Noonan syndrome

A 41-year-old woman had Noonan's syndrome. Her heart was complicated by asymmetric septal hypertrophy, hypertrophy of the left ventricular free wall, severe pulmonary stenosis, and right ventricular hypertension. On autopsy, a quantitative histologic analysis of the heart revealed that the area of disarray was limited both to the ventricular septum and the left ventricular free wall as in a normal heart. This is not typical of hypertrophic cardiomyopathy because the extent of disarray is high in most cases of hypertrophic cardiomyopathy. Some form of hypertrophic cardiomyopathy, however, seemed to be present in this patient because right ventricular pressure overload did not affect the left ventricular free wall. To clarify the relation between hypertrophic cardiomyopathy and Noonan's syndrome, quantitative histologic analysis is necessary.

Pulmonary stenosis (PS) and asymmetric septal hypertrophy (ASH) are sometimes found in patients with Noonan's syndrome.[1] Generally, ASH in Noonan's syndrome is considered to be the result of combined hypertrophic cardiomyopathy (HCM). However, secondary ASH frequently followed marked right ventricular hypertension that is found in PS or mitral stenosis.[2] In such cases, the extent of disarray in the ventricular septum, which is diffuse in HCM, is as minimal as that found in normal hearts. At autopsy, we carried out a quantitative analysis of disarray of the heart in a patient with Noonan's syndrome coexisting with PS and ASH.

CASE REPORT

A 41-year-old was admitted to our hospital because of syncopal attacks. Her history included a normal delivery, mild cyanosis, and a systolic heart murmur at birth. She had experienced palpitations, chest discomfort on exertion, and occasional syncopal attacks for several years before hospital admission. She had no history of hypertension or family history of HCM. Her height was 141 cm and her weight was 45 kg. Her pulse was 84/min and irregular, and her blood pressure was 120/80 mm Hg. She had clubbed fingers and cyanotic nail beds. Typical features of Noonan's syndrome were present. A grade 3/6 systolic ejection murmur and wide splitting of the second heart sound were present. The cardiothoracic ratio was 66 percent. The electrocardiogram showed an abnormal frontal QRS axis (- 145[degrees]) rsR in [V.sub.1], rS in [V.sub.5], and QS in [V.sub.6]. Multifocal premature ventricular contractions and frequent ventricular tachycardia were also observed. Laboratory examination revealed marked polycythemia (red blood cell count, 10, 140,000/cu mm) and a normal 46,XX karyotype. The echocardiogram (Fig 1) revealed ASH (septum/posterior wall=28/13=2.2), systolic anterior motion (SAM) of the anterior leaflet of the mitral valve, and semiclosure-like movement of the aortic valve. Cardiac catheterization revealed a pressure gradient of 130 mm Hg across the pulmonary valve and 41 percent right-to-left shunt at the atrial level. A right ventriculogram showed a thickened and dome-like pulmonary valve and marked dilatation of the main pulmonary artery. No pressure gradient was recorded at the left ventricular outflow tract. She died of septic complication of acute cholecystitis 11 months after her first hospital admission.

Autopsy revealed a markedly hypertrophic heart (650 g) with normal coronary arteries. The right ventricular wall was 12 mm thick, the ventricular septum was 28 mm thick, and the left ventricular posterior wall was 16 mm thick (Fig 2). In general, the left ventricular free wall on autopsy is thicker than that detected on echocardiogram. The heart was cut transversely from base to apex serially at 1-cm intervals. The slices were sectioned in a plane perpendicular to the long axis of the left ventricle at 25-[mu]m thickness by a microtome.[3] Hematoxylin-eosin-stained tissue sections were directly enlarged 50 times (50 x 50 in the area) on a large sheet of white paper using a projector. Areas of disarray were traced and automatically measured using an image analyzer (VIP-21, Olympus Optical Co, Ltd). Quantitative histologic analysis revealed that the area of disorganization of myocardial fibers was less than 5 percent both in the ventricular septum and in the left ventricular free wall (normal range of disarray by our method: 0 to 10 percent).[4] Diffuse interstitial fibrosis was observed in the right ventricular free wall and on the right side of the ventricular septum (Fig 2).

DISCUSSION

Nora et al[1] reported that 45 of 81 patients with Noonan's syndrome had cardiovascular lesions such as PS and atrial septal defect. Asymmetric septal hypertrophy was also found in seven patients, of whom five had PS and two had no other cardiac anomalies. They did not include any mention of the histopathologic features. Hirsch et al[5] and Battiste et al[6] reported cases of patients with Noonan's syndrome with cardiomyopathy. On microscopic examination, disarray was observed but the extent of disarray was not calculated in their reports.

Asymmetric septal hypertrophy, SAM, and cellular disorganization are the three hallmarks of HCM. However, they are not pathognomonic of HCM.[2] Conditions resulting in long-standing right ventricular pressure overload and the consequent right ventricular hypertrophy, such as PS and primary pulmonary hypertension, result in disproportionate septal thickening (DST) without affecting the free wall of the left ventricle. Our patient was found to have DST and hypertrophy of the left ventricular posterior wall and seemed to have had some form of HCM.

However, disarray is not specific to HCM; there is a quantitative relation between HCM and the extent of disarray.[2,4,7,8] The percentage of cellular disorganization in the ventricular septum is very high in most cases of HCM, while in other cardiac diseases it is very low (<5 percent) even in secondary ASH.[2] The extent of cellular disarray of HCM in Noonan's syndrome may be as high as that in HCM alone. In our patient, quantitative analysis revealed that the disorganized area was less than 5 percent of the ventricular septum and left ventricular free wall. This is not typical of HCM but it is compatible with secondary ASH. Severe PS and marked right ventricular hypertension might have contributed in causing DST in our patient.

To clarify the relation between Noonan's syndrome and HCM, quantitative histologic analysis of the heart is necessary.

REFERENCES

[1] Nora JJ, Nora AH, Sinha AK, Spangler RD, Lubs AH. The Ullrich-Noonan syndrome. Am J Dis Child 1974; 127:48-55

[2] Maron BJ, Epstein SE. Hypertrophic cardiomyopathy. Am J Cardiol 1980; 45:141-54

[3] Fujiwara H, Kawai C, Hamashima Y. Myocardial facsimile and fiber disarray in 25 [mu] thick sections. Circulation 1979; 59:1293-8

[4] Fujiwara H, Hoshino T, Kawai C, Hamashima Y. Classification and distribution of myocardial fascicle and fiber disarray in 14 hearts with hypertrophic cardiomyopathy in 25[mu] thick sections. Jpn Circ J 1982; 465:225-34

[5] Hirsch HD, Gelband H, Garcia O, Gottlieb S, Tamer DM. Rapidly progressive obstructive cardiomyopathy in infants with Noonan's syndrome. Circulation 1975; 52:1161-5

[6] Battiste CE, Feldt RH, Lie JT. Congestive cardiomyopathy in Noonan's syndrome. Mayo Clin Proc 1977; 52:661-4

[7] Sutton MGJ, Lie JT, Anderson KR, O'Brien PC, Frye RL. Histopathological specificity of hypertrophic obstructive cardiomyopathy: myocardial fiber disarray and myocardial fibrosis. Br Heart J 1980; 44:433-43

[8] Davies MJ. The current status of myocardial disarray in hypertrophic cardiomyopathy. Br Heart J 1984; 51:361-3

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