Background: Hirschsprung's disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to assist clinical decision-making regarding diagnostics and management. Aims: This guideline aims to cover the diagnostics and management of rectosigmoid HSCR up to adulthood. It aims to describe the preferred approach of ERNICA, the European Reference Network for rare inherited and congenital digestive disorders. Methods: Recommendations within key topics covering the care pathway for rectosigmoid HSCR were developed by an international workgroup of experts from 8 European countries within ERNICA European Reference Network from the disciplines of surgery, medicine, histopathology, microbiology, genetics, and patient organization representatives. Recommendation statements were based on a comprehensive review of the available literature and expert consensus. AGREE II and GRADE approaches were used during development. Evidence levels and levels of agreement are noted. Results: Thirty-three statements within 9 key areas were generated. Most recommendations were based on expert opinion. Conclusion: In rare or low-prevalence diseases such as HSCR, there remains limited availability of high-quality clinical evidence. Consensus-based guidelines for care are presented.
Background-Germline mutations of the RET proto-oncogene identical to those found in the tumour predisposition syndrome multiple endocrine neoplasia type 2A (MEN2A), were detected in 2.5-5% of sporadic and familial cases of Hirschsprung's disease. Some patients with Hirschsprung's disease may therefore be exposed to a highly increased risk of tumours. Aims-To define clinical use of RET gene testing in Hirschsprung's disease and related patient management from an oncological point of view. Methods-Sixty patients with Hirschsprung's disease were screened for RET mutations. In three, MEN2A type RET mutations were detected. Case reports for these three patients are presented. Results and conclusions-Only 22 families or sporadic patients with Hirschsprung's disease and MEN2A type RET mutations have been reported. Therefore, it is diYcult to predict tumour risk for patients with familial or sporadic Hirschsprung's disease, and their relatives, who carry these mutations. For these mutation carriers, periodic screening for tumours as in MEN2A is advised, but prophylactic thyroidectomy is oVered hesitantly. RET gene testing in familial or sporadic Hirschsprung's disease is not recommended at present outside a complete clinical research setting. In combined MEN2A/Hirschsprung's disease families RET gene testing, tumour screening, and prophylactic thyroidectomy are indicated as in MEN2A. (Gut 1998;43:542-547)
Objectives To determine whether offering cardiac screening to relatives of patients with left ventricular outflow tract obstructions (LVOTOs) would be justified.
Hirschsprung disease (HSCR) is a common genetic disorder characterized by intestinal obstruction secondary to enteric aganglionosis. HSCR demonstrates a complex pattern of inheritance, with the RET proto-oncogene acting as a major gene and with several additional susceptibility loci related to the Ret-signaling pathway or to other developmental programs of neural crest cells. To test how the HSCR phenotype may be affected by the presence of genetic variants, we investigated the role of a single-nucleotide polymorphism (SNP), 2508C-->T (S836S), in exon 14 of the RET gene, characterized by low frequency among patients with HSCR and overrepresentation in individuals affected by sporadic medullary thyroid carcinoma. Typing of several different markers across the RET gene demonstrated that a whole conserved haplotype displayed anomalous distribution and nonrandom segregation in families with HSCR. We provide genetic evidence about a protective role of this low-penetrant haplotype in the pathogenesis of HSCR and demonstrate a possible functional effect linked to RET messenger RNA expression.
In several families, multiple endocrine neoplasia type 2A (MEN 2A) has been found in association with cutaneous lichen amyloidosis. It has been debated, however, whether the skin amyloidosis found in MEN 2A families, localized exclusively in the interscapular area, represents the same anomaly as that found in autosomal dominant familial cutaneous lichen amyloidosis, which is more generalized. We screened two MEN 2A families with associated skin amyloidosis for germline mutations in the RET gene responsible for the MEN 2A cancer syndrome, and found the same mutation characteristic of MEN 2A in both families. We also screened probands from three pedigrees with familial cutaneous lichen amyloidosis for RET mutations. In none of the RET coding and flanking intronic sequences was a mutation detected. This most probably indicates that skin amyloidosis found in some MEN 2A families and familial cutaneous lichen amyloidosis are different conditions. Consequently, patients with apparent familial cutaneous lichen amyloidosis do not appear to be at risk for MEN 2A.
Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10−7), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10−7); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10−7 and OR = 1.09, P = 7.4 × 10−8); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10−9), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P < 2.90 × 10−6). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10−4) and DNA mismatch repair genes (P = 6.1 × 10−4) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
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