Background
Capillary malformation, usually referred to as a port-wine stain or nevus flammeus, is the most common type of vascular malformation. As a congenital malformation of the superficial dermal blood vessels, capillary malformation is present at birth and grows in size commensurate with the child; capillary malformations remain present for life and have no tendency toward involution. A rare form of capillary malformation that is not present at birth is referred to as an acquired capillary malformation; however, this article focuses on the more common congenital lesion.
Past nosology of this lesion has resulted in much confusion, and an excessive number of descriptive terms have been applied to it. Confusion originated from difficulty in differentiating vascular malformations from vascular proliferative lesions, such as hemangiomas, and from the use of wholly clinical descriptions in categorizing these lesions. According to the International Society for the Study of Vascular Anomalies (ISSVA) classification, vascular malformations are classified according to their predominant vessel type, such as arterial, venous, lymphatic, capillary, or complex (a combination of different vessels). [1]
Although some capillary malformations may be associated with other vessel malformations, most occur alone as venulocapillary malformations. Happle contends that the term capillary malformation should be used as a more generalized designation for several congenital disorders of dilated capillaries (eg, angiokeratomas, nevus anemicus, cutis marmorata telangiectatica congenita). [2] While this notion has merit, the accepted nomenclature is that capillary malformation be reserved for a patch of red-colored skin, historically referred to as a port-wine stain or a nevus flammeus.
Pathophysiology
Capillary malformations and other vascular malformations are the result of abnormal morphogenesis. Capillary malformations are characterized by ectatic papillary dermal capillaries and postcapillary venules in the upper reticular dermis, with some evidence of increased vessel density and no apparent proliferation of vessels. These ectatic vessels are lined by flat, benign-appearing endothelial cells, similar to the vessels of normal skin, with similar staining characteristics for endothelial antigens, including fibronectin, von Willebrand factor, and collagenous basement membrane proteins. The endothelial cells also exhibit cell turnover similar to normal vessels, supported by a paucity of mitoses or an uptake of tritiated thymidine. One study demonstrated a mean vessel depth of 0.46 mm in capillary malformations, suggesting that most of the vessels are superficial.
Evidence supports a neural role in both the development and progression of capillary malformations. Animal studies show that the sympathetic nervous system influences the composition and functional properties of the vessel wall during development.
Immunohistochemical studies of capillary malformations reveal a significantly decreased density of perivascular nervous tissue in lesional skin, suggesting that inadequate innervation may be in part responsible for decreased vascular tone and progressive vascular dilatation. [3] Confocal microscopic studies demonstrate an inverse correlation between nerve density and blood vessel diameter and evidence that capillary malformations with the lowest nerve density exhibit the highest blood vessel density and the poorest response to laser intervention. [4] The finding of increased vessel diameter and/or decreased nerve density may be secondary to other factors, such as local cytokine production or abnormal receptors; however, this has not been elucidated.
The potent endothelial cell mitogen vascular endothelial growth factor (VEGF)–A and its most active receptor VEGF-R2 expression are significantly increased in capillary malformation skin tissue compared with control skin. [5] This may suggest that VEGF and VEGF-R could contribute to the pathogenesis of capillary malformations by inducing vessel proliferation and/or vasodilatation. If this is indeed a pathogenic factor, antiangiogenic treatments using VEGF blocking agents may prove to be useful for capillary malformations. Conversely, one report describes expansion of a biopsy-proven capillary malformation following partial surgical excision in an adult in whom the newly expanded capillary malformation expressed marked elevations of both tyrosine kinase receptor (Tie2) and its ligand angiopoietin-1 and no increase in VEGF. [6] Tie2 and angiopoietin-1 are known regulators of vascular remodeling during angiogenesis, mutations of which have been demonstrated in familial venous malformations.
A somatic activating mutation encoding a p.Arg183Gln amino acid substitution in GNAQ, a q class of G-protein alpha subunits that mediates signals between G-protein–coupled receptors and their downstream effectors, has been shown to be the etiology of capillary malformations. [7] This specific mutation was found in both lesional skin of nonsyndromic capillary malformations and in the lesional skin and affected brain tissue of patients with Sturge-Weber syndrome (SWS). Additionally, the endothelial cells of capillary malformations possess a higher density of the GNAQ mutation than other cells in the affected tissue. [8] Other mutations in this G-protein have been identified in blue nevi, nevus of Ota, and in uveal melanoma. This helps explain the occurrence of both melanocytic nevi and capillary malformations co-localizing to the same area in phakomatosis pigmentovascularis. This G protein is in the MAP/MEK cell proliferation pathway. It has been posited that the timing of the mutation explains the tissue involvement and severity of the condition, with an earlier mutation occurring in SWS and a later one in nonsyndromic capillary malformations.
An inactivating mutation of RASA1 on 5q has been detected in some kindreds with multiple, small, round-to-oval, pink capillary malformations. [9] RASA1 encodes a GTPase-activating protein, which negatively regulates Ras activity. These kindreds all had members who also had arteriovenous malformations (AVMs) or arteriovenous fistulae (AVFs). This disease has been coined capillary malformation-AVM syndrome to denote the 2 types of vascular malformations observed in these kindreds. One kindred with a novel RASA1 -inactivating mutation included a member with a large lower extremity capillary malformation with associated ipsilateral limb enlargement [10] ; however, another large kindred has been identified that has only capillary malformations and no evidence of AVMs or AVFs, suggesting that RASA1 mutations may be implicated more often than previously believed. [11]
Use of transcutaneous videomicroscopy and handheld dermoscopy reveals two distinct patterns of vascular ectasia in capillary malformations. The type 1 abnormality is composed of superficial, tortuous, dilated end-capillary loops in the superficial papillary dermis. The type 2 abnormality consists of dilated, ectatic vessels in the superficial horizontal vascular plexus. Some patients exhibit a combination of both abnormal patterns. Evidence suggests that the type 1 abnormality has a better response to 585-nm flashlamp-pumped pulsed-dye laser (PDL) therapy than the type 2 abnormality. [12] Moreover, one study found a correlation between the depth and pattern of the capillary malformations and the location of the lesions, demonstrating improved responses to laser therapy with locations demonstrating a type 1 pattern (V3 region of the face, neck, and trunk).
Etiology
There is strong evidence associating postzygotic somatic activating mutations in the gene GNAQ to capillary malformations from both nonsyndromic capillary malformations and those associated with Sturge-Weber syndrome. [7] This may account for some of the observed mosaic and twin-spotting phenotypes. [13] Capillary malformations have also demonstrated a neural deficiency of sympathetic innervation of the superficial dermal blood vessels. [3]
Epidemiology
Frequency
United States
Capillary malformation occurs in 0.3-0.5% of newborns.
International
Worldwide, capillary malformation occurs in 0.1-2% of newborns.
Race
According to at least one survey, capillary malformations are more common in whites than in African Americans. [14]
Sex
The sex distribution of capillary malformations is equal.
Age
Capillary malformations are present at birth. Some lesions may not be readily observed at birth because of anemia or plethora. In certain lesions, some lightening of the lesions may occur during the first year of life; however, beyond that time, further lightening is generally not observed.
The very rare acquired port-wine stain can occur at any age after birth and is identical to congenital capillary malformations both clinically and histologically. The etiology of these lesions is unknown and most are idiopathic; however, trauma, chronic UV exposure, hormonal influences, infections, solid brain tumor, and various internal vascular disorders have been implicated. [15]
Prognosis
Isolated capillary malformations do not appear to cause an increase in mortality; however, psychosocial disability secondary to facial disfigurement can be overwhelming. Several studies demonstrate that patients with facial capillary malformations exhibit greater self-concern, ruminative self-doubt in interpersonal interactions, social inhibition, isolated and passive orientation in interpersonal relationships, stigmatization from society, and limitations of privileges and opportunities otherwise afforded to those without facial disfigurement. One study demonstrated that the psychosocial difficulties not only persisted but actually worsened in adulthood. [16]
Development of lobulated capillary hemangiomas (pyogenic granulomas) within capillary malformations often results in bleeding. [17, 18] The destruction of these lesions usually results in minor scarring of the skin.
Any morbidity involved with capillary malformations is associated with more extensive vascular malformations.
Patient Education
Patients and parents benefit from an organized, informative, multidisciplinary effort to address psychological, medical, and surgical needs for optimal outcomes from medical care, especially surgical or laser procedures.
In the author's experience, a frank discussion with the affected child's classmates early in the school year is most beneficial. A brief classroom discussion, which can be facilitated by the patient's parent or teacher, offers an opportunity to educate the child's classmates about the birthmark and to reassure them that it is neither painful nor contagious. Once the capillary malformation has been explained adequately and questions answered, most children cease to further question the child. This helps to alleviate some of the patient's psychological burden.
Buddy Booby's Birthmark, by Evan Ducker, a child with a capillary malformation, and his mother, Donna Cardenia Ducker, is a children's picture book depicting a baby booby bird on the Galapagos Islands that was born with a capillary malformation (birthmark) on his beak. It is the first children's book of its kind to depict the social stressors associated with facial capillary malformations. It is available for purchase at http://www.amazon.com/Buddy-Boobys-Birthmark-Donna-Ducker/dp/0979441315.
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Histopathologic features of a capillary malformation (nevus flammeus) showing telangiectatic vessels lined by mature-appearing endothelial cells.
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Capillary malformation on the left preauricular aspect of the cheek, the ear, and the neck in a neonate (same patient as in Media Files 3-4).
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Same patient as in Media Files 2 and 4 immediately after test spots with the pulsed-dye laser at 585 nm. Note the purpuric macules where the laser impacted in a linear distribution on the preauricular aspect of the cheek.
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Same patient as in Media Files 2-3 after 4 treatments with the pulsed-dye laser. Treatments were given at 2-month intervals in an outpatient setting using topical anesthetic.
