Combined Vascular Malformations

Combined vascular malformations are defined as two or more vascular malformations that are found within one lesion. As the name suggests, combined vascular malformations involve more than one type of vascular channel (i.e., capillary, venous, arterial, lymphatic). These combined malformations may also be associated with other genetic syndromes, some of which are listed below.

  • Klippel-Trenaunay Syndrome (KTS)
  • Parkes Weber Syndrome (PWS)
  • Sturge-Weber Syndrome (SWS)
  • Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi and Skeleptal/Spinal Abnormalities Syndrome (CLOVES)
  • Proteus Syndrome
  • Bannayan-Riley-Ruvalcaba Syndrome (BRRS)
  • Capillary Malformation of the Lower Lip, Lymphatic Malformation of the Face/Neck, and Partial or Generalized Overgrowth Syndrome (CLAPO)
  • Servelle-Martorell Syndrome (SMS)
  • Maffucci Syndrome
  • Posterior Fossa Brain Malformations, Hemangiomas of the Face, Arterial Anomalies, Cardiac Anomalies and Eye Abnormalities Syndrome (PHACE)
  • Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM)

KTS is a rare vascular anomaly that is present at birth (congenital). It may be diagnosed on a pre-natal ultrasound and has characteristic features, such as:

  • Capillary malformations
  • Venous malformation
  • Hemi hypertrophy of the affected extremity
  • Lymphatic malformation or lymphedema

Most cases of KTS are caused by a mutation of the PIK3CA gene. The mutation of this gene is responsible for many of the overgrowth syndromes identified. These mutations are only present in some of the body’s cells, and therefore symptoms of KTS only affect those parts of the body with the genetic mutation. These mutations are known to occur after conception, and likely very early in fetal development. KTS is not known to be inherited.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan.

Additional testing may include:

  • Doppler ultrasound
  • MRI
  • Coagulation studies
  • Genetic testing

Treatment:

Since there is no cure for KTS, managing this disorder is based on a patient’s unique symptoms. Treatment modalities are conservative and may include:

  • Sclerotherapy
  • Compression garments
  • Complete decongestive therapy to manage lymphedema
  • Surgeries to de-bulk tissue overgrowth, and procedures or orthotics to manage limb length discrepancies
  • Laser therapy to treat skin lesions
  • Anti-immunologic medications, such as sirolimus
  • Medications to manage blood clotting, as well as pain management

PWS is another rare vascular anomaly that is congenital. Hallmark characteristics of this condition include:

  • Capillary malformations
  • Arterio-venous malformations/fistula(e) (AVM/AVF)
  • Hemi hypertrophy of the affected extremity
  • Lymphatic malformation or lymphedema

People with multiple capillary malformations may have a mutation of the RASA1 gene. About 30% of affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), which are fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine and brain. These can be associated with life-threatening complications including abnormal bleeding and heart failure. Symptoms from intracranial AVMs/AVFs appear to occur early in life.

People with Parkes Weber syndrome who do not have multiple capillary malformations are unlikely to have mutations in the RASA1 gene; in these cases, the cause of the condition is unknown.

When Parkes Weber syndrome is caused by mutations in the RASA1 gene, it is sometimes inherited from an affected parent.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan.

Additional testing may include:

  • Doppler ultrasound
  • MRI of affected extremity and brain
  • Coagulation studies
  • Genetic testing of the affected individual and parents

Treatment:

As with many of these combined disorders, no cure currently exists. Treatment modalities are conservative and based on symptoms exhibited. Management involves a coordinated effort by several specialists including interventional radiologists, plastic reconstructive surgeons, general/vascular surgeons, neurosurgeons, dermatologists and orthopaedic surgeons.

Treatment may include embolization, surgical debulking of tissue overgrowth and procedures or orthotics to manage limb length discrepancies. Capillary malformations can be treated with laser therapy if troublesome. If the associated AVM/AVF is affecting heart function, a consultation and management by a cardiologist may be needed. Affected individuals should be referred to a geneticist for testing as well as counseling when indicated.

SWS, also known as encephalotrigeminal angiomatosis, is a rare congenital vascular anomaly. It is a neurocutaneous disorder that affects the leptomeninges of the brain as well as facial and ophthalmic distributions of the trigeminal nerve.

An infant born with a capillary malformation (CM) on the face has approximately a 6% chance of having Sturge–Weber syndrome, and this risk increases to 26% when the CM is located in the distribution of the ophthalmic branch of the trigeminal nerve. Because the brain is involved, these children are prone to seizures, developmental delay, cognitive impairment and one-sided body weakness or paralysis. The ophthalmic component of the condition predisposes children to glaucoma.

The hallmark of SWS is extensive capillary malformation of the facial region. These malformations may have an underlying soft tissue or bony overgrowth, which may be mild or massive.

SWS is not hereditary and is caused by a mutation of the GNAQ gene.

There are three main types of SWS:

  • Type 1 is the most common. Type 1 is characterized by vascular malformations on the face and brain. This type can lead to seizures. It can also delay a child’s development and cause learning disabilities. There is associated glaucoma.
  • Type 2 involves a capillary malformation on the face. This type of SWS doesn’t usually affect the brain. It can lead to glaucoma, differences in blood flow and headaches. These symptoms can last into adulthood.
  • Type 3 often involves unusual blood vessel growth on the brain. Type 3 has no capillary malformations and usually no glaucoma. Diagnosing type 3 can be difficult, and it is often confused with other conditions. Doctors use brain scans to identify and diagnose this type.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan.

Diagnosis is based on:

  • Clinical features
  • MRI of the brain
  • Ophthalmologic exam

Your child will be referred to a neurosurgeon if the MRI confirms brain involvement and to an ophthalmologist for a comprehensive eye evaluation.

Treatment:

There is no cure for SWS and treatment is focused on symptoms that the child is experiencing. These treatments may include:

  • Anticonvulsant medications to decrease seizure activity
  • Ophthalmic drops to decrease pressure within the eye, and possibly surgery to treat glaucoma
  • Laser treatment to lighten facial capillary malformation
  • Physical/occupational therapies to correct any weakness
  • Cognitive/education therapies if delays are present

CLOVES syndrome is a rare condition that is present at birth. Characteristics of the condition include:

  • Fatty overgrowth: Soft fatty masses of variable size are noted at birth and can be located in the back, flanks, axilla, abdomen and buttocks. These masses may affect one or both sides of the body. The skin over the mass is typically covered with a red-pinkish birthmark (capillary malformation or port-wine stain).
  • Vascular anomalies: Patients may have dilated veins in the chest, upper and lower extremities or lymphatic malformations, which are frequently noted within the fatty masses or in the abdomen, chest and extremities; a small subgroup of patients may have an arteriovenous malformation around the spinal cord.
  • Abnormal extremities (arms and legs): Large, wide hands or feet, large fingers or toes, wide space between digits (sandal gap toe) and uneven size of extremities are common.
  • Spinal anomalies: These can include scoliosis (curving of the spine), fatty masses and vessels pushing on the spinal cord, and a tethered cord (spinal cord fixed by abnormal band).
  • Vascular lesion: Some patients may have capillary malformations, prominent veins, lymphatic vesicles, moles and epidermal nevus (slightly raised areas of skin with light brownish color).
  • Kidney anomalies: The size of the kidneys could be asymmetric (one is larger) and may show some abnormal features on imaging studies. Wilms tumor has been noted in a small number of young patients with CLOVES syndrome. This requires screening with serial ultrasound examinations during childhood.

Additional findings that can occur in CLOVES syndrome include bleeding from the intestine or the bladder or an asymmetric face and head.

The severity of the condition and the associated signs and symptoms vary significantly from person to person. CLOVES syndrome is caused by somatic mutations in the PIK3CA gene. PIK3CA-related overgrowth syndromes (PROS) refer to a group of disorders caused by PIK3CA gene mutations.

CLOVES is not known to be inherited.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan.

Additional testing may include:

  • Molecular genetic testing for the PIK3CA gene mutation to confirm diagnosis
  • Imaging studies such as X-rays; MRIs of the chest, abdomen, pelvis, spine and limbs; or an ultrasound for vascular anomalies and kidneys

Treatment:

Currently, there is no cure for CLOVES. Treatment for the syndrome involves addressing each symptom or complication and improving quality of life. Palliative care aims to relieve symptoms caused by masses and minimize disease progression and disability. Managing the condition is very individualized since symptoms can vary in severity and location.

Treatment modalities may include:

  • Sclerotherapy and/or embolization
  • Surgical debulking of lipomatous masses
  • Orthopaedic or neurosurgical procedures to address spinal/skeletal involvement
  • Anti-immunologic medications such as sirolimus

Proteus syndrome is a rare condition in which there is excessive growth of a portion of the body. There may be no evidence of the condition at birth; instead, it becomes apparent between 6-18 months of age and becomes more severe with age. Proteus syndrome is not an inherited condition and is characterized by various cutaneous and subcutaneous lesions, including vascular malformations, lipomas, hyperpigmentation and several types of nevi. Cerebriform nevi are thought to be characteristic of the disorder.

The following have been noted in patients with Proteus syndrome:

  • Hemi hypertrophy
  • Abnormal fat distribution
  • Absent or decreased subcutaneous fat-wasting syndrome
  • Facial involvement, which may be associated with asymmetric mandibular growth, maxillary growth, or both, as well as with premature dental eruption and idiopathic root resorption
  • Eye conditions such as strabismus or epibulbar dermoids or cysts
  • Scoliosis or kyphoscoliosis
  • Kidney or bladder problems, though these are less common
  • Cutaneous and subcutaneous lesions:
    • Lipomas
    • Connective tissue nevi and epidermal nevi
    • Vascular malformations
  • Ovarian cystadenomas
  • Cystic lung malformations
  • Intrathoracic or intra-abdominal lipomas
  • Coagulopathies
  • Learning disabilities or developmental delays

Proteus syndrome is caused by a mutation in the AKT1 gene. This is a condition that arises randomly during the early stages of fetal development.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan. Diagnosis is primarily based on the physical examination.

There are three general characteristics or features that must be present to consider a diagnosis of Proteus syndrome:

  1. Mosaic distribution: Areas of overgrowth are patchy and that only some body parts show signs of overgrowth while others are unaffected.
  2. Sporadic occurrence: No one else in the affected person’s family has similar features of overgrowth.
  3. Progressive course: The overgrowth has noticeably altered the appearance of the affected body parts over time or that new areas of overgrowth have appeared over time.

A diagnosis of Proteus syndrome requires all three general features to be present and either one feature from category A, two features from category B or three features from category C, as shown below.

Category A

  • Cerebriform connective tissue nevus

Category B

  • Linear epidermal nevus
  • Asymmetric, disproportionate overgrowth
  • Specific tumors before being 20 years old of age
  • Bilateral ovarian cystadenoma
  • Parotid monomorphic adenoma

Category C

  • Abnormal growth and/or distribution of fat
    • Fatty tumors (lipomas)
    • Lack of fat under the skin (regional lipohypoplasia)
  • Vascular malformations
  • Lung cysts
  • Specific facial features:
    • A long and narrow head (dolichocephaly)
    • Long face
    • Down slanting palpebral fissures and/or minor dropping of the eyelids (ptosis)
    • Depressed nasal bridge
    • Wide or opening nares
    • Open mouth at rest

Treatment:

There is no cure for Proteus syndrome and individualized treatment is focused on symptoms that the child is experiencing.Patients with Proteus syndrome are followed by several specialists. These specialists may include:

  • Orthopaedic surgeons who will address overgrowth and provide procedures to delay or stop linear bone growth and correction of skeletal deformities
  • General surgeons
  • Plastic reconstructive surgeons
  • Interventional radiologists
  • Hematologists who will monitor and treat any blood clotting issues
  • Oncologists who would monitor any tumor development
  • Dermatologists to monitor skin lesions
  • Physical/occupational therapists
  • Cognitive/education therapists if delays are present

BRRS is a rare condition that is usually present at birth. Occasionally, it may become apparent in early childhood. It is characterized by the following:

  • Large head size
  • Benign polyps in the intestine
  • Lipomas
  • Pigmented lesions on the penis

Individuals with this disorder may also exhibit the following:

  • Intellectual disability
  • Delayed development
  • Hypotonia
  • Seizure disorders
  • Skeletal abnormalities
  • Pectus Excavatum

About 60% of all cases of Bannayan-Riley-Ruvalcaba syndrome result from mutations in the PTEN gene. This condition is inherited in an autosomal dominant pattern. Due to commonality in mutation of the PTEN gene, BRRS is closely related to Cowden syndrome.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan.

Diagnosis of BRRS includes the presence of macrocephaly and the presence of four sub-criteria:

  • Autism spectrum disorder
  • Dermatologic features
  • Vascular malformations
  • Gastrointestinal polyposis

BRRS is inherited autosomal dominantly. Genetic counseling can be offered to patients with PTEN mutations, and asymptomatic family members should also be tested for the mutation to identify those who need to be monitored before symptom onset.

Treatment:

BRRS is not curable. Treatment is based on the specific signs and symptoms present in the individual. Management and treatment is multidisciplinary and could include:

  • Thyroid ultrasound exam once a PTEN mutation is identified, and annually thereafter until age 18 years
  • Annual skin check until age 18 
  • Colonoscopy and renal imaging biennially, beginning between the ages of 35-40 years
  • Monthly breast self-examinations for women and yearly breast screenings as well as transvaginal ultrasounds or endometrial biopsies beginning at the age of 30

CLAPO syndrome is the acronym for a rare vascular malformation composed of capillary malformations of the lower lip, lymphatic malformation of the face/neck, and partial or generalized overgrowth. The common clinical manifestation of this disorder is a capillary malformation of the lower lip, which is present at birth, or shortly thereafter. Other clinical findings may include:

  • Lymphatic malformation
  • Overgrowth syndrome
  • Lymphedema

CLAPO is likely caused by a mutation of the PIK3CA gene. This is not an inherited condition.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan. Diagnosis is primarily based on clinical features. Additional diagnostic studies may include:

  • Plain radiographs
  • MRI
  • Genetic testing

Treatment:

There is no cure for CLAPO syndrome. Treatment is focused on individual symptoms. Individuals with this condition may need to be followed closely by experts from the following specialties:

  • Dermatology
  • Orthopaedics
  • Interventional radiology

Those with lymphedema may benefit from using compressive garments and decongestive therapy.

Servelle-Martorell syndrome, also known as Servelle-Martorell angiodysplasia or phlebectatic osteohypoplastic angiodysplasia, involves partial or a complete lack of valves in the deep venous system and intra-osseous vascular malformations. It is an extremely rare condition with characteristics including:

  • Venous malformations
  • Bone hypoplasia
  • Limb (usually upper extremity) hypertrophy

Findings may also include venous thrombosis as well as consumptive coagulopathy.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan. Diagnosis is based on:

  • Clinical features
  • Plain radiograph of upper extremity (which show phleboliths and bony hypoplasia)
  • MRI (to discern from other vascular anomalies)

Treatment:

There is no cure for patients with this condition. Conservative management may include external compression garments to help alleviate pain as well as protect the affected region from external trauma. Wearing a compression garment has no effect on the ultimate size of the limb.

Treatment modalities may involve sclerotherapy. As the extent of the venous malformations can be extensive, complete excision of the affected vessels is generally not possible. Symptomatic varicosities or localized venous malformations can be removed in some patients with good results provided that there is a functioning deep vein system. Patients with recurrent attacks of cellulitis may benefit from prophylactic antibiotic therapy. Anticoagulants are indicated after deep vein thrombosis or pulmonary embolus. Patients with recurrent superficial thrombophlebitis frequently require daily administration of aspirin. Pain can be managed with oral anti-inflammatory medication, such as ibuprofen.

Maffucci syndrome is a rare disorder that affects the bones, skin and blood vessels. The abnormal growths may become cancerous over time. These individuals are also prone to cancer in other parts of the body. Signs of the syndrome may not be evident at birth, but typically manifest by the age of 5. It is not an inherited condition.

Characteristics of the syndrome include:

  • Multifocal hemangiomas
  • Osteolysis
  • Coagulopathies-specifically venous clotting

In most cases of Maffucci syndrome, the disorder is caused by mutations in the IDH1 or IDH2 gene.

Diagnosis:

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan. Diagnosis is primarily based on:

  • Clinical features
  • Plain radiograph
  • Genetic testing

Treatment:

There is no cure for Maffucci syndrome. Management focuses on relieving symptoms and early detection of malignancies. Patients with Maffucci syndrome need to be followed closely by the following specialists:

  • Radiologists
  • Orthopaedic surgeons
  • Dermatologists
  • Oncologists

PHACE is the acronym for a condition that includes a large hemangioma in combination with one or more other defined abnormalities. General characteristics of this syndrome include:

  • Posterior fossa malformations, which are present at birth
  • Hemangioma, which usually covers a large area on the skin of the head or neck (greater than 5 cm)
    • The term "segmental" is sometimes used to describe these hemangiomas.
  • Arterial lesions, or abnormalities of the blood vessels in the neck or head
  • Cardiac abnormalities, which could include aortic coarctation and/or other abnormalities of the heart or the blood vessels 
  • Eye abnormalities

This syndrome is not inherited and to date, there is no known cause.

Diagnosis

Infants presenting with a large facial hemangioma should be initially evaluated by a dermatologist or a specialist in vascular anomalies. If PHACE syndrome is suspected, then the following tests will be needed:

  • MRI/MRA of the head, neck and chest
  • Echocardiogram

If the above studies are indicative of PHACE, then the following specialists may be consulted in your child’s care:

  • Dermatologists
  • Cardiologists
  • Ophthalmologists
  • Hematologists/oncologists
  • Radiologists
  • Neurologists
  • Geneticists
  • Otolaryngologists

Potential Complications

Complications can vary based on each patient, and symptoms are more likely to persist even after the hemangiomas have improved.

  • If the hemangioma is extensive, it may lead to skin breakdown, bleeding and pain. Encroachment of the hemangioma on the eye of mouth may lead to vision and feeding difficulties.
  • If the child has posterior brain fossa anomalies, then neurological symptoms such as headaches, seizures, developmental delays, speech delays and risk of ischemic strokes may persist.
  • If the child has associated cardiac findings, these may require surgical correction.
  • If there is eye involvement, the child will need to be followed closely by an ophthalmologist to monitor for vision impairment.

Treatment

Treatment for PHACE syndrome focuses on the individual’s specific findings and depends on the severity of the disease.

Managing the extensive hemangioma may include:

  • Timolol maleate, a topical medication
  • Propranolol, which is used extensively but should be closely monitored for patients with heart or blood vessel problems due to the risk of stroke
  • Pain medication

In addition, specific medications may be prescribed for associated cardiac conditions. For example, low-dose aspirin could be prescribed for those individuals at high risk of stroke.

Corrective surgeries and procedures will depend on individual medical problems. These may include:

  • Neurosurgery
  • Cardiac surgery
  • Ophthalmologic surgery

CM-AVM is a combined vascular anomaly with characteristic features including:

  • Capillary malformations
  • Arteriovenous malformations

The capillary malformations occur as small pink lesions on the skin. They mostly appear on the face, arms and legs. These spots may be present at birth, but may appear anytime through childhood and adolescence. They do not cause any complications.

Some individuals may have the associated vascular malformation known as arteriovenous malformation (AVM). This represents an abnormal connection between the arteries, vein and capillaries. Although AVMs may occur anywhere in the body, they are most commonly seen in the brain and spine. Complications associated with AVM include bleeding, seizures, headaches and heart failure.

This condition is inherited in an autosomal dominant pattern, although cases of new mutations occur without known family history.

CM-AVM 1 is caused by a mutation in the RASAI gene while CM-AVM 2 is caused by a mutation in the EPHB4 gene.

Diagnosis

You/your child will meet with the Vascular Anomalies Center team during the initial clinic visit for a comprehensive review of the patient’s medical history, any imaging studies and/or laboratory tests that have been performed, and a complete physical examination. The medical specialists will then confer and diagnose the condition and propose a treatment plan.

Additional testing may include:

  • Ultrasound
  • CT
  • MRI (brain/body)
  • Selective angiography
  • Genetics testing for the child as well as suspected affected members of the family
  • Cardiology consult, if large or multiple AVMs are present

Treatment could include:

  • Laser treatment for any capillary malformations, which are causing concern
  • Embolization of AVM
  • Complete surgical resection of AVM when indicated