|Year : 2018 | Volume
| Issue : 4 | Page : 293-303
Infantile hemangiomas: An update on pathogenesis, associations, and management
Karina L Vivar, Anthony J Mancini
Division of Pediatric Dermatology, Ann and Robert H. Lurie Children's Hospital of Chicago; Departments of Pediatrics and Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
|Date of Web Publication||28-Sep-2018|
Dr. Karina L Vivar
225 East Chicago Avenue, Box 107, Chicago, IL 60611-2605
Source of Support: None, Conflict of Interest: None
Infantile hemangiomas (IH) are the most common vascular neoplasm in infants. The typical clinical course of IH follows a pattern of growth (proliferation) followed by spontaneous involution. The majority of IH are isolated to the skin; however, some cutaneous IH can be associated with internal organ involvement or anomalies. IH which are functionally impairing, ulcerated or potentially disfiguring require therapy. Treatment options include systemic or topical beta-blockers, systemic or intralesional corticosteroids, pulsed dye laser therapy, or surgical excision. In this article, we review the updated understanding of IH pathogenesis, clinical presentations and associations, and approaches to management.
Keywords: Infantile hemangioma, propranolol, timolol, vascular
|How to cite this article:|
Vivar KL, Mancini AJ. Infantile hemangiomas: An update on pathogenesis, associations, and management. Indian J Paediatr Dermatol 2018;19:293-303
|How to cite this URL:|
Vivar KL, Mancini AJ. Infantile hemangiomas: An update on pathogenesis, associations, and management. Indian J Paediatr Dermatol [serial online] 2018 [cited 2018 Oct 16];19:293-303. Available from: http://www.ijpd.in/text.asp?2018/19/4/293/242416
| Introduction|| |
Infantile hemangiomas (IH) are the most common soft tissue neoplasm of infancy. Most IH are uncomplicated, do not require intervention, and regress spontaneously. However, certain subsets of IH may warrant special considerations based on location, size, growth features, potential complications, or possible association with underlying anomalies. Over the past two decades, research has elucidated several pathways contributing to the pathogenesis of IH, and advances have been observed in their treatment. Herein, we review the updated literature on pathogenesis, clinical presentation, associations, and management options for IH.
| Nomenclature, Epidemiology, and Pathogenesis|| |
Historically, the nomenclature of vascular anomalies was clinically descriptive and nonuniform, leading to diagnostic confusion. To clarify the terminology, a standardized nomenclature of vascular lesions was proposed by Mulliken and Glowacki in 1982. Vascular anomalies were classified as either vascular tumors or vascular malformations based on biological features including clinical behavior and histopathologic features. This classification was recognized by the International Society of the Study of Vascular Anomalies, subsequently updated in 2014 and is now widely accepted., This standardized nomenclature has helped to more accurately determine the true incidence of IH by excluding other vascular anomalies, such as venous or capillary malformations, and has contributed to the identification of the most appropriate treatment options for the respective conditions.
The incidence of IH is estimated to be around 4%–5% of infants., Prospective studies in the United States and Europe have shown that infants who develop IH are more likely to be female (with female to male ratios ranging from 1.4:1 to 3:1), Caucasian, premature, and of low birth weight.,,,, A retrospective study from India found a female predominance of 2.3:1, which is comparable to other studies. Other reported risk factors include placental anomalies, most notably, preeclampsia and placenta previa, placental disruption as with chorionic villus sampling, multiple gestation pregnancy, and advanced maternal age.,,In utero exposure to medications has not been confirmed as an etiologic factor in large or prospective studies.
Although the majority of IH are sporadic and no single mutation has been identified, genetic factors may play a role. The relative risk for IH in siblings of an affected individual is increased, and in some families, an autosomal dominant inheritance has been suggested., In a prospective cohort study comparing IH in concordant and discordant twin pairs from twelve pediatric dermatology centers, no significant differences were noted in rates of concordance for IH between monozygotic and dizygotic twins, suggesting that zygosity is not a significant risk factor. It has been suggested that a mutation may underlie the small subset of IH that is associated with multiple organ defects, as in posterior fossa abnormalities, hemangioma, arterial abnormalities, cardiac anomalies, and eye defects (PHACE) and lower body hemangioma and other cutaneous defects, urogenital anomalies and ulceration, myelopathy, bony deformities, anorectal malformations and arterial anomalies, and renal anomalies (LUMBAR) syndromes, which are discussed later., Genetic analyses indicate that some PHACE syndrome patients have alterations in chromosomal region 7q33.
Research investigating the pathogenesis of IH has identified two potential cell lines of origin including multipotent stem cells and cells of placental origin. Hemangioma progenitor cells, including hemangioma stem cells (HemSC), are present in proliferating IH. HemSC form GLUT1-positive vessels reminiscent of IH when grafted into immunodeficient mice. On the other hand, IH stain positive for GLUT1, Lewis Y antigen, FcRII, and merosin which are typical placental stains. This staining pattern, along with the epidemiologic associations of IH with placental disruption, supports the theory of placental origin.
The rapid proliferation of IH is driven by several cell signaling pathways resulting in both vasculogenesis and angiogenesis. In vasculogenesis, new blood vessels are made from multipotent progenitor cells, such as HemSC, leading to the development of disorganized blood vessels within the tumor. In angiogenesis, new vessels develop off of existing blood vessels, and proliferative IH stain positive for angiogenic promoters such as vascular endothelial growth factor A and basic fibroblast growth factor.
Extrinsic factors, such as tissue hypoxia, are likely to contribute to IH development and growth. GLUT1 is both the characteristic cellular marker of IH and a marker for hypoxia. Growth factors such as VEGF, which are induced by hypoxia, may attract circulating hemangioma stem cells to areas of hypoxia. This theory of hypoxia is also supported by the epidemiologic association of IH with placental disruption and low birth weight, as well as by the finding of blanching which can be a premonitory finding in IH.
| Clinical Presentation|| |
IH may be classified by tissue depth, morphological subtype, and pattern of growth [Table 1]. IH that are situated primarily on the surface of the skin are described as superficial IH. These appear as bright red papules and plaques [Figure 1] which are warm to touch, nonpulsatile, and nontender. Deep IH lie primarily within the deep dermis and subcutaneous tissue, appearing as flesh-colored to blue masses that are warm to touch [Figure 2]; they are also nonpulsatile and nontender. Some IH may have surrounding vasoconstriction (manifested as pallor) and/or dilatation of surrounding veins. In the past, superficial and deep IH were named in the literature as strawberry and cavernous hemangiomas, respectively. Mixed-type IH contain components which are both superficial and deep [Figure 3].
Morphologically, IH may be categorized as focal, segmental, indeterminate, or multifocal. This classification system may identify IH at risk for complications and/or associated internal abnormalities. Focal IH are discrete, typically circular, and solitary [Figure 4] whereas segmental IH involve an expansive surface area usually within an anatomic or developmental territory and often appear more plaque-like [Figure 5]. Multifocal IH are numerous, discrete, localized lesions present at more than one anatomic site [Figure 6]. Indeterminate IH are not definitively focal or segmental. One large retrospective study found that almost three-fourths (72%) of IH were focal, 18% were segmental, 8% were indeterminate, and 3% were multifocal. Similarly, a large prospective, multicenter study found that 3% of patients referred to a pediatric dermatology clinic had multifocal cutaneous IH, defined as numbering ≥10.
The natural history of IH typically follows a predictable clinical pattern of proliferation and eventual spontaneous involution. IH may not be visible at birth or may be preceded by any of several premonitory findings, including vasoconstriction, telangiectasias, ecchymosis, or ulceration [Figure 7]. Lesions are typically clinically apparent by 4 weeks of age. Rapid growth (representing endothelial cell proliferation) occurs in early infancy, leading to enlargement of the IH with more elevation. A large multicenter prospective cohort study demonstrated that IH attain 80% of their final size by 3 months of age and by 5 months, IH have usually completed most of their growth. Later in the proliferative phase, a slower rate of growth occurs. By around 12 months of age, IH begin to slowly and spontaneously involute. Most regression is accomplished before 4 years of age. IH residua after involution may include fibrofatty tissue, telangiectasias, scarring, pigment change, or atrophic skin [Figure 8].
|Figure 7: Precursor lesion to an infantile hemangioma with telangiectatic patch and ulceration|
Click here to view
|Figure 8: Residuum of an infantile hemangioma, demonstrating hyperpigmentation and fibrofatty tissue|
Click here to view
Some IH do not strictly adhere to this typical growth history. IH with minimal or arrested growth (IH-MAG) are a subset of IH which exhibit abortive or minimal growth in <25% of the lesion's surface area. IH-MAG appear as telangiectatic patches with or without surrounding small proliferative papules [Figure 9], commonly on the lower body. Some IH subtypes show varied time courses for the growth phases. Deep IH tend to appear later than superficial IH and may grow for a longer period. After 6 months of age, segmental hemangiomas have higher growth rates than focal hemangiomas. Moreover, although growth after 9 months of age is rare, occurring in only around 3% of IH, this late growth is more common in deep, mixed type, segmental, and indeterminate hemangiomas than in superficial IH., IH of the parotid gland may also demonstrate prolonged proliferative stages beyond 9 months of age.
|Figure 9: Infantile hemangioma with minimal to arrested growth. (a) Telangiectatic patch with peripheral pallor and small component of proliferation (darker red) at superior portion; (b) Vascular patch studded with tiny proliferative vascular papules|
Click here to view
| Associations and Syndromes|| |
Cutaneous IH may serve as heralding signs of internal IH (as in the case of multiple cutaneous hemangiomas or segmental lesions in a beard distribution) or regional internal anomalies (as in PHACE and LUMBAR syndromes).
Multiple cutaneous IH may be a marker for extracutaneous IH, most notably, involving the liver. A literature review of radiologic and histologic features of hepatic hemangiomas revealed that hepatic hemangiomas could be classified as focal, multifocal, and diffuse as shown in [Table 2], and this classification scheme is supported by findings in a large retrospective study of a single center registry., In a multicenter, prospective study of 151 infants younger than 6 months, 24 of the infants with five or more cutaneous IH had hepatic hemangiomas on ultrasound whereas none of the infants with fewer than five cutaneous IH had hepatic hemangiomas. Hepatic hemangiomas of all subtypes can cause arteriovenous shunting and lead to heart failure. Multifocal and diffuse hepatic hemangiomas can be associated with acquired hypothyroidism.
Cutaneous IH in the “beard” distribution, which includes the bilateral preauricular cheeks, lower lip, chin, and anterior neck [Figure 10] may be markers for upper airway or subglottic IH. In a large retrospective study of patients with head and neck hemangiomas, out of 11 patients with superficial cutaneous IH in 1–2 of these five key areas, one patient (9%) had a symptomatic airway hemangioma. In contrast, out of 16 patients with IH in 4–5 of these 5 key areas, 10 patients (63%) had symptomatic airway hemangiomas, highlighting the importance of assessing extent of the segmental IH as a predictor for airway IH risk. In another study of patients with cutaneous IH involving the beard area, patients were more likely to have subglottic IH if the cutaneous IH were telangiectatic in appearance and if they were bilateral. Airway hemangiomas can present with respiratory obstruction, as biphasic inspiratory and expiratory stridor, noisy breathing, hoarse cry, respiratory distress, or a progressive croup-like cough., These symptoms are more likely to become apparent during the proliferative phase , and if present, immediate referral for direct laryngoscopy is advisable.
|Figure 10: Early infantile hemangioma in the “beard” distribution; this child was found to have a subglottic hemangioma|
Click here to view
Large, segmental IH of the face, scalp, and/or neck can be a marker for several other anomalies; an association which has been termed PHACE or PHACES (posterior fossa abnormalities, hemangioma, arterial abnormalities, cardiac anomalies, eye defects, sternal cleft and/or supraumbilical raphe) syndrome. PHACE syndrome was first described in 1996, and the diagnostic criteria were updated in 2016., [Table 3] highlights the more common clinical features in PHACE syndrome. In one study, one-third of patients with head and neck IH measuring ≥22 cm 2 had PHACE syndrome, and segmental frontotemporal and frontonasal IH were the most commonly involved facial IH segment patterns. Anomalies of the cerebral arteries occurred in 91% of patients; cardiac anomalies, such as aortic arch anomalies, occurred in 67% of patients; structural brain anomalies, such as cerebellar hypoplasia, occurred in 52% of patients; and ocular anomalies, such as persistent retinal vessels, were observed in 24% of patients. Therefore, screening with magnetic resonance imaging and magnetic resonance angiography of the head and neck, echocardiography and eye examination are recommended for patients with large segmental IH of the face, scalp, or neck. In addition, PHACE syndrome, though originally described in association with large facial, scalp, and/or neck segmental hemangiomas, can be seen in patients with segmental hemangiomas of the upper trunk and/or upper extremities with minimal or absent facial IH. A “lower body” variant of PHACE syndrome is also recognized, under the auspice of various mnemonics [Table 4], and in these patients, segmental IH are associated with underlying regional anomalies of the renal, genitourinary, lower gastrointestinal, and skeletal systems and lower spinal cord.,,
|Table 3: Some common clinical features in posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/coarctation of the aorta, eye anomalies (PHACE) syndrome|
Click here to view
|Table 4: Various mnemonics for lower body infantile hemangioma associations|
Click here to view
| Complications of Infantile Hemangiomas and Management|| |
A minority of IH, up to 24%, may warrant intervention. Indications for therapy include ulceration, potentially life-threatening complications, functional impairment, and potential or actual disfigurement. IH of the face can be cosmetically sensitive with both a risk of disfigurement and adverse psychosocial sequelae.
Life-threatening complications of IH are rare but do occur, typically in association with airway and hepatic IH. IH in the respiratory tract, from the oral cavity to the trachea, can obstruct air flow. A segmental (but not focal) IH in the beard distribution or the presence of biphasic stridor or persistent croup-like cry should raise suspicion for possible airway IH. These patients should be promptly evaluated by a pediatric otolaryngologist if there are concerns. Patients with hepatic IH can develop high-output congestive heart failure and severe hypothyroidism. In patients with 5 or more cutaneous IH, abdominal ultrasound should be used to screen for hepatic hemangiomas, and if present, follow-up ultrasonography, thyroid screening, and occasionally other studies (i.e., echocardiogram or electrocardiogram) may be indicated.,
Potential functional complications of IH can also occur and warrant prompt evaluation and therapy. Periocular IH have the potential to cause amblyopia or impaired vision due to abnormal visual axis development. IH can contribute to amblyopia due to pressure on the globe causing distortion of the eye shape, obstruction of the visual field, or production of strabismus by displacing the globe or affecting the function of extraocular muscles. IH of the lip or mouth can hinder feeding and the development of dentition. IH within the parotid gland and in the periauricular area may narrow the external auditory canal with the potential to cause conductive hearing loss. IH of the breast can disturb mammary gland development and lead to breast hypoplasia.
Ulceration is the most common complication seen in IH, occurring in 16% of patients with IH referred to pediatric dermatology clinics in a large, multicenter study. Ulceration is most likely to occur at a median age of 4 months, during the proliferative phase, suggesting that an IH may outgrow its blood supply during rapid expansion. Hemangiomas of the lower lip, neck, and anogenital regions are most likely to ulcerate. Additional risk factors for ulceration include large surface area, mixed superficial and deep type hemangiomas, and segmental hemangiomas. Ulcerated IH can bleed, be painful, provide a nidus for secondary infection, and almost always lead to permanent scarring. Bleeding is generally mild, with rare need for hospitalization or blood transfusions., Culture-positive infections are generally uncommon, although cultures of Staphylococcus aureus, Pseudomonas (particularly in the anogenital region), Group A beta-hemolytic streptococcus, and Candida have been reported.,
Management of ulcerated hemangiomas
To date, there are no high level evidence studies on the management of ulcerated IH. Management is often influenced by provider experience. [Table 5] summarizes treatment approaches to ulcerated IH.
Medical management of infantile hemangiomas
Options for medical therapy of IH include topical agents and systemic medications. Propranolol is a nonselective beta-blocker which has become the gold standard first-line therapy for most IH requiring therapy. In 2008, Léauté-Labrèze et al. reported the improvement of IH in patients treated with propranolol for cardiac disorders. A subsequent randomized, controlled trial of oral propranolol at a dose of 3.4 mg/kg/day demonstrated safety for use in infants aged 1–5 months for 6 months as well as a primary endpoint (complete/near complete resolution) success rate of 60%. A systematic review of 41 reports of 1264 patients revealed that 98% of patients responded positively to treatment with propranolol. Proposed mechanisms of action include vasoconstriction, inhibition of vasculogenesis and angiogenesis, and induction of apoptosis. In 2014, propranolol hydrochloride oral solution was approved by both the United States Food and Drug Administration (FDA), formulated as 4.28 mg/mL, and the European Medicines Agency (EMA), formulated as 3.75 mg/mL, for the treatment of proliferating infantile hemangioma requiring systemic therapy., Propranolol is also available in a generic oral solution (20 mg/5 mL or 40 mg/5 mL), which is not approved by the FDA for treatment of IH. If used off-label, the 40 mg/5 mL solution is not recommended given the small volumes and inherently increased risk of overdose. [Table 6] summarizes propranolol contraindications and potential adverse events.
|Table 6: Propranolol treatment for IH: Contraindications and potential adverse events|
Click here to view
Recommendations for safe and effective initiation and subsequent monitoring of propranolol have been proposed by several consensus groups in the United States, Europe, Spain, and Australia.,,, According to these consensus statements, treatment with oral propranolol is generally considered if there is functional impairment, current or potential ulceration, or risk of disfigurement and/or psychosocial impact. According to the U.S. guidelines, published in 2013, a baseline physical examination should be performed, with consideration for a screening electrocardiogram in patients with measured or history of bradycardia or arrhythmia and/or with a family history of arrhythmia, congenital heart conditions, or maternal history of autoimmune connective tissue disease. The goal dose is 1–3 mg/kg/day depending on individual response. The U.S. consensus statement recommends inpatient propranolol initiation for infants <8 weeks of gestational corrected age or with comorbid conditions such as cardiovascular, respiratory, or endocrine conditions, with a starting dose of 0.33 mg/kg three times daily and increased as tolerated to 0.66 mg/kg three times daily (with minimum of 6 hours between doses). Outpatient initiation of propranolol is best suited for infants older than 8 weeks of age, lacking comorbid conditions, and with adequate social support. Per the U.S. guidelines, outpatient initiation is recommended to start at 0.33 mg/kg three times daily, with increase to 0.5 mg/kg three times daily after 3-7 days and subsequent increase to 0.66 mg/kg three times daily after another 3-7 days, if tolerated. The escalation protocol listed in the package insert for propranolol hydrochloride suggests a starting dose of 0.6 mg/kg twice daily, with an increase after 1 week to 1.1 mg/kg twice daily, and further increase after 2 weeks to 1.7 mg/kg twice daily if tolerated. Monitoring at the time of initiation and with each dose increase includes heart rate and blood pressure at baseline and 1 and 2 h after administration, as this is the peak effect of oral propranolol on these parameters. Hypoglycemia is best avoided by administering each dose with a feeding and by advising parents to avoid long periods of fasting. Despite the need for rigorous monitoring and despite several challenges including the lack of liquid propranolol, a retrospective review at an academic teaching hospital in Afghanistan demonstrated that propranolol can be managed safely and successfully for IH patients in resource-limited settings.
Other systemic beta-blockers, including nadolol and atenolol, have been shown to also effectively treat IH. Nadolol, like propranolol, is a nonselective beta-blocker but with decreased penetration of the blood-brain barrier, and, hence, a potentially lower side effect profile than propranolol, such as decreased sleep disturbances. Atenolol is a selective β1 antagonist. Like nadolol, atenolol is less lipophilic than propranolol and may have less effect on sleep. Moreover, given its beta receptor selectivity, nadolol may pose less risk of bronchospasm and hypoglycemia.
Topical timolol, a nonselective beta-blocker utilized for treatment of glaucoma, has gained favor as an off-label treatment of uncomplicated, superficial IH. Adverse effects include local irritation and possibly bronchospasm, although it has been very well tolerated overall, and a large multicenter retrospective study found no associated cardiovascular adverse events. However, use on large, ulcerated, mixed-type, or deep IH; use on IH on mucous membranes or occluded areas, or use in young and preterm infants may be associated with increased timolol absorption and risk of systemic adverse effects.,, The topical solution can be formulated as timolol maleate 0.25% or 0.5% ophthalmic solution or as an ophthalmic gel-forming solution, the latter of which is preferred given the decreased propensity toward systemic absorption., Timolol is typically applied as one drop twice daily to the surface of the IH [Figure 11].
|Figure 11: (a) Superficial hemangioma prior to treatment with timolol maleate 0.5% topical gel-forming solution. (b) Same hemangioma following timolol therapy|
Click here to view
Before the discovery of propranolol's effect on IH, systemic corticosteroids were the standard therapy. Successful treatment of IH with systemic corticosteroids was first reported in 1967 by Zarem and Edgerton after treatment of a child with thrombocytopenia and an incidental large hemangioma which improved on oral prednisolone. The mechanism of action of corticosteroids on IH has not been completely elucidated but may include effects on vasculogenesis and adipogenesis. In a systematic review of the literature, the most common side effects of oral corticosteroids in patients with IH were behavior changes, cushingoid features, gastric irritation and transient growth delay, and no life-threatening effects were reported. In this study, a high response rate of 84% was found at a mean prednisone equivalent daily dose of 2.9 mg/kg/day. Although no guidelines have been published and a wide range of dosing has been reported, optimal dosing is generally considered to be oral prednisone or prednisolone at 2–3 mg/kg/day. Long-term corticosteroid treatment for IH can lead to hypertension and hypothalamic-pituitary-adrenal (HPA) axis suppression, and systemic steroid-mediated immunosuppression has been associated with diminished tetanus and diphtheria antibody vaccine responses and rare reports of Pneumocystic carinii pneumonia.,
Intralesional corticosteroids are a consideration for treatment of select small, isolated, and focal IH. In a single center retrospective review, intralesional triamcinolone was associated with treatment response in 100% of patients with proliferating IH, with 63% showing regression and 37% showing stabilization. Locally, subcutaneous atrophy may occur. At individual intralesional doses of triamcinolone acetonide (40 mg/mL) <3 mg/kg/dose given every 4–6 weeks, no systemic side effects were observed. Higher doses, though, have been associated with cushingoid appearance and HPA axis suppression., Special care must be taken when injecting periocular IH given rare reports of retinal artery occlusion when injecting large volumes and injecting under high pressures.
Procedural management of infantile hemangiomas
Pulsed dye laser (PDL), the gold standard laser for pediatric vascular lesions, has been used in the treatment of IH. PDL is most adept at treating superficial vascular lesions and therefore may be useful in treating early superficial IH on the face. In addition, treating the superficial component of mixed type IH can preserve skin in cosmetically sensitive areas. Ulcerated IH recalcitrant to medical therapy may benefit from PDL, and the telangiectatic residua of IH can also be treated with this modality. Risks of PDL in the treatment of IH include ulceration, skin atrophy, scarring, and hypopigmentation.
Depending on the size and location of an IH, surgical removal may be a consideration. Surgery during the proliferative phase may be complicated by greater blood loss and risks leaving IH remnants which can continue to grow after surgery. However, for functionally-impairing IH as in the airway or for ulcerated IH recalcitrant to medical therapy, surgical removal in the proliferative phase may be indicated. For most IH where excision may play a therapeutic role, though, it is most often performed during or after involution. Allowing time for proliferation can be helpful as the growing IH can act as its own tissue expander, especially in cosmetically sensitive areas such as the face and scalp, allowing for single stage surgery. Surgery may also be indicated for excision of IH residua. The timing of elective surgical removal should take into consideration the patient's onset of self-image, preferably removing an IH before any untoward effects on psychosocial development.
| Conclusion|| |
In the past two decades, research and clinical experience have greatly increased our understanding of IH pathogenesis, risk factors, and the clinical spectrum of disease. The discovery of beta-blockers as an effective therapy has significantly altered the treatment landscape, and as pathways contributing to IH development continue to be elucidated, other therapeutic approaches may emerge. Clinicians caring for IH patients should appreciate their natural history and potential complications and initiate treatment (or referral to a hemangioma specialist) as early as feasible in an effort to optimize outcomes and minimize morbidities.
The authors would like to thank Daniel Krowchuk, MD, for assistance in preparation of the photographs.
Financial support and sponsorship
Conflicts of interest
Dr. Mancini has served as a consultant for Pierre Fabre.
| References|| |
Finn MC, Glowacki J, Mulliken JB. Congenital vascular lesions: Clinical application of a new classification. J Pediatr Surg 1983;18:894-900.
Dasgupta R, Fishman SJ. ISSVA classification. Semin Pediatr Surg 2014;23:158-61.
ISSVA Classification of Vascular Anomalies. International Society for the Study of Vascular Anomalies; 2014. Available from: http://www.issva.org/classification
. [Last accessed on 2018 Mar 25].
Kilcline C, Frieden IJ. Infantile hemangiomas: How common are they? A systematic review of the medical literature. Pediatr Dermatol 2008;25:168-73.
Kanada KN, Merin MR, Munden A, Friedlander SF. A prospective study of cutaneous findings in newborns in the United States: Correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr 2012;161:240-5.
Dickison P, Christou E, Wargon O. A prospective study of infantile hemangiomas with a focus on incidence and risk factors. Pediatr Dermatol 2011;28:663-9.
Munden A, Butschek R, Tom WL, Marshall JS, Poeltler DM, Krohne SE, et al.
Prospective study of infantile haemangiomas: Incidence, clinical characteristics and association with placental anomalies. Br J Dermatol 2014;170:907-13.
Hemangioma Investigator Group, Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, et al.
Prospective study of infantile hemangiomas: Demographic, prenatal, and perinatal characteristics. J Pediatr 2007;150:291-4.
Hoornweg MJ, Smeulders MJ, Ubbink DT, van der Horst CM. The prevalence and risk factors of infantile haemangiomas: A case-control study in the dutch population. Paediatr Perinat Epidemiol 2012;26:156-62.
Pandey A, Gangopadhyay AN, Gopal SC, Kumar V, Sharma SP, Gupta DK, et al.
Twenty years' experience of steroids in infantile hemangioma – A developing country's perspective. J Pediatr Surg 2009;44:688-94.
Bauland CG, Smit JM, Scheffers SM, Bartels RH, van den Berg P, Zeebregts CJ, et al.
Similar risk for hemangiomas after amniocentesis and transabdominal chorionic villus sampling. J Obstet Gynaecol Res 2012;38:371-5.
Grimmer JF, Williams MS, Pimentel R, Mineau G, Wood GM, Bayrak-Toydemir P, et al.
Familial clustering of hemangiomas. Arch Otolaryngol Head Neck Surg 2011;137:757-60.
Walter JW, Blei F, Anderson JL, Orlow SJ, Speer MC, Marchuk DA, et al.
Genetic mapping of a novel familial form of infantile hemangioma. Am J Med Genet 1999;82:77-83.
Greco MF, Frieden IJ, Drolet BA, Garzon MC, Mancini AJ, Chamlin SL, et al.
Infantile hemangiomas in twins: A prospective cohort study. Pediatr Dermatol 2016;33:178-83.
Iacobas I, Burrows PE, Frieden IJ, Liang MG, Mulliken JB, Mancini AJ, et al.
LUMBAR: Association between cutaneous infantile hemangiomas of the lower body and regional congenital anomalies. J Pediatr 2010;157:795-8010.
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;132:307-11.
Mitchell S, Siegel DH, Shieh JT, Stevenson DA, Grimmer JF, Lewis T, et al.
Candidate locus analysis for PHACE syndrome. Am J Med Genet A 2012;158A: 1363-7.
Khan ZA, Boscolo E, Picard A, Psutka S, Melero-Martin JM, Bartch TC, et al.
Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest 2008;118:2592-9.
North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: A newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000;31:11-22.
Takahashi K, Mulliken JB, Kozakewich HP, Rogers RA, Folkman J, Ezekowitz RA, et al.
Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 1994;93:2357-64.
Kleinman ME, Blei F, Gurtner GC. Circulating endothelial progenitor cells and vascular anomalies. Lymphat Res Biol 2005;3:234-9.
Drolet BA, Frieden IJ. Characteristics of infantile hemangiomas as clues to pathogenesis: Does hypoxia connect the dots? Arch Dermatol 2010;146:1295-9.
Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N
Engl J Med 1999;341:173-81.
Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: Clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol 2002;138:1567-76.
Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, et al.
Prospective study of infantile hemangiomas: Clinical characteristics predicting complications and treatment. Pediatrics 2006;118:882-7.
Hidano A, Nakajima S. Earliest features of the strawberry mark in the newborn. Br J Dermatol 1972;87:138-44.
Chang LC, Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, et al.
Growth characteristics of infantile hemangiomas: Implications for management. Pediatrics 2008;122:360-7.
Bauland CG, Lüning TH, Smit JM, Zeebregts CJ, Spauwen PH. Untreated hemangiomas: Growth pattern and residual lesions. Plast Reconstr Surg 2011;127:1643-8.
Suh KY, Frieden IJ. Infantile hemangiomas with minimal or arrested growth: A retrospective case series. Arch Dermatol 2010;146:971-6.
Brandling-Bennett HA, Metry DW, Baselga E, Lucky AW, Adams DM, Cordisco MR, et al.
Infantile hemangiomas with unusually prolonged growth phase: A case series. Arch Dermatol 2008;144:1632-7.
Christison-Lagay ER, Burrows PE, Alomari A, Dubois J, Kozakewich HP, Lane TS, et al.
Hepatic hemangiomas: Subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg 2007;42:62-7.
Kulungowski AM, Alomari AI, Chawla A, Christison-Lagay ER, Fishman SJ. Lessons from a liver hemangioma registry: Subtype classification. J Pediatr Surg 2012;47:165-70.
Horii KA, Drolet BA, Frieden IJ, Baselga E, Chamlin SL, Haggstrom AN, et al.
Prospective study of the frequency of hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. Pediatr Dermatol 2011;28:245-53.
Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a “beard” distribution. J Pediatr 1997;131:643-6.
Piram M, Hadj-Rabia S, Boccara O, Couloigner V, Hamel-Teillac D, Bodemer C, et al.
Beard infantile hemangioma and subglottic involvement: Are median pattern and telangiectatic aspect the clue? J Eur Acad Dermatol Venereol 2016;30:2056-9.
Suh KY, Rosbe KW, Meyer AK, Frieden IJ. Extensive airway hemangiomas in two patients without beard hemangiomas. Pediatr Dermatol 2011;28:347-8.
Garzon MC, Epstein LG, Heyer GL, Frommelt PC, Orbach DB, Baylis AL, et al.
PHACE syndrome: Consensus-derived diagnosis and care recommendations. J Pediatr 2016;178:24-33.e2.
Haggstrom AN, Garzon MC, Baselga E, Chamlin SL, Frieden IJ, Holland K, et al.
Risk for PHACE syndrome in infants with large facial hemangiomas. Pediatrics 2010;126:e418-26.
Nabatian AS, Milgraum SS, Hess CP, Mancini AJ, Krol A, Frieden IJ, et al.
PHACE without face? Infantile hemangiomas of the upper body region with minimal or absent facial hemangiomas and associated structural malformations. Pediatr Dermatol 2011;28:235-41.
Stockman A, Boralevi F, Taïeb A, Léauté-Labrèze C. SACRAL syndrome: Spinal dysraphism, anogenital, cutaneous, renal and urologic anomalies, associated with an angioma of lumbosacral localization. Dermatology 2007;214:40-5.
Girard C, Bigorre M, Guillot B, Bessis D. PELVIS syndrome. Arch Dermatol 2006;142:884-8.
Hoeger PH, Harper JI, Baselga E, Bonnet D, Boon LM, Ciofi Degli Atti M, et al.
Treatment of infantile haemangiomas: Recommendations of a european expert group. Eur J Pediatr 2015;174:855-65.
Williams EF 3rd
, Hochman M, Rodgers BJ, Brockbank D, Shannon L, Lam SM, et al.
Apsychological profile of children with hemangiomas and their families. Arch Facial Plast Surg 2003;5:229-34.
Dickie B, Dasgupta R, Nair R, Alonso MH, Ryckman FC, Tiao GM, et al.
Spectrum of hepatic hemangiomas: Management and outcome. J Pediatr Surg 2009;44:125-33.
Rialon KL, Murillo R, Fevurly RD, Kulungowski AM, Zurakowski D, Liang M, et al.
Impact of screening for hepatic hemangiomas in patients with multiple cutaneous infantile hemangiomas. Pediatr Dermatol 2015;32:808-12.
Spence-Shishido AA, Good WV, Baselga E, Frieden IJ. Hemangiomas and the eye. Clin Dermatol 2015;33:170-82.
Léauté-Labrèze C, Prey S, Ezzedine K. Infantile haemangioma: Part II. Risks, complications and treatment. J Eur Acad Dermatol Venereol 2011;25:1254-60.
Greene AK, Rogers GF, Mulliken JB. Management of parotid hemangioma in 100 children. Plast Reconstr Surg 2004;113:53-60.
Theiler M, Hoffman WY, Frieden IJ. Breast hypoplasia as a complication of an untreated infantile hemangioma. Pediatr Dermatol 2016;33:e129-30.
Chamlin SL, Haggstrom AN, Drolet BA, Baselga E, Frieden IJ, Garzon MC, et al.
Multicenter prospective study of ulcerated hemangiomas. J Pediatr 2007;151:684-9, 689.e1.
Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: Clinical characteristics and response to therapy. J Am Acad Dermatol 2001;44:962-72.
Yan AC. Pain management for ulcerated hemangiomas. Pediatr Dermatol 2008;25:586-9.
Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A, et al.
Propranolol for severe hemangiomas of infancy. N
Engl J Med 2008;358:2649-51.
Léauté-Labrèze C, Hoeger P, Mazereeuw-Hautier J, Guibaud L, Baselga E, Posiunas G, et al.
Arandomized, controlled trial of oral propranolol in infantile hemangioma. N
Engl J Med 2015;372:735-46.
Marqueling AL, Oza V, Frieden IJ, Puttgen KB. Propranolol and infantile hemangiomas four years later: A systematic review. Pediatr Dermatol 2013;30:182-91.
Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of infantile haemangiomas: An update on potential mechanisms of action. Br J Dermatol 2015;172:24-32.
Drolet BA, Frommelt PC, Chamlin SL, Haggstrom A, Bauman NM, Chiu YE, et al.
Initiation and use of propranolol for infantile hemangioma: Report of a consensus conference. Pediatrics 2013;131:128-40.
Baselga Torres E, Bernabéu Wittel J, van Esso Arbolave DL, Febrer Bosch MI, Carrasco Sanz Á, de Lucas Laguna R, et al.
Spanish consensus on infantile haemangioma. An Pediatr (Barc) 2016;85:256-65.
Smithson SL, Rademaker M, Adams S, Bade S, Bekhor P, Davidson S, et al.
Consensus statement for the treatment of infantile haemangiomas with propranolol. Australas J Dermatol 2017;58:155-9.
McMichael J, Lawley LP. Propranolol for infantile hemangiomas in developing countries. Dermatol Online J 2017;23. pii: 13030/qt5hs9c24f.
Bernabeu-Wittel J, Narváez-Moreno B, de la Torre-García JM, Fernández-Pineda I, Domínguez-Cruz JJ, Coserría-Sánchez F, et al.
Oral nadolol for children with infantile hemangiomas and sleep disturbances with oral propranolol. Pediatr Dermatol 2015;32:853-7.
Bayart CB, Tamburro JE, Vidimos AT, Wang L, Golden AB. Atenolol versus propranolol for treatment of infantile hemangiomas during the proliferative phase: A retrospective noninferiority study. Pediatr Dermatol 2017;34:413-21.
Püttgen K, Lucky A, Adams D, Pope E, McCuaig C, Powell J, et al.
Topical timolol maleate treatment of infantile hemangiomas. Pediatrics 2016;138. pii: e20160355.
McMahon P, Oza V, Frieden IJ. Topical timolol for infantile hemangiomas: Putting a note of caution in “cautiously optimistic”. Pediatr Dermatol 2012;29:127-30.
Frommelt P, Juern A, Siegel D, Holland K, Seefeldt M, Yu J, et al.
Adverse events in young and preterm infants receiving topical timolol for infantile hemangioma. Pediatr Dermatol 2016;33:405-14.
Bennett ML, Fleischer AB Jr., Chamlin SL, Frieden IJ. Oral corticosteroid use is effective for cutaneous hemangiomas: An evidence-based evaluation. Arch Dermatol 2001;137:1208-13.
Zarem HA, Edgerton MT. Induced resolution of cavernous hemangiomas following prednisolone therapy. Plast Reconstr Surg 1967;39:76-83.
Darrow DH, Greene AK, Mancini AJ, Nopper AJ; Section on Dermatology, Section on Otolaryngology–Head and Neck Surgery, and Section on Plastic Surgery. Diagnosis and management of infantile hemangioma. Pediatrics 2015;136:e1060-104.
George ME, Sharma V, Jacobson J, Simon S, Nopper AJ. Adverse effects of systemic glucocorticosteroid therapy in infants with hemangiomas. Arch Dermatol 2004;140:963-9.
Kelly ME, Juern AM, Grossman WJ, Schauer DW, Drolet BA. Immunosuppressive effects in infants treated with corticosteroids for infantile hemangiomas. Arch Dermatol 2010;146:767-74.
Maronn ML, Corden T, Drolet BA. Pneumocystis carinii pneumonia in infant treated with oral steroids for hemangioma. Arch Dermatol 2007;143:1224-5.
Couto JA, Greene AK. Management of problematic infantile hemangioma using intralesional triamcinolone: Efficacy and safety in 100 infants. J Plast Reconstr Aesthet Surg 2014;67:1469-74.
Chen MT, Yeong EK, Horng SY. Intralesional corticosteroid therapy in proliferating head and neck hemangiomas: A review of 155 cases. J Pediatr Surg 2000;35:420-3.
Shorr N, Seiff SR. Central retinal artery occlusion associated with periocular corticosteroid injection for juvenile hemangioma. Ophthalmic Surg 1986;17:229-31.
Lacour M, Syed S, Linward J, Harper JI. Role of the pulsed dye laser in the management of ulcerated capillary haemangiomas. Arch Dis Child 1996;74:161-3.
Batta K, Goodyear HM, Moss C, Williams HC, Hiller L, Waters R, et al.
Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood haemangiomas: Results of a 1-year analysis. Lancet 2002;360:521-7.
Hochman M. The role of surgery in the management of infantile hemangiomas: What is the best timing? Otolaryngol Clin North Am 2018;51:119-23.
Brennan TE, Waner M, Teresa MO. The tissue expander effect in early surgical management of select focal infantile hemangiomas. JAMA Facial Plast Surg 2017;19:282-6.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]