions
Most patients with ICCC had decreased innervation of the rectal mucosa. Because mucosal nerves are critical for the peristaltic reflex, water secretion, and absorption, their deficiency can be related to patient constipation. Mucosal nerve density provides a pathologic basis for diagnosis of dysfunction in children who do not have HSCR but are chronically constipated. The study validates the neuron tracing method for objective evaluation of mucosal innervation. 相似文献19.
Background
Hirschsprung's disease (HSCR) represents a complex disorder of signaling molecules, resulting from the effects of at least 9 known susceptibility genes. Affected families carry 200 times higher risk, but genetic counseling via pedigree analysis is difficult and the significance of genetic variations is unclear. This study evaluated a set of patients affected by HSCR with familial recurrence to evaluate factors of greatest value in genetic counseling.Patients and Methods
One hundred twenty patients with HSCR (including 18 kindreds) were screened for genetic variations of the 2 major susceptibility genes (RET and endothelin B receptor [EDNRB]) and compared with 60 control samples (20 per ethnic group). Familial recurrence patterns were studied for patient sex, pattern of recurrence, presence of associated syndromic features, and genetic features of major susceptibility genes. Polymerase chain reaction and HEX-SSCP analysis were performed on DBA extracted from blood/microdissected tissue samples. SSCP variants were validated and automated sequencing techniques performed on polymerase chain reaction products showing conformational variants in acrylamide gel.Results
Familial cases had a male-female ratio of 1.5:1, male-to-male transmission (n = 10; 2 father to son), female-to-male transmissions (n = 4; 3 female carriers, female-to-female (n = 4; 2 mother to daughter), and 1 paternal RET deletion—female with very long segment aganglionosis. Increasing gene penetrance occurred in 3 pedigrees. An increased incidence of long segment HSCR was noted in families with recurrence and appeared important. No consistent mendelian trends or specific genetic sites were observed, but 3 suggested autosomal dominant and recessive in a further 3.Identified genetic variations included deletions, frame shifts, and missense mutations, as well as a number of significant single nucleotide polymorphism variations. Transmitted RET mutations occurred in 5 (30%) of 16 kindreds. Splice RET mutation plus variants of exon 17 (973L) affected 2 children with identical total colonic aganglionosis. In a 3-generation family, variations in RET exons 6, 13, and 18 (928) affected 3 male children with increasing penetration to recur as total intestinal aganglionosis in a grandchild.Conclusions
Mendelian transmission appears mediated by the RET proto-oncogene. EDNRB mutations suggest haplotypic gene-gene interaction. Genetic counseling remains a challenge in HSCR because of its multfactorial etiology. 相似文献20.
Martin Lacher Johanna Helmbrecht Sibylle Koletzko Martin Classen Jochen Hubertus Peter Lohse Roland Kappler 《Journal of pediatric surgery》2010,45(8):1591-1597