Vascular malformations are rare but important skin disorders in children, which often require multidisciplinary care. The goal of this article is to orient pediatricians to the various types of vascular malformations. We discuss the clinical characteristics, diagnostic criteria, and management of capillary, venous, arteriovenous, and lymphatic malformations. Associated findings and syndromes are also discussed briefly.
Cutaneous vascular malformations are uncommon birthmarks that represent errors in vascular development and occur in approximately 0.3% to 0.5% of the population. These lesions are much less common than infantile hemangiomas but are frequently confused with them. It is essential to properly diagnose these lesions because of their differences in morbidity, prognosis, and treatment.
Classification of vascular lesions
The classification of vascular anomalies has been hampered by the use of inaccurate terminology. Early classifications published by Virchow characterized vascular lesions according to the vessel’s pathologic appearance, dividing them into angiomas and lymphangiomas. The biologic behavior and natural history of the vascular lesions were not considered when classifying them. Thus, there was a tendency to identify any type of vascular anomaly as a hemangioma.
Mulliken and Glowacki made great strides in clarifying this confusion when they published their landmark classification of vascular birthmarks in 1982, which grouped them into 2 major categories: hemangiomas and malformations. This classification has served as the foundation for the proper identification, investigation, and management of vascular birthmarks. Mulliken’s biologic classification was modified slightly in 1996 to reflect new knowledge and the importance of other distinct types of vascular tumors, including the tumors that can cause Kasabach-Merritt phenomenon and others. The newer classification divided vascular birthmarks into vascular tumors and vascular malformations . This classification of vascular anomalies has been widely adopted by clinicians and is the accepted classification of the International Society for the Study of Vascular Anomalies(ISSVA) ( Table 1 ).
| Vascular Tumors | Vascular Malformations |
|---|---|
| Infantile hemangioma Congenital hemangioma (RICH, NICH) Pyogenic granuloma Tufted angioma Kaposiform hemangioendothelioma Hemangiopericytoma |
|
Although there are several types of vascular tumors, hemangiomas represent the overwhelming number of vascular tumors encountered by pediatricians. Hemangiomas are differentiated from vascular malformations by their clinical appearance, histopathologic features, and biologic behavior. Pediatricians should be most knowledgeable about differentiating hemangiomas from vascular malformations based on their clinical presentation. Hemangiomas are found to be more common in girls , whereas vascular malformations have an equal sex distribution. The natural course of hemangiomas involves rapid proliferation for the first several months of life with subsequent spontaneous regression, often leaving fibrofatty deposition, overlying anetoderma, and telangiectasias. Vascular malformations are often recognized at birth and grow proportionately with the child, with many becoming more prominent at puberty. In challenging cases, histopathologic evaluation, including immunohistochemical markers as well as radiologic studies, can further help to distinguish these two types of vascular anomalies ( Table 2 ). Despite these differences, the use of confusing nomenclature persists in the literature.
| Characteristic | Infantile Hemangioma | Vascular Malformation |
|---|---|---|
| Age of Occurrence and Course | Infancy and childhood | Persistent if untreated |
| Sex Prevalence (Girl/Boy) | 3–9:1 | 1:1 |
| Natural History | Rapid growth followed by spontaneous regression | Proportional growth |
| Treatment | Spontaneous involution, pharmacologic treatment, surgery, lasers | Lasers, sclerotherapy, surgery |
Vascular malformations can be further subdivided into groups based on vessel type and flow characteristics. Capillary, venous, and lymphatic malformations (LM) are slow-flow lesions, and arteriovenous malformations (AVM) and fistulae are fast-flow lesions. Combined lesions may also occur (see Table 1 ). Each type of vascular malformation is discussed in this article.
Capillary malformations
Capillary malformations (CM), including fading capillary stains and port-wine stains, are among the most common vascular malformations affecting the skin ( Fig. 1 ). True CM (the non-fading type) occur in approximately 3 of 1000 infants, are present at birth, and are equally common in the male and female sex. They usually arise sporadically; however, familial cases in association with AVM have been described.
Clinical Characteristics
A CM is usually noted at birth but may initially be misdiagnosed as a bruise or erythema from birth trauma. In young infants, CM may be pale pink macules and patches. They may present in small focal areas or involve an entire limb or portion of the face. Single or multiple lesions may occur. CM may arise on any surface of the skin but are frequently present on the head and neck area. When they are located on the head, they may extend to the lips, gingiva, or oral mucosa. Parents may note that the CM is somewhat darker in the immediate newborn period and lightens slightly in the first few weeks of life. This might be secondary to the higher hemoglobin concentration present in the immediate newborn period.
The natural history of CM vary according to their anatomic location. The terms salmon patch, angel’s kiss, stork bite, nevus simplex, and vascular stain are used to describe a subset of CM that are very common and located on the central face or nape of the neck. They are sometimes termed fading capillary stains rather than true CM, because these lesions typically lighten significantly or disappear early in life. Some, often those located on the nape of the neck, persist into adulthood without significant darkening. Commonly used terms, such as angel’s kiss, help to convey the benign nature of these common birthmarks to parents. Sometimes, it may prove difficult to differentiate a fading capillary stain located on the eyelid from true CM, infantile hemangioma precursors, or minimally proliferative infantile hemangiomas; so, reassessment within the first few months of life may be required.
In contrast to these benign fading stains, as the patient matures, true facial CM may become darker, more violaceous, and thicker and develop blebs. These lesions are also known as port-wine stains and may also be associated with underlying soft-tissue hypertrophy.
Associated Findings and Syndromes
CM of the skin may occur in association with other congenital malformations, including underlying vascular anomalies or other structural abnormalities of ectodermal origin, such as bony or soft-tissue hyperplasia or atrophy, or neurologic defects. In particular, limb CM may be associated with congenital hypertrophy of underlying bone and soft tissue.
Some of these associated anomalies occur with more frequency and have been assigned various eponyms ( Table 3 ). The most common of these is Sturge-Weber syndrome, a neuroectodermal syndrome characterized by a CM in the V1 (and sometimes V2) distribution of the trigeminal nerve, ipsilateral leptomeningeal angiomatosis, and glaucoma ( Fig. 2 ). Seizures are the most common neurologic feature, often present within the first year of life, and they may be difficult to control.
| Vascular Malformation | Syndromes/Inheritance/Genes | Comments |
|---|---|---|
| CM | Sturge-Weber Inheritance/gene unidentified Phakomatosis pigmentovascularis Inheritance/gene unidentified Beckwith Wiedemann Inheritance unidentified Mutations in KIP2, H19, LIT1 OMIM#130650 Macrocephaly-CM Inheritance/gene unidentified Proteus Inheritance/gene unidentified OMIM#176920 | CM in V1>V2 distribution Ipsilateral leptomeningeal angiomatosis Presents with seizures Ipsilateral glaucoma CM Epidermal nevus Dermal melanocytosis Nevus anemicus and/or nevus spilus Facial CM of midforehead, glabella, or upper eyelids Omphalocele Macrosomia Macroglossia CM of central face Reticulated CM on trunk/extremities Macrocephaly Facial or limb asymmetry Somatic overgrowth Occasional CM Progressive overgrowth Epidermal nevus Cerebriform connective tissue nevus, often on soles |
| VM | Blue rubber bleb nevus Inheritance/gene unidentified Multiple cutaneous and mucosal VM Autosomal dominant Activating mutation in TIE2 OMIM#600195 GVMs Autosomal dominant Mutation in glomulin OMIM#138000 Maffucci Inheritance unidentified Mutation in PTHR1 OMIM#166000 | Cutaneous and gastrointestinal VM Risk of gastrointestinal hemorrhage Cutaneous and mucosal VM May have visceral VM Multiple GVM No systemic involvement or associated findings reported VM more common on hands and feet Dyschondroplasia Enchondromas Risk of chondrosarcoma |
| LM | Gorham Inheritance/gene unidentified | Most likely cutaneous LM Diffuse progressive osteolysis resulting in pathologic fractures |
| CLVM | Klippel-Trenaunay Inheritance/gene unidentified CLOVE Inheritance/gene unidentified | CLVM involving extremity (leg most common) Hyperplasia of soft tissue and bone Truncal CLVM Congenital lipomas Scoliosis Enlarged bony structures without progressive overgrowth |
| AVM | Parkes-Weber Inheritance unidentified Mutation in RASA1 OMIM#608355 CM-AVM Autosomal dominant Mutation in RASA1 OMIM#608354 Hereditary hemorrhagic telangiectasia Autosomal dominant Multiple mutations including: Type 1: endoglin OMIM#187300 Type 2: ALK1 OMIM#600376 Coexisting juvenile polyposis: SMAD4 OMIM#175050 Bannayan-Riley-Ruvalcaba Inheritance unidentified Mutation in PTEN OMIM#153480 Cobb Inheritance/gene unidentified | AVM of extremity Hyperplasia of soft tissue and bone Multiple cutaneous CM Cutaneous, subcutaneous, intraosseous, and/or cerebral AVM AVM of lungs, liver, gastrointestinal tract, and/or brain Mucocutaneous telangiectasias Presents commonly with epistaxis Risk of visceral hemorrhage AVM or AVF Macrocephaly Lipomas Genital lentigines Association of CM with underlying spinal AVM |
Macrocephaly-CM syndrome is characterized by CM on the central face and macrocephaly, which can be progressive. Reticulated CM may also be located on the trunk or extremities. Often, these patients also have structural brain abnormalities. Other minor features include developmental delay, limb abnormalities, and joint or skin laxity. Proteus syndrome is a rare overgrowth syndrome that is characterized by progressive overgrowth (typically of a limb), epidermal nevi, and connective tissue nevi. CM are reported in some patients.
A less well-recognized anomaly associated with CM is underlying spinal dysraphism, which may occur in the lumbar region, and in the neck area when the CM is associated with an underlying mass or pit. A retrospective review has suggested that the combination of two or more midline cutaneous lesions is highly suggestive of occult spinal dysraphism in children. However, this study did not include other types of birthmarks. The significance of these CM as a marker of spinal dysraphism when they occur in isolation is unclear and controversial, and specific evidence-based guidelines regarding screening spinal evaluations with magnetic resonance imaging (MRI) or ultrasonography do not exist.
CM may also be associated with other vascular malformations. The development of blebs and hyperkeratotic areas within CM on the extremities is virtually always seen in association with a lymphatic and/or venous malformation (VM). As mentioned previously, familial cases of CM in association with cutaneous, subcutaneous, and/or cerebral AVM, so-called CM-AVM, have been reported. Finally, CM overlying the spinal cord may be a cutaneous sign of an underlying spinal AVM and has been called Cobb syndrome. CM-AVM and Cobb syndrome are discussed in more detail in the AVM section of this article.
Diagnosis and Management
CM are diagnosed based on their appearance and behavior. Cutaneous erythema overlying a deeper AVM or a minimally proliferative infantile hemangioma may mimic a CM. For suspected cases, Doppler ultrasound evaluation is helpful but not always diagnostic in differentiating an arteriovenous fistula or shunt from a CM.
Once the diagnosis of CM is established, the patient should be evaluated for the presence of underlying vascular malformations and associated congenital anomalies. Multiple different subspecialists can care for CM and other vascular malformations. Referral to a vascular anomalies center, where multidisciplinary care is provided, is advised for further evaluation and treatment of CM.
The flashlamp-pumped pulsed dye laser (PDL) is the treatment of choice for CM. The most commonly used lasers use a wavelength that selectively targets oxyhemoglobin (577, 585, 595 nm) resulting in intravascular coagulation, as well as pulse durations that limit destruction and heat dissipation to the CM vasculature without causing damage to the surrounding structures in the epidermis or dermis. The current generation of PDLs uses epidermal cooling devices that minimize damage to the surrounding structures and lessens discomfort associated with treatment. Response to treatment is variable, with some investigators reporting good response in as many as 80% of treated subjects. Parents should be counseled that complete disappearance of the lesion is unlikely; however, cosmetically acceptable results occur in most patients after multiple treatments. Some patients who have initially undergone successful lightening using the traditional PDL may show re-darkening of their lesions several years after successful therapy. Although other laser types and light sources, such as the alexandrite, neodymium-doped yttrium-aluminium-garnet (Nd:YAG), and intense pulsed light, and photodynamic therapy have been used, the efficacy and associated risks are still uncertain. Thus, PDL remains the standard of care for laser treatment of CM.
Laser treatment is often used in conjunction with local or general anesthesia. Younger patients may require general anesthesia to treat extensive CM. Treatment during early childhood is desirable to minimize the psychosocial impact of a significant congenital malformation. In some situations, smaller lesions on older children may be treated without anesthesia. Sessions are scheduled every 6 to 8 weeks over the course of several months to years, depending on the size and responsiveness of the lesion. CM located on the central face and limb are generally less responsive to laser therapy than those on other regions of the face, neck, and trunk. There is no minimum age required. It has been suggested that younger patients may respond better, with more significant lightening, than older patients. This observation remains controversial, because some authors found no evidence that treatment of CM with PDL in early childhood is more effective than treatment later in the first decade of life.
Capillary malformations
Capillary malformations (CM), including fading capillary stains and port-wine stains, are among the most common vascular malformations affecting the skin ( Fig. 1 ). True CM (the non-fading type) occur in approximately 3 of 1000 infants, are present at birth, and are equally common in the male and female sex. They usually arise sporadically; however, familial cases in association with AVM have been described.
Clinical Characteristics
A CM is usually noted at birth but may initially be misdiagnosed as a bruise or erythema from birth trauma. In young infants, CM may be pale pink macules and patches. They may present in small focal areas or involve an entire limb or portion of the face. Single or multiple lesions may occur. CM may arise on any surface of the skin but are frequently present on the head and neck area. When they are located on the head, they may extend to the lips, gingiva, or oral mucosa. Parents may note that the CM is somewhat darker in the immediate newborn period and lightens slightly in the first few weeks of life. This might be secondary to the higher hemoglobin concentration present in the immediate newborn period.
The natural history of CM vary according to their anatomic location. The terms salmon patch, angel’s kiss, stork bite, nevus simplex, and vascular stain are used to describe a subset of CM that are very common and located on the central face or nape of the neck. They are sometimes termed fading capillary stains rather than true CM, because these lesions typically lighten significantly or disappear early in life. Some, often those located on the nape of the neck, persist into adulthood without significant darkening. Commonly used terms, such as angel’s kiss, help to convey the benign nature of these common birthmarks to parents. Sometimes, it may prove difficult to differentiate a fading capillary stain located on the eyelid from true CM, infantile hemangioma precursors, or minimally proliferative infantile hemangiomas; so, reassessment within the first few months of life may be required.
In contrast to these benign fading stains, as the patient matures, true facial CM may become darker, more violaceous, and thicker and develop blebs. These lesions are also known as port-wine stains and may also be associated with underlying soft-tissue hypertrophy.
Associated Findings and Syndromes
CM of the skin may occur in association with other congenital malformations, including underlying vascular anomalies or other structural abnormalities of ectodermal origin, such as bony or soft-tissue hyperplasia or atrophy, or neurologic defects. In particular, limb CM may be associated with congenital hypertrophy of underlying bone and soft tissue.
Some of these associated anomalies occur with more frequency and have been assigned various eponyms ( Table 3 ). The most common of these is Sturge-Weber syndrome, a neuroectodermal syndrome characterized by a CM in the V1 (and sometimes V2) distribution of the trigeminal nerve, ipsilateral leptomeningeal angiomatosis, and glaucoma ( Fig. 2 ). Seizures are the most common neurologic feature, often present within the first year of life, and they may be difficult to control.
| Vascular Malformation | Syndromes/Inheritance/Genes | Comments |
|---|---|---|
| CM | Sturge-Weber Inheritance/gene unidentified Phakomatosis pigmentovascularis Inheritance/gene unidentified Beckwith Wiedemann Inheritance unidentified Mutations in KIP2, H19, LIT1 OMIM#130650 Macrocephaly-CM Inheritance/gene unidentified Proteus Inheritance/gene unidentified OMIM#176920 | CM in V1>V2 distribution Ipsilateral leptomeningeal angiomatosis Presents with seizures Ipsilateral glaucoma CM Epidermal nevus Dermal melanocytosis Nevus anemicus and/or nevus spilus Facial CM of midforehead, glabella, or upper eyelids Omphalocele Macrosomia Macroglossia CM of central face Reticulated CM on trunk/extremities Macrocephaly Facial or limb asymmetry Somatic overgrowth Occasional CM Progressive overgrowth Epidermal nevus Cerebriform connective tissue nevus, often on soles |
| VM | Blue rubber bleb nevus Inheritance/gene unidentified Multiple cutaneous and mucosal VM Autosomal dominant Activating mutation in TIE2 OMIM#600195 GVMs Autosomal dominant Mutation in glomulin OMIM#138000 Maffucci Inheritance unidentified Mutation in PTHR1 OMIM#166000 | Cutaneous and gastrointestinal VM Risk of gastrointestinal hemorrhage Cutaneous and mucosal VM May have visceral VM Multiple GVM No systemic involvement or associated findings reported VM more common on hands and feet Dyschondroplasia Enchondromas Risk of chondrosarcoma |
| LM | Gorham Inheritance/gene unidentified | Most likely cutaneous LM Diffuse progressive osteolysis resulting in pathologic fractures |
| CLVM | Klippel-Trenaunay Inheritance/gene unidentified CLOVE Inheritance/gene unidentified | CLVM involving extremity (leg most common) Hyperplasia of soft tissue and bone Truncal CLVM Congenital lipomas Scoliosis Enlarged bony structures without progressive overgrowth |
| AVM | Parkes-Weber Inheritance unidentified Mutation in RASA1 OMIM#608355 CM-AVM Autosomal dominant Mutation in RASA1 OMIM#608354 Hereditary hemorrhagic telangiectasia Autosomal dominant Multiple mutations including: Type 1: endoglin OMIM#187300 Type 2: ALK1 OMIM#600376 Coexisting juvenile polyposis: SMAD4 OMIM#175050 Bannayan-Riley-Ruvalcaba Inheritance unidentified Mutation in PTEN OMIM#153480 Cobb Inheritance/gene unidentified | AVM of extremity Hyperplasia of soft tissue and bone Multiple cutaneous CM Cutaneous, subcutaneous, intraosseous, and/or cerebral AVM AVM of lungs, liver, gastrointestinal tract, and/or brain Mucocutaneous telangiectasias Presents commonly with epistaxis Risk of visceral hemorrhage AVM or AVF Macrocephaly Lipomas Genital lentigines Association of CM with underlying spinal AVM |
Macrocephaly-CM syndrome is characterized by CM on the central face and macrocephaly, which can be progressive. Reticulated CM may also be located on the trunk or extremities. Often, these patients also have structural brain abnormalities. Other minor features include developmental delay, limb abnormalities, and joint or skin laxity. Proteus syndrome is a rare overgrowth syndrome that is characterized by progressive overgrowth (typically of a limb), epidermal nevi, and connective tissue nevi. CM are reported in some patients.
A less well-recognized anomaly associated with CM is underlying spinal dysraphism, which may occur in the lumbar region, and in the neck area when the CM is associated with an underlying mass or pit. A retrospective review has suggested that the combination of two or more midline cutaneous lesions is highly suggestive of occult spinal dysraphism in children. However, this study did not include other types of birthmarks. The significance of these CM as a marker of spinal dysraphism when they occur in isolation is unclear and controversial, and specific evidence-based guidelines regarding screening spinal evaluations with magnetic resonance imaging (MRI) or ultrasonography do not exist.
CM may also be associated with other vascular malformations. The development of blebs and hyperkeratotic areas within CM on the extremities is virtually always seen in association with a lymphatic and/or venous malformation (VM). As mentioned previously, familial cases of CM in association with cutaneous, subcutaneous, and/or cerebral AVM, so-called CM-AVM, have been reported. Finally, CM overlying the spinal cord may be a cutaneous sign of an underlying spinal AVM and has been called Cobb syndrome. CM-AVM and Cobb syndrome are discussed in more detail in the AVM section of this article.
Diagnosis and Management
CM are diagnosed based on their appearance and behavior. Cutaneous erythema overlying a deeper AVM or a minimally proliferative infantile hemangioma may mimic a CM. For suspected cases, Doppler ultrasound evaluation is helpful but not always diagnostic in differentiating an arteriovenous fistula or shunt from a CM.
Once the diagnosis of CM is established, the patient should be evaluated for the presence of underlying vascular malformations and associated congenital anomalies. Multiple different subspecialists can care for CM and other vascular malformations. Referral to a vascular anomalies center, where multidisciplinary care is provided, is advised for further evaluation and treatment of CM.
The flashlamp-pumped pulsed dye laser (PDL) is the treatment of choice for CM. The most commonly used lasers use a wavelength that selectively targets oxyhemoglobin (577, 585, 595 nm) resulting in intravascular coagulation, as well as pulse durations that limit destruction and heat dissipation to the CM vasculature without causing damage to the surrounding structures in the epidermis or dermis. The current generation of PDLs uses epidermal cooling devices that minimize damage to the surrounding structures and lessens discomfort associated with treatment. Response to treatment is variable, with some investigators reporting good response in as many as 80% of treated subjects. Parents should be counseled that complete disappearance of the lesion is unlikely; however, cosmetically acceptable results occur in most patients after multiple treatments. Some patients who have initially undergone successful lightening using the traditional PDL may show re-darkening of their lesions several years after successful therapy. Although other laser types and light sources, such as the alexandrite, neodymium-doped yttrium-aluminium-garnet (Nd:YAG), and intense pulsed light, and photodynamic therapy have been used, the efficacy and associated risks are still uncertain. Thus, PDL remains the standard of care for laser treatment of CM.
Laser treatment is often used in conjunction with local or general anesthesia. Younger patients may require general anesthesia to treat extensive CM. Treatment during early childhood is desirable to minimize the psychosocial impact of a significant congenital malformation. In some situations, smaller lesions on older children may be treated without anesthesia. Sessions are scheduled every 6 to 8 weeks over the course of several months to years, depending on the size and responsiveness of the lesion. CM located on the central face and limb are generally less responsive to laser therapy than those on other regions of the face, neck, and trunk. There is no minimum age required. It has been suggested that younger patients may respond better, with more significant lightening, than older patients. This observation remains controversial, because some authors found no evidence that treatment of CM with PDL in early childhood is more effective than treatment later in the first decade of life.
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