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CME ARTICLE
Year : 2018  |  Volume : 19  |  Issue : 1  |  Page : 1-8

Vascular birthmarks: A hidden world behind a word


Department of Pathophysiology and Transplantation, University of Milan; Department of Woman, Child and Newborn, Unit of Pediatric Dermatology, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy

Date of Web Publication28-Dec-2017

Correspondence Address:
Dr. Carlo Gelmetti
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. Unit of Pediatric Dermatology, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico, Milan
Italy
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_124_17

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  Abstract 

A confusing nomenclature concerning the subject of vascular birthmark and angiomas lead (and leads!) to the consequence that parents with children affected by this kind of disorders become medical nomads, and therefore, the best treatment, when available, is frequently postponed. The concept of maternal imprint that began to crumble in the XVIII century is, unfortunately, still widespread. While a maternal responsibility as it has been conceived in the past has been definitively excluded, the pivotal classification proposed by John Mulliken that divides vascular anomalies in vascular tumors and vascular malformations is practically very useful. The rapid progress of genetic studies has explained to medical community a huge number of genotype-phenotype correlations, and it will individuate new forms in the next future. Understanding the biology of vascular birthmarks is a fundamental step forward to implement effective and specific drugs for specific forms. Discoveries by serendipity occur but are rare.

Keywords: Angiomas, vascular birthmark, vascular malformations, vascular tumors


How to cite this article:
Gelmetti C. Vascular birthmarks: A hidden world behind a word. Indian J Paediatr Dermatol 2018;19:1-8

How to cite this URL:
Gelmetti C. Vascular birthmarks: A hidden world behind a word. Indian J Paediatr Dermatol [serial online] 2018 [cited 2018 Jan 20];19:1-8. Available from: http://www.ijpd.in/text.asp?2018/19/1/1/221776


  Introduction Top


Almost 30 years ago, in 1988, John Mulliken and Anthony Young published a book that was a real revolution in the medical community.[1] In the PREFACE, you can read the following sentence: “A confusing nomenclature has been largely responsible for illogic thinking on the subject of vascular birthmark. Mindful of this concept, we have made a concerted effort to free our subject form its old terminological chamber of horrors.” Despite a long time that has passed, still the terminology used in many countries to designate vascular anomalies of dermatological interest is vernacular and confusing. Consequently, parents with children affected by this kind of disorders become “medical nomads, searching for someone who understands their problems.” Pediatricians, surgeons (vascular, plastic, maxillofacial, orthopedics), radiologist, and dermatologists, all are consulted, often speaking a different language.[2],[3] Needless to say, a good communication between doctors and patients (parents of the patients in case of children) cannot be achieved in the midst of this confusion and the best treatment, when available, is frequently postponed when not denied.

In many cultures, neonatal vascular anomalies have been attributed to the misconduct of the mother at the time of conception or during pregnancy. Indeed for “angiomas,” the terms used in different countries to define this group of disorders, often imply a causal relationship between maternal behavior and defect in the newborn. Even today, the popular names given in Europe for these abnormalities include the following: “voglia” (lit.: “wish;” e.g., wish of strawberries) in Italy; “envie” (lit.: “wish” or “desire”) in France; “estigma” (lit.: “stigma”) or “frutilla” (lit.: “strawberry”) in Spain; “muttermal” (lit.: “mark of the mother”) in Germany and “birthmark” in the English speaking world. The concept of maternal imprint reflects a belief documented since ancient times as in ancient Greece, where it was believed that mothers gave birth to children who resembled those statues observed by them during pregnancy. The belief of maternal “fault” became stronger during the European Middle Age also in medicine with the term of “imaginatio gravidarum” (lat.: “imagination of the pregnant [mothers]). During the age of enlightenment, the concept of the mother imprint began to crumble, and some doctors observed that women, shocked by horrific scenes during their pregnancy, had not given birth to children with defects. In the 19th century, despite the contrasting opinion of the many doctors, the doctrine of maternal imprint, revived; thus, the “angiomas” were attributed to the mother's desire or act of eating colorful fruits such as strawberries, raspberries, and cherries. Another popular belief ascribes the so-called “port-wine stains (PWS)” to conception occurred during the menstrual period. This superstition is rooted in the ancient Jewish law that prohibited sexual intercourse during and immediately after the menstrual period (“period of impurity”) since it was believed that this could produce a malformed baby as in the story of Jacob and Laban in the Bible (Genesis 30.25–36). These assumptions, unfortunately still widespread, can be explained by the fact that the human mind does not accept the fate as the cause of an event, but imagine that someone or something, human or divine, has caused it for a specific reason (usually a sin against the gods). The current knowledge excludes definitely a maternal responsibility as it has been conceived in the past.[1],[2],[3] In the 19th century, histology, the new branch of medicine at that time, added further confusion; for example, the histologic term of “cavernous hemangioma” was mixed with the old terminology, already including fruits (strawberries), animals (salmon), and beverages (port wine) making the chaos complete. A simple example can clarify this concept: the word “angioma” (the term “angioma” literally means, from Greek: “tumor of the vessels”; the suffix “-oma” does not imply malignancy, but indicates a mass, regardless of its biological behavior) is still used by many to describe congenital or acquired lesions that have completely different nature and course, and the same term “nevus flammeus” (lat.: “nevus in shape of a flame”) is frequently employed to denote both the innocent vascular stain visible on the nape of most Caucasian children, and the “PWS,” which is often syndromic as in Sturge– Weber syndrome More Details.


  Classification Top


Mulliken proposed that vascular anomalies could be divided into the two classes: vascular malformations and vascular tumors.[1],[2] Vascular malformations are structural abnormalities, congenital errors of morphogenesis that occur during embryogenesis, and present a normal endothelial cell turnover. Although the vascular malformations are, by definition, present at birth, some manifest in adolescence or adulthood. Therefore, the term “acquired,” should be used with caution in this case. Vascular malformations can be classified anatomically in subgroups according to the type of vessel involved: capillary malformation (CM), venous malformation (VM), arterial malformation (AM), and lymphatic malformation (LM). All these can be variously associated giving rise to complex malformation: capillary-VM (CVM), capillary-lymphatic-VM, and arterio-VM (AVM). It is also clinically important to differentiate between slow-flow malformation, the most frequent, and fast-flow malformation, which in practice are only arteriovenous fistulas and AVM. Vascular tumors are, in most cases, hyperplasias or benign neoplasms with spontaneous regression. Rarely some forms are of intermediate malignancy, and extremely rare are the malignancies. Infantile hemangiomas (IHs) are by far the most common tumors of childhood. They are benign endothelial tumors that enlarge with rapid cell proliferation. There is increased endothelial cell turn over and hypercellularity. During the 1st month of life, they proliferate and become cell masses that need to be fed and drained by newly formed vascular channels (proliferating phase). These vessels may predominate in some large lesions, simulating clinically, radiologically, and functionally, as seen in Doppler ultrasound, a fast-flow vascular malformation. All IHs undergo spontaneous regression within 3–9 years (involuting phase).

The Mulliken classification has been basically adopted by the International Society for the Study of Vascular Anomalies (ISSVA) in the following years. The pivotal classification of Mulliken that divides vascular anomalies in vascular tumors and vascular malformations is genially simple, useful and still valid in most of cases. However, the term “vascular birthmarks,” to be precise, is not fully correct since the vast majority of IHs are not present at birth, but they usually appear within the 1st weeks of life and some vascular malformations such as lymphangiomas can become evident only after months or years after birth even though, theoretically, they are already formed in utero. In [Table 1], the so-called abbreviate present classification approved in 2014 by ISSVA including13 headlines (!) is reported. In reality, the single disorders are more numerous, and as far as the science will progress, this number will grow in the next future and the number of acronyms, which is already large, will expand further.
Table 1

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  Pathogenesis Top


The rapid development of genetics together with the implementation of the next generation sequencing (NGS) and single-nucleotide polymorphism (SNP) microarrays has brought out a huge number of genotype-phenotype correlations, so geneticians speak today about the group of genomic (germline or heritable) mutations which occur during meiosis and the group of somatic mutations that are expressed as a mosaic [Figure 1].[4] Genomic mutations are represented by RASopathies (a group of rare genetic conditions caused by mutations in genes of the Ras-MAPK pathway) that include CM of CV-AVM and Parkes–Weber syndrome; glomuvenous malformations; hereditary hemorrhagic telangiectasia; phosphatase and tensin (homolog) hamartoma syndrome; and many others.[5] Somatic mutations are represented by GNAQ mutations that include the capillary malformation with CNS and/or ocular anomalies aka  Sturge-Weber syndrome More Details [6]; the group of the PROS (= PIK3CA-Related Overgrowth spectrum) that includes CLOVES [1] syndrome, Megalencephaly-capillary malformation, Klippel-Trenaunay syndrome, CLAPO [2] syndrome, FINCA [3]syndrome, FAVA [4] and isolated lymphatic malformations[7-9]. CLOVES is an acronym for: Congenital, Lipomatous, Overgrowth, Vascular malformations, Epidermal nevi, Spinal/Skeletal anomalies; CLAPO is an acronym foror: Capillary Malformation Of The Lower Lip, Lymphatic Malformation Of Face And Neck, Asymmetry Of Face And Limbs, And Parti al/Generalized Overgrowth; FINCA is an acronym for: FINgertip Capillary malformation and Associated disorder; FAVA is an acronym for: FibroAdipose Vascular Anomaly.[6],[7],[8],[9] Other mutations, as in the case of Proteus syndrome caused by an SNP in AKT1 gene, show the growing spectrum of this field.[9]
Figure 1: Vascular anomalies and the time of their onset

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It is becoming evident that somatic mosaicism plays a major role in the formation of vascular lesions. The conceptual difference between genomic and somatic mutations, besides the obvious heritability, is the fact that somatic mutations are postzygotic mutations which occur after fertilization and therefore occur just in the affected cells; so the timing of the mutation is crucial. If a mutation occurs very early in the embryonic period, it is more likely to cause widespread vascular malformations involving tissues other that vascular ones; if it occurs a little bit later, it is more likely to be a small vascular anomaly not associated with other congenital defects [Figure 1]. An example of this situation could be illustrated by Sturge–Weber syndrome (early mutation) and the simple CM (late mutation). A second consequence is that, in those cases, the mutation should be investigated only in the affected tissue because all the other cells in the body will be normal. It is also evident that cutaneous vascular malformations, even if they are small, can project their effects centripetally and internally as is the case of Sturge–Weber syndrome, Cobb syndrome, and FINCA.[8]

In this paper, we illustrate the most common vascular anomalies of infancy, while other common (pyogenic granuloma, cherry angiomas) or rare (Kaposi's sarcoma) forms affecting other periods of life will not be discussed.


  Vascular Malformations Top


Vascular malformations should be, theoretically, stable disorders. However, the aging of the vascular structures together with local condition and physiological/or accidental events causes a worsening of the lesion that can be only cosmetic as in simple CM or devastating as in unstable AVM [Figure 2].
Figure 2: Usual course of vascular malformations

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Capillary malformations

CMs often improperly called: “macular (flat) angiomas” or nevi flammei are low-flow vascular anomalies affecting the skin and mucosae at birth. Two main subtypes of CM can be distinguished.

Medial congenital macula (synonyms: Nevus flammeus neonatorum, nevus simplex, “salmon patch” or “fading capillary stain”)

Extremely common in Caucasian babies, it clinically appears as a skin stain evident at birth, of pinkish-red color vanishes with digital pressure, typically characterized by a progressive fading within the 1st years of life. The most common location is, in a decreasing order, along the body midline: the nape of neck and occipital area (“stork bite”); mid-forehead (“angel kiss”); sacral region (“butterfly mark”). CM on nape of neck (syn: Erythema nuchae, Unna nevus) are seen in light-skinned newborns, and very common in many European countries and are called as “stork bite mark;” they are innocent as those of midfront. Sacral stains are less common and require a careful observation since they may be associated with other signs such as faun tail, pit, bumps, or other lesions that could raise the suspicion of an underlying defect in the spine such as spina bifida or to be syndromic as in Cobb syndrome.

Lateral congenital macula (synonyms: Port-wine stain, nevus flammeus)

Rare in all ethnic groups, it presents at birth as a pinkish-red skin stain of variable size with sharp edges, typically vanishing with finger pressing. The macule can manifest on any part of the body with a predilection for the face, where often takes a segmental distribution. Extension to the mucosal surfaces is possible. Distribution of CM on the forehead can be an indicator of underlying Sturge–Weber syndrome. The distribution of CM on lower limb can be associated with venous and lymphatic abnormalities (Klippel–Trenaunay syndrome). The frequency of lateral congenital macula is low (0.3%). Due to its nature, it often presents with pathological associations. The etiopathogenesis is unknown; however, it is not due to trauma during childbirth since they manifest also in children born through cesarean section. The color, almost always pink-red at birth, darkens over time becoming red or even purple. The head is the most affected region and can pose an esthetic problem or could be part of a syndrome.

Histopathologically, CMs are formed by dermal ectatic capillaries without hypercellularity or endothelial proliferation. However, S-100 staining shows a decrease in nerve fibers around vessels; therefore, “PWSs” would be the result of a deficit in sympathetic innervation; in other words, they would be anatomically normal but functionally dilated vessels, due to a lack of normal tone; this would provoke a stable anatomic defect.

In the treatment of CM, a variety of vascular lasers may be employed, with the pulsed dye laser being the most common and well studied.[10] Photodynamic therapy represents an option for port- PWSs. Intense pulsed light are less effective than laser treatment but may be preferred by patients for nonpurpuric sequelae.

Cutis marmorata telangiectatica congenita (Synonyms: van lohuizen syndrome, congenital phlebectasia)

CMTC is a rare capillary-venous anomaly of the dermis and subcutaneous tissue. It has no gender predilection. Lesions can be generalized or localized, affecting more frequently the trunk and limbs. Clinically, CMTC is characterized by purple serpiginous striations with a network pattern. They become more evident with cold and gravity and resolve partially in the 1st months of life, leaving a variable atrophy. Many associated anomalies have been reported, virtually in all organs. Histologically, veins and capillaries are dilated. CMTC should be distinguished from the physiologic livedo of the newborn, which is evenly distributed, manifests with lowering of the temperature and then resolves within a few minutes after normalization of the environmental conditions and manifests with a regular network in small meshes.

Venous malformations

VMs are low flow malformations characterized by slow growth through all tissue layers. Therefore, treatment should be initiated at an early stage in order to prevent functional and esthetic impairment. VMs consist of congenital lesions (sometimes with a late-onset) that can be isolated, regional, or diffuse. They include a variety of anomalies ranging from cutaneous varicosities or phlebectasiasto complex lesions involving more tissues which may deform the skeletal structures. On the surface, they appear as painless purple masses, more or less lobulated. On palpation, they feel like nontender elastic nodules which can be emptied by pressure; the overlying skin may be normal or present a bluish tinge. Phlebolith scan be palpated and visualized radiologically. VM can be compressed and reduced in size; they increase in size with gravity or with the Valsalva maneuver. Percutaneous sclerotherapy is the treatment of choice in all lesions not accessible by intravascular route. Complications of sclerotherapy may be necrosis due to drug extravasation into adjacent tissue and nerve damage. Thus, sclerotherapy in proximity to the facial nerve should be discouraged. After volume reduction, subsequent reconstructive correction may be needed.


  Arteriovenous Malformations Top


AVMs are high-flow vascular malformations. These are more often deep masses of various sizes covered by normal skin or, sometimes, by a red macule resembling a CM. They are malformations that can be apparent in the neonatal period, but more often appears later in life. AVM develop gradually during childhood but may suddenly worsen in response to local trauma, surgical resection, vascular ligatures, hormonal stimuli (puberty, pregnancy), and drugs. The skin is frequently hyperthermic, may ulcerate with hemorrhages, and patients may feel pulsating pain. Objectively, a throb is perceived at the touch and a murmur at auscultation. Doppler ultrasound examination is confirmatory. AVM may lead to bone destruction or accelerated local skeletal growth, and more rarely to heart failure. AVM represent a challenge to any therapeutic decision and require a careful interdisciplinary evaluation, in particular for lesions in the craniofacial area where any incomplete treatment may stimulate a destructive growth of the malformation comparable to the behavior of a malignant tumor. Conceptually, the basic principle of treatment for high-flow malformations is a radical resection of the nidus, which is facilitated by prior embolization. Recently, rapamycin has been proved to be effective in some cases.

Lymphatic malformations

LMs are usually papulovesicular translucent lesions, at least when near the skin surface, and tend to merge easily. Two-thirds of them are evident at birth and 90% appear within 2 years of age. The most frequent location is the cervicocephalic area. Lesions manifest in many forms: some are purely cystic (cystic hygroma, lymphatic cysts) and more frequent on the neck; others consist of compact lymphoid tissue and predominate on the face and tongue; still others are formed by a combination of the two types. Other involved sites, in decreasing frequency, are the axillary region and mediastinum, but also other internal organs. LM can be associated with skeletal deformities and hypertrophy. Some LM appears to evolve both for recurrences after therapy, both for infectious or inflammatory episodes. Ultrasound, computed tomography, magnetic resonance imaging, and lymphoscintigraphy can detect these lesions better than a simple clinical observation. For large LM, surgery is the best option sometimes accompanied with sclerotherapy with picibanil (OK-432). Most recently, sildenafil, a drug that selectively inhibits phosphodiesterase-5, has been used in some cases of LM.[11] Rapamycin has also been employed in few cases.[12]

Complex vascular malformations

Sturge–Weber syndrome (encephalotrigeminal angiomatosis) is a complex disorder present at birth. It is characterized by a PWS on the forehead and upper eyelid of one side of the face that can be complicated by a variable degree of CNS and eye anomalies. This disorder is the manifestation of a somatic mutation in the gene GNAQ, which increases cell proliferation and inhibits apoptosis. The birthmark does not correspond to nerves distribution as it is frequently stated: facial PWS distribution appears to follow the embryonic vasculature of the face, rather than the trigeminal nerve. CNS anomalies can provoke neurological symptoms including seizures that begin in infancy and may worsen with age. Convulsions usually happen on the side of the body opposite the birthmark and vary in severity. Some children manifest developmental delays and cognitive impairment. When vascular lesion is present in the eye, ocular abnormalities (e.g., glaucoma, megalocornea, retinal detachment and buphthalmos) are observed. X-rays can reveal cerebral calcifications. Therapy should be individualized case by case, up to early neurosurgery when anticonvulsants do not control seizures. Laser treatment may be used to clear the birthmark. A strict follow-up is advised in the first 2 years of age because intellectual impairment is more likely when seizures start before this time and are resistant to treatment.

Klippel–trenaunay syndrome

KTS combines capillary, venous, and lymphatic vascular malformations. The manifestations consist of CM, present at birth, on a limb with varicose veins that develop along with hypertrophy during growth. The association is of variable intensity; the symptoms depend on the size and location of underlying anomalies. Extensive CM on the limbs may be an indicator of this syndrome and therefore radiological and arteriographic investigations are recommended. Treatment of KTS includes steroids, antiplatelet agent (aspirin), alpha-interferon, antifibrinolytics agent therapy, chemotherapy, propranolol, surgical excision with or without embolization, and sirolimus.


  Vascular Tumors Top


Among the list of vascular tumors that appears in ISSVA classification, we illustrate the most common benign forms of infancy. Kasabach–Merritt syndrome will be also briefly discussed.

Infantile hemangioma

IH is the most common tumor of infancy ranging from a tiny red papule to a giant mass. Its typical natural history is characterized by an early rapid growth following birth and a slow spontaneous regression phase during childhood [Figure 3].[13] The cause of underlying IH is yet to be fully understood, but the role of fetal hypoxic stress has been suggested. Another hypothesis suggests that IH can be derived from embolized placental cells. Immunohistochemical studies confirm that these endothelial cells possess peculiar immunohistochemical markers (glucose transporter 1 [GLUT-1], Lewis Y antigen, FCγ II receptor, and merosin), which are also present on placental blood endothelial cells and other blood-tissue barrier vessels (e.g., brain and retina). Although IH are not the mere result of ectopic placental tissue, the theory of emboli could explain the high incidence of localized IH after chorionic villus biopsy and the frequent association of IH with prematurity or low birth weight, conditions that are related to placental damage and could theoretically cause detachment and intravascular dissemination of placental cells.
Figure 3: Usual course of hemangiomas (Infantile Hemangiomas, Rapidly Involuting Congenital Hemangioma, Non Involuting Congenital Hemangioma)

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IHs occur in up to 4%–5% of neonates although up to 30% are premature babies with low birth weight (<1 kg). They are significantly more frequent in females, with a 3:1–5:1 female/male ratio. The majority of IHsis noticed in the postnatal period, even though they may be visible at birth, although usually with very different clinical features. In fact, when IH is present at birth, as a precursor, it is very small and flat, usually represented by an erythematous macula or, paradoxically, by an ischemic patch (“herald patch”), or by telangiectasias surrounded by an ischemic halo. Most IHs appear more often during the 1st–2nd week, as a single lesion; although there is no limit to their numbers, it is very rare to see more than 5–6 lesions. Visceral IHs, usually hepatic, are equally rare. Topographically, the head is the most affected region, accounting, alone, for about 50% of the lesions.[14]

Anamnesis and phenotype allow, in most cases, the diagnosis without additional investigations. The diagnosis is confirmed by the rapid expansion of the lesion in the 1st weeks. The discovery that a cellular marker called GLUT-1 is expressed in IH, but not in vascular malformations nor in other congenital or acquired benign vascular tumors, has improved the diagnosis in dubious cases, represented mainly by deep lesions.[15] GLUT-1 has also enabled the identification of two new types of neonatal lesions that were confused with common IH. These hemangiomas are called with the acronyms of rapidly involuting congenital hemangioma and not involuting congenital hemangioma. More recently, a third member of this group, called partially involuting congenital hemangioma, has been described. These lesions are usually solitary and already fully expressed at birth and do not favor the female gender.

After onset, IH grows rapidly in diameter and volume until the 4th–6th month of life, rarely until the 9–12th month with the notable exception of parotid IH.[16] The importance of morphology and especially of topography of IH has determined the development of a recent classification that indicates, in particular, the risk of these lesions. According to this classification, IH can be divided into four types: focal, multifocal, segmental, and indeterminate. Focal IH represents the vast majority of lesions and arises from a single site; they favor a small central area of the face (central area of the cheek, lateral side of the upper lip, upper eyelid). These areas overlap well with the sites of embryonic fusion, mesenchymal, or mesenchymal-ectodermal. Segmental IH manifests as a geographically-shaped plaque or a dermatomeric-like lesion. While most of IH are nodular and not syndromic, some segmental IHs may be associated with developmental abnormalities (PHACES and lower body hemangioma and other cutaneous defects [LUMBAR]/perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin tag [PELVIS]/spinal dysraphism, anogenital anomalies, cutaneous abnormalities, renal and urologic anomalies, angioma of lumbosacral localization [SACRAL syndromes]) and are more frequently associated with ulceration and orificial localizations.[17],[18],[19] PHACES is an acronym for: Posterior (brain) fossa malformation, hemangiomas, arterial anomalies, coarctation of the aorta along with cardiac defects, eye abnormalities, sternum, and/or a supraumbilical abdominal raphe clefts; LUMBAR/PELVIS/SACRAL are acronyms that denotes the association of hemangioma and malformations in the pelvic region; for example, LUMBAR, urogenital anomalies, ulceration, myelopathy, bony deformities, anorectal malformations, arterial anomalies, and renal anomalies; PELVIS; SACRAL.

Consumptive hypothyroidism is a very rare condition related to massive IH producing an excess of the thyroid-hormone-inactivating enzyme type 3 iodothyronine deiodinase.[20]

In the stable phase, IH present three different clinical aspects: superficial, subcutaneous (deep), and mixed. In the stable phase, the superficial form (in the past aka: “tuberous angioma”), appears as a red nodule, more or less lobulated, warm, elastic, which increases slightly in volume and consistency during exertion or crying, and that does not empty with pressure. After a few months of apparent stability, the lesion starts to regress beginning in the center, with small white-greyish areas that progress centrifugally, giving a paler appearance to the lesion, which simultaneously decreases in consistency, and becomes less warm. Spontaneous regression is usually completed by 5–7 years of age, but in smaller lesions already by 3–4 years.

Subcutaneous or deep IH (in the past aka “cavernous angioma”) appears as a well-delimited elastic mass, only slightly depressible, covered with normal skin or with a slight cyanotic hue. Sometimes, the differential diagnosis with VMs or cystic lymphangioma or encephalocele is a problem. In most cases, deep IH is associated with a superficial IH, facilitating the diagnosis. It should be noted that the deep localization, in the absence of a superficial “sentinel” angioma, delays greatly the observation of the lesion.[21]

The spontaneous regression of IH leaves minimal sequelae in about half the cases. It can heal with scars, telangiectasias, yellowish hypoelastic patches, especially on the head. It is difficult to predict the quality of the final regression, which is not influenced by gender, race, site or size of the lesion, presence or absence at birth, and duration of the proliferating phase. Smaller lesions have a better outcome and deeper lesions rarely produce sequelae that alter the skin surface. In addition to the esthetic changes, IH may ulcerate, producing hemorrhages that can obstruct the respiratory and digestive tract. Large IH with rapid regression may form a scab with cicatricial sequelae. In periocular localizations, impaired vision may occur like amblyopia. IH with laryngeal localization can produce aspiration pneumonia and suffocation.

The majority of cases of IH are managed conservatively, but intervention is necessary in approximately 10% of cases because of the threat to life or function or because of tissue distortion or destruction. Spontaneous regression of IH could suggest therapeutic abstention but this attitude is not wise in the majority of cases. However, it is better to continue to follow the patients and their parents, reassuring them of the favorable outcome, with the aid of illustrations and photographs that show the evolution of these lesions. Systemic treatment is the therapy of choice in some situations: (1) rapid growth of the lesion; (2) location of the lesion in critically aesthetic areas; (3) recurrent hemorrhages, ulcerations, or infections; (3) in lesions interfering with important physiological functions (breathing, feeding, vision, hearing) as in the case of cutaneous-laryngeal IH (the so-called: “Beard” angioma); and (4) large or multicentric IH that can cause heart failure as in the case of diffuse neonatal hemangiomatosis. The mainstay treatment for IH is pharmacologic therapy with propranolol, a lipophilic nonselective β-blocker that was discovered serendipitously in 2008. Oral propranolol has dramatically changed the therapeutical approach of IH: its action is rapid, almost without side effects and effective also after the growing phase of IH. Of interest is the fact that hyperkalemia as a side effect to propranolol is actually due to tumor lysis syndrome following ulceration of IH and not to the drug.[22]

Most of the patients respond satisfactory at 2–3 mg/kg per day in two divided doses. The average treatment of duration is 6 months. Rebound growth, although mild, can occur in some patients. Adverse events (hypotension, somnolence, wheezing, insomnia, agitation, and/or nightmares, hypoglycemia) are rare and uneventful.[23],[24] Oral atenolol, a hydrophilic, selective β1-blocker and likely not associated with side effects attributable to β2-adrenergic receptor blockade, is also under consideration.[25] Topical propranolol and topical timolol have also been used with satisfactory results on superficial IH.[26],[27],[28] A critical consideration concerns the treatment of IH. We agree with those authors who recommend therapeutic abstention but only for very small IH and for those whose locations do not create problems either objectively or subjectively. Otherwise, we recommend treating the IH, because, first, by limiting the expansion we can limit the symptoms, and second, a small IH will have, in any case, a negligible fibrofatty residue. Finally, it should be considered that even a small IH located in an exposed site can cause variable psychological damage from the time of socialization onward as in the case of the so-called “Cyrano” angioma. Early intervention is recommended also in this case. In short, and especially after the propranolol era, the sentence: “Leave it alone-it will go away” is no longer acceptable for most IH.[5] With regard to IH treatment, in addition to propranolol ( first choice) and corticosteroids (second choice), there is the possibility of using topical ultrapotent corticosteroids, interferon-alpha, vincristine and cyclophosphamide are possible options for nonresponding lesions. Vascular laser remains the first choice in the treatment for ulcerated IH.

Kasabach-merritt syndrome (Synonyms: kasabach–merritt phenomenon)

KMS is a rare condition in which a large vascular tumor or also numerous small vascular tumors (cutaneous or subcutaneous or mixed), present since birth or the 1st weeks of life, are associated with thrombocytopenia, anemia, and splenomegaly. Clinically, when KMS is not too deep, a warm reddish-brown or red-wine mass is visible, covered with taut and shiny skin, with possible peripheral dyschromias due to hemorrhages and increased destruction of platelets in the lacunae of the lesion. The biological behavior of KMS, as well as its histology, presenting aspects ranging from tufted angioma to kaposiform hemangioendothelioma, can be aggressive. Corticosteroids and interferon alfa-2a have been successful in many cases, but no single therapy, including ε-aminocaproic acid, aspirin, dipyridamole, ticlopidine, pentoxifylline, cryoprecipitate, heparin, propranolol, vincristine, cyclophosphamide, and actinomycin D, has been proved effective in all patients with KMS.


  Conclusions Top


The world of “angiomas” and “birthmarks” is a complex territory that we are just getting to know. The fundamental distinction between vascular malformations and vascular tumors made by Mulliken and better detailed by ISSVA, explains well why, in the past, the majority of treatments were unsatisfactory in vascular malformations (malformations do not heal spontaneously!) and were instead successful in IH (because they fade spontaneously!). The advances of genetics have opened new perspectives in genotype-phenotype correlation, while the availability of a specific pediatric drug such as propranolol hydrochloride in oral solution resulted in a dramatic advantage for the treatment of the most common birthmarks, namely, the IH.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Mulliken JB, Young AE. Vascular Birthmarks; Hemangiomas and Malformations. Philadelphia: WB Saunders Company; 1988.  Back to cited text no. 1
    
2.
Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, et al. Vascular anomalies classification: Recommendations from the international society for the study of vascular anomalies. Pediatrics 2015;136:e203-14.  Back to cited text no. 2
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Abstract
Introduction
Classification
Pathogenesis
Vascular Malform...
Arteriovenous Ma...
Vascular Tumors
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