Atrioventricular canal defect and associated genetic disorders: new insights into polydactyly syndromes
AbstractAtrioventricular canal defect (AVCD) is a common congenital heart defect (CHD), representing 7.4% of all cardiac malformations, considered secondary to an extracellular matrix anomaly. The AVCD is associated with extracardiac defects in about 75% of the cases. In this review we analyzed different syndromic AVCDs, in particular those associated with polydactyly disorders, which show remarkable genotype-phenotype correlations. Chromo - some imbalances more frequently associated with AVCD include Down syndrome, deletion 8p23 and deletion 3p25, while mendelian disorders include Noonan syndrome and related RASopathies, several polydactyly syndromes, CHARGE and 3C (cranio-cerebello-cardiac) syndrome. The complete form of AVCD is prevalent in patients with chromosomal imbalances. Additional cardiac defects are found in patients affected by chromosomal imbalances different from Down syndrome. Left-sided obstructive lesions are prevalently found in patients with RASopathies. Patients with deletion 8p23 often display AVCD with tetralogy of Fallot or with pulmonary valve stenosis. Tetralogy of Fallot is the only additional cardiac defect found in patients with Down syndrome and AVCD. On the other hand, the association of AVCD and tetralogy of Fallot is also quite characteristic of CHARGE and 3C syndromes. Heterotaxia defects, including common atrium and anomalous pulmonary venous return, occur in patients with AVCD associated with polydactyly syndromes (Ellis-van Creveld, short rib polydactyly, oral-facial-digital, Bardet-Biedl, and Smith-Lemli-Opitz syndromes). The initial clinical evidence of anatomic similarities between AVCD and heterotaxia in polydactyly syndromes was corroborated and explained by experimental studies in transgenic mice. These investigations have suggested the involvement of the Sonic Hedgehog pathway in syndromes with postaxial polydactyly and heterotaxia, and ciliary dysfunction was detected as pathomechanism for these disorders. Anatomic differences in AVCD in the different groups are probably due to different genetic causes.
Perry LW, Neill CA, Ferencz C, et al. Infants with congenital heart disease: the cases. In: Ferencz C, Rubin JD, Loffredo CA, Magee CA, editors. Pediatric Cardiology. Epidemiology of congenital heart disease. The Baltimore-Washington Infant Study 1981-1989. Mount Kisco, New York: Futura Publishing Company, Inc; 1993. pp. 33-62.
Clark EB. Mechanism in the pathogenesis of congenital heart defects. In: Pierpont ME, Moller J. The Genetics of Cardiovascular Disease. Boston, MA: Martinus-Nijoff;1986. pp.3-11.
Ferencz C, Loffredo CA, Correa-Villasenor A, Wilson PD (eds). Genetic and environmental risk factors of major cardiovascular malformations. The Baltimore-Washington Infant Study 1981-1989. Armonk, New York: Futura Publishing Company Inc; 1997.
Digilio MC, Marino B, Toscano A, Giannotti A, Dallapiccola B. Atrioventricular canal defect without Down syndrome: a heterogeneous malformation. Am J Med Genet 1999;85:
Hunter AGW. Down syndrome. In: Cassidy SB, Allanson JE, (eds). Management of genetic syndromes. Hoboken, New Jersey: John Wiley & Sons Inc; 2005. pp. 191-210.
De Biase L, Di Ciommo V, Ballerini L, et al. Prevalence of left-sided obstructive lesions in patients with atrioventricular canal without Down’s syndrome. J Thorac Cardiovasc Surg 1986;91:467-9.
Marino B. Left-sided cardiac obstruction in patients with Down sindrome. J Pediatr 1989;115:834-5.
Marino B, Vairo U, Corno A, et al. Atrioventricular canal in Down syndrome. Prevalence of associated cardiac malformations compared with patients without Down syndrome. Am J Dis Child 1990;144:1120-2.
Marino B. Patterns of congenital heart disease and associated cardiac anomalies in children with Down syndrome. In: Marino B, Pueschel SM (eds). Heart Disease in Persons with Down Syndrome. Baltimore: Brookes Publishing; 1996. pp. 33-140.
Carmi R, Boughman JA, Ferencz C. Endocardial cushion defect: further studies of “isolated” versus “syndromic” occurrence. Am J Med Genet 1992;43:569-75.
Formigari R, Di Donato RM, Gargiulo G, et al. Better surgical prognosis for patients with complete atrioventricular septal defect and Down’s syndrome. Ann Thorac Surg 2004;78:666-72.
Korenberg JR, Barlow GM, Chen X-N, et al. Down syndrome congenital heart disease: narrowed region and DSCAM as a candidate gene. In: Clark EB, Nakazawa M, Takao A (eds). Etiology and morphogenesis of congenital heart disease: Twenty years of progress in genetics and developmental biology. Armonk, New York: Futura Publishing Co, Inc; 2000. pp. 365-370.
Jongewaard IN, Lauer RM, Behrendt DA, et al. Beta 1 integrin activation mediates adhesive differences between trisomy 21 on non-trisomic fibroblasts on type VI collagen. Am J Med Genet 2002;109:298-305.
Arron JR, Winslow MM, Polleri A, et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 2006;441:595-600.
Brocker-Vriends AH, Mooji PD, Van Bell F, et al. Monosomy 8p: an easily overlooked syndrome. J Med Genet 1986;23:153-4.
Hutchinson R, Wilson M, Voullaire L. Distal 8p deletion (8p23.1----8pter): a common deletion? J Med Genet 1992;29:407-11.
Wu B-L, Schneider GH, Sabatino DE, et al. Distal 8p deletion (8)(p23.1): an easily missed chromosomal abnormality that may be associated with congenital heart defect and mental retardation. Am J Med Genet 1996;62:77-83.
Digilio MC, Marino B, Guccione P, et al. Deletion 8p sindrome. Am J Med Genet 1998;75:534-6.
Paez MT, Yamamoto T, Hayashi K, et al. Two patients with atypical interstitial deletions of 8p23.1: mapping of phenotypical traits. Am J Med Genet 2008;146A:1158-65.
Marino B, Reale A, Giannotti A, et al. Non-random association of atrioventricular canal and del (8p) syndrome. Am J Med Genet 1992;42:424-7.
Digilio MC, Giannotti A, Marino B, Dallapiccola B. Atrioventricular canal and 8p- syndrome. Am J Med Genet 1993;47:437-8.
Devriendt K, K, Matthijs G, Van Dael R, et al. Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. Am J Hum Genet 1999;64:1119-26.
Pehlivan T, Pober BR, Brueckner M, et al. GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease. Am J Med Genet 1999;83:201-6.
Giglio S, Graw SL, Gimelli G, et al. Deletion of a 5-cM region at chromosome 8p23 is associated with a spectrum of congenital heart defects. Circulation 2000;102:432-7.
Phipps ME, Latif F, Prowse A, et al. Molecular genetic analysis of
the 3p- syndrome. Hum Molec Genet 1994;3:903-8.
Drumheller T, McGillivray C, Behrner D, et al. Precise localization of 3p25 breakpoints in four patients with the 3p- syndrome. J Med Genet 1996;33:842-7.
Green EK, Priestley MD, Waters J, et al. Detailed mapping of a congenital heart disease gene in chromosome 3p25. J Med Genet 2000;37:581-7.
Ramer JC, Ladda RL, Franckel C. Two infants with del(3)(p25pter) and a review of previously reported cases. Am J Med Genet 1989;33:108-12.
Rupp PA, Fouad GT, Egelston CA, et al. Identification, genomic organization and mRNA expression of CRELD1, the founding member of a unique family of matricellular proteins. Gene 2002;293:47-57.
Robinson SW, Morris CD, Goldmuntz E, et al. Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet 2003;72:1047-52.
Schubbert S, Bollag G, Shannon K. Deregulated Ras signaling in developmental disorders: new tricks for an old dog. Curr Opinion Genet Dev 2007;17:15-22.
Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 2009;19:230-6.
Tartaglia M, Zampino G, Gelb BD. Noonan syndrome: clinical aspects and molecular pathogenesis. Molec Syndromol 2010;1:2-26.
Marino B, Digilio MC, Toscano A, et al. Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr 1999;135:703-6.
Sarkozy A, Conti E, Seripa D, et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet 2003;40:704-8.
Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002;71:389-94.
Sarkozy A, Conti E, Digilio MC, et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD sindrome. J Med Genet 2004;41:e68.
Marino B, Gagliardi MG, Digilio MC, et al. Noonan sindrome: structural abnormalities of the mitral valve causing subaortic obstruction. Eur J Pediatr 1995;154:949-52.
Gow RM, Freedom RM, Williams WG, et al. Coarctation of the aorta or subaortic stenosis with atrioventricular septal defect. Am J Cardiol 1984;53:1421-8.
Klues HG, Roberts WC, Maron BJ. Anomalous insertion of the papillary muscle directly into anterior mitral leaflet in hypertrophic cardiomyopathy. Significance in producing left ventricular outflow obstruction. Circulation 1991;84:1188-97.
Klues HG, Maron BJ, Dollar AL, Roberts WC. Diversity of structural mitral valve alterations in hypertrophic cardiomyiopathy. Circulation 1992;85:1651-60.
Amman G, Sherman FS. Myocardial dysgenesis with persistent sinusoids in a neonate with Noonan’s phenotype. Pediatr Pathol 1992;12:83-92.
Sarkozy A, Lepri F, Marino B, et al. Additional evidence that PTPN11 mutations play only a minor role in the pathogenesis of non-syndromic atrioventricular canal defect. Am J Med Genet 2006;140:1970-2.
Weismann CG, Hager A, Kaemmerer H, et al. PTPN11 mutations play a minor role in isolated congenital heart disease. Am J Med Genet 2005;136A:146-51.
Trip J, van Stuijvenberg M, Dikkers FG, Pijnenburg MW. Unilateral CHARGE association. Eur J Pediatr 2002;161:78–80.
Vissers LELM, van Ravenswaaij CM, Admiral R, et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 2004;36:955-7.
Lalani SR, Safiullah AM, Fernbach SD, et al. Spectrum of CHD7 mutations in 110 individuals with CHARGE syndrome and genotype-phenotype correlation. Am J Hum Genet 2006;78:303-14.
Wyse RK, al-Mahdawi S, Burn J, Blake K. Congenital heart disease in CHARGE association. Pediatr Cardiol 1993;14:75-81.
Ritscher D, Schinzel A, Boltshauser E, et al. Dandy-Walker(like) malformation, atrio-ventricular septal defect and a similar pattern of minor anomalies in 2 sisters: a new syndrome? Am J Med Genet 1987;26:481-91.
Digilio MC, Marino B, Giannotti A, et al. Atrioventricular canal and 3C (cranio-cerebello-cardiac) syndrome. Am J Med Genet 1995;58:97-8.
Vergara P, Digilio MC, de Zorzi A, et al. Genetic heterogeneity and phenotypic anomalies in children with atrioventricular canal and tetralogy of Fallot. Clin Dysmorphol 2006;15:65-70.
Digilio MC, Marino B, Ammirati A, et al. Cardiac malformations in patients with oral-facial-skeletal syndromes: clinical similarities with heterotaxia. Am J Med Genet 1999;84:350-6.
Digilio MC, Marino B, Giannotti A, et al. Specific congenital heart defects in RSH/Smith-Lemli-Opitz sindrome: postulated involvement of the sonic hedgehog pathway in syndromes with postaxial polydactyly or heterotaxia. Birth Defects Res A Clin Mol Teratol 2003;67:149-53.
Digilio MC, Dallapiccola B, Marino B. Atrioventricular canal defect in Bardet-Biedl syndrome: clinical evidence supporting the link between atrioventricular canal defect and polydactyly syndromes with ciliary dysfunction. Genet Med 2006;8:536-8.
Beighton P, Giedion A, Gorlin R, et al. International classification of osteochondrodysplasias. International Working Group on Constitutional Diseases of Bone. Am J Med Genet 1992;44:223-9.
Franceschini P, Guala A, Vardeu MP, et al. Short rib–dysplasia group (with/without polydactyly): report of a patient suggesting the existence of a continuous spectrum. Am J Med Genet 1995;59:359-64.
Neri G, Guerrieri F, Genuardi M. Oral-facial-skeletal syndromes. Am J Med Genet 1995;59:365-8.
Digilio MC, Marino B, Giannotti A, Dallapiccola B. Orocardiodigital sindrome: an oral-facial-digital type II-variant associated with atrioventricular canal. J Med Genet 1996;33:416-8.
Hingorani SR, Pagon RA, Shepard TH, Kapur RP. Twin fetuses with abnormalities that overlap with three midline malformation complexes. Am J Med Genet 1991;41:230-5.
Muenke M, Ruchelli ED, Rorke LB, et al. On lumping and splitting: a fetus with clinical findings of the oral-facial-digital syndrome type VI, the hydrolethalus syndrome, and the Pallister-Hall syndrome. Am J Med Genet 1991;41:548-56.
Yapar EG, Ekici E, Aydogdu T, et al. Diagnostic problems in a case with mucometrocolpos, polydactyly, congenital heart disease, and skeletal dysplasia. Am J Med Genet 1996;66:343-6.
Phoon CK, Neill CA. Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies. Am J Cardiol 1994;73:581-7.
Peoples WM, Moller JH, Edwards JE. Polysplenia: a review of 146 cases. Pediatr Cardiol 1983;4:129-38.
Webber SA, Taylor GP, Colwell K, et al. Extracardiac malformations in asplenia syndrome. Cardio Young 1992;2:136-40.
Belloni C, Beluffi G. Short rib-polydactyly syndrome, type Verma-Naumoff. Rofo 1981;134:431-5.
Fraser FC, Jequier S, Chen MF. Chondrodysplasia, situs inversus totalis, cleft epiglottis and larynx, hexadactyly of hands and feet, pancreatic cystic dysplasia, renal dysplasia/absence, micropenis and ambiguous genitalia, imperforate anus. Am J Med Genet 1989;34:401-5.
Brueton LA, Dillon MJ, Winter RM. Ellis–van creveld syndrome, Jeune syndrome, and renal-hepatic-pancreatic dysplasia: separate entities or disease spectrum? J Med Genet 1990;27:252-5.
Tsai YC, Chang JM, Changchien CC, et al. Unusual short rib-polydactyly syndrome. Am J Med Genet 1992;44:31-6.
de Sierra TM, Ashmead G, Bilenker R. Prenatal diagnosis of short rib (polydactyly) syndrome with situs inversus. Am J Med Genet 1992;44:555-7.
Urioste M, Martinez-Frias ML, Bermelo E, et al. Short-rib-polydactyly sindrome and pericentric inversion of chromosome 4. Am J Med Genet 1994;49:94-7.
Slavotinek AM, Biesecker LG. Phenotypic overlap of McKusick-Kaufman syndrome with Bardet-Biedl syndrome: a literature review. Am J Med Genet 2000;95:208-15.
Lorda-Sanchez I, Ayuso C, Ibanez A. Situs inversus and Hirschprung disease: Two uncommon manifestations in Bardet- Biedl syndrome. Am J Med Genet 2000;90:80-1.
Beals PL, Elcioglu N, Woolf AS, et al. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet 1999;36:437-46.
Karmpous-Benailly H, Martinovic J, Gubler M-C, et al. Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome. Am J Hum Genet 2005;76:493-504.
Slavotinek AM, Biesecker LG. Phenotypic overlap of McKusick-Kaufman syndrome with Bardet-Biedl syndrome: a literature review. Am J Med Genet 2000;95:208-15.
Ansley SJ, Badano JL, Blacque OE, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 2003;425:628-33.
Kim JC, Badano JL, Sibold S, et al. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet 2004;36:462-70.
Fan Y, Esmail MA, Ansley SJ, et al. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet 2004;36:989-93.
Li JB, Gerdes JM, Haycraft CJ, et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 2004;117:541-52.
Supp DM, Wite DP, Potter SS, Brueckner M. Mutation in an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature 1997;389:963-6.
Okada Y, Nonaka S, Tanaka Y, et al. Abnormal nodal flow precedes situs inversus in iv and inv mice. Mol Cell 1999;4:459-68.
Ferrante MI, Zullo A, Barra A, et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet 2006;38:112-7.
Ruiz-Perez VL, Blair HJ, Rodriguez-Andres ME, et al. EVC is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development 2007;134:2903-12.
Ruiz-Perez VL, Goodship JA. Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to hedgehog ligands. Am J Med Genet 2009;151C:341-51.
Mill P, Lockhart PJ, Fitzpatrick E, et al. Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis. Am J Hum Genet 2011;88:508-15.
Ruiz-Perez V, Tompson S, Blair H, et al. Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am J Hum Genet 2003;72:728-32.
Kelley RI, Hennekam RC. The Smith-Lemli-Opitz syndrome. J Med Genet 37:321-35.
Lin AE, Ardinger HH, Ardinger RH Jr, et al. Cardiovascular malformations in Smith-Lemli-Opitz syndrome. Am J Med Genet 1997;68:270-8.
Shefer S, Salen G, Batta AK, et al. Markedly inhibited 7-dehydrocholesterol-delta7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes. J Clin Invest 1995;96:1779-85.
Moebius FF, Fitzky BU, Lee JN, et al. Molecular cloning and expression of the human delta7-sterol reductase. Proc Natl Acad Sci USA 1998;95:1899-902.
Chamoun Z, Mann RK, Nellen D, et al. Skinny hedgehog, an acyltransferase required for palmitolation and activity of the hedgehog signal. Science 2001;293:1080-2084.
Chiang C, Litingtung Y, Lee E, et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996;383-407-13.
Meyers EN, Martin GR. Differences in left-right axis pathways in mouse and chick: functions in FGF8 and SHH. Science 1999;285:403-6.
Tsukui T, Capdevila J, Tamura K, et al. Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1. Proc Natl Acad Sci USA 1999;96:11376-81.
Putoux A, Thomas S, Coene KL, et al. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet 2011;43:601-6.
Ng D, Thakker N, Corcoran CM, et al. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Nat Genet 2004;36:411-6.
Hilton EN, Manson FD, Urquhart JE, et al. Left-sided expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination. Hum Mol Genet 2007;16:1773-82.
Formigari R, Michielon G, Digilio MC, et al. Genetic syndromes and congenital heart defects: how is surgical management affected? Eur J Cardiothorac Surg 2009;35:606-14.
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