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Pediatric Surgery International
Published in: Pediatric Surgery International 1/2018

01-01-2018 | Review Article

A review of genetic factors contributing to the etiopathogenesis of anorectal malformations

Authors: Kashish Khanna, Shilpa Sharma, Noel Pabalan, Neetu Singh, D. K. Gupta

Published in: Pediatric Surgery International | Issue 1/2018

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Abstract

Background

Anorectal malformation (ARM) is a common congenital anomaly with a wide clinical spectrum. Recently, many genetic and molecular studies have been conducted worldwide highlighting the contribution of genetic factors in its etiology. We summarize the current literature on such genetic factors.

Materials and methods

Literature search was done using different combinations of terms related to genetics in anorectal malformations. From 2012 to June 2017, articles published in the English literature and studies conducted on human population were included.

Observations and results

A paradigm shift was observed from the earlier studies concentrating on genetic aberrations in specific pathways to genome wide arrays exploring single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) in ARM patients. Rare CNVs (including 79 genes) and SNPs have been found to genetically contribute to ARM. Out of disrupted 79 genes one such putative gene is DKK4. Down regulation of CDX-1 gene has also been implicated in isolated ARM patients. In syndromic ARM de novo microdeletion at 17q12 and a few others have been identified.

Conclusion

Major genetic aberrations proposed in the pathogenesis of ARM affect members of the Wnt, Hox (homebox) genes, Sonic hedgehog (Shh) and Gli2, Bmp4, Fgf and CDX1 signalling pathways; probable targets of future molecular gene therapy.
Literature
1.
Holschneider A, Hutson J, Pena A et al. (2005) Preliminary report on the International Conference for the Development of Standards for the Treatment of Anorectal Malformations. J Pediatr Surg 40:1521–1526CrossRefPubMed
2.
Fitzgerald MJT, Fitzgerald M (1994) Human Embryology. Bailliere Tindall, Philadelphia, pp 1–251
3.
Wijers CH, van Rooij IA, Marcelis CL, Brunner HG, de Blaauw I, Roeleveld N (2014) Genetic and non genetic etiology of non syndromic anorectal malformations: a systematic review. Birth Defects Res C Embryo Today 102:382–400. doi:10.​1002/​bdrc.​21068 CrossRefPubMed
4.
Wang C, Li L, Cheng W (2015) Anorectal malformation: the etiological factors. Pediatr Surg Int 31:795–804CrossRefPubMed
5.
Stoll C, Alembik Y, Roth MP et al (1997) Risk factors in congenital anal atresias. Ann Genet 40(4):197–204PubMed
6.
Roberts D (2000) Molecular mechanisms of development of the gastrointestinal tract. Dev Dyn 219:1009–1020CrossRef
7.
Runck LA, Method A, Bischoff A, Levitt M, Pena A, Collins MH, Gupta A, Shanmukhappa S, Wells JM, Guasch G (2014) Defining the molecular pathologies in cloaca malformation: similarities between mouse and human. Dis Model Mech 7:483–493CrossRefPubMedPubMedCentral
8.
Jonsson M, Andersson T (2001) Repression of Wnt-5a impairsDDR1 phosphorylation and modifies adhesion and migration of mammary cells. J Cell Sci 114(Pt 11):2043–2053PubMed
9.
Seifert AW, Bouldin CM, Choi KS et al (2009) Multiphasic and tissue-specific roles of sonic hedgehog in cloacal septation and external genitalia development. Development 136(23):3949–3957CrossRefPubMedPubMedCentral
10.
Mullor JL, Dahmane N, Sun T et al (2001) Wnt signals are targets and mediators of Gli function. Curr Biol 11(10):769–773CrossRefPubMed
11.
Brewster R, Mullor JL, Ruiz IAA (2000) Gli2 functions in FGF signaling during antero-posterior patterning. Development 127(20):4395–4405PubMed
12.
Kondo T, Dolle P, Zakany J et al (1996) Function of posterior HoxD genes in the morphogenesis of the anal sphincter. Development 122(9):2651–2659PubMed
13.
Gambarini AG, Miranda MT, Viviani W et al (1996) Structure and function of fibroblast growth factor. Braz J Med Biol Res 29(7):835–839PubMed
14.
van den Akker E, Forlani S, Chawengsaksophak K et al (2002) Cdx1 and Cdx2 have overlapping functions in anteroposterior patterning and posterior axis elongation. Development 129:2181–2193PubMed
15.
Allan D, Houle M, Bouchard N et al (2001) RARgamma and Cdx1 interactions in vertebral patterning. Dev Biol 240:46–60CrossRefPubMed
16.
Subramanian V, Meyer BI, Gruss P (1995) Disruption of the murine homeobox gene Cdx1 affects axial skeletal identities by altering the mesodermal expression domains of Hox genes. Cell 83:641–653CrossRefPubMed
17.
Schramm C, Draaken M, Tewes G et al (2011) Autosomal-dominant non-syndromic anal atresia: sequencing of candidate genes, array-based molecular karyotyping, and review of the literature. Eur J Pediatr 170:741CrossRefPubMed
18.
Jia H, Chen Q, Zhang T et al (2012) The expression analysis ofNotch-1 and Jagged-2 during the development of the hindgut in rat embryos with ethylene thiourea induced anorectal malformations. J Surg Res 172(1):131–136CrossRefPubMed
19.
Ince TA, Cviko AP, Quade BJ et al (2002) p63 Coordinates anogenital modeling and epithelial cell differentiation in the developing female urogenital tract. Am J Pathol 161(4):1111–1117CrossRefPubMedPubMedCentral
20.
Wong EH, Cui L, Ng CL et al (2013) Genome-wide copy number variation study in anorectal malformations. Hum Mol Genet 22(3):621–631CrossRefPubMed
21.
Schramm C, Draaken M, Bartels E et al (2011) De novo microduplication at 22q11.21 in a patient with VACTERL association. EurJ Med Genet 54:9–13CrossRef
22.
Zhang T, Tang XB, Wang LL et al (2013) Mutations and down regulation of CDX1 in children with anorectal malformations. IntJ Med Sci 10:191–197CrossRef
23.
Carter TC, Kay DM, Browne ML et al (2013) Anorectal atresia and variants at predicted regulatory sites in candidate genes. Ann Hum Genet 77:31–46CrossRefPubMed
24.
25.
van de Putte R, Wijers CH, de Blaauw I, Feitz WF, Marcelis CL et al (2015) Sequencing of the DKK1 gene in patients with anorectal malformations and hypospadias. Eur J Pediatr 174(5):583–587CrossRefPubMed
26.
Garcia-Barcelo MM, Chi-Hang Lui V, Miao X et al (2008) Mutational analysis of SHH and GLI3 in anorectal malformations. Birth Defects Res A Clin Mol Teratol 82:644–648CrossRefPubMed
27.
Dworschak GC, Draaken M, Hilger AC et al (2015) Genome wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities. Birth Defects Res A Clin Mol Teratol 103:235–242CrossRefPubMed
28.
Gao H, Wang D, Bai Y, Zhang J, Wu M, Mi J, Jia H, Wang W (2016) Hedgehog gene polymorphisms are associated with the risk of Hirschsprung’s disease and anorectal malformation in a Chinese population. Mol Med Rep 13(6):4759–4766CrossRefPubMed
29.
30.
Dworschak GC, Draaken M, Marcelis C et al (2013) De novo 13q deletions in two patients with mild anorectal malformations as part of VATER/VACTERL and VATER/VACTERL-like association and analysis of EFNB2 in patients with anorectal malformations. Am J Med Genet A 161A:3035–3041CrossRefPubMed
31.
Hilger A, Schramm C, Pennimpede T et al (2013) De novo microduplications at 1q41, 2q37.3, and 8q24.3 in patients with VATER/VACTERL association. Eur J Hum Genet 21:1377–1382CrossRefPubMedPubMedCentral
32.
Zhang R, Marsch F, Kause F, Degenhardt F, Schmiedeke E et al (2017) Array-based molecular karyotyping in 115 VATER/VACTERL and VATER/VACTERL-like patients identifies disease-causing copy number variations. Birth Defects Res. doi:10.​1002/​bdr2
33.
McDonald-McGinn DM, Sullivan KE, Marino B et al (2015) 22q11.2 deletion syndrome. Nat Rev Dis Primer 1:15071CrossRef
34.
Brosens E, Marsch F, de Jong EM et al (2016) Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula. Eur J Hum Genet 24:1715–1723CrossRefPubMedPubMedCentral
35.
Reutter H, Ludwig M (2013) VATER/VACTERL association: evidence for the role of genetic factors. Mol Syndromol 4:16–19PubMed
36.
Su P, Yuan Y, Huang Y et al (2013) Anorectal malformation associated with a mutation in the P63 gene in a family with split hand-foot malformation. Int J Colorectal Dis 28(12):1621–1627CrossRefPubMedPubMedCentral
37.
Hilger AC, Halbritter J, Pennimpede T, van der Ven A, Sarma G, Braun DA et al (2015) Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association. Hum Mutat 36(12):1150–1154CrossRefPubMedPubMedCentral
38.
Gurung N, Grosse G, Draaken M, Hilger AC, Nauman N, Müller A, Gembruch U, Merz WM, Reutter H, Ludwig M (2015) Mutations in PTF1A are not a common cause for human VATER/VACTERL association or neural tube defects mirroring Danforth’s short tail mouse. Mol Med Rep 12:1579–1583CrossRefPubMed
39.
Stoll C, Alembik Y, Dott B, Roth MP (2007) Associated malformations in patients with anorectal anomalies. Eur J MedGenet 50:281–290
40.
Cuschieri A, EUROCAT Working Group (2002) Anorectalanomalies associated with or as part of other anomalies. Am J Med Genet 110:122–130CrossRefPubMed
41.
42.
Endo M, Hayashi A, Ishihara M et al (1999) Analysis of 1,992 patients with anorectal malformations over the past two decades in Japan. Steering Committee of Japanese Study Group of Anorectal Anomalies. J Pediatr Surg 34(3):435–441CrossRefPubMed
43.
44.
Marcelis C, de Blaauw I, Brunner H (2011) Chromosomal anomalies in the etiology of anorectal malformations: a review. Am J Med Genet A 155:2692–2704CrossRef
45.
Towne PL, Brock WA (1972) Hereditary syndrome of imperforate anus with hand foot and ear anomalies. J Pediatr 81:321–326CrossRef
46.
Hall JG, Pallister PD, Clarren SK et al (1980) Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly–a new syndrome? Part I: clinical, causal, and pathogenetic considerations. Am J Med Genet 7(1):47–74CrossRefPubMed
47.
Thompson EM, Baraitser M, Lindenbaum RH, Zaidi ZH, Kroll JS (1985) The FG syndrome: 7 new cases. Clin Genet 27:582–594CrossRefPubMed
48.
Kaufman RL, Hartman A, McAlister WH et al (1972) Family studies of congenital heart disease: a syndrome of hydrometrocolpos, proximal polydactyly and congenital heart disease. Birth Defects Orig Ser 8:85–8784
49.
Arron JR, Winslow MM, Polleri A et al (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441(7093):595–600CrossRefPubMed
50.
Lynch SA, Bond PM, Copp AJ et al (1995) A gene for autosomal dominant sacral agenesis maps to the holoprosencephaly region at 7q36. Nat Genet 11(1):93–9528CrossRefPubMed
51.
Currarino G, Coln D, Votteler T (1981) Triad of anorectal, sacral, and presacral anomalies. Am J Roentgen 137:395–39829CrossRef
52.
Ross AJ, Ruiz-Perez V, Wang Y et al (1998) A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nat Genet 20:358–361CrossRefPubMed
53.
Hagan DM, Ross AJ, Strachan T, Lynch SA, Ruiz-Perez V, Wang YM et al (2000) Mutation analysis and embryonic expression of the HLXB9 Currarino syndrome gene. Am J Hum Genet 66:1504–1515 (PubMed: 10749657)CrossRefPubMedPubMedCentral
54.
Cuturilo G, Hodge JC, Runke CK, Thorland EC, Al-Owain MA, Ellison JW, Babovic-Vuksanovic D (2016) Phenotype analysis impacts testing strategy in patients with Currarino syndrome. Clin Genet 89(1):109–114CrossRefPubMed
55.
56.
Marlin S, Blanchard S, Slim R, Lacombe D, Denoyelle F, Alessandri JL et al (1999) Townes-Brocks syndrome: detection of a SALL1 mutation hot spot and evidence for a position effect in one patient. Hum Mutat 14:377–386CrossRefPubMed
57.
Prontera P, Ottaviani V, Rogaia D, IsidoriI I, Mencarelli A, Malerba N et al (2016) A novel MED12 mutation: evidence for a fourth phenotype. Am J Med Genet Part A 170A:2377–2382CrossRef
58.
Hall JG (2014) Pallister–Hall syndrome has gone the way of modern medical genetics. Am J Med Genet Part C Semin Med Genet 166C:414–418CrossRefPubMed
59.
Vlangos CN, Siuniak A, Ackley T, van Bokhoven H, Veltman J, Iyer R et al (2011) Comprehensive genetic analysis of OEIS complex reveals no evidence for a recurrent microdeletion or duplication. Am J Med Genet A 155A(1):38–49. doi:10.​1002/​ajmg.​a.​33757 CrossRefPubMed
60.
61.
Kang S, Allen J, Graham JJ et al (1997) Linkage mapping and phenotypic analysis of autosomal dominant Pallister–Hall syndrome. J Med Genet 34(6):441–446CrossRefPubMedPubMedCentral
62.
Martinez-Frias ML (2004) Segmentation anomalies of the vertebrasand ribs: one expression of the primary developmental field. Am J Med Genet A 128:127–131 (1992: second international workshop on fetal genetic pathology)CrossRef
Metadata
Title
A review of genetic factors contributing to the etiopathogenesis of anorectal malformations
Authors
Kashish Khanna
Shilpa Sharma
Noel Pabalan
Neetu Singh
D. K. Gupta
Publication date
01-01-2018
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Surgery International / Issue 1/2018
Print ISSN: 0179-0358
Electronic ISSN: 1437-9813
DOI
https://doi.org/10.1007/s00383-017-4204-2

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