DOI:10.1542/peds.113.2.

412
2004;113;412-415 Pediatrics
Andrea Donti, Roberto Formigari, Marco Bonvicini and Fernando Maria Picchio
Gabriele Bronzetti, Alessandro Giardini, Annalisa Patrizi, Daniela Prandstraller,
Review
and Cardiac Defects and Eye Abnormalities (PHACE) Anomaly: Report and
Malformations, Hemangiomas, Arterial Anomalies, Coarctation of the Aorta,
Ipsilateral Hemangioma and Aortic Arch Anomalies in Posterior Fossa
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Ipsilateral Hemangioma and Aortic Arch Anomalies in Posterior Fossa
Malformations, Hemangiomas, Arterial Anomalies, Coarctation of the
Aorta, and Cardiac Defects and Eye Abnormalities (PHACE) Anomaly:
Report and Review
Gabriele Bronzetti, MD*; Alessandro Giardini, MD*; Annalisa Patrizi, MD; Daniela Prandstraller, MD*;
Andrea Donti, MD*; Roberto Formigari, MD*; Marco Bonvicini, MD*; and Fernando Maria Picchio, MD*
ABSTRACT. Posterior fossa malformations, hemangio-
mas, arterial anomalies, coarctation of the aorta, and car-
diac defects and eye abnormalities (PHACE) is a rare
congenital anomaly with a broad spectrum of clinical
manifestations with a striking female predominance. We
describe an infant with PHACE anomaly and aortic co-
arctation who underwent cardiac catheterization to
clearly define the complex anatomy of the aortic lesion
before surgical repair. Review of the literature docu-
ments a highly significant association between ipsilat-
eral hemangiomas and cerebrovascular and aortic arch
anomalies. We conclude that cardiac catheterization is
required to define the complex anatomy of aortic lesions
and should be performed in all patients with PHACE and
evident aortic involvement to plan appropriate and safe
surgical repair. Pediatrics 2004;113:412415; PHACE, aor-
tic arch, hemangioma, aortic coarctation, cardiac cathe-
terization.
ABBREVIATION. PHACE, posterior fossa malformations, heman-
giomas, arterial anomalies, coarctation of the aorta, and cardiac
defects and eye abnormalities.
I
nfantile hemangiomas are common vascular le-
sions, occurring in 8% of all newborns, and are
usually solitary (90%). However, segmental hem-
angiomas, which may occur in unusual locations in
deep tissue, occur in several syndromes.
1
Posterior
fossa malformations, hemangiomas, arterial anoma-
lies, coarctation of the aorta, and cardiac defects and
eye abnormalities (PHACE) is an uncommon con-
genital neurocutaneous syndrome with a striking fe-
male predominance. Approximately 70% of affected
infants have no more than 1 of the extracutaneous
manifestations.
2,3
Hemangiomas and cardiovascular
malformations are seen also in supraumbilical mid-
line raphe and midline defects.
47
Several case re-
ports exist of PHACE-associated cardiovascular
anomalies, most often aortic coarctation or interrup-
tion.
129
We describe a further case with PHACE
syndrome with complex coarctation. A review of the
reported cases of PHACE shows a highly significant
prevalence of ipsilateral hemangiomas and aortic
arch anomalies.
CASE REPORTS
A 2-month-old girl with an extensive, left facial hemangioma
extending to the cheek, lips, and eye (Fig 1 a) was referred for
suspected aortic coarctation. Echocardiography showed normal
intracardiac anatomy with a persistent left superior vena cava
draining into the coronary sinus. A suprasternal scan documented
a complex aortic anomaly with severe narrowing of the posterior
aspect of the aortic arch and absent antegrade flow at the level of
the aortic isthmus. A color Doppler scan showed multiple collat-
eral vessels running close to the aorta and evidence of periaortic
extension of the hemangioma. Magnetic resonance imaging ex-
cluded gross intracranial anomalies but confirmed the extension
of the hemangioma to the left orbit and the mediastinum with
severe aortic coarctation (Fig 1 b). Cardiac catheterization demon-
strated type A interruption of the left-sided aortic arch distal to the
take-off of the left carotid artery followed by a tortuous and
narrow (3-mm) tract of descending aorta, receiving its sole supply
from the left vertebral artery (Fig 1 c). The same examination
showed a distal take-off of the left subclavian artery with cranial-
caudal flow toward the normal diaphragmatic aorta. The patient
underwent successful repair with interposition of a patch of cryo-
preserved pericardium between the aortic arch and the diaphrag-
matic aorta, using the interrupted tract as the roof of the recon-
structed aorta.
A 40-day-old boy with a left-sided hemangioma extended to
the face and neck was referred to us a few months later. In this
patient, aortic angiography showed a looped left aortic arch with
significant segmental narrowing of the descending thoracic aorta
and with a stenotic and distally displaced origin of the left sub-
clavian artery (Fig 1, d and e).
DISCUSSION
A review documents that the clinical sequence
described above is actually rather typical of other
cases (n 32) with cardiovascular involvement
230
traced by us in the MEDLINE database (using
PHACE, aorta, aortic coarctation, hemangioma, and
hemangioma as abstract search terms; Table 1). In
13 cases there was a right aortic arch with coarcta-
tion or interruption, which is generally a rare find-
ing.
35,913,15,20,27
We considered the possibility that,
as already suggested for epi-aortic vessel anomalies
in patients with PHACE anomaly,
3,22
an ipsilateral
relationship might exist between the location of the
hemangioma and the side of the aortic arch.
Excluding the 4 cases with undescribed hemangi-
oma location, we noticed that all reported cases (11
of 11) of right aortic arch also had a right hemangi-
oma. Furthermore, a similar ipsilateral association
From *Pediatric Cardiology and Institute of Dermatology, University of
Bologna, Bologna, Italy.
Received for publication May 29, 2003; accepted Oct 29, 2003.
Reprint requests to (G.B.) Pediatric Cardiology and Adult Congenital Unit,
University of Bologna, Policlinico S. Orsola-Malpighi, Via Massarenti 9,
40138 Bologna, Italy. E-mail: gabronz@hotmail.com
PEDIATRICS (ISSN 0031 4005). Copyright 2004 by the American Acad-
emy of Pediatrics.
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was present in 22 of 23 (95%) patients with left aortic
arch. Both of these associations are highly significant
(Fishers exact test: P .00001). Thus, a close associ-
ation seems to exist between aortic arch (with/with-
out coarctation) and hemangioma laterality. This ob-
servation lead us to hypothesize that a single genetic
defect involved in lateralization may be responsible
for the aortic arch defects, great artery anomalies,
and facial hemangiomas found in patients with
PHACE anomaly.
Hemangiomas associated with midline develop-
mental defects (including sternal cleft and supraum-
bilical abdominal raphe) usually involve the face.
12
Opitz
31,32
postulated that sternal clefting and hem-
angiomas probably occur between 8 and 10 weeks of
gestation via an abnormality in a developmental
field. Field development is 1 of the phylogenetic
consequences of regression of metamerism, with 6
pairs of arterial branches coming to form a single
aortic arch system. This theory implies that certain
insults of embryonic development at a specific criti-
cal time may give rise to very similar developmental
outcomes, as in PHACE anomaly.
31,32
The concept
that a single defect may be responsible for the anom-
alies observed in PHACE could explain why some
patients show cardiovascular defects only, without
any intracranial and skeletal involvement, as ob-
served in both of the patients seen by us and in other
remarkably similar reported cases.
3,8,15,27
Such cases
confined to cardiovascular defects would seem to
suggest that they may represent a partial expression
of this defect rather than a separate clinical entity.
This concept is reinforced by the many observations
of patients with PHACE anomaly without any car-
diovascular involvement.
2,5,7,12,13,18,22
Other authors
3,15
have also described highly com-
plex aortic arch morphology similar to that observ-
able in the 2 patients seen by us (Fig 1, d and e). This
suggests that, in contrast to simple aortic coarctation
or the type of aortic arch interruption observed in
patients with DiGeorge syndrome, the aortic anom-
alies found in the context of PHACE may represent a
distinctive morphologic entity with unusually com-
plex and unpredictable anatomic involvement. In
fact, both of the patients seen by us presented a long
tract of markedly narrowed aorta (from the posterior
arch to diaphragmatic aorta). Interestingly, in both
the patients observed by us, histopathologic exami-
nation of the diseased aorta showed microstructural
anomalies in the intimal and medial layers, possibly
due to inflammation or dysplasia of the aortic wall.
In our experience, patients referrals were due to
clinical findings consistent with aortic coarctation
(absent femoral pulses and precordial systolic mur-
mur), which led us to perform transthoracic echocar-
diography. However, the echo scans, although sug-
gesting an aortic anomaly, were unable to clearly
define the complex aortic anatomy (ie, coarctation/
Fig 1. a, Cutaneous extension at presentation of the hemangioma to the left side of the face of the patient reported herein. Angio-magnetic
resonance imaging (b) and angiographic (c) views of the thoracic aorta show that the morphology of the aortic arch is complex with an
interrupted aortic segment (arrows) followed by a long, tortuous pseudocoarctation. All these anomalies are also observable (d and e) in
another patient with PHACE anomaly seen by us.
8
EXPERIENCE AND REASON 413
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interruption and blood supply to the descending
thoracic aorta). On clinical grounds, these observa-
tions imply that routine transthoracic echocardiogra-
phy
33
cannot provide a complete preoperative func-
tional and anatomic definition in patients with
PHACE. We think that cardiac catheterization and
angiography and/or magnetic resonance should be
mandatory to plan safe, complete surgical repair of
the aortic defect.
ACKNOWLEDGMENTS
We acknowledge Mr Robin M.T. Cooke for scientific editing
and Ms Claudia Cavicchi for valuable help.
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TABLE 1. Presentation Characteristics of the 33 Reported Cases of PHACE Syndrome
Authors Intracardiac
Defect
Aortic Arch Anomaly Side of
Hemangioma
Crisponi et al
5
ASD RAA, AC R
Kishnani et al
4
RAA, AC, ALSA R
Honey et al
9
Infracristal VSD RAA, AC, ALSA R
Vaillant et al
10
RAA, AC, ALSA R
Geller et al
11
TA, PS RAA R
Reese et al
12
RAA, AC, ALSA R
Burrows et al
13
ToF, PLSVC RAA, ALSA, LCAo, occluded R
RICA
Wong et al
3
DAA (right dom), IAA B, ALSA R
DAA (right dom), IAA B, ALSA R
Yates et al
27
VSD RAA, AC Both sides
Patel et al
19
RAA, AC, ARSA, PDA R
Schneeweiss et al
15
LAA, AC, aneurism of RSA L
LAA, AC, aneurism of RSA L
RAA, AC, aneurism of RSA
RAA, AC
Goh et al
14
LAA, IAA A, ARSA R
LAA, AC, ARSA L
Raas-Rothschild et al
6
ASD, VSD LAA, AA Both sides
Sawaya and McLaurin
24
ASD LAA, PDA L
Bruyere et al
23
ASD LAA, PDA L
Coats et al
28
ASD LAA L
Frieden et al
2
LAA, aortic dilation, no LCA Both sides
Hijii et al
16
LAA, AC L
Quecedo et al
17
LAA, AC L
Hirsch et al
18
Dextrocardia LAA, PDA L
Molland and Purcell
20
AC, LSA
Buzenet et al
21
LAA, AC, stenosis of brachiocephalic
trunk and LCA
L
Pasic et al
25
PLSVC LAA, AA, anomalous coronary arteries L
Schieken et al
26
LAA, AA, absent right innominate artery Both sides
Metry et al
7
VSD LAA
VSD LAA, AC L
LAA, AC, ARSA L
Pascual-Castroviejo et al
22
LAA, AC, PDA L
TA LAA, AC, ALCA L
LAA, AC, ALCA L
Matsui et al
30
LAA, ALSA L
Zeevi and Berant
28
LAA, CAA, AA L
Gargiulo et al
8
PLSVC LAA, AC, ALSA L
Present report PLSVC LAA, IAA, A, ALSA L
AA indicates aortic aneurysm; AC, aortic coarctation; ALCA, absent left carotid artery; ALSA, anomalous left subclavian artery; Ao, aorta;
ARSA, anomalous right subclavian artery; ASD, atrial septal defect; CAA, cervical aortic arch; DAA, double aortic arch; IAA, interrupted
aortic arch; L, left; LAA, left aortic arch; LCA, left carotid artery; PDA, patent ductus arteriosus; PLSVC, persistent left superior vena cava;
PS, pulmonary stenosis; R, right; RAA, right aortic arch; RICA, right internal carotid artery; RSA, right subclavian artery; TA, tricuspid
atresia; ToF, tetralogy of Fallot; VSD, ventricular septal defect.
414 AORTIC FACES OF PHACE ANOMALY
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14211425
AMERICAS SHAME
There are approximately two million people in jail in America today, 2 166 260
at last count: more than four times as many people as thirty years ago. It is the
largest number in our history. More than 500 in every 100 000 Americans are
behind bars, between four and ten times the incarceration rate of any civilized
country in the world . . . But gross numbers are only part of the story. The other
part is racial imbalance. Twelve percent of African-American men between twenty
and thirty-four are currently behind bars (the highest figure ever recorded by the
Justice Department) compared with 1.6% of white men of comparable ages. And
according to the same source, 28% of black men will be sent to jail in their
lifetimes.
Bruner JS. Do not pass go. New York Review of Books. September 25, 2003
Submitted by Student
EXPERIENCE AND REASON 415
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DOI:10.1542/peds.113.2.412
2004;113;412-415 Pediatrics
Andrea Donti, Roberto Formigari, Marco Bonvicini and Fernando Maria Picchio
Gabriele Bronzetti, Alessandro Giardini, Annalisa Patrizi, Daniela Prandstraller,
Review
and Cardiac Defects and Eye Abnormalities (PHACE) Anomaly: Report and
Malformations, Hemangiomas, Arterial Anomalies, Coarctation of the Aorta,
Ipsilateral Hemangioma and Aortic Arch Anomalies in Posterior Fossa
& Services
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