Congenital Heart Diseases: Associated Syndromes and Anomalies

Introduction

• CHD is the most common congenital defect, affecting 1-75 per 1000 live births. CHD is often associated with genetic syndromes and/or other extracardiac congenital anomalies.¹
• Affected patients present unique clinical challenges as associated anomalies may add complexity to the management of CHD, influence decision-making for curative and/or palliative procedures, and/or change the expected course of a cardiac disease process.
• Conversely, patients with syndromes or congenital anomalies that are highly associated with CHD presenting for noncardiac procedures should be evaluated for CHD.
• Awareness of the syndromes and conditions associated with CHD is essential for the safe anesthesia management of these patients.

Midline Birth Anomalies

Omphalocele²

• Rare anomaly with a male predominance
• Cardiac defects are identified in ~35% of patients with omphalocele, with the most common being atrial septal defects (ASD), and ventricular septal defects (VSD) (see Summary Link). Less commonly associated cardiac defects include tricuspid atresia, hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TOF), inferior vena cava abnormalities, and ectopia cordis.
• A displaced cardiac axis is found in the majority of patients with omphalocele.
• Larger omphaloceles are more likely to be associated with cardiac defects.
• The addition of CHD worsens the prognosis for this patient population.
• Omphalocele is associated with several syndromes that may carry with them additional considerations for difficult airway management.

Pentalogy of Cantrell³

• Extremely rare anomaly with a male predominance
• Combined finding of defects to the midline abdominal wall, lower sternum, anterior diaphragm, diaphragmatic pericardium, and some form of intracardiac defect. The most severe form includes ectopia cordis, where the heart is located outside of the chest.
• The most commonly associated intracardiac defect is the VSD. Other defects include ASD, pulmonary stenosis/atresia, and TOF. Less commonly associated cardiac defects include patent ductus arteriosus (PDA) (see Summary Link), transposition of the great arteries (TGA) (see Summary Link), left-sided superior vena cava, dextrocardia, and HLHS.
• Depending on the severity and quality of their underlying defects, patients may additionally have respiratory symptoms and/or cyanosis.

Associations

VACTERL/VATER⁴

• Rare association with a known familial component
• Cardiac manifestations are a core feature and are seen in the majority of patients. Common defects of VACTERL include VSD, ASD, PDA, TOF, and double outlet right ventricle (DORV).
• The typical noncardiovascular system findings are skeletal, gastrointestinal, and renal. The most common of these abnormalities include imperforate Anus, Esophageal atresia, Tracheoesophageal fistula, unilateral Renal agenesis, hemiVertebrae, rib malformations, and Limb defects (radial aplasia).

Genetic Syndromes

Alagille¹

• Very rare syndrome
• The most commonly associated cardiac lesions are peripheral pulmonary artery stenosis, TOF, and pulmonary atresia.
• Noncardiac anomalies include bile duct paucity, corneal findings (posterior embryotoxon), butterfly vertebrae, and renal defects.

CHARGE⁵

• Rare syndrome associated with a mutation in the CHD7 gene
• Cardiac manifestations are not a major diagnostic criterion but are seen in the majority of patients with CHARGE syndrome. Patients with the CHD7 mutation have a strong likelihood of CHD. Cardiac lesions include conotruncal defects (e.g., TOF), atrioventricular canal defects, and aortic arch anomalies.
• Noncardiac associations with CHARGE syndrome are Coloboma, choanal Atresia, Retarded growth and mental development, Genital anomalies, and Ear malformations with hearing loss. Cleft palate, tracheoesophageal fistula, limb abnormalities, and, rarely, immune deficiencies are also possible.

DiGeorge/Velocardiofacial Syndrome/22q11.2 Microdeletion Syndrome⁶

• Relatively rare syndrome caused by a microdeletion within the long arm of chromosome 22 (~ 30-50 genes affected) with an autosomal dominant inheritance pattern.
• Most common microdeletion syndrome with an incidence of 1:2,000 live births.
• Most commonly associated with conotruncal abnormalities: TOF, pulmonary atresia, VSD, truncus arteriosus, interrupted aortic arch, DORV, double aortic arch
• Noncardiac findings include thymic dysfunction/immunodeficiency, hypoparathyroidism, cleft palate, dysmorphic facies, and learning disability.

Duchenne Muscular Dystrophy⁷

• Relatively rare X-linked disorder in patients with XY chromosomal makeup
• Arrhythmia and cardiomyopathy are the most common cardiac diseases.
• Cardiomyopathy (CM) (see Summary Link) is present in all patients older than 18 years. Young patients may be asymptomatic due to a relative lack of physical activity.
• Noncardiac findings include skeletal muscle weakness (classically with early proximal lower extremity and truncal weakness with progressive worsening to include upper extremities and distal muscles), restrictive lung disease, learning disabilities, scoliosis, and joint contractures.
• Succinylcholine should be avoided, and volatile anesthetics should be used cautiously due to the risk of life-threatening rhabdomyolysis and hyperkalemia.

Ehlers-Danlos⁸

• Relatively rare genetic defect of collagen with variable presentations.
• The cardiac-valvular (cvEDS) subtype is rare and involves progressive, severe aortic and/or mitral valvulopathy.
• The vascular subtype (vEDS) is characterized by arterial fragility and is associated with arterial aneurysms (e.g., aortic root), dissections, and/or rupture.
• The more common subtypes of classical (cEDS) and hypermobile (hEDS) have not been shown to correlate with a significantly increased risk of cardiac involvement.
• Associated noncardiac manifestations depend on the subtype. These include joint laxity, fragile skin and blood vessels, joint hypermobility with risk of subluxation/dislocation, scoliosis, increased risk of spontaneous pneumothorax, arteriovenous malformations, autonomic dysfunction, and/or ocular abnormalities.

Marfan Syndrome⁹

• Relatively rare connective tissue disorder involving the glycoprotein fibrillin that is inherited in an autosomal dominance manner.
• Ghent diagnostic criteria define cardiovascular disease as either major (aortic root dilatation, ascending aortic dissection) or minor (mitral valve prolapse, calcification of the mitral valve, pulmonary artery dilatation, descending aortic dissection.)
• Aortic dissection is described in nearly 50% of patients with Marfan syndrome younger than 40 years, and arrhythmias are seen in approximately 25% of patients.
• A rare “neonatal” subtype of Marfan syndrome exists that manifests as significant atrioventricular valvulopathy in addition to aortic root disease.
• Associated noncardiac manifestations include ectopia lentis, pectus excavatum, scoliosis, tall stature, arachnodactyly, spontaneous pneumothorax, and joint hypermobility.

Noonan Syndrome¹⁰

• It is the most common nonchromosomal syndrome seen in children with an inheritance pattern suggesting autosomal dominance with variable expressivity. RAS/mitogen-activated protein kinase signaling pathway is implicated in the majority of cases.
• CHD is present in the majority of patients with Noonan syndrome, with pulmonic stenosis being the most common. Other cardiovascular findings include ASD, septal hypertrophy with a subset demonstrating hypertrophic CM, VSD, PDA, and atrioventricular canal (AVC) defects.
• Noncardiovascular findings include short stature, dysmorphic facial features, chest wall deformity, and variable degrees of developmental delay.

Trisomy 21 (Down syndrome)¹¹

• The most common chromosomal abnormality seen in newborns with an incidence of ~1:800 live births.
• An estimated 50% of trisomy 21 patients have associated CHD. In Europe and the United States, endocardial cushion defects are most common, followed by VSD, secundum ASD, TOF, and PDA. In contrast, VSD is the most commonly associated CHD in Asia.
• The typical endocardial cushion defect is a “simple type” complete AVC defect that lacks obstructive left-sided abnormalities like coarctation of the aorta (CoA).
• Pulmonary hypertension incidence is as high as 45% in trisomy 21 patients with CHD.
• Associated noncardiac anomalies include intellectual impairment, hypotonia, hearing loss, obstructive sleep apnea, ophthalmologic disease, hypothyroidism, and hip dislocation. There is a significantly increased risk for leukemia, intestinal atresia, and Hirschsprung disease.

Trisomy 18 (Edwards’ syndrome)¹²

• It is the second most common genetic trisomy defect with an incidence of ~1:5000 and a female predominance of 3:1. About 70% result in fetal demise.
• An estimated 90% of patients have associated CHD. The most common of these include VSD, DORV, CoA, and TOF.
• The majority of patients have congenital anomalies affecting at least two organ systems.
• Associated anomalies include limb deformities, neurological, gastrointestinal, and urological. Commonly seen conditions include microcephaly, micrognathia, cleft lip, hypertelorism, choroid plexus cysts, radial aplasia, overlapping fingers, omphalocele, cryptorchidism, and horseshoe kidney.

Trisomy 13 (Patau syndrome)¹³

• It is the third most common genetic trisomy defect. Nearly 50% result in fetal demise.
• A majority of patients have associated CHD. The most common of these include ASD, VSD, and DORV.
• The majority of patients have congenital anomalies affecting at least two organ systems.
• Associated anomalies include limb deformities, orofacial clefts, neurological, and ophthalmological. Commonly seen conditions include microcephaly, polydactyly, microphthalmia, deafness, cleft palate, cryptorchidism, seizures, and intellectual disability.

Turner¹⁴

• Most common female-only genetic disorder. The associated karyotype is a 45 X monosomy in around half of the cases. The remainder have a mosaic chromosomal component.
• An estimated 50% of Turner syndrome patients have associated CHD. The most common defects include bicuspid aortic valve, CoA, thoracic aortic aneurysm, persistent left superior vena cava, and partial anomalous pulmonary venous return.
• It is hypothesized that fetal lymphedema and resultant poor blood flow lead to the development of cardiac lesions. Long-term complications include accelerated coronary artery disease and ascending aortic dilatation (seen in 15-30%) leading to dissection.
• Associated anomalies include short stature, webbed neck, micrognathia, osteopenic fractures, scoliosis, infertility, insulin resistance, and autoimmune disorders such as Hashimoto’s thyroiditis, psoriasis, celiac disease, and ulcerative colitis.

Williams Syndrome¹⁵

• It is a rare elastin gene mutation caused by a deletion within chromosome band 7q11.23.
• Most commonly caused by a random spontaneous deletion
• Cardiovascular structural abnormalities are present in ~80% of patients. Increased arterial stiffness and stenosis can be present anywhere within the arterial system.
• The most common CHD lesion is supravalvular aortic stenosis presenting (45-75%), followed by pulmonary artery stenosis. Other CHD anomalies include aortic arch abnormalities, thoracic aortic stenosis, coronary artery abnormalities (ostial stenosis, diffuse stenosis, dilation/obstruction), aortic and/or mitral valvular abnormalities, and VSD.
• Patients are at an increased risk of sudden cardiac death (25-100x compared to the general population), with many occurring in the perianesthetic setting.
• Prolonged QT is present in ~13% of Williams syndrome patients.
• Noncardiovascular findings include hypercalcemia, developmental delay, visuospatial deficits, poor coordination, joint contractures, short stature, dysmorphic facies, and gregarious personality.