Phakomatoses - neurocutaneous syndromes, dysplastic nature
Categories of phakomatoses
  1. Hyperpigmented lesions
    1. Neurofibromatosis
      1. Type I
      2. Type II
      3. Schwannomatosis
    2. Epidermal nevus syndrome
    3. Neurocutaneous melanosis
    4. Incontinentia pigmenti
  2. Hypopigmented lesions
    1. Tuberous sclerosis complex
    2. Incontinentia pigmenti achromians
  3. Angiomatous lesions
    1. Sturge-Weber syndrome
    2. Mafucci’s syndrome
    3. Osler-Weber-Rendu syndrome
    4. Fabry’s disease
  4. Hemiatrophy / hemihypertrophy
    1. Klippel-Trénaunay-Weber syndrome
  5. Retinal involvement
    1. Von Hippel-Lindau disease
    2. Wyburn-Mason syndrome
  6. Connective tissue disorders
    1. Ehlers-Danlos syndrome
    2. Pseudoxanthoma elasticum
    3. Kinky hair syndrome (Menke’s disease)
  7. Other disorders
    1. Ataxia-telangectasia
    2. Cerebrotendinous xanthomatosis
    3. Xeroderma pigmentosum
Neurofibromatosis Type I
Diagnostic Criteria
  1. ≥ 6 café-au-lait macules >5mm (prepubertal) or >15mm (postpubertal) in diameter
  2. ≥ 2 neurofibromas or 1 plexiform neuroma
  3. Freckling in axillary or inguinal region
  4. Optic pathway glioma
  5. ≥ 2 Lisch nodules (iris hamartomas)
  6. Distinctive osseous lesion
    1. sphenoid dysplasia
    2. thinning of long bone cortex w/ or w/o pseudoarthrosis
  7. Diagnosis of NF1 in 1∘relative
  1. Autosomal dominant inheritance, variable expression, 50% new mutations
  2. NF1 gene - chr 17q11.2 - protein neurofibromin
  3. Expressed in Schwann cells, oligodendrocytes, neurons
  4. GTPase-activating protein (GAP) stimulates Ras-GTPase activity
  5. Germline mutation is first “hit”, second “hit” induces cellular proliferation
  6. Additional mutations (e.g. p53 loss) results in malignancy
  7. Variable expression
    1. large deletion - early onset neurofibromas, facial dysmorphism, mental retardation, increased cancer risk
    2. missense/splicing mutation - familial spinal NF (spinal neurofibromas, subcutaneous tumours only, no café-au-lait macules or dermal tumours
    3. somatic mosaicism - germline mosaicism, segmental distribution of findings
  8. Genetic testing to confirm diagnosis if inadequate criteria / unusual presentation, prenatal testing
Skin manifestations
  1. café au lait macules
  2. cutaneous neurofibromas
  3. hypopigmented spots
  4. patchy/diffuse hyperpigmentation
  5. juvenile xanthogranulomas
  6. angiomas
  1. cutaneous neurofibromas
  2. plexiform neurofibromas - grow along nerve and multiple branches
  3. dorsal root / spinal canal in “dumbbell” shape
  4. orbit or limbs (causing deformities)
  5. neurofibromas or ganglioneuromas of GI tract (obstruction, bleeding)
Ophthalmologic features
  1. Lisch nodules - melanocytic hamartomas, from age 6 yrs
  2. Glaucoma - congenital glaucoma (buphthalmos) when neurofibroma involves eyelid
  3. Optic glioma (15% patients) - pilocytic astrocytoma
    1. usually asymptomatic, but can cause decreased visual acuity, visual field defects, precocious puberty
    2. can involve optic nerves, chiasm, optic radiations, hypothalamus
  1. optic pathway gliomas
  2. astrocytoma of cerebrum, brainstem, cerebellum
  3. malignant peripheral nerve sheath tumours (MPNST, 10%)
    1. pain / sudden growth within a preexisting plexiform neurofibroma
  4. leukemia (esp. juvenile myelomonocytic leukemia)
  5. pheochromocytoma
Skeletal effects
  1. macrocephaly
  2. short stature
  3. thoracic scoliosis
  4. bowing of tibia, fibula, and other long bones w/ spontaneous fractures (pseudarthrosis)
Neuro-cognitive effects
  1. learning disabilities in 50%
  2. verbal, nonverbal learning
  3. attention-deficit disorder
  4. hypotonia
  5. mental retardation in 10% (esp. in large deletions)
  6. seizures in 6-10%
  7. abnormal cortical architecture, heterotopias (esp. in those with cognitive deficits)
  8. Unidentified bright objects on T2 (in basal ganglia, brainstem, cerebellum, internal capsule) may be associated with learning disabilites
Vascular anomalies
  1. intimal proliferation, fibromuscular changes in small arteries
  2. renal artery stenosis ➔ hypertension
  3. vascular insufficiency or hemorrhage from arterial wall dissection
  4. stenosis of internal carotid artery ➔ moyamoya ➔ stroke
  5. can be spontaneous or after radiation therapy for brain tumours
  1. neurofibromas, plexiform neurofibromas, MPNST originate from Schwann cells
  2. other features are dysplastic and not proliferative
  1. symptomatic
  2. MRI - guidelines do not recommend routine imaging
Neurofibromatosis Type II
NF1 is peripheral form, NF2 is central form, with vestibular schwannomas.
Schwannomas also occur in other cranial nerves, especially CN5, and spinal nerves.
Dermal schwannomas are plaque-like with hair growth.
Multiple meningiomas and spinal ependymomas.
Posterior subcapsular cataracts or cortical wedge opacities.
Diagnostic criteria
  1. Confirmed NF2
    1. bilateral vestibular schwannomas OR
    2. NF2 in 1∘relative, plus
      1. unilateral vestibular schwannoma before age 30
      2. 2 of: meningioma, schwannoma, glioma, juvenile lens opacity
  2. Presumptive NF2
    1. unilateral vestibular schwannoma before age 30, plus one of
      1. meningioma, schwannoma, glioma, juvenile lens opacity
    2. ≥ 2 meningiomas, plus
      1. unilateral vestibular schwannoma before age 30, OR
      2. one of: meningioma, schwannoma, gliomas, juvenile lens opacity
  3. Manchester criteria
    1. bilateral vestibular schwannomas
    2. 1∘relative with NF2, and unilateral vestibular schwannoma or 2 of meningioma, schwannoma, gliomas, neurofibroma, posterior subcapsular lenticular opacity
    3. unilateral vestibular schwannoma and 2 of meningioma, schwannoma, gliomas, neurofibroma, posterior subcapsular lenticular opacity
    4. ≥ 2 meningiomas, and unilateral vestibular schwannoma or 2 of meningioma, schwannoma, gliomas, neurofibroma, posterior subcapsular lenticular opacity
  1. autosomal dominant, complete penetrance, variable expression, 50% new mutation
  2. NF2 gene - chr 22 - protein schwannomin or merlin
  3. Cytoskeletal protein controlling cell growth, tumour suppressor gene
  4. Missense/splice mutations predict milder disease than deletions
  5. Somatic mosaicism produces localized disease
  1. monitoring for vestibular schwannomas by audiometry and periodic MRI
  2. surgical treatment for symptomatic tumours (or stereotactic radiosurgery)
  3. management must attempt to optimize preservation of hearing
  4. surgical excision of meningiomas
  1. Schwannomas of cranial and spinal nerves, but not the vestibular nerve.
  2. Manifests as pain and nerve compression
  3. Sporadic, rare familial cases are autosomal dominant with incomplete penetrance
  4. Gene is on chr 22 near NF2 locus, but distinct
Tuberous Sclerosis Complex
Multisystem disorder of cellular migration, proliferation, differentiation ➔ hamartomas
Diagnostic criteria
  1. Major features
    1. facial angiofibromas or forehead plaque
    2. nontraumatic ungual or periungual fibroma
    3. hypopigmented macules (> 3)
    4. shagreen patch (connective tissue nevus)
    5. cortical tuber
    6. subependymal nodule
    7. subependymal giant cell astrocytoma (SEGA)
    8. multiple retinal nodular hamartomas
    9. cardiac rhabdomyoma (single or multiple)
    10. lymphangiomyomatosis
    11. renal angiomyolipoma
  2. Minor features
    1. dental pits (>14), randomly distributed
    2. hamartomatous rectal polyps
    3. bone cysts
    4. cerebral white matter radial migration lines
    5. gingival fibromas
    6. nonrenal hamartomas
    7. retinal achromic patch
    8. “confetti” skin lesions
    9. multiple renal cysts
  3. Diagnostic certainty criteria
    1. Definite TSC - 2 major or 1 major + 2 minor features
    2. Probable TSC - 1 major + 1 minor feature
    3. Possible TSC - 1 major or 2+ minor features
  1. autosomal dominant, variable penetrance, 2/3 spontaneous mutation
  2. incidence of 1 in 5800 live births
  3. Two genes (85% of all cases)
    1. TSC1 gene - chr 9q34 - protein hamartin
    2. TSC2 gene - chr 16p13 - protein tuberin - GTPase activating protein
    3. hamartin and tuberin interact as tumour suppressor molecules
    4. loss of heterozygosity found within hamartomas
    5. participate in PI3-kinase-Akt-S6 kinase pathway regulating cell size
    6. tuberin is phosphorylated by Akt
    7. TSC1/TSC2 complex inhibits pathway of mTOR for cell growth
Clinical features
  1. criteria allow diagnosis based on brain or skin findings alone
  2. Epilepsy
    1. epilepsy is most common presenting feature, esp in childhood (80-90% incidence)
    2. infantile spasms in up to 1/3 children with TSC, related to tuber load
      1. 25% of children with IS have TSC
      2. TSC + IS ➔ increased risk of mental impairment
      3. EEG - hypsarrhythmia or modified (70% do not have hypssarhythmia)
    3. other seizure types include tonic, clonic, tonic-clonic, atonic, myoclonic, atypical absence, partial, complex partial. No “pure” absence seizures.
  3. Cognitive and behavioural manifestations
    1. 50% normal intelligence
    2. 50% mild learning disabilities to severe mental retardation
    3. Autism spectrum disorders in 50%
    4. ADHD and related disorders in 50%
    5. Anxiety disorders, depression, mood disorders in adolescence/adulthood
  4. Cutaneous manifestations in 96%
    1. angiofibroma - adenoma sebaceum - age 1-4 years
    2. hypopigmented spots seen on Wood’s lamp (UV light)
      1. polygonal (thumbprint-like)
      2. ash leaf-shaped
      3. confetti-shaped
      4. poliosis - patch of grey/white hair if spot on scalp
    3. Shagreen patch - connective tissue hamartoma
      1. asymmetric on dorsal body, esp. lumbosacral skin
    4. Koenen’s tumours - subungual or periungual fibromas
      1. from adolescence, on toes > fingers
    5. Oral fibromas / papillomas - anterior aspect of gingiva
    6. Dental enamel pits in adults
  5. Renal manifestations
    1. angiomyolipoma - asymptomatic, or flank pain, hemorrhage
    2. renal cysts - polycystic kidney disease gene adjacent to TSC2-tuberin on chr 16
  6. Cardiac manifestations
    1. rhabdomyoma (50-60% incidence) - maximally at birth, spontaneous regression
    2. outflow tract obstruction, valvular dysfunction, dysrhythmias
  7. Pulmonary involvement (only in women!)
    1. lymphangioleimoyomatosis, multifocal micronodular pneumocyte hyperplasia, pumonary cysts in up to 40% women (often asymptomatic)
  8. Visual involvement
    1. retinal hamartomas in 50% patients
    2. nodular (mulberry) tumour of optic nerve head
    3. iridic pigmentary changes, colobomas
  9. Other hamartomas
    1. stomach, intestine, colon, pancreas, liver, bone (usually asymptomatic)
  10. Brain hamartomas
    1. Cortical tubers - in cortex, subcortical white, usually grey-white junction. Contain giant cells (large, bizarre neurons)
    2. Subependymal nodules - walls of lateral ventricle (astrocytes) often in caudothalamic groove near the foramen of Monro (from germinal matrix)
    3. Subependymal giant cell astrocytomas (5-10%) result in increased ICP, behavioural change, or seizures
Clinical testing
  1. MRI and CT brain - for diagnosis (T1, T1, FLAIR)
    1. neonates - tubers T1 bright, T2 dark
    2. post-myelination - tubers T1 isointense, T2 bright
  2. Testing at diagnosis
    1. MRI brain
    2. Neuropsych testing (also at school entry)
    3. EEG (if seizures)
    4. Ophthalmology
    5. Echo, EEG
    6. Renal U/S
    7. Chest CT (at onset of adulthood in women)
  3. Annual testing (1-3 years)
    1. MRI brain until age 20
    2. Renal ultrasound
  1. Regular follow-up for anticipatory guidance, counselling, and early treatment
  2. vigabatrin particularly effective for infantile spasms
  3. epilepsy surgery for pharmacoresistant epilepsy
Sturge-Weber syndrome (encephalofacial angiomatosis)
Facial angioma (port-wine stain, nevus flammeus) + ipsilateral leptomeningeal angioma
Clinical features
  1. angiomas of leptomeninges and ipsilateral skin of face (esp V1 and V2 distribution)
  2. can extend to nasopharynx, mucous membrane, ocular choroidal membrane
  3. results in glaucoma in 25%
  4. ocular symptoms - iridic heterochromia, strabismus, optic atrophy, dilated retinal veins
  5. leptomeningeal angioma usually parietal-occipital, also temporal or bilateral
  6. intracranial calcifications typically serpentine (“tram-track sign”) 90% by adulthood
  7. seizures in 75-90%
    1. hypothesized to be due to cortical irritability from regional hypoxia, ischemia, gliosis, or associated cortical dysgenesis
    2. usually partial motor (40%), also 1∘or 2∘GTC, often refractory
    3. surgical - focal resection, hemispherectomy, corpus callosotomy
  8. contralateral hemiparesis in 33%
    1. can be from ischemia and venous congestion
  9. developmental delay and mental retardation in 50-60%
  10. vascular headaches, migraine-like in 60%
  11. EEG - decreased amplitude over affected hemisphere, MISF
  12. Hemianopsia in 25-50% patients
  13. Glaucoma (either side) in 1/3, half of those have buphthalmos (ipsilateral)
  1. CT for calcifications, MRI for cortical abnormalities, contrast for vasculature
  2. Angiogram for decreased cerebral venous drainage, dilatation of deep cerebral veins
  3. serial PET for monitoring metabolic impairment
  1. thought to be caused by residual embryonal blood vessels affecting the surrounding tissues (vascular plexus around cephalic portion of neural tube under facial ectoderm formed at wk6, resorbed by wk9)
  2. meningeal vessels are small and tortuous, rarely enter brain parenchyma
  3. calcification of small cerebral vessels and underlying pyramidal and molecular cell layers
  1. management of seizures and headaches
  2. if refractory, consideration for epilepsy surgery
  3. laser therapy for facial angioma, best done as early as possible
  4. glaucoma treatment
Von Hippel-Lindau disease
Disorder of capillary hemangioblastomas - retinal, cerebellar, spinal
Cystic tumours of pancreas, kidney, epididymis
Renal cell carcinoma
Clinical features
  1. Reinal hemangioblastoma - earliest manifestation, usually 3rd decade
    1. aneurysmal dilatation of peripheral retinal vessel, increased tortuosity
    2. small elevated retinal lesions
    3. fluorescein angiography can help identification
    4. accumulation of fluid behind retina - retinal detachment, progressive visual loss
  2. Cerebellar hemangioblastomas (also medulla, spinal cord, rarely cerebrum)
    1. usually 3rd decade, rarely children
    2. symptoms of posterior fossa space-occupying lesion
    3. medulla / spinal cord ➔ syringomyelia
    4. rare involvement of pituitary gland, 3rd ventricle, cerebrum
  3. Renal lesions
    1. benign cysts, hemangiomas, adenomas, malignant hypernephromas
    2. unilateral, bilateral, or multiple - can mimic polycystic kidney disease
    3. renal cell carcinoma
  4. Elevated RBC count, hematocrit due to erythropoetin activity of cerebellar hemangioblastoma or malignant hypernephroma cysts
  5. Elevated epinephrine and vanillylmandelic acid (VMA) in pheochromocytoma
  1. autosomal dominant, near complete penetrance
  2. von Hippel-Lindau gene - chr 3p25-26 - tumour suppressor
  3. protein regulates a cellular system that senses and responds to hypoxia
Maffucci’s syndrome
Rare, sporadic, congenital disease with multiple enchondromas and 2∘hemangiomas, phlebolithiasis, bony malformations. Occasional associated skin changes, with vitiligo, café au lait spots, hyperpigmented patches and nevi.
Ollier’s disease - multiple endochondromas without hemangiomas
PTH/PTHrp type I receptor gene mutation in endochondromatosis
Neurologic complications from cerebral encroachment by cranial osteochondromas or primary brain tumours.
Epidermal nevus syndrome
Heterogeneous group of sporadic disorders with patchy cutaneous hamartomatous lesions, CNS abnormalities, and other manifestations.
  1. Nevi can be verrucous, sebaceous, lentiginous
  2. Nevi follow Blaschko’s lines, some may involve somatic mosaicism
  3. CNS - lissencephaly, paucity of white matter, heterotopic grey matter, schizencephaly, unilateral colpocephaly, megalencephaly. Mental retardation, seizures, ocular abnormalities, corticospinal tract dysfunction
Sebaceous nevus syndrome (Schimmelpenning’s syndrome)
  1. congenital sebaeous nevus, neurologic dysfunction, skeletal, ocular anomalies
  2. sporadic
Nevus comedonicus syndrome
  1. congenital hyperkeratotic papules of follicular origin, ipsilateral eye/skeletal defects, seizures, mental retardation
  2. sporadic
Becker nevus syndrome
  1. hyperpigmented plaque with hair growth, smooth muscle hyperplasia, rib defects, breast hypoplasia
  2. sporadic, more in males
Phakomatosis pigmentokeratotica
  1. sebaceous and speckled lentiginous nevus, ipsilateral weakness, hypohidrosis, seizures, mental retardation
  2. sporadic
Proteus syndrome
  1. epidermal nevi, asymmetrical overgrowth of soft tissue and bone
  2. sporadic, PTEN mutations
Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD)
  1. ichthyosiform nevus, skeletal aplasia/hypoplasia, abnormalities in brain, lung, heart, kidneys
  2. X-linked dominant, mutation in 3β-hydroxysteroid dehydrogenase gene
Parry-Romberg Syndrome (Facial hemiatrophy)
  1. progressive loss of facial soft tissue, cartilage, and bone
  2. atrophy ceases by around 30 years
  3. recurrent headaches, ipsilateral Horner’s, contralateral partial seizures, hemiparesis
  4. rare association with multiple benign tumours
Neurocutaneous melanosis
Rare, nonfamilial condition with abnormally pigmented cutaneous areas (giant hairy pigmented nevi, multiple hyperpigmented cutaneous nevi, large congenital melanocytic nevi) and leptomeningeal melanoma.
Symptoms include hydrocephalus, behavioral abnormalities, seizures.
CSF high protein, low glucose, cytology includes melanin-containing cells.
Poor prognosis, death by age 20.
Klippel-Trélaunay-Weber syndrome
Cutaneous/subcutaneous hemangiomas, varicosities, hypertrophy of soft tissues and bone of a limb.
Macrocephaly, hydrocephalus, lymphangiomas, hemangiomas of the trunk, intenstine, and bladder, abnormalities of digits.
Sporadic mutation in VG5Q gene involved in angiogenesis.
Incontinentia pigmenti (Bloch-Sulzberger syndrome)
X-linked dominant trait affecting only females (male lethal) in NEMO gene (chr Xq28) which participates in NF-κB signaling pathway. Eosinophil-selective chemokine (eotaxin) found in blister fluid. Diagnosis by skin biopsy for histology. MRI/MRA for infarcts, small vessel disease. Genetic testing for NEMO gene.
Hyperpigmented lesions, abnormalities in CNS, eyes, hair, teeth, and bone.
Skin manifestation:
  1. 1.Vesiculobullous lesions from birth-weeks following Blaschko lines, containing eosinophilia. Lesions rupture, ooze, and crust for up to 4 months.
  2. 2.Verrucous lesions from 6th week of life. Hyperpigmented, hyperkeratotic papules.
  3. 3.Hyperpigmented brown/grey macular lesions (streaks or whorls) become prominent in first few years then fade, sometimes disappears through adolescence.
Neurologic manifestations:
  1. developmental retardation (15% sporadic cases, 3% familial cases)
  2. spasticity, delayed motor development
  3. seizures (infantile spasms)
  4. ataxia
  5. microcephaly, hydrocephalus, dysgenesis of corpus callosum
  6. recurrent encephalomyelitis
  7. ocular abnormalities - retinal pigmentation, nystagmus, strabismus, cataracts, visual loss, retinal detachment, fibrovascular retrolental membrane
  8. pathology - polymicrogyria, neuronal heterotopia, neuronal loss
Ophthalmologic findings:
  1. cataracts, keratitis, strabismus, nystagmus, uveitis, retinal pigment epithelial abnormalities, foveal hypoplasia, vitreous hemorrhage, optic atrophy
  2. retinal ischemia most common, can progress to scarring or retinal detachment
  3. serious visual impairment in 43%
Other lesions:
  1. delayed / absent / abnormal teeth (peg-shaped, cone-shaped) w/ normal enamel
  2. alopecia, coarse wiry hair near vertex
  3. nail dystrophy (ridging, pitting, onychogryposis)
  4. painful subungula hyperkeratotic tumors of phalanges
  5. supernumerary nipples, breast hypoplasia
Incontinentia pigmenti achromians (hypomelanosis of Ito)
Congential hypopigmented streaks or whorls following lines of Blaschko.
CNS manifestations:
  1. mental retardation, language disabilities, seizures, motor dysfunction
  2. white matter signal abnormalities in parietal, periventricular, subcortical regions
Ocular abnormalities:
  1. strabismus, epicanthal folds, myopia, optic nerve hypoplasia, fundus hypopigmentation
  2. rarely corneal asymmetry, pannus, atrophic irides and irregular pupillary margins, cataracts, retinal detachment
Sporadic, mosaicism - sometimes hypopigmented, sometimes hyperpigmented
Wyburn-Mason syndrome (Retinocephalic angiomatosis)
Unilateral AV malformation of retina, brain, face, head. Esp. with tortuous angioma of the fundus. Retinal lesions usually unilateral optic atrophy
Also known as Bonnet-Dechaum-Blanc syndrome or retinocephalic vascular malformation.
Ehlers-Danlos syndrome
At least 10 subtypes with different inheritance and gene defects.
Characterized by fragile / hyperelastic skin, hyperextensible joints, vascular lesions, easy bruising, and excessive scarring after injury.
Neurologic manifestations of peripheral neuropathy, aneurysm, and arterial dissection.
> 80% patients - Type I, II, or III
Neurovascular complications in Type IV - COL3A1 gene - Chr 2 - type III collagen
Intracranial aneurysm
  1. Most commonly internal carotid artery within (or just after) cavernous sinus
  2. Spontaneous rupture or with vigorous activity
  3. Other vessels also involved - subarachnoid hemorrhage
Carotid-cavernous fistula
  1. usually spontaneous, sometimes minor head trauma
  2. symptoms - propotosis, chemosis, diplopia, pulsatile tinnitus
  3. can occur from ICA aneurysm or without
Arterial dissection
  1. intracranial and extracranial arteries
  2. surgery difficult as arteries are friable an difficult to suture
Pseudoxanthoma elasticum
Skin, ophthalmic, vascular manifestations.
Autosomal dominant or recessive forms - ABCC6 gene - chr 16p13.1 - ATP-binding cassette, subfamily C, member 6 - same gene in all cases
Skin findings
  1. yellow plaques or papules on neck, axilla, abdomen, inguinal, decubital, popliteal
  2. mucous membranes, intestinal mucosa
  3. lax redundant cutaneous changes with age
  4. pregnancy, puberty, emotional stress increases rate of progression
Vascular effects
  1. occlusive / hemorrhagic vascular complications in adulthood
  2. angioid streaks of ocular fundus, ruptures of Bruch’s membrane
  3. gradual visual loss from macular degeneration or acute from retinal hemorrhage
  4. progressive occlusion of large arteries, calcification - intermittent claudication, GI hemorrhage, epistaxis, hematuria, hemoptysis
Neurological effects
  1. arterial occlusion or rupture, or from systemic HTN, CV disease
  2. angiographic pattern of severe artherosclerosis
  3. can occur slowly and result in sufficient collateral flow
Osler-Weber-Rendu syndrome
Hereditary hemorrhagic telangiectasia (HHT)
  1. HHT1 gene - chr 9q33-34 - endoglin - TGF-β binding protein
  2. HHT2 gene - chr 12q13 - activin receptor-like kinase
  3. 30% spontaneous mutations
  4. variable expression
Clinical features
  1. cutaneous telangiectasias on face, lips, hands, trunk
  2. nasal mucosa telangiectasia - epistaxis
  3. conjunctival telangiectasias, retinal vascular malformation
  4. telangiectasias not prominent in 1st decade, but progressive
  5. involvement of lungs, GI, GU causing bleeding
Neurologic features
  1. headache, dizziness, seizures
  2. cerebral infarcts from paradoxical embolism from pulmonary AV fistulae
  3. TIAs during hemoptysis from air emboli
  4. cerebral abscess or meningitis from septic microemboli bypassing pulmonary filtration
  5. multiple cerebrovascular malformations (AVMs >>> aneurysms)
Fabry’s disease
Angiokeratoma corporis diffusum
X-linked - minimal penetrance in females, complete penetrance in males
lysosomal storage disease - α-galactosidase A deficiency
diagnosis by enzyme analysis of cultured leukocytes or fibroblasts
Clinical features
  1. dark red / purple papules in clusters around umbilicus, buttocks, scrotum, hips, thighs
  2. lesions grow with age, but asymptomatic
  3. Ocular effects usually do not affect vision:
    1. whorl-like pattered corneal deposits
    2. anterior capsule deposits
    3. abnormalities in conjunctival vessels
  4. Temperature-sensitive painful dysesthesias of limbs (from 1st decade)
    1. sensory neuropathy, loss of small myelinated and unmyelinated nerve fibers and small cell bodies of spinal ganglia, glycolipid inclusion granules in cytoplasm of perineural and vascular endothelial cells
  5. Vascular changes from glycolipid in arterial endothelium and vascular smooth muscle narrowing / occluding lumen
    1. renal failure in early adulthood
    2. cerebral thrombosis / hemorrhage (cerebral > brainstem)
  1. infusion of deficient enzyme or plasmapheresis to decrease ceramide trihexoside level not helpful
  2. renal transplantation alleviates renal failure and provides enzyme activity
  3. carbamazepine or phenytoin for painful paresthesias
  4. bone marrow transplant may be helpful
Slowly progressive ataxia from early childhood.
Later developing telangiectasias, immunodeficiency, and sensitivity to ionizing radiation
Autosomal recessive - ATM gene - chr 11q22-23 - PI3-kinase involved in cell-cycle progresion and checkpoint response to DNA damage
Skin manifestations
  1. telangiectasias - sclerae, earlobes, bridge of nose common. Eyelids, neck, antecubital / popliteal fossae rare - develop by age 3-6 years
  2. hypertrichosis esp of forearms
  3. progeric features of poikiloderma, loss of subcutaneous fat, sclerosis
  4. basal cell carcinoma in young adults
  5. cutaneous granulomas assoc w/ SCID and X-linked hypogammaglobulinemia
Neurologic manifestations
  1. truncal ataxia noted when child begins to walk
    1. normal strength and early motor milestones
    2. progressive - wheelchair bound by age 12
  2. limb ataxia, intention tremor, segmental myoclonus, choreoathetosis, progressive finger dystonia (2-3rd decade)
  3. oculomotor apraxia
    1. nystagmus
    2. apraxia of voluntary gaze
    3. disorder of smooth pursuit
    4. limitation of upgaze
    5. transient strabismus
  4. progressive neuropathy
    1. progressive distal muscle atrophy and fasciculations
    2. gradual loss of vibration / proprioception (dorsal columns)
    3. peripheral polyneuropathy
  5. nonprogressive cerebellar atrophy
  6. degeneration of substantia nigra, brainstem nuclei, spinal cord in adults
Immunological / neoplastic features
  1. 10-15% lymphoid malignancy by early adulthood (T-cell > B-cell)
  2. many neoplasms increased
  3. increased sinopulmonary infections
Laboratory testing
  1. elevated α-fetoprotein in 80%
  2. decreased serum IgA, IgE, IgG
  3. early diagnosis and screening for leukemia / lymphoma
Kinky hair syndrome (Menke’s disease)
X-linked disorder of connective tissue and neuronal metabolism due to inborn error of copper metabolism
  1. ATP7A gene - chr Xq13.3 - P-type ATPase - transmembrane copper transport protein
  2. large deletion ➔ Menke’s
  3. promoter / splice mutation ➔ occipital horn syndrome (Ehler’s Danlos type IX, X-linked cutis laxa - prominent cutaneous features)
  4. ATP7B ➔ Wilson’s disease
  5. expressed in many cell types, but not liver
  6. cuproenzymes affected - tyrosinase, cytochrome C oxidase, dopamine β-hydroxlyase, Cu/Zn superoxide dismutase
Clinical features
  1. prematurity, low birthwt, neonatal jaundice, temperature instability, chronic diarrhea
  2. hypotonia progressing to spastic quadriplegia
  3. deafness, decreased facial expression, prominent forehead, full cheeks, narrow palate
  4. hypopigmented skin, cutis laxa, pili torti, joint laxity, inguinal hernia, bladder diverticula
  5. hepatomegaly
  6. pectus excavatum, Wormian skull bones, metaphyseal spurring of long bones
  7. ataxia, seizures (esp myoclonic), intracranial hemorrhage
  8. cerebellar / cerebral atrophy, white matter abnormalities, subdural fluid collections, dilated / tortuous intracranial / extracranial blood vessels, cerebral edema
  1. attempting to restore normal copper levels in brain and other tissues
  2. copper-histidine S/C improves in specific mutations
Cerebrotendinous xanthomatosis
Autosomal recessive disorder
CYP27 gene - sterol 27-hydroxylase - bile acid synthesis - accumulation in cholestanol (and cholesterol), esp Achilles tendon, brain, lungs
Tendon xanthomas, cataracts, progressive neurological deterioration
Elevated cholestanol in serum and tissue, decreased bile production. Normal serum cholesterol levels.
Neurologic features
  1. Progressive dementia
  2. Bulbar symptoms, palatal / pharyngeal myoclonus
  3. Hyperreflexia / loss of reflexes, peripheral neuropathy, pes cavus deformities
  4. Ataxia, nystagmus, dysarthria, Parkinsonism
  5. EEG abnormalities, cerebral / cerebellar atrophy
  6. Cataracts
Behavioral abnormalities
  1. personality changes, irritability, agitation, aggressiveness, paranoid ideation, auditory hallucinations, catatonia
  1. xanthomas after age 10, especially Achilles tendon
  2. osteoporosis and bone fractures
  3. large paranasal sinuses
Renal disorders
  1. nephrolithiasis
  2. nephrocalcinosis
  3. renal tubular acidosis
  1. lowering cholestanol with chenodeoxycholic acid or other lipid-lowering agents
  2. improve xanthomas and peripheral nerves, but not neuroradiology
Xeroderma pigmentosum
Autosomal recessive susceptibility to sun-induced skin disorders
Variable / progressive neurological deterioration
Studied using complementation groups, where 2 abnormal cells fuse to form a normal cell to determine genetics.
Eight groups described:
  1. 1.XP-A - XPAC gene - in Japan - chr 9q34 - nucleotide excision repair
  2. 2.XP-B - XPBC gene - rare - chr 2q21 - TFIIIH/BTF2 subunit (DNA transcription/repair)
  3. 3.XP-C - XPCC gene - non-neuro - chr 3p25.1 - global gene repair
  4. 4.XP-D - XPDC gene - mild-severe neuro - chr 9q13 - TFIIH/BTF2 subunit (like XP-B)
  5. 5.XP-E - XPEC gene - mild neuro - not localized
  6. 6.XP-F, XP-G , variant group - non-neuro
Related syndromes
DeSanctis-Cacchione syndrome - progressive cognitive deficiency, dwarfism, gonadal hypoplasia
Trichothiodystrophy - XP-B/D - brittle hair/nails, ichthyosis, mental retardation
PIBI(D)S syndrome - Photosensitivity, Ichthyosis, Brittle hair, Impaired intelligence, Decreased fertility, Short stature (XP-D)
Tay’s syndrome - dysplastic nails, lack of subcutaneous fatty tissue, low birthwt, short stature, mental retardation
Cockayne’s syndrome - XP-B/D/G
Cutaneous features
  1. sunlight sensitivity, freckling
  2. atrophy, xerosis / scaling, telangiectasia
  3. actinic keratosis, angioma, keratoacanthoma, fibroma
  4. malignant tumours, basal cell carcinoma, squamous cell carcinoma, melanoma, fibrosarcoma
Ocular findings
  1. eyelids - atrophy, loss of lashes, ectropion, entropion, neoplasm
  2. conjunctiva - conjunctivitis, pinguecula, pigmentation, telangiectases, dryness, symblepharon, inflammatory nodules, neoplasm
  3. cornea - exposure keratitis, corneal clouding, dryness, ulceration, scarring, vascularization, neoplasm
  4. iris - iritis, synechiae, atrophy
Neurologic findings (based on XP-A studies)
  1. severity correlates with mutation
  2. progressive dementia, sensorineural hearing loss, tremor, choreoathetosis, ataxia
  3. begins in preschool years
  4. microcephaly in 50%
  5. EEG generalized slowing or focal slow wave / spike discharges
  6. peripheral neuropathy from 1st decade, absent DTRs / delayed NCS after age 6 yrs
  7. EMG, nerve biopsy shows loss of myelinated fibres / neuropathic process