PHACES syndrome is a neurocutaneous syndrome (phakomatosis) characterized by a large cervicofacial segmental infantile hemangioma accompanied by multiple structural anomalies. OMIM number 606519. Phakomatoses are a group of disorders with benign tissue proliferations in the skin, central nervous system, and eyes, and are considered a type of neurocristopathy.
The components indicated by the acronym are as follows.
P (Posterior fossa malformation): Posterior fossa malformation
Pascual-Castroviejo first reported it in 1978, and Frieden established the PHACES acronym in 1996 1). In 1998, Boulinguez expanded the concept as PHACES. It is also known as “PHACE association” or “Pascual-Castroviejo type II syndrome (P-CIIS).” The ICD-10 code is Q28.8.
The epidemiological characteristics are as follows1).
Occurs in 2–3% of all infantile hemangiomas
Complicated in about 20% of cervicofacial hemangiomas. In large or segmental hemangiomas, 20–31%.
Male-to-female ratio 8:1 to 10:1 (X-linked dominant inheritance hypothesis proposed)
More common in White and Hispanic populations
Sporadic, not hereditary
QHow rare is PHACES syndrome?
A
It occurs in 2–3% of all infantile hemangiomas and about 20% of cervicofacial hemangiomas 1). Although over 250 cases have been reported, it remains a rare disease, and long-term longitudinal studies have not yet been conducted.
Since this disease is discovered in infancy, subjective symptoms are usually not present. Parents often notice a reddish-purple mass on the face, misalignment of the eyes, or lack of eye contact and seek medical attention.
A segmental cervicofacial hemangioma larger than 5 cm is characteristic 1). It spreads along the distribution of the trigeminal nerve V1 to V3 dermatomes. Hemangiomas on the frontotemporal area pose a high risk for brain and eye involvement, while those on the mandibular area carry a high cardiovascular risk. The hemangioma usually regresses spontaneously by around age 7 2). When accompanied by subglottic hemangioma, airway stenosis occurs in 25–50% of cases 1).
Other ocular findings include proptosis, congenital glaucoma, Horner syndrome, strabismus, and conjunctival/choroidal hemangiomas. In up to two-thirds of cases, facial hemangiomas can cause amblyopia or strabismus.
The etiology is unknown and is considered sporadic and non-hereditary. The following hypotheses have been proposed.
X-linked dominant inheritance hypothesis: A male-to-female ratio of 8:1 to 10:1 suggests an X-linked gene mutation 1). There may be a high rate of spontaneous abortion in male fetuses.
Embryonic developmental failure hypothesis: A theory that embryonic developmental disorders occur during the 3rd to 12th week of pregnancy.
Neural crest-derived somatic mutation hypothesis: Supported by the distribution patterns of midline defects and arterial abnormalities matching the migration route of neural crest cells. Abnormal neural crest cell development may be the root cause of ocular symptoms in phakomatoses.
Multifactorial: A genome-wide copy number variation analysis of 98 individuals found no common mutations, suggesting a multifactorial etiology.
Significantly higher frequencies of preeclampsia and placenta previa have been reported. Hypoxia is also listed as a risk factor. No primary prevention recommendations are available.
PHACES syndrome is suspected when there is a cervicofacial hemangioma larger than 5 cm. Diagnostic criteria were established in 2009 and revised in 20161).
Definite PHACES: Head hemangioma >5 cm + 1 major criterion or 2 minor criteria
Suspected case: Head hemangioma >5 cm + 1 minor criterion
The details of the major and minor criteria are as follows1).
System
Major criteria
Minor criteria
Brain structure
Posterior fossa malformation
Midline abnormalities and cortical dysplasia
Blood vessels and arteries
Cerebral and cervical artery abnormalities, persistent carotid-vertebrobasilar anastomosis
Sturge-Weber syndrome: Facial hemangioma (trigeminal V1/V2 distribution, unilateral) + ipsilateral leptomeningeal angioma + glaucoma. When eyelid hemangioma is present, glaucoma comorbidity rate is 30–70%. Early-onset glaucoma develops in about 60% of cases from birth to 4 years of age.
Isolated infantile hemangioma: Single lesion that does not meet PHACES criteria.
Port-wine stain: Capillary malformation that does not regress.
LUMBAR syndrome: Lumbosacral hemangioma with pelvic organ abnormalities.
Wyburn-Mason syndrome: arteriovenous malformations of the retina and central nervous system
QWhat are the criteria for a definitive diagnosis?
A
According to the diagnostic criteria revised in 2016 1). A definitive diagnosis of PHACES is made when a head hemangioma larger than 5 cm is present along with one major criterion (or two minor criteria). If only one minor criterion is present, it is considered a suspected case. Systematic screening with MRI/MRA, echocardiography, and ophthalmologic examination is necessary for diagnosis.
Multidisciplinary collaboration (neurology, cardiology, ophthalmology) is essential. There is no established standard protocol, and individualized management according to each symptom is required.
Dosage and administration: 2 mg/kg/day divided into three doses2). First-line drug for infantile hemangioma.
Caution in PHACES patients: If cerebral artery stenosis is present, a drop in blood pressure may induce cerebral ischemia1). Cerebrovascular evaluation with MRA etc. is necessary before initiation.
Management of side effects: If bradycardia occurs, consider atropine1).
Adjuvant medications
Aspirin: Used for prevention of ischemic events.
Captopril: Used in cases with heart failure 1).
Sirolimus: Used in propranolol-refractory cases 1)2). As an mTOR inhibitor, it suppresses hemangioma growth.
Corticosteroids: Dexamethasone 1) or prednisolone 2 mg/kg/day 2). Currently not recommended.
Continuous multidisciplinary follow-up is necessary. Prognosis depends on the type and severity of extracutaneous symptoms. Hemangiomas spontaneously regress by around age 7 2), but early intervention is important during the proliferative phase when there is a risk of organ compression 2).
QWhat are the precautions for propranolol administration?
A
In PHACES patients, the rate of cerebral artery stenosis is high, so propranolol-induced decreases in blood pressure and heart rate pose a risk of cerebral ischemia 1). Before administration, evaluate cerebral vessels with MRA, etc., and use cautiously while maintaining cerebral perfusion pressure. If bradycardia occurs, consider atropine administration.
This theory suggests that developmental insufficiency occurs during the embryonic period (3–12 weeks of gestation) when craniofacial, brain, cardiovascular, and ocular tissues are coordinately formed. Vascular malformation and arterial wall destruction are thought to be involved.
Hypothesis 2: Somatic Mutations in Neural Crest-Derived Cells
This hypothesis is supported by the observation that the distribution patterns of midline defects and arterial abnormalities coincide with the migration pathways of neural crest cells. Since most mesenchymal cells in ocular formation are derived from neural crest cells, developmental abnormalities of neural crest cells may be the root cause of ocular symptoms in phakomatoses.
A male-to-female ratio of 8:1 to 10:1 suggests X-linked dominant inheritance 1), but comparative studies have not confirmed a severe phenotype in males. Genome-wide copy number variation analysis in 98 individuals detected no common variants, suggesting a multifactorial disease. Abnormal vascular formation and arterial wall fragility are thought to be involved in combination.
7. Latest Research and Future Prospects (Research Stage Reports)
Genome-wide analyses have not identified common variants, and the need for whole-genome analysis is recognized. Although more than 250 cases have been reported, long-term longitudinal studies have not been conducted 1), and elucidating the natural history remains a future challenge.
The use of sirolimus, an mTOR inhibitor, for propranolol-resistant hemangiomas has been reported 1)2).
AbouZeid et al. (2021) reported two cases with dorsal cutaneous hemangioma and mediastinal paravertebral hemangioma that required sirolimus after standard treatment with propranolol and prednisolone 2). The importance of early intervention for proliferative hemangiomas at risk of organ compression (renal atrophy, airway stenosis) is emphasized.
In the anesthetic management of PHACES patients, the usefulness of cerebral oxygenation monitoring (rSO2) using near-infrared spectroscopy (NIRS) has been reported 1). Continuous assessment of cerebral perfusion may enable early detection of ischemic events during anesthesia.
Abtahi D, Shakeri A, Tajbakhsh A. Facing PHACES Syndrome; Anesthesiologist’s Point of View. Anesth Pain Med. 2024;13(6):e141896.
AbouZeid AA, Mohammad SA, Ragab IA, Aly HG. Posterior Mediastinal and Cutaneous Back Hemangiomas in Infants: A New Association. Eur J Pediatr Surg Rep. 2021;9:e37-e40.
Hartemink DA, Chiu YE, Drolet BA, Kerschner JE. PHACES syndrome: a review. Int J Pediatr Otorhinolaryngol. 2009;73(2):181-7. PMID: 19101041.
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