= TSC = BOURNEVILLE DISEASE = EPIPLOIA

[Désiré-Magloire Bourneville (1840–1909), French neurologist at Salpêtrière, Bicêtre, Hôpital Saint-Louis, Pitié]

= autosomal-dominant neuroectodermal disorder characterized by multifocal systemic hamartomas + malformations that may affect CNS, eye, kidney, lung, liver, skin, heart with a spectrum of phenotypic expressions

CLASSIC TRIAD (of Vogt, 1908) in only 29% of patients:

1. Facial angiofibromas
2. Epileptic seizures
3. Mental retardation

mnemonic: zits, fits, nitwits

Prevalence: 1÷6,000 to 1÷150,000 live births

• family history of TSC in 25–50%

Cause: autosomal-dominant germ line mutation inhibiting cell proliferation with low penetrance (frequent skips in generations); sporadic mutations in 50–60–80%

Genetics: gene mutations of

1. TSC1 on chromosome 9q34 → protein hamartin
2. TSC2 on chromosome 16p13 → protein tuberin

Dx:

1. Major features
   1. Cortical / subcortical tubers
   2. Subependymal giant cell astrocytoma
   3. Cardiac rhabdomyoma
   4. Facial angiofibroma
   5. Retinal hamartoma
   6. Renal angiomyolipoma
   7. Shagreen patches
   8. Ash-leaf spots
   9. Lymphangioleiomyomatosis
2. Minor features
   1. Gingival fibroma
   2. Dental pits
   3. Hamartomatous rectal polyps
   4. Renal cysts
   5. Cerebral white matter migration lines
   6. Confetti skin lesions
   7. Bone cysts

A diagnosis is definite with 2 major / 1 major + 2 minor features!

Prognosis: 30% dead by age 5; 75% dead by age 20

Rx: antiepileptic medication; ketogenic diet

• CNS INVOLVEMENT (>95%)
  • intractable myoclonic seizures (75–80%): often first and most common sign of tuberous sclerosis with onset at 1^st–2^nd year, decreasing in frequency with age
  • mental retardation (50–82%): moderate to severe cognitive deficits (⅔), mild to moderate (⅓); progressive; observed in adulthood; common if onset of seizures before age 5 years
  • autism, behavioral + sleep + psychiatric disorders
  1. Subependymal hamartomas
     Location: along ventricular surface of caudate nucleus, on lamina of sulcus thalamostriatus immediately posterior to foramen of Monro (most often), along frontal + temporal horns or 3^rd + 4^th ventricle (less commonly)
     • multiple subependymal nodules of 1–12 mm:
       • “candle drippings” appearance
     • periventricular calcification with increasing age (in up to 88%)
     
     MR:
     • subependymal nodules protruding into adjacent ventricle isointense with white matter
     • iso- to hyperintense on T1WI + hyper- and hypointense on T2WI relative to gray and white matter
     • minimal contrast enhancement (in up to 56%)
  2. Giant cell astrocytoma (in 15–20%)
     = SUBEPENDYMAL GIANT CELL TUMOR (SGCT)
     Incidence: 5–15%; M÷F = 1÷1
     Mean age: 11 years (range, birth to 5^th decade); typically <20 years
     Origin: ? subependymal nodule
     Histo: low-grade astrocytoma (WHO grade I lesion) with large cells resembling astrocytes / ganglion cells with abundant cytoplasm
     Immunohisto: markers for both glial + neuronal proteins
     Location: in the region of foramen of Monro; uncommonly in other locations
     • well-circumscribed solid intraventricular neoplasm
     • typically >13 mm in diameter with interval growth
     • ± variable degrees of calcification ± cystic changes
     • uniform avid enhancement
     • frequent extension into frontal horn / body of lateral ventricle
     • occasionally hemorrhagic
     
     CT:
     • hypo- / isodense well-demarcated round mass
     
     MR:
     • hypo- to isointense to gray matter on T1WI
     • iso- to hyperintense to gray matter on T2WI
     
     Prognosis: tendency to enlarge + growth into ventricles → obstruction at foramen of Monro → progressive obstructive hydrocephalus
     Cx: degeneration into higher grade astrocytoma
     Surveillance: imaging every 2 (3) years with TSC2 (TSC1) mutation; once identified follow-up imaging at yearly intervals
     Subependymal GCT is considered PATHOGNOMONIC for TS (rare without manifestations of TS, then likely representing somatic mosaicism of the TS gene)
  3. Cortical / subcortical tubers (in 56%)
     = CORTICAL / SUBCORTICAL HAMARTOMAS
     Histo: clusters of atypical glial cells surrounded by giant cells with frequent calcifications (if >2 years of age)
     Frequency: multiple (75%); bilateral (30%)
     • large misshapen broadened gyri with central hypodense regions ← abnormal myelination
     • masslike / curvilinear calcification of cortical tubers (in 15% <1 year of age, in 50% by age 10)
     
     MR:
     • relaxation time similar to white matter (if uncalcified)
     • multiple nodules hyperintense on T2WI / FLAIR + iso- to hypointense on T1WI ← fibrillary gliosis / demyelination
     • enhancement extremely rare
  4. Heterotopic gray matter islands in white matter
     Histo: grouping of bizarre and gigantic neuronal cells associated with gliosis + areas of demyelination
     Frequency: in up to 93%
     Location: along lines of neuronal migration
     • straight / curvilinear bands extending radially from ventricular wall
     • wedge-shaped lesion with apex at ventricular wall
     • conglomerate masses
     • calcification of all / part of nodule
     • may show contrast enhancement
     
     CT:
     • hypodense well-defined regions within cerebral white matter
     
     MR:
     • iso- to hypointense region on T1WI + well-defined hyperintense area on T2WI relative to normal white matter

DDx of CNS lesions:

1. Intrauterine CMV / Toxoplasma infection (smaller lesions, brain atrophy, microcephaly)
2. Basal ganglia calcification in hypoparathyroidism / Fahr disease (different location)
3. Sturge-Weber, calcified AVM (diffuse atrophy, not focal)
4. Heterotopic gray matter (along medial ventricular wall, isodense, associated with agenesis of corpus callosum, Chiari malformation)
5. Focal cortical dysplasia
6. Subependymal heterotopia

• SKIN INVOLVEMENT (90%)
  • Facial angiofibroma (former misnomer: adenoma sebaceum) in 80–90%
    Path: small hamartomas from neural elements with blood vessel hyperplasia = angiofibromas
    Age: first discovered at age 1–5 years; family history in 30%
    • wartlike nodules of red-brown / red color averaging 4 mm in size with tendency to enlarge + increase in number over time
    
    Location: CHARACTERISTIC bimalar distribution (“butterfly rash”); initially nasolabial folds, eventually covering nose + middle of cheeks
  • Ungual fibroma = Koenen tumor (15–50%)
    Age: develop in adolescent / adult
    Location: sub- / periungual region of toes
    • erosion of distal tuft
  • Shagreen rough skin patches (80%)
    = “pigskin” = “peau d'orange”
    Histo: connective tissue nevus (collagenoma) = patches of fibrous hyperplasia
    • irregularly shaped skin-colored / brown soft plaque
    
    Age: early childhood
    Location: posterior trunk / buttocks + intertriginous
  • Ash leaf patches = hypomelanotic / hypopigmented macules shaped like ash / spearmint leaf
    • may be visible only under ultraviolet light
    
    Age: typically present at birth, persist throughout life
    Location: trunk, lower extremity
  • “Thumbprint” / “confetti” macules
  • Café-au-lait spots
    Incidence: similar to that in general population
    DDx: neurofibromatosis type 1, fibrous dysplasia
  • Fibrous forehead plaques
• OCULAR INVOLVEMENT (50%)
  • Phakoma (>5%) = whitish disk-shaped retinal hamartoma
    = astrocytic proliferation in / near optic disc, plaques often multiple + usually in both eyes
  • small calcifications in region of optic nerve head
  • optic nerve glioma
• RENAL INVOLVEMENT (70–90%)
  • usually asymptomatic; flank pain, hematuria, hypertension
  • renal failure in severe cases (5%) ← mass effect of cysts and angiomyolipomas
    • 75% of patients die from complications of renal failure by age 20
  1. Angiomyolipoma (55–89%): usually multiple
     Cx: spontaneous retroperitoneal hemorrhage (subcapsular / perinephric) → shock
  2. Multiple cysts of varying size in cortex + medulla mimicking adult polycystic kidney disease (15%)
     Path: cysts lined by columnar epithelium with foci of hyperplasia projecting into cyst lumen
     • polycystic involvement in infants
  3. Renal cell carcinoma / Malignant epithelioid form of angiomyolipoma (1–3%), bilateral in 40%;
     Average age: 28 years (= 25 years younger than for RCC in general population)
     • rapid growth + presence of calcifications
     
     Recommendation:
     • US evaluation every 2–3 years before puberty + yearly thereafter to identify growing lesions
• LUNG INVOLVEMENT (1–4%)
  Age: 3^rd–5^th decade; in women
  • progressive respiratory insufficiency
  • interstitial fibrosis in lower lung fields + miliary nodular pattern may progress to honeycomb lung (lymphangioleiomyomatosis = smooth muscle proliferation around blood vessels)
  • multiple bilateral small cysts in lung parenchyma on CT (26–39%)
  • repeated episodes of spontaneous pneumothorax (50%)
  • chylothorax
  • cor pulmonale
• HEART INVOLVEMENT in children
  Prevalence: decreases with increasing age ← spontaneous tumor regression + better survival of patients without cardiac tumor
  • congenital cardiomyopathy; typically clinically silent
  • circumscribed / diffuse subendocardial rhabdomyoma (in 5–30%) of ventricle (70%) / atrium (30%)
  • aortic aneurysm
• BONE INVOLVEMENT
  • bone cysts with undulating periosteal reaction in distal phalanges (most common), metacarpals, metatarsals of hand (DDx: sarcoidosis, neurofibromatosis)
  • “bone islands”:
    • dense sclerotic calvarial patches (45%)
      Location: frontal and parietal diploe + internal table; pelvic brim, vertebral neural arch, long bones
  • bone thickening:
    • thickening of diploe ← long-term phenytoin therapy
    • expansion + sclerosis of rib (may be isolated)
    • periosteal thickening of long bones
  • dysplasia of sphenoid body (DDx: NF1 with dysplasia of sphenoid wing)
• OTHER VISCERAL INVOLVEMENT
  1. Adenomas + lipomyomas of liver
  2. Adenomas of pancreas
  3. Tumors of spleen
• VASCULAR INVOLVEMENT (rare)
  • thoracic + abdominal arterial aneurysms
    Path: vascular dysplasia with intimal + medial abnormalities of large muscular + musculoelastic arteries

Prognosis: 75% mortality by 20 years