Methods

A total of 155 patients with definite PHACE were identified from the Institutional Review Board–approved PHACE Syndrome International Clinical Registry and Genetic Repository housed at the Medical College of Wisconsin and Children’s Hospital of Wisconsin. All available clinical, radiologic, and histopathologic data for anatomic abnormalities of the heart, aortic arch, brachiocephalic vessels, and cerebrovascular bed were reviewed by a team of pediatric dermatologists and a pediatric cardiologist from the Medical College of Wisconsin. Five subjects were excluded because of insufficient records ( Figure 1 ). Patent foramen ovale was considered a normal variant and was excluded. A patent ductus arteriosus was considered pathologic if it persisted past the neonatal period and was not associated with significant aortic arch obstruction or complex heart disease. Pearson chi-square and Fisher’s exact tests were used to analyze data for hemangioma location and associated cardiovascular anomalies. Follow-up information (>2 years) was available for 10 subjects with coarctation cared for at the Medical College of Wisconsin, allowing for preliminary assessment of aortic disease progression over time.

Flowchart demonstrating subject inclusion process and cardiovascular anomaly frequencies. Individual subjects may have >1 anomaly. Values are expressed as percentage of total eligible registry population (n = 150). PDA = patent ductus arteriosus; PFO = patent foramen ovale.

Aortic coarctation histologic specimens from surgical resection were available for 7 of the 17 patients with PHACE who had a section of aorta removed during aortic arch reconstruction. Paraffin blocks were available for 3 of the 7 patients, and 4 of 7 patients had only hematoxylin and eosin slides for review. These samples were reviewed centrally at the Medical College of Wisconsin and compared with control specimens from 52 consecutive surgical coarctation repairs (non-PHACE) performed at Children’s Hospital of Wisconsin.

Results

Figure 1 summarizes the cardiovascular anomalies: 62 (41%) of 150 patients with PHACE had associated intracardiac, aortic arch, and/or brachiocephalic vessel anomalies. There were 51 females (82%) and 11 males (18%) with cardiovascular anomalies giving a female/male ratio of 4.6:1. This ratio was similar to that of the entire registry (4.2:1). Importantly, 57 (92%) of 62 patients with cardiovascular anomalies also had associated cervical or cerebral arterial anomalies (dysgenesis, narrowing, nonvisualization, primitive embryonic carotid-vertebrobasilar connections, and/or anomalous origin or course). In total, 23 (37%) of 62 subjects required procedural or surgical intervention for their cardiovascular anomalies.

Coarctation or interrupted aortic arch was found in 28 (45%) of 62 patients, characterized by unusual long-segment transverse arch narrowing with adjacent segments of aneurysmal dilatation that is quite distinctive from the typical isolated juxtaductal coarctation anatomy seen in those without PHACE ( Figure 2 ). None of the aortic arch defects in patients with PHACE were associated with bicuspid aortic valve, mitral valve anomalies, or left ventricular hypoplasia. Intervention for significant aortic arch obstruction was required in 17 (61%) of 28 subjects with coarctation of the aorta, and the age range for the intervention was 4 days to 3.5 years with a median age of 2 months. Three patients required interposition grafts as infants because of the long-segment nature of the obstruction. One patient with coarctation and stent placement died at the age of 5 years due to aortic rupture secondary to bacterial aortitis at the site of aortic stenting.

Three-dimensional magnetic resonance imaging aortic reconstruction in this patient with PHACE with severe coarctation with multiple areas of narrowing and aneurysms in the transverse arch (as outlined by arrows in A) . Both SCAs arise distal to areas of obstruction (arrows in B) , and the right SCA has an aberrant origin.

Of the 10 patients with coarctation and follow-up data available at the Medical College of Wiscosin, 7 have undergone surgical repair and 3 have been followed without intervention because of a mild gradient at presentation. Mean age at follow-up was 8 years (range 3 to 15 years). All of the patients without intervention have continued to demonstrate only mild arch gradients without progression, and none have required late intervention. Of the subjects who had surgery, 5 of 7 have stable aortic arch patency without progressive narrowing or dilation and have not required reintervention. The 2 children who required interposition graft placement as infants have developed expected progressive narrowing with growth, and 1 graft has been replaced at the age of 11 years.

Brachiocephalic abnormalities were the most common cardiovascular anomaly, identified in 35 (56%) of 62 subjects. Aberrant origin of a subclavian artery (SCA) was found in 31 (50%) of 62 subjects, with 22 having aberrant origin of the right SCA from a left aortic arch, 8 having aberrant origin of a left SCA from a right aortic arch, and 1 having an aberrant origin of a left SCA from a left aortic arch. Of the 28 subjects with coarctation, 16 (57%) also had aberrant SCA origin so that both SCAs arose distal to the obstruction. Origin of both carotid arteries from a common trunk (“bovine” arch) was identified in 5 (8%) of 62 subjects, and 1 subject had isolated aneurysmal dilatation of the right SCA. Abnormal aortic arch sidedness was seen in 10 (16%) of 62 subjects having a dominant right aortic arch. A vascular ring was present in 5 subjects (all with a dominant right aortic arch), and 3 required surgical division. Finally, 7 subjects had ascending aortic dilatation without evidence of aortic valve pathology.

Intracardiac anomalies were also found in the cohort, with 19 (31%) of 62 patients having a ventricular septal defect (VSD). Isolated VSDs without associated intracardiac abnormalities were most common (16 of 19 patients), and they frequently did not require surgical intervention (8 of 8 muscular VSDs and 5 of 8 perimembranous VSDs closed spontaneously). Complex congenital heart disease was rarely seen (3 of 62 patients), with 2 cases of tetralogy of Fallot and 1 case of tricuspid atresia, as were other intracardiac heart defects (2 pulmonary stenosis, 1 atrial septal defect, 1 patent ductus arteriosus, and 1 bicuspid aortic valve without arch anomalies). One subject had dextrocardia with a left-sided aortic arch and situs solitus without other cardiovascular anomalies. In addition, superior systemic venous anomalies were identified in 12 (19%) of 62 patients, with 7 having a retroaortic innominate vein and 5 having bilateral superior vena cavae with a left superior vena cava draining to the coronary sinus.

Histologic examination of surgically excised aortic segments demonstrated strikingly similar abnormalities in the 7 PHACE specimens. In 5 of 7 specimens, there were large, well-delineated mural zones of scarring and necrosis with almost complete loss of arterial smooth muscle cells and elastic fibers in the intima and media ( Figure 3 ). The remaining 2 PHACE coarctation segments had smaller areas of decreased arterial smooth muscle cells in the tunica media and evidence of increased adventitial collagen deposition.

Low-power hematoxylin and eosin stain of aortic coarctation tissue from a patient with PHACE demonstrating intimal hyperplasia and large arcuate zones with loss of smooth muscle and elastic tissue. Inset shows elastin stain.

The excised aortic segments from patients without PHACE were notably different from those with PHACE, with 47 (90%) of 52 of the non-PHACE coarctation control specimens exhibiting typical coarctation findings with a short, asymmetrical, postductal narrowing, often viewed as an intimal shelf. In addition, there was intimal fibrosis and tunica media showing multiple fascicles of muscular elastic tissue occasionally extending from the ductus onto the adjacent aortic wall. Only 5 of 52 non-PHACE segments contained zones of medial necrosis similar to the PHACE specimens, and 3 of those were likely related to suture scar formation from previous surgical intervention. Although the adventitial layer appeared thicker in the PHACE specimens compared to the non-PHACE specimens, the majority of excised segments in both cohorts lacked extra-adventitial soft tissues so that analysis of adventitial thickness was difficult.

All PHACE patients with cardiovascular anomalies had a segmental infantile hemangioma of the head and neck region. A greater percentage of infantile hemangiomas were located on the left side of the head and neck in patients with coarctation (46%) compared with those without coarctation in our registry population (39%; p = 0.048). However, hemangioma laterality (left, right, or bilateral) did not predict the presence of congenital heart disease overall (p = 0.243). Additionally, there was no ipsilateral association between the aortic arch direction and the cervicofacial hemangioma location. Of the 10 patients with a right-sided aortic arch, 4 had a right-sided hemangioma, 1 hemangioma was left-sided, and 5 hemangiomas were bilateral (p = 0.216). Hemangioma distribution involving the mandibular (S3) facial segment was not associated with cardiovascular anomalies, as 47% of subjects with S3 involvement had cardiovascular anomalies versus 38% of those without S3 involvement (p = 0.316). The presence of a midline anomaly (sternal cleft or median raphe) did not significantly differ between subjects with (31%) and without (24%) congenital heart disease (p = 0.448). Additionally, there did not seem to be differences in the prevalence of other features of PHACE.