PHACE Syndrome

Article Author:
Amal Chamli
Article Editor:
Noureddine Litaiem
Updated:
4/10/2019 4:26:33 PM
PubMed Link:
PHACE Syndrome

Introduction

Infantile hemangioma is the most prevalent benign tumor of infancy. The estimated incidence is between 4 and 5 %. Large facial segmental hemangioma has associations with PHACES syndrome (PS) which is an acronym of Posterior fossa malformations, Hemangioma of the cervicofacial region, Arterial anomalies, Cardiac anomalies, Eye anomalies, and Sternal or abdominal clefting or ectopia cordis. It was first described in 1996 by Frieden and colleagues and named PHACE syndrome. After that, Boulinguez and colleagues changed the acronym to PHACES syndrome by adding sternal defects (S). PS is a rare congenital cervicofacial infantile hemangioma. It occurs in 2% of cases.[1][2] It is a neurocutaneous syndrome, characteristically demonstrating a segmental distribution usually involving the face, neck, and scalp, either as one lesion or many lesions. This rare congenital disease includes dermatological, cardiac, neurological, and ocular manifestations. The most common extracutaneous manifestations are the structural brain, cerebrovascular, and cardiovascular abnormalities.

Etiology

PHACE syndrome is considered a non-hereditary condition. The etiology is not fully understood. Most cases are sporadic, but suggestions exist that it may correlate to a mutation in the X linked genes since its female predominance, with prenatal male lethality.[3] It corresponds with various genetic and phenotypic anomalies. Some authors suggest a developmental error between 6 and 8 weeks of gestation, before or during vasculogenesis.

Epidemiology

PS is more prevalent in the Caucasian and Hispanic populations. There is a female predominance with a female to male ratio of 9 to 1.[1] Approximately, 20 % of children with facial hemangioma will develop one of the abnormalities of PS.[4]The risk of extracutaneous abnormalities increases with increasing hemangioma size and when the hemangioma involves multiple facial segments.[5]

Pathophysiology

The physiopathology of PHACE syndrome is different from that of isolated hemangioma. It is not fully understood and demonstrates no family heritance pattern.

The ipsilateral malformation in PS suggests an abnormal embryonic or fetal development.

Also, the vascular abnormalities may result from regional arterial insufficiency and disruption of the normal arterial wall and therefore alteration in blood flow and hypoxia. Thus, these changes lead to the formation of hemangioma and abnormalities in brain structures.[3]

History and Physical

PHACE syndrome is a neurocutaneous disorder. Cutaneous anomalies are manifested by hemangioma which can be absent, subtle at birth, or obvious after birth. It can be present at birth as premonitory lesions as an erythematous patch or a telangiectatic red macule. It is typically characterized by a large segmental cervicofacial hemangioma as red-bluish soft masses covering a broad cutaneous territory or manifests as confluent plaques or small individual papules clustered that assume a specific distribution. The pattern, in some cases, has a dermatomal involvement, occurring trigeminal patterns V1, V2, and V3 facial hemangioma is the most frequent localization. It can occur unilaterally or bilaterally. Lesions undergo proliferative phase followed by slow involution often leading to complete regression. There are reports of a suspected link between the distribution of facial hemangioma and extracutaneous manifestations.

The face divides into four segments related to the prominences of facial develo­pment: frontotemporal (segment 1), maxillary (segment 2), mandibular (segment 3), and frontonasal (segment 4). Hemangioma on the frontotemporal and frontonasal segments have been reported with a higher risk of ocular, cerebrovascular and brain involvement, whereas those on the mandibular segment correlate with a potential risk of midline and cardiovascular defects. However, these correlations have not been fully elucidated.[6]

Furthermore, the hemangioma may occur elsewhere in the body; the most common association is with the segmental hemangioma or the subglottic (airway hemangioma) and occasionally may be seen in the gastrointestinal tract.

The extracutaneous manifestations include abnormalities of the brain, cerebral vasculature, aorta, eyes, and chest wall. The most common associated extracutaneous findings are cerebrovascular (91%), cardiovascular (67%), and brain (52%) abnormalities. Thereon, the cerebrovascular involvement typically is related to the ipsilateral internal carotid artery.  The most frequent cardiovascular abnormalities are aberrant subclavian artery and coarctation of the aorta, which are present in 20% of cases. Brain abnormalities mainly involve the posterior fossa and may include cerebral hypoplasia, cortical dysgenesis, and Danky-Walker malformation. Additionally, neurological symptoms are variable, depending on the associated territory of the occluded artery. The ophthalmologic manifestations include microphthalmia, glaucoma, and coloboma.[6][7][8]

Evaluation

PHACE syndrome should be suspected in the presence of cervicofacial infantile hemangioma over 5cm in size, and a systemic evaluation is required. Thus, history taking and careful physical examination are necessary. Imaging with magnetic resonance imaging (MRI) and/or magnetic resonance angiography (MRA) of the head and neck should be ordered if PS is suspected. Moreover, an ophthalmic evaluation should be performed to look for eye abnormalities associated with PS. Also, an echocardiogram should be performed looking for heart and aortic abnormalities.

PS can be suspected during pregnancy. Antenatal ultrasound screening can detect abnormalities of the posterior fossa, and therefore an MRI is recommended to assess the diagnosis in the antenatal period.[9] Additionally, an appropriate endocrinologic workup should be performed according to the clinical signs.

A multidisciplinary group of specialists has established the 2009 diagnostic criteria, which had an update in 2016. The diagnostic basis of definite PS is the presence of a facial hemangioma more than 5 cm with one major criterion or two minor criteria. Possible PS requires the presence of cervicofacial hemangioma with one minor criterion.

Major criteria:

  • Arterial: anomalies of major cerebral or cervical arteries, stenosis, occlusion, dysplasia, hypoplasia, persistent carotid-vertebrobasilar anastomosis
  • Structural brain: posterior fossa anomalies: Danky-Walker complex, unilateral or bilateral cerebral dysplasia or hypoplasia
  • Cardiovascular: aortic arch anomalies, aneurysm, an aberrant origin of the subclavian artery
  • Ocular: posterior segment anomaly, retinal vascular anomalies
  • Ventral or midline: sternal defect, sternal cleft

Minor criteria:

  • Arterial: aneurysm of cerebral arteries
  • Structural brain: midline anomaly, malformation of cortical development, neuronal migration disorder
  • Cardiovascular: ventricular septal defect, right aortic arch
  • Ocular: anterior segment anomalies, cataract, sclerocornea, microphthalmia
  • Ventral or midline: hypopituitarism, ectopic thyroid, midline sternal papule

Treatment / Management

The management should be multidisciplinary. There is no standardized treatment protocol for affected children. The treatment directs itself toward the specific symptoms in each patient. Patients with PS may need to be managed by the cardiologists and neurologists, depending on their extracutaneous manifestations. The hemangioma is generally treated successfully with oral propranolol with caution, because of the risk of stroke in patients with heart or blood vessels problems. Also, treatment of hemangioma may involve systemic steroids, surgery or laser therapy. Therapy with aspirin is generally recommended to prevent ischemic accidents. Cardiovascular abnormalities may require early surgical intervention.[10]

Differential Diagnosis

  • Sturge-Weber syndrome
  • Infantile hemangioma
  • Visceral hemangioma
  • Wyburn-Mason syndrome
  • LUMBAR syndrome

Prognosis

The prognosis is variable. It depends on the associated manifestations. Neurological and cognitive impairments are very common, and they constitute the most significant source of morbidity.

Complications

  • Hemangioma: ulceration, bleeding, visual compromise, cause issue with vital function
  • Cardiovascular: coarctation of the aorta is the most common (14,5 %), other aortic arch abnormalities
  • Neurological: migraine headaches, developmental delays, seizures, speech delays, and rarely ischemic strokes or hemorrhage
  • Ophthalmological: cataract, glaucoma
  • Occasionally, dental hypoplasia, impaired hearing and endocrine abnormalities (hypopituitarism and hypothyroidism)

Deterrence and Patient Education

PHACE syndrome is a rare neurocutaneous condition. It presents with anomalies involving different organ system. It may have a potential psychosocial impact for the patient as well as the family. Thus, psychosocial support is essential for the entire family. Children with PS may experience a delay in attaining speech, swallowing dysfunction, migraine headaches. Therefore, periodic screening is mandatory to detect language abnormalities and to treat precociously and prevent other complications.[11]

Enhancing Healthcare Team Outcomes

Children with PS should receive a multidisciplinary approach including a team of a pediatric dermatologist, ophthalmologist, cardiac surgeon, cardiologist, sociologist, outpatient visiting nurse and neurologist. Moreover, awareness of this entity and early diagnosis is important for appropriate treatment. PS requires a regular follow-up, particularly through the school-age period, to watch for complications and to monitor development.


References

[1] Castellano-Martínez A,Rodriguez-Gonzalez M,Benavente-Fernandez I,Zuazo-Ojeda A, Hemangioma, aortic coarctation and intracranial dolichoectasia: PHACE syndrome. Pediatrics international : official journal of the Japan Pediatric Society. 2017 Feb;     [PubMed PMID: 28211225]
[2] Bellaud G,Puzenat E,Billon-Grand NC,Humbert P,Aubin F, PHACE syndrome, a series of six patients: clinical and morphological manifestations, propranolol efficacy, and safety. International journal of dermatology. 2015 Jan;     [PubMed PMID: 24962639]
[3] Foster KA,Ares WJ,Tempel ZJ,McCormick AA,Panigrahy A,Grunwaldt LJ,Greene S, PHACE syndrome is associated with intracranial cavernous malformations. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2016 Aug;     [PubMed PMID: 27125518]
[4] Hartemink DA,Chiu YE,Drolet BA,Kerschner JE, PHACES syndrome: a review. International journal of pediatric otorhinolaryngology. 2009 Feb;     [PubMed PMID: 19101041]
[5] Heyer GL, PHACE(S) syndrome. Handbook of clinical neurology. 2015;     [PubMed PMID: 26564079]
[6] PHACE syndrome: clinical manifestations, diagnostic criteria, and management., Rotter A,Samorano LP,Rivitti-Machado MC,Oliveira ZNP,Gontijo B,, Anais brasileiros de dermatologia, 2018 Jun     [PubMed PMID: 29924216]
[7] Metry D,Heyer G,Hess C,Garzon M,Haggstrom A,Frommelt P,Adams D,Siegel D,Hall K,Powell J,Frieden I,Drolet B, Consensus Statement on Diagnostic Criteria for PHACE Syndrome. Pediatrics. 2009 Nov;     [PubMed PMID: 19858157]
[8] Samuelov L,Kinori M,Mancini AJ,Kruse LL,Wagner A,Yoon H,Chamlin SL, Ocular Complications in PHACE Syndrome: A True Association or a Coincidence? The Journal of pediatrics. 2019 Jan;     [PubMed PMID: 30270159]
[9] Assari R,Ziaee V,Moghimi S,Akbari MR,Mirmohammadsadeghi A, PHACE(S) syndrome: Report of a case with new ocular and systemic manifestations. Journal of current ophthalmology. 2017 Jun;     [PubMed PMID: 28626825]
[10] Winter PR,Itinteang T,Leadbitter P,Tan ST, PHACE syndrome--clinical features, aetiology and management. Acta paediatrica (Oslo, Norway : 1992). 2016 Feb;     [PubMed PMID: 26469095]
[11] Martin KL,Arvedson JC,Bayer ML,Drolet BA,Chun R,Siegel DH, Risk of dysphagia and speech and language delay in PHACE syndrome. Pediatric dermatology. 2015 Jan-Feb;     [PubMed PMID: 25440893]