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Selected References

Neurofibromatosis and Schwannomatosis

Vijapura C et al: Genetic syndromes associated with central nervous system tumors. Radiographics. 37(1):258-280, 2017

Kresak JL et al: Neurofibromatosis: a review of NF1, NF2, and schwannomatosis. J Pediatr Genet. 5(2):98-104, 2016

Neurofibromatosis Type 1

Evans DGR et al: Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 1. Clin Cancer Res. 23(12):e46-e53, 2017

Karmakar S et al: The role of the immune system in neurofibromatosis type 1-associated nervous system tumors. CNS Oncol. 6(1):45-60, 2017

Ahlawat S et al: Current whole-body MRI applications in the neurofibromatoses: NF1, NF2, and schwannomatosis. Neurology. 87(7 Suppl 1):S31-9, 2016

Neurofibromatosis Type 2

Evans DGR et al: Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 2 and related disorders. Clin Cancer Res. 23(12):e54-e61, 2017

Lloyd SK et al: Hearing optimization in neurofibromatosis type 2: a systematic review. Clin Otolaryngol. ePub, 2017

Miller ME et al: Long-term MRI surveillance after microsurgery for vestibular schwannoma. Laryngoscope. ePub, 2017

Schwannomatosis

Kehrer-Sawatzki H et al: The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis. Hum Genet. 136(2):129-148, 2017

Other Common Familial Tumor Syndromes

Tuberous Sclerosis Complex

Cardis MA et al: Cutaneous manifestations of tuberous sclerosis complex and the paediatrician's role. Arch Dis Child. ePub, 2017

Gokare P et al: The tuberous sclerosis complex gets fatter. Oncotarget. 8(26):41780-41781, 2017

Ji S et al: Combined targeting of mTOR and Akt using rapamycin and MK-2206 in the treatment of tuberous sclerosis complex. J Cancer. 8(4):555-562, 2017

von Hippel-Lindau Disease

Huntoon K et al: Biological and clinical impact of hemangioblastoma-associated peritumoral cysts in von HippelLindau disease. J Neurosurg. 124(4):971-6, 2016

Shanbhogue KP et al: von Hippel-Lindau disease: review of genetics and imaging. Radiol Clin North Am. 54(3):409-22, 2016

Rare Familial Cancer Syndromes

Kennedy RA et al: An overview of autosomal dominant tumour syndromes with prominent features in the oral and maxillofacial region. Head Neck Pathol. ePub, 2017

Vijapura C et al: Genetic syndromes associated with central nervous system tumors. Radiographics. 37(1):258-280, 2017

Li-Fraumeni Syndrome

Guha T et al: Inherited TP53 mutations and the Li-Fraumeni syndrome. Cold Spring Harb Perspect Med. 7(4):a026187, 2017

Kratz CP et al: Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 23(11):e38-e45, 2017

Cowden Syndrome

Heaney RM et al: Cowden syndrome: serendipitous diagnosis in patients with significant breast disease. Case series and literature review. Breast J. 23(1):90-94, 2017

Ngeow J et al: Clinical implications for germline PTEN spectrum disorders. Endocrinol Metab Clin North Am. 46(2):503-517, 2017

Turcot Syndrome

Waller A et al: Familial adenomatous polyposis. J Pediatr Genet. 5(2):78-83, 2016

Nevoid Basal Cell Carcinoma Syndrome

Kennedy RA et al: An overview of autosomal dominant tumour syndromes with prominent features in the oral and maxillofacial region. Head Neck Pathol. ePub, 2017

Shiohama T et al: Brain morphology in children with nevoid basal cell carcinoma syndrome. Am J Med Genet A. 173(4):946-952, 2017

Rhabdoid Tumor Predisposition Syndrome

Foulkes WD et al: Cancer surveillance in Gorlin syndrome and rhabdoid tumor predisposition syndrome. Clin Cancer Res. 23(12):e62-e67, 2017

Johansson G et al: Recent developments in brain tumor predisposing syndromes. Acta Oncol. 55(4):401-11, 2016

Meningioangiomatosis

Nascimento FA et al: Meningioangiomatosis: a disease with many radiological faces. Can J Neurol Sci. 43(6):847-849, 2016

Neurocutaneous Melanosis

Kolin DL et al: CSF cytology diagnosis of NRAS-mutated primary leptomeningeal melanomatosis with neurocutaneous melanosis. Cytopathology. 28(3):235-238, 2017

Levy R et al: Melanocytic nevi in children: a review. Pediatr Ann. 45(8):e293-8, 2016

Encephalocraniocutaneous Lipomatosis

Kocak O et al: Encephalocraniocutaneous lipomatosis, a rare neurocutaneous disorder: report of additional three cases. Childs Nerv Syst. 32(3):559-62, 2016

Epidermal Nevus Syndrome

Israni A et al: Cutaneous and brain malformations of epidermal nevus syndrome: a classical image. J Pediatr Neurosci. 11(3):285286, 2016

Proteus Syndrome

Nathan N et al: Mosaic disorders of the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway. Dermatol Clin. 35(1):51-60, 2017

Sachdeva P et al: Proteus syndrome with neurological manifestations: a rare presentation. J Pediatr Neurosci. 12(1):109111, 2017

A number of syndromes with prominent cutaneous manifestations occur without associated neoplasms. Many of these are disorders in which both cutaneous and intracranial vascular lesions are the predominant features. These vascular phakomatoses may be segmental, involve a large region, or occur as a localized vascular lesion.

Some vascular phakomatoses, such as Sturge-Weber syndrome, are present at birth (i.e., congenital) but are not inherited. Others, including hereditary hemorrhagic telangiectasia, have specific gene mutations and known inheritance patterns. We delineate these and other pertinent features of the major vascular neurocutaneous syndromes here.

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(40-1) SWS shows pial angiomatosis , deep medullary collaterals , enlarged choroid plexus, and atrophy of the right cerebral hemisphere.

(40-2) Gross image (L), photomicrograph (R) of SWS show cortical atrophy, calcifications , and pial angioma within sulci. (AFIP Archives.)

angioma (either with or without glaucoma), and (3) a cerebral capillaryvenous leptomeningeal angioma.

Etiology

Once considered an enigma, the pathoetiology of SWS is now demystified. In 2013, postzygotic somatic activating mutations in GNAQ were identified in both SWS and nonsyndromic PWB-type capillary malformations (so-called SWS type II, i.e. PWB without a vascular pial malformation).

Endothelial cells in SWS skin and brain lesions strongly express somatic R183Q GNAQ mutation. The mutation results in hyperactivation of several downstream pathways including RAS-MEK-ERK and (indirectly) mTOR.

GNAQ mutations cause an overlapping phenotypic 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 (phakomatosis pigmentovascularis).

Pathology

A tangle of thin-walled vessels—multiple enlarged capillaries and venous channels—forms the characteristic leptomeningeal (pial) angioma. The angioma covers the brain surface, dipping into the enlarged sulci between shrunken apposing gyri (40-1).

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 (40-2). Frank hemorrhage and large territorial infarcts are rare.

Clinical Issues

Demographics. SWS is rare with an estimated prevalence of 1:40,000-50,000 live births. There is no sex predilection.

Presentation. The vast majority of SWS patients exhibit a nevus flammeus—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. CN V (forehead and/or eyelid) or a combination of CN V -V (plus cheek) are the most common sites (40-3). All three trigeminal divisions are involved in 13% of cases. Approximately one-third of patients have ocular or orbital abnormalities such as a diffuse choroidal hemangioma ("tomato catsup fundus") (40-5A), 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. No facial nevus flammeus is present in 5% of cases, so lack of a visible port-wine nevus does not rule out SWS!

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

(40-5A) T1 C+ FS in a patient with SWS and left vision loss shows a diffuse choroidal angioma, seen here as a thick crescent of contrast enhancement around the posterior segment of the globe.

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.

Occasionally, children with SWS also have extensive cutaneous capillary malformations, limb hypertrophy, and vascular and/or lymphatic malformations. These children are diagnosed as having Klippel-Trenaunay syndrome (KTS), which is also known as angioosteohypertrophy or hemangiectatic hypertrophy. SWS and KTS most likely represent phenotypic variations within the same spectrum.

Endocrine disorders are a newly recognized aspect of SWS. Patients with SWS have a significantly increased risk of growth hormone deficiency and central hypothyroidism.

Natural History. SWS-related seizures are often medically refractory and worsen with time. Progressive hemiparesis and stroke-like episodes with focal neurologic deficits are common. Most patients are mentally retarded.

Treatment Options. Despite adequate treatment with antiepileptic drugs, seizure control is achieved in less than half of all cases. Early lobectomy or hemispherectomy in infants with drug-resistant epilepsy and widespread hemispheric angioma may be an option in severe cases.

Imaging

General Features. Neuroimaging is used to identify the intracranial pial angioma and the sequelae of longstanding venous ischemia. This enables the radiologist to (1) establish or confirm the diagnosis of SWS and (2) evaluate the extent and severity of intracranial involvement.

(40-5B) T1 C+ FS in the same case shows left occipital pial enhancement with enlarged, enhancing ipsilateral choroid plexus . The left hemisphere is slightly atrophic, and the left frontal sinus is enlarged .

Sequential examinations of SWS patients show progressive cerebral cortical-subcortical atrophy, especially during the first years of life. Findings may be minimal or absent in newborn infants, so serial imaging is necessary in suspected cases.

CT Findings. NECT is especially useful to depict the dystrophic cortical/subcortical calcifications that are one of the imaging hallmarks of SWS (40-4B). (Note that the calcifications are in the underlying brain, not the pial angioma). Cortical calcification, atrophy, and enlargement of the ipsilateral choroid plexus are typical findings in older children and adults with SWS.

Heavily calcified cortex correlates with decreased perfusion in the underlying WM and is also associated with more severe epilepsy.

Bone CT shows thickening of the diploë and enlargement with hyperpneumatization of the ipsilateral frontal sinuses secondary to longstanding volume loss in the underlying brain. Dense cortical calcifications may obscure enhancement of the pial angioma on CECT, but an enlarged enhancing choroid plexus can usually be identified.

MR Findings. T1 and T2 scans show volume loss in the affected cortex with enlargement of the adjacent subarachnoid spaces (40-4C) (40-7). Myelination is usually normal or even accelerated, and malformations of cortical development may be present. White matter ischemic damage with subcortical T2/FLAIR hyperintensities in the affected hemisphere is common in older patients.

Prominent trabeculae and enlarged veins often cross the subarachnoid space, making the CSF appear somewhat grayish or "dirty" (40-4E).

(40-7) Variant SWS case shows focal Ca++ , atrophy , and a very localized enhancing pial angioma that fills just a few adjacent sulci .

Dystrophic cortical/subcortical calcifications are seen as linear hypointensities on T2WI that "bloom" on T2* (GRE, SWI) (404D). SWI scans often demonstrate linear susceptibility in enlarged medullary veins (40-6E).

FLAIR scans may demonstrate serpentine hyperintensities in the sulci, the "ivy" sign (40-6A). DWI is usually negative unless acute ischemia is present.

Postcontrast T1WI or FLAIR sequences best demonstrate the pial angioma. Serpentine enhancement covers the underlying gyri, extending deep into the sulci and sometimes almost filling the subarachnoid space (40-6C). Enlarged medullary veins—sources of compensatory collateral venous drainage—can sometimes be identified as linear enhancing foci extending deep into the hemispheric white matter (406D). The ipsilateral choroid plexus is almost always enlarged and enhances intensely (40-5B).

T1 C+ is particularly helpful in the newborn, infant, or young child with dark skin pigmentation and SWS who presents with seizures and has not yet exhibited focal brain atrophy.

Angiography. DSA typically demonstrates a lack of superficial cortical veins with corresponding dilatation of deep medullary and subependymal veins (40-6F). The arterial phase is normal.

Differential Diagnosis

The major differential diagnoses of SWS are other vascular neurocutaneous syndromes. Patients with meningioangiomatosis (MA) typically lack the PWB seen in SWS. The meningeal angioma of MA often extends into the adjacent brain along the perivascular spaces. Cutaneous or ophthalmoscopic findings help differentiate other vascular

(40-8) Images from a 17y boy with KTS show bilateral gyriform parenchymal calcifications that "bloom" on T2* , parietal occipital atrophy , and extensive bilateral enhancing pial angiomata .

neurocutaneous syndromes, such as blue rubber bleb nevus syndrome and Wyburn-Mason syndrome from SWS.

STURGE-WEBER SYNDROME

Etiology

•Congenital but sporadic, not inherited

•Postzygotic (i.e., somatic) mutation in GNAQ

○Causes both SWS, nonsyndromic "port-wine birthmarks" (PWBs)

Pathology

•Pial (leptomeningeal) angioma

•Cortical venous ischemia, atrophy

•Parietooccipital > frontal

Clinical Issues

•Unilateral facial nevus flammeus

○Also known as PWB

•Usual cutaneous distribution = CN V1 , V > V

○Can be bilateral or even absent

Imaging

•CT

○Atrophic cortex

○Ipsilateral calvaria thick, sinuses enlarged

○Cortical Ca++ (not in angioma!) increases with age

•MR

○Cortical/subcortical hypointensity on T2

○Ca++ "blooms" on T2*

○Angioma enhances (unilateral 80%, bilateral 20%)

○Ipsilateral choroid plexus enlarged

○Enlarged medullary veins

(40-9) Clinical photograph of a patient with HHT and multiple episodes of severe epistaxis shows multiple mucocutaneous telangiectasias of the scalp , nose , and lips .

(40-10) ECA (top), ICA (bottom) angiograms in a patient with HHT and epistaxis show tiny capillary telangiectases in the nasal and orbital mucosa.

Klippel-Trenaunay Syndrome

Klippel-Trenaunay syndrome (KTS)—also called Klippel- Trenaunay-Weber syndrome—is characterized by capillary- lymphatic-venous malformations anywhere in the body. The classic clinical triad of KTS includes (1) capillary malformation, seen in 98% of patients either as cutaneous hemangiomas or port-wine stains, (2) limb overgrowth, which may include the underlying bones and soft tissues, and (3) venous varicosities.

KTS shares overlapping features with SWS. Intracranial lesions, i.e., pial angiomas, are rare. When present, they are often bilateral (40-8).

Capillary Malformation-

Arteriovenous Malformation

Capillary malformation-arteriovenous malformation (CMAVM) is characterized by small multifocal capillary malformations that may occur anywhere on the body, typically on the face and limbs. CM-AVM syndrome is a RASA1 disorder. About 30% of affected individuals also have associated AVMs or arteriovenous fistulas (AVFs) in the skin, muscle, bone, spine, or brain.

Some patients with a RASA1 pathogenic variant have the clinical diagnosis of Parkes-Weber syndrome (PWS). PWS patients have capillary malformations and limb overgrowth but also have AVFs. Here multiple micro-AVFs are associated with a cutaneous capillary stain and overgrowth of an affected limb. In contrast to PWS and KTS, patients with CM-AVM do not exhibit limb overgrowth.

Cutaneous and/or mucosal capillary malformations can also occur with microcephaly (capillary malformation-

microcephaly syndrome) or megalencephaly (megalencephaly-capillary malformation syndrome).

Other Vascular

Phakomatoses

Hereditary Hemorrhagic

Telangiectasia

Terminology

Hereditary hemorrhagic telangiectasia (HHT) is also known as Osler-Weber-Rendu or Rendu-Osler-Weber syndrome. HHT is an autosomal-dominant monogenetic disorder with considerable intrafamilial variability and is characterized pathologically by widely distributed, multisystem angiodysplastic lesions.

Etiology

Mutations in three genes (ENG, ACVRL1/ALK1, and SMAD4) cause approximately 85-95% of HHT cases by affecting the TGF-β signaling pathway, leading to downstream changes in vascular cell proliferation. These changes ultimately result in the formation of telangiectasias and AVMs in multiple organ systems, including the brain.

ENG (endoglin) gene mutations cause type 1 HHT and are associated with mucocutaneous telangiectases, early onset of epistaxis, pulmonary arteriovenous fistulas (AVFs), and brain arteriovenous malformations (AVMs). ACVRL1/ALK1 mutation causes type 2 HHT, is associated with lower penetrance and

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milder disease, and presents primarily as GI bleeds and pulmonary arterial hypertension. SMAD4 mutations cause

HHT/juvenile polyposis combined syndrome.

HEREDITARY HEMORRHAGIC TELANGIECTASIA:

ETIOLOGY AND PATHOLOGY

Etiology

•Type 1 HHT

○Endoglin (ENG) mutation

○Mucocutaneous telangiectases, epistaxis, pulmonary AVFs/brain AVMs

•Type 2 HHT

○ACVRL1/ALK1 mutation

○Milder; predominantly GI bleeds

Pathology

•Neurovascular malformations 10-20%

○> 50% multiple

•Two main types

○Approximately 50:50

○"Nidal" brain AVMs

○Capillary vascular malformations

•Other intracranial vascular malformations

○Developmental venous anomaly 12%

○Cavernous malformations 2-4%

○Capillary telangiectases (mucocutaneous common; rare in brain 1-3%)

○Pial AVF < 1%

Pathology

Between 10-20% of patients with a diagnosis of definite HHT have brain vascular malformations. Two main types are 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 less than half of all HHT neurovascular manifestations and are found in 10% of all patients. Nearly 60% are solitary, whereas multiple lesions are present in 40%; approximately 80% are supratentorial, whereas 20% are infratentorial.

Capillary vascular malformations account for slightly over half 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

Epidemiology and Demographics. HHT is a rare but probably underdiagnosed disease, with a prevalence of 1-2:10,000. There is no sex predilection.

Presentation. The most common features of HHT are nosebleeds and telangiectases on the lips, hands, and oral mucosa (40-9). Epistaxis typically begins by age 10, and 8090% have nosebleeds by age 21 (40-10). The onset of visible telangiectases is generally 5-30 years later than for epistaxis. Almost 95% of affected individuals eventually develop mucocutaneous telangiectases.

The diagnosis of HHT is considered "confirmed" in an individual with three or more of the following: (1) nosebleeds,

(2) mucocutaneous telangiectases, (3) visceral AVM, and (4) a first-degree relative in whom HHT has been diagnosed. Identification of a heterozygous pathogenic variant in one of the causative genes can establish the diagnosis if clinical features are inconclusive.

Most experts agree that patients with HHT should be screened for cerebral vascular malformations at least once during their clinical evaluation. Repeat screening is low-yield, as the rate of de novo formation of brain AVMs in this population is exceedingly low.

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.

Approximately 50% of adults with HHT eventually develop gastrointestinal bleeding, usually after the age of 50 years. Iron deficiency anemia is more common than acute GI hemorrhage.

Shunting of air, thrombi, and bacteria through pulmonary AVMs can cause TIAs, strokes, and cerebral abscesses.

Treatment Options. Laser coagulation of mucosal telangiectases can be effective. Cerebral AVMs greater than 1.0 cm in diameter are usually treated with surgery, embolotherapy, and/or stereotactic radiosurgery.

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.

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(40-13A) Axial T1 C+ FS scans in an 11y girl with HHT show multiple foci of fluffy "stain-like" enhancement .

(40-13B) Lateral DSA in a 54y woman with HHT shows five small capillary vascular malformationsin the left cerebral hemisphere.

(40-14) (L) T1 C+ FS, (R) CTA in an asymptomatic 16y girl with HHT show focus of tubular enhancement . This is a dural AVF.

Although some HHT-associated AVMs are large, nearly 90% are small (Spetzler-Martin 2 or less). Large lesions can demonstrate prominent "flow voids" on T2WI (40-11A); smaller lesions are seen as "speckled" enhancing foci on T1 C+ studies (40-12A).

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 (40-13A). A dilated feeding artery that empties directly into a draining vein is typical of an AVF (40-14).

Capillary telangiectasias are most common in the pons and are usually invisible on T2/FLAIR. A faint "brush-like" area of enhancement is seen on T1 C+, whereas T2* sequences show decreased signal intensity.

HEREDITARY HEMORRHAGIC TELANGIECTASIA: IMAGING

Capillary Vascular Malformations

•Slightly > 50% of HHT vascular malformations

•No "flow voids" on MR

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

AVMs

•Slightly < 50%

•Most are Spetzler grades ≤ 2

○Multiple AVMs 40%

•Large lesions rare

○"Flow voids" on T2WI

•Small lesions show "speckled" enhancement on T1 C+

•Feeding artery, nidus, draining vein on DSA

•Other vascular malformations less common

•Perisylvian polymicrogyria 12%

PHACE Syndrome

Children with CNS vascular malformations often have associated broader vascular conditions, such as HHT (considered above), PHACES, and the RASA1 mutation-related disorder capillary malformation-arteriovenous malformation syndrome. We close this chapter with a discussion of these uncommon but important phakomatoses.

Terminology

PHACE syndrome is an acronym for posterior fossa malformations, hemangioma, arterial cerebrovascular anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (sometimes called PHACES with the addition of the less common sternal clefting or supraumbilical raphe).

PHACE is characterized clinically by a large infantile hemangioma (IH) that is associated with developmental defects. A definitive diagnosis of PHACE is determined when a craniofacial hemangioma is present together with one or more characteristic extracutaneous anomalies (see below).

Etiology

The precise etiology of PHACE is unknown, and genetic studies of PHACE syndrome are ongoing. A germ-line mutation has been ruled out, as there are no known familial cases.

The infantile hemangioma and cerebral vasculopathy appear to be linked by common in utero morphogenic event(s) with the insult occurring early in embryogenesis, probably during the fifth fetal week or even earlier.

Developmental errors in the neural plate, neural crest, and adjacent cephalic mesoderm have been implicated in the PHACE structural anomalies. Segmental neural crest cell disturbances could result in the formation of facial and intracranial hemangiomas in the same embryonic metamere. Neural crest cells also contribute to formation of the optic vesicles, possibly explaining the eye malformations that often occur as part of the syndrome.

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lesions in the upper half of the face typically have structural brain, cerebrovascular, and ocular abnormalities (40-15), whereas hemangiomas in a mandibular ("beard-like") distribution are associated with ventral developmental defects, such as sternal abnormalities and supraumbilical raphe.

The hemangiomas in PHACE can be single (70%) or multiple (30%). Transand multispatial lesions are common.

Pathology

Hemangiomas are—by definition—found in 100% of PHACE patients. Hemangiomas are true vascular neoplasms and are the most common benign tumor of infancy, occurring in 2-3% of neonates and 10-12% of children under 1 year of age. The majority are sporadic, nonsyndromic lesions; only 20% meet the diagnostic criteria for PHACE.

Cutaneous Hemangiomas. The topographic distribution of PHACE-associated hemangiomas is significant. Patients with

Extracutaneous Hemangiomas. Extracutaneous hemangiomas occur in 20-25% of patients. The subglottis is the most common site and can cause potentially lifethreatening airway obstruction.

Ophthalmologic findings are present in 30% of cases. Choroidal hemangiomas, colobomas, microphthalmos, and optic atrophy are common eye lesions in PHACE.

(40-15) Clinical photograph of a patient with PHACES shows a typical facial infantile hemangioma. (Courtesy S. Yashar, MD.) (40-16A) T2WI in an infant with PHACES shows a hemangioma filling the right orbit , extending posteriorly into the cavernous sinus and cerebellopontine angle. Note hypoplasia of the ipsilateral cerebellar hemisphere .

(40-17A) Axial T1 C+ FS in a patient with PHACE(S) shows an enhancing facial angioma . There is no left ICA flow void as a result of ICA atresia. Contrast with normal right ICA flow void .

Although not included in the acronym PHACE, otologic abnormalities are also common. These include middle ear atelectasis, tympanic membrane hemangiomas with conductive hearing loss, skin and cartilage ulcerations, and dysphagia.

Intracranial Hemangiomas. Intracranial hemangiomas are relatively uncommon. When present, they exhibit a predilection for the cavernous sinus and cerebellopontine angle cistern and are generally ipsilateral to the facial hemangioma.

Other Intracranial Malformations. Nonvascular intracranial malformations are present in 30-80% of all PHACE patients. Posterior fossa malformations are identified in 50-75% of these cases and range from focal regions of cerebellar dysplasia or hypoplasia to various cystic malformations, including Dandy-Walker spectrum. Other associated anomalies include corpus callosum dysgenesis, septi pellucidi anomalies, polymicrogyria, gray matter heterotopias, and arachnoid cysts.

Noncutaneous Systemic Manifestations. Over 90% of PHACE patients have more than one extracutaneous finding. Ventral developmental defects such as sternal clefting and supraumbilical raphe are common. Two-thirds of all patients have vasculopathy or exhibit cardiac anomalies.

PHACE-Associated Arteriopathy. PHACE-related vasculopathy includes a number of congenital and progressive large vessel lesions. Arterial anomalies of the craniocervical vasculature are seen in over 75% of patients. Aortic coarctation (35%), arterial occlusions (21%), progressive stenoses (18%), and saccular aneurysms (13%) are the most common potentially symptomatic anomalies. Persistent

(40-17B) T2WI in the same case shows cerebellar hypoplasia and cortical malformation with a prominent retrocerebellar CSF space . The fourth ventricle also appears malformed . (From DI: Head and Neck, 3e.)

embryonic arteries (most often a persistent trigeminal artery) are seen in 17% of cases. Aberrant course or origin, extreme dolichoectasia, and dysgenesis/agenesis of the internal carotid and/or vertebral arteries and circle of Willis are also frequent anomalies.

Clinical Issues

A large segmental IH of the face or scalp should prompt screening for PHACE syndrome. Smaller IHs with other characteristic/major anomalies (e.g., midline ventral defects, aortic coarctation, etc.) should also undergo complete evaluation for PHACE.

Epidemiology and Demographics. PHACES is a rare syndrome, but the exact incidence is unknown. The F:M ratio is 9:1.

Presentation. The cutaneous hemangiomas in PHACE are typically bulky, plaque-like geographic lesions (40-15). Unlike the port-wine birthmark of Sturge-Weber syndrome, PHACErelated hemangiomas are not always confined to a specific dermatome and are often transspatial.

Natural History. The prognosis in PHACE typically depends on the type and severity of the associated anomalies, not the hemangioma itself. Hemangiomas generally proliferate during the first year of life and then involute spontaneously over the next 5-7 years (or more). Most remain asymptomatic and are managed by close observation. Occasionally hemangiomas behave more aggressively, causing visual impairment, skeletal deformities, airway obstruction, high-output cardiac failure, bleeding, or ulceration.

Treatment Options. Treatment options for symptomatic hemangiomas include steroids or propranolol and pulsed dye

laser. Saccular aneurysms can be treated by coiling or clipping, whereas progressive stenoocclusive disease is sometimes treated with neurosurgical revascularization.

Imaging

CT Findings. NECT may demonstrate soft tissue masses in the orbit, face, and neck as well as cerebellar hypoplasia. CECT depicts hemangiomas as lobulated or plaque-like, intensely enhancing, infiltrating masses. Bone CT may show a small or absent carotid canal.

MR Findings. MR is the best technique to evaluate the presence and extent of craniofacial hemangiomas and to delineate coexisting intracranial malformations (40-16).

T1 scans depict callosal dysgenesis and cerebellar anomalies. Gray matter heterotopias are best seen on T2WI. Proliferating hemangiomas appear hyperintense on T2WI (40-16A) and may exhibit prominent internal "flow voids." Intense

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homogeneous enhancement following contrast administration is typical (40-16) (40-17).

Angiography. The prevalence of congenital heart disease in PHACE ranges from 40-67% with aortic coarctation in 20-30%. Aortic arch anomalies are common and unusually complex. The arch obstruction is most often long segment rather than the discrete juxtaductal narrowing seen in nonsyndromic coarctation.

Various anomalies of the craniofacial vasculature also occur in PHACE. These include hypoplasia or aplasia of the internal carotid or vertebral arteries, aberrant origin and/or course of cranial arteries, persistent embryonic vascular anastomoses (typically persistent trigeminal artery), kinking and/or ectasia of major arteries, saccular aneurysms, and progressive arterial stenoses (40-18).

(40-19) (Top) Sagittal autopsy in ataxia-telangiectasia shows severe atrophy of vermis and cerebellum. (Bottom) 4y child with ataxia-telangiectasia shows striking vermian atrophy. (Courtesy S. Blaser, MD.)

PHACE(S) SYNDROME

Terminology

•Posterior fossa malformations

•Hemangioma

•Arterial cerebrovascular anomalies

•Coarctation of the aorta and cardiac defects

•Eye abnormalities

•± Sternal clefting or supraumbilical raphe

Pathology

•Hemangiomas (vascular neoplasm, not malformation)

•Ipsilateral cerebellar hypoplasia

•Posterior fossa cystic lesions (e.g., Dandy-Walker) common

•Arterial stenoses/occlusions, saccular aneurysms, aberrant vessels

Clinical Issues

• Hemangiomas proliferate, then involute

Imaging

•T1 C+ FS MR to delineate hemangiomas

•CTA/MRA to evaluate for vascular anomalies

Differential Diagnosis

The major differential diagnosis of PHACE is Sturge-Weber syndrome (SWS). The facial hemangioma can be (and often is) mistaken for the port-wine stain (nevus flammeus) of SWS. Patients with SWS lack the noncutaneous systemic manifestations of PHACE. The leptomeningeal angioma of SWS appears relatively thin and serpentine, covering the pial surface of the underlying dystrophic cortex, which is shrunken and contains linear calcifications. The intracranial hemangioma

(40-20) (Top) T2WI in a 19y man with ataxia-telangiectasia shows marked cerebellar atrophy , large fourth ventricle . (Bottom) Note severe atrophy, enlarged lateral recesses of the 4th ventricle . The supratentorial brain was entirely normal.

of PHACE usually involves the cavernous sinus and/or cerebellopontine angle, appearing more focal and mass-like.

Ataxia-Telangiectasia

Terminology and Etiology

Ataxia-telangiectasia (AT), also known as Louis-Bar syndrome, is a genetically based multisystem disorder. AT is a rare autosomal-recessive disorder characterized by progressive cerebellar atrophy and ataxia, oculocutaneous telangiectasias, immunodeficiency, radiosensitivity, and predisposition to malignancies. AT is caused by a mutation in the ataxia telangiectasia mutated gene, ATM. ATM mutations cause cells to be driven to oxidative stress and carcinogenesis.

Pathology

The major neuropathologic findings of AT occur in the cerebellum (40-19). The cerebellar hemispheres and vermis show marked atrophy, reflecting the pronounced loss of Purkinje and granule cells that is the pathologic marker of this disease.

At least one-third of all AT patients develop malignancies. The most common cancers in younger patients are lymphomas and lymphoid leukemias. Nonlymphoid epithelial tumors, mainly breast and gastric carcinomas, represent 15-25% of ATrelated neoplasms and develop primarily in adults.

Clinical Issues

AT patients demonstrate heterogeneous clinical manifestations. Mucocutaneous telangiectasis usually begin to appear in early childhood but may be minimal or absent.

Neurologic findings include hyperkinesia, progressive truncal and cerebellar ataxia, dysarthria, oculomotor apraxia, choreoathetosis, and progressive neurodegeneration.

Imaging and Differential Diagnosis

Diagnostic tests involving ionizing radiation should be avoided when possible to minimize the risk of mutations and subsequent tumor development, so MR is the procedure of choice for evaluating the intracranial manifestations of AT.

Initial MR in early childhood is typically normal. By the age of 10 years, cerebellar atrophy is the most consistent finding. The atrophy is initially evident in the vermis and eventually progresses to the cerebellar peduncles and hemispheres (40-20).

Multiple capillary telangiectasias in the cerebral hemispheres, cerebellum, and brainstem can be seen as faint brush-like enhancing foci on T1 C+ scans or multifocal "blooming black dots" on T2* (GRE, SWI) sequences. MRS may show increased Cho in the cerebellum.

The major clinical differential diagnosis of AT is cerebral palsy. Cerebral palsy rarely involves the cerebellum. Serum α-fetoprotein (AFP) is markedly elevated in AT and helps distinguish the disorder.

Unless imaging evidence for multiple cutaneous and/or brain capillary telangiectasias is present, the cerebellar atrophy can be indistinguishable from an ever-growing number of recessive inherited spinocerebellar degenerations with progressive ataxia. In Freidreich ataxia—the most common—the cerebellum is generally normal, whereas the spinal cord and brainstem are atrophic. The pons is typically normal in AT. Elevated Cho on MRS may also help distinguish early AT from other forms of ataxia.

Blue Rubber Bleb Nevus Syndrome

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by multiple venous malformations. BRBNS is caused by a somatic mutation in the receptor tyrosine kinase or TEK, the gene encoding TIE2. TEK is a controller of endothelial cell assembling and remodeling that organizes the vascular network and recruits the perivascular cells necessary for stabilizing vessel walls. The same mutation also occurs in sporadic multifocal venous malformations.

BRBNS usually affects the skin, oral cavity, and gastrointestinal tract. Small raised bluish, compressible rubberor "bleb-like" nevi are the clinical hallmarks of this disorder (40-21).The most common presentation is iron deficiency anemia caused by intestinal bleeding.

CNS lesions occur in 15-20% of cases. Reported imaging manifestations include an extensive network of developmental venous anomalies with or without sinus pericranii (40-22) (40-23).

Wyburn-Mason Syndrome

Wyburn-Mason syndrome, also known as congenital unilateral retinocephalic vascular malformation syndrome, is a rare nonhereditary neurocutaneous syndrome that presents with unilateral AVMs of the brain, orbit, and face. Craniofacial vascular malformations can involve the eyelids and orbits as well as the retina and optic nerve (40-24) (40-25). Lesions range from barely visible to large tangles of dilated, tortuous vessels. Patients with extensive retinal AVMs are at high risk for visual loss, whereas patients with brain AVMs are at risk for parenchymal hemorrhage (40-26).

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(40-21) Photo of a patient with BRBNS shows multiple elevated and bluish skin "blebs" on the foot. (Courtesy AFIP Archives.)

(40-22) Axial cut section through the cerebellum shows multiple developmental venous anomalies (DVAs) characteristic of BRBNS. (R. Hewlett, MD.)

(40-23) (Top) T1 C+ FS scan in a patient with probable BRBNS shows bilateral enhancing DVAs. (Bottom) AP DSA shows bilateral DVAs .