Down Syndrome Association With Ventricular Septal Defect

A 20-year-old woman presented to our clinic with midsternal chest pain radiating to the left arm.

History. The patient had a history of Down syndrome and ventricular septal defect (VSD). She reported having intermittent chest pain for several months for which she had been seen by a cardiologist with suspicion of pericarditis. She did not have any other associated symptoms.

Upon physical examination, the patient was alert and oriented to person, place, time, and situation; her speech was clear, and behavior was appropriate for the situation. A PERRLA assessment demonstrated full and intact extraocular movements and bilaterally clear conjunctivae. She appeared to have a flat facial profile, protruding tongue, upslanting palpebral fissures, and a short neck with excess skin. The patient had a grade 2/6 harsh holosystolic murmur best heard in the left lower sternal border with a systolic thrill. The abdomen was soft with no hepatosplenomegaly. Her blood pressure was 118/77 mm Hg, pulse was 88 beats/min, and respiratory rate was 18 breaths/min. The patient’s height was 142 cm and weight was 63.7 kg, with a BMI of 31.6.

Diagnostic testing. Laboratory test results included the following values (Table):

Results of the electrocardiogram (ECG) showed normal sinus rhythm with nonspecific T wave abnormality in lateral leads (Figure 1). These findings were abnormal compared with an ECG taken approximately 4 years prior.

Figure 1. Normal sinus rhythm with nonspecific T wave abnormalities.

Results of the transthoracic 2D echocardiogram with doppler indicated normal left ventricular systolic function, an ejection fraction of 72%, and no regional wall motion abnormalities. The echocardiogram found normal diastolic function. However, a small perimembranous VSD with left-to-right shunting was confirmed and indicated by color flow doppler (Figure 2). No enlargement of the shunt or significant pericardial effusion was noted, so no further testing modalities were utilized to maintain a less invasive and minimalistic approach.

Figure 2. Small perimembranous ventricular septal defect with left-to-right shunting.

Differential diagnoses. Among the differential diagnoses are isolated hypotonia, congenital hypothyroidism, and Zellweger syndrome for Down syndrome. The differential diagnoses for VSD include fetal alcohol syndrome, cri-du-chat syndrome (also known as 5p minus syndrome), and Trisomy disorders including Trisomy 13, Trisomy 18, and Edwards syndrome. It is important to obtain a thorough clinical history and related laboratory tests to establish a proper diagnosis, as shown in this case.

Treatment and management. After the initial assessment and workup, the patient was referred to and is being closely monitored by her cardiologist and pediatrician.

Outcome and follow-up. The patient is currently stable with some intermittent chest pain; however, there are no further associated symptoms. The patient is doing well overall and visits the clinic as needed for symptom management.

Discussion. Down syndrome (DS) is the most widely recognized chromosomal abnormality in humans with various gene articulations.¹ A major goal of understanding the molecular pathology of DS is identifying its genotype-phenotype features. DS is characterized by the presence of an additional copy of chromosome 21 in the cells of the body. This occurs when chromosome 21 fails to separate properly during the process of gametogenesis, resulting in an extra chromosome being present in all cells.² Trisomy 21 can also arise from two other possible causes: Robertsonian translocation and mosaicism. In Robertsonian translocation, a portion of the long arm of chromosome 21 becomes attached to another chromosome, typically chromosome 14.² This rearrangement occurs in a small percentage of individuals, ranging from 2% to 4% of cases. Furthermore, mosaicism involves the presence of two different cell lines in the individual due to an error in cell division that occurs after fertilization.²

The clinical phenotype of DS is diverse and can vary from person to person. Certain features are commonly observed to some extent in most individuals with trisomy 21. These include distinctive facial characteristics, a smaller brain with fewer cells, and the characteristic histopathology associated with Alzheimer disease, which typically manifests by the age of 40 years.³ Cognitive impairment is a universal characteristic among individuals with DS, although the degree of severity can vary greatly. Additionally, hypotonia and decreased gait stability are frequently observed in newborns with DS.⁴

Extensive research has demonstrated that the risk of DS is influenced by a multifaceted interplay involving genetic factors, environmental influences, and sociocultural dynamics. These risk factors encompass a wide range of possibilities, including but not limited to consanguinity, rural residence, lower educational status of parents, paternal habits (such as smoking and alcohol consumption), lack of prenatal scanning, and the reproductive performance of the mother.⁵

When considering congenital heart disease in patients with DS, VSD is the second most common cardiac abnormality after atrioventricular septal defects.⁶ VSD displays an opening located just inferior to the inlet valves (tricuspid and mitral) within the inlet part of the right ventricular septum.⁶ The apical 4-chamber echocardiographic view is often preferred for visualizing membranous VSDs. This view provides a comprehensive visualization of the heart's structures, including the ventricular septum. The membranous VSD, being located in the membranous portion of the ventricular septum, can be well visualized from this particular angle.⁷ In addition, the use of doppler echocardiogram combined with Bernoulli principle can help calculate right ventricular systolic pressure. The peak velocity of the blood jet through the defect is measured, and the pressure gradient across the VSD is estimated using the simplified Bernoulli equation.⁸ Furthermore, ECG findings are typically normal in most patients with VSD; however, when the ECG findings are abnormal, it may reveal left ventricular hypertrophy in those with large shunts. In people with pulmonary arterial hypertension, the ECG may show right bundle branch block, right axis deviation, and right ventricular hypertrophy.²

In normal cardiac circulation, the deoxygenated blood returns to the right atrium and proceeds to the right ventricle, which is then pumped into the lungs where it becomes oxygenated. Subsequently, oxygenated blood returning to the left atrium from the lungs proceeds into the left ventricle, and finally travels through systemic circulation via the aorta. In VSD, oxygenated blood travels from the left ventricle through the opening in the interventricular septum, which then integrates with the deoxygenated blood from the right ventricle.⁶ This complication may lead to disrupted cellular metabolism and dyspnea.

Significant left-to-right shunting results in pulmonary over-circulation and pulmonary hypertension, easy fatigability, and congestive heart failure. Over time, this can lead to the development of Eisenmenger syndrome, a condition characterized by severe pulmonary vascular resistance, which eventually leads to reversal of the shunt and ultimately causes right-to-left shunting and cyanosis.^9,10 Eisenmenger syndrome is characterized by several distinct physical examination findings. These include cyanosis, a bluish discoloration of the skin, lips, and nail beds commonly seen among neonates, due to reduced oxygen levels in the blood.¹⁰ Additionally, clubbing of the fingertips and nails may be present, indicating chronic hypoxemia. Jugular venous distention, an enlargement of the jugular veins in the neck, can be observed due to increased pressure on the right side of the heart. These physical examination findings help clinicians recognize and diagnose Eisenmenger syndrome.¹⁰

Surgical repair of VSD for patients with DS offers substantial benefits, yielding improved outcomes compared with those who decline surgery. Patients with DS have a four-to-eight-times increase in mortality risk compared with the normal population due to cardiac causes.¹¹ The incidence of congenital heart disease in the general population is 0.8% compared with 40% to 60% in those with DS, with most cases being septal deformities.¹²

The primary cause of death in patients with DS is often cardiac failure, pulmonary hypertension, or arrhythmias.¹³ Smaller VSDs are more likely to spontaneously close during childhood and have an excellent prognosis. The management of patients with VSD depends upon the severity and size of the shunt and whether there are any associated complications, including aortic regurgitation or pulmonary hypertension.¹⁴ In those who have larger VSDs, the absence of treatment often leads to death within the first year of life.¹⁴ Direct patch closure under cardiopulmonary bypass is the procedure of choice when treating a child with VSD who requires surgical intervention.¹⁵

There are multiple approaches to surgical closure based on the location of the defect: transatrial, transaortic, right ventriculotomy, or apical ventriculotomy.¹⁵ Indications for VSD closure include patients with hemodynamically significant shunts represented by left ventricular volume overload, significant or worsening aortic regurgitation, or a history of infective endocarditis.¹⁶ Observational data suggest that surgical closure helps decrease the risk of endocarditis in patients with VSD by 50%.¹⁷ Studies have also shown that surgical closure in patients who have a significant shunt reduces pulmonary artery pressure and leads to improved long-term survival.^18,19

Percutaneous repair with transcatheter devices is also an option for isolated, uncomplicated cases of VSD in patients with suitable anatomy. The appropriate anatomy for this procedure includes a VSD that is remote from the tricuspid and aortic valves.²⁰ Although percutaneous repair and direct closure with surgical intervention have similar success rates, one benefit of percutaneous repair is the significant reduction in blood transfusions and length of hospital stays.¹²

As this case report highlights, the management of VSD in people with DS typically involves the expertise of a congenital heart disease specialist. Due to the unique considerations associated with DS and VSD, early identification of any complications is crucial to determine appropriate candidates for surgical intervention and to plan the most suitable surgical approach.

Recognizing early complications associated with VSD in those with DS is of utmost importance. Symptoms such as recurrent respiratory infections, failure to thrive, or signs of congestive heart failure should be promptly identified to allow health care providers to closely monitor the condition, evaluate symptom severity, and determine the appropriate course of action.