Possible PHACE Syndrome With Multifocal Infantile Hemangiomas

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PHACE syndrome is a congenital disorder characterized by the presence of posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and other cardiac defects, and eye abnormalities. Large infantile hemangiomas are often present on the head and neck, in conjunction with a spectrum of anomalies. Although the primary features include facial hem- angiomas greater than 5 cm,¹ the presence of a large cervicofacial hemangioma is not an absolute requirement for PHACE syndrome diagnosis.² Major and minor criteria include a variety of anomalies, including arterial, structural brain, cardiovascular, ocular, and ventral malformations (Table 1).

PHACE syndrome can be definitively diagnosed with:³

• Hemangioma greater than 5 cm (diameter) of the head, including the scalp, PLUS 1 major criterion or 2 minor criteria OR
• Hemangioma of the neck, upper trunk, or trunk and proximal extremity PLUS 2 major criteria

Possible PHACE syndrome can be diagnosed with:³

• Hemangioma greater than 5 cm (diameter) of the head, including the scalp, PLUS 1 minor criterion
• Hemangioma of the neck, upper trunk, or trunk and proximal upper extremity PLUS 1 major criterion or 2 minor criteria
• No hemangioma PLUS 2 major criteria

The prevalence of PHACE syndrome is estimated to be less than 1 per million.^4,5 Its precise etiology has not been elucidated, although it is believed to result from an embryologic field defect with associated structural anomalies occurring between approximately 6 and 9 weeks’ gestation.² The mutations are hypothesized to affect the growing fetus temporally and spatially, thereby affecting specific cells in their migration, growth, and differentiation. Possible theories include postzygotic somatic mutations, de novo genetic variants, copy number variants, epigenetic mechanisms, and environmental factors or hypoxic events occurring in utero.² For unknown reasons, PHACE syndrome affects females at a greater rate than males.⁶

We report on a case of a 2-month-old infant girl presenting to dermatology for evaluation of multifocal infantile hemangiomas. She had a past medical history significant for Dandy-Walker malformation, a perimembranous ventricular septal defect (VSD), and a fenestrated atrial septum. The presence of hemangiomas of the upper trunk and proximal upper extremity, Dandy-Walker malformation (major criterion), and VSD (minor criterion) qualified this patient for a diagnosis of possible PHACE syndrome.

Case Report

The infant was born at 39 weeks and 1 day via caesarean delivery. The pregnancy was complicated by maternal COVID-19. At delivery, multiple cutaneous hemangiomas ranging in size from 1 to 5 mm were noted on the trunk and extremities (Figure 1). Due to a prenatal ultrasound suggestive of Dandy-Walker malformation, the patient underwent a multiplanar, multisequence magnetic resonance imaging (MRI) of the brain without contrast to assess for congenital brain malformation. Hypoplasia of the vermis, mild enlargement of the fourth ventricle, enlargement of the posterior fossa, and increased retrocerebellar cerebrospinal fluid space were consistent with Dandy-Walker malformation.

During a newborn wellness visit 4 days later, the patient was referred to pediatric cardiology due to the presence of a grade 2 harsh, systolic murmur heard loudest at the left sternal border. She was subsequently diagnosed with a perimembranous VSD and a fenestrated atrial septum via echocardiogram. There was no evidence of aortic anomaly.

At age 2 months, she presented to dermatology with 11 enlarging 1- to 5.5-mm dome-shaped, red papules dispersed on the trunk, upper extremities, and lower extremities, clinically consistent with multifocal infantile hemangiomas. Due to the presence of greater than 5 cutaneous hemangiomas, a liver ultrasound was ordered to assess for hepatic hemangiomas. This was negative for liver involvement.

Although the patient did not have a segmental cervicofacial hemangioma, she met the criteria for possible PHACE syndrome due to hemangiomas of the upper trunk and proximal upper extremity plus 1 major criterion, Dandy-Walker malformation, and 1 minor criterion, a VSD. Although arterial anomalies are a common extracutaneous finding in PHACE syndrome, magnetic resonance angiography was not performed because there were no concerns for arterial anomalies based on previous brain MRI im- aging and physical examination. The patient had been evaluated by ophthalmology and did not exhibit PHACE-associated ocular anomalies. It is possible that the multifocal hemangiomas were of unrelated etiology; however, the presence of PHACE-associated congenital anomalies with hemangiomas on potentially implicated sites, including the upper trunk and extremity, suggested that this was a unique presentation of PHACE syndrome.

Discussion

Reports have detailed patients meeting PHACE syndrome or possible PHACE syndrome criteria without an associated segmental hemangioma on the face or scalp (eTable).^7-19 Authors have suggested that this presentation represents a part of the continuum of infantile hemangiomas in patients with PHACE syndrome,⁷ prompting the revision of diagnostic criteria in 2016.3 Six cases have depicted a segmental hemangioma of the trunk and/or extremities, and 1 case noted a spontaneously-regressing hemangioma of the neck with unclear distribution.

In addition, 2 cases exhibited focal hemangiomas. Torer et al presented a case of PHACE syndrome with 2 small hemangiomas of the lip and neck with associated sternal nonunion, a supraumbilical raphe, VSD, and right-sided aortic arch.¹⁹ Whereas the neck hemangioma was focal, the lip hemangioma appeared indeterminate with a possible segmental distribution, albeit smaller than the 5-cm cutoff for PHACE syndrome diagnostic criteria. As such, it is possible that the patient exhibited a facial segmental hemangioma associated with PHACE syndrome with an incidental focal hemangioma of the neck. Poindexter et al reported on a case of possible PHACE syndrome with 10 focal hemangiomas ranging from 3 mm to 1.6 cm scattered over the trunk and neck. PHACE- associated characteristics included a persistent left trigeminal artery and hypopituitarism.¹⁷ Yet, it is possible that the multifocal hemangiomas arose coincidentally given present risk factors, including female sex, advanced maternal age, prematurity, and preeclampsia. However, because multifocal hemangiomas concurrent with PHACE-associated characteristics may instead exist on the continuum of PHACE syndrome, a complete workup should be considered in the presence of known PHACE-associated anomalies, even when atypical hemangioma morphotypes are present.

Conclusion

This report has presented the case of an infant girl with Dandy-Walker malformation, a perimembranous VSD, atrial septal fenestrations, and multifocal infantile hemangiomas; thus, possible PHACE syndrome. Few reports have highlighted multifocal infantile hemangiomas and PHACE-associated structural anomalies. Whereas PHACE syndrome has been historically associated with segmental infantile hemangiomas of the face, only 2 reports to our knowledge highlight PHACE syndrome with multifocal infantile hemangiomas. It is possible that our patient’s multifocal hemangiomas arose independent of her cardiac and brain anomalies; however, we propose that multifocal hemangiomas with concurrent congenital anomalies may exist on the continuum of PHACE syndrome. Therefore, even with atypical hemangioma morphotypes, a complete workup should be considered when known PHACE- associated anomalies are present.

References

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