Phace Syndrome: Symptoms, Types, Causes and Treatment

PHACE syndrome is a rare but notable neurocutaneous disorder that links striking skin findings in infants—most often a large facial hemangioma—with a spectrum of systemic anomalies affecting the brain, blood vessels, heart, eyes, and sometimes the midline of the body. While it was only defined in the late 20th century, our understanding of PHACE continues to evolve, with new research revealing its complex presentation, uncertain origins, and the need for careful, multidisciplinary care. In this comprehensive article, we explore the symptoms, types, causes, and current treatments for PHACE syndrome, providing a practical and accessible guide for families, clinicians, and anyone seeking to understand this fascinating condition.

Symptoms of Phace Syndrome

PHACE syndrome is defined by a combination of major and minor symptoms that span several organ systems. While the hallmark sign is a large, segmental infantile hemangioma—usually on the face, scalp, or neck—affected children may also have brain malformations, vascular defects, heart and eye anomalies, and various neurodevelopmental issues. Recognizing these diverse symptoms early is essential for timely diagnosis and management.

Symptom	Description	Frequency/Context	Source(s)
Hemangioma	Large, segmental birthmark (face/scalp/neck)	Hallmark; >5cm in diameter	6 7 10 16
Brain anomalies	Posterior fossa defects, cerebellar hypoplasia, Dandy–Walker complex	35–52% of patients	7 9 16
Vascular defects	Cerebral arterial anomalies, coarctation	Most common extracutaneous feature	7 8 10 11
Cardiac defects	Coarctation, septal defects, arch anomalies	Up to 41% have cardiac issues	5 8 11
Eye anomalies	Microphthalmia, optic nerve defects	11–18% have ocular findings	5 9 10
Neurologic symptoms	Headaches, developmental delays, strokes	Headaches in 62.7%; strokes rare	1 3 9
Endocrine issues	Pituitary/thyroid dysfunction	Up to 55% in some cohorts	4 9
Feeding/speech	Dysphagia, speech/language delay	Significant subset affected	3

Table 1: Key Symptoms

Skin and Hemangioma Manifestations

The most recognizable feature of PHACE syndrome is a large, segmental infantile hemangioma typically present on the face, scalp, or neck. These hemangiomas are usually larger than 5 cm and have a distinctive plaque-like or geographic appearance. Unlike the capillary malformations seen in other syndromes, PHACE hemangiomas are true proliferative vascular tumors that often require medical attention due to their size, location, or potential for complications 6 7 10 16.

Brain and Neurologic Involvement

Structural brain anomalies are present in roughly 35–52% of PHACE patients, most frequently in the posterior fossa region of the brain. Common findings include cerebellar hypoplasia, fourth ventricle abnormalities, Dandy–Walker complex, and malformations of cortical development. These can be associated with neurological problems such as developmental delays, intellectual disability, and focal deficits. Recurrent or severe headaches with migrainous features are also common, starting as early as four years old, and a minority may experience ischemic strokes 1 3 9.

Cerebrovascular and Cardiac Defects

Cerebral arterial anomalies, such as abnormal development or narrowing of the arteries in the brain and neck, are the most common extracutaneous features of PHACE. These may increase the risk of stroke and other complications. Cardiac anomalies—including coarctation of the aorta, septal defects, and abnormal origins of the subclavian artery—are seen in up to 41% of patients and can require surgical intervention 7 8 11.

Ocular, Endocrine, and Feeding/Speech Issues

Eye anomalies, such as microphthalmia (small eyes), optic nerve defects, and retinal degeneration, can occur in 11–18% of patients. Endocrine disturbances, particularly of the pituitary and thyroid glands, are increasingly recognized and may manifest as growth or hormonal issues 4 9. Feeding (dysphagia) and speech or language delays are reported in a significant subset, especially in those with brain anomalies or hemangiomas near the oropharynx 3.

Types of Phace Syndrome

PHACE syndrome does not have rigid subtypes but instead represents a spectrum of disease with variable involvement of different organ systems. Classification is often based on the constellation and severity of systemic findings in addition to the characteristic hemangioma.

Type	Defining Features	Diagnostic Criteria	Source(s)
Classic PHACE	Hemangioma + ≥1 major criterion	Consensus criteria	6 16
Possible PHACE	Hemangioma + 1 minor criterion	Consensus criteria	6 16
PHACES variant	Classic features + sternal/ventral defects	Sternal cleft or raphe	10 11
Atypical/Incomplete	Extracutaneous features, no hemangioma	Rare, diagnosis debated	6

Table 2: PHACE Syndrome Types and Diagnostic Criteria

Classic PHACE Syndrome

The classic form requires the presence of a large, segmental facial (or scalp) hemangioma plus at least one major extracutaneous anomaly, such as a significant brain malformation, arterial abnormality, cardiac defect, or eye anomaly. This is the most commonly recognized presentation and forms the basis of the consensus diagnostic criteria 6 16.

Possible PHACE Syndrome

This is diagnosed when a child has a large facial hemangioma and at least one minor extracutaneous anomaly, or a hemangioma in an atypical location (such as the neck, chest, or arm) with additional systemic findings. This category is designed to include patients with incomplete or unusual presentations 6.

PHACES Variant (with Sternal or Ventral Defects)

When the syndrome also includes ventral midline defects, such as sternal clefting or a supraumbilical raphe, the acronym is expanded to PHACES. These features are less common but highlight the developmental spectrum of the disorder 10 11.

Atypical and Incomplete Presentations

Rarely, patients may present with systemic features of PHACE without a classic cutaneous hemangioma, or with only extracutaneous anomalies. Such cases are difficult to classify, and the diagnosis is debated in the literature. Ongoing research may further clarify these atypical variants 6.

Causes of Phace Syndrome

Despite decades of research, the underlying causes of PHACE syndrome remain incompletely understood. Current evidence points toward a complex interplay of genetic, embryological, and possibly environmental factors.

Cause	Description	Evidence/Notes	Source(s)
Sporadic Mutation	No familial inheritance observed	Most cases are isolated	12 13
Genetic Variation	Rare CNVs identified in patients	No single gene found	13
Embryologic Error	Disrupted vasculogenesis in 1st trimester	Explains multisystem defects	5 7 10 18
Female Predominance	80–90% are girls	X-linked or hormonal factors suspected	2 10 11 12

Table 3: Suspected Causes and Risk Factors

Genetic and Chromosomal Factors

Most reported cases of PHACE are sporadic, with no family history or consistent pattern of inheritance. Early hypotheses suggested possible X-linked dominant inheritance due to the strong female predominance, but this has not been confirmed, and no familial cases have been conclusively documented 12. Copy number variation studies have identified rare chromosomal duplications or deletions in some patients, but no single genetic mutation or locus has been implicated in all cases. This suggests a complex or multifactorial genetic basis 13.

Embryologic and Developmental Origins

PHACE is widely believed to result from disruptions in vasculogenesis—formation of blood vessels—during the first trimester of pregnancy. This would explain the simultaneous occurrence of hemangiomas and malformations in the brain, heart, and major arteries, all of which develop during this early embryonic window 5 7 10 18.

Environmental and Other Risk Factors

No specific environmental or prenatal risk factors have been identified with certainty. However, PHACE is much more common in girls (up to 88–90%), pointing to a possible role for sex chromosomes or hormonal influences during fetal development 2 10 11 12. Some studies note a slightly higher maternal age or gestational age in PHACE cases, but these findings are not consistent 11.

Treatment of Phace Syndrome

Managing PHACE syndrome requires a tailored, multidisciplinary approach given the diversity of potential organ involvement. Treatment focuses on addressing both the cutaneous hemangioma and any associated systemic anomalies, while also monitoring for potential complications.

Treatment	Indication/Target	Key Considerations	Source(s)
Propranolol	Infantile hemangioma	Safe, effective; cautious use in cerebrovascular anomalies	14 15 16 17 18
Corticosteroids	Refractory hemangioma	Second-line; less common now	17 16
Surgery/Procedures	Cardiac/vascular anomalies	Needed for coarctation, septal defects, etc.	8 5
Neurodevelopmental therapy	Speech, feeding, developmental delays	Early intervention recommended	3 9
Endocrine replacement	Hormonal deficiencies	Monitor pituitary/thyroid function	4 9
Multidisciplinary care	All patients	Involvement of dermatology, neurology, cardiology, ophthalmology	7 16 18

Table 4: Main Treatment Options

Medical Therapy for Hemangiomas

Propranolol, a beta-blocker, is now the first-line treatment for problematic infantile hemangiomas—including those seen in PHACE syndrome. Recent multicenter studies show that propranolol is generally safe, with no increased risk of stroke or major adverse events in PHACE patients, despite early concerns about its use in those with arterial anomalies. However, caution is advised for children with severe cerebral arterial narrowing or other high-risk features; careful neurological monitoring and slow dose titration are recommended 14 15 16 17 18.

Corticosteroids may be considered if propranolol is contraindicated or ineffective, but are used less frequently today due to the superior safety and efficacy profile of propranolol 17 16.

Management of Systemic Anomalies

• Cardiac and vascular anomalies: Some children may require surgery or procedural intervention, particularly for coarctation of the aorta or significant septal defects 8 5.
• Brain malformations: Neurologic surveillance is crucial, as some children may develop seizures, strokes, or developmental delays. Early intervention and rehabilitation services can optimize developmental outcomes 9.
• Endocrine issues: Regular screening for pituitary or thyroid dysfunction allows for prompt hormone replacement therapy if needed 4 9.
• Feeding and speech problems: Children with dysphagia or language delays benefit from evaluation by speech-language therapists and tailored intervention plans 3.

The Role of Multidisciplinary Care

Given the potential for multisystem involvement, all children with PHACE syndrome should be managed by a team that includes (at minimum) dermatologists, neurologists, cardiologists, ophthalmologists, and, when needed, endocrinologists and speech therapists. Imaging studies—especially MRI/MRA of the brain and vessels, echocardiography, and ophthalmologic exams—are essential to guide care 7 16 18.

Conclusion

PHACE syndrome is a complex, multisystem disorder that demands early recognition and comprehensive, individualized care. While its hallmark is a large facial hemangioma, the potential for associated anomalies in the brain, vessels, heart, eyes, and endocrine system underscores the need for vigilance and multidisciplinary management. Ongoing research continues to shed light on its enigmatic causes and optimal therapies.

Key Takeaways:

• PHACE syndrome involves large facial hemangiomas plus variable anomalies of the brain, arteries, heart, eyes, and sometimes the midline or endocrine system.
• Symptoms can range from skin findings and headaches to developmental delays and life-threatening cardiac or vascular defects.
• Diagnosis is based on consensus criteria involving major and minor features; atypical and variant forms exist.
• The cause is unknown but likely reflects sporadic genetic changes or embryologic errors in early vasculogenesis; strong female predominance is observed.
• Propranolol is safe and effective for hemangioma treatment, but high-risk vascular anomalies require careful monitoring. Other systemic issues may call for surgery, hormonal therapy, or developmental support.
• Multidisciplinary, team-based care is essential for optimal outcomes.

By understanding the diverse symptoms, diagnostic spectrum, and evolving treatments, families and clinicians can better navigate the challenges and opportunities of PHACE syndrome.