Echocardiographic Studies
of Left Ventricular Disease in Ullrich-Noonan Syndrome James J. Nora, MD; Randall H. Lortscher, MD; Richard D.
Echocardiography has been used for cardiovascular evaluation of individuals and families with Ullrich-Noonan syndrome. Previously undiagnosed left ventricular disease has been found as a discrete lesion or in association with other cardiac abnormalities. This raises the estimated frequency of heart disease in the Ullrich-Noonan syndrome to about 50%. Since left ventricular disease in this syndrome may not be entirely typical of asymmetric septal hypertrophy, caution should be exercised in the echocardiographic diagnosis. To date, one notable difference between the echocardiograms in these patients and other patients with asymmetric septal hypertrophy is the absence of systolic anterior motion of the mitral valve. Since the most common cardiac lesion in the Ullrich-Noonan syndrome is pulmonary stenosis, the potential for septal thickening produced by severe pulmonary stenosis must also be taken into account. (Am J Dis Child 129:1417-1420, 1975) \s=b\
The
Ullrich-Noonan syndrome (Noonan syndrome, Turner phenotype) is becoming more widely rec¬ ognized and may be one of the most common of Mendelian disorders. We have recently reviewed our series of 81 patients1 and have described clini¬ cal features and cardiovascular ab¬ normalities found in this syndrome. The clinical features are briefly summarized below. Clinical Features Characteristic facies Short stature
Abnormal ears Undescended testes
Eye problems (eg, ptosis) Low posterior hairline Cubitus valgus
% of Patients 100 83 78 72 (of males) 58 57 54
Received for publication Sept 23, 1974; acDec 20. From the Department of Pediatric Cardiology (Dr Nora), the Department of Pediatrics (Dr Lortscher), and the Department of Medicine (Dr Spangler), the University of Colorado Medical Center, Denver. Reprint requests to the Director of Pediatric Cardiology, University of Colorado Medical Center, 4200 E Ninth Ave, Denver, CO 80220 (Dr
Spangler,
MD
Cardiovascular disorders 50 48 Webbed neck Hand (eg, clinodactyly) 35
A variety of cardiovascular dis¬ orders were encountered, the most
commonly reported being pulmonary stenosis (with or without atrial septal defect). The next most frequent heart problem in our series was left ventric¬ ular disease, first reported by Ehlers and colleagues2 as eccentric left ven¬ tricular hypertrophy. Whether this left ventricular disease properly be¬ longs in the continuum from asym¬ metric septal hypertrophy to idiopathic hypertrophie subaortic stenosis or represents another entity is ques¬
tionable. It is this disease that is most likely to go unrecognized clinically, and yet is most accessible to echo¬ cardiographic evaluation. Because septal hypertrophy is so common in this form of left ventricular disease, we have used (with reservations to be discussed) the term "asymmetric sep¬ tal hypertrophy" to describe our pa¬ tients' conditions. In this study we have asked the fol¬ lowing questions: (1) How common is asymmetric septal hypertrophy in Ullrich-Noonan syndrome? (2) How frequently does asymmetric septal hypertrophy occur in patients with other cardiovascular diagnoses? (3)
Does unsuspected asymmetric septal hypertrophy, which can be detected by echocardiogram, occur with sufficient frequency in these patients to repre¬ sent a legitimate clinical concern? (4) Finally, does the discovery of a sym¬ metric septal hypertrophy increase the true frequency rate of congenital heart disease in this syndrome?
cepted
SUBJECTS AND METHODS
Nora).
Echocardiographic studies were per¬ formed on 38 individuals from the families of 15 probands with Ullrich-Noonan syn¬ drome. Thirteen first-degree relatives who had Ullrich-Noonan stigmas and ten firstdegree relatives who did not were also studied echocardiographically. The 15 pro-
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were referred by the pediatrie cardi¬ ology service of the University of Colorado Medical Center, Colorado General Hospi¬ tal, and Children's Hospital, 12 for possible
bands
cardiovascular disease and three for eval¬ uation of Ullrich-Noonan stigmas. At least one first-degree relative of a proband with Ullrich-Noonan stigmas was studied in 11 of the 15 families. Eleven of the subjects in this report were not included in our earlier series of 81 patients, the studies were ob¬ tained by means of an ultrasonoscope and 2.25-, 2.50-, and 3.0-MHz focused trans¬ ducers with 9-mm crystals. The scanning plane was slightly inferior to the mitral leaflets and permitted comparison of the septum with the posterobasal free wall of the left ventricle (LV). Measurements were made at the end of diastole. The criteria for septal hypertrophy will be elaborated in the "Comment" section; they included septal thickness 50% above the upper limits of normal for weight or body surface area.'
RESULTS
patients (32%) with Ull¬ syndrome had echo¬ cardiographic evidence of left ven¬ tricular hypertrophy, most often de¬ tectable as asymmetric septal hypertrophy, but also involving the Nine of 28 rich-Noonan
1 and 2). The mean wall in the nine pa¬ ratio septal-LV tients whose conditions were diag¬ nosed as asymmetric septal hyper¬ trophy was 1.44:1. All patients except two had a septal-LV wall ratio greater than 1.3:1. The mean percent¬ age increase in septal thickness above the upper limits of normal for weight or body surface area was 62%. Five of 12 patients (42%) referred for cardiac evaluation had asymmetric septal hy¬ pertrophy alone or in combination with other heart diseases. Six of the nine patients with asymmetric septal hypertrophy had cardiac catheterization and angiocardiographic con¬ firmation of this diagnosis. Three of the probands (or first-de¬ gree relatives) who had asymmetric septal hypertrophy also had another
free wall
(Tables
heart disease and four of whom (25%) had asymmetric septal hypertrophy alone or in combination with another cardiac problem.
Table 1.—Cardiac Disease in Ullrich-Noonan Families Studied by Echocardiography
Cardiac Status ASH* suspected ASH not suspected ASH + other CHD*
Probands
First-Degree Relative With Ullrich-Noonan
First-Degree Relative Without Ullrich-Noonan
Syndrome
Syndrome
Total
suspected ASH + other CHD not suspected Other CHD No heart disease Total '
15
11 18 38
10 10
13
ASH indicates asymmetric septal hypertrophy; CHD, congenital heart disease.
Table 2.—Clinical and Echocardiographic Findings in 28 Patients with Ullrich-Noonan Syndrome
Patient/Age (yr)/Sex 1V14/M 2/12/M 3/41/F 4V12/M 5/8/F 6/33/F 7V4/M 8V7/F 9V9/M 10/44/F 11V11/M 12/12/M 13V13/F
Septal-LV Wall Ratio 1.5 1.2 1.4 1.5 1.4 1.4 1.2 2.1 1.3 0.9 0.9 1.0 0.9
Septal Thickness,
Cardiovascular
Defecrf & WPW
1.5 1.6 1.6 1.5 1.1 1.8 1.4 1.6 1.1 1.0 0.7 0.8 0.7
ASH ASH ASH ASH ASH ASH ASH ASH ASH
0.6 1.2 0.9 0.6 0.7 0.6 1.3 0.6 1.1 0.6 0.8 1.0 0.7 1.0 0.7
PS PS PS PS & ASD VSD PS AS None None None None None
Catheterization & Angiography
Coronary fistula
Yes Yes No Yes Yes No Yes No Yes Yes
PS & ASD WPW Parachute mitral
Yes No Yes
& AV canal & PS
& PS
complex 14/9/F 15V12/M 16V13/M 17V5/M 18V6/M 19/6/F 20V8/M 21V4/M 22/44/F 23/4/F 24V12/M 25/29/F 26V9/M 27/33/F 28/7/F *
0.9 1.4
1.1 0.8
1.1 0.9 1.0 1.0 1.0 1.0
0.9 0.9 1.0 1.1 1.0
None None None
Yes Yes Yes Yes Yes Yes Yes No No No No No No No No
Proband.
t PS Indicates pulmonary stenosis; AV, atrioventricular; VSD,
ventricular septal defect; WPW, Wolff-Parkinson-White syndrome; AS, aortic stenosis; and ASD, atrial septal defect.
cardiovascular malformation. None of these were suspected clinically of hav¬
ing asymmetric septal hypertrophy until echocardiography was per¬ formed. Three of the six patients who had asymmetric septal hypertrophy with
no
were
not
other cardiovascular lesion thought to have cardiac ab¬ normalities prior to echocardiog¬
raphy.
The ten first-degree relatives who did not have Ullrich-Noonan stigmas also had no echocardiographic evi¬ dence of asymmetric septal hyper¬ trophy. An approximation of the fre¬ quency rate of heart disease in the Ullrich-Noonan syndrome would have to exclude the probands referred spe¬ cifically for heart disease. This leaves 16 patients, eight of whom (50%) had
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COMMENT
The answers to the questions posed by this study depend on the echo¬ cardiographic diagnosis of left ven¬ tricular disease. Figure 1 shows an echocardiogram and angiocardiogram of a typical patient with UllrichNoonan syndrome and left ventricu¬ lar involvement. Commonly accepted criteria for asymmetric septal hyper¬ trophy in patients without UllrichNoonan syndrome include the septalLV wall thickness ratio equal to or greater than 1.3:1 and systolic ante¬
rior motion of the mitral valve. Other useful observations also involve the septum, the mitral valve, and left ventricular chamber size. The septal motion, amplitude of excursion, sys¬ tolic thickening,4 and the measure¬ ment of septal thickness compared with normal values for weight or body surface area must also be con¬ sidered. In all but two cases, our patients had a thickened septum, with a sep¬ tal-LV wall ratio greater than 1.3:1. The thickness exceeded the upper lim¬ its of normal for weight and body surface area by more than 50%. How¬ ever, none of our patients have yet shown systolic anterior motion, a hall¬ mark of asymmetric septal hyper¬ trophy. It should be noted that Henry and associates' have found patients who have other clear evidence of asymmetric septal hypertrophy in the absence of systolic anterior motion of the mitral valve (which appears with the progression of outflow obstruc¬ tion). Figure 2 illustrates the typical appearance of systolic anterior mo¬ tion in a patient with asymmetric septal hypertrophy who does not have Ullrich-Noonan syndrome. Allen et al6 have raised the ques¬ tion (in response to our earlier re¬ port1) that septal involvement sec¬ ondary to pulmonary stenosis may be the true cause of asymmetric septal hypertrophy in patients who have both lesions. Pulmonary hyperten¬ sion7 has been shown to produce echo¬ cardiographic evidence of asymmetric septal hypertrophy, and pulmonary valve stenosis theoretically could
Fig 1.—Left, Typical echocardiogram of 10-year-old boy with Ull¬ rich-Noonan syndrome and left ventricular disease. Note absence of systolic anterior motion of the mitral valve. Angiocardiographic confirmation is given in anteroposterior (center) and lateral a similar abnormality. We have two patients with echo¬ cardiographic and angiocardiographic findings of asymmetric septal hyper¬ trophy and pulmonary stenosis. (In our three other previously described cases of these conditions, we have only angiocardiograms.) In this series, no patient with clinical evi¬ dence of pulmonary stenosis is in¬ cluded who did not have cardiac catheterization and angiocardiography. Figure 3 shows the echocardiogram of a patient with Ullrich-Noonan syn¬ drome who has severe pulmonary ste¬ nosis (gradient of 80 mm Hg at rest and 120 mm Hg with exercise) but does not have angiocardiographic evi¬ dence of asymmetric septal hyper¬ trophy. The septal-LV ratio is 1.4:1. However, the relatively normal septal excursion and systolic thickening shown in Fig 3 and in other views from this patient (and the absence of systolic anterior motion if the patient did not have Ullrich-Noonan syn¬ drome) might restrain the physician from diagnosing asymmetric septal hypertrophy without further study. As in this case, cardiac catheterization may be required not only to define the severity of the pulmonary stenosis, but to assess the possibility of associated left ventricular disease. Asymmetric septal hypertrophy is an early finding of the left ventricu¬ lar disease of the asymmetric septal
produce now
hypertrophy
to
idiopathic hyper-
(right) views of left ventricular hypertrophy. Note small ventricular cavity size and concentrically thickened ventricular wall. (IVS in¬ dicates interventricular septum; AMVL, anterior mitral valve leaf¬ let; and LVW, left ventricular free wall.)
trophic
subaortic stenosis continuum. The first description of the left ven¬ tricular disease in Ullrich-Noonan syndrome emphasized the free-wall deformity in these patients, namely the superolateral and posteroinferior inward bulging. These abnormalities, especially those located posteroin-
feriorly,
are
not
as
readily
acces¬
sible to echocardiographic evaluation as is septal thickening. Fortunately, septal hypertrophy is an indicator present in all of the patients in our series; in fact, a 1.3:1 septal-LV wall ratio, diagnostic of asymmetric septal hypertrophy, was found in all but two of our patients with left ventricular disease. Angiocardiographically, our patients most commonly have had findings of concentric hypertrophy and outflow obstruction rather than eccentric hypertrophy, whereas the patients in the series of Ehlers et al2 had eccentric hypertrophy. Although we suspect that all of these patients may fit into the asymmetric septal
hypertrophy to idiopathic hypertrophic subaortic stenosis continuum of disease, we have yet to see a case of eccentric hypertrophy progress to concentric disease in the way a case of asymmetric septal hypertrophy may progress.
All of our probands and the major¬ ity of our patients are children, so the findings of the disease may be less advanced than in adults in whom the disease has had the opportunity to
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longer course. However, since asymmetric septal hypertrophy is a progressive disease, it is useful to try to recognize its presence at the earliest stage at which the diagnosis may be made with confidence, and it is equally valuable to follow by echocardiography the progression (or sta¬ bility) of the disease. The noninvasive nature of echocardiography makes this a particularly desirable tech¬ nique. Because patients with UllrichNoonan Syndrome are at high risk of having heart disease, it would be pru¬ dent to follow up, with periodic echocardiograms, those who initially may run a
have had normal
or
borderline find¬
ings.
In family studies, if the phenotypic stigmas in a given individual are of a
borderline nature, the echocardiographic demonstration of somewhat
asymmetric septal hypertrophy not only helps to establish the diagnosis, but provides a basis for genetic coun¬ seling and treatment of the patient. To answer the specific questions we
raised, let
us
first try to suggest how
asymmetric septal hyper¬ trophy may be in Ullrich-Noonan syn¬ drome. Sixteen family members with stigmas of Ullrich-Noonan syndrome common
who were not referred for cardio¬ vascular evaluation were studied echocardiographically. Four of these patients (25%) had asymmetric septal hypertrophy alone or in combination with other heart lesions. Thus, 25%
Fig 2.—Typical echocardiographic findings in patient with asymmetric septal hypertrophy but without Ullrich-Noonan syndrome. Note thick¬ ened ventricular septum and cardinal findings of systolic anterior mo¬ tion of mitral valve (arrows). (PLVW indicates posterior left ventricular wall.) may be offered
as a
current
approxi¬
mation of the frequency of this condi¬ tion in individuals having UllrichNoonan stigmas.
Twenty patients
or
first-degree
relatives with Ullrich-Noonan stig¬ mas had heart disease of some type. Eleven of the patients had heart lesions other than asymmetric septal hypertrophy (most often pulmonary stenosis), six had asymmetric septal hypertrophy alone, and in three cases it was not suspected. Three patients had asymmetric septal hypertrophy in addition to other cardiovascular anomalies, and in none of these cases was it suspected prior to echocardiography or cardiac catheterization. Therefore, three of 14 pa¬ tients in this study (21%) who had other cardiovascular diagnoses also had asymmetric septal hypertrophy. This figure applies exclusively to this study and does not include some pa¬ tients from earlier studies who have possibly had asymmetric septal hy¬ pertrophy with other cardiac defects (established at cardiac catheterization), but did not have echo¬ cardiographic evaluation. Again, the sample is small, but it provides an ap¬ proximation that may be clinically useful. It appears that about 20% of patients with Ullrich-Noonan syn-
drome and cardiovascular
Fig 3.—Echocardiogram of 12-year-old boy with severe pulmonary stenosis, but without hemodynamic or angio¬ cardiographic evidence of left ventricular disease, could be interpreted as asymmetric septal hypertrophy because of the septal-LV ratio of 1.4:1.
diagnoses of other disease
may
have
unsuspected asymmetric septal hypertrophy as well. That six of our nine patients with this condition were not suspected clinically of hav¬ ing the diagnosis prior to a specific search for the abnormality suggests that unsuspected asymmetric septal hypertrophy represents a legitimate for concern. The overall frequency rate of heart disease of all types in Ullrich-Noonan syndrome has been previously esti¬ mated by us at 35%' on the basis of examination of relatives and elimi¬ nating probands referred because of heart disease. We have now shown that there is a great deal of unsus¬ cause
pected asymmetric septal hyper¬ trophy in Ullrich-Noonan syndrome that may be detected by echocardiography. Many of our previously described patients (some seen as long as a decade ago) did not have echo¬ cardiographic examination. Exclud¬ ing those patients referred specifi¬ cally for cardiac disorders, 50% of individuals in this study with UllrichNoonan stigmas had some form of
cardiovascular disease, and we are in¬ clined to believe that 50% more closely approximates the frequency rate of heart disease in this syn-
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drome. Within this high-risk group, left ventricular disease is a serious, po¬ tentially life-threatening, and fre¬ quently unsuspected feature of Ull¬ rich-Noonan syndrome, which may be detected and followed up longitudi¬
nally by echocardiography.
This investigation was supported by grant 05981 from the National Heart and Lung Insti¬ tute and a project grant from the Junior League of Denver and the Vida Francis Ellison Trust, Denver.
References 1. Nora JJ, Nora AH, Sinha AK, et al: The Ullrich-Noonan syndrome (Turner phenotype). Am J Dis Child 127:48-55, 1974. 2. Ehlers KH, Engle MA, Levin AR, et al: Eccentric ventricular hypertrophy in familial and sporadic instances of 46 XX,XY Turner phenotype. Circulation 45:639-652, 1972. 3. Feigenbaum H: Echocardiography. Philadelphia, Lea & Febiger Publishers, 1973. 4. Tajik AJ, Giuliani ER: Echocardiographic observations in idiopathic hypertrophic subaortic stenosis. Mayo Clin Proc 49:89-97, 1974. 5. Henry WL, Clark CE, Epstein SE: Asymmetric septal hypertrophy: Echocardiographic identification of the pathognomonic anatomic abnormality of IHSS. Circulation 47:225-233, 1973. 6. Allen HD, Larter WE, Goldberg SJ: The Ullrich-Noonan syndrome. Am J Dis Child 128:115, 1974. 7. Brown OR: Echocardiographic study of right ventricular hypertension producing asymmetric septal hypertrophy. Circulation 48(suppl 5):47, 1973.
of Left Ventricular Disease in Ullrich-Noonan Syndrome James J. Nora, MD; Randall H. Lortscher, MD; Richard D.
Echocardiography has been used for cardiovascular evaluation of individuals and families with Ullrich-Noonan syndrome. Previously undiagnosed left ventricular disease has been found as a discrete lesion or in association with other cardiac abnormalities. This raises the estimated frequency of heart disease in the Ullrich-Noonan syndrome to about 50%. Since left ventricular disease in this syndrome may not be entirely typical of asymmetric septal hypertrophy, caution should be exercised in the echocardiographic diagnosis. To date, one notable difference between the echocardiograms in these patients and other patients with asymmetric septal hypertrophy is the absence of systolic anterior motion of the mitral valve. Since the most common cardiac lesion in the Ullrich-Noonan syndrome is pulmonary stenosis, the potential for septal thickening produced by severe pulmonary stenosis must also be taken into account. (Am J Dis Child 129:1417-1420, 1975) \s=b\
The
Ullrich-Noonan syndrome (Noonan syndrome, Turner phenotype) is becoming more widely rec¬ ognized and may be one of the most common of Mendelian disorders. We have recently reviewed our series of 81 patients1 and have described clini¬ cal features and cardiovascular ab¬ normalities found in this syndrome. The clinical features are briefly summarized below. Clinical Features Characteristic facies Short stature
Abnormal ears Undescended testes
Eye problems (eg, ptosis) Low posterior hairline Cubitus valgus
% of Patients 100 83 78 72 (of males) 58 57 54
Received for publication Sept 23, 1974; acDec 20. From the Department of Pediatric Cardiology (Dr Nora), the Department of Pediatrics (Dr Lortscher), and the Department of Medicine (Dr Spangler), the University of Colorado Medical Center, Denver. Reprint requests to the Director of Pediatric Cardiology, University of Colorado Medical Center, 4200 E Ninth Ave, Denver, CO 80220 (Dr
Spangler,
MD
Cardiovascular disorders 50 48 Webbed neck Hand (eg, clinodactyly) 35
A variety of cardiovascular dis¬ orders were encountered, the most
commonly reported being pulmonary stenosis (with or without atrial septal defect). The next most frequent heart problem in our series was left ventric¬ ular disease, first reported by Ehlers and colleagues2 as eccentric left ven¬ tricular hypertrophy. Whether this left ventricular disease properly be¬ longs in the continuum from asym¬ metric septal hypertrophy to idiopathic hypertrophie subaortic stenosis or represents another entity is ques¬
tionable. It is this disease that is most likely to go unrecognized clinically, and yet is most accessible to echo¬ cardiographic evaluation. Because septal hypertrophy is so common in this form of left ventricular disease, we have used (with reservations to be discussed) the term "asymmetric sep¬ tal hypertrophy" to describe our pa¬ tients' conditions. In this study we have asked the fol¬ lowing questions: (1) How common is asymmetric septal hypertrophy in Ullrich-Noonan syndrome? (2) How frequently does asymmetric septal hypertrophy occur in patients with other cardiovascular diagnoses? (3)
Does unsuspected asymmetric septal hypertrophy, which can be detected by echocardiogram, occur with sufficient frequency in these patients to repre¬ sent a legitimate clinical concern? (4) Finally, does the discovery of a sym¬ metric septal hypertrophy increase the true frequency rate of congenital heart disease in this syndrome?
cepted
SUBJECTS AND METHODS
Nora).
Echocardiographic studies were per¬ formed on 38 individuals from the families of 15 probands with Ullrich-Noonan syn¬ drome. Thirteen first-degree relatives who had Ullrich-Noonan stigmas and ten firstdegree relatives who did not were also studied echocardiographically. The 15 pro-
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 06/20/2015
were referred by the pediatrie cardi¬ ology service of the University of Colorado Medical Center, Colorado General Hospi¬ tal, and Children's Hospital, 12 for possible
bands
cardiovascular disease and three for eval¬ uation of Ullrich-Noonan stigmas. At least one first-degree relative of a proband with Ullrich-Noonan stigmas was studied in 11 of the 15 families. Eleven of the subjects in this report were not included in our earlier series of 81 patients, the studies were ob¬ tained by means of an ultrasonoscope and 2.25-, 2.50-, and 3.0-MHz focused trans¬ ducers with 9-mm crystals. The scanning plane was slightly inferior to the mitral leaflets and permitted comparison of the septum with the posterobasal free wall of the left ventricle (LV). Measurements were made at the end of diastole. The criteria for septal hypertrophy will be elaborated in the "Comment" section; they included septal thickness 50% above the upper limits of normal for weight or body surface area.'
RESULTS
patients (32%) with Ull¬ syndrome had echo¬ cardiographic evidence of left ven¬ tricular hypertrophy, most often de¬ tectable as asymmetric septal hypertrophy, but also involving the Nine of 28 rich-Noonan
1 and 2). The mean wall in the nine pa¬ ratio septal-LV tients whose conditions were diag¬ nosed as asymmetric septal hyper¬ trophy was 1.44:1. All patients except two had a septal-LV wall ratio greater than 1.3:1. The mean percent¬ age increase in septal thickness above the upper limits of normal for weight or body surface area was 62%. Five of 12 patients (42%) referred for cardiac evaluation had asymmetric septal hy¬ pertrophy alone or in combination with other heart diseases. Six of the nine patients with asymmetric septal hypertrophy had cardiac catheterization and angiocardiographic con¬ firmation of this diagnosis. Three of the probands (or first-de¬ gree relatives) who had asymmetric septal hypertrophy also had another
free wall
(Tables
heart disease and four of whom (25%) had asymmetric septal hypertrophy alone or in combination with another cardiac problem.
Table 1.—Cardiac Disease in Ullrich-Noonan Families Studied by Echocardiography
Cardiac Status ASH* suspected ASH not suspected ASH + other CHD*
Probands
First-Degree Relative With Ullrich-Noonan
First-Degree Relative Without Ullrich-Noonan
Syndrome
Syndrome
Total
suspected ASH + other CHD not suspected Other CHD No heart disease Total '
15
11 18 38
10 10
13
ASH indicates asymmetric septal hypertrophy; CHD, congenital heart disease.
Table 2.—Clinical and Echocardiographic Findings in 28 Patients with Ullrich-Noonan Syndrome
Patient/Age (yr)/Sex 1V14/M 2/12/M 3/41/F 4V12/M 5/8/F 6/33/F 7V4/M 8V7/F 9V9/M 10/44/F 11V11/M 12/12/M 13V13/F
Septal-LV Wall Ratio 1.5 1.2 1.4 1.5 1.4 1.4 1.2 2.1 1.3 0.9 0.9 1.0 0.9
Septal Thickness,
Cardiovascular
Defecrf & WPW
1.5 1.6 1.6 1.5 1.1 1.8 1.4 1.6 1.1 1.0 0.7 0.8 0.7
ASH ASH ASH ASH ASH ASH ASH ASH ASH
0.6 1.2 0.9 0.6 0.7 0.6 1.3 0.6 1.1 0.6 0.8 1.0 0.7 1.0 0.7
PS PS PS PS & ASD VSD PS AS None None None None None
Catheterization & Angiography
Coronary fistula
Yes Yes No Yes Yes No Yes No Yes Yes
PS & ASD WPW Parachute mitral
Yes No Yes
& AV canal & PS
& PS
complex 14/9/F 15V12/M 16V13/M 17V5/M 18V6/M 19/6/F 20V8/M 21V4/M 22/44/F 23/4/F 24V12/M 25/29/F 26V9/M 27/33/F 28/7/F *
0.9 1.4
1.1 0.8
1.1 0.9 1.0 1.0 1.0 1.0
0.9 0.9 1.0 1.1 1.0
None None None
Yes Yes Yes Yes Yes Yes Yes No No No No No No No No
Proband.
t PS Indicates pulmonary stenosis; AV, atrioventricular; VSD,
ventricular septal defect; WPW, Wolff-Parkinson-White syndrome; AS, aortic stenosis; and ASD, atrial septal defect.
cardiovascular malformation. None of these were suspected clinically of hav¬
ing asymmetric septal hypertrophy until echocardiography was per¬ formed. Three of the six patients who had asymmetric septal hypertrophy with
no
were
not
other cardiovascular lesion thought to have cardiac ab¬ normalities prior to echocardiog¬
raphy.
The ten first-degree relatives who did not have Ullrich-Noonan stigmas also had no echocardiographic evi¬ dence of asymmetric septal hyper¬ trophy. An approximation of the fre¬ quency rate of heart disease in the Ullrich-Noonan syndrome would have to exclude the probands referred spe¬ cifically for heart disease. This leaves 16 patients, eight of whom (50%) had
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COMMENT
The answers to the questions posed by this study depend on the echo¬ cardiographic diagnosis of left ven¬ tricular disease. Figure 1 shows an echocardiogram and angiocardiogram of a typical patient with UllrichNoonan syndrome and left ventricu¬ lar involvement. Commonly accepted criteria for asymmetric septal hyper¬ trophy in patients without UllrichNoonan syndrome include the septalLV wall thickness ratio equal to or greater than 1.3:1 and systolic ante¬
rior motion of the mitral valve. Other useful observations also involve the septum, the mitral valve, and left ventricular chamber size. The septal motion, amplitude of excursion, sys¬ tolic thickening,4 and the measure¬ ment of septal thickness compared with normal values for weight or body surface area must also be con¬ sidered. In all but two cases, our patients had a thickened septum, with a sep¬ tal-LV wall ratio greater than 1.3:1. The thickness exceeded the upper lim¬ its of normal for weight and body surface area by more than 50%. How¬ ever, none of our patients have yet shown systolic anterior motion, a hall¬ mark of asymmetric septal hyper¬ trophy. It should be noted that Henry and associates' have found patients who have other clear evidence of asymmetric septal hypertrophy in the absence of systolic anterior motion of the mitral valve (which appears with the progression of outflow obstruc¬ tion). Figure 2 illustrates the typical appearance of systolic anterior mo¬ tion in a patient with asymmetric septal hypertrophy who does not have Ullrich-Noonan syndrome. Allen et al6 have raised the ques¬ tion (in response to our earlier re¬ port1) that septal involvement sec¬ ondary to pulmonary stenosis may be the true cause of asymmetric septal hypertrophy in patients who have both lesions. Pulmonary hyperten¬ sion7 has been shown to produce echo¬ cardiographic evidence of asymmetric septal hypertrophy, and pulmonary valve stenosis theoretically could
Fig 1.—Left, Typical echocardiogram of 10-year-old boy with Ull¬ rich-Noonan syndrome and left ventricular disease. Note absence of systolic anterior motion of the mitral valve. Angiocardiographic confirmation is given in anteroposterior (center) and lateral a similar abnormality. We have two patients with echo¬ cardiographic and angiocardiographic findings of asymmetric septal hyper¬ trophy and pulmonary stenosis. (In our three other previously described cases of these conditions, we have only angiocardiograms.) In this series, no patient with clinical evi¬ dence of pulmonary stenosis is in¬ cluded who did not have cardiac catheterization and angiocardiography. Figure 3 shows the echocardiogram of a patient with Ullrich-Noonan syn¬ drome who has severe pulmonary ste¬ nosis (gradient of 80 mm Hg at rest and 120 mm Hg with exercise) but does not have angiocardiographic evi¬ dence of asymmetric septal hyper¬ trophy. The septal-LV ratio is 1.4:1. However, the relatively normal septal excursion and systolic thickening shown in Fig 3 and in other views from this patient (and the absence of systolic anterior motion if the patient did not have Ullrich-Noonan syn¬ drome) might restrain the physician from diagnosing asymmetric septal hypertrophy without further study. As in this case, cardiac catheterization may be required not only to define the severity of the pulmonary stenosis, but to assess the possibility of associated left ventricular disease. Asymmetric septal hypertrophy is an early finding of the left ventricu¬ lar disease of the asymmetric septal
produce now
hypertrophy
to
idiopathic hyper-
(right) views of left ventricular hypertrophy. Note small ventricular cavity size and concentrically thickened ventricular wall. (IVS in¬ dicates interventricular septum; AMVL, anterior mitral valve leaf¬ let; and LVW, left ventricular free wall.)
trophic
subaortic stenosis continuum. The first description of the left ven¬ tricular disease in Ullrich-Noonan syndrome emphasized the free-wall deformity in these patients, namely the superolateral and posteroinferior inward bulging. These abnormalities, especially those located posteroin-
feriorly,
are
not
as
readily
acces¬
sible to echocardiographic evaluation as is septal thickening. Fortunately, septal hypertrophy is an indicator present in all of the patients in our series; in fact, a 1.3:1 septal-LV wall ratio, diagnostic of asymmetric septal hypertrophy, was found in all but two of our patients with left ventricular disease. Angiocardiographically, our patients most commonly have had findings of concentric hypertrophy and outflow obstruction rather than eccentric hypertrophy, whereas the patients in the series of Ehlers et al2 had eccentric hypertrophy. Although we suspect that all of these patients may fit into the asymmetric septal
hypertrophy to idiopathic hypertrophic subaortic stenosis continuum of disease, we have yet to see a case of eccentric hypertrophy progress to concentric disease in the way a case of asymmetric septal hypertrophy may progress.
All of our probands and the major¬ ity of our patients are children, so the findings of the disease may be less advanced than in adults in whom the disease has had the opportunity to
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longer course. However, since asymmetric septal hypertrophy is a progressive disease, it is useful to try to recognize its presence at the earliest stage at which the diagnosis may be made with confidence, and it is equally valuable to follow by echocardiography the progression (or sta¬ bility) of the disease. The noninvasive nature of echocardiography makes this a particularly desirable tech¬ nique. Because patients with UllrichNoonan Syndrome are at high risk of having heart disease, it would be pru¬ dent to follow up, with periodic echocardiograms, those who initially may run a
have had normal
or
borderline find¬
ings.
In family studies, if the phenotypic stigmas in a given individual are of a
borderline nature, the echocardiographic demonstration of somewhat
asymmetric septal hypertrophy not only helps to establish the diagnosis, but provides a basis for genetic coun¬ seling and treatment of the patient. To answer the specific questions we
raised, let
us
first try to suggest how
asymmetric septal hyper¬ trophy may be in Ullrich-Noonan syn¬ drome. Sixteen family members with stigmas of Ullrich-Noonan syndrome common
who were not referred for cardio¬ vascular evaluation were studied echocardiographically. Four of these patients (25%) had asymmetric septal hypertrophy alone or in combination with other heart lesions. Thus, 25%
Fig 2.—Typical echocardiographic findings in patient with asymmetric septal hypertrophy but without Ullrich-Noonan syndrome. Note thick¬ ened ventricular septum and cardinal findings of systolic anterior mo¬ tion of mitral valve (arrows). (PLVW indicates posterior left ventricular wall.) may be offered
as a
current
approxi¬
mation of the frequency of this condi¬ tion in individuals having UllrichNoonan stigmas.
Twenty patients
or
first-degree
relatives with Ullrich-Noonan stig¬ mas had heart disease of some type. Eleven of the patients had heart lesions other than asymmetric septal hypertrophy (most often pulmonary stenosis), six had asymmetric septal hypertrophy alone, and in three cases it was not suspected. Three patients had asymmetric septal hypertrophy in addition to other cardiovascular anomalies, and in none of these cases was it suspected prior to echocardiography or cardiac catheterization. Therefore, three of 14 pa¬ tients in this study (21%) who had other cardiovascular diagnoses also had asymmetric septal hypertrophy. This figure applies exclusively to this study and does not include some pa¬ tients from earlier studies who have possibly had asymmetric septal hy¬ pertrophy with other cardiac defects (established at cardiac catheterization), but did not have echo¬ cardiographic evaluation. Again, the sample is small, but it provides an ap¬ proximation that may be clinically useful. It appears that about 20% of patients with Ullrich-Noonan syn-
drome and cardiovascular
Fig 3.—Echocardiogram of 12-year-old boy with severe pulmonary stenosis, but without hemodynamic or angio¬ cardiographic evidence of left ventricular disease, could be interpreted as asymmetric septal hypertrophy because of the septal-LV ratio of 1.4:1.
diagnoses of other disease
may
have
unsuspected asymmetric septal hypertrophy as well. That six of our nine patients with this condition were not suspected clinically of hav¬ ing the diagnosis prior to a specific search for the abnormality suggests that unsuspected asymmetric septal hypertrophy represents a legitimate for concern. The overall frequency rate of heart disease of all types in Ullrich-Noonan syndrome has been previously esti¬ mated by us at 35%' on the basis of examination of relatives and elimi¬ nating probands referred because of heart disease. We have now shown that there is a great deal of unsus¬ cause
pected asymmetric septal hyper¬ trophy in Ullrich-Noonan syndrome that may be detected by echocardiography. Many of our previously described patients (some seen as long as a decade ago) did not have echo¬ cardiographic examination. Exclud¬ ing those patients referred specifi¬ cally for cardiac disorders, 50% of individuals in this study with UllrichNoonan stigmas had some form of
cardiovascular disease, and we are in¬ clined to believe that 50% more closely approximates the frequency rate of heart disease in this syn-
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drome. Within this high-risk group, left ventricular disease is a serious, po¬ tentially life-threatening, and fre¬ quently unsuspected feature of Ull¬ rich-Noonan syndrome, which may be detected and followed up longitudi¬
nally by echocardiography.
This investigation was supported by grant 05981 from the National Heart and Lung Insti¬ tute and a project grant from the Junior League of Denver and the Vida Francis Ellison Trust, Denver.
References 1. Nora JJ, Nora AH, Sinha AK, et al: The Ullrich-Noonan syndrome (Turner phenotype). Am J Dis Child 127:48-55, 1974. 2. Ehlers KH, Engle MA, Levin AR, et al: Eccentric ventricular hypertrophy in familial and sporadic instances of 46 XX,XY Turner phenotype. Circulation 45:639-652, 1972. 3. Feigenbaum H: Echocardiography. Philadelphia, Lea & Febiger Publishers, 1973. 4. Tajik AJ, Giuliani ER: Echocardiographic observations in idiopathic hypertrophic subaortic stenosis. Mayo Clin Proc 49:89-97, 1974. 5. Henry WL, Clark CE, Epstein SE: Asymmetric septal hypertrophy: Echocardiographic identification of the pathognomonic anatomic abnormality of IHSS. Circulation 47:225-233, 1973. 6. Allen HD, Larter WE, Goldberg SJ: The Ullrich-Noonan syndrome. Am J Dis Child 128:115, 1974. 7. Brown OR: Echocardiographic study of right ventricular hypertension producing asymmetric septal hypertrophy. Circulation 48(suppl 5):47, 1973.
