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infantile hemangiomas represent the most common type of benign tumors of the infancy , with a prevalence estimated at 110% of the infants worldwide . even though the disorder is mostly harmless
these tumors develop in the period of infancy , only 20%   of them being present at birth , with an increased frequency in the female gender , the white race   and in low birth weight infants .
some studies reported the disorder in many siblings of the same family , with non - affected parents , pointing out a possible genetic immixture .
the hypothesis of pathogenesis supports the idea that hemangiomas develop by cellular hyperplasia and by the proliferation of endothelial cells .
important research has shown that angiogenic and vasculogenic factors stimulate their proliferation   and these markers influence all the evolutionary phases of hemangiomas . to date , the most used therapeutic agents were represented by corticotherapy , either systemic or topical .
their effects on the evolution of hemangioma are beneficial , but the side - effects are significant . since the discovery in 2008 by laute - labreze , propranolol has been used in infantile hemangioma therapies , with good results and few adverse effects , which are of minimal severity .
still , there are multiple possibilities of therapeutic approaches that include surgery , radiotherapy , laser therapy , embolization , imiquimod or vincristine , therapies that need to be individualized .
infantile hemangiomas remain a current challenge for the medical science , raising constant questions about risk factors , prognostic factors , pathogenesis , evolution and treatment .
researchers worldwide presently consider the disorder a pressing issue , and that is why several studies have been conducted in order to elucidate the exact mechanism of developing infantile hemangioma .
hypoxia and acidosis are known to create a disturbance of the equilibrium between proangiogenic and antiangiogenic factors .
in addition to the proliferation of endothelial cells , intrauterine or perinatal hypoxia and acidosis , both stimulate angiogenesis by increasing the secretion of vegf ( vascular endothelial growth factor ) .
alpha ( hypoxia - inducible factor 1 alpha ) induces the gene - transcription of vegf , which is the most powerful angiogenic factor .
the injury of placenta is supposed to cause the embolization of endothelial cells and the consecutive overflow of these into the fetal circulation . through the pof ( patent foramen ovale ) the cells
the placenta releases angiostatic factors ( sflt1 ) , but after birth these inhibitory factors are wasted , which allows the development of the infantile hemangioma by endothelial cell proliferation .
a high number of cd133 + , cd34 + endothelial cells have been detected in the blood of children with proliferative infantile hemangiomas .
high levels of 17-beta - estradiol were noted in several studies , simultaneously with high numbers of estradiol receptors at hemangioma tissue - surfaces in their proliferative phase .
the injury of placenta is supposed to cause the embolization of endothelial cells and the consecutive overflow of these into the fetal circulation . through the pof ( patent foramen ovale ) the cells
the placenta releases angiostatic factors ( sflt1 ) , but after birth these inhibitory factors are wasted , which allows the development of the infantile hemangioma by endothelial cell proliferation .
a high number of cd133 + , cd34 + endothelial cells have been detected in the blood of children with proliferative infantile hemangiomas .
high levels of 17-beta - estradiol were noted in several studies , simultaneously with high numbers of estradiol receptors at hemangioma tissue - surfaces in their proliferative phase .
infantile hemangiomas present as one or more tumors of variable dimensions and aspects , with predilection in the head and neck area .
other areas , as well as organs , can be affected . in the majority of cases they are singular , only in 1025% of cases they are multiple tumors .
a tight connection between these has been observed , a proportion of 83% cases with multiple hemangiomas are with concurrent visceral involvement .
superficial hemangiomas present as round or oval tumors , lobulated or with a fine surface , more often in the head - neck area , 1 to 25 cm in size .
deep hemangiomas come as soft , bluish masses , some with superficial telangiectasia , and are the rarest type - 15% .
i ) in most of the cases , hemangiomas develop in the first 24 weeks of life , but 20% of them can be present at birth .
the lesion is at first a pale - white to blue - grey macula , depending on its profoundness , or a papule with the same characteristics .
they grow during a variable period of time until 69 months , after which they involute , following the characteristic evolution .
thus 50% regress by the age of 5 years and 90% regress by the age of 9 .
the regression is established by the reduction of dimensions , the colour intensity ; the skin comes back to normal , or remains with a residue of telangiectasia , hypopigmentation , scars or fiber - fatty deposits .
an airway hemangioma is accompanied by feeding difficulty , stridor , loud breathing and a typical cry , all of them representing signs of airway obstruction .
visceral hemangiomas , for example hepatic ones , present with hepatomegaly and an abdominal compartment syndrome .
concurrent thyroid damage , often seen in hepatic hemangiomatosis , manifests with the specific symptoms of hypothyroidism , and is a high - mortality risk emergency .
usually , with the resolution of the hemangioma hypothyroidism also subsides , but in some cases intravenous substitute thyroid hormones are necessary .
anogenital hemangiomas associate with malformations in the area , such as the absence of small or big labia , hemiclitoris or the absence of the anal canal .
hemangiomas of the auditory canal lead to obstructive hearing loss and can destroy the helix or the auricular pavilion .
systemic complications come with kassabach meritt syndrome , characterized by the association of cutaneous and visceral lesions of variable aspects and dimensions , and with extracutaneous manifestations , such as consumption coagulopathy .
consumption coagulopathy is accompanied by thrombocytopenia , hypofibrinogenemia , low d - dimmers and low coagulation factors .
phace syndrome ( posterior fossa abnormalities , hemangiomas , arterial lesions , cardiac abnormalities , eye abnormalities ) or lumber syndrome are also disorders seen with infantile hemangiomas and are characterized by the association with several other anomalies in the upper or lower part of the body .
most of the infantile hemangiomas lend themselves to the  wait - and - see  therapy , but some of them need immediate treatment .
hemangiomas in the periocular , eyelid , airway or ano - genital area , are at high risk of complications and need an early individualized therapy approach   ( see fig .
corticotherapy has been used as a first - line therapy for a long time , using its inhibitory effects on angiogenesis .
prednisolone is of choice , in a dose of 25mg / kg / day , once a day , for 48 weeks .
if no effect is seen in the first 4 weeks , the hemangioma is considered corticoresistant and other options are taken into consideration .
an important aspect of steroid therapy is that of adverse reactions , which are frequent and significant .
growth retardation , gastro - esophageal reflux , vomiting , behavior disorders , high blood pressure , acne , cushingoid facies , increased appetite which leads to weight gain [ 4 , 24 ] , obstructive hypertrophic cardiomyopathy   are some of the adverse effects of steroids .
this highlights the importance of follow - up of patients taking this kind of treatment .
topical steroids or intralesional steroids can also be used in order to avoid systemic effects , but these can only be used in small hemangiomas and without serious complications . nowadays , the therapeutic options are multiple and can be individualized based on the hemangioma characteristics .
since 2008 , therapy with propranolol has been a first - option therapy in most of the situations .
several studies have pointed out its use in infantile hemangiomas treatment , even in situations with complications .
it may be used in every type of hemangioma , even in big , complicated ones . the usual dose starts with 0.5 mg / kg / day with a possibility to increase the dose up to 2 mg / kg / day .
the duration is based on dimensions , location and complications , but on average is of 1 year .
as with corticotherapy , if there are no responses in the first 4 weeks , they are considered to be non - responsive to propranolol . however , there are studies suggesting that there might be a slow rhythm of healing and propose a longer period of therapy until declaring a hemangioma non - responsive .
severe allergic reactions are rarely seen , and present themselves as lingual edema , dyspnea and angina pectoris .
conversely , blood pressure and heart rate variations are considered markers of good response to the treatment . in some cases ,
used once or twice a day by applying it on the surface of the lesion , it has increased compliance to the treatment .
severe life - threatening hemangiomas , corticoresistant ones or kassabach meritt syndrome sometimes need a more aggressive therapy , such as vincristine . this an antineoplastic agent with antiangiogenic actions , that leads to tumoral cell apoptosis .
it is administered orally , a dose a week of 0.52mg / m   for 15 weeks .
adverse reactions consist of peripheral neuropathy , mandibular pain , anemia , leucopenia or constipation   and an inadequate secretion of adh .
other therapeutic options for small , superficial and uncomplicated hemangiomas are imiquimod , an immune mediator or laser - therapy of different types ( e.g. laser - argon , nd - yag laser , co2 laser , fractionate photothermolisis or dye - pulsed laser . both types can present with disfiguring side effects , such as disfiguring scars , or ulceration .
laser therapy can also be used for residual hemangiomas with fibro - fatty tissue remnants .
hemangiomas localized periocularly can cause serious damage to vision , disorders like amblyopia , caused by deprivation or astigmatism .
the most important advantage is that it leads to nearly the complete resolution of the hemangioma , but entails risks of bleeding .
each type of therapy has its indications , contraindications , side effects and risks ; therefore , the treatment of hemangiomas remains a challenge .
because the exact mechanisms of action of several therapies remain unknown , the subject is of great interest for researchers .
therefore a high number of studies are performed and more are need to be conducted in order to achieve target - therapies .
infantile hemangiomas as frequent infancy tumors have been a controversial issue of medical scientists worldwide . 
 their clinical aspects are various and their physiopathology is yet to be fully understood . 
 numerous publications outline the characteristics , causes , evolution possibilities and therapeutic approaches . deciding whether to treat or not is the main question of this kind of pathology . 
 hemangiomas that have complications or can cause irreversible damage need therapy . 
 this is a brief review of up - to - date information regarding the presentation of infantile hemangiomas and target - therapies .