|Year : 2018 | Volume
| Issue : 4 | Page : 347-350
Propranolol: A miracle drug for infantile hemangioma associated with PHACES syndrome
Vasudha Abhijit Belgaumkar1, Nitika Sanjay Deshmukh1, Ravindranath Brahmdeo Chavan1, Sharad Dattatray Mutalik2
1 Department of Skin and VD, BJGMC, Pune, Maharashtra, India
2 Department Dermatology and Cosmetology, Maharashtra Medical Foundation's Joshi Hospital, Pune, Maharashtra, India
|Date of Web Publication||28-Sep-2018|
Dr. Vasudha Abhijit Belgaumkar
Department of Skin and VD, BJGMC, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
We report successful treatment with propranolol in a 4-month-old preterm infant diagnosed as PHACES syndrome based on the presence of a massive facial hemangioma, myoclonic spasms, delayed motor milestones, and posterior fossa anomalies. PHACES is an acronym for posterior fossa brain malformation, cervicofacial segmental hemangioma, arterial anomalies, cardiac defects/coarctation of aorta, eye and endocrine abnormalities, sternal defect, and supraumbilical raphe. The hemangioma was progressively enlarging with ulceration and ocular occlusion. Propranolol was initiated after complete evaluation and resulted in significant regression of the hemangioma without any adverse events or recurrence over a 2-year follow-up period. Mechanism of action of propranolol includes vasoconstriction and inhibition of vascular endothelial growth factor. This case report highlights the importance of investigating all infants with large hemangiomas for syndromes such as PHACES and the need to rule out intracranial vascular anomalies before initiating propranolol.
Keywords: Hemangioma, PHACES syndrome, propranolol
|How to cite this article:|
Belgaumkar VA, Deshmukh NS, Chavan RB, Mutalik SD. Propranolol: A miracle drug for infantile hemangioma associated with PHACES syndrome. Indian J Paediatr Dermatol 2018;19:347-50
|How to cite this URL:|
Belgaumkar VA, Deshmukh NS, Chavan RB, Mutalik SD. Propranolol: A miracle drug for infantile hemangioma associated with PHACES syndrome. Indian J Paediatr Dermatol [serial online] 2018 [cited 2020 Oct 27];19:347-50. Available from: https://www.ijpd.in/text.asp?2018/19/4/347/242402
| Introduction|| |
Most hemangiomas of infancy are not serious and require little or no treatment unless complicated by bleeding, ulceration, or obstruction of vital structures. However, a small group of infants with facial hemangiomas may have certain associations which warrant thorough investigation and urgent intervention. PHACES syndrome may be suspected in a child with large hemangiomas on the face, head, and/or neck. This syndrome is a phakomatosis/neurocutaneous syndrome comprising posterior fossa brain malformation, cervicofacial segmental hemangioma, arterial anomalies, cardiac defects/coarctation of aorta, eye and endocrine abnormalities, sternal defect, and supraumbilical raphe. Management calls for a multidisciplinary approach including medical therapy for the hemangioma and attention to other involved organs or structures.
| Case Report|| |
A 4-month-old preterm male baby ( first product of second-degree consanguineous marriage) was brought with large progressively enlarging bright red soft mass over the face and occluding left eye for 3 months. The baby was born as breech presentation by forceps-assisted vaginal delivery at 32-week gestation. History of single episode of myoclonic jerks during neonatal period was elicited. Parents denied a history of breathlessness or stridor and bluish discoloration of lips or acral areas. General examination was unremarkable. Dermatological examination revealed a massive well-defined bright red soft, lobulated, nontranslucent, compressible, and partially blanchable swelling over the face, occiput, neck, upper lip, and involving both eyelids of the left eye occluding it completely [Figure 1]. Lower eyelid showed ulceration with crusting. Cardiovascular and respiratory system examination was normal. Bilateral reducible inguinal hernia was noted. Neurological examination revealed limb hypotonia with delayed motor milestones, particularly absent neck holding. Skeletal system did not reveal any sternal, spinal, or cranial anomalies. Head circumference was greater than normal (43 cm). Clinical findings suggested a differential diagnosis of infantile hemangioma with PHACES syndrome or arteriovenous malformation. Routine hematological investigations with ocular examination (fundoscopy and ultrasound B scan) were normal. Local ultrasound showed hemangioma involving face, both parotids, and muscular plane. Magnetic resonance imaging (MRI) confirmed hemangioma with left cerebellar hypoplasia and vermian agenesis without cerebrovascular anomalies [Figure 2]. Clinical and radiological features clinched diagnosis of definite PHACES syndrome (Pediatric Consensus Criteria 2009). Oral propranolol was started as 0.5 mg/kg/day in three divided doses with heart rate, blood sugar, blood pressure monitoring, and escalated to 2 mg/kg/day after 48 h. Within a week, there was noticeable decrease in hue and size, flattening of contours and softening [Figure 3]. Both visible and subcutaneous components of the hemangioma regressed dramatically with near complete resolution at 4 months as confirmed with digital photography and MRI [Figure 4]. Propranolol was discontinued after 6 months with stringent pediatric, pediatric neurology and ophthalmology surveillance. No rebound, recurrence, or adverse event has been observed over a 2-year follow-up period.
|Figure 1: Clinical image showing extent of hemangioma over the face involving subcutaneous plane and occluding left eye|
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|Figure 2: Magnetic resonance imaging film showing left cerebellar hypoplasia with vermian agenesis|
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|Figure 3: Clinical improvement 1 month after starting propranolol therapy|
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|Figure 4: Clinical image showing complete regression of hemangioma with residual telangiectasia after propranolol for 4 months|
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| Discussion|| |
PHACES syndrome, first described by Dr. Ilona Frieden in 1996, is a rare association between infantile hemangiomas and malformations of the eyes, heart, major arteries, and brain. The large hemangiomas on the face, scalp, neck, or rarely arm and forearm may be painful, ulcerate, or bleed. Hemangiomas near the eye can occlude it and interfere with vision as seen in our case. Abnormalities of blood vessels or other structures within the brain may lead to strokes, seizures, and developmental delay, which manifested as myoclonic jerks with absent neck holding in the current case. The cutaneous hemangioma provides a vital clue as its specific site or segment can indicate likely aberrations in underlying tissues. Hemangiomas on the face affect four primary segments – frontotemporal (highest risk for brain abnormalities), maxillary, mandibular (greater risk of cardiac and airway anomalies), and frontonasal. A consensus statement for diagnostic criteria for PHACES syndrome published in 2009 proposed major and minor criteria within various organ systems. The combination of large facial hemangioma and unilateral cerebellar hypoplasia with vermian agenesis led to diagnosis of definite PHACES syndrome in our child. Potential complications are maceration, bleeding, ulceration, ischemia, stroke, developmental delay, anisometropia, amblyopia, cyanosis, breathlessness, difficulty in feeding, ptosis, visual axis deviation and strabismus, high output cardiac failure, and Kasabach-Merritt syndrome. In our baby, bilateral inguinal hernia may be a hitherto unreported association or a co-incidental finding.
There is no known cause for PHACES with no specific genetic or chromosomal abnormality identified. The relationship of abnormalities suggests an error in embryonic development at a specific critical time (3–12 weeks' gestation) when blood vessels are developing. Infants with large hemangiomas (>24 cm 2) of the cervicofacial area should undergo investigations to establish whether they have PHACES syndrome. These include MRI and MR angiography of head and neck, ocular, and ear examinations with audiometric testing and echocardiogram. The management depends on the affected organ systems and requires a team of experts including dermatologist, ophthalmologist, pediatrician, and neurologist. Armamentarium for the hemangioma includes propranolol, atenolol (0.5 mg/kg/day – escalated to 1 mg/kg/day), oral prednisolone (2–4 mg/kg/day), subcutaneous interferon α3 million units/sq.m/day, topical timolol 0.5% drops twice/day, lasers – pulsed dye laser (in older children with nonregressing hemangioma), vincristine, imiquimod, cyclophosphamide, cryotherapy, and sclerotherapy., Some of these modalities may not be feasible due to cost constraints or potential toxicity.
Propranolol is a synthetic, nonselective b-adrenergic receptor-blocking agent. Propranolol is highly lipophilic and undergoes first-pass metabolism by the liver with only ∼25% of oral propranolol reaching the systemic circulation. Its mechanism of action in hemangioma is considered to be vasoconstriction, endothelial cell apoptosis with vascular endothelial growth factor, and fibroblastic growth factor inhibition.
Solomon et al. documented response to propranolol in a 29-week preterm infant with PHACES. The hemangiomas had caused airway distortion and failed to involute with corticosteroids and vincristine. Leaute-Labreze used propranolol as 2 mg/kg/day with satisfactory results. Consensus group advocates that the daily dose of propranolol be divided in three equal doses with a minimum interval of 6 h between doses, balancing considerations of safety, efficacy, and convenience.
Due to nonavailability of propranolol oral solution, we devised a novel drug-delivery technique easily performed by parents at home. Tablet propranolol 10 mg was dissolved completely in 10 ml of boiled and cooled water to prepare a solution of strength 1 mg/ml and administered with sterile syringe according to weight. Distilled water and normal saline are other sterile options without additional advantage as solvents. Parents were counseled regarding recognition of early signs of hypoglycemia such as sweating and irritability.
Contraindications for propranolol in children include personal or family history of atopy or asthma, cardiogenic shock, chronic and significant sinus bradycardia, hypotension, bronchospasm/wheezing, known hypersensitivity to propranolol, and preterm infants (corrected age <5 weeks). Adverse effects of propranolol are bradycardia, hypotension, hypoglycemia, and bronchospasm. High output failure can occur with large lesions, PHACES, PELVIS syndrome, and diffuse neonatal hemangiomatosis. It may precipitate stroke or vascular “steal” in infants with PHACES and intracranial vascular malformations. Hence, careful evaluation of all major vessels in the heart and brain is mandatory before initiating propranolol. Fortunately, our baby did not have any cardiovascular or cerebrovascular anomalies and tolerated the treatment well.
| Conclusion|| |
We report this case to emphasize that infants with large cervicofacial hemangiomas deserve investigation for PHACES syndrome. Propranolol can be used successfully with caution.
The authors gratefully acknowledge Dr. Sunil N Tolat (Hon. Associate professor, Dermatology, BJGMC, Pune) and Dr. Pallavi Patil (Senior Resident) for their valuable contribution in patient management and manuscript preparation.
Dr. Vasudha Belgaumkar is supported by the Fogarty International Center of the US National Institutes of Health (grant # D43TW00957). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]