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Tuberous sclerosis ( epiloia )


DEFINITION:

A neurocutaneous syndrome characterized by cutaneous and neurologic manifestations (mental retardation and seizures), and tumors.

EPIDEMIOLOGY:

  • incidence: 1/30,000
  • age of onset:
    • 1st decade
  • risk factors:
    • familial - autosomal dominant with variable penetrance
      • chrom.#: 9q33-34 (Type 1)
        • ?11q23 (Type 2)
        • ?12q23.3 (Type 3)
        • 16p13 (Type 4)
    • if 2 or more siblings with Tuberous Sclerosis (TS) then one parent always has at least one skin manifestation of TS
    • sporadic rate varies from 58-77%
    • if both parents are normal the TS in a child is probably a new mutation

HISTORY:

1880-1900 - Bourneville and Brissaud

    • first pathologic description of TS
    • first to call the disease tuberous sclerosis
    • first to relate cerebral sclerosis to the renal tumors

1908 - Vogt

    • emphasized association of adenoma sebaceum & cerebral sclerosis
    • emphasized cardiac and renal tumors are constituents of TS
    • triad: mental retardation (MR), seizures, adenoma sebaceum

PATHOLOGY:

1. Tubers

    • basic cause is unknown but considered a disorder of early embryogenesis
    • greater the # of tubers the greater the neurologic impairment
    • found anywhere within the cerebral hemispheres:
      • typically present in the subependymal region (located in the walls of the lateral ventricles and on the surface of the basal ganglia) and may extend into the ventricles
      • in the region of the foramen of Monro where they may cause obstruction -> hydrocephalus
      • also cortical gyri, sulcus terminalis

2. Sclerosis

    • areas of:
      • decreased numbers of neurons
      • areas of increased numbers of oddly-shaped, multinucleated "monster" giant neurons
      • proliferation (overgrowth) of fibrillary astrocytes which occasionally differentiate into malignant astrocytomas
      • demyelination
      • calcium deposition in gliotic areas
      • blood vessels with hyaline degeneration of their walls

CLINICAL FEATURES:

  • clinical presentation is extremely variable depending on the age of the patient, which organs are involved, and the severity of involvement
  • clinical variability even within the same family

1. Cutaneous Manifestations

1. Adenoma Sebaceum (80%)

      • rarely present at birth
      • usually presents between 4-6 years of age:
        • are present in 12% at 1 year
        • are present in 33% at 2 years
        • are present in 40% at 3 years
      • are angiofibromas:
        • usually pink or red papules appearing in patches or in a butterfly-shaped distribution on or about the nose, cheeks, and chin
        • with time may enlarge, coalesce, and assume a fleshy appearance

2. Ash-leaf Spots (90%)

      • hypopigmented oval or leaf-shaped spots
      • vary in size from mm -> cm
      • vary in number from several to 75 or more
      • found on the trunk and limbs in a linear orientation
      • apparent at birth and seen prior to 2 years in 50% of patients
      • visualized using a Wood's light (melanin absorbs wavelengths at 360 nm)
      • represent depigmented macules inwhich the melanocytes are normal but the melanosomes are reduced in number and contain less melanin

3. Shagreen Patches (35%)

      • isolated "leathery" raised and thickened plaques
      • have an orange-peel consistency
      • may be grayish-green or light brown in colour
      • found over the lumbosacral or gluteal region
      • develop in late infancy or early childhood but may also be present at birth
      • may be preceded by patches of grey or white hair (these hairy patches may be the first manifestation of TS)

4. Others

      • cafe-au-lait spots (7-16%)
      • fibromas:
        • flattened and can appear on the trunk, gingivae, periungual region, and along the hairline or eyebrows
      • angiomas

2. Neurologic Manifestations

1. Seizures (90%)

      • most common symptom of TS
      • initally present as infantile spasms:
        • 25-50% of patients with infantile spasms later develop signs of TS
        • can appear as early as 1 week of age
      • later develop other types of generalized seizures:
        • tonic, clonic, myoclonic, akinetic, Lennox-Gastaut Syndrome
      • epileptogenic focus may occur independently of tubers

2. Mental Retardation (60-70%)

      • highly variable but when present is irreversible
      • may be initally normal but then deteriorate intellectually during the latter part of the 1st decade (secondary to seizure or increased intracranial pressure)
      • earlier the onset of seizures the greater the likelihood of mental retardation (if seizures begin <1>
      • all who have mental retardation (MR) have had seizures
      • 33% of TS have normal intelligence

3. Others

      • hydrocephalus:
        • if tubers obstruct the foramina of Monro or the
        • Sylvian aqueduct
      • developmental delay
      • may develop autistic features

3. Tumors

1. Retinal (50-80%)

1. Mulberry Tumor

        • a nodular astrocytoma of the retina on or about the optic nerve head
        • refractile, yellowish, multinodular cystic lesions

2. Hamartomas

        • round or oval grey-yellow glial flat patches found centrally or peripherally
        • complications do not include papilledema or impaired vision

2. Renal (50-80%)

1. Angiomyolipomas

        • multiple yellow-white nodules or cystic tumors embedded within the parenchyma
        • usually benign but may cause hematuria, pain, and renal failure

3. Heart (50%)

1. Cardiac Rhabdomyomas

        • solitary or multiple; infiltrative and/or diffuse
        • solitary lesions usually found at the apex of the left ventricle
        • may cause congestive heart failure or arrhythmias but tend to slowly resolve spontaneously
        • may cause death before skin manifestations evident

4. Cutaneous (20%)

1. Koenen's Tumors

        • subungual or periungual fibromas
        • usually first appear in adolescence
        • toes > fingers

5. Intracranial (15%)

1. Astrocytomas

        • fibrillary astrocytomas may differentiate into giant cell astrocytomas
        • occur around the walls of the lateral ventricle or the anterior portion of the 3rd ventricle
        • may present as:
          • elevated intracranial pressure (papilledema, headache, nausea, vomiting)
          • diminished vision
          • lateralizing signs (hemiparesis)

6. Oral

      • oral fibromas or papillomas
      • usually found on the anterior aspect of the gingiva

4. Other Manifestations

1. Respiratory

      • lesions in lungs are either cystic or fibrous
      • angiomyolipomas may produce these generalized multicystic or fibrous pulmonary changes
      • may present with SOBE, and/or spontaneous pneumothorax
      • females more affected than males

2. Musculoskeletal

      • cystic changes and periosteal thickening of bones in hands and feet

INVESTIGATIONS:

1. Imaging Studies

1. CT

· 1. Intracranial Calcifications (60%)
        • most reliable finding in TS is calcified subependymal tubers
        • also occur in the region of the foramina of Monro and periventricular regions
        • multiple scattered calcium deposits may vary in size up to several cm
        • occur as early as 5 months and become more prominent with time (typically around 3-4 years of age)
· 2. Others
        • only 5% of patients with the clinical features of TS have normal CT's
        • may also identify cerebral atrophy, subependymal tumors, ventriculomegaly, and areas of diffuse demyelination

2. MRI

      • preferable for the visualization of cortical tubers, areas of heteropias, and hamartomas
      • tubers which project into the lateral and 3rd ventricles may appear as "candle drippings"
      • important to identify heteropias as these may act as seizure foci

3. Skeletal X-Rays

      • cystic rarefaction of phalanges and metacarpals (67%) appear around puberty
      • sclerotic areas of long bones
      • areas of variable skull bone density with thickened calvaria

4. Chest X-Rays

      • fine reticular infiltrates and/or multicystic changes

2. EEG

1. Infantile Spasms

      • hypsarrhythmias, can persist up to 8 years of age

2. Generalized Seizures

      • generalized slow wave-and-spike activity or independent multifocal spike discharges

3. Cerebral Spinal Fluid

    • elevated protein with elevated intracranial pressure (ICP)

MANAGEMENT:

1. Supportive

    • a multidisciplinary approach involving:
      • Paediatrics, Neurology, Ophthalmology, Nephrology, Cardiology, Dermatology, Neurosurgery, Orthopedics, PT, OT, Respirology
      • ensure regular follow-up for tumor surveillence
      • supplemental education

2. Cutaneous Manifestations

    • surgical resection if lesions are continually irritated or subjected to trauma

3. Neurologic Manifestations

1. Infantile Spasms

      • hormonal therapy: ACTH, prednisone
      • anticonvulsants: clonazepam, VPA, nitrazepam, clobazam
      • ? pertussis immunization -> triggers infantile spasm
        • recommend not giving pertussis immunization to infants with TS

2. Generalized Seizures

      • anticonvulsant therapy and may be difficult to control

3. Developmental delay

      • physiotherapy, early intervention

4. Tumors

1. Surgical Resection

      • of intracranial tumors if complications:
        • elevated ICP -> hydrocephalus
        • malignant transformation
      • of other tumors if complications:
        • cardiac -> congestive heart failure or arrhythmias
        • renal -> renal failure

5. Others

1. Genetic Couselling

      • 25% of parents without personal or family history of TS may be shown by careful history, physical (Wood's light, fundoscopic exam), & investigations (CT, renal ultrasound) to be affected
      • incompletely affected parents (those with isolated findings such as adenoma sebaceum, retinal hamartomas, viseral tumors) can have children with complete TS

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