Disorders of Vascularization

Sturge-Weber Syndrome

Synonym

Encephalotrigeminal angiomatosis

Inheritance

Sporadic

Prenatal Diagnosis

None

Incidence

Rare; 2% to 11% of children with facial capillary malformation (0.3% to 0.6% of infants are born with facial capillary malformation) approximately 10% with V₁ distribution; M=F

Age at Presentation

Birth; seizures at 1 to 2 years old

Pathogenesis

Defect in morphogenesis within the cephalic neural crest with subsequent abnormal vasculature in the upper facial dermis, choroid, and pia-arachnoid (mesoectodermal tissue); may be an autosomal lethal mutation surviving by mosaicism

Key Features

Skin

Facial capillary malformation

Trigeminal nerve distribution (V₁ ± V₂, V₃)

Unilateral more common than bilateral

Progressive soft tissue and skeletal hypertrophy beneath malformation

Central Nervous System

Cerebral atrophy

Capillary, venous, and arteriovenous malformations ipsilateral to skin malformation in leptomeninges

Tram-track calcification in temporal and occipital cortex beneath leptomeningeal malformation

Seizures(> 70%), intellectual impairment (50%), hemiparesis, headache

Eyes

Choroid malformation

Ipsilateral glaucoma with secondary buphthalmos, visual loss

Differential Diagnosis

Periorbital hemangioma

Salmon patch

Laboratory Data

Magnetic resonance imaging (MRI) with gadolinium; computed tomography (CT) with contrast

Less than 6 months: positron emission tomography/single-photon emission computed tomography (PET/SPECT) scan may be useful

EEG (if above positive)

Management

Referral to dermatologist—laser treatment of capillary malformation

Referral to ophthalmologist—at presentation to detect and manage glaucoma, preserve vision

Referral to neurologist—seizure control

Referral to orthodontist/oral surgeon-treat complications of maxillary hypertrophy (occlusion deformity, cross-bite), gingival hypertrophy

Prognosis

If seizures are difficult to control, there is an increased frequency of intellectual impairment over time; visual impairment if glaucoma left untreated; normal life span

Clinical Pearls

Having a port wine stain in the distribution of the first branch of the trigeminal nerve is not uncommon; the minority will have Sturge-Weber syndrome … We only perform an MRI scan if the neonate or young infant shows evidence of neurologic disorder, most commonly seizure activity … Atrophic changes may be detected prior to calcifications on MRI … If MRI is initially normal and there is suspicion, I would repeat the scan at 2 to 3 years of age … I get an ophthalmologic examination … Seizures are often controlled at least partially with anticonvulsants, but may require hemispherectomy … Pulsed dye laser can be initiated early for the facial port wine stains. AP

3.1 Unilateral facial capillary malformation overlying marked soft tissue and bony hypertrophy. (1)

3.2. MRI with gadolinium revealing leptomeningeal malformation. (5)

Klippel-Trenaunay Syndrome

Synonym

Angio-osteohypertrophy syndrome

Inheritance

Sporadic

Prenatal Diagnosis

None

Incidence

M > F

Age at Presentation

Birth; capillary malformation first sign

Pathogenesis

Increased vascular supply hypothesized as cause of limb hypertrophy

Key Features

Skin

Capillary malformation involving lower extremity (95%), upper extremity (5%), or combined (15%); unilateral in 85%

Musculoskeletal

Soft tissue, muscle and bony hypertrophy below cutaneous malformation with increased limb length and/or girth; rarely hypotrophic limb, polydactyly, syndactyly

Vascular

Superficial venous varicosities, phleboliths, deep venous malformation, arteriovenous fistulas (Parkes-Weber variant), superficial thrombophlebitis, deep vein thrombosis complicated by pulmonary embolism (rare)

Lymphatic

Lymphatic malformation with/without lymphedema

Differential Diagnosis

Proteus syndrome (p. 106)

Neurofibromatosis l (p. 82)

Maffucci syndrome (p. 118)

Capillary malformation

Laboratory Data

Doppler ultrasound in childhood

MRI, magnetic resonance angiography (MRA), venography, lymphography

Management

Compression wraps (young infant), stockings, pump

Routine measurement of limb length and circumference

Referral to orthopedist—correction of limb length discrepancy

Referral to vascular surgeon—treatment of symptomatic varicosities, arteriovenous fistulas

Referral to laser specialist—pulsed dye laser correction of capillary malformation

Prognosis

Progressive limb hypertrophy after birth-degree of hypertrophy dependent on extent of malformation, lymphedema and presence of A-V fistulas

High-output cardiac failure if A-V fistula untreated

Clinical Pearls

Probably the most useful intervention is the use of a compression garment once hypertrophy and varicosities begin to develop … Practically speaking, compression may be very difficult when you are treating a child wearing diapers … If we see a leg length discrepancy > 1 cm, we will consider a leg lift … Doppler imaging is very useful for following patients, particularly if an A-V fistula is present … Distal foot bacterial infections, paronychias, and warts are very common in a lymphedematous leg … May be confused with Proteus syndrome. AP

3.3. Unilateral capillary malformation overlying massive venous-lymphatic malformation in a newborn. (35)

3.4. Angiography reveals discrete areas of arteriovenous malformation (arrows) in the calf of a patient. (40)

Cobb Syndrome

Synonym

Cutaneomeningospinal angiomatosis

Inheritance

Sporadic

Prenatal Diagnosis

None

Incidence

Rare; spinal arteriovenous malformations (AVMs) more common without skin involvement, M=F

Age at Presentation

Birth; neurologic complications develop in early adulthood

Pathogenesis

Unknown

Key Features

Skin

Posterior thoracic/lumbar/limb vascular lesion in a dermatomal distribution overlying a corresponding segment of spinal cord

Central Nervous System

Fast-flow vascular malformation within the intramedullary (most common) spinal cord with secondary compression/anoxia-secondary pain, weakness, muscle atrophy, and sensation loss below the level of compression; bladder and sphincter dysfunction if malformation extensive; subarachnoid hemorrhage; malformation may involve vertebral body

Differential Diagnosis

Capillary malformation overlying a meningoencephalocele, spinal dysraphism, tethered spinal cord

Laboratory Data

MRI, MRA

Spinal angiography

Management

Referral to neurologist—complete neurologic examination

Referral to neurosurgeon—extirpation of lesion, embolization

Prognosis

Dependent on degree of symptomatology prior to intervention—may be irreversible

3.5. Extensive capillary malformation extending to involve the lumbosacral spine. (41)

3.6. Arteriovenous malformation (arrow) within the spinal cord (^*). (42)

Proteus Syndrome

Synonym

Most likely includes Riley-Smith and Bannayan syndromes

Inheritance

Sporadic

Prenatal Diagnosis

None

Incidence

Rare; M=F

Age at Presentation

Birth; may develop over time

Pathogenesis

Mosaicism for an autosomal lethal mutation in the PTEN tumor suppressor gene has been reported in some patients

Key Features

Skin

Soft, subcutaneous masses (likely lymphatic and venous-lymphatic malformations), lipomas, capillary malformations, linear epidermal nevi, plantar/palmar hyperplasia, varicose veins

Musculoskeletal

Macrocephaly, facial asymmetry, skull hyperostoses, frontal bossing, syndactyly, asymmetric soft tissue and bony hypertrophy of hands, feet, limbs; kyphoscoliosis Reports of cataracts, strabismus, microphthalmos, blindness, testicular tumors, penile hypertrophy

Differential Diagnosis

Klippel-Trenaunay-Weber syndrome (p. 102)

Maffucci syndrome (p. 118)

Neurofibromatosis I (p. 82)

Laboratory data

Bone x-rays/MRI

Management

Referral to plastic surgeon, orthopedic surgeon, physiatrist

Referral to symptom-specific subspecialist

Prognosis

Potential for gross deformity and debilitation exists; malignant potential unknown

3.7. Characteristic plantar hyperplasia. (43)

3.8. Unilateral epidermal nevus with syndactyly and massive soft tissue and bony hypertrophy in a 2-year-old girl. (44)

Beckwith-Wiedemann Syndrome

Synonym

Exomphalos-macroglossia-gigantism (EMG) syndrome

Inheritance

Most cases are sporadic; variety of transmissions described; p57 (KIP2) gene on 11p15.5

Prenatal Diagnosis

Ultrasound—macrosomia, visceromegaly, omphalocele visualized

DNA analysis in familial cases

Incidence

Unknown; M=F

Age at Presentation

Birth

Pathogenesis

Mutation in the p57 (KIP2) gene, a cyclin-dependent kinase inhibitor gene acting as a negative regulator of cell proliferation, leads to overgrowth of organs and increased susceptibility to malignancies

Key Features

Skin

Capillary malformation on mid-forehead, glabella, and upper eyelids extending to nose and upper lip in some cases

Mouth

Macroglossia

Ears

Linear earlobe crease, circular depressions on rim of posterior helices

Viscera

Hepatomegaly, splenomegaly, nephromegaly, pancreatomegaly, cardiomegaly

Omphalocele

Intestinal malrotation

Endocrine

Neonatal hypoglycemia with secondary neurologic sequelae if unrecognized

Musculoskeletal

Somatic gigantism—birth weight and length greater than 90th percentile

Hemihypertrophy (33%)

Neoplasms (10%)

Wilms’ tumor > hepatoblastoma > adrenal cortical carcinoma, rhabdomyosarcoma; increased in patients with hemihypertrophy

Differential Diagnosis

Down syndrome (p. 346)

Mucopolysaccharidoses (p. 318)

Congenital hypothyroidism

Laboratory Data

Blood glucose level

Abdominal and renal ultrasound at 3-month intervals through early childhood

Serum alpha-fetoprotein levels (screen for hepatoblastoma)

Management

Monitor blood glucose in the neonate

Complete physical examination

Referral to pediatric surgeon

Referral to appropriate subspecialist as necessary

Prognosis

Normal intellect as long as hypoglycemia well controlled in the neonate; typically large (approximately 2 standard deviations above the mean) adults leading normal lives; may have shortened life span secondary to neoplasm

3.9. Newborn with omphalocele, macroglossia. (45)

3.10. Open mouth with protruding macroglossia. (46)

Von Hippel-Lindau Syndrome

Inheritance

Autosomal dominant; VHL gene on 3p26-p25

Prenatal Diagnosis

DNA linkage analysis or mutation detection

Incidence

1:50,000-60,000; M=F

Age at Presentation

Usually by the fourth decade of life

Pathogenesis

Mutation in the VHL tumor suppressor gene leads to phenotype

Key Features

Eyes

Retinal hemangioblastomas with secondary visual impairment, blindness if untreated

Central Nervous System

Cerebellar > medullary, spinal cord hemangioblastomas with secondary signs of increased intracranial pressure (i.e., headache, vomiting, vertigo, ataxia, mental changes) or spinal cord compression (loss of sensation, proprioception, spastic paraparesis)

Kidneys

Renal-cell carcinoma, cysts

Endocrine

Pheochromocytoma, pancreatic cysts, adrenal carcinoma

Skin (< 5%)

Capillary malformation—head and neck

Hematologic

Polycythemia secondary to cerebellar hemangioblastoma and renal cell carcinoma production of erythropoietin

Differential Diagnosis

Cerebellar tumors

Laboratory Data

CT/MRI scan of brain/spinal cord

Abdominal CT/MRI scan

Urinary vanillylmandelic acid (VMA) level screen

Serum catecholamine level screen

Complete blood cell count

Management

Referral to ophthalmologist—photocoagulation or cryocoagulation of tumor

Referral to neurosurgeon/neurologist—surgical removal

Referral to urologist—surgical removal

All first-degree relatives: annual retinal examination, neurologic examination, regular screening with brain and abdominal scans, VMA and catecholamine screens

Prognosis

Premature death secondary to progressive growth of central nervous system (CNS) hemangioblastomas or metastatic renal cell carcinoma

Clinical Pearls

This is a progressive, universally fatal disease with death by the fourth decade … Hematuria is a common presenting sign … We screen with a sonogram of the belly, MRI and CT of the brain (to pick up both cerebellar tumors and calcifications), and an eye examination … DNA testing for mutations in the VHL gene is available and indicated for appropriate screening in children of affected patients and for confirmation of diagnosis … Angiography usually performed preoperatively … If kidney involvement, these patients may be candidates for renal transplantation. KH, JW

3.11. MRI shows four enhancing cerebellar hemangioblastomas. (36)

3.12. Retinal hemangioblastoma. (47)

Ataxia-Telangiectasia

Synonym

Louis-Bar syndrome

Inheritance

Autosomal recessive; Ataxia-telangiectasia mutated (ATM) gene on 11q22-23

Prenatal Diagnosis

Amniocentesis: chromosomal breaks in amniocytes

Maternal serum: elevated alpha-fetoprotein levels

Molecular DNA analysis

Incidence

1:30,000-100,000 live births; M=F

Age at Presentation

Ataxia presents initially in second or third year of life when child begins to walk; telangiectasias by 3 to 6 years old

Pathogenesis

ATM gene codes for protein important in DNA repair, especially after ionizing radiation exposure; activates (via phosphorylation) repair mechanism utilizing a p53-dependent pathway that regulates apoptosis and cell cycle arrest; defective cellular and humoral immunity

Progressive depletion of Purkinje cells in the cerebellum

Key Features

Skin

Telangiectasias—bulbar conjunctiva first with subsequent ear, eyelid, cheeks, neck, upper chest, and flexor forearms involvement; progeric facies with decreased subcutaneous fat, atrophy, sclerosis; granulomas, café au lait macules

Hair

Canities

Central Nervous System

Cerebellar ataxia, progressive nystagmus, slurred speech, oculomotor apraxia, growth retardation, intellectual impairment

Sinopulmonary

Recurrent viral or bacterial infections, progressive respiratory impairment

Endocrine

Ovarian dysgenesis, insulin-resistant diabetes

Neoplasms

Lymphoreticular, breast carcinoma (heterozygotes)

Differential Diagnosis

Hereditary Hemorhagic Telangiectasia Syndrome (p. 114)

Generalized essential telangiectasia

Bloom syndrome (p. 234)

Laboratory Data

Increased T-suppressor cells, decreased T-helper cells

Alpha-fetoprotein (AFP) elevated

Immunoglobulin (Ig) A, IgG2, IgE decreased or absent

Management

Evaluate family members for carriers of ATM mutation-increased incidence of breast cancer and lymphoid malignancies (dominant negative missense mutations most closely associated with carrier morbidity)

Referral to hematologist—oncologist-intravenous γ-globulin, malignancy management

Referral to pulmonologist/infectious disease specialist

Referral to neurologist

Avoid x-rays, radiotherapy, bleomycin

Sun avoidance, sunscreen may help prevent progeric changes

Prognosis

Most patients confined to wheelchair by 10 years of age; premature death secondary to lymphoreticular malignancy or infection in the second decade of life

Clinical Pearls

Major caretaker is the neurologist … While patients usually present to neurology initially, I follow a wheelchair-bound 20-year-old patient who developed telangiectasias in the first years of life and did not develop ataxia until 8 years old … While x-irradiation is a problem, patients seem to be UV sensitive as well … We tend to cover them with sunscreen and protective clothing … If radiotherapy used to treat lymphoma, one must use very small fractionated doses … Family members who are carriers are at increased risk of developing malignancies, and may show chromosomal breaks after irradiation … Risk of breast cancer in female heterozygotes is 5 times that of the normal population … Ultrasound and good physical examination are theoretically safer than mammograms for screening these women. AP