BioMed Central

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Orphanet Journal of Rare Diseases

Open AccessReviewComplete atrioventricular canalRaffaele Calabrò* and Giuseppe Limongelli

Address: Cardiologia pediatrica, Azienda Ospedaliera Monaldi, Via Bianchi Leonardo, 80131 Napoli, Italy

Email: Raffaele Calabrò* - raffaele.calabro@unina2.it; Giuseppe Limongelli - limongelligiuseppe@libero.it

* Corresponding author

AbstractComplete atrioventricular canal (CAVC), also referred to as complete atrioventricular septaldefect, is characterised by an ostium primum atrial septal defect, a common atrioventricular valveand a variable deficiency of the ventricular septum inflow. CAVC is an uncommon congenital heartdisease, accounting for about 3% of cardiac malformations. Atrioventricular canal occurs in two outof every 10,000 live births. Both sexes are equally affected and a striking association with Downsyndrome was found. Depending on the morphology of the superior leaflet of the commonatrioventricular valve, 3 types of CAVC have been delineated (type A, B and C, according toRastelli's classification). CAVC results in a significant interatrial and interventricular systemic-to-pulmonary shunt, thus inducing right ventricular pressure and volume overload and pulmonaryhypertension. It becomes symptomatic in infancy due to congestive heart failure and failure tothrive. Diagnosis of CAVC might be suspected from electrocardiographic and chest X-ray findings.Echocardiography confirms it and gives anatomical details. Over time, pulmonary hypertensionbecomes irreversible, thus precluding the surgical therapy. This is the reason why cardiaccatheterisation is not mandatory in infants (less than 6 months) but is indicated in older patients ifirreversible pulmonary hypertension is suspected. Medical treatment (digitalis, diuretics,vasodilators) plays a role only as a bridge toward surgery, usually performed between the 3rd and6th month of life.

Disease name and synonymsComplete atrioventricular canal (CAVC); Common atrio-ventricular canal; Complete atrioventricular septal defect.

European paediatric cardiac codeReference of Complete atrioventricular canal is 06.06.09.

DefinitionCAVC is a complex cardiac malformation characterised bya variable deficiency of the atrioventricular area (cruxcordis) in the developing heart. The malformationinvolves the atrial, ventricular and atrioventricular septaand both atrioventricular valves.

Diagnosis criteriaDiagnosis of CAVC might be clinically suspected inpatients presenting in the first few months of life withcongestive heart failure, cardiomegaly on chest X-ray andleft axis deviation, bi-atrial enlargement and bi-ventricu-lar pressure and volume overload on electrocardiogram(ECG). Echocardiography is the key tool for the diagnosisand anatomic classification of this malformation. Itshows the ostium primum atrial septal defect, with theunderlying common atrioventricular valve, and the defectof the ventricular septal inflow (Figure 1).

Published: 05 April 2006

Orphanet Journal of Rare Diseases2006, 1:8 doi:10.1186/1750-1172-1-8

Received: 25 February 2006Accepted: 05 April 2006

This article is available from: http://www.OJRD.com/content/1/1/8

© 2006Calabrò and Limongelli; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The anatomic subgroups (Rastelli's type A, B and C) canbe classified on the basis of the chordal insertions andmorphology of the superior bridging leaflet of the com-mon atrioventricular valve (Table 1). Similarly, a thor-ough echocardiographic examination shows the degree ofdysfunction of the common atrioventricular valve, as wellas the presence of associated cardiac malformations. Todate, cardiac catheterisation is not considered as manda-tory for the diagnosis, but can be indicated in patientsolder than 6 months with suspected irreversible pulmo-nary hypertension. Cardiac catheterisation allows accu-rate quantification of the left-to-right shunt as well asassessment of the degree of pulmonary hypertension andthe reversibility of the pulmonary artery resistances byhyperoxia and/or pharmacological tests. On left ventricu-lar angiography, the appearance of the "gooseneckdeformity" of the left ventricular outflow tract is peculiarof atrioventricular canal malformations.

Differential diagnosisDifferential diagnosis of CAVC involves mainly the unre-strictive ventricular septal defect, associated or not to

mitral valve insufficiency. The clinical picture of conges-tive heart failure, the bi-atrial and bi-ventricular overloadon ECG, and cardiomegaly and pulmonary congestion onchest X-ray are common to the ventricular septal defect.However, on ECG the left axis deviation of QRS at -30°,usually combined with a various degree of right bundlebranch block, appears to be suggestive of CAVC. Eventu-ally, the echocardiographic examination is the corner-stone for diagnosis and is of help for that of any furtherassociated cardiac malformation.

EpidemiologyCAVC accounts for about 3% of all cardiac malforma-tions. Atrioventricular canal occurs in two out of every10,000 live births. Both sexes are equally affected, with aslightly higher frequency in female (female/male ratio1.3/1) and a striking association with Down syndromewas found [1,2].

PathologyThe complete form of AVC shows an ostium primumatrial septal defect, a common atrioventricular valve and avariable deficiency of the interventricular septum inlet[2,3]. This anatomic arrangement gives a scooped outappearance to the ventricular inlet and a long and narrowmorphology to the left ventricular outlet. The key findingfor the anatomic classification in type A, B or C of thismalformation is the morphology of the common atriov-entricular valve [4]. It is basically built-up of five leaflets(superior, inferior, mural in the right and left ventricle andantero-superior), embryologically derived from the origi-nal endocardial cushions. The size of the antero-superiorleaflet is reciprocal with the extent of bridging of the supe-rior leaflet. In type A, the superior bridging leaflet isalmost completely adherent to the left ventricle and isfirmly attached on the ventricular septum by multiplechordal insertions. In type B, the superior bridging leafletis larger and overhangs the ventricular septum more thanin type A, attached over it by an anomalous papillary mus-cle of the right ventricle. In type C, the superior bridgingleaflet is larger and is not attached to the ventricular sep-tum (free-floating leaflet), thus provoking an unrestrictedinterventricular communication. Type A CAVC is mostfrequently associated with left-sided obstructions. Type B

Echocardiography of Complete atrioventricular canalFigure 1Echocardiography of Complete atrioventricular canal.

Table 1: Anatomic classification of CAVC [4]

Type Athe superior bridging leaflet is almost completely adherent to the left ventricle and is firmly attached on the ventricular septum by multiple chordal insertionsType Bthe superior bridging leaflet is attached over the ventricular septum by an anomalous papillary muscle of the right ventricleType Cthe superior bridging leaflet is not attached to the ventricular septum (free-floating leaflet)

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is the least common form of atrioventricular canal. Type Cis often associated with other complex cardiac malforma-tions such as tetralogy of Fallot. Other cardiac malforma-tions are the left ventricular inflow and outflowobstructions, mainly due to anomaly of the left compo-nent of the common atrioventricular valve, and to ven-tricular imbalance, with right ventricular dominance.These additional left-sided anomalies are more frequentin children without Down syndrome [5-7].

A "partial variant" of AVC exists (also known as ostiumprimum atrial septal defect). Nevertheless, some authorsobserved how "complete" and "partial" are inappropriateadjectives to describe these variants [8-11]. Indeed,despite the septal deficiency, the essence of the atrioven-tricular canal malformations (or atrioventricular septaldefects) is the common atrioventricular junction [8-11].Within this common junction, there may be a commonatrioventricular valvar orifice (so called "complete"defects), or separate right and left valvar orifices for theright and left ventricles (so called "partial" defects).

The space between the left ventricular components of thesuperior and inferior bridging leaflets is traditionallycalled "cleft". Morphological studies suggested that thisgap functions as a commissure, even though it is not sup-ported by a papillary muscle [12]. In Rastelli's type A mal-formation, the space in the common anterior leaflet isalso called "cleft". Again, it potentially functions as a com-missure, being supported by the medial papillary muscleof the right ventricle [12].

Clinical descriptionSymptoms occur in infancy as a result of high pulmonaryblood flow associated with pulmonary hypertension, andoften complicated by insufficiency of the common atriov-entricular valve. Failure to thrive, as well as congestiveheart failure and frequent pulmonary infections, areinvariably seen. Thus, patients with CAVC often havefeeding problems and are virtually symptomatic in thefirst few months of life. Signs of congestive heart failureconsist in feeding difficulties, excessive sweating, tachy-cardia, tachypnea, subcostal and intercostal retractions,mild wheezing, hepatic enlargement and poor peripheralblood perfusion [13]. If a significant regurgitation of thecommon atrioventricular valve is present, a systolic car-diac murmur and gallop rhythm are frequently heard.Over time, irreversible pulmonary hypertension develops,improving the signs of congestive heart failure but wors-ening tolerance to effort. When pulmonary artery resist-ances becomes higher than systemic artery resistances, theintracardiac shunt reverses and cyanosis develops, furtherdecreasing the exercise capacity.

Natural historyHalf of children with untreated CAVC die in the first yearof life [1,13,14]. The main cause of death in infancy iseither heart failure or pneumonia. In surviving patientswith unrepaired complete atrioventricular canal, irrevers-ible pulmonary vascular disease becomes increasinglycommon, and affects virtually all patients older than 2years of age [15]. Long-term prognosis in patients withirreversible pulmonary hypertension is poor.

TreatmentMedical treatmentMedical therapy aims to improve the signs and symptomsof congestive heart failure. Thus, it should be just consid-ered as a bridge toward surgery. Pharmacological therapyis based on digitalis, diuretics and vasodilators. Oral ther-apy with digoxin starts with a loading dose of 20–40 µg/kg (depending on the patient's age, from premature tochild) in 3 doses over 24 h, continuing with a mainte-nance dose of 8–10 µg/kg/day in 2 doses. Diuretic therapyis mainly based on furosemide, at the dose of 1–6 mg/kg/day, and spironolactone, at the dose of 2–3.5 mg/kg/day.Vasodilator therapy consists chiefly in the angiotensinconverting enzyme inhibitors, captopril (0.5–3 mg/kg/day, tid) or enalapril (0.1–0.4 mg/kg/day, bid). Increasinginterest is raising regarding the utilisation and potentialbenefits of beta-blockers (mainly, propanolol, metopro-lol and carvedilol) in infants and children heart failuredue to congenital heart defects with left to right shunt,although long-term results are needed. Finally, the newgeneration of pulmonary vasodilators dramaticallyimproved the post-operative course and the overall prog-nosis of the patients [16].

Surgical treatmentSurgical treatment is preferably scheduled before 6–12months of life. Generally, the great majority of surgeonsperform the repair between the 3rd (to reduce the inci-dence of pulmonary hypertension crisis) and the 6thmonth of life. Surgical palliation with pulmonary arterybanding is now seldom indicated in high-risk infants(very low weight and/or in critical conditions). It reducesthe pulmonary artery flow and pressure, so controlling thecongestive heart failure, promoting the patient's growthand preventing the development of pulmonary vasculardisease, but is contra-indicated in patients with severe atri-oventricular valve regurgitation. However, more fre-quently complete intracardiac repair is indicated. Itconsists in closure of the intracardiac communicationswith a single or separate atrial and ventricular patches, inconstruction of two separate and competent atrioventricu-lar valves using the available tissue from the common atri-oventricular valve leaflet, and in repair of associatedcardiac anomalies [13,17,18]. An alternative technique,using a direct suture closure of the ventricular component,

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accompanied by pericardial patch closure of the atrialcomponent, was first suggested by Wilcox et al. [19].Depending on the specific anatomic findings (i.e., inabsence of severe "scooping" of the ventricular septum),the lesion can be adequately repaired in most instances bysewing down the bridging leaflets to the crest of the ven-tricular septum.

Risk factors for surgical repair include the patient's age,the severity of pre-operative common valve incompe-tence, the presence of associated cardiac malformationsand the degree of the functional class [20][21][22][23].The prognosis is directly related to the repair of the left A-V valve [20]. To date, the overall mortality for primaryrepair of CAVC is below 5–10%. Long-term survival isgood and in 80%–95% of cases there is no need for reop-eration [18,21]. Of note, the closure of the cleft results inlonger times before a reoperation is necessary [24].

AetiologyFormation of atrioventricular canal results from complexinteractions of components of the extracellular matrix.Septation of the atrioventricular junction is brought aboutby downgrowth of the primary atrial septum, fusion of theendocardial cushions and forward expansion of the ves-tibular spine between atrial septum and cushions [3].Thus, atrioventricular canal can result from arrest or inter-ruption of the normal endocardial cushion development[25,26]. Experimental studies showed that environmentalteratogens [27] or endogenous metabolic abnormalities[28] might result in abnormal development of the atriov-entricular area, which may be due to altered apoptosis ofthese forming cells [29]. Trancription factors (TBX2,Foxp1 among the others) and signal pathways (ErbBreceptor activation) involved during embryogenesis in theheart development process have been strongly suggestedto have a role in atrioventricular septation [30-32].

Epidemiological studies [2,33] showed that complete atri-oventricular canal tends to be associated with chromo-somal abnormalities, mainly Down syndrome [10], del[8p] syndrome [34], trisomy 9, trisomy 18 [6,35]. Further-more, CAVC with Down syndrome has been less fre-quently associated with left cardiac anomalies than theisolated form [5,7]. In this latter subset of patients, theanalysis of potential risk factors revealed an associationwith maternal diabetes and antitussive drugs [36]. How-ever, in patients with Down syndrome and complete AVC,no strong association other than maternal age has beenfound. In the asplenia syndrome, the CAVC is virtuallyalways present, while it occurs in about 25% of patientswith polisplenia [37]. An association between nonchro-mosomal defects and atrioventricular malformationshave also been reported [5,6].

Genetic counselling and antenatal diagnosisIn the presence of a single affected family member, therisk of siblings of inheriting the defect is about 2%, with ahigher percentage for the offspring of an affected parent.Concordance for atrioventricular malformations amongsiblings is higher than for other types of congenital heartdefects [38].

Due to the strict association with Down syndrome andother chromosomal anomalies, genetic antenatal counsel-ling after the foetal echocardiographic diagnosis of CAVCis mandatory. At present, prenatal diagnosis of CAVC hasbeen associated with a 58% risk of aneuploidy, mainly tri-somy 21 [39]. Again, due to the strong associationbetween chromosomal abnormalities and CAVC, whenthis malformation seems isolated at antenatal echocardi-ography, the risk of trisomy 21 is significantly higher thanwhen other associated cardiac lesions are diagnosed.

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3. Kim JS, Viragh S, Moorman AF, Anderson RH, Lamers WH: Devel-opment of the myocardium of the atrioventricular canal andthe vestibular spine in the human heart. Circ Res 2001,88:395-402.

4. Rastelli GC, Kirklin JW, Titus JL: Anatomic observations on com-plete form of common atrioventricular canal with specialreference to atrioventricular valves. Mayo Clinic Proc 1966,41:296.

5. Marino B, Vairo U, Corno A, Nava S, Guccione P, Calbro R, Marcel-letti C: Atrioventricular canal in Down syndrome. Prevalenceof associated cardiac malformations compared with patientswithout Down syndrome. Am J Dis Child 1990, 144:1120-1122.

6. Digilio MC, Marino B, Toscano A, Giannotti A, Dallapiccola B: Atri-oventricular canal defect without Down syndrome: a heter-ogeneous malformation. Am J Med Genet 1999, 85:140-146.

7. De Biase L, Di Ciommo V, Ballerini L, Bevilacqua M, Marcelletti C,Marino B: Prevalence of left-sided obstructive lesions inpatients with atrioventricular canal without Down's syn-drome. J Thorac Cardiovasc Surg 1986, 91:467-479.

8. Penkoske PA, Neches WH, Anderson RH, Zuberbuhler JR: Furtherobservations on the morphology of atrioventricular septaldefects. J Thorac Cardiovasc Surg 1985, 90:611-622.

9. Falcão S, Daliento L, Ho SY, Rigby ML, Anderson RH: Cross sec-tional echocardiographic assessment of the extent of theatrial septum relative to the atrioventricular junction in atri-oventricular septal defect. Heart 1999, 81:199-205.

10. Ebels T, Ho SY, Anderson RH, Meijboom EJ, Eijgelaar A: The surgi-cal anatomy of the left ventricular outflow tract in atrioven-tricular septal defect. Ann Thorac Surg 1986, 41:483-488.

11. Anderson RH, Ho SY, Falcao S, Daliento L, Rigby ML: The diagnos-tic features of atrioventricular septal defect with commonatrioventricular junction. Cardiol Young 1998, 8:33-49.

12. Anderson RH, Zuerbuhler JR, Penkoske PA, Neches WH: Of clefts,commisssures, and things. J Thorac Cardiovasc Surg 1985,90:605-610.

13. Marsico F, Violini R, Calabrò R, et al.: Atrioventricular septaldefects. Natural history and clinical picture. In Pediatric Cardi-ology – Atrioventricular Septal Defects Edited by: Quero Jimenez M,Arteaga Martinez M. Ediciones Norma, Madrid; 1988:194-203.

14. Santoro G, Marino B, Di Carlo D, Formigari R, Santoro G, MarcellettiC, Pasquini L: Patient selection for repair of complete atriov-

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entricular canal guided by echocardiography. Eur J Cardio-Tho-rac Surg 1996, 10:439-442.

15. Berger TJ, Blackstone EH, Kirklin JW: Survival and probability ofcure without and with surgery in complete atrioventricularcanal. Ann Thorac Surg 1979, 27:104-111.

16. Trachte AL, Lobato EB, Urdaneta F, Hess PJ, Klodell CT, Martin TD,Staples ED, Beaver TM: Oral sildenafil reduces pulmonaryhypertension after cardiac surgery. Ann Thorac Surg 2005,79:194-197.

17. Crawford FA Jr, Stroud MR: Surgical repair of complete atriov-entricular septal defect. Ann Thorac Surg 2001, 72:1621-1628.

18. Atrioventricular canal defect. In Cardiac Surgery Edited by: KirklinJW, Barratt-Boyes BG. Churchill Livingstone, UK; 1993:749-825.

19. Wilcox BR, Jones DR, Frantz EG, Brink LW, Henry GW, Mill MR,Anderson RH: Anatomically sound, simplified approach torepair of "complete" atrioventricular septal defect. Ann Tho-rac Surg 1997, 64:487-493.

20. Boening A, Scheewe J, Heine K, Hedderich J, Regensburger D,Kramer HH, Cremer J: Long term results after surgical correc-tion of atrioventricular septal defects. Eur J Cardiothorac Surg2002, 22:167-173.

21. Merrill WH, Hoff SJ, Bender HW Jr: The surgical treatment ofatrioventricular septal defects. In Pediatric Cardiac Surgery 2ndedition. Edited by: Mavroudis C, Backer CL. Mosby Year Book, Inc. StLouis, Missouri, USA; 1994:225-237.

22. Gunther T, Mazzitelli D, Haehnel CJ, Holper K, Sebening F, MeisnerH: Long-term results after repair of complete atrio-ventricu-lar septal defects: analysis of risk factors. Ann Thorac Surg 1998,65:754-759.

23. Najm HK, Coles JG, Endo M, Stephens D, Rebeyka IM, Williams WG,Freedom RM: Complete atrioventricular septal defects:results of repair, risk factors and freedom from reoperation.Circulation 1997, 96:311-315.

24. Bando K, Turrentine MW, Sun K, Sharp TG, Ensing GJ, Miller AP, Kes-ler KA, Binford RS, Carlos GN, Hurwitz RA, et al.: Surgical man-agement of complete atrioventricular septal defects. Atwenty-year experience. J Thorac Cardiovac Surg 1995,110:1543-1552.

25. de la Cruz MV, Markwald RR: Living Morphogenesis of the Heart Editedby: Markwald R, de La Cruz M, Markwald R. Springer-Verlag; NewYork; 1998:223.

26. Pierpont ME, Markwald RR, Lin AE: Genetic aspects of atrioven-tricular septal defects. Am J Med Genet 2000, 974:289-296.

27. Bouman HG, Broekhuizen ML, Baasten AM, Gittenberger-de GrootAC, Wenink AC: Diminished growth of atrioventricular cush-ion tissue in stage 24 retinoic-treated chicken embryos. DevDyn 1998, 213:50-58.

28. Santoro G, Ambrosio G, Formigari R, Marcelletti C, Chiariello M,Marino B: Low level of myocardial Superoxide Dismutase inpatients with atrioventricularcanal. J Am Coll Cardiol 1994,23:-306A.

29. Saphier CJ, Yeh J: Altered apoptosis levels in hearts of humanfetuses with Down syndrome. Am J Obstet Gynecol 1998,179:962-965.

30. Harrelson Z, Kelly RG, Goldin SN, Gibson-Brown JJ, Bollag RJ, SilverLM, Papaioannou VE: Tbx2 is essential for patterning the atrio-ventricular canal and for morphogenesis of the outflow tractduring heart development. Development 2004, 131:5041-5052.

31. Wang B, Weidenfeld J, Lu MM, Maika S, Kuziel WA, Morrisey EE,Tucker PW: Foxp1 regulates cardiac outflow tract, endocar-dial cushion morphogenesis and myocyte proliferation andmaturation. Development 2004, 131:4477-4487.

32. Camenisch TD, Schroeder JA, Bradley J, Klewer SE, McDonald JA:Heart-valve mesenchyme formation is dependent onhyaluronan-augmented activation of ErbB2-ErbB3 recep-tors. Nat Med 2002, 8:850-855.

33. Carmi R, Boughman JA, Ferencz C: Endocardial cushion defect:further studies of "isolated" versus "syndromic" occurrence.Am J Med Genet 1992, 43:569-575.

34. Marino B, Reale A, Giannotti A, Digilio MC, Dallapiccola B: Nonran-dom association of atrioventricular canal and del(8p) syn-drome. Am J Med Genet 1992, 42:424-427.

35. Francalanci P, Marino B, Boldrini R, Abella R, Iorio F, Bosman C: Mor-phology of the atrioventricular valve in asplenia syndrome: apeculiar type of atrioventicular canal defect. Cardiovasc Pathol1996, 5:145-151.

36. Loffredo CA, Hirata J, Wilson PD, Ferencz C, Lurie IW: Atrioven-tricular septal defects: possible etiologic differences betweencomplete and partial defects. Teratology 2001, 63:87-93.

37. Rose V, Izukawa T, Moes CA: Syndromes of asplenia and polys-plenia. A review of cardiac and non-cardiac malformations in60 cases with special reference to diagnosis and prognosis. BrHeart J 1975, 37:840-852.

38. Nora JJ, Nora AH: Maternal transmission of congenital heartdiseases: new recurrence risk figures and the questions ofcytoplasmic inheritance and vulnerability to teratogens. AmJ Cardiol 1987, 59:459-463.

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Congenital heart disease

ATRIOVENTRICULAR SEPTAL DEFECT:FROM FETUS TO ADULT

Brian Craig

Heart 2006;92:1879–1885. doi: 10.1136/hrt.2006.093344

Take the online multiple choicequestions associated with thisarticle (see page 1885)

_________________________

Correspondence to:Dr Brian Craig, Royal BelfastHospital for Sick Children,Belfast, Northern Ireland,BT12 6BE, UK; brian.craig@royalhospitals.n-i.nhs.uk_________________________

The term ‘‘atrioventricular septal defect’’ (AVSD) covers a spectrum of congenital heart

malformations characterised by a common atrioventricular junction coexisting with deficient

atrioventricular septation. In ostium primum atrial septal defect (ASD) there are separate

atrioventricular valvar orifices despite a common junction, while in complete AVSD the valve

itself is also shared.

The estimated incidence of the condition in the era of two-dimensional echocardiography varies

from 0.24/1000w1 live births to 0.31/1000w2 live births. There is a strong association with Down’s

syndrome, with half of patients with AVSD in the population of Bohemia also complicated by

Down’s syndrome.w3 Conversely in a Toronto study about one third of patients with Down’s

syndrome had a complete AVSD and 5% had an ostium primum ASD.w4 In a prospective

screening study within the relatively static Northern Irish population the incidence of AVSD in

Down’s syndrome was 17% and the overall incidence of congenital heart disease in Down’s

syndrome was 42%.1

Three different genetic patterns are described in AVSD: the association with Down’s syndrome,

as an autosomal dominant trait, and isolated. Molecular studies of patients with congenital heart

disease and partial duplications of chromosome 21 have proposed DSCAM (Down’s syndrome cell

adhesion molecule) as a candidate gene causing congenital heart disease in Down’s syndrome.2

Cases with autosomal dominant inheritance, however, are not linked to chromosome 21.w5

Over the past four decades the management of the complete form of the condition has evolved

from palliative pulmonary artery banding in infancy with later repair to primary repair in early

infancy to prevent the development of pulmonary vascular obstructive disease. Decreasing

operative mortality has significantly altered the prognosis of these patients with and without

Down’s syndrome. The improved prognosis for patients with Down’s syndrome and AVSD has

implications for the management of patients diagnosed antenatally. The postnatal and longer

term outcomes are influenced by the presence of associated defects, such as ventricular

hypoplasia, and the management of these may be both difficult and controversial.

SPECTRUM OF ANATOMYcThe essential morphological hallmark of an AVSD is the presence of a common atrioventricular

junction as compared to the separate right and left atrioventricular junction in the normal heart.

Other morphological features include defects of the muscular and membranous atrioventricular

septum and an ovoid shape of the common atrioventricular junction with unwedging of the left

ventricular outflow tract from the normal position between the tricuspid and mitral valve. There

is disproportion of outlet and inlet dimensions of the left ventricle, with the former greater than

the latter as compared to the normal heart where both dimensions are similar.

The valve leaflet morphology in AVSD bears little resemblance to the arrangement of the

leaflets of normal mitral and tricuspid valves. There are essentially five leaflets, two of which are

bridging leaflets across the crest of the interventricular septum (fig 1). In ostium primum ASD

there are separate right and left valve orifices due to a tongue of valvar tissue joining the bridging

leaflets, but the atrioventricular junction remains a common structure (fig 2). In complete AVSD

there is a space between the bridging leaflets and therefore the atrioventricular valvar orifice is

common.

The potential for left to right shunting is related to the bridging leaflets being attached to the

atrial septum, to the ventricular septum, or floating within the AVSD (fig 3). In Rastelli’s

classification the superior bridging leaflet was mostly contained within the left ventricle in type A,

with increased extension into the right ventricle in types B and C.w6 The potential for ventricular

shunting tended to increase from type A to type C. This classification has been superseded by a

simpler independent description of the two aspects of the anatomy which determine the

variability and clinical presentation.3 The first is the individual leaflet arrangement within the

common atrioventricular junction. The second is the relationship of the bridging leaflets of the

common valve to the atrial and ventricular septal structures.

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ASSOCIATED DEFECTSSubaortic stenosisThe left ventricular outflow tract is elongated and appears

relatively narrowed in patients with AVSD. This is mainly due to

the anterior unwedged position of the outflow tract and is

particularly notable in patients with ostium primum ASD where

the superior bridging leaflet is firmly fixed to the crest of the

ventricular septum.w7 Preoperatively significant obstruction,

however, is usually due to additional lesions, such as fibrous

subaortic shelf or fibromuscular tunnel, w8 fibrous tissue tagsw9

or anomalous insertion of left ventricular papillary muscles.w10

Ventricular hypoplasiaIn most patients with AVSD the right and left components of

the common atrioventricular junction are comparable and the

ventricles are similarly sized (balanced AVSD). In a minority of

cases the common atrioventricular junction is committed to the

right or left ventricle leading to right or left ventricular

dominance and relative hypoplasia of the opposing ventricular

chamber.w11 Extreme commitment of the common atrioven-

tricular junction to the left ventricle has been termed ‘‘double

inlet left ventricle with a common valve’’.w12

Tetralogy of FallotThe reported incidence of the combination of AVSD and

tetralogy of Fallot is 5% of all patients with AVSD, while the

latter complicates 16.5% of cases of tetralogy of Fallot.w13 The

combination is more common in patients with Down’s

syndrome whereas most other associated lesions complicat-

ing AVSD are more common in patients without Down’s

syndrome.4

Atrial isomerismComplex forms of AVSD are found in the majority of hearts

with right atrial isomerism and in around half with left atrial

isomerism.w14 The former tend to have univentricular hearts,

often with a common atrium, while the latter tend to have

biventricular hearts. Complete heart block is common in left

atrial isomerism associated with AVSD.

Other associated lesions include double-orifice atrioven-

tricular valve,w15 parachute left atrioventricular valve,w15 and

coarctation of the aorta.w8 There are occasional case reports

of associated truncus arteriosus,w16 transposition of the great

arteriesw17 and congenitally corrected transposition of the

great arteries.w18 Ebstein’s anomaly,w19 hypertrophic cardio-

myopathy,w20 cor triatrium,w21 and absent pulmonary valve

syndromew22 have also been reported.

FETAL DIAGNOSISThe view of the heart most commonly used in routine antenatal

ultrasound anomaly scanning is the four-chamber view. AVSD

is one of the lesions potentially detectable on this view.

The key diagnostic feature on the obstetric four-chamber

view of the heart is the presence of a common atrioven-

tricular valve. In a good four-chamber view the defects in the

atrial and ventricular septum should also be visible (fig 4).

Antenatal detection rates of AVSD, however, remain lower

than might be expected. In one UK study of 92 consecutive

liveborn infants with AVSD, only 29% were detected by

routine obstetric ultrasound.5 Machlitt has recently reported

that antenatal detection using the four-chamber view can be

significantly improved by measuring the ratio of atrial to

ventricular length (AVL).w23 In this study if a cut-off value

for the AVL ratio over 0.6 was chosen the detection rate of

AVSD was 82.6% with a 5.7% false positive rate.

The spectrum of AVSD in fetal life is different from that

diagnosed postnatally. Up to 45% of those diagnosed in utero

may have associated heterotaxy syndromes, particularly left

atrial isomerism.6 w24 w25 Fetal echocardiography in cases of

AVSD therefore should include determination of atrial situs,

ventriculo-arterial connections, ventricular size and aortic

arch calibre. The detection of these associated abnormalities

is very important so that when counselling parents an

accurate indication of outcome can be given. The mortality is

higher in those with other associated cardiac abnormalities;

in particular, the combination of left atrial isomerism, AVSD

and congenital complete heart block, often with fetal

hydrops, has a very poor prognosis with a large fetal loss.7

Right antero superior

Zones of apposition

Right inferiorInferior bridging

Left mural

Superior bridging

Common valvar orifice

Figure 1 The arrangement of the atrioventricular valve leaflets incomplete atrioventricular septal defect (AVSD) with a commonatrioventricular junction and common valve.

Zone of apposition

Connecting tongue

Separate right and left valvar orifices

Figure 2 The arrangement of the atrioventricular valve leaflets in ostiumprimum atrial septal defect (ASD) with a common atrioventricular junctionbut separate valvar orifices for right and left ventricles.

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Antenatal diagnosis of this lesion is particularly important

because of the strong association with chromosomal prob-

lems, especially trisomy 21. Abnormal karyotype is more

common in isolated AVSD (48–58%).5–7 w25 The relative risk

of trisomy 21 in a pregnancy in which a diagnosis of AVSD is

the only cardiac defect has been reported to be 107.w26

CLINICAL PRESENTATIONThe clinical presentation (table 1) and course in AVSD relate

to the specific morphology of the defect and the presence of

associated defects. In infants with complete AVSD and a

sizeable interventricular component, congestive cardiac fail-

ure is likely to develop within the first few months of life as

pulmonary vascular resistance falls. If there is significant

regurgitation of the common atrioventricular valve, asso-

ciated coarctation of the aorta or ventricular imbalance,

cardiac failure may occur much earlier and often within the

first week of life. Without surgery many of these patients will

die in infancy and those who survive will develop pulmonary

vascular disease and eventually die with Eisenmenger’s

syndrome.8 There is a subgroup of patients with complete

AVSD and a large interventricular component, often with

Down’s syndrome, where cardiac failure does not occur, and

this phenomenon relates to persisting elevation of pulmonary

vascular resistance from birth.w27

The newborn with AVSD may present with a mild degree of

central cyanosis. This finding relates to bidirectional shunting at

both the atrial and ventricular level in the presence of elevated

pulmonary vascular resistance at birth. The only positive

precordial findings of a congenital heart defect at this time

may be a right ventricular impulse and accentuated pulmonary

component of the second heart sound. A precordial murmur

may, at this stage, be much abbreviated or absent.1

A B

Exclusively ventricular shuntingExclusively atrial shuntingAtrial and ventricular shunting

C

Figure 3 The potential for shunting in AVSD relates to the connections between the bridging leaflets and the atrial and ventricular septum.

RV LV

Figure 4 Fetal cardiac ultrasound at 23 weeks gestationdemonstrating complete AVSD with a common atrioventricular valveand large atrial and ventricular septal defects. LV, left ventricle; RV,right ventricle.

Table 1 Postnatal diagnosis of AVSD

c Clinical

– cyanosis mild or absent

– congestive cardiac failure

– right ventricular impulse

– increased pulmonic component second heart sound

– variable ejection systolic murmur, apical mid-diastolic murmur (inlarge left to right shunt), pansystolic murmur (with atrioventricularvalve regurgitation)

c ECG

– prolonged PR interval

– superior frontal QRS axis

– partial right bundle branch block

– superior p wave axis (in associated left atrial isomerism)

c Chest radiograph

– cardiomegaly

– prominent pulmonary conus

– increased pulmonary vascularity

– left aortic arch

– left bronchial isomerism (in associated left atrial isomerism)

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Down’s syndromeIn patients with AVSD the onset of pulmonary vascular

disease is earlier in patients with associated Down’s

syndrome dictating early surgical repair.w65 The spectrum of

anatomy in AVSD also varies in patients with coexisting

Down’s syndrome where extensive bridging of both superior

and inferior bridging leaflets is more common and left

ventricular hypoplasia and left heart obstructive lesions less

common.w66 This anatomy may in fact be more favourable for

surgical repair and Rizzoli has demonstrated that Down’s

syndrome per se is not a risk factor for surgery.w67 A Japanese

study concludes that Down’s syndrome does not affect the

long term results of complete AVSD when the defect is

repaired during the first year of life.w68 A recent report from

Italy involving over 200 patients demonstrates a decreased

risk for biventricular repair in Down’s syndrome and lower

mortality in cases with associated defects.w69 Twenty years

ago there was considerable debate regarding cardiac surgery

in patients with Down’s syndrome versus a non-interven-

tional approach.18 These recent studies together with quality

of life issues have swung the pendulum towards surgical

intervention in most patients.

FOLLOW-UPComplete AVSDWithout surgery the natural history of complete AVSD has

been well documented by Berger et al with only 4% survival

beyond 5 years old.8 In surviving patients following surgery

the most common reason for reoperation in the large Toronto

series was left atrioventricular valve regurgitation followed by

subaortic stenosis, residual ventricular septal defect and late

onset complete heart block.16 The overall 10 year survival was

83%. Al-Hay reported an increased incidence of postoperative

left atrioventricular valve regurgitation in the chromosomally

normal patients related to a higher incidence of dysplastic

atrioventricular valve.w70 Rhodes reports a mild increase in

the degree of residual left atrioventricular valve regurgitation

in the initial 30 months postoperatively with little further

deterioration thereafter.19 Table 3 lists the long-term compli-

cations following surgical repair in AVSD.

Ostium primum ASDThe natural history of ostium primum ASD without surgery

carries a 50% mortality before 20 years of age with atrial

fibrillation an important cause of morbidity.w28 Following

surgery the Mayo Clinic reports a 40 year survival of 76%.17

The reoperation rate in this large series was 11%. The most

common cause for reoperation was left atrioventricular valve

regurgitation followed by subaortic stenosis and complete

heart block. Supraventricular dysrhythmias were observed in

16%. These increased with increasing age at primary

operation. Bergin reports low mortality and good long-term

survival in patients with ostium primum ASD presenting for

surgical repair in later life (. 40 years old).20

CONCLUSIONEarly diagnosis of AVSD is important in order to institute

appropriate medical and supportive treatment and to plan

timely surgical intervention. In the current era the operative

mortality is low with a good long term outlook for most

patients, with or without Down’s syndrome. As the most

common cause for reoperation is left atrioventricular valve

regurgitation, detailed attention should be given to atrioven-

tricular valve repair at the primary operation with the aid of

transoesophageal echocardiography. A minority of patients

with associated defects such as ventricular hypoplasia will

require alternative surgical strategies. Long term follow-up

should focus on atrioventricular valve function, left ventri-

cular outflow tract obstruction and dysrhythmia including

late-onset heart block.

Additional references appear on the Heart website—http://

www.heartjnl.com/supplemental

ACKNOWLEDGEMENTSI am grateful to Dr F Casey for contributing the section on Fetaldiagnosis. I am grateful to Professor R Anderson and G Price at theInstitute for Child Health, UCL, for provision of figs 1–3, Mrs LDavidson for fig 5 and Dr A Sands for fig 6.

In compliance with EBAC/EACCME guidelines, all authors participatingin Education in Heart have disclosed potential conflicts of interest thatmight cause a bias in the article

REFERENCES1 Tubman RJ, Shields MD, Craig BG, et al. Congenital heart disease in Down’s

syndrome: two year prospective early screening study. BMJ1991;302:1425–7.

c Early postnatal echocardiography in Down’s syndrome can detectcongenital heart disease which may be missed by clinical examination,radiography and electrocardiography.

2 Barlow GM, Chen Xn, Shi ZY, et al. Down syndrome congenital heart disease:a narrowed region and a candidate gene. Genet Med 2001;3:91–101.

c Study of 19 individuals with partial trisomy 21 suggests a candidategene for the spectrum of Down’s syndrome and congenital heartdisease.

Table 3 Long-term complications following surgicalrepair in AVSD

c Left atrioventricular valve regurgitation

c Left ventricular outflow tract obstruction

c Late onset complete heart block

c Pulmonary vascular disease

c Atrial or ventricular dysrhythmias

c Left atrioventricular valve stenosis

c Right atrioventricular valve stenosis/regurgitation

c Residual ventricular septal defect

c Aortic incompetence

Atrioventricular septal defect (AVSD): key points

c The spectrum of AVSD diagnosed antenatally is differentfrom that diagnosed postnatally. Up to 45% of thosediagnosed antenatally may have associated heterotaxysyndromes

c Early postnatal diagnosis is important in planning timelysurgical intervention

c A detailed transthoracic echocardiogram with Doppler isessential preoperatively to assess atrioventricular valvemorphology and function and the relationship of thebridging leaflets to atrial and ventricular septum.Associated defects such as outflow tract obstruction orventricular imbalance must be identified

c Surgical correction should attempt to minimise residual leftatrioventricular valve regurgitation as this is the mostcommon reason for reoperation and the most importantcause of long term morbidity

c The operative mortality and outcome in AVSD is notsignificantly adversely affected in patients with Down’ssyndrome

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3 Anderson RH, Ho SY, Falcao S, et al. The diagnostic features ofatrioventricular septal defect with common atrioventricular junction. CardiolYoung 1998;8(1):33–49.

c Review of the morphological diagnostic features of AVSD.4 Marino B, Vairo U, Corno A, et al. Atrioventricular canal in Down syndrome.

Prevalence of associated cardiac malformations compared with patientswithout Down syndrome. Am J Dis Child 1990;144:1120–2.

c Down’s syndrome is associated with a simpler form of AVSD ascompared to patients with normal chromosomes. The exception is themore common association of AVSD in Down’s syndrome with tetralogyof Fallot.

5 Ter Heide H, Thompson JDR, Wharton GA, et al. Poor sensitivity of routinefetal anomaly scanning ultrasound screening for antenatal detection ofatrioventricular septal defect. Heart 204;90:916–7.

c In a series of 92 consecutive patients with AVSD, only 29% werediagnosed antenatally.

6 Delisle MF, Sandor GG, Tessier F, et al. Outcome of fetuses diagnosed withatrioventricular septal defect. Obstet Gynecol 1999;94(pt1):763–7.

c Prenatal diagnosis of AVSD was associated with a 58% risk ofaneuploidy (mainly trisomy 21).

7 Huggon IC, Cook AC, Smeeton NC, et al. Atrioventricular septal defectsdiagnosed in fetal life: associated cardiac and extra-cardiac abnormalitiesand outcome. J Am Coll Cardiol 1000;36:593–601.

c AVSD diagnosed prenatally associated with heterotaxy syndromes in32% of cases.

8 Berger TJ, Blackstone EH, Kirklin JW, et al. Survival and probability of curewithout and with operation in complete atrioventricular canal. Ann ThoracSurg 1979;27:104–11.

c Early era of surgical repair of AVSD in infancy compared with naturalhistory without surgery.

9 Silverman NJ, Zuberbuhler JR, Anderson RH. Atrioventricular septal defects:cross-sectional echocardiographic and morphologic comparisons. Int J Cardiol1986;13:309–31.

c The accuracy of cross-sectional echocardiography in AVSD asconfirmed by angiography, surgery and/or autopsy.

10 Sulafa AK, Tamimi O, Najm HK, Godman MJ. Echocardiographicdifferentiation of atrioventricular septal defects from inlet ventricular septaldefects and mitral valve clefts. Am J Cardiol 2005;95:607–10.

c Important echocardiographic distinction between AVSDs, inletventricular septal defects and isolated mitral valve clefts.

11 Sittiwangkul R, Ma RY, McCrindle BW, et al. Echocardiographic assessmentof obstructive lesions in atrioventricular septal defects. J Am Coll Cardiol2001;38:253–61.

c Ability of transthoracic echocardiography to identify obstructive leftheart lesions in AVSD is explored. Most common missed lesions weredouble-orifice left atrioventricular valve and non-obstructive chordae inthe left ventricular outflow tract.

12 Cohen MS, Jacobs ML, Weinberg PM, et al. Morphometric analysis ofunbalanced common atrioventricular canal using two-dimensionalechocardiography. J Am Coll Cardiol 1996;28:1017–23.

c Echocardiographic morphometry of atrioventricular valve suggested toqualitate unbalance in AVSD and to guide in selection for singleventricle repair.

13 Smallhorn JF. Cross-sectional echocardiographic assessment ofatrioventricular septal defect: basic morphology and preoperative risk factors.Echocardiography 2001;18:415–32.

c Important overview of echocardiographic features of AVSD includingrisk factors to be identified preoperatively.

14 Haworth SG. Pulmonary vascular bed in children with completeatrioventricular septal defect: relation between structural and hemodynamicabnormalities. Am J Cardiol 1986;57:833–9.

c Pulmonary vascular structural changes in AVSD increase with age inparallel with pulmonary artery pressure and resistance.

15 Prifti E, Bonacchi M, Bernabei M, et al. Repair of complete atrioventricularseptal defects in patients weighing less than 5 kg. Ann Thorac Surg2004;77:1717–26.

c Survival following surgery for AVSD is similar above and below 5 kgbody weight. There is an increased incidence of late operation for leftatrioventricular valve repair in the latter group.

16 Najm HK, Coles JG, Endo M, et al. Complete atrioventricular septal defects:results of repair, risk factors, and freedom from reoperation. Circulation1997;96:311–15.

c Large series review of 363 patients following surgical repair ofcomplete AVSD reports early mortality of 10.5% and 10-year survivalof 83%.

17 El-Najdawi EK, Driscoll DJ, Puga FJ, et al. Operation for partialatrioventricular septal defect: a forty-year review. J Thorac Cardiovasc Surg2000;119:880–90.

c Long term outcome after surgical repair of ostium primum ASD in 334patients; 40-year survival was 76%.

18 Bull C, Rigby ML, Shinebourne EA. Should management of completeatrioventricular canal be influenced by coexistent Down’s syndrome. Lancet1985;i:1147–9.

c Combined early surgical mortality of 20% in patients with Down’ssyndrome and AVSD in 1985 compared to life expectancy of 80% at15 years without surgery.

19 Rhodes J, Warner KG, Fulton DR, et al. Fate of mitral regurgitation followingrepair of atrioventricular septal defect. Am J Cardiol 1997;80:1194–7.

c Deterioration in left atrioventricular valve regurgitation after surgeryfor AVSD occurs primarily in the initial 30 postoperative months.

20 Bergin ML, Warnes CA, Tajik AJ, et al. Partial atrioventricular canal defect:long-term follow-up after initial repair in patients . or = 40 years old. J AmColl Cardiol 1995;25:1189–94.

c Early mortality of 6% in adults following primary repair of ostiumprimum ASD.

Additional references appear on the Heart website—http://www.heartjnl.com/supplemental

MULTIPLE CHOICE QUESTIONS

Education in Heart Interactive (www.heartjnl.com/misc/education.shtml)

There are six multiple choice questions associated with each Education in Heart article (thesequestions have been written by the authors of the articles). Each article is submitted to EBAC(European Board for Accreditation in Cardiology; www.ebac-cme.org) for 1 hour of externalCPD credit.

How to find the MCQs: Click on the Online Learning: [Take interactive course] link on thetable of contents for the issue online or on the Education in Heart collection(www.heartjnl.com/cgi/collection/heart_education).

Free access: This link will take you to the BMJ Publishing Group’s online learning website.Your Heart Online user name and password will be recognised by this website. As a Heartsubscriber you have free access to these MCQs but you must register on the site so you cantrack your learning activity and receive credit for completed courses.

How to get access: If you have not yet activated your Heart Online access, please do so byvisiting http://www.bmjjournals.com/cgi/activate/basic and entering your six digit (allnumeric) customer number (found above your address label with your print copy). If you haveany trouble activating or using the site please contact subscriptions@bmjgroup.com

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REVIEW Open Access

“Down syndrome: an insight of the disease”Ambreen Asim, Ashok Kumar, Srinivasan Muthuswamy, Shalu Jain and Sarita Agarwal*

Abstract

Down syndrome (DS) is one of the commonest disorders with huge medical and social cost. DS is associated withnumber of phenotypes including congenital heart defects, leukemia, Alzeihmer’s disease, Hirschsprung disease etc. DSindividuals are affected by these phenotypes to a variable extent thus understanding the cause of this variation is a keychallenge. In the present review article, we emphasize an overview of DS, DS-associated phenotypes diagnosis andmanagement of the disease. The genes or miRNA involved in Down syndrome associated Alzheimer’s disease,congenital heart defects (AVSD), leukemia including AMKL and ALL, hypertension and Hirschprung disease arediscussed in this article. Moreover, we have also reviewed various prenatal diagnostic method from karyotyping to rapidmolecular methods - MLPA, FISH, QF-PCR, PSQ, NGS and noninvasive prenatal diagnosis in detail.

IntroductionDown syndrome is one of the most leading causes of in-tellectual disability and millions of these patients facevarious health issues including learning and memory,congenital heart diseases(CHD), Alzheimer’s diseases(AD), leukemia, cancers and Hirschprung disease(HD).The incidence of trisomy is influenced by maternal ageand differs in population (between 1 in 319 and 1 in1000 live births) [1-5]. DS has high genetic complexityand phenotype variability [6-8]. Trisomic fetuses are atelevated risk of miscarriages and DS people have in-creased incidence of developing several medical condi-tions [9]. Recent advancement in medical treatment withsocial support has increased the life expectancy for DSpopulation. In developed countries, the average life spanfor DS population is 55 years [10].

ReviewHuman Chromosome 21DS complex phenotype results from dosage imbalance ofgenes located on human chromosome 21(Hsa 21). Thegenetic nature of DS together with the relatively smallsize of Hsa 21 encouraged scientist to concentrate effortstowards the complete characterization of this chromo-some in the past few years. The length of 21q is 33.5 Mb[11] and 21 p is 5–15 Mb [12]. A total 225 genes was es-timated when initial sequence of 21q was published [11].Hsa 21 has 40.06% repeat content out of which the repeat

content of SINE’s, LINE’s, and LTR are 10.84%, 15.15%,9.21% respectively. The Table 1 given below highlightssome of the genes present on chromosome 21.

Features of DSThere are various conserved features occurring in all DSpopulation, including learning disabilities, craniofacial ab-normality and hypotonia in early infancy [13]. Some peopleof DS are affected by variant phenotypes including atrio-ventricular septal defects (AVSD) in heart, leukemia’s (bothacute megakaryoblastic leukemia(AMKL) and acutelymphoblastic leukemia(ALL)), AD and HD. DS individualhave variety of physical characteristics like a small chin,slanted eye, poor muscle tone, a flat nasal bridge, a singlecrease of the palm and a protuding due to small mouthand large tongue [14]. Other features includes big toe,abnormal pattern of fingerprint and short fingers.

Genetics of the diseaseThe most common cause of having a DS babies is pres-ence extra copy chromosome 21 resulting in trisomy.The other causes can be Robertsonian translocation andisochromosomal or ring chromosome. Ischromosome isa term used to describe a condition in which two longarms of chromosome separate together rather than thelong and short arm separating together during eggsperm development. Trisomy 21 (karyotype 47, XX, + 21for females and 47, XY, + 21 for males) is caused by afailure of the chromosome 21 to separate during egg orsperm development. In Robertsonian translocationwhich occurs only in 2-4% of the cases, the long arm of

* Correspondence: saritasgpgi@gmail.comDepartment of Medical Genetics, Sanjay Gandhi Post Graduate Institute ofMedical Sciences, Lucknow 226014, India

© 2015 Asim et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Asim et al. Journal of Biomedical Science (2015) 22:41 DOI 10.1186/s12929-015-0138-y

observe degeneration of basal forebrain cholinergic neu-rons (BFCNs). Ts65Dn mice is dependent on trisomy ofAPP expression of retrograde axonal transport [29]. Stud-ies have also revealed that BACE2 which encodes enzymebeta secretase 2 is also involved in AD. APP and BACE 2genes are located on chromosome 21. The current data onDS support the association of haplotypes in BACE2 withAD [30]. Besides APP and BACE2 genes, other genes likePICALM and APOE are also found to be associated withthe age of onset of Alzheimer’s dimentia in DS [31].

Cardiac problemsThe incidence of CHD in newborn babies with DS is upto 50% [32]. Endocardial cushion defect also called asatrioventricular cushion defect is most common formwhich affects up to 40% of the patients. Ventricular sep-tal defect (VSD) is also present in these populationwhich affects up to 35% of the patients [33]. The essen-tial morphological hallmark of an AVSD is the presenceof a common atrioventricular junction as compared tothe separate right and left atrioventricular junction inthe normal heart. Other morphological features includedefects of the muscular and membranous atrioventricu-lar septum and an ovoid shape of the common atrioven-tricular junction. There is disproportion of outlet andinlet dimensions of the left ventricle, with the formergreater than the latter as compared to the normal heartwhere both dimensions are similar [34]. While in case ofVSD, the defect lies in ventricular septum of the heartdue to which some of the blood from the left ventricleleaks into the right ventric leading to pulmonary hyper-tension. Mutation in non Hsa 21 CRELD1 (Cysteine richEGF like domain1) gene contributes to the developmentof AVSD in DS [35]. CRELD1 is located on chromosome3p25. It encodes a cell surface protein that functions ascell adhesion molecule and is expressed during cardiaccushion development. CRELD1 gene contains 11 exonsspanning approximately 12 kb [36]. To the present, twospecific genetic loci for AVSD have been identified. Onewas AVSD 1 locus present on chromosome 1p31-p21[37]. Other locus was present on chromosome 3p25 andthe corresponding gene was CRELD1 [36,38]. Maslen etal. in [33] have identified two heterozygous missensemutation (p.R329C and p.E414K) with two subjects inDS and AVSD. They have recruited 39 individual of DSwith complete AVSD and have found the same mutations.In the same study, DNA of 30 individual of trisomy withoutCHD was studied for both mutations, no such mutationwas identified [35]. R329C which was originally reported inan individual with sporadic partial AVSD and now it is alsodetected in individual of DS with AVSD. Interestingly, withthe same mutation (p.R329C), the severity of heart defectwas greater in patients of DS with AVSD. Thus, identifica-tion of CRELD 1 mutation in 2/39 individual (5.1%) of DS

with complete AVSD suggests the defects in CRELD 1contribute to pathogenesis of AVSD in context withtrisomy 21.

Hematological problemsPatients with DS display a unique spectrum of malignan-cies, which include leukemia’s as well as solid tumors. Thefirst report of leukemia in a DS patient occurred in 1930[39] and the first systematic study in 1957 [40]. Studiesindicate that patients with DS have a 10–20 fold in-creased relative risk of leukemia, with a cumulative riskof 2% by age 5 and 2.7% by age 30 [41]. They constituteapproximately 2% of all pediatric acute lymphoblastic leu-kemia(ALL) and approximately 10% of pediatric acutemyeloid leukemia (AML). Leukemogenesis of acute mega-karyoblastic leukemia (AMKL) in DS patients is associatedwith the presence of somatic mutations involving GATA 1gene (or also called as GATA-binding factor 1) [42].GATA 1 is a chromosome X- linked transcription factorwhich is essential for erythoid and megakaryocytic differ-entiation. Because of these GATA 1 mutations, there is aproduction of shorter GATA 1 protein thereby leading touncontrolled proliferation of immature megakaryocytes[42,43]. On the other hand, acquired gain of function mu-tation in Janus Kinase 2 gene are present in approximately30% of cases with ALL in DS [44,45].

HypertensionPeople with DS have been reported to have a reduced inci-dence of hypertension [46,47]. Trisomy of the Hsa21microRNA hsa-miR-155 contributes to this [48]. Hsa-miR-155 is proposed to specifically target one allele of thetype-1 angiotensin II receptor (AGTR1) gene, resulting init’s under- expression, which contribute to a reduced riskof hypertension. Further studies are required to validatethis hypothesis and determine whether other genes mayalso protect people with DS against hypertension.

Gastrointestinal problemsDS patients constitute ~12% of all cases of HD. Duodenalstenosis (DST) and imperforate anus (IA) are 260 and 33times more likely to occur DS [23,49]. HD is a form of lowintestinal obstruction caused by the absence of normalmyenteric ganglion cells in a segment of the colon [50]. InHD children, the absence of ganglion cells results in thefailure of the distal intestine to relax normally. Peristalticwaves do not pass through the aganglionic segment andthere is no normal defecation, leading to functionalobstruction. Abdominal distention, failure to pass meco-nium, enterocolitis and bilious vomiting are the predomin-ant signs and symptoms and appear within a few daysafter birth. Infants with duodenal atresia or DST presentwith bilious vomiting early in the neonatal period. If leftuntreated, it will result in severe dehydration and

Asim et al. Journal of Biomedical Science (2015) 22:41 Page 3 of 9

Ž .Progress in Pediatric Cardiology 10 1999 115]127

Pathology and embryology of common atrioventricularcanal

Richard Van PraaghU, Silvio Litovsky

Cardiac Registry, Children’s Hospital, Departments of Pathology and Cardiology, Har̈ ard Medical School, 300 Longwood A¨enue,Boston, MA 02115, USA

Abstract

This paper focuses on the terminology, classification, pathologic anatomy, embryology, and etiology of common atrioventric-Ž .ular AV canal. The designation common AV canal is preferred because it includes both the characteristic septal and leaflet

defects; i.e. common AV canal is much more than an AV septal defect, as the cleft in the anterior mitral leaflet indicates. ThisŽ . Žcleft is indeed a cleft not a commissure , and the left-sided AV valve is a malformed mitral valve not a trileaflet non-mitral

.valve . Common AV canal is classified as complete, partial, transitional, intermediate, balanced, left ventricular type, and rightventricular type. The complete form is subclassified as Rastelli types A, B, and C. The normal embryology of AV canal divisionis presented in man and in the rat. In humans, the superior and inferior endocardial cushions of the AV canal normally fuseduring Streeter’s horizon XVII, i.e. 34]36 days of age. An understanding of the spatial geometry of the endocardial cushionsof the AV canal relative to the ventricular and atrial septa helps to explain normal and abnormal development and theclassification of common AV canal. Normal morphogenesis is a three-step process. An increase in fibroblast cell-surfaceadhesiveness may well be important in the morphogenesis of common AV canal in Down syndrome. Etiologically, a singlegene stochastic model is now thought more likely than the polygenic multifactorial hypothesis. The Down syndrome congenital

Ž . Ž .heart disease gene or genes is are now thought to be located on chromosome 21 from q22.1 to q22.3. Common AV canalmay be non-syndromic or syndromic, the latter including Down syndrome and the heterotaxy syndromes with asplenia andpolysplenia. There are statistically highly significant differences between Down and non-Down canals, and between asplenicand polysplenic canals. Q 1999 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Common atrioventricular canal; Atrioventricular septal defect; Endocardial cushion defect; Cleft mitral valve; Down syndrome;Heterotaxy syndrome; Asplenia; Polysplenia

An understanding of the pathologic anatomy andŽ .embryology of common atrioventricular AV canal is

very helpful both diagnostically and surgically.

U Corresponding author. Tel.: q1-617-355-7437; fax: q1-617-731-0954.

Ž .E-mail address: gaskill@a1.tch.harvard.edu R. Van Praagh

1. Terminology

Many different names have been applied to theseanomalies, including: Atrioventricularis communis,common AV canal, common AV orifice, endocardialcushion defect, and AV septal defect.

We prefer the designation common AV canal be-cause this has been the standard term for many years;

1058-9813r99r$ - see front matter Q 1999 Elsevier Science Ireland Ltd. All rights reserved.Ž .PII: S 1 0 5 8 - 9 8 1 3 9 9 0 0 0 2 5 - 9