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Congenital heart disease, deaf-mutism and associated somatic malformations occurring in several members of one family
Congenital
Heart
and Associated Occurring
Disease, Deaf-Mutism Somatic
in Several
Malformations Members
of
One Family* GABRIEL
T. KOROXENIDIS,
CHRISTOS
B. MOSCHOS,
M.D., N. CONANT WEBB,
JR.,
M.D. and PATRICK H. LEHAN,
M.D., M.D.
Jersey City, New Jersey association of this syndrome with pulmonary valvular stenosis in one child suggests that the same mode of inheritance may be responsible for the transmission and aggregation of pulmonary stenosis in this family. The peripheral blood leukocyte chromosomes of the affected and some of the nonaffected members of the family were examined. No abnormality in the number of chromosomes was found and their morphology appeared to be normal.
herein is a unique family in which the mother and four of her eight children from two marriages have pulmonary valvular and/or infundibular stenosis in association with other cardiac and noncardiac malformations. In 1958 Lewis et al. [I] reported the results of right heart catheterizations on the two members of this family who had associated deaf-mutism. Since then another child has been born from a second marriage who also shows clinical evidence of pulmonary stenosis. This aggregation of congenital heart disease led to a genetic and hemodynamic re-evaluation of the whole family. In 1960 combined right and left heart catheterizations were performed in the mother and the four of her eight children who presented clinical evidence of heart disease. All were found to have valvular and/or infundibular pulmonary stenosis. One of the two deaf-mute children was found to have the syndrome of idiopathic ventricular hypertrophy with combined muscular outflow tract obstruction in addition to pulmonary valvular stenosis. Comparison of the hemodynamic data with those obtained four years earlier in two of the older children suggests progression of the severity of pulmonary stenosis. The aggregation of cardiac and noncardiac malformations in this family suggests a hitherto unreported form of inheritance of pulmonary valvular stenosis. Transmission by a single nonsex-linked genetic factor (dominant autosomal inheritance) has been described for familial idiopathic ventricular hypertrophy [Z-4]. The
D
ESCRIBED
CASE REPORTS CASE I. This thirty-nine year old Negro woman (A. W., m-2, P.H. No. 31718), para 8, gravida 8, was the product of a normal pregnancy and delivery. She had no family history of heart disease. She was found to have a heart murmur in early childhood, and her activities were restricted. She was asymptomatic through the pregnancies and until the age of thirtyseven when she began to experience mild exertional dyspnea. Physical examination revealed a cooperative, intelligent woman in no distress. The blood pressure was llOj65 mm. Hg in the arms and 140/80 mm. Hg in the legs. There was a slight cervicodorsal scoliosis. Examination of the heart showed the point of maximal impulse to be in the fifth intercostal space at the midclavicular line. There were no palpable thrills or lifts. The second sound at the base was normally split but the pulmonary component was decreased in intensity. The first sound at the lower left sternal border and at the apex was loud, followed by an ejection sound. A grade 3/6 ejection systolic murmur was best heard along the left sternal border. Fluoroscopy and barium swallow roentgenograms
* From the Division of Cardiovascular Diseases, Department of Medicine, and the Department of Preventive Medicine, New Jersey College of Medicine, and B. S. Pollak Hospital, Jersey City, New Jersey. This study was supported by Grants 5TIHE5510 and HE06376, National Heart Institute, U. S. Public Health Service and Hudson County Heart Association. Manuscript received April 22, 1965. VOL.
40,
JANUARY
1966
149
Congenital Heart Disease-Koroxenidis
150
el al.
TABLEI* HEMODYNAMIC
DATA
FROM
THE CATHETERIZATIONS
PERFORMED
IN
1956
AND
1960
Pressure Case No. t
Patient
A. W.
Year of Study
III-2
1956 1960
H. W. IV-2
1956 1960
B. W.
1956 1960
IV-G
P. w. w-8
IV-~ M.
Right Atrium
(mm. Hg)
Right Ventricle
Pulmonary Artery
Left Ventricle
10/5
38/3 36/2$
15/5 20/2
10278
102’/70
16j2
115/o 200/16§
12/6 36/4
20Glo
154/;0
20/4
60/O 125/15§
24/12 38/3
1960
13/4
150/12$
2114
105/11
1960
..
25111
105/45
118’/68
w.
-
42168
-
cardiomegaly.
The
pulmonary
artery
segment was not dilated. The electrocardiogram showed normal sinus rhythm with a mean QRS axis of +50 degrees in the frontal plane. There were deep S waves in leads Vr and VZ. There was no evidence of right ventricular hypertrophy. In November 1960 this patient underwent combined right and left heart catheterization. The results are given in Table I. She was found to have valvular pulmonary stenosis with a systolic gradient of 16 mm. Hg. CASE II. A fifteen year old Negro boy (H. W., IV-~, P.H. No. 31719), was the product of an uncomplicated pregnancy and low forceps delivery. He was the second child in the family and the first with congenital heart disease, which was discovered when he was two years old. He presented a feeding problem during infancy and his growth has been retarded. His exercise tolerance has been difficult to evaluate because of deaf-mutism. However, he seems to be fairly active. There have been no episodes of syncope, chest pains, cyanosis or frequent respiratory tract infections. Physical examination revealed a pleasant, deafmute boy with broad nasal root and slight asymmetry of the head and facial features. There was flattening of the left side of the occiput, hypertelorism, low set ears with hypoplastic auricular helices, mild cervicodorsal scoliosis, moderate pectus excavatum and hypoplastic fifth digits. The left testes was undescended, the right one was felt in the inguinal canal. There was no pubic hair. The precordium was hyperactive with the point of maximum impulse in the sixth intercostal space at the mid-clavicular line.
105156
. -
L
* Letters refer to the initials of the patients, the roman numerals refer to the generation identify the individual in each generation. t Present study. $ Valvular stenosis. Q Combined valvular and infundibular stenosis. 7 Infundibular stenosis. did not reveal
Aorta
and the arabic
numerals
There were both right and left ventricular heaves. A systolic thrill was felt along the upper left sternal border with radiation to the neck. The second sound at the base was normally split and the pulmonic component was decreased in intensity. A prominent atria1 sound was heard along the left sternal border. A third heart sound was heard at the apex. A grade 5/6 harsh, ejection systolic murmur was heard at the base and radiated to the neck bilaterally. A separate grade 2/6 holosystolic murmur was heard at the apex with radiation to the left axilla. The carotid upstroke was brisk. Fluoroscopy and barium swallow roentgenograms showed slight cardiomegaly with right ventricular and right atria1 enlargement. There was no poststenotic dilatation of either of the great vessels. The electrocardiogram showed normal sinus rhythm with a mean QRS axis of - 140 degrees. In lead Vr there was an Rs pattern with an R wave of 20 mm. and an S wave of 7 mm. when the patient was first examined in 1960. The T waves were deeply inverted. There were deep S waves in leads Vs and VS. The amplitude of the R wave decreased and became minimal from leads V4 to Vs and Vg. It was interpreted as showing right atria1 enlargement and systolic overloading of the right ventricle and possible left ventricular hypertrophy. A subsequent electrocardiogram obtained in 1963 showed further progression of these changes with larger P and R waves in lead VI. In November 1960 right heart catheterization was performed. A pullback tracing from the pulmonary artery revealed severe valvular and infundibular stenoAMERICAN
JOURNAL
OF
MEDICINE
Congenital
Heart
Disease-Koroxenidis
sis. A systolic gradient of 80 mm. Hg was found between the body and the outflow tract of the right ventricle, and an additional gradient of 84 mm. Hg between the infundibulum and the pulmonary artery. (Table I.) The catheter was advanced through an atria1 srptal defect into the left atrium and left ventricle. Simultaneous pressures from the left ventricle and brachial artery revealed a systolic gradient varying from 0 to 100 mm. Hg at different times during the study, a phenomenon reported to occur in idiopathic hypertrophic subaortic stenosis [4,5]. The brachial artery pressure pulse displayed a fast upstroke and the postextrasystolic beats demonstrated a narrowing of the pulse pressure (61. A left ventricular cineangiocardiogram confirmed the presence of muscular subaortic stenosis and moderate mitral insufficiency. The patient underwent surgery in January 1964, but only the right ventricular outflow obstruction was corrected. The left ventricle was a slit-like chamber with hypertrophied myocardium. CASE
III.
This
ten year
old Negro
girl
(B.
W.,
IV-~, P.H. No. 31720) was the product of an uncomplicated pregnancy and delivery. She was the fourth child in the family and the second with congenital heart disease. A heart murmur and deafness were recognized early in childhood. Growth and development were normal, but there were feeding problems in infancy. The patient tires easily and cannot keep up with other children of the same age. Physical examination revealed a well developed child with hypertelorism and deaf-mutism. The fifth digits were hypoplastic and there was overriding of the fifth toe bilaterally. The child had a broad nasal root, low set ears with hypoplastic auricular helices, pectus excavatum and mild cervicodorsal scoliosis. The external genitalia appeared normal. On examination of the heart, the point of maximum impulse was in the fifth intercostal space at the midclavicular line. A systolic thrill was felt along the upper left sternal border. The second sound at the base was single. A grade 4/6 harsh, ejection systolic murmur was heard along the upper left sternal border. Fluoroscopy and barium swallow roentgenograms did not reveal cardiomegaly. The electrocardiogram showed normal sinus rhythm and a mean QRS axis of f140 degrees in the frontal plane with clockwise rotation in the precordial leads and an rS pattern in leads Vi to VS. There was a decrease in the amplitude of the R wave from leads Vh to Vs and Vs. Right heart catheterization performed in November 1960 revealed moderately severe pulmonary stenosis with a systolic gradient of 87 mm. Hg and a definite infundibular chamber confirmed by withdrawal tracings and a right ventricular cineangiocardiogram. The oxygen saturation samples suggested a left-toright shunt at the atria1 level. CASE IV. IV-~, P.H. VOL.
40,
This five year old Negro girl (M. W., No. 31722) was the product of an uncomJANUARY
1966
plicated
pregnancy
151
Pt ul. and delivery.
She \vas the sixth
child in the family and the third with congenital
heart
disease that was discovered in infancy. Her growth and development have been normal but she tires easily and becomes dyspneic while playing. Physical examination revealed a well developed child who sho\l;ed hypertelorism, broad nasal root, low set ears with hypoplastic auricular helices, pectus excavatum, mild cervicodorsal scoliosis and hypoplastic fifth digits bilaterally. Hearing was normal. Examination of the heart showed a hyperactive precordium and a parasternal heave. A systolic thrill was felt along the upper left sternal border. The second sound at the base was single. A harsh grade 4,1’6 ejection systolic murmur was heard over the entire precordium but was maximal at the pulmonary area. Fluoroscopy and barium swallow roentgenograms showed right ventricular hypertrophy and moderate dilatation of the pulmonary artery segment. The electrocardiogram showed normal sinus rhythm with a mean QRS axis of +180 degrees in the frontal plane. In lead Vr there was an Rsr’ pattern with an R wave of 23 mm. and an S wave of 2 mm. There were deep S waves in leads Vz through Vi. There was a decrease in the amplitude of the R wave from leads Vs through Vs. The tracing was interpreted as showing right ventricular hypertrophy. Combined right and left heart catheterization performed in November 1960 showed a persistent left superior vena cava draining into the coronary sinus. A systolic gradient of 129 mm. Hg Jvas found at the pulmonary valvular level. No infundibular chamber was demonstrated. There were no aortic or mitral valve gradients. (Table I.) CASE v. A one and a half year old Negro boy (P. W., IV-~, P.H. No. 31724) was born to the same mother but by another father. He was the product of an uncomplicated pregnancy and delivery. A heart murmur was noted soon after birth. He was the eighth child in the family and the fourth with congenital heart disease. Physical examination revealed prominent frontal bossing, hypertelorism, broad nasal root and low set ears with hypoplastic auricular helices. The chest wall showed pectus carinatum. There were supernumerary sixth digits bilaterally. Hearing was normal. Examination of the heart revealed the point of maximum impulse to be at the fifth intercostal space within the mid-clavicular line. The second sound at the base was single. A grade 4;‘6 ejection systolic murmur was heard along the upper left sternal border. Chest roentgenograms did not shovv cardiomegaly. The electrocardiogram showed normal sinus rhythm with a mean QRS axis of + 110 degrees in the frontal plane. The precordial leads suggested neither right or left ventricular hypertrophy. Right heart catheterization performed in November 1960 indicated the presence of infundibular stenosis with a systolic gra-
152
Congenital
Heart
Disease-Koroxenidis
l&S
0
et al.
1p_7
MALE
El0
qs El8
IF8
OFEMALE
CONG. HEART DISEASE DEAF MUTISM SUPERNUMERARY
DIGITS
FIG. 1. Pedigree of family. dient of 17 mm. Hg between the main body and the outflow of the right ventricle. (Table I.) No valvular stenosis was demonstrated. COMMENTS
The pedigree of this family is given in Figure 1. Any relationship between the parents of the affected children seems unlikely since their ancestors come from different parts of the country. The first father had been married twice previously and none of his three children from those two marriages are known to have any cardiac abnormality. The second father had also been married previously and the one child from that marriage is not known to have any heart disease. The mother is the first from her family to have congenital pulmonary stenosis. None of her brothers or sisters is known to have any form of congenital malformations. She had eight children ; the last one from the second marriage. Four of these children had pulmonary valvular and/or infundibular stenosis. Two of the affected children born from the first marriage were also deaf-mutes and had evident hypertelorism. The pulmonary stenosis was associated in both
with an atria1 septal defect and in one of the two it was complicated by the presence of idiopathic ventricular hypertrophy with combined muscular outflow obstruction and mitral insufficiency. The youngest child, although born from a second marriage, also had a cardiac malformation. That this child had indeed a different father was also suggested by the fact that both the child and his father had identical supernumerary digits. While the etiology of some forms of congenital heart disease, such as those associated with Turner’s and Down’s syndrome, is clearly chromosomal [7-l 7 1, in the vast majority of cases the etiology is less certain. When a chromosomal abnormality is not demonstrable, proof of a genetic etiology requires familial aggregation and exclusion of environmental factors known to play a role [ 72-751. Evidence for environmental factors such as viral infections during the first trimester of pregnancy and threatened abortions was not found in this family. Carleton et al. [76] have collected and reviewed the reports of multiple familial congenital heart disease described in the literature since AMERICAN
JOURNAL
OF
MEDICINE
Congenital
Heart
I)isease~E;oroxprlidis
1941. There was no report of a family in which more than two members of the same generation were affected with pulmonary stenosis or in which the disease was present in two successive generations. Coblentz and Mathivat [77] reported the presence of pulmonary stenosis in two sisters. Fournier et al. [7S] recently described a family in which four of five children had clinical and/‘or autopsy evidence of pulmonary stenosis and congenital nephrotic syndrome. The present family is the only one in which more than one generation is known to be affected with pulmonary stenosis. Heiner and Nadas [79] reported that in pulmonary stenosis without patent ductus arteriosus, the occurrence of somatic malformations is unusual. In the family discussed here, several somatic malformations were observed in the children affected with pulmonary stenosis. Hypertelorism, broad nasal root and low set ears with flattened auricular helices were present in all the affected children. The first deaf-mute child (Case II) also had undescended testicles, absent public hair, hypoplastic fifth digits, asymmetrical development of the cranial bones with acrocephalia and flattened occiput on the left side. The second deaf-mute child (Case III) had hypoplastic fifth digits, pectus excavatum, scoliosis of the vertebral column and overriding of the fifth toe bilaterally. The third affected child (Case IV) had pectus excavatum, cervicodorsal scoliosis and hypoplastic fifth digits. The last child (Case v) had pectus carinatum and supernumerary digits that were also present in his father. The rest of the children without heart disease had no obvious somatic malformations. Campbell [20], in a review of 125 cases of pulmonary stenosis, found the incidence of noncardiac malformations to be 13 per cent. He suggested that such findings as well as the high incidence of pulmonary stenosis in consanguineous marriages are consistent with a genetic effect. Lamy et al. [27] reported fifty-six children with pulmonary stenosis. In two cases the child’s parents were first cousins. This is significantly different (~~0.05) than their controls would lead one to expect, suggesting a recessive form of pulmonary stenosis. Furthermore, they found one sib of 107 (the fifty-six children had 107 sibs) who also had pulmonary stenosis; this, too, is unlikely to be a chance occurrence. In any event, their evidence for two doses inheritance (consanguinity) may not be relevant here, as only- one of the fifty-six families had a second VOL.
40,
JANUARY
1966
rt al.
153
case of pulmonary stenosis, none of the families had an affected parent and child pair, and they do not report infundibular stenosis either alone or in association with valvular stenosis. The striking aggregation in the present family. of pulmonary stenosis and several other somatic malformations, and the presence of the disease in two generations (the mother and four of her eight children) despite two unrelated husbands, indicate that the mother has received and transmitted abnormal genetic material. Multifactorial inheritance is thought to be unlikely. That four of her eight children are affected is consistent with her being heterozygous for the genetic defect. It appears that transmission of a single dose of the abnormal genetic material can cause heart disease in her children. This type of transmission is consistent with trisomy or a single dose of a translocation, deletion or point mutation. However, we do not know of a trisomic or translocation syndrome with these manifestations. The finding of forty-six morphologically normal chromosomes in the mother and the children suggests that a point mutation is the most likely abnormality although a small translocation or deletion cannot be excluded. The deaf-mutism could be part of a single genetic syndrome involving congenital heart disease with variable expressivity for deafness, or it could be separate. Roentgenograms of the skull did not reveal any abnormality of the bony structure of the auditory canal. Deafness occurred in only two of the seven children from the first marriage. This is consistent with variable expression of an autosomal dominant trait that produces congenital heart disease as well. It is also consistent with the most common kind of genetic deafness which is transmitted as a Mendelian recessive. The lack of parental consanguinity is not strongly against recessive inheritance of deafness as consanguinity is common only when a recessive gene is rare. The absence of deafness in the parents and other ancesters is perfectly consistent with separate recessive deafness. In short, the deafness is more likely to be a variably expressed part of the cardiac syndrome than independent of it, but this is far from proved. The finding of muscular subaortic stenosis in the first child is of interest. It is conceivable that hypertrophy of the septum secondary to the pulmonary stenosis led to progressive obstruction of the left ventricular outflow and development of subaortic stenosis. However, the asso-
154
Congenital
Heart
Disease-Koroxenidzs
ciation of mitral insufficiency and the finding at surgery of an extremely thick left ventricular wall makes it more likely that the case belongs to the syndrome of idiopathic hypertrophic subaortic stenosis. In the rest of the affected children there was no evidence of left ventricular outflow obstruction. However, exercise and Isuprel@ were not used during the catheterizations. In cases of idiopathic hypertrophic subaortic stenosis, the use of exercise or Isuprel has been shown to bring out a dynamic obstruction which may be absent at rest [4,5]. Teare [Z], in an autopsy study, has described eight cases of “asymmetrical hypertrophy of the ventricular septum in young adults.” All were characterized by massive hypertrophy of the ventricular septum of unknown etiology. Since then similar cases have been described by several workers in which hypertrophy of the septum and the derangement of the muscle bands caused subaortic stenosis and/or associated mitral insufficiency [4,23,24]. However, in some cases, there was associated mild or even predominant right ventricular outflow obstruction [25-281. There has been considerable speculation concerning the acquired or congenital nature of this anomaly. Evidence that the disease is, at least in some instances, congenital is provided by the report of Neufeld et al. [29], who described autopsy findings in two babies with idiopathic hypertrophic stenosis and obstruction to both ventricular outflows. In this case the association of idiopathic subaortic stenosis with congenital pulmonary valvular stenosis and atria1 septal defect indicates that the subaortic stenosis is also probably congenital. A familial form of idiopathic hypertrophic subaortic stenosis has been described, and several reports have been concerned with the occurrence of the disease in several members of a family in one or more generations. Brent [2] has suggested that the disease is inherited as a dominant autosomal (non-sex-linked) Mendelian trait. Braunwald [4] has suggested that the disease occurs either as a congenital nonfamilial or as a familial noncongenital form. An acquired nonfamilial form is also described. The occurrence of the disease in a family in which the other siblings had a different form of congenital disease is unknown to us. The finding of idiopathic hypertrophic subaortic stenosis in one of the children of this family suggests that a congenital hereditary form of the disease also exists which can produce pulmonary valvular stenosis as well.
et al.
Comparison of the hemodynamic data of this study with those of the study performed four years previously indicate that the pulmonary stenosis has not progressed in the mother. During the first study the mother was found to have a right ventricular systolic pressure of 38 mm. Hg. Four years later the pressure was unchanged, indicating that the pulmonary stenosis remained mild during this period. In contrast, there is evidence of considerable progression of the disease in the two older children, who have been studied twice. The oldest affected child (Case II) had a right ventricular systolic pressure of 115 mm. Hg initially, indicating moderate pulmonary stenosis. Four years later the pressure in the right ventricle had increased to 200 mm. Hg, indicating progression from moderate to severe pulmonary stenosis. The second child (Case III) was found initially to have mild pulmonary stenosis with a right ventricular pressure of 60 mm. Hg. Over the period of four years the stenosis became moderately severe as the pressure increased to 125 mm. Hg. It is realized that such comparison of the data may not be absolutely valid since data on left heart pressures and cardiac outputs are not available from the first study and the ratio of the right to left heart pressures is not known. However, in view of the considerable increase in right ventricular pressures and further progression of the electrocardiographic findings, it is considered that the disease has indeed become more severe. These findings are consistent with the opinion expressed by Engle et al. [30] concerning the evolution of pulmonary stenosis. They state that pulmonary stenosis may become progressively more severe as the child grows but whether the disease will progress or remain stable cannot be predicted in any individual patient. The mother and the second child (Case III) had mild pulmonary stenosis from childhood ; in the mother the disease remained stable whereas in the child it progressed rapidly over the period of four years to become moderately severe. It is not known whether this progression means that the valvular orifice actually becomes smaller or only in relation to the growth of the heart and the increased cardiac output accompanying general body growth. SUMMARY
A unique family is described in which the mother and four of her eight children have pulmonary stenosis. Two of the four affected chil-
Congenital
Heart
disease---l;oroxPnidis
drcn are deaf-mutes; one of these has, in addition to the pulmonary valvular stenosis, idiopathic hypertrophic subaortic stenosis. All the affected children had several associated somatic malformations. Genetic and nongenetic factors and their role in the development of the malformations are discussed. It is suggested that the cardiac defect is transmitted by a single non-sexlinked genetic factor (dominant autosomal inheritance). In the presence of a normal karyotype it appears that a single dose of either a point mutatimqn, or a small deletion or translocation is the most likely cause.
13.
4.
5.
6.
17.
REFERENCES 1. LEWIS, S. M., SONNENBLICK,B. P., GILBERT, L. and BIBER, D. Familial pulmonary stenosis and deafmutism. Clinical and genetic considerations. Am. Heart J., 55: 458, 1958. 2. BRENT, L. B., ABURANO, A., FISCHER, D. L., MORAN, T. J., MYERS, J. D. and TAYLOR, W. J. Familial muscular subaortic stenosis. An unrecognized form of “idiopathic heart disease” with clinical and autopsy observations. Circulation, 21 : 167, 1960. 3. PARE, J. A. P., FRASER, R. G., PIROZYNSKI, W. J,. SHANKS, J. A. and STUBBINGTON, D. Hereditary cardiovascular dysplasia. Am. J. Mrd., 31: 37, 1961. 4. BRAUNWALD, E., LAMBREW, C. T., ROCKOFF, S. D., Ross, T., JR. and MORROW, A. G. Idiopathic hypertrophic subaortic stenosis. A description of the disease based upon an analysis of 64 patients. Circulation, vol. 30, supp. IV, 1964. 5. KRASNOW, N., ROLETT, E., HOOD, LV. B., JR., YURCHAK, P. M. and GORLIN, R. Reversible obstruction of the left ventricular outflow tract. Am. J. Cardiol., 11 : 1, 1963. 6. BROCKENBROUGW, E. C., BRAUNWALD, E. and MORROW, A. G. A hemodynamic technic for the detection of hypertrophic subaortic stenosis. Circulation, 23: 189, 1961. 7. MCKUSICK, V. A. A genetical view of cardiovascular disease. The Lewis A. Conner Memorial Lecture. Circulation, 30: 326, 1964. 8. HADDAD, H. M. and WILKINS, L. Congenital anomalies associated with gonadal aplasia. Review of 55 cases. Pediatrics, 23: 885, 1959. 9. ROWE, R. D. Cardiac malformations in mongolism. Am. Heart J., 64: 567, 1962. 10. BOOK, J. A., SANTESSON, B., and ZETTERQVIST, P. Association between congenital heart malformation and chromosomal variations. Acta pnediat., 50: 217, 1961. 11. SMITH, D. W., PATAW, K., THERMAN, E. and INHORN, S. L. A new autosomal trisomy syndrome. Multiple congenital anomalies caused by an extra chromosome. J. Pediat., 57: 338, 1960. 12. RUTSTEIN, D. D., NICKERSON, R. J. and HEALD, F. P. Seasonal incidence of patent ductus ar-
VOL.
40,
JANUARY
1966
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teriosus and maternal rubella. Am. .J. Di,r. Child.. 84: 199, 1952. CAMPBELL, M. Genetic and environmental factors in congenital heart disease. Quart. J. Med.. 18: 379,1949. Fox, M. J. and BORTIN, M. M. Rubella in pregnancy causing malformations in newborn. J. A. .M. A., 130: 568. 1946. AXDERSON, R. C. Causative factors underlying congenital heart malformations. I. Patent ductus arteriosus. Pediatrics, 14: 143, 1954. CARLETON, R. A., ABELMANN,W. H. and HANCOCK, E. W. Familial occurrence of congenital heart disease: report of three families and review of the literature. ,VPWEqland J. MPd., 259: 1237, 1958. COBLENTZ, B. and MATHIVAT, 4. Stenose pulmonaire congenitale chez deux socurs. Arch. mal. coeur, 45: 490, 1952. FOURNIER, A., PAGET, M., PAULI, A. and DEVIN, P. Syndromes nephrotiques familiaux. Syndrome nephrotique associe B une cardiopathie congenitale chez quatre soeurs. Pediatrk, 18: 677? 1963. HEINER, D. C. and NADAS, A. S. Patent ductus arteriosus in association with pulmonic stenosis. ?r report of six cases with additional non-cardiac congenital anomalies. Circulation, 17: 232, 1958. CAMPBELL, M. Factors in the aetiology of pulmonary stenosis. Bit. Heart J., 24: 625, 1962. LAMY, M., DEGROUCHY, J. and SCHWEISGIJTH, 0. Genetic and nongenetic factors in the etiology of con;enital heart disease. A study of 1188 cases. Am. J. Human. Cenet.. 9:17, 1957. TEARE, R. D. Asymmetrical hypertrophy of the heart in young adults. &it. Heart J., 20: 1, 1958. GOODWIN, J. F.. GORDON, H., HOLLMAN, A. and BISHIP, M. B. Clinical aspects of cardiomyopathy. Rrrt. M. J.. 1: 69, 1961. MENGES, H., JR., BRANDENBURG,R. 0. and BROWN. A. L., JR. The clinical, hemodynamic, and pathologic diagnosis of muscular subvalvular aortic stenosis. Circulation, 24: 1126, 1961. MORROW, A. G. and BRAUNWALD, E. Functional aortic stenosis: A malformation characterized by resistance to the left ventricular outflow without anatomic obstruction. Circulation, 20: 181, 1959. GOODWIN, J. F., HOLLMAN, A., CLELAND, W. P. and TEARE, D. Obstructive cardiomyopathy simulating aortic stenosis. Rrit. HPart J., 22: 403, 1960. BRACHFIELD, N. and GORLIN, R. Functional subaortic stenosis. Ann. Znt. Med., 54: 1, 1961. BRAUNWALD,E., MORROW, A. G., CORNELL, W. P., AYGEN, M. M. and HILBISH, T. F. Idiopathic hypertrophic subaortic stenosis. Am. J. Med., 29: 924, 1960. NEUFELD, H. N., ONGLEY, P. A. and EDWARDS, J. E. Combined congenital subaortic stenosis and infundibular pulmonary stenosis. &it. Heart J., 22: 686> 1960. ENGLE, M. A., TAMIKO, I. and GOLDBERT, H. P. The fate of the patient with pulmonic stenosis. Circulation, 30: 554, 1964.
Heart
and Associated Occurring
Disease, Deaf-Mutism Somatic
in Several
Malformations Members
of
One Family* GABRIEL
T. KOROXENIDIS,
CHRISTOS
B. MOSCHOS,
M.D., N. CONANT WEBB,
JR.,
M.D. and PATRICK H. LEHAN,
M.D., M.D.
Jersey City, New Jersey association of this syndrome with pulmonary valvular stenosis in one child suggests that the same mode of inheritance may be responsible for the transmission and aggregation of pulmonary stenosis in this family. The peripheral blood leukocyte chromosomes of the affected and some of the nonaffected members of the family were examined. No abnormality in the number of chromosomes was found and their morphology appeared to be normal.
herein is a unique family in which the mother and four of her eight children from two marriages have pulmonary valvular and/or infundibular stenosis in association with other cardiac and noncardiac malformations. In 1958 Lewis et al. [I] reported the results of right heart catheterizations on the two members of this family who had associated deaf-mutism. Since then another child has been born from a second marriage who also shows clinical evidence of pulmonary stenosis. This aggregation of congenital heart disease led to a genetic and hemodynamic re-evaluation of the whole family. In 1960 combined right and left heart catheterizations were performed in the mother and the four of her eight children who presented clinical evidence of heart disease. All were found to have valvular and/or infundibular pulmonary stenosis. One of the two deaf-mute children was found to have the syndrome of idiopathic ventricular hypertrophy with combined muscular outflow tract obstruction in addition to pulmonary valvular stenosis. Comparison of the hemodynamic data with those obtained four years earlier in two of the older children suggests progression of the severity of pulmonary stenosis. The aggregation of cardiac and noncardiac malformations in this family suggests a hitherto unreported form of inheritance of pulmonary valvular stenosis. Transmission by a single nonsex-linked genetic factor (dominant autosomal inheritance) has been described for familial idiopathic ventricular hypertrophy [Z-4]. The
D
ESCRIBED
CASE REPORTS CASE I. This thirty-nine year old Negro woman (A. W., m-2, P.H. No. 31718), para 8, gravida 8, was the product of a normal pregnancy and delivery. She had no family history of heart disease. She was found to have a heart murmur in early childhood, and her activities were restricted. She was asymptomatic through the pregnancies and until the age of thirtyseven when she began to experience mild exertional dyspnea. Physical examination revealed a cooperative, intelligent woman in no distress. The blood pressure was llOj65 mm. Hg in the arms and 140/80 mm. Hg in the legs. There was a slight cervicodorsal scoliosis. Examination of the heart showed the point of maximal impulse to be in the fifth intercostal space at the midclavicular line. There were no palpable thrills or lifts. The second sound at the base was normally split but the pulmonary component was decreased in intensity. The first sound at the lower left sternal border and at the apex was loud, followed by an ejection sound. A grade 3/6 ejection systolic murmur was best heard along the left sternal border. Fluoroscopy and barium swallow roentgenograms
* From the Division of Cardiovascular Diseases, Department of Medicine, and the Department of Preventive Medicine, New Jersey College of Medicine, and B. S. Pollak Hospital, Jersey City, New Jersey. This study was supported by Grants 5TIHE5510 and HE06376, National Heart Institute, U. S. Public Health Service and Hudson County Heart Association. Manuscript received April 22, 1965. VOL.
40,
JANUARY
1966
149
Congenital Heart Disease-Koroxenidis
150
el al.
TABLEI* HEMODYNAMIC
DATA
FROM
THE CATHETERIZATIONS
PERFORMED
IN
1956
AND
1960
Pressure Case No. t
Patient
A. W.
Year of Study
III-2
1956 1960
H. W. IV-2
1956 1960
B. W.
1956 1960
IV-G
P. w. w-8
IV-~ M.
Right Atrium
(mm. Hg)
Right Ventricle
Pulmonary Artery
Left Ventricle
10/5
38/3 36/2$
15/5 20/2
10278
102’/70
16j2
115/o 200/16§
12/6 36/4
20Glo
154/;0
20/4
60/O 125/15§
24/12 38/3
1960
13/4
150/12$
2114
105/11
1960
..
25111
105/45
118’/68
w.
-
42168
-
cardiomegaly.
The
pulmonary
artery
segment was not dilated. The electrocardiogram showed normal sinus rhythm with a mean QRS axis of +50 degrees in the frontal plane. There were deep S waves in leads Vr and VZ. There was no evidence of right ventricular hypertrophy. In November 1960 this patient underwent combined right and left heart catheterization. The results are given in Table I. She was found to have valvular pulmonary stenosis with a systolic gradient of 16 mm. Hg. CASE II. A fifteen year old Negro boy (H. W., IV-~, P.H. No. 31719), was the product of an uncomplicated pregnancy and low forceps delivery. He was the second child in the family and the first with congenital heart disease, which was discovered when he was two years old. He presented a feeding problem during infancy and his growth has been retarded. His exercise tolerance has been difficult to evaluate because of deaf-mutism. However, he seems to be fairly active. There have been no episodes of syncope, chest pains, cyanosis or frequent respiratory tract infections. Physical examination revealed a pleasant, deafmute boy with broad nasal root and slight asymmetry of the head and facial features. There was flattening of the left side of the occiput, hypertelorism, low set ears with hypoplastic auricular helices, mild cervicodorsal scoliosis, moderate pectus excavatum and hypoplastic fifth digits. The left testes was undescended, the right one was felt in the inguinal canal. There was no pubic hair. The precordium was hyperactive with the point of maximum impulse in the sixth intercostal space at the mid-clavicular line.
105156
. -
L
* Letters refer to the initials of the patients, the roman numerals refer to the generation identify the individual in each generation. t Present study. $ Valvular stenosis. Q Combined valvular and infundibular stenosis. 7 Infundibular stenosis. did not reveal
Aorta
and the arabic
numerals
There were both right and left ventricular heaves. A systolic thrill was felt along the upper left sternal border with radiation to the neck. The second sound at the base was normally split and the pulmonic component was decreased in intensity. A prominent atria1 sound was heard along the left sternal border. A third heart sound was heard at the apex. A grade 5/6 harsh, ejection systolic murmur was heard at the base and radiated to the neck bilaterally. A separate grade 2/6 holosystolic murmur was heard at the apex with radiation to the left axilla. The carotid upstroke was brisk. Fluoroscopy and barium swallow roentgenograms showed slight cardiomegaly with right ventricular and right atria1 enlargement. There was no poststenotic dilatation of either of the great vessels. The electrocardiogram showed normal sinus rhythm with a mean QRS axis of - 140 degrees. In lead Vr there was an Rs pattern with an R wave of 20 mm. and an S wave of 7 mm. when the patient was first examined in 1960. The T waves were deeply inverted. There were deep S waves in leads Vs and VS. The amplitude of the R wave decreased and became minimal from leads V4 to Vs and Vg. It was interpreted as showing right atria1 enlargement and systolic overloading of the right ventricle and possible left ventricular hypertrophy. A subsequent electrocardiogram obtained in 1963 showed further progression of these changes with larger P and R waves in lead VI. In November 1960 right heart catheterization was performed. A pullback tracing from the pulmonary artery revealed severe valvular and infundibular stenoAMERICAN
JOURNAL
OF
MEDICINE
Congenital
Heart
Disease-Koroxenidis
sis. A systolic gradient of 80 mm. Hg was found between the body and the outflow tract of the right ventricle, and an additional gradient of 84 mm. Hg between the infundibulum and the pulmonary artery. (Table I.) The catheter was advanced through an atria1 srptal defect into the left atrium and left ventricle. Simultaneous pressures from the left ventricle and brachial artery revealed a systolic gradient varying from 0 to 100 mm. Hg at different times during the study, a phenomenon reported to occur in idiopathic hypertrophic subaortic stenosis [4,5]. The brachial artery pressure pulse displayed a fast upstroke and the postextrasystolic beats demonstrated a narrowing of the pulse pressure (61. A left ventricular cineangiocardiogram confirmed the presence of muscular subaortic stenosis and moderate mitral insufficiency. The patient underwent surgery in January 1964, but only the right ventricular outflow obstruction was corrected. The left ventricle was a slit-like chamber with hypertrophied myocardium. CASE
III.
This
ten year
old Negro
girl
(B.
W.,
IV-~, P.H. No. 31720) was the product of an uncomplicated pregnancy and delivery. She was the fourth child in the family and the second with congenital heart disease. A heart murmur and deafness were recognized early in childhood. Growth and development were normal, but there were feeding problems in infancy. The patient tires easily and cannot keep up with other children of the same age. Physical examination revealed a well developed child with hypertelorism and deaf-mutism. The fifth digits were hypoplastic and there was overriding of the fifth toe bilaterally. The child had a broad nasal root, low set ears with hypoplastic auricular helices, pectus excavatum and mild cervicodorsal scoliosis. The external genitalia appeared normal. On examination of the heart, the point of maximum impulse was in the fifth intercostal space at the midclavicular line. A systolic thrill was felt along the upper left sternal border. The second sound at the base was single. A grade 4/6 harsh, ejection systolic murmur was heard along the upper left sternal border. Fluoroscopy and barium swallow roentgenograms did not reveal cardiomegaly. The electrocardiogram showed normal sinus rhythm and a mean QRS axis of f140 degrees in the frontal plane with clockwise rotation in the precordial leads and an rS pattern in leads Vi to VS. There was a decrease in the amplitude of the R wave from leads Vh to Vs and Vs. Right heart catheterization performed in November 1960 revealed moderately severe pulmonary stenosis with a systolic gradient of 87 mm. Hg and a definite infundibular chamber confirmed by withdrawal tracings and a right ventricular cineangiocardiogram. The oxygen saturation samples suggested a left-toright shunt at the atria1 level. CASE IV. IV-~, P.H. VOL.
40,
This five year old Negro girl (M. W., No. 31722) was the product of an uncomJANUARY
1966
plicated
pregnancy
151
Pt ul. and delivery.
She \vas the sixth
child in the family and the third with congenital
heart
disease that was discovered in infancy. Her growth and development have been normal but she tires easily and becomes dyspneic while playing. Physical examination revealed a well developed child who sho\l;ed hypertelorism, broad nasal root, low set ears with hypoplastic auricular helices, pectus excavatum, mild cervicodorsal scoliosis and hypoplastic fifth digits bilaterally. Hearing was normal. Examination of the heart showed a hyperactive precordium and a parasternal heave. A systolic thrill was felt along the upper left sternal border. The second sound at the base was single. A harsh grade 4,1’6 ejection systolic murmur was heard over the entire precordium but was maximal at the pulmonary area. Fluoroscopy and barium swallow roentgenograms showed right ventricular hypertrophy and moderate dilatation of the pulmonary artery segment. The electrocardiogram showed normal sinus rhythm with a mean QRS axis of +180 degrees in the frontal plane. In lead Vr there was an Rsr’ pattern with an R wave of 23 mm. and an S wave of 2 mm. There were deep S waves in leads Vz through Vi. There was a decrease in the amplitude of the R wave from leads Vs through Vs. The tracing was interpreted as showing right ventricular hypertrophy. Combined right and left heart catheterization performed in November 1960 showed a persistent left superior vena cava draining into the coronary sinus. A systolic gradient of 129 mm. Hg Jvas found at the pulmonary valvular level. No infundibular chamber was demonstrated. There were no aortic or mitral valve gradients. (Table I.) CASE v. A one and a half year old Negro boy (P. W., IV-~, P.H. No. 31724) was born to the same mother but by another father. He was the product of an uncomplicated pregnancy and delivery. A heart murmur was noted soon after birth. He was the eighth child in the family and the fourth with congenital heart disease. Physical examination revealed prominent frontal bossing, hypertelorism, broad nasal root and low set ears with hypoplastic auricular helices. The chest wall showed pectus carinatum. There were supernumerary sixth digits bilaterally. Hearing was normal. Examination of the heart revealed the point of maximum impulse to be at the fifth intercostal space within the mid-clavicular line. The second sound at the base was single. A grade 4;‘6 ejection systolic murmur was heard along the upper left sternal border. Chest roentgenograms did not shovv cardiomegaly. The electrocardiogram showed normal sinus rhythm with a mean QRS axis of + 110 degrees in the frontal plane. The precordial leads suggested neither right or left ventricular hypertrophy. Right heart catheterization performed in November 1960 indicated the presence of infundibular stenosis with a systolic gra-
152
Congenital
Heart
Disease-Koroxenidis
l&S
0
et al.
1p_7
MALE
El0
qs El8
IF8
OFEMALE
CONG. HEART DISEASE DEAF MUTISM SUPERNUMERARY
DIGITS
FIG. 1. Pedigree of family. dient of 17 mm. Hg between the main body and the outflow of the right ventricle. (Table I.) No valvular stenosis was demonstrated. COMMENTS
The pedigree of this family is given in Figure 1. Any relationship between the parents of the affected children seems unlikely since their ancestors come from different parts of the country. The first father had been married twice previously and none of his three children from those two marriages are known to have any cardiac abnormality. The second father had also been married previously and the one child from that marriage is not known to have any heart disease. The mother is the first from her family to have congenital pulmonary stenosis. None of her brothers or sisters is known to have any form of congenital malformations. She had eight children ; the last one from the second marriage. Four of these children had pulmonary valvular and/or infundibular stenosis. Two of the affected children born from the first marriage were also deaf-mutes and had evident hypertelorism. The pulmonary stenosis was associated in both
with an atria1 septal defect and in one of the two it was complicated by the presence of idiopathic ventricular hypertrophy with combined muscular outflow obstruction and mitral insufficiency. The youngest child, although born from a second marriage, also had a cardiac malformation. That this child had indeed a different father was also suggested by the fact that both the child and his father had identical supernumerary digits. While the etiology of some forms of congenital heart disease, such as those associated with Turner’s and Down’s syndrome, is clearly chromosomal [7-l 7 1, in the vast majority of cases the etiology is less certain. When a chromosomal abnormality is not demonstrable, proof of a genetic etiology requires familial aggregation and exclusion of environmental factors known to play a role [ 72-751. Evidence for environmental factors such as viral infections during the first trimester of pregnancy and threatened abortions was not found in this family. Carleton et al. [76] have collected and reviewed the reports of multiple familial congenital heart disease described in the literature since AMERICAN
JOURNAL
OF
MEDICINE
Congenital
Heart
I)isease~E;oroxprlidis
1941. There was no report of a family in which more than two members of the same generation were affected with pulmonary stenosis or in which the disease was present in two successive generations. Coblentz and Mathivat [77] reported the presence of pulmonary stenosis in two sisters. Fournier et al. [7S] recently described a family in which four of five children had clinical and/‘or autopsy evidence of pulmonary stenosis and congenital nephrotic syndrome. The present family is the only one in which more than one generation is known to be affected with pulmonary stenosis. Heiner and Nadas [79] reported that in pulmonary stenosis without patent ductus arteriosus, the occurrence of somatic malformations is unusual. In the family discussed here, several somatic malformations were observed in the children affected with pulmonary stenosis. Hypertelorism, broad nasal root and low set ears with flattened auricular helices were present in all the affected children. The first deaf-mute child (Case II) also had undescended testicles, absent public hair, hypoplastic fifth digits, asymmetrical development of the cranial bones with acrocephalia and flattened occiput on the left side. The second deaf-mute child (Case III) had hypoplastic fifth digits, pectus excavatum, scoliosis of the vertebral column and overriding of the fifth toe bilaterally. The third affected child (Case IV) had pectus excavatum, cervicodorsal scoliosis and hypoplastic fifth digits. The last child (Case v) had pectus carinatum and supernumerary digits that were also present in his father. The rest of the children without heart disease had no obvious somatic malformations. Campbell [20], in a review of 125 cases of pulmonary stenosis, found the incidence of noncardiac malformations to be 13 per cent. He suggested that such findings as well as the high incidence of pulmonary stenosis in consanguineous marriages are consistent with a genetic effect. Lamy et al. [27] reported fifty-six children with pulmonary stenosis. In two cases the child’s parents were first cousins. This is significantly different (~~0.05) than their controls would lead one to expect, suggesting a recessive form of pulmonary stenosis. Furthermore, they found one sib of 107 (the fifty-six children had 107 sibs) who also had pulmonary stenosis; this, too, is unlikely to be a chance occurrence. In any event, their evidence for two doses inheritance (consanguinity) may not be relevant here, as only- one of the fifty-six families had a second VOL.
40,
JANUARY
1966
rt al.
153
case of pulmonary stenosis, none of the families had an affected parent and child pair, and they do not report infundibular stenosis either alone or in association with valvular stenosis. The striking aggregation in the present family. of pulmonary stenosis and several other somatic malformations, and the presence of the disease in two generations (the mother and four of her eight children) despite two unrelated husbands, indicate that the mother has received and transmitted abnormal genetic material. Multifactorial inheritance is thought to be unlikely. That four of her eight children are affected is consistent with her being heterozygous for the genetic defect. It appears that transmission of a single dose of the abnormal genetic material can cause heart disease in her children. This type of transmission is consistent with trisomy or a single dose of a translocation, deletion or point mutation. However, we do not know of a trisomic or translocation syndrome with these manifestations. The finding of forty-six morphologically normal chromosomes in the mother and the children suggests that a point mutation is the most likely abnormality although a small translocation or deletion cannot be excluded. The deaf-mutism could be part of a single genetic syndrome involving congenital heart disease with variable expressivity for deafness, or it could be separate. Roentgenograms of the skull did not reveal any abnormality of the bony structure of the auditory canal. Deafness occurred in only two of the seven children from the first marriage. This is consistent with variable expression of an autosomal dominant trait that produces congenital heart disease as well. It is also consistent with the most common kind of genetic deafness which is transmitted as a Mendelian recessive. The lack of parental consanguinity is not strongly against recessive inheritance of deafness as consanguinity is common only when a recessive gene is rare. The absence of deafness in the parents and other ancesters is perfectly consistent with separate recessive deafness. In short, the deafness is more likely to be a variably expressed part of the cardiac syndrome than independent of it, but this is far from proved. The finding of muscular subaortic stenosis in the first child is of interest. It is conceivable that hypertrophy of the septum secondary to the pulmonary stenosis led to progressive obstruction of the left ventricular outflow and development of subaortic stenosis. However, the asso-
154
Congenital
Heart
Disease-Koroxenidzs
ciation of mitral insufficiency and the finding at surgery of an extremely thick left ventricular wall makes it more likely that the case belongs to the syndrome of idiopathic hypertrophic subaortic stenosis. In the rest of the affected children there was no evidence of left ventricular outflow obstruction. However, exercise and Isuprel@ were not used during the catheterizations. In cases of idiopathic hypertrophic subaortic stenosis, the use of exercise or Isuprel has been shown to bring out a dynamic obstruction which may be absent at rest [4,5]. Teare [Z], in an autopsy study, has described eight cases of “asymmetrical hypertrophy of the ventricular septum in young adults.” All were characterized by massive hypertrophy of the ventricular septum of unknown etiology. Since then similar cases have been described by several workers in which hypertrophy of the septum and the derangement of the muscle bands caused subaortic stenosis and/or associated mitral insufficiency [4,23,24]. However, in some cases, there was associated mild or even predominant right ventricular outflow obstruction [25-281. There has been considerable speculation concerning the acquired or congenital nature of this anomaly. Evidence that the disease is, at least in some instances, congenital is provided by the report of Neufeld et al. [29], who described autopsy findings in two babies with idiopathic hypertrophic stenosis and obstruction to both ventricular outflows. In this case the association of idiopathic subaortic stenosis with congenital pulmonary valvular stenosis and atria1 septal defect indicates that the subaortic stenosis is also probably congenital. A familial form of idiopathic hypertrophic subaortic stenosis has been described, and several reports have been concerned with the occurrence of the disease in several members of a family in one or more generations. Brent [2] has suggested that the disease is inherited as a dominant autosomal (non-sex-linked) Mendelian trait. Braunwald [4] has suggested that the disease occurs either as a congenital nonfamilial or as a familial noncongenital form. An acquired nonfamilial form is also described. The occurrence of the disease in a family in which the other siblings had a different form of congenital disease is unknown to us. The finding of idiopathic hypertrophic subaortic stenosis in one of the children of this family suggests that a congenital hereditary form of the disease also exists which can produce pulmonary valvular stenosis as well.
et al.
Comparison of the hemodynamic data of this study with those of the study performed four years previously indicate that the pulmonary stenosis has not progressed in the mother. During the first study the mother was found to have a right ventricular systolic pressure of 38 mm. Hg. Four years later the pressure was unchanged, indicating that the pulmonary stenosis remained mild during this period. In contrast, there is evidence of considerable progression of the disease in the two older children, who have been studied twice. The oldest affected child (Case II) had a right ventricular systolic pressure of 115 mm. Hg initially, indicating moderate pulmonary stenosis. Four years later the pressure in the right ventricle had increased to 200 mm. Hg, indicating progression from moderate to severe pulmonary stenosis. The second child (Case III) was found initially to have mild pulmonary stenosis with a right ventricular pressure of 60 mm. Hg. Over the period of four years the stenosis became moderately severe as the pressure increased to 125 mm. Hg. It is realized that such comparison of the data may not be absolutely valid since data on left heart pressures and cardiac outputs are not available from the first study and the ratio of the right to left heart pressures is not known. However, in view of the considerable increase in right ventricular pressures and further progression of the electrocardiographic findings, it is considered that the disease has indeed become more severe. These findings are consistent with the opinion expressed by Engle et al. [30] concerning the evolution of pulmonary stenosis. They state that pulmonary stenosis may become progressively more severe as the child grows but whether the disease will progress or remain stable cannot be predicted in any individual patient. The mother and the second child (Case III) had mild pulmonary stenosis from childhood ; in the mother the disease remained stable whereas in the child it progressed rapidly over the period of four years to become moderately severe. It is not known whether this progression means that the valvular orifice actually becomes smaller or only in relation to the growth of the heart and the increased cardiac output accompanying general body growth. SUMMARY
A unique family is described in which the mother and four of her eight children have pulmonary stenosis. Two of the four affected chil-
Congenital
Heart
disease---l;oroxPnidis
drcn are deaf-mutes; one of these has, in addition to the pulmonary valvular stenosis, idiopathic hypertrophic subaortic stenosis. All the affected children had several associated somatic malformations. Genetic and nongenetic factors and their role in the development of the malformations are discussed. It is suggested that the cardiac defect is transmitted by a single non-sexlinked genetic factor (dominant autosomal inheritance). In the presence of a normal karyotype it appears that a single dose of either a point mutatimqn, or a small deletion or translocation is the most likely cause.
13.
4.
5.
6.
17.
REFERENCES 1. LEWIS, S. M., SONNENBLICK,B. P., GILBERT, L. and BIBER, D. Familial pulmonary stenosis and deafmutism. Clinical and genetic considerations. Am. Heart J., 55: 458, 1958. 2. BRENT, L. B., ABURANO, A., FISCHER, D. L., MORAN, T. J., MYERS, J. D. and TAYLOR, W. J. Familial muscular subaortic stenosis. An unrecognized form of “idiopathic heart disease” with clinical and autopsy observations. Circulation, 21 : 167, 1960. 3. PARE, J. A. P., FRASER, R. G., PIROZYNSKI, W. J,. SHANKS, J. A. and STUBBINGTON, D. Hereditary cardiovascular dysplasia. Am. J. Mrd., 31: 37, 1961. 4. BRAUNWALD, E., LAMBREW, C. T., ROCKOFF, S. D., Ross, T., JR. and MORROW, A. G. Idiopathic hypertrophic subaortic stenosis. A description of the disease based upon an analysis of 64 patients. Circulation, vol. 30, supp. IV, 1964. 5. KRASNOW, N., ROLETT, E., HOOD, LV. B., JR., YURCHAK, P. M. and GORLIN, R. Reversible obstruction of the left ventricular outflow tract. Am. J. Cardiol., 11 : 1, 1963. 6. BROCKENBROUGW, E. C., BRAUNWALD, E. and MORROW, A. G. A hemodynamic technic for the detection of hypertrophic subaortic stenosis. Circulation, 23: 189, 1961. 7. MCKUSICK, V. A. A genetical view of cardiovascular disease. The Lewis A. Conner Memorial Lecture. Circulation, 30: 326, 1964. 8. HADDAD, H. M. and WILKINS, L. Congenital anomalies associated with gonadal aplasia. Review of 55 cases. Pediatrics, 23: 885, 1959. 9. ROWE, R. D. Cardiac malformations in mongolism. Am. Heart J., 64: 567, 1962. 10. BOOK, J. A., SANTESSON, B., and ZETTERQVIST, P. Association between congenital heart malformation and chromosomal variations. Acta pnediat., 50: 217, 1961. 11. SMITH, D. W., PATAW, K., THERMAN, E. and INHORN, S. L. A new autosomal trisomy syndrome. Multiple congenital anomalies caused by an extra chromosome. J. Pediat., 57: 338, 1960. 12. RUTSTEIN, D. D., NICKERSON, R. J. and HEALD, F. P. Seasonal incidence of patent ductus ar-
VOL.
40,
JANUARY
1966
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rt al.
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