Familial hirschsprung’s disease: a systematic review

Laughlin, Danielle Mc; Puri, Prem

doi:10.1007/s00383-015-3730-z

Cited by 27 publications

(16 citation statements)

References 66 publications

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“…However, not only does HD present differently with regards to penetrance between the sexes but also regarding disease phenotype. In fact, it is very likely that epigenetic effects involving the RET locus modulate the clinical expression of the disease phenotype [6], which can range from 7.6 % for HD and 20 % for TCA, as shown in the systematic review by McLaughlin et al of familial occurrence of colonic aganglionosis [2].…”

Section: Summary and Discussionmentioning

confidence: 99%

“…It is characterized by the absence of enteric ganglia along a variable length of the intestine, due to neural crest progenitor cells' failure to migrate, proliferate, differentiate, or survive [1][2][3][4]. The length of the aganglionic segment is crucial, because it determines the appropriate surgical method as well as the expected outcome of the patients [2,5]. HD can occur isolated, together with other congenital malformations, or as part of syndromic diseases, like Down syndrome [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…HD can occur isolated, together with other congenital malformations, or as part of syndromic diseases, like Down syndrome [3,4]. Given the (1) high number of sporadic cases, (2) incomplete penetrance of causative gene mutations, (3) variation in length of the aganglionic segment, and (4) observed sex bias, a multifactorial and polygynous genesis is assumed [2,6]. In fact, as early as 1990, Badner et al observed a 4 % increased risk for developing HD among siblings in comparison to the general population (incidence rate 0.02 %), as well as a significantly elevated sex ratio (3.9 male:female) [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Hirschsprung Disease – Clinical Relevance of RET Mutations

Wenskus

Vincent

Hempel

et al. 2020

Z Geburtshilfe Neonatol

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Introduction To date, several genes involved in the pathogenesis of HD have been recognized. Out of these, the RET gene (chromosomal locus 10q11), one of the first genes identified in combination with HD, is still considered the basis for HD development. However, even with over a hundred RET gen coding sequence mutations identified, the mutations do not fully explain the observed sex bias of HD and the elevated risk of developing HD among siblings. Thus, our aim was to evaluate the clinical relevance of an as yet undescribed genotype in a family with HD to improve genetic counseling for families with RET mutation-associated HD.Patients This case report provides an overview of a family with a history of HD with a novel, unreported autosomal dominant RET mutation.Results/Summary The family examined in this study clearly demonstrates that (1) the genotype to phenotype correlation of patients with RET mutation-associated HD is not directly related, and (2) genetic mechanisms underlying the different HD phenotypes, as well as the model of inheritance of HD, are complex and not yet fully understood. As such, a multifactorial genesis of HD appears more likely and should be the center of genetic counseling for concerned families. Having identified another RET mutation with a possible correlation of severity of HD and gender will aid in filling the gaps of the incomplete picture of the pathogenesis of HD.

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Section: Summary and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hirschsprung Disease – Clinical Relevance of RET Mutations

Wenskus

Vincent

Hempel

et al. 2020

Z Geburtshilfe Neonatol

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“…For example, familial occurrence of Hirschsprung's disease is recorded in 18 twin pairs; in 4331 index cases of Hirschsprung's disease, there was evidence of familial recurrence in 7.6%, although among cases with total colonic aganglionosis, 20% of cases were familial . Familial recurrence was observed usually in siblings (62%) and in multiple generations in 15% of families . Such patients almost invariably present in the neonatal period or infancy, rather than adolescence or adulthood.…”

Section: Introductionmentioning

confidence: 99%

“…For example, familial occurrence of Hirschsprung's disease is recorded in 18 twin pairs 12 ; in 4331 index cases of Hirschsprung's disease, there was evidence of familial recurrence in 7.6%, although among cases with total colonic aganglionosis, 20% of cases were familial. 13 Familial recurrence was observed usually…”

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confidence: 99%

Familial chronic megacolon presenting in childhood or adulthood: Seeking the presumed gene association

Camilleri

Wieben

Eckert

et al. 2019

Neurogastroenterology Motil

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Objective We identified a pedigree over five generations with 49 members, some of whom had chronic megacolon presenting in adolescence or adulthood. We aimed to assess the genetic cause of chronic megacolon through clinical and DNA studies. Design After ethical approval and informed consent, family members provided answers to standard bowel disease questionnaires, radiological or surgical records, and DNA (buccal mucosal scraping). Exome DNA sequencing of colon tissue or blood DNA from seven family members with colon or duodenal dilatation, or no megacolon (n = 1) was carried out. Sanger sequencing was performed in 22 additional family members to further evaluate candidate variants. The study focused on genes of potential relevance to enteric nerve (ENS) maturation and Hirschsprung's disease or megacolon, based on the literature (GFRA1, NKX2‐1, KIF26A, TPM3, ACTG2, SCN10A, and C17orf107 [CHRNE]) and other genetic variants that co‐segregated with megacolon in the six affected family members. Results Information was available in all except five members alive at time of study; among 30 members who provided DNA, six had definite megacolon, one megaduodenum, seven significant constipation without bowel dilatation, and 16 normal bowel function by questionnaire. Among genes studied, SEMA3F (g.3:50225360A>G; c1873A>G) was found in 6/6 family members with megacolon. The SEMA3F gene variant was assessed as potentially pathogenic, based on M‐CAP in silico prediction. SEMA3F function is associated with genes (KIT and PDGFRB) that impact intestinal pacemaker function. Conclusion Familial chronic megacolon appears to be associated with SEMA3F, which is associated with genes impacting enteric nerve or pacemaker function.

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