PHACE/S Syndrome: A Syndromic Infantile Segmental ... - Springer Link

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PHACE/S Syndrome: A Syndromic Infantile Segmental Hemangioma Siddram J. Patil, Amol A. Moray1, Viralam S. Kiran1 and Ravindra R. Battu2 Departments of Medical Genetics, 1Pediatric Cardiology and 2Ophthalmology, Narayana Hrudayalaya Institute of Medical Sciences, Bangalore, Karnataka, India

ABSTRACT PHACES syndrome is a neurocutaneous disorder characterized by posterior fossa brain malformations, hemangiomas, cardiac anomalies and coarctation of aorta, eye anomalies ± sternal clefts. All reported cases are sporadic and notably common in females. The underlying cause is unknown. Here is described, one of the twin baby with characteristic features of PHACE syndrome. The presence of large segmental hemangioma, especially on face should prompt the primary care provider to act early, to prevent complications related to facial hemangiomas and other associated anomalies. [Indian J Pediatr 2010; 77 (8) : 911-913] E-mail: [email protected]

Key words: PHACES syndrome; Infantile hemangioma; Coarctation of aorta; Dandy- Walker malformation

Infantile hemangiomas (IHs) are common vascular tumors primarily involving skin, and various other visceral organs. They are seen in 10% of children less than 1 yr of age.1 Based on the extent of skin involvement and morphology, IHs are categorized into localized, segmental, indeterminate and multifocal.2 Most of the IHs are benign, localized and solitary. Segmental hemangiomas cover larger area of skin, occurring in isolation or as a part of a syndrome. Fifty percent of IHs are seen in head and neck region; of these 20% are segmental.2 Segmental hemangiomas are at higher risk for complications and can be associated with visceral hemangiomas/structural defects.3 PHACE/S is a syndromic form of infantile segmental hemangioma, often confused with Sturge-Weber syndrome. PHACE/S is an acronym, P = Posterior fossa brain malformation, H = Hemangiomas, A= Arterial anomalies, C = Cardiac anomalies and coarctation of aorta, E = Eye anomalies and S = sternal defects.1 In a cohort of 1096 children with hemangiomas, 25 [2.3% of all IHs] were diagnosed to have PHACE syndrome.4 Twenty percent of all segmental hemangiomas has PHACE/S syndrome. 4 Here is described a case of PHACE syndrome with the characteristic findings like complex coarctation of aorta, right large segmental and indeterminate hemangiomas with localized multifocal hemangioma on the left side, right cerebral and cerebellar hypoplasia, and right eye anomalies. Correspondence and Reprint requests : Dr Siddram J. Patil, MD(ped) DM (Medical Genetics), Narayana Hrudayalaya Institute of Medical Sciences, Bangalore, Karnataka, India. [DOI-10.1007/s12098-010-0136-8] [Received August 31, 2009; Accepted April 16, 2010]

Indian Journal of Pediatrics, Volume 77—August, 2010

One of the twins (Twin 1), female baby presented at 9 months of age with congenital heart disease and facial skin lesions. She was born to a non-consanguineous couple at 7 months gestational age (normal vaginal delivery) with a birth weight of 1.5 kg. Her developmental milestones were appropriate for age at 9 months and 16 months of age. There was no history suggestive of stroke episodes. Hearing was apparently normal. On examination, she had a large facial hemangioma involving right side of the face and nose extending to right scalp region. The nasal tip was disfigured along with notched right ala nasi and a scar extended from the collumela to the right lateral end of her upper lip. (Fig. 1) In addition,

Fig. 1. Right side facial segmental hemangioma, narrow palpebral fissure, deformed nasal tip and scar tissue in the philtral region.

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S.J. Patil et al hemangiomas were also seen in the occipital region (solitary lesion, to the right of midline) and a left sided inguinal lesion (multifocal lesions). Other facial features include upslant eyes, depressed nasal bridge, long philtrum, and thin upper lip. No sternal defects were seen. Growth parameters were normal for the age. Right eye examination revealed narrow palpebral fissure, anterior micropthalmos, superonasal iris coloboma and a hypoplastic optic nerve. Left eye examination was unremarkable. Cardiac investigation revealed long segment coarctation of aorta proximal to the left subcalvian artery and diffuse narrowing of the left subclavian artery. In addition, there was double aortic arch with dominant left arch. MRI brain done at age 1 month and 21 days revealed right cerebral (mild) and cerebellar hemiatrophy with mild dilatation and shift to the right of 4th ventricle. Thyroid function tests were normal. Evaluation of the twin 2nd girl was normal. Zygosity of twin pregnancy was not clear. DISCUSSION PHACE syndrome is a neurocutaneous syndrome, first described by Pascual-Castroviejo in the year 1978. 5 PHACES syndrome, sternal clefts–telangiectasia/ hemangiomas, sternal malformations/vascular dysplasia have been suggested to represent spectrum manifestations of the same condition of unknown etiopathogenesis. 6 Diagnosis of PHACES syndrome requires facial segmental hemangioma and one or more extracutaneous manifestations. IHs are more frequently seen in females (3 to 4 times) than males. In a review of 272 cases of PHACE/S syndrome, 213 (78%) were females. The cause for increased prevalence of PHACE/S in females is not yet clear. Severity of disease among males (59) was comparable to females (213). 7 However, incidence of structural brain malformations among males was significantly higher in comparison to female patients. Suggested explanations for any genetic disorders with female predominance - X linked dominant inheritance with male lethality or post zygotic mutations survival by mosaicism are an unlikely cause.7 Anita et al proposed four segmental regions of face to describe patterns of facial hemangiomas. 2 In the present case, the hemangioma involved all four segments. In addition, other types of hemangiomas (localized and multifocal) were also present. Facial patterns of segmental hemangiomas helps in predicting underlying structural defects.2 Further, such division helps in understanding etiopathogenesis and molecular mechanisms. What decides extent and type of cutaneous hemangiomas is unclear. The present case had scarring and disfigurement involving the nose and surrounding region. IHs are generally evident at or soon after birth, 912

as a scratch or a bruise. Most cases of cutaneous IHs grow in the first 5 months. Segmental hemangiomas can grow till 9 months of age. This proliferative phase is followed by involution. During their growth (proliferative) phase, IHs particularly facial and perineal segmental hemangiomas are prone to complications like ulceration, pain, scarring, and visual compromise. Associated visceral hemangiomas pose a threat depending upon the location (e.g., airway obstruction by subglottic hemangiomas). Identifying segmental hemangiomas early (< 5 months) helps in monitoring, early treatment and preventing complications.3 Eye anomalies are seen in 12.5 – 17% of cases.4,7 The present case had right sided eye anomalies. Cardiac investigation revealed complex coarctation of aorta, the commonest cardiac lesion reported. The Complexity of cardiac lesion in PHACE varies. Defining complex anatomy of coarctation and associated lesions is recommended before cardiac surgery.8 Structural heart defects are seen in around 15% of cases.4 Forty percent of cases are known to have vascular anomalies of cerebral and cervical region. Children with vascular anomalies are at risk of acute ischemic stroke and other related neurological problems. 4, 7 Cerebral and cerebellar hemiatrophy and other congenital structural brain defects could be due to in-utero or perinatal stroke episodes and vascular insufficiency. 9 Structural brain malformations are seen in around 45% of cases and are at risk of developmental delay.7 Posterior fossa lesions are the most common defects (43 -81%), Dandy-Walker malformation being the commonest.7 In majority of the cases, laterality of lesions (cutaneous hemangiomas and structural defects) is ipsilateral.8 Either gene and/or insult during left-right embryonic patterning might be responsible for the disease. Bilateral lesions and contralateral involvement of cutaneous hemangiomas/structural defects are reported and were noted in the present case.8 Opitz et al had suggested such disorders represent development field defects.10 Early referral is necessary to monitor and prevent complications related to hemangiomas (proliferative phase). Infantile segmental hemangiomas especially over the face should be screened for associated structural defects and vascular anomalies. REFERENCES 1. Frieden IJ, Reese V, Cohen D. PHACE syndrome. The association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects and eye abnormalities. Arch Dermatol 1996; 132: 307-311. 2. Haggstrom AN, Lammer EJ, Schneider RA, Marcuio R,


PHACE Syndrome : A Syndromic Infantile Segmental Hemangioma

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Frieden IJ. Patterns of infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics 2006; 117 : 698-703. Chang LC, Haggstrom AN, Drolet BA et al. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics 2008;122 : 360-367. 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: 975-986. Pascual-Castroviejo I. Vascular and nonvascular intracranial malformation associated with external capillary hemangiomas. Neuroradiol 1978; 16: 82-84. Vermeer S, van Oostrom CG, Boetes C, Verrips A, Knoers NV. A unique case of PHACES syndrome confirming the assumption that PHACES syndrome and sternal


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malformation – vascular dysplasia association are part of the same spectrum of malformations. Clin Dysmorphol 2005; 14: 203-206. Metry DW, Siegel DH, Cordisco MR et al. A comparison of disease severity among affected male versus female patients with PHACE syndrome. J Am Acad Dermatol 2008; 58: 81-87. Bronzetti G, Giardini A, Patrizi A et al. Ipsilateral hemangioma and aortic arch anomalies in posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta, and cardiac defects and eye abnormalities (PHACE) anomaly: report and review. Pediatrics 2004; 113 : 412-415. Heyer LG, Millar WS, Ghatan S, Garzon MC. The neurological aspects of PHACE: case report and review of literature. Pediatr Neurol 2006; 35: 419-424. Opitz JM, Gilbert EF. CNS anomalies and the midline as “developmental field” Am J Med Genet 1982; 12: 443-455.

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