Vascular Neurocutaneous Syndromes

Main Text

Preamble

A number of syndromes with prominent cutaneous manifestations occur without associated neoplasms and can be inherited or occur spontaneously. Many of these are disorders in which both cutaneous and intracranial vascular lesions are the predominant features.

Some vascular neurocutaneous syndromes [e.g., Sturge-Weber syndrome (SWS)] are present at birth (i.e., congenital) but have somatic mutations and are not inherited. Others, including hereditary hemorrhagic telangiectasia, have specific gene mutations with known inheritance patterns.

In the most recent (2018) classification scheme adopted by the International Society for the Study of Vascular Anomalies (ISSVA), vascular malformations are nonneoplastic structural anomalies that are distinguished from true vascular tumors that result from neoplastic proliferation of vascular endothelial cells). Port-wine stains and associated syndromes (e.g., SWS and others) are classified as low-flow vascular malformations and then grouped under the heading of “clinical syndromes with low-flow vascular malformations associated with other anomalies.”

Capillary Malformation Syndromes

Preamble

Capillary malformations (CMs) are the most common cutaneous vascular anomalies. Most CMs occur sporadically without any syndromic findings. Genetic disorders that feature CMs include Sturge-Weber syndrome (SWS), diffuse CM with overgrowth (DCMO), Klippel-Trenaunay syndrome (KTS), and CLOVES syndrome (among others).

Sturge-Weber Syndrome

SWS is one of the very few neurocutaneous syndromes that are sporadic, i.e., not familial and not inherited. It is also one of the most disfiguring syndromes, as a prominent facial CM (commonly referred to as port-wine birthmark [PWB]) is seen in the vast majority of cases.

Terminology

SWS is a congenital neurocutaneous syndrome that is also known as encephalo-trigeminal angiomatosis. Its hallmarks are variable combinations of (1) a facial capillary-venular malformation (the PWB) in the sensory distribution of the trigeminal nerve, (2) retinal choroidal angioma (either with or without glaucoma), and (3) a cerebral capillary-venous leptomeningeal angioma.

Etiology

Approximately 80-90% of patients with SWS have a pathogenic, somatic mosaic R183Q GNAQ or GNA11/GNAB2 missense mutation. Germline variants in RASA1, EPHB4, or KIT have been reported in patients with atypical clinical characteristics, so broad germline and somatic genetic testing in these patients may have implications for medical care, prognosis, and trial eligibility.

GNAQ mutations cause a spectrum of vascular and melanocytic birthmarks. Depending on when they occur, they can lead to differing dermal phenotypes, either vascular alone (SWS), pigmentary alone (extensive dermal melanocytosis), or both.

Pathology

A tangle of thin-walled vessels—multiple enlarged capillaries, small veins, and postcapillary venules—forms the characteristic leptomeningeal (pial) angioma. The angioma covers the brain surface, dipping into the enlarged sulci between shrunken apposing gyri (45-1)(45-2).

The most common location is the parietooccipital region followed by the frontal and temporal lobes. Part or all of one hemisphere can be affected. SWS is unilateral in 80% of cases and is typically ipsilateral to the facial angioma. Bilateral involvement is seen in 20% of cases. Infratentorial lesions are seen in 11% of cases.

Dystrophic laminar cortical calcifications are typical (45-2). Frank hemorrhage and large territorial infarcts are rare.

Clinical Issues

Presentation

The vast majority of SWS patients exhibit a facial CM—formerly termed a facial “angioma” or “port-wine stain”—that is plainly visible at birth. It can be uni- (63%) or bilateral (31%) and is distributed over the skin innervated by one or more sensory branches of the trigeminal nerve. CNV1 (forehead &/or eyelid) or a combination of CNV1-V2 (plus cheek) are the most common sites (45-3). All three trigeminal divisions are involved in 13% of cases. Approximately 1/3 of patients have ocular or orbital abnormalities, such as a diffuse choroidal hemangioma (“tomato catsup fundus”), congenital glaucoma with an enlarged globe (buphthalmos), and optic disc colobomas.

Occasionally, the facial vascular malformation involves the midline and may even extend to the chest, trunk, and limbs. Approximately 10% of patients have isolated SWS brain or eye involvement without a facial PWB so lack of a visible port-wine nevus does not rule out SWS!

Similarly, the presence of a PWB is not sufficient in and of itself for the definitive diagnosis of SWS. Patients with PWBs in the CNV1 distribution have only a 10-20% risk of SWS, although the risk increases with size, extent, and bilaterality of the nevus flammeus.

Seizures developing in the first year of life (75-90%), glaucoma (70%), hemiparesis (30-65%), and migraine-like headaches are other common manifestations of SWS.

Imaging

General Features

Neuroimaging is used to identify the intracranial pial angioma and the sequelae of longstanding venous ischemia. Findings may be minimal or absent in newborn/young infants, so serial imaging is necessary in suspected cases.

CT Findings

Dystrophic cortical/subcortical calcifications are one of the imaging hallmarks of SWS (45-5B). (Note that the calcifications are in the underlying brain, not the pial angioma). “Tram-track” cortical calcifications along the cerebral sulci under the pial angioma, atrophy, and enlargement of the ipsilateral choroid plexus are typical findings in older children and adults with SWS.

Bone CT shows thickening of the diploë and enlargement with hyperpneumatization of the ipsilateral frontal sinuses.

MR Findings

T1 and T2 scans show volume loss in the affected cortex with enlargement of the adjacent subarachnoid spaces (45-5C). Prominent trabeculae and enlarged veins often cross the subarachnoid space, making the CSF appear somewhat grayish or “dirty”(45-4)(45-10).

Dystrophic cortical/subcortical calcifications are seen as linear hypointensities on T2WI that “bloom” on T2* (GRE, SWI) (45-5D). SWI scans often demonstrate linear susceptibility in enlarged medullary veins (45-7E)(45-9). FLAIR scans may demonstrate serpentine hyperintensities in the sulci, the ivy sign (45-7A)(45-10).

T1 C+ shows serpentine enhancement that extends deep into the sulci (45-11) and sometimes almost completely fills the subarachnoid space (45-7C)(45-8D). Enlarged medullary veins can sometimes be identified as linear enhancing foci extending deep into the hemispheric white matter (45-7D). The ipsilateral choroid plexus is almost always enlarged and enhances intensely (45-5E)(45-9).

Angiography

DSA typically demonstrates a lack of superficial cortical veins with corresponding dilatation of deep medullary and subependymal veins (45-7F). The arterial phase is normal.

PIK3CA- Related Overgrowth Spectrum

Somatic mutations in the PIK3CA gene cause cells to grow and divide abnormally. PIK3CA mutations have been identified in patients with a variety of syndromes that are characterized by vascular anomalies and segmental overgrowths. Predominant areas of asymmetric overgrowth include the brain, limbs (including fingers and toes), trunk, and face.

Prior to the identification of PIK3CA as the causative gene, PIK3CA-related overgrowth spectrum (PROS) was separated into distinct clinical syndromes. Among many others, these include CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome), MCAP (megalencephaly-ca pillary malformation), CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry of the face and limbs, partial or generalized overgrowth), and Klippel-Trenaunay syndrome.

The most common malformation in PIK3CA mutation syndromes is a fibroadipose vascular anomaly, usually appearing as a venous malformation or mixed lymphatic-venous malformation. The lower extremity muscles are the most common involved site.

Klippel-Trenaunay syndrome (KTS)—also called Klippel-Trenaunay-Weber syndrome—is a congenital, sporadic disease characterized by a triad of capillary, lymphatic, and venous malformations with overgrowth of the affected limb. Some KTS cases are linked to somatic activating mutations in PIK3CA and are thus classified in PROS disorder.

Capillary malformations are seen in 98% of patients and occur either as cutaneous hemangiomas or port-wine stains. Limb overgrowth, which may include the underlying bones and soft tissues, occurs in 2/3 of KTS patients. Nearly 90% involve the lower limb, and over 2/3 involve a single limb.

Venous varicosities occur in 72% of patients and present as large valveless truncal veins with large varicosities along the lateral aspect of the lower extremities. Lymphatic malformations occur in 11% of KTS patients.

Intracranial neurovascular anomalies occur in 1/3 of cases. Developmental venous anomalies and craniofacial venous malformations are the most common imaging findings (45-12).

Capillary Malformation-Arteriovenous Malformation

Capillary malformation-arteriovenous malformation (CM-AVM) is a distinct entity that is characterized by a broad phenotypic variability. Multifocal small CMs may occur anywhere in the body, especially in the CNS, spine, and skin. One-third of patients have an arteriovenous fistula (AVF) in muscles, soft tissue, or the CNS.

CM-AVM syndrome is an autosomal dominant syndrome due to mutations in RASA1 (50% of cases) or EBHB4 (25%). RASA1 mutations have been identified in patients with Parkes-Weber syndrome. Affected patients present with large CMs, AVFs, and progressive overgrowth of the involved limb.

Other Neurovascular Syndromes

Hereditary Hemorrhagic Telangiectasia

Terminology

Hereditary hemorrhagic telangiectasia (HHT), formerly known as Osler-Weber-Rendu or Rendu-Osler-Weber syndrome, is an autosomal dominant monogenetic disorder characterized pathologically by multisystem angiodysplastic lesions. Lesions vary in size from small cutaneous or mucosal telangiectasias to large solid organ arteriovenous malformations (AVMs).

Etiology

Genetic testing has established several pathogenic gene mutations in HHT. Mutations in two genes (ENG and ACVRL1/ALK1) cause up to 60-80% of cases (N.B. a negative genetic test does not exclude the diagnosis of HHT). Penetrance increases during lifetime, and in adults over the age of 40 years, it is estimated to exceed 95%.

ENG (endoglin) gene mutations cause type 1 HHT and are associated with mucocutaneous telangiectases, early onset of epistaxis, pulmonary AVFs, and brain AVMs. ACVRL1/ALK1 mutation causes type 2 HHT, is associated with milder disease, and presents primarily as GI bleeds and pulmonary arterial hypertension. This mutation causes 35-40% of HHT cases while mutations in a third gene—SMAD4—occur in juvenile polyposis/HHT overlap syndrome and account for 2% of cases. Pathogenic mutations in the HHT3 locus on chromosome 5 and the HHT4 gene on chromosome 7 result in HHT type 3and HHT type 4.

Pathology

Pulmonary AVMs or fistulae develop in ~ 50% of patients with HHT and are most common in HHT type 1 (60-65% compared to 10-20% in HHT type 2). The most common cerebrovascular complication from pulmonary AVMs/AVFs is emboli resulting in brain infarction &/or abscess.

Between 10-20% of patients with a diagnosis of definite HHT have intracranial vascular malformations. Multiple types of cerebral vascular malformations may develop in HHT patients, but two main types are most common: (1) Nidus-type AVMs and (2) capillary vascular malformations. AVFs—common in the lung—are rare in the brain. Nonshunting lesions in HHT include developmental venous anomalies, capillary telangiectasias, and cavernous malformations.

“Nidal” brain AVMs account for slightly < 1/2 of all HHT neurovascular manifestations and are found in 10% of all patients. Nearly 60% are solitary, whereas multiple lesions are present in 40%; ~ 80% are supratentorial, whereas 20% are infratentorial. Most brain AVMs in the HHT population are symptomatic, although between 85-90% are Spetzler-Martin grade 2 or less.

Capillary vascular malformations account for slightly over 1/2 of all neurovascular manifestations of HHT. They are typically supratentorial (86%), are often peripherally located in the brain, and are almost always < 1 cm.

Capillary telangiectasias are distinct from capillary vascular malformations and consist of numerous thin-walled ectatic capillaries interspersed in normal brain parenchyma. Feeding arteries are absent, although sometimes a draining vein can be identified. Brain capillary telangiectasias are relatively rare in HHT (2-4%). They are typically found in the pons or medulla and are occult on DSA.

Other manifestations of HHT include pial AVFs and nonshunting lesions, such as developmental venous anomalies (12%) and cavernous malformations (3-4%). Pial AVFs are rare, accounting for just 1% of all HHT-related brain vascular malformations. Malformations of cortical development—usually perisylvian polymicrogyria—are found in 12% of HHT cases.

Clinical Issues

Presentation

The long-established 2000 Curaçao criteria are the mainstay of HHT clinical diagnosis and include (1) epistaxis (spontaneous, recurrent), (2) telangiectasias (multiple at characteristic sites, such as oral cavity, lips, fingers, and nose), (3) visceral lesions (e.g., pulmonary, hepatic, cerebral or spinal AVMs), and (4) family history (first-degree relative with HHT). Three or more criteria establish the definite diagnosis of HHT. The recent integration of nasal endoscopy in children with suspected HHT has increased the diagnostic sensitivity of the Curaçao criteria.

The most common features of HHT are epistaxis and telangiectases on the lips, hands, tongue, and oral mucosa. Epistaxis typically begins by age 10 while 80-90% have nosebleeds &/or GI bleeding by age 21. The onset of visible telangiectases is generally 5-30 years later than for epistaxis. Almost 95% of affected individuals eventually develop mucocutaneous telangiectases.

HHT patients should be screened for cerebral vascular malformations at least once during their clinical evaluation. Current guidelines also suggest careful attention to all family members (including children) of an index case.

Natural History

HHT displays age-related penetrance with increasing manifestations developing over a lifetime; penetrance approaches 100% by age 40. Epistaxis increases in frequency and severity and, in some cases, can require multiple transfusions or even become life threatening.

Although most HHT-associated brain AVMs are small and have a low Spetzler-Martin grade, 20% present with rupture, and nearly 50% are symptomatic. Treatment options include surgical resection, stereotactic radiosurgery, &/or embolization.

Shunting of air, thrombi, and bacteria through pulmonary AVMs can cause TIAs, strokes, and cerebral abscesses. Heritable pulmonary arterial hypertension (HPAH) is a rare but severe complication of HHT.

Imaging

Brain MR without and with contrast enhancement is the recommended screening procedure for patients diagnosed with HHT and, when possible, should be obtained within the first six months of life. Molecular diagnostics may obviate further imaging. In adults, if no AVMs are detected on initial MR scans, further screening for cerebral AVMs is unnecessary.

Although some HHT-associated AVMs are large (45-14), nearly 90% are small (Spetzler-Martin ≤ 2). Large lesions can demonstrate prominent “flow voids” on T2WI; smaller lesions are seen as “speckled” enhancing foci on T1 C+ studies (45-13).

Capillary vascular malformations do not show “flow voids” on MR and are defined by a “blush” of abnormal vessels on the late arterial/capillary phase on DSA or an area of fluffy stain-like enhancement on T1 C+ MR. A dilated feeding artery that empties directly into a draining vein is typical of an AVF.

Capillary telangiectasias are most common in the pons and are angiographically occult without a visible feeding artery or draining vein on DSA. Capillary telangiectasias are usually invisible on T2/FLAIR. A faint brush-like area of enhancement is seen on T1 C+, whereas T2*/SWI sequences show decreased signal intensity.

HEREDITARY HEMORRHAGIC TELANGIECTASIA: IMAGING

Capillary Vascular Malformations

• < 1 cm in diameter

• Feeding artery, vein often visible on DSA but not enlarged

• No “flow voids” on MR

• “Blush” of fluffy, stain-like enhancement on T1 C+

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