Autosomal Dominant Secundum Atrial SeptalDefect With Various Cardiac and NoncardiacDefects: A New Midline Disorder

Andre Megarbane,1* Edouard Stephan,2 Roland Kassab,3 Ramzi Ashoush,4 Nabiha Salem,1Patrice Bouvagnet,5 and Jacques Loiselet1

1Unite de Genetique Medicale, Faculte de Medecine, Universite Saint-Joseph, Beirut, Lebanon2Faculte de Medecine, Universite Saint-Joseph, Beirut, Lebanon3Service de Cardiologie, Hotel-Dieu de France, Beirut, Lebanon4Service de Chirurgie Cardio-Vasculaire, Hotel-Dieu de France, Beirut, Lebanon5Laboratoire de Genetique Moleculaire Humaine, Faculte de Pharmacie, Universite Claude Bernard, Lyon, France

We report on a Lebanese family in which 12persons had an atrial septal defect and vari-ous cardiac and noncardiac anomalies. Car-diac anomalies are left axis deviation ofQRS, right bundle branch block, atrial fi-brillation, Wolff-Parkinson-White syn-drome, nodal atrioventricular rhythm, aor-tic stenosis, pulmonic valve stenosis, mitralstenosis (Lutembacher syndrome), and lowimplantation of the tricuspid valve (Ebsteindisease). Noncardiac abnormalities con-sisted specially of the presence of hypertel-orism, cleft lip, and pectus excavatum. Thiscombination appears to constitute a hith-erto undescribed autosomal dominant mid-line disorder of the heart and upper half ofthe body with almost full penetrance andvariable expressivity. The mutation doesnot map to any known locus involved inatrial septal defect or conduction block. Am.J. Med. Genet. 83:193–200, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: autosomal dominant; atrialseptal defect; conduction ab-normalities; heart defects;hypertelorism; pectus exca-vatum

INTRODUCTION

Secundum atrial septal defect (SASD) alone or asso-ciated with other various anomalies may segregate infamilies as an inherited mendelian trait [McKusick,1997]. Some associations are common, such as pro-longed atrioventricular conduction time, sometimesprogressive, or left axis deviation of the QRS and/orright bundle branch block (RBBB) and unexpecteddeath. Other associations are rare and might be com-ponents of different well-characterized syndromes suchas Holt-Oram syndrome (MIM 142900), TAR syndrome(MIM 274000), Ellis-van Creveld syndrome (MIM225500), and Opitz G-BBB syndrome (MIM 145410).The localization of different genes on chromosome 5[Benson et al., 1998; Schott et al., 1998] demonstratedrecently that familial SASD is a heterogeneous condi-tion.

We describe a familial form of SASD associated withdifferent heart defects, conduction abnormalities, andmidline noncardiac malformations. These patients mayhave a hitherto unreported autosomal dominant disor-der including cardiac malformations and body defectsalong the midline of the upper half of the body.

CLINICAL REPORT

Members of the kindred (Fig. 1) belong to the Leba-nese Christian Maronite community. No consanguine-ous marriages were noted. Eighteen individuals, 13males and 5 females, in three generations had beensurveyed and assessed on clinical, electrocardiographic(ECG), and two-dimensional echocardiographic(ECHO) grounds. There were nine affected males andfour affected females (Table I). Three patients had un-dergone cardiac surgery. The ancestor of this family(I-1) died at age 66 years of chronic heart failure. Oneof his sisters (I-3) had a median cleft lip and palate. Shenever married and died of heart failure at age 60 years.Birth control was used in the third generation becauseof genetic counseling.

Contract grant sponsor: Saint Joseph University for ScientificResearch; Contract grant sponsor: Lebanese CNRS.

*Correspondence to: Andre Megarbane, MD, PhD, Unite de Ge-netique Medicale, Faculte de Medecine, Bureau de Liaison del’Universite Saint-Joseph, 42, rue de Grenelle, 75007 Paris,France. E-mail: megarban@dm.net.lb

Received 31 August 1998; Accepted 2 December 1998

American Journal of Medical Genetics 83:193–200 (1999)

© 1999 Wiley-Liss, Inc.

Case II-2

A 66-year-old woman had a systolic murmur at thepulmonic area. ECG disclosed biatrial hypertrophywith an rSS8 configuration of the QRS in V1, QRSwidth at 0.109, and wide terminal forces in the frontalplane suggestive of RBBB. ECHO disclosed a SASD of

18 mm with moderate pulmonary hypertension, and noother abnormalities. She has an affected son (III-2) andgrandson (IV-2).

Case II-3Propositus’ grandfather was age 64 years. Par-

oxysmal atrial fibrillation began at age 40 years.

Fig. 1. Pedigree of the family. Propositus is indicated by an arrow and SASD surgically repaired by an asterisk. Various associated anomalies arerepresented within the four divided square or circle and detailed in the text. Dotted symbols represent nondocumented cases.

TABLE I. Cardiac and Noncardiac Body Malformations and Disorders of the Present Family*

CaseAge

(years)

Malformations and Disorders

Cardiac

BodyAtrial Others Functional

I-1 – ? ? Heart failureI-3 – ? ? Heart failure Cleft lip/palateII-2 66 SASD RBBB; pulmonary hypertensionII-3 64 SASD QRS left axis deviation; RBBB;

atrial fibrillation; pulmonaryhypertension

Pectus excavatum

II-6 62 SASD Pulmonary hypertensionIII-2 43 SASD (Op.) Pulmonic stenosis QRS left axis deviation; RBBBIII-4 34 SASD (Op.) RBBB; sinus bradycardia Pectus excavatum; kyphoscoliosisIII-5 37 SASD Lutembacher syndrome RBBBIII-6 35 SASD W-P-W syndrome; pulmonary

hypertensionIII-7 31 Foramen ovale Apical tracts? Left ventricular hypertrophy;

left P axisIV-2 12 SASD Pectus excavatumIV-4 1 SASD (Op.) Aortic stenosis Pulmonary hypertension; heart

failureHypertelorism; pectus excavatum;

malignant hyperthermia?IV-5 7 SASD Pulmonic stenosis Pulmonary hypertension; nodal

atrioventricular rhythmHypertelorism; cleft lip; pectus

excavatum; diastemaIV-6 7 SASD Ebstein syndrome RBBB; right atrial hypertrophy Hypertelorism; pectus excavatumIV-8 1 SASD RBBB

*SASD, secundum atrial septal defect; RBBB, right bundle branch block; Op., operated.

194 Megarbane et al.

Fig. 2. Case III-5 at age 37 years. (a) ECG showing biatrial and right ventricle hypertrophy with RBBB: rsR8s’ configuration in V2 and QRS at 0.129.(b) ECHO showing a SASD at 45 mm with moderate mitral-thickened valve stenosis of approximately 1.77 cm2 surface, slight mitral regurgitation, andmoderate right chambers enlargement, which are characteristics of Lutembacher syndrome.

Autosomal Dominant SASD 195

He had a moderate pectus excavatum and a mildsystolic ejection murmur at the midleft sternalborder. ECG showed QRS left axis deviation (LAD)at −45° with rR8 configuration in V1 and QRS widthat 0.129 suggestive of RBBB. ECHO showed an

SASD of 25 mm with left auricular-right auricular(LA-RA) continuous shunt and a systolic pulmonicarterial pressure of 32 mm with overload of the rightchambers. He has normal son (III-3) and grandson(IV-3).

Fig. 3. Case IV-5 at age 7 years. (a) Photograph of the patient. Note the mild hypertelorism, the asymmetric nose, and the midline cleft lip. (b) ECGshowing right atrial and ventricular hypertrophy, an alternating nodal atrioventricular rhythm. (c) ECHO showing a SASD at 22 mm, tight pulmonicvalve stenosis of the dome-shaped type with dysplasic valves, and dilated right chambers.

196 Megarbane et al.

Case II-6

A 62-year-old man was normal at physical examina-tion and ECG. ECHO disclosed an isolated SASD of20-mm diameter and moderate pulmonary hyperten-sion. He has three affected children (III-5, III-6, III-7).

Case III-2

A 43-year-old man presented with exertional dys-pnea and was operated for a SASD 10 years ago. Healso had a pulmonic valve stenosis that was dilatedduring the same operation. A preoperative ECGshowed LAD of the QRS at −45°, and findings of incom-plete RBBB: rR8 configuration in V1, QRS width at0.119, and broad terminal forces in the frontal plane.His present condition, 10 years after surgery, is normalwith an ECG still showing LAD at −45° and the samefindings of incomplete RBBB.

Case III-4

The 34-year-old father of the propositus was seen atthe same time as his son. He had been operated for anasymptomatic SASD at the age of 23 years. He hadpronounced pectus excavatum and a right kyphoscolio-sis. A preoperative ECG disclosed sinus bradycardia at45–50 per min and evidence of incomplete RBBB. Hispresent condition 10 years after surgery is normal. Pre-sent ECG still showed sinus bradycardia, and signs ofincomplete RBBB with QRS width at 0.119, broad ter-minal forces in the frontal plane, and rsS8 configura-tion in V1.

Case III-5

A normal 37-year-old gravida2 para3 woman hadhad exertional dyspnea since childhood. She had a sys-tolic murmur at the left sternal border and a distinctsystolic heave with a mitral opening snap at the apexand diastolic rumble. An ECG showed signs of biatrialand right ventricular hypertrophy and of RBBB con-sisted of broad terminal forces in L1 and aVL, rsR8s’configuration in V2, and QRS width at 0.129 (Fig. 2a).ECHO disclosed marked right atrial dilatation with avery large SASD at 45 mm, moderate mitral stenosiswith mild regurgitation, and marked left to rightshunt, which are all features of Lutembacher syndrome(Fig. 2b). Her dizygotic twin daughters (IV-5, IV-6) areaffected as well. Her son (IV-7) is normal.

Case III-6

A normal 35-year-old man presented since childhoodwith short bouts of undocumented paroxystic tachycar-dia. During examination, a mild systolic ejection mur-mur was detected. ECG showed Wolff-Parkinson-White syndrome of the B type. ECHO disclosed a SASDof moderate size. There was a mild pulmonary hyper-tension.

Case III-7

An asymptomatic normal, well-developed 31-year-old man had normal physical and cardiac findings. Hepresented a puzzling ECG with P axis deviated to theleft and evidence of left ventricular hypertrophy: RV5 +SV2 4 55 mm. ECHO showed a normal atrial septumexcept for a moderate patent foramen ovale with a

Fig. 3 (Continued).

Autosomal Dominant SASD 197

slight LA-RA shunt and rudimentary residual tracts atthe left ventricle apex. All cardiac chambers with in-terventricular septum and walls were normal. Endo-cardiac biopsy was not accepted.

Case IV-2

A 12-year-old boy with normal cardiac and ECG find-ings had a marked pectum excavatum and at ECHO aSASD of 25 mm without any other abnormality.

Case IV-4

This is the propositus. When he was born, the fatherwas age 34 years and the mother age 24 years. Gesta-tion was unremarkable and there was no exposure totoxins or known teratogens. The baby was delivered bycephalic presentation at 40 weeks. Birth weight was3,850 g (90th centile), length 52 cm (90th centile), andoccipitofrontal circumference (OFC) 36 cm (90th cen-tile). Cardiac malformation was discovered at 3 monthsduring a routine pediatric consultation.

We first examined him at age 11 months. There hadbeen growth arrested from the 8th month and difficultysucking. There was no history of cyanosis and no lunginfections. He weighed 8,200 g (3rd centile), had alength of 74 cm (35th centile), and had an OFC of 45 cm(15th centile). Anomalies detected were moderate hy-pertelorism, pectus excavatum, and mild systolic mur-mur at the pulmonic area with a distinct systolic heave.ECG showed signs of hypertrophy of the right atriumand right ventricle. ECHO disclosed a medium sizeSASD with severe pulmonary hypertension with dila-tation of the right chambers and tight congenital val-vular aortic stenosis. Chest radiograph showed amuch-enlarged cardiac shadow related to right cham-bers dilatation, prominent pulmonary artery, andmarked lung vascularity. The patient was in heart fail-ure. Right-left chamber catheterization confirmed theECHO data. Surgery disclosed a SASD of 20 mm withstenotic aortic valve due to fusion of 2 cusps of 3 attheir ridges. The baby underwent aortic valvulotomyand closure of the ASD with a pericardial patch. Hedied 4 days later of complications of malignant hyper-thermia. There are no other known post-operativecases of malignant hyperthermia in this family.

Chromosome study of lymphocytes with high resolu-tion G- and R-banding showed a normal 46,XY karyo-type. Fluorescent in situ hybridization using probesfrom the CATCH 22 region was normal.

Case IV-5

This is an asymptomatic normally developed 7-year-old twin girl. Birth weight was 2,000 g (<3rd centile)and length 50 cm (60th centile). At examination, herweight was 21 kg (50th centile), and the height 117 cm(35th centile). She had mild hypertelorism, an asym-metric nose with a flattened tip secondary to scarringfrom a midline cleft lip repair (Fig. 3a), high archedpalate, diastema of the two upper incisors, pectus ex-cavatum, and a loud systolic ejection murmur over thepulmonic area with a distinct thrill. ECG showed rightatrial and ventricular hypertrophy with irregular peri-

ods of nodal atrioventricular rhythm (Fig. 3b). She hadexperienced rare paroxysms of tachycardia. ECHO dis-closed a large SASD of 22 mm and severe pulmonicvalve stenosis with thickened dome shaped valve, sys-tolic pressure gradient right ventricle of 70 mm, smallLA-RA shunt, and moderately dilated right chambers(Fig. 3c).

Case IV-6

Her twin sister was born with a weight of 2,120 g(3rd centile), a length of 44 cm (<3rd centile), and anOFC of 31.5 cm (5th centile). At examination, herweight was 19 kg (10th centile) and the height 112 cm(5th centile) with relatively retarded growth in com-parison with her sister. She had moderate hypertelor-ism, pectus excavatum, loud systolic ejection murmurover the pulmonic area, and a distinct but mild systolictricuspid regurgitation murmur. ECG showed rightatrial hypertrophy with incomplete RBBB of the rsS8type in V1 (Fig. 4a). ECHO showed a large SASD of 25mm with a systolic and diastolic permanent LA-RAshunt, low implantation of the tricuspid valve withatrialization of a large part of the right ventricle, thick-ening of this valve, and mild regurgitation, which areall characteristics of Ebstein disease (Fig. 4b).

Case IV-8

He was age 12 months when we saw him. His birthweight was 3,300 g (50th centile), length 50 cm (60thcentile), and OFC 34 cm (50th centile). At examination,he weighed 10 kg (50th centile), had a length of 78 cm(75th centile), and an OFC of 44.5 cm (10th centile).Mild left sternal border murmur was noted. His ECGshowed a rR8 configuration in V1 and a QRS width at0.119. ECHO disclosed a moderate SASD of 15 mm withLA-RA shunt and a moderate elevation of pressure inthe right cavities.

DISCUSSION

Abnormal findings in the family reported herein arerepresented in Table I. The main cardiac malformationis a SASD. It was present in 12 of 13 affected cases.Only case III-7 showed, instead, a patent foramenovale with left heart involvement. There were no labo-ratory blood abnormalities or osseous malformations.

Ostium secundum atrial septal defect, a result of afaulty septation, is a common heart malformation ac-counting for 10% of isolated congenital heart disease[Braunwald, 1997]. Familial ASD cases have been re-ported in few pedigrees as autosomal dominant traitsin two forms, one with and the other without associateddisorders [Lynch et al., 1978]. With the wide range ofvarious other cardiac and noncardiac defects associ-ated to the SASD, our family falls into the first group.

Associated cardiac malformations disclosed in ourkindred (Table I) involve tissues or structures adjacentto the septum such as the mitral valve, which is ste-notic resulting in a Lutembacher syndrome (Fig. 2b),and the medial septal aspect of the tricuspid valve,resulting in an Ebstein syndrome (Fig. 4b). These syn-dromes have never been reported in familial SASD.Pulmonic stenosis seen in two of our cases has been

198 Megarbane et al.

seen in ASD. In a mother and two children, these lasttwo malformations were also associated with ECG ab-normalities [Ciuffo et al., 1985]. The nodal atrioventric-ular rhythm, present in case IV-5, has never been ob-served with SASD in contrary to the W-P-W syndrome.Nevertheless, in one report, the W-P-W syndrome andthe Lown-Ganong-Levine syndrome were present inmonozygotic twins, one of whom had an ASD [Mi-spireta et al., 1976]. Intraventricular-associated car-diac conduction defects are also very common in SASD.

Nevertheless, we think that our family is different fromall other kindreds reported so far.

First, to our knowledge, this is the first association inthe same family of SASD and all the heart defects andconduction abnormalities described here. The rarity ofeach of these abnormalities makes the possibility of achance association unlikely. Second, none of our pa-tients showed evidence of any AV block, such as pro-longed PR interval, 2/1, 3/1, or complete heart block,considered to be an important manifestation in auto-

Fig. 4. Case IV-6 at 7 years. (a) ECG showing a right atrial hypertrophy with incomplete RBBB: QRS width at 0.119, rsS8 configuration in V1. (b)ECHO showing a SASD at 25 mm, low half-way septal insertion of a thickened tricuspid valve, the upper part of the right ventricle being atriolised(Ebstein disease).

Autosomal Dominant SASD 199

somal dominant ASD [Bizarro et al., 1970]. On the con-trary, cases of intraventricular block were common inour series and presented as LAD and/or complete orincomplete RBBB (Table I). Third, none of the reportedkindreds presenting SASD had any of the noncardiacmalformations described in some of our patients suchas hypertelorism, upper incisors diastema, cleft lip,pectum excavatum, and the kyphoscoliosis (Table I).One cannot but notice all noncardiac defects distrib-uted along a virtual midline in the upper half of thebody. Together with major cardiac malformations, sep-tal and paraseptal, a midline embryonic disorder maybe postulated.

LAD is indicative of left anterior fascicular block.RBBB is characterized by increased QRS width at0.10–0.119 for incomplete, 0.129 or more for completeRBBB, broad terminal forces in the frontal plane, anda rsR8, rsS8, or rss8 configuration of V1. LAD andRBBB, indicate respectively, involvement of the ante-rior division of the left bundle branch and that of theright branch of His bundle. The posterior division of theleft branch is spared, as suggested by the absence ofany right axis deviation alone or LBBB. The last hasnever been reported yet in any kindreds of SASD.RBBB is not related to any right ventricle hypertrophy,as it did not disappear or regress even long after sur-gical repair (cases III-2 and III-4). LAD and/or RBBBare the main expressions of a genetic disease of theconducting system designated as “hereditary bundlebranch defect” (HBBD) [Stephan et al., 1997]. It occursisolated not related to any other disease and was re-cently mapped to chromosome 19 [de Meeus et al.,1995]. The bundle of His and proximal roots are withinthe membranous ventricular septum.

Thus, we have reported on a family with a midlinedisorder consisting of SASD, different heart defects,conduction abnormalities, and noncardiac malforma-tions. The family history did not show any suddendeath, showing that this disorder is well tolerated.Even in complicated cases, heart failure had been de-layed. The analysis of the pedigree (Fig. 1) shows au-tosomal dominant transmission with variable expres-sivity and almost full penetrance. An anticipation phe-nomenon is possible since the fourth generation is moreseverely affected than parents and grandparents. Nev-ertheless, the family size is too limited for any preciseprediction. Genotyping analysis with polymorphicmarkers covering the region of gene mutation in HBBD(D19S596, D19S1172) (P. Bouvagnet, personal commu-

nication) and atrial septal defect 1 (ASD1: D5S429,D5S394 and D5S2108) [Kostrzewa et al., 1996; Schottet al., 1998] excluded these two regions in our family,demonstrating that another gene is involved. The lo-calization of this gene will help in understanding betterthe origin of the SASD.

ACKNOWLEDGMENTS

We are indebted to the members of the family fortheir cooperation, to Dr. Ghanem Elias for informationconcerning two of our cases, to Drs. William Zoghbyand Huda El-Hibri Zoghby (Baylor University, Hous-ton, Texas) for their criticism and helpful advice, andDr. Elie Chucrallah. This work has been supported bygrants from the Saint Joseph University for ScientificResearch and in part by the Lebanese CNRS.

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