INTRODUCTION

Background: Interrupted aortic arch (IAA) is a relatively rare genetic disorder that occurs in association with a usually nonrestrictive ventricular septal defect and ductus arteriosus or, less commonly, with a large aortopulmonary window or truncus arteriosus. Although most cases occur in normally connected great arteries, IAA can coexist with any ventriculoarterial alignment and also with single ventricle. IAA and complete common atrioventricular canal can be observed in the context of CHARGE association (coloboma, heart disease, atresia choanae, retarded growth and development and/or CNS anomalies, genital hypoplasia, and ear anomalies and/or deafness). Approximately 50% of IAA patients have DiGeorge syndrome.

Surgical reconstruction of the arch is now considered straightforward; hence, attention is increasingly focused on the preoperative identification and surgical management of the aortic valve and subaortic hypoplasia found in approximately half of cases. IAA is the first cardiovascular pattern formation anomaly to be demonstrated to have a genetic basis in both mouse and human.

Embryology

The embryology of this lesion is still unknown. However, approximately half of IAA patients have a deletion of a 1.5-3 Mb region of chromosome band 22q11.2, the most common deletion syndrome in humans. Although 30 genes lie within the 3 Mb deleted region, which ones contribute to the IAA phenotype is not known. In addition, 2 independent lines of evidence suggest that IAA type A is etiologically different from IAA type B (see “Anatomy” for definition of types). The variety of associated ventricular septal defects is different in the 2 types. The prevalence of 22q11.2 hemizygosity is also different; approximately three fourths of patients with IAA type B have the deletion, while exceedingly few patients with IAA type A have the deletion.

In 1999, Lindsay et al deleted the region of mouse chromosome 16 (Df1), which is homologous to the human chromosome band 22q11.2. Heterozygously Df1-deleted mice display IAA type B, and this phenotype can be rescued by genetic complementation using a chromosome duplicated for Df1. This argues strongly that the Df1/+ phenotype results from haploinsufficiency of gene(s) located within the Df1 deletion.

Anatomy

IAA has been classified into 3 types (A, B and C) based on the site of aortic interruption. In type A interrupted left aortic arch, the arch interruption occurs distal to the origin of the left subclavian artery. In type B interrupted left aortic arch, the interruption occurs distal to the origin of the left common carotid artery. In type C interrupted left aortic arch, the interruption occurs proximal to the origin of the left common carotid artery.

In any of the 3 types, the right subclavian artery may arise normally or abnormally; the 2 most common abnormal sites are distal to the left subclavian artery (aberrant right subclavian artery) and from a right ductus arteriosus (isolated right subclavian artery). Type B interruptions account for about two thirds of cases, type A occur in about one third of cases, and type C are present in less than 1% of cases.

Pathophysiology: During fetal development, left ventricular output supplies the arterial circulation proximal to the interruption while right ventricular output supplies arterial circulation distal to the interruption via the left ductus arteriosus. Postnatally, this arrangement continues, with the addition of the pulmonary blood flow to the load of the left ventricle.

Frequency:

• In the US: The incidence is approximately 2 cases per 100,000 live births.

Mortality/Morbidity: Circulatory compromise manifested by metabolic acidosis begins when the ductus arteriosus reduces in caliber, thus decreasing flow to the circulation distal to the arch interruption. Prior to this, even severe aortic and subaortic hypoplasia is physiologically masked because of the presence of the ventricular septal defect. Patients are at risk for severe low output syndrome because of both the effect of the profound metabolic acidosis on cardiac performance and the reduced distal systemic arterial circulation imposed by falling pulmonary vascular resistance.

Age: Nearly all patients with IAA present in the first 2 weeks of life as the ductus arteriosus closes. Most patients present in the first day of life.

CLINICAL

History: Symptoms in the neonate include tachypnea, poor feeding, and lethargy.

Physical:

• Recognizing IAA is difficult prior to reduction in the caliber of the ductus arteriosus. The hallmark thereafter is a mottled or grey appearance to the lower body, representing poor perfusion to that portion of the circulation located distal to the arch interruption.

• A difference in systolic blood pressure between the right arm and the lower extremities may or may not be present. Frequently, a lack of discrepancy in blood pressure is due to the profound reduction in cardiac performance. If the right subclavian artery is aberrant, no disparity occurs between the systolic blood pressure in the right arm and that in the lower extremities because the right subclavian origin is distal to the arch interruption.

• Although a difference in oxygen saturation between the right arm and the lower body may occur in cases without an aberrant right subclavian artery, this can be quite subtle in cases of high pulmonary blood flow. In normally connected great arteries, the oxygen saturation is higher in the right arm than in the lower body. In IAA with transposition of the great arteries, the reverse occurs.

• The first heart sound is normal. The second heart sound is usually single.

• A grade 2 or grade 3 systolic ejection murmur is usually present at the base, representing pulmonary blood flow. The mid diastolic rumble of flow-related mitral stenosis is uncommonly heard in neonates.

• The liver is usually normal in size, but in neonates, this is principally a reflection of intravascular volume status.

• Finally, because approximately 50% of IAA patients have DiGeorge syndrome, facial dysmorphism is frequently present.

Causes: Abnormal cranial neural crest proliferation, migration, survival, or terminal function is hypothesized to be causal. This hypothesis is grounded largely on the basis of ablation studies in the chick and targeted gene disruptions in the mouse. The actual cause of human IAA is unknown, but progress has been made in the understanding of DiGeorge syndrome, which frequently coexists.

• Genetic causes

• Several single-gene mouse knockouts display IAA as a principal phenotype. Among the genes investigated are the ones encoding the winged helix transcription factors MF-1 and MFH-1 and those encoding components of the endothelin-1/endothelin A receptor-mediated signaling pathway.

• Approximately 90% of patients with DiGeorge syndrome have deletions within 22q11. This fact leads to the current model that the syndrome results from haploinsufficiency for a gene or genes mapping to this deleted region.

DIFFERENTIALS

Coarctation of the Aorta
DiGeorge Syndrome
Neonatal Sepsis
Velocardiofacial Syndrome