Hereditary Survey
bundle
of a family
with
branch four
system
affected
defect
generations
Edouard Stephan, M.D. Beirut, Lebanon
A man, presumed to have died with heart block, had married three wives who, in four generations, engendered more than 260 members. Of the 209 family members examined, 32 showed obvious abnormalities of the conducting system. Twelve showed complete right bundle branch block (RBBB), seven exhibited incomplete RBBB, six had right bundle branch block with left axis deviation, four showed RBBB with right axis deviation, one had left axis deviation alone, and two exhibited complete heart block. The pedigree pattern is compatible with the autosomal dominant mode of inheritance. The onset, likely congenital, and the course of the disorder are discussed. It is now well established that, in many instances, disorders of the conducting system show a hereditary distribution. Since our first two reports on a Lebanese family,‘, 2 several examples have been described where various forms and degrees of block occurred in a parent and offspring, or in two or more generations.3-‘3 An autosomal dominant defect of the conducting system has been suggested. The present family is rather unique in that it descends from a man who married three wives who engendered more than 260 members in four generations. Impairment of the intraventricular conduction, predominantly the right, had been documented in many individuals through three and four successive generations, suggesting a hereditary defect of the bundle branch system. From
the French
Received Accepted Reprint Medicine,
January
Faculty
of Medicine,
for publication
Nov.
for publication
Jan.
requests: French
Edward Faculty
Beirut,
Lebanon.
M.D.,
Professor
Beirut,
Lebanon.
18, 1976. 5, 1977.
Stephan, of Medicine,
1978, Vol. 95, No. 1, pp. 89-95
of
Internal
The
proband
This 76-year-old man complained in March, 1974, of dizziness. Examination disclosed diabetes, and evidence of right bundle branch block with left axis deviation. Chest x-ray films were normal. During the following two years he was symptom-free, with no changes in the electrocardiograms. In February, 1976, he fainted for the first time and was then found to present an intermittent complete heart block with an atria1 rate of 30 to 90 a minute, a ventricular rate of 34 to 36 a minute, and QRS complexes similar to those seen when the patient was in sinus rhythm. A pervenous pacemaker was successfully inserted. When we realized that a halt-brother of the proband presented complete heart block, we decided to investigate all available members of the family.
Family
members
The proband was the eldest son of a man who married three wives with whom he had had 16 children. This man was known to suffer from heart disease with fainting attacks. He died suddenly, at an advanced age, some 30 years ago. Numerous stillbirths and early deaths occurred in the second and third generations. Some members had emigrated to Africa. Therfore we could only represent in the pedigree individuals known to be alive in 1976. These numbered about 260, all progeny of the common progenitor. Only two marriages of first cousins in the third and fourth generations were known. All others were non-consanguineous, including’ the three progenitor unions.
Method Personal contact was established with all members living in Lebanon. The aim of the survey was explained to all responsible persons. Excellent cooperation was always obtained. Several family branches could not be entirely covered, as approach to certain remote villages in the south of the country was not always safe during the Lebanese civil war. However, a total number of 209 family members could be examined. The survey included a clinical examination, with a 12-lead electrocardiogram, and additional right precordial leads, V,, and V,,, when it was necessary. Due to a shortage of x-ray films, only 18 affected persons could have a chest roentgenogram. We also had to examine 26 partners of married members of the family, including the proband’s wife, and partners of her
American
Heart
Journal
89
Stephan
Table
I. Analysis of survey results Generation
Number Number Offspring
in each examined with first-degree
relatives Number Per cent of offspring
affected
with
gree affected relatives Sex Male Female Type of anomaly RBBB Complete Incomplete With LAD With RAD LAD alone Complete heart block
first-de-
Sex
2nd
3rd
4th
5th
Total
12
54
11 11
42 22
163 124 49
32 32 16
M
F
Average
261 209 98
109
100
16
54
44
5
7
13
7
32
22
10
46
32
27
44
33
41
23
3
5
9
5
2
2
4
2
22 10
1
2 3
5 2
4 2
2
2 4
1 -
22 days-76
yrs.
13 mos.-60 8 mos.-38
yrs. yrs.
17 16 30
-
4
3
1
0 0
16 72
-
-
1
1
-
-
2
2.
*A and B indicate the family branches issued from the first and second wife, Roman numerals indicate the generations, Arabic numerals the individual serial number in each generation in the pedigree.
23
4 1 4
-
Of the 209 family members examined, 32 showed obvious electrocardiographic abnormalities related to the conducting system. They were represented by symbols in the family pedigree (Fig. l), and are listed in Table I. They included: Complete heart block: Two cases: the proband and his halfbrother, B-11-3*. This case B-ZZ-3, a healthy man 41 years old, experienced exertional dizziness 4 to 5 times during the last 3 years. Repeated electrocardiograms showed complete heart block with an atria1 rate of 70 to 85 a minute, a ventricular rate of 35 to 38 a minute, and wide QRS complexes not unlike those seen in left bundle branch block. General examination, routine laboratory analysis, and chest x-rays, were normal. Insertion of a pervenous pacemaker was not accepted. Right bundle-branch block (RBBB): Criteria proposed by the New York Heart Association (1966) for this diagnosis were applied. However, in infants and young children, a shorter QRS duration, from 0.08 to 0.10 sec., was accepted provided the right ventricular activation time was prolonged. Values of at least 0.06 sec. were adopted by us for the diagnosis of complete RBBB, and of 0.04 to 0.06 sec. for incomplete RBBB. 1st degree: Complete RBBB: 12 cases. Average age 17 years (range 1 to 60 years).
yrs. yrs.
8
1
Results
21
6 2
2
22 days-76 22 days-76
7 6
1
Range
-
12
-
progeny, and no conduction abnormality was found in the electrocardiograms. In the present report, only well-defined abnormalities of the conducting system are retained. All other abnormal electrocardiographic findings were discarded.
90
Age
2-55 yrs. 22 days-37 yrs. 72 yrs. 41-76 yrs.
58
2nd degree: Incomplete RBBB: Seven cases. Average age 16 years (range 8 months to 38 years). RBBB with left axis deviation (LAD) (frontal plane axis of the initial 0.04 portion of the QRS): Six cases. Average age 30 (range 2 to 55 years). Five of these cases showed axes of -30” to -75”. The sixth case, A-11-25*, a 3-year-old boy, showed an axis of about -5’. RBBB with right axis deviation (RAD) frontal plane axis of the initial 0.04 portion of the QRS): Four cases. Average age 16 years (range 22 days to 37 years). These cases were three males, A-IV-2, A-IV-16, and A-IV-22, aged 37,14, arid 14, years, respectively, with axes of + 90” to + loo”, and a 22-day-old baby girl, A-IV-27, with an axis of + 150’ (Fig. 4). Left axis deviation (LAD): One case: a man of 72 years, with an axis of -75”. Figs. 2 and 3 are examples of eight cases of RBBB of different ages and from each generation. Fig. 4 shows the electrocardiogram of the 22-day-old baby girl, A-IV-27, who, to the best of our knowledge, is the youngest case of RBBB ever observed in an otherwise normal subject. There was no instance of prolongation of the PR interval. Sinus bradycardia was not encountered. There were several borderline cases with an rr’s or rsr’s’ configuration in the right precordial leads, without definite prolongation of the QRS (Fig. 6). A few other cases showed mild degrees of left axis deviation. We also encountered several instances of the Sl S2 S3 syndrome. All these cases, being ill-defined or equivocal, were not retained in the present series. We also discarded four young cases with deep q and tall R waves in left precordial leads, because technical facilities to rule out cardiomyopathy and congenital cardiac lesion were not available. Two first-cousin marriages in the third and fourth generations resulted in 3 children with an rr’s pattern, out of five. Incidence and distribution. The 32 affected individuals included 22 males and 10 females. Offspring with first-degree-
January,
1978,
Vol.
95, No.
1
Hereditary
.^--~--
RC
OmPk’te
tieart
A
bundle branch system defect
151 Wife @ ---A
Block
Fig. 1. Pedigree of the family. The three family branches issued from the unit of the progenitor with the three wives indicated by the capital letters A, B and C, the generations denoted by Roman numerals, individual’s serial number designated by Arabic numerals below circles and squares, and age by Arabic numerals above; the Proband is indicated by an arrow. affected relatives were 98, with males 54 and females 44. Incidence is thus 33 per cent, with 41 per cent males and 23 per cent females. Most cases came from the second generation and the proband progeny, with a total number of 22 affected persons to 24 non-affected relatives, an incidence of 48 per cent. Affected males were 15 to 11 non-affected, females 7 to 13 non-affected. This sex discrepancy is not significant. Average age of all affected individuals ia 23 years; it is 21 years for all offspring with first-degree-affected relatives. The ratio of affected to non-affected individuals in the different age groups is represented in Fig 5.
American Heart Journal
Clinical findings. There were many stillbirths and early deaths in the second and third generations. Two sisters, A-IIII6 and A-111-18, had had ten and seven stillbirths, respectively. Serology for syphilis was found negative. Later, A-III16 delivered nine healthy children, one of whom, A-IV-88 presented RBBB. According to the family, early deaths were mainly due to common diseases of infancy and childhood, and not to cardiac diseases. No special physical finding was noted. There were three adult cases of ischemic heart disease. Fainting only occurred in the proband case. All other persons were healthy and free of
91
Stephan
Fig. 2. Four instances of RBBB from four successive generations. his eldest daughter, A-III-, aged 55, (c), her eldest son, A-IV-P, axis deviation in a, b, d, and right deviation in c.
symptoms common
related progenitor,
to the heart. With the exception of the no sudden death had occurred to date.
Comment
Impairment of conduction in the right branch of His bundle is an almost constant feature of the affection in this family. The anterior division of the left branch, as indicated by left axis deviation, also seemsto be involved in several cases.Impairment of the posterior division is doubtful, as right axis deviation in babies and young thin subjects can be normal. Development of complete heart block, as it occurred in the proband case, could represent total impairment of the two branches, or the right branch and the two divisions of the left. The same development could be incriminated in subject B-11-3, though heart block in this case may already have been complete from the onset of the defect. As for borderline casesand caseswith equivocal
92
(a), the proband in a period of sinus rhythm; aged 37, (d), his third son, A-V-, aged 2. Note
(b), left
findings, not included in the series, some of them may correspond to minor forms of interventricular block, especially when encountered in offspring of affected individuals, and more particularly in parents of affected children. They will be discussed in a subsequent paper. The pedigree pattern (Fig. l), with affected individuals, males and females, through successive generations, and in the absence of consanguinity, is compatible with the autosomal dominant mode of inheritance. The trait obviously had been transmitted by the common progenitor to five children from two of his three wives, and down to the fourth and fifth generation in several unbroken lines. Other lineages showed skipped generations. The proband’s first brother, A-11-3, is affected with left anterior hemiblock. None of his seven examined children were affected. Then RBBB recurred in one grandson, A-IV-88, after one skipped generation, and in three great-grand-
January,
1978, Vol. 95, No. 1
Hereditary
Fig. 3. Four examples of RBBB (c), a 2.5-year-old girl, A-V-16; incomplete. In d, QRS duration which we consider deviated to
in four young subjects. (a), a 3-year-old boy, A-V-8; (b), a 3-year-old girl, A-IV-25; (d), an &month-old baby boy, A-V-10. Panels a, b and c show complete RBBB, d is 0.08 sec., right ventricular activation time 0.04 sec. Axis in b’is about & 0 degrees, the left for that age.
children, A-V-13, A-V-16, and A-V-17, after two skipped generations. The 33 per cent incidence probably is below the actual one, since borderline cases have not been included. However, the expected ratio, one to one, in an inherited dominant trait is closely obtained . in the generation of the proband and his progeny, with 22 affected persons to 24 non-affected individuals. The low female incidence, though not significant, may correspond to a relatively low expressivity in females. Scrutiny of the pedigree shows, indeed, eight instances where affected children are born to non-affected parents, of whom five are females: A-111-8, A-111-16, A-IV-g, A-IV-77 and A-111-14; and three males: A-11-6, A-111-3, and A-N-5. Distribution according to age (Fig. 5) shows a high number of affected individuals in the young age groups, with six affected to four non-affected individuals between 0 and 2.5 years of age. There is no hom*ogeneity in ages in the different genera-
American Heart Journul
bundle branch system defect
Fig. 4. An instance of RRBB, complete, in a 22-day-old baby girl, A-IV-2 QRS duration is 0.08 sec., right ventricular activation time 0.08 sec. Note the marked right axis deviation of the QRS, which could be normal for that age.
93
Stephan
Niirn
btar 1
4
4 l-l
,...~c11 15 .“-” 16 za-
Fig. 5. Age and sex distribution
of affected
tions, with the exception of the fifth, where there are seven affected persons to nine non-affected individuals, with an average age of two years for the affected ones. Evidently, this is an early, if not congenital onset. It has been customary to separate familial congenital block from block of late or adult onset, according to the age at which the disorder has been detected. We now recommend that no case should be considered of late or adult onset unless documented by previous normal ECGs. Right bundle branch block associated with left anterior or posterior hemiblock is a more severe disorder than right bundle branch block alone. Both probably correspond to different degrees in the expressivity of the genetic defect, since they are encountered in the same family branches, in aged as well as in young persons. One can assume that both types of block had been manifest at the same time, unless proved by serial electrocardiograms. At the age of 76 years, the proband advanced from right bundle branch block with left anterior hemiblock to intermittent complete heart block. Progress from lesser to more advanced forms and degrees of block had been observed many times; the subject has been well reviewed.? James’” looks on the region of His bundle “as a locus minoris resistentia, both electrophysiologically and in its tendency to undergo focal ischaemic degenera94
individuals
ii21 30
.‘*
and non-affected
Age
first-degree
Group
relatives.
tion.” In our series, the bundle branch system is already affected with one or two impaired pathways. Our cases, from the beginning, are in the precursor stages of heart block. Theoretically, we could presume that the conducting system, in our cases, is more vulnerable to the effect of extraneous agents, such as infection, stretching, and especially, deficiency in blood supply. These agents may, at any time, provoke further damage and so precipitate heart block. However, there are casesof heart block from birth.’ These casesmay represent a severe degree in the expressivity of the genetic defect. There was no clinical evidence to relate the conducting system disorder in this family to other familial or cardiovascular disease. Two recent studie9, I7 demonstrated in two casesof familial heart block pathology of the distal portion of His bundle and the proximal portions of the two branches. In James’ caseI of a 26-day-old baby, pathology consisted of severe caseous degeneration of these portions. Without His bundle recordings, it is not possible to indicate the site of the defect, whether it is at the level of His bundle or below. Clinically, we know that the defect had impaired the bundle branch system, predominantly the right bundle branch. Many individual cases presented as bilateral bundle branch disease. The evolution in the January,
1978, Vol. 95, No. 1
Hereditary
bundle branch system defect
Fig. 6. Minor abnormalities in two parents of affected children. a, A as-year-old woman (A-IV-O), showing a double peaked r, with a mild degree of left axis deviation. b, Her 31-year-old brother (A-IV-B), showing an embryonic r’. In both cases the time from the onset of r to the summit of r’ is 0.05 to 0.06 sec.
proband case was that of so-called chronic idiopathic heart block.” Familial survey of cases of heart block6 would prove to be informative and of preventive value. Much also is to be known from a long follow-up of this family.
7. Sarachek,
We wiah to thank Dr. V. Der Kaloustian of the Department of Pediatrics, American University of Beirut, for his valued advice. The author is grateful to his nephews, Robert Cook, of the Department of Chemistry, American University of Beirut, and Ramzi Ashoush, a medical student, for their painstaking work in recording data and the pedigree.
9.
REFERENCES 1.
2. 3.
StBphan, E.: Bloc auriculo-ventriculaire chez trois membres d’une mdme famille, Rev. Med. Moyen-Orient 11: 246, 1954. StBphan, E.: Bloc auriculo-ventriculaie familial, Arch. Mal. Coeur 54~333, 1961. Combrink, J. M., Davis, W. H., and Snyman, H. W.: Familial bundle branch block, AM. HEART J. 64:397,
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1962. 4.
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Gazes, P. C., Culter, R. M., Taber, E., and Kelly, T. E.: Congenital familial cardiac conduction defects, Circulation 32:32, 1965. Lynch, H. T., Mohiuddin, S., Sketch, M. H., Krush, A. J., Carter, S., and Runco, V.: Hereditary progressive atrioventricular conduction defect. A new syndrome? J.A.M.A. 225:1465, 1973. Morgans, C. M., Gray, K. E., and Robb, G. H.: A survey of familial heart block, Br. Heart J. 36:693, 1974.
American Heart Journal
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M. S., and Leonard, J. L.: Familial heart block and sinus bradycardia. Classification and natural history, Am. J. Cardiol. 29:451, 1972. Schaal. S. F.. Seidenstricker. J.. Goodman. R.. and Wooley, C. F.: Familial right bunhle branch bloci, left axis deviation, complete heart block, and early death: A heritable disorder of cardiac conduction, Am. Intern. Med. 7Q:63, 1973. Segall, H. N.: Congenital arrhythmias and conduction abnormalities in a father and four children, Can. Med. Assoc. J. 65:1283, 1961. Simonsen, E. E., and Madsen, E. G.: Four cases of rightsided bundle branch block and one case of atrioventricular block in three generations of a family, Br. Heart J. 32:501, 1970. Tsagaris, T. J., Bustamente, R. A., and Friesendofi, R. A.: Familial heart disease, Dis. Chest 52:153, 1967. Vallianos, G., and Sideris, D. A.: Familial conduction defects, Cardiology 39:190, 1974. Waxman, M. B., Catching, J. D., Felderhof, C. H., Downar, E., Silver, M. D., and Abbott, M.: Familial atrioventricular heart block. An autosomal dominant trait, Circulation 5 1:226, 1975. LenBgre, J.: Etiology and pathology of bilateral bundle branch block in relation to complete heart block, Progr. Cardiovasc. Dis. 6:409, 1964. James, T. N.: Cardiac conduction system: Fetal and postnatal development, Am. J. Cardiol. 25213, 1970. James, T. N., McKone, R. C., and Hudspcth, A. S.: De Subitaneis Mortibus. X. Familial congenital heart block, Circulation 5 1:379, 1975. Hudson, G. S., Blackman, M. S., Rogers, M. C., Bharati, S., and Lev, M.: Familial congenital bundle branch system disease, Am. J. Cardiol. 32:365, 1973.
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