Unusual Association of Hypertrophic Cardiomyopathy with Complete Atrioventricular Canal Defect and Down Syndrome

Abstract

Hypertrophic cardiomyopathy typically presents as an isolated cardiac lesion. Transient hypertrophic cardiomyopathy in infancy has been described as a result of exposure to maternal metabolic disorders or to corticosteroids. In addition, hypertrophic cardiomyopathy has been described in association with genetic syndromes and, in rare cases, as a primary lesion associated with other congenital heart defects. We describe the unusual association of hypertrophic cardiomyopathy and complete atrioventricular canal defect in an infant with trisomy 21.

Complete atrioventricular canal defects (CAVC) occur in 4% to 5% of patients who have congenital heart disease, and these defects are common in patients with chromosomal anomalies, most notably trisomy 21. ^1,2 Forty percent of neonates with Down syndrome have congenital heart disease; complete atrioventricular canal is one of the most common defects. ³ Concomitant congenital lesions can occur, including tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, coarctation of the aorta, and heterotaxia. In addition, acquired left ventricular outflow tract obstruction is a well recognized complication of CAVC. ⁴

Hypertrophic cardiomyopathy is typically an isolated cardiac lesion. In the newborn or the fetus, transient hypertrophic cardiomyopathy is commonly attributed to certain maternal metabolic disorders (in particular, diabetes mellitus) or to antenatal or postnatal exposure to steroids. ^5,6 It is uncommon to find hypertrophic cardiomyopathy as a primary lesion in neonates who have congenital heart disease. Case reports have documented the occurrence of hypertrophic cardiomyopathy in patients who have congenital atrial and ventricular septal defects, coarctation of the aorta, and, recently, tetralogy of Fallot. ^7–9 Moreover, in certain syndromes, such as Noonan's syndrome and LEOPARD syndrome, hypertrophic cardiomyopathy can occur in conjunction with congenital heart disease. ^10,11 To the best of our knowledge, hypertrophic cardiomyopathy has not been reported in association with CAVC in a newborn with trisomy 21.

Case Report

In October 1997, a male infant was born to a healthy, non-diabetic, 40-year-old gravida 2, para 2. Repeated tests for gestational diabetes during pregnancy had been negative. Features of Down syndrome were evident on routine prenatal ultrasound during the early 3rd trimester. No amniocentesis or detailed fetal cardiovascular evaluation was performed. Delivery was uncomplicated at 36 weeks' gestation, and initial Apgar scores were 5 (1 minute), 7 (5 minutes), and 9 (10 minutes). Birth weight was 2.8 kg.

The initial physical examination was significant for facies typical of Down syndrome, redundant nuchal folds, generalized hypotonia, an undescended left testicle, a sacral dimple, and an imperforate anus. Cardiovascular examination revealed a quiet precordium, a normal 1st heart sound, a loud 2nd heart sound, and a grade 1/6 systolic murmur at the left sternal border. Peripheral pulses were normal.

Mild cardiomegaly and normal pulmonary vascular markings were present on the chest radiograph. A 12-lead electrocardiogram showed normal sinus rhythm, left axis deviation, and biventricular hypertrophy. Transthoracic echocardiography revealed the following: complete atrioventricular canal defect (Type A), severe asymmetric septal hypertrophy without obstruction of the left or right ventricular outflow tracts, normal biventricular chamber size and function, normal aortic and pulmonary valves, and a normal left-sided aortic arch. In diastole, the ventricular septum measured 10 mm in thickness (normal for age, 3 to 4 mm); the posterior wall of the left ventricle measured 3 mm in thickness (normal for age, 3 to 4 mm). Two-dimensional and M-mode echocardiographic images are shown in Figures 1, 2, and 3.

Fig. 1 Parasternal long-axis scan of hypertrophied interventricular septum and large ventricular septal defect.

Fig. 2 M-mode tracing from parasternal short-axis scan at level of papillary muscles, demonstrating marked septal hypertrophy.

Fig. 3 Apical 4-chamber view demonstrates typical echocardiographic features of complete atrioventricular canal defect.

A high-resolution karyotype demonstrated 46, XY, +21. A 24-hour Holter monitor revealed no serious ventricular ectopy. Screening echocardiograms of both parents and the sibling were also normal. The family history was negative for hypertrophic cardiomyopathy or sudden death.

Serial echocardiograms in our index case revealed persistent hypertrophic cardiomyopathy on repeated examinations at 2 weeks and at 2, 3, 7, and 12 months of age. Mild dynamic right ventricular outflow tract obstruction (Fig. 4) developed at 2 months (peak gradient ranging from 20 to 35 mmHg), and this persisted despite administration of propranolol (1 mg/kg 4 times daily). The patient remained asymptomatic throughout the 1st year of life. His systemic-pulmonary hemodynamics were well balanced, and his growth was adequate. He is awaiting definitive intracardiac repair.

Fig. 4 A) Parasternal short-axis view demonstrates the prominent septum protruding into the right ventricular outflow tract (RVOT). B) Pulse-wave Doppler demonstrates classic late-peaking outflow tract velocity consistent with mild dynamic RVOT obstruction.

Discussion

The occurrence of congenital heart disease in patients with Down syndrome is well established. ³ The most common congenital heart lesions in these patients are defects in the atrioventricular septum (partial or complete atrioventricular canal defects and isolated atrial or ventricular septal defects). A minority of patients have additional cardiac defects in association with atrioventricular canal, usually defects of conotruncal development that include truncus arteriosus, tetralogy of Fallot, pulmonary atresia, and left-sided obstructive lesions (coarctation or subaortic stenosis). Acquired defects in these patients, which occur either de novo or as the result of operative repair, also contribute to overall morbidity and mortality. The development of marked progressive left ventricular outflow tract obstruction is especially common and frequently requires additional surgical intervention. ⁴

The presence of asymmetric septal hypertrophy in an unoperated newborn patient with complete atrioventricular canal defect is most unusual and has not been reported, to the best of our knowledge. We describe a patient with Down syndrome in whom nonobstructive asymmetric septal hypertrophy was documented in the immediate newborn period and has persisted throughout the 1st year of life. This patient's hypertrophic cardiomyopathy does not appear to result from intrauterine exposure to maternal metabolic abnormalities, nor from altered postnatal hemodynamics. Rather, this is a primary finding associated with CAVC and Down syndrome.

Recent genetic studies in families with sporadic and familial hypertrophic cardiomyopathy have identified a variety of mutations that have been localized to chromosomes 1, 11, 14, and 15. ^12,13 Familial hypertrophic cardiomyopathy is inherited in an autosomal dominant fashion. Mutations have been identified in both cardiac myosin heavy and light chains, as well as in alpha-tropomyosin and troponin. These deletions lead to alterations in myofiber formation, arrangement, and function. ¹⁴ It is known that primary hypertrophic cardiomyopathy can occur in association with other congenital heart lesions, such as ventricular septal defects and tetralogy of Fallot. ^9,15 In addition, studies in WKY/NCrj rat fetuses have reported an association between tetralogy of Fallot and hypertrophic cardiomyopathy. ¹⁶ Other WKY/NCrj rats have dem-onstrated atrioventricular canal, which suggests the presence of a related gene defect that produces a spectrum of congenital heart lesions. While exact genetic evidence is lacking at present, the combination of hypertrophic cardiomyopathy and CAVC defects in Down syndrome is more likely an inherited disorder with a common genetic mechanism than a rare, sporadic event.

The clinical expression and prognosis of hypertrophic cardiomyopathy in infancy may be variable. Limited case reports from large centers, where selection bias might exist, have demonstrated a poor prognosis for primary hypertrophic cardiomyopathy in infancy. ⁸ Conversely, our patient has reached 1 year of age and has thrived. The prognosis for this combination of defects is unknown.