5 Hemangioma Syndromes
Infantile hemangiomas (IHs) are common tumors that are typically confined to the skin. Some “high-risk” types of IH, however, are associated with developmental anomalies or extracutaneous hemangiomas. This chapter reviews the clinical characteristics, natural history, diagnosis, and management of (1) PHACES association (posterior fossae anomalies, hemangioma, arterial anomalies, cardiac and cerebrovascular anomalies, eye anomalies, and midline sternal or supraumbilical defects); (2) infantile hemangioma of the skin and airway; and (3) multifocal hemangiomas with a risk for extracutaneous hemangiomas.
5.1.1 Definition and Spectrum of Anomalies
PHACES association (Online Mendelian Inheritance in Man [OMIM] no. 606519) is a neurocutaneous disorder characterized by the association of hemangiomas, typically large, segmental IH of the face, with one or more of the following: cerebrovascular anomalies, cardiovascular anomalies, eye anomalies, and ventral developmental defects, specifically, sternal defects or supraumbilical raphe. 1 The term cutaneous hemangioma–vascular complex syndrome is a synonymous term used in the European literature. 2 In 2009, diagnostic criteria were published that aimed to identify patients with PHACE more accurately ( Table 5.1 ). 3 About 90% of patients with PHACE have more than one extracutaneous manifestation. 4
Anomaly of major cerebral arteries
Persistent trigeminal artery
Persistent embryonic artery other than trigeminal artery
Posterior fossa anomaly
Neuronal migration disorder
Aortic arch anomaly
Coarctation or aortic dysplasia
Aberrant subclavian artery
Ventricular septal defect
Right aortic arch
Posterior segment abnormalitiy
Anterior segment abnormality
Sternal defect or supraumbilical raphe
Note: Definite PHACE syndrome is defined as facial hemangioma > 5 cm in diameter plus one major criteria or two minor criteria. Possible PHACE syndrome is defined as facial hemangioma > 5 cm in diameter PLUS one minor criteria, hemangioma of the neck or upper torso plus one major criteria, or two minor criteria, no hemangioma plus two major criteria.
Used with permission from Metry DW, Haggstrom AN, Drolet BA, et al. A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications. Am J Med Genet A. 2006;140(9):975–986.
A precise incidence of PHACES in the general population is not known; however, in a prospective study of 108 patients with facial hemangiomas larger than 22 cm2 who had systematic investigation with magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) of the head and neck, echocardiogram, and eye examination, 31% met the diagnostic criteria for PHACES. 4 Whereas infants with hemangiomas are more likely to be female, premature, low-birth-weight, and white, those with PHACES have an even stronger female predominance (ranging from 5:1 to 9:1 compared with 2 or 3:1 as seen in hemangiomas in general), and they are less likely to be premature, although prematurity per se is not protective against PHACES. 4 , 5 , 6 , 7 , 8 , 9
No heritable cases of PHACES have been reported. The observed female predominance has been hypothesized by some researchers to be due to skewed X-linked inactivation in asymptomatic carriers. Levin and Kaler identified a family in whom the proband exhibited random X activation, but the child’s unaffected mother displayed skewed X-inactivation supporting the theory of an X-linked process. 10 Larger studies, however, have not supported a significant role for skewed X-inactivation in the pathogenesis of PHACE. 11 Moreover, unlike many X-linked disorders that display severe phenotypes associated with male lethality, male infants with PHACES do not appear to exhibit increased disease severity, and maternal miscarriage rates are not increased. 12
The constellation of observed central nervous system, cardiac, and ocular anomalies suggests that PHACES is a consequence of an early error in embryogenesis that occurs during the first 6 weeks of life, affecting a “developmental field.” 6 , 13 , 14 , 15 Patterns of facial segmental hemangiomas resemble facial primordia that mirror neural crest migration patterns, suggesting that neural crest derivatives may play a role in pathogenesis.
5.1.4 Clinical Features
Hemangiomas in PHACES syndrome are typically plaque type, segmental hemangiomas involving the face, although isolated cases of PHACES have been reported in large nonfacial hemangiomas and small, localized hemangiomas. 5 , 16 The plaque-type appearance of the hemangiomas associated with PHACES can vary from superficial to deep or mixed-type hemangiomas and from flat, telangectatic, barely proliferative patches to exophytic, bulky tumors. Segmental hemangioma is a term used to describe hemangiomas that display a linear or geographic distribution resembling a developmental unit. The patterns correspond closely with embryologic facial primordia and can be classified into four primary segments (S1–S4) ( Fig. 5.1 ). 17 , 18 Cutaneous complications of the hemangiomas seen in PHACES are more common because of the segmental morphology. In general, segmental hemangiomas have been associated with increased rates ulceration, bleeding, and visual compromise. 6 , 19 In addition, segmental hemangiomas often display more aggressive proliferative tendencies. They grow, on average, 1 month longer than nonsegmental hemangiomas and rarely may continue to proliferate after the child is 1 year of age. 20 , 21
Hemangioma distribution may be an important clinical clue to predicting manifestations of PHACES. Larger and multisegment hemangiomas have a higher risk of PHACES, and upper face hemangiomas (S1 and S4) portend an increased risk of cerebrovascular anomalies. 4 Patients with maxillary hemangiomas (S2) in isolation appear to be at least risk ( Fig. 5.2 ).
Central Nervous System
See Fig. 5.3 . The relationship between infantile hemangioma and intracranial malformations was first recognized in 1978 by Pascual-Castroviejo. 22 The posterior fossa brain abnormalities originally described in the acronym PHACES 1 are now recognized to be less common than cervical and cerebrovascular vascular anomalies, which occur in 91% of patients with large facial hemangiomas. 4 Some affected individuals may have dynamic and progressive changes, including vessel stenosis and occlusion, 13 , 23 , 24 , 25 and strokes have been reported in a minority of patients (average age of onset, 13.6 months). 26 Patients at highest risk for stroke appear to be those with major cerebral artery anomalies or patients with more pervasive multivessel anomalies ( Table 5.1 ). 26
Cerebrovascular anomalies frequently manifest as dysgenesis, narrowing, anomalous course, or nonvisualization. 13 , 27 Both structural and cerebrovascular anomalies typically occur ipsilateral to the cutaneous hemangioma. 13 , 14 , 27 , 28 , 29 Cerebrovascular and structural anomalies are more common in patients with S1, frontotemporal involvement alone or in combination with other segments compared with those without S1 involvement. 4
Developmental delay has been observed in a minority of cases of older patients with a history of PHACES. In a retrospective series of 93 patients who underwent neurodevelopmental testing after age 1 (mean age, 4 years), 69% had neurodevelopmental abnormalities, of which speech delay was the most common finding. 30 Prospective studies to assess the incidence of other long-term sequelae are needed.