Cardiogenetics 2011; volume 1:e7

Atrioventricular canal defect as pathomechanism for these disorders. Anatomic differences in AVCD in the different Correspondence: M. Cristina Digilio, Medical and associated genetic groups are probably due to different genetic Genetics, Bambino Gesù Hospital, IRCCS, Piazza disorders: new insights causes. S. Onofrio 4, 00165, Rome, Italy. Tel: +39.06-68592227 - Fax: +39.06.68592004. into polydactyly syndromes E-mail: [email protected]

M. Cristina Digilio,1 Paolo Versacci,2 Key words: atrioventricular canal defect, chromo- Francesca Lepri,1 Anwar Baban,1 Introduction somal syndrome, , polydactyly, later- Bruno Dallapiccola,1 Bruno Marino2 ality defect. Atrioventricular canal defect (AVCD) is a 1Medical Genetics, Pediatric common (CHD), repre- Received for publication: 1 July 2011. Accepted for publication: 8 July 2011. and Cytogenetics, Bambino Gesù senting 7.4% of all cardiac defects.1 This mal- 2 Pediatric Hospital, IRCCS; Department formation is characterized by a spectrum of of , Pediatric Cardiology, This work is licensed under a Creative Commons anomalies of the atrioventricular valves, atrial Attribution NonCommercial 3.0 License (CC BY- University La Sapienza, Rome, Italy and ventricular septa. In the complete form a NC 3.0). single common atrioventricular valve is found together with an atrial septal defect (ostium ©Copyright M.C. Digilio et al., 2011 primum), and a confluent posterior ventricular Licensee PAGEPress, Italy Abstract septal defect in the inlet portion of the ventric- Cardiogenetics 2011; 1:e7 doi:10.4081/cardiogenetics.2011.e7 ular septum. In the partial form, two separate Atrioventricular canal defect (AVCD) is a right and left atrioventricular valves are found common congenital heart defect (CHD), repre- with a cleft of the mitral valve, an atrial septal senting 7.4% of all cardiac malformations, con- defect (ostium primum), and no ventricular as l-loop of the ventricles, atresia of the atri- sidered secondary to an extracellular matrix septum communication. According to Clark et oventricular valves and transposition of the anomaly. The AVCD is associated with extrac- al.,2 this malformation is classified in the greatonly arteries are virtually absent in subjects 9 ardiac defects in about 75% of the cases. In group of defects of the extracellular matrix. with Down syndrome. this review we analyzed different syndromic AVCD is associated with extracardiac mal- It has been shown that surgical correction of AVCDs, in particular those associated with formations in about 75% of the cases.3,4 Four AVCD in individuals with Down syndrome polydactyly disorders, which show remarkable major groups can be distinguished, including results in lower mortality and morbidity rates, use 11 genotype-phenotype correlations. Chromo- patients with Down syndrome (45%), or other compared to the children without trisomy 21. some imbalances more frequently associated syndromes (15%), or heterotaxia (15%), or a The relationship between AVCD and Down with AVCD include Down syndrome, deletion non-syndromic AVCD (25%).4 syndrome is still unclear. A number of genes 8p23 and deletion 3p25, while mendelian dis- In this review we analyzed the various forms located in the CHD critical region on chromo- orders include Noonan syndrome and related of AVCD, with particular attention to polydacty- some 21 have been considered pathogenetical- RASopathies, several polydactyly syndromes, ly syndromes, which display remarkable geno- ly related to AVCD, including DSCAM,12 CHARGE and 3C (cranio-cerebello-cardiac) type-phenotype correlations. COL6A1,13 and DSCR1.14 syndrome. The complete form of AVCD is prevalent in patients with chromosomal imbal- Atrioventricular canal defect and Atrioventricular canal defect and ances. Additional cardiac defects are found in chromosomal anomalies patients affected by chromosomal imbalances Down syndrome Down syndrome, due to trisomy 21, is the different from Down syndrome. Left-sided Deletion 8p23 obstructive lesions are prevalently found in more frequently associated Terminal deletion of the short arm of chromo- patients with RASopathies. Patients with dele- with AVCD. Clinical manifestations include some 8 (del8p23) is the second chromosomal tion 8p23 often display AVCD with tetralogy of facial anomalies, mental retardation, CHD, 5 anomaly more frequently associated with Fallot or with pulmonary valve stenosis. and gastrointestinal malformations (Table 1). 4 Tetralogy of Fallot is the only additional cardiac CHD occur in about 40-50% of these patients, AVCD. The number of patients with this anom- defect found in patients with Down syndromeNon-commercialand cardiac care can prevent morbidity and aly has increased progressively in parallel with and AVCD. On the other hand, the association mortality due to congestive heart failure and the improved ability of molecular and cytogenet- of AVCD and tetralogy of Fallot is also quite pulmonary vascular disease. The anatomic pat- ic techniques to recognize small imbalances. characteristic of CHARGE and 3C syndromes. terns of AVCD and the associated cardiac mal- Clinical characteristics of the syndrome include Heterotaxia defects, including common atrium formations are quite distinct in this syndrome. microcephaly, mental retardation, CHD, 15-19 and anomalous pulmonary venous return, The complete form of AVCD is the most fre- hypospadia, and facial anomalies (Table 1). occur in patients with AVCD associated with quent type of CHD associated with trisomy 21, Cardiac malformations are present in two third polydactyly syndromes (Ellis-van Creveld, short and about 70% of all children with complete of the patients,18 and AVCD is found in about rib polydactyly, oral-facial-digital, Bardet-Biedl, AVCD display this aneuploidy. Children with 40% of the cases. In general, the AVCD is com- and Smith-Lemli-Opitz syndromes). The initial Down syndrome show a simple form of AVCD, plete, and often associated with pulmonary clinical evidence of anatomic similarities which is usually complete, and rarely associat- valve stenosis (Table 2).17,18,20-22 The GATA4 between AVCD and heterotaxia in polydactyly ed with additional cardiac anomalies (with the gene, which maps to the 8p23.1 region, and is syndromes was corroborated and explained by only notable exception of tetralogy of Fallot) often deleted in these patients, is candidate to experimental studies in transgenic mice. (Table 2). Left-sided obstructive lesions are CHD in del8p23, being expressed in the devel- These investigations have suggested the significantly rare in children with AVCD and oping heart.22-24 Other genes within this criti- involvement of the Sonic Hedgehog pathway in Down syndrome compared to patients with cal region could contribute to these defects,24 syndromes with postaxial polydactyly and het- AVCD without Down syndrome.4,6-10 Accord - since GATA4 is not invariably deleted in sub- erotaxia, and ciliary dysfunction was detected ingly, some types of situs abnormalities such jects with CHD and del8p23.1. However,

[page 24] [Cardiogenetics 2011; 1:e7] Article impaired expression of GATA4 gene secondary with NS and AVCD are similar to those found should be considered in the pathogenesis of to a positional effect should also be considered. in patients with hypertrophic cardiomyopa- CHD in patients with NS. Cardiac jelly and Dextrocardia, abnormalities of the pul- thy.40,41 This is not surprising, considering that extracellular matrix anomalies could account monary and systemic vein returns, common myocardial disarray and cardiac hypertrophy for CHDs in NS, and are likely responsible also atrium, pulmonary stenosis, single ventricle, are common features of patients with NS. An for AVCD.2,42 and transposition of the great arteries are abnormal developmental mechanism of the left PTPN11 gene have been detected found in a number of del8p23 patients,18 sug- ventricular myocardium and of the mitral valve in patients with AVCD associated with gesting that monosomy of the short arm of is responsible for laterality defects in a subset of these subjects. Table 1. Clinical characteristics of genetic disorders associated with atrioventricular canal defect. Deletion 3p25 Deletion 3p25 syndrome can be associated Syndrome Genetic defect Extracardiac features with AVCD.25-27 Clinical features of this syn- Down syndrome Trisomy 21 Facial anomalies drome include mental retardation, micro- Gastrointestinal malformations cephaly, facial anomalies (, telecanthus Mental retardation and micrognathia) (Table 1). Differences in Deletion 8p23 Deletion 8p23 Facial anomalies proximal breakpoints lead to clinical variabili- Microcephaly ty, including CHD, postaxial polydactyly, renal Hypospadia anomalies, gastrointestinal malformations, Mental retardation and cleft palate. CHD, including AVCD, is Deletion 3p25 Deletion 3p25 Facial anomalies found in about one-third of del3p25 patients.27 Microcephaly Complete AVCD has been reported in at least Cleft palate one individual.28 A cell adhesion molecule, Postaxial polydactyly Gastrointestinal malformations coded by CRELD1 gene, has been identified as Renal anomalies a likely candidate for AVCD, based on its map only position on chromosome 3p25 and the expres- Noonan syndrome PTPN11 and other RAS cascade Facial anomalies sion pattern in the developing heart.29 Analysis gene mutations Growth retardation Skeletal defects of the CRELD1 gene in patients with non-syn- dromic partial AVCD has identified heterozy- use Cognitive deficit gous missence mutations in about 6% of the CHARGE syndrome CHD7 gene mutations Ocular coloboma cases, associated with heterotaxia in at least 30 Choanal atresia one of them. Ear anomalies Deafness Atrioventricular canal defect and Urogenital anomalies mendelian disorders Growth retardation 3C syndrome Unknown Facial anomalies RASopathies (Noonan syndrome and relat- ed disorders) Cerebellar malformation Noonan Syndrome (NS) and related disor- Ocular coloboma ders including LEOPARD, Noonan-like with Mental retardation loose anagen hair, Cardio-Facio-Cutaneous Ellis-van Creveld syndrome EVC gene mutations Short-limb and Costello syndromes (the so-called EVC2 gene mutations Short ribs RASopathies) are caused by mutations affect- Postaxial polydactyly ing several genes participating in the RAS- Median cleft lip MAP (MAPK) signaling pathway.31-33 Oral frenula Clinical features include facialNon-commercial anomalies, Oral-facial digital syndromes OFD1: CXORF5 gene mutations CHD, growth retardation, ectodermal and OFD6: TMEM216 gene mutations Tongue hamartoma skeletal defects, and variable cognitive deficits Oral frenula (Table 1). CHD is found in about 65-85% of the Cleft palate Postaxial and central polydactyly cases, depending on the mutated genes. AVCD is the third most frequent CHD in Noonan syn- Bardet-Biedl syndrome BBS1-BBS9 genes mutations Obesity drome after pulmonary valve stenosis and Retinitis pigmentosa Postaxial polydactyly hypertrophic ,34,35 and can be 36,37 Urogenital malformations also a feature of LEOPARD syndrome. AVCD Cognitive deficit in RASopathies is usually partial, and may be Smith-Lemli-Opitz syndrome DHCR7 gene mutations Facial anomalies associated with subaortic stenosis or aortic 34,38,39 Mental retardation coarctation (Table 2). Structural abnor- Microcephaly malities causing congenital subaortic stenosis Growth retardation include accessory fibrous tissue and/or anom- Feeding difficulties alous insertion of the mitral valve and anom- Cleft palate alous papillary muscle of the left ventricle. Postaxial polydactyly Anomalies of the mitral valve leaflets and of Hypospadia the subvalvular mitral apparatus in patients 2-3 toe syndactyly

[Cardiogenetics 2011; 1:e7] [page 25] Review

Table 2. Cardiac characteristics of genetic syndromes associated with atrioventricular canal defect. Syndrome AVCD Associated CHDs TOF PVS Common atrium APVR (anatomic type) Left-sided obstruction Down syndrome Complete -+--- Deletion 8p23 Complete -+++- Deletion 3p25 Partial/complete ---+- Noonan syndrome Partial +-+-- CHARGE syndrome Complete -+--- 3C syndrome Complete -+--- Ellis-van Creveld syndrome Partial ---+- Oral-facial digital syndromes Partial ---+- Bardet-Biedl syndrome Partial ----- Smith-Lemli-Opitz syndrome Partial ----+ AVCD, atrioventricular canal defect; CHD, congenital heart defect ; TOF, tetralogy of Fallot; PVS, pulmonary valve stenosis; APVR, abnormal pulmonary venous return. + present, - absent

RASopathies, in particular in patients with dromes and oral-facial-digital (OFD) syn- der is characterized by obesity, retinitis pig- Noonan and LEOPARD syndromes.35,43 Two dromes,56,57 prompting the denomination of mentosa, postaxial polydactyly, genito-urinary adjacent mutations in exon 2 (L43F and T42A) oral-facial-skeletal syndromes.57 The OFD syn- malformations, cognitive impairment, and have been found in patients with AVCD, in dromes are characterized by anomalies of the CHD.73 The phenotype of BBS overlaps with association with NS43 and with apparently non- oral cavity (hamartoma of the tongue and gin- that of other disorders with postaxial poly- syndromic AVCD.44 gival frenula), hypertelorism, cleft palate, hand dactyly, including Meckel syndrome74 and and/or feet polydactyly, brachydactyly and clin- Kaufmann-McKusickonly syndrome.75 BBS is a CHARGE and 3C (cranio-cerebello-cardiac) odactyly (Table 1). At least 12 different types of genetically heterogeneous disorder with at syndromes OFD syndrome have been delineated based on least 15 mutated loci and 9 cloned genes, CHD occurs in about 84% of patients with clinical manifestations and inheritance pat- whose proteins are involved in ciliary function CHARGE syndrome.45 This disorder is charac- terns. AVCD is the commonest CHD in use OFD regulation. 76-79 The association between BBS terized by ocular coloboma, choanal atresia, syndrome type II.58 Examples of transitional and AVCD, which is considered a partial mani- growth and mental retardation, genital anom- phenotypes have been observed.59-61 The festation of heterotaxia, in a subset of these alies, and hearing loss (Table 1). Mutations in anatomic types of CHDs occurring in these patients is of interest. In fact, while the BBS the CHD7 gene are detected in the majority of syndromes also support the clinical overlap proteins do affect the ciliary function, the 46,47 these patients. AVCD is the second most between these conditions. Published reports nodal cilium dysfunction is a known cause of frequent CHD in CHARGE syndrome, often in corroborate the association between these left-right axis defects in vertebrates.80,81 48 association with tetralogy of Fallot (Table 2). syndromes and heterotaxia heart defects.52 In Interestingly, failure of the left-axis specifi- AVCD with tetralogy of Fallot is also character- particular, the association of AVCD and com- cation with abnormal cardiac tube retaining a istic of 3C (cranio-cerebello-cardiac) syn- mon atrium found in patients with oral-facial- midline position or reversal of the heart loop drome, a genetic condition of unknown etiolo- skeletal syndrome is rare in the nonsyndromic have been demonstrated also in knock-out gy displaying some overlap with CHARGE syn- patients, while is common in the oral-facial- male mouse embryos lacking the OFD type 1 drome. The 3C syndrome is clinically defined skeletal syndromes, and in heterotaxia syn- gene (Ofd1).82 Ultrastructural analysis in these by the association of cranial anomalies, cere- drome with asplenia62 or polysplenia syn- experiments showed a lack of cilia in the bellar malformations (prevalently Dandy- dromes.63 The heterotaxia syndrome is charac- embryonic node, and a specific role of the Ofd1 Walker anomaly), and CHD.49-51 terized by an abnormal arrangement of the protein in cilium assembly through basal body Syndromes with polydactyly Non-commercialabdominal and thoracic organs with complex dysfunction. AVCD, particularly in association with com- CHDs, including AVCD, common atrium, Ciliary anomalies have been demonstrated 83,84 mon atrium, has been reported in several syn- anomalous systemic and pulmonary venous also in Ellis-van Creveld syndrome, and in dromes with postaxial polydactyly, including drainage, persistent left superior vena cava some patients with severe forms of SRP syn- Ellis-van Creveld syndrome and other short rib- with unroofed coronary sinus, and conotruncal dromes.85 Using positional cloning, two genes polydactlyly (SRP) disorders, oral-facial-digital defects.62,64 Complete situs inversus has been (EVC and EVC2) were found to be mutated in syndromes, Bardet-Biedl syndrome, hydro- also found in patients with transitional pheno- most of the patients with Ellis-van Creveld syn- lethalus syndrome, and Smith-Lemli-Opitz syn- types or lethal SRP syndromes.65-70 Intere - drome.86 Mutations in the WRD35 gene have drome.52-54 stingly, continuity in severity in the clinical been detected in patients with SRP syn- The Ellis-van Creveld syndrome is an auto- spectrum of SRP syndromes has a counterpart drome.85 Experimental studies investigating somal recessive disorder characterized by also in the cardiac phenotype showing transi- molecular pathways and developmental short-limb dwarfism, short ribs, postaxial poly- tion from AVCD and common atrium in Ellis- processes perturbated in Ellis-van Creveld syn- dactyly of hands and feet, ectodermal defects, van Creveld syndrome to complete situs inver- drome have demonstrated that EVC gene is an and CHD (Table 1). This syndrome belongs to sus in Jeune and lethal SRP syndromes. intracellular component of the hedgehog sig- the group of SRP syndromes, together with AVCD, dextrocardia without structural car- nal transduction pathway that is required for Jeune syndrome and the I and IV subgroups of diac defects and abdominal situs inversus are normal transcriptional activation of the Indian lethal SRP syndromes.55 In the 90’s a clinical also found in Bardet-Biedl syndrome hedgehog (Ihh) target genes.83 In particular, overlap was established between SRP syn- (BBS).52,54,71,72 This autosomal recessive disor- EVC is a positive mediator of the Ihh-regulated

[page 26] [Cardiogenetics 2011; 1:e7] Review bone-growth that localises at the base of chon- with polydactyly, CHARGE and 3C (cranio-cere- Down syndrome: a heterogeneous malfor- drocyte cilia.83 Mouse models for the WDR35 bello-cardiac) syndrome. The complete form of mation. Am J Med Genet 1999;85:140-6. gene mutations resulted in congenital abnor- AVCD is prevailing in patients with chromoso- 5. Hunter AGW. Down syndrome. In: Cassidy malities usually associated with defects in the mal imbalances. Additional cardiac defects are SB, Allanson JE, (eds). Management of Hedgehog signaling pathway.85 found in patients with syndromes different genetic syndromes. Hoboken, New Jersey: Following the observations in Smith-Lemli- from Down syndrome. Left-sided obstructive John Wiley & Sons Inc; 2005. pp. 191-210. Opitz (SLO) syndrome, perturbations of the lesions are mainly found in patients with Ras- 6. De Biase L, Di Ciommo V, Ballerini L, et al. different components of Sonic hedgehog opathies. Patients with deletion 8p23 may be Prevalence of left-sided obstructive lesions (SHH) pathway have been associated with dif- affected by AVCD with tetralogy of Fallot or in patients with atrioventricular canal ferent developmental errors in patients mani- with pulmonary valve stenosis. Tetralogy of without Down’s syndrome. J Thorac festing partially overlapping features.53 SLO Fallot is the only additional cardiac defect Cardiovasc Surg 1986;91:467-9. syndrome is an autosomal recessive disorder detected in patients with Down syndrome and 7. Marino B. Left-sided cardiac obstruction in caused by an inborn error of cholesterol metab- AVCD. On the other hand, the association of patients with Down sindrome. J Pediatr olism. Clinical manifestations include mental AVCD and tetralogy of Fallot is also character- 1989;115:834-5. retardation, microcephaly, growth retardation istic of CHARGE and 3C syndromes. CHDs in 8. Marino B, Vairo U, Corno A, et al. Atrio - with feeding difficulties, facial anomalies, the spectrum of heterotaxia syndrome, includ- ventricular canal in Down syndrome. cataract, cleft palate, hypospadia, postaxial ing common atrium and anomalous pulmonary Prevalence of associated cardiac malfor- polydactyly, 2-3 toe syndactyly, and CHD.87 venous return, are diagnosed in patients with mations compared with patients without Septal defects and AVCD are the most common AVCD and polydactyly syndromes (Ellis-van Down syndrome. Am J Dis Child 1990;144: CHDs in SLO syndrome, and AVCD is often Creveld, short rib polydactyly, oral-facial-digi- 1120-2. associated with anomalous pulmonary venous tal, Bardet-Biedl, SLO syndromes). The initial 9. Marino B. Patterns of congenital heart dis- return, the latter feature being also a cardiac clinical observation of phenotypical similari- ease and associated cardiac anomalies in manifestation of heterotaxia syndrome.88 ties between the anatomy of AVCD and hetero- children with Down syndrome. In: Marino Deficient 7-dehydrocholesterol-Δ-7 reductase taxia in syndromes with polydactyly has been B, Pueschel SM (eds). Heart Disease in (DHCR7) activity results in reduced plasma supported by experimental studies in trans- Persons with Down Syndrome. Baltimore: and tissue cholesterol levels and elevated 7- genic mice, and the suggested involvement of onlyBrookes Publishing; 1996. pp. 33-140. dehydrocholesterol concentrations.89 The the Sonic Hedgehog pathway in syndromes 10. Carmi R, Boughman JA, Ferencz C. human DHCR7 gene has beeen found to be with postaxial polydactyly and heterotaxia has Endocardial cushion defect: further stud- responsible for the syndrome.90 Cholesterol been confirmed by the detection of ciliary dys- ies of “isolated” versus “syndromic” occur- has a critical role in the formation of normally function in several disorders with polydactyly.use rence. Am J Med Genet 1992;43:569-75. active hedgehog proteins.91 Abnormal process- Anatomic differences in AVCD are probably 11. Formigari R, Di Donato RM, Gargiulo G, et ing of the Hedgehog proteins secondary to related to distinct genetic causes. The study of al. Better surgical prognosis for patients abnormal cholesterol mechanism may have a peculiar cardiovascular defects associated with with complete atrioventricular septal role in the development of malformations in extracardiac anomalies occurring in the differ- defect and Down’s syndrome. Ann Thorac SLO syndrome. In particular, Sonic Hedgehog ent syndromes may improve the assessment of Surg 2004;78:666-72. proteins are involved in left-right axis develop- prognostic factors and the understanding of 12. Korenberg JR, Barlow GM, Chen X-N, et al. ment, and the phenotype of Sonic Hedgehog genotype-prognostic correlates.98 Down syndrome congenital heart disease: (-/-) mice shows CHDs in the setting of hetero- narrowed region and DSCAM as a candi- taxia and left pulmonary isomerism.92-94 date gene. In: Clark EB, Nakazawa M, Accordingly, the association of AVCD and Takao A (eds). Etiology and morphogene- anomalous pulmonary venous return as partial References sis of congenital heart disease: Twenty manifestation of heterotaxia in SLO syndrome years of progress in genetics and develop- is not surprising. 1. Perry LW, Neill CA, Ferencz C, et al. Infants mental biology. Armonk, New York: Futura The clinical spectrum of ciliopathies linked with congenital heart disease: the cases. 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