Tuberous Sclerosis

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Tuberous Sclerosis

• Sigal Peter-Wohl, MD
• MetroHealth Medical Center

2
Case Presentation

• 33 6/7 weeks gestation baby boy.
• 34yo G1P1, blood type A
• Prenatal screen negative. Normal chromosomes.
• PET, Betha x 3
• Induction, Forceps delivery, APGAR 2,4,7.
• BW 1972 gram AGA, Blood type A

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Case Presentation

• Clinical course
• CNS notice to be irritable with increased cry.
• RDS, Was on CPAP. Weaned to room air at DOL 9.
• CVS - Stable
• Tolerated his feedings.
• 48h R/O sepsis.
• Hyperbillirubinemia was on phototherapy.

4
Case Presentation

• Routine HUS on DOL 3 Echogenic foci in the
  brain periphery suggesting ischemic changes or
  hemorrhage.

5
Case Presentation

• F/U CT showed multiple hyperdense foci along the
  periventricular region, extending to white
  matter. The impression was of grade IV germinal
  hemorrhage.

6
Case Presentation

• F/U MRI showed multiple nodular subependymal
  lesions along the lateral ventricles. Largest
  lesion - Lt foramen of Monro, measuring 9 mm.
  There was both white matter and gray matter
  tubers. There is no hydrocephalus. The lesions
  strongly suggest subependymal tumors of tuberous
  sclerosis and represent hamaratomas.

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Case Presentation

• EEG - diffuse cortical abnormalities.
• US of kidneys and bladder - normal
• Eye exam - normal
• ECHO - multiple scattered rhbdomyomas. Two of
  them are large RV apex, below aortic valve. No
  obstructive pattern at that time.
• No skin lesion
• Parents history and skin exam was negative.

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Introduction

• Epiloia or Bournevilles disease.
• 15000-110000
• Damage of one of two genes which regulate growth.
• Hamartomas in variety of organ.
• Most common - brain, kidneys, skin.
• Can present at any age.
• Variation in severity

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Genetics

• AD transmission, variability in symptoms.
• Mutation on either TSC1 (Tuberous sclerosis) gene
  (chromosome 9) or TSC2 gene (chromosome 16).
• Gross deletion/insertions and micromutations.
• 60-70 are sporadic (new mutations).

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• Counseling -
• history, exam, investigation allows definitive
  diagnosis in 95-98.
• Affected parents have a 50 chance of having an
  affected child.
• In new mutation with normal parents 2-5 chance
  for other children due to possible gonadal
  mosaicism.
• Ante-natal genetic tests for parents with
  identified gene mutation in the family.

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Diagnostic criteria(Tuberous Sclerosis
Association)

• Major features (Definitive diagnosis of TSC
  requires two major features)
• Facial angiofibromas or forehead plaque.
• Non-traumatic ungual or periungual fibroma.
• Shagreen patch (connective tissue nevus).
• Multiple retinal nodular hamartomas (phakomas).
• Cortical tube.
• Calcified subependymal nodule.
• Subependymal giant cell astrocytoma.
• Cardiac rhabdomyoma, single or multiple.
• Lymphangiomyomatosis and/or Renal angiomyolipoma.

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Diagnostic criteria

• Suggestive features
• Hypomelanotic macules - Ash leaf.
• Multiple randomly distributed pits in dental
  enamel.
• Hamartomatous rectal polyps.
• Bone cysts.
• Gingival fibromas.
• Multiple renal cysts.
• Skin tags
• Positive family history.

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Clinical Features

• Cutaneous Manifestations
• Adenoma Sebaceum (80)
• rarely present at birth
• usually presents between 4-6 years of age
• 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 and require repeated
  procedures for cosmetic reasons.

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Adenoma Sebaceum
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• Cutaneous Manifestations
• Shagreen Patches (35)
• Connective tissue hamartomas found over the
  lumbosacral or gluteal region.
• Leathery raised and thickened plaques,
  orange-peel consistency, grayish-green or light
  brown in colour.
• Late infancy or early childhood but may also be
  present at birth.
• May be preceded by patches of gray or white hair
  (these hairy patches may be the first
  manifestation of TS).

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• Cutaneous Manifestations
• Ash-leaf Spots (90)
• Angiomas
• Hypopigmented oval or leaf-shaped spots
• Vary in size and in number.
• Found on the trunk and limbs in a linear
  orientation.
• Apparent at birth.
• Visualized using a Wood's light.

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Ash-leaf Spots
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• Cutaneous Manifestations
• Others
• Cafe-au-lait spots (7-16)
• Fibromas flattened and can appear on the trunk,
  gingivae, periungual region, and along the
  hairline or eyebrows.
• Koenen's Tumors (20) Subungual or periungual
  fibromas, usually first appear in adolescence,
  toesgtfingers.

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• Neurologic Manifestations
• Cortical tubers
• Focal, gray-white matter interface
• Microscopically - loss of normal
  cytoarchitecture, abnormal neurons and glial
  cells.
• MRI gt CT
• Number and size correlate with seizures and
  mental retardation.

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• Neurologic Manifestations
• Subependymal nodules
• Usually line the third ventricle. Large,
  irregular cells that are more densely aggregated
  and more uniform in appearance compared with the
  cortical tubers.
• Some will grow gt than 3 cm in diameter gt called
  subependymal giant cell astrocytomas (5).
• Histologic features similar to cortical nodules.
• Subependymal giant cell astrocytomas can cause
  severe clinical manifestations elevated
  intracranial pressure, diminished vision,
  hemiparesis.
• Later in life, subependymal nodules often calcify.

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• Neurologic Manifestations
• Seizures (60-90)
• Most common symptom of TS.
• Risk of sudden epileptic death.
• Initially may 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.

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• Mental health -
• Very common, very difficult.
• More in children with epilepsy.
• May be associated with tubers in temporal area.
• Autism (25) and autism spectrum disorders (50).
• Sleep disturbances.
• ADDH /- hyperactivity.
• Anxiety and depression.

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• Development and learning disorders
• Developmental delay (40-60).
• Learning difficulties (40-60).
• More in children who present with infantile spasm
  and epilepsy.
• The earlier the onset of seizures the greater the
  likelihood of mental retardation (if seizures
  begin lt1 year of age a 92 chance of MR).

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• Cardiac (50)
• Rhabdomyomas
• Rarely cause complication
• Solitary or multiple, solitary lesions usually
  found at the apex of the left ventricle.
• May cause outflow obstruction or arrhythmias
  (WPW), but tend to slowly resolve spontaneously.
• May cause death before skin manifestations
  evident.

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• Renal
• Angiomyolipomas (AML) (80)
• Benign hemartoma.
• Multiple yellow-white nodules or cystic tumors in
  the parenchyma.
• Symptoms usually in adults.
• Mainly intraperitoneal or intrarenal/uretic
  hamorrhage.
• If large - may cause obstruction.
• polycystic kidney disease (lt5)
• HTN, RF
• simple cysts (20).
• No clinical significance.
• Renal cell carcinoma. (lt1).

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Enlarge Lt. kidney from 1 day old term baby who
died from cardiac tumor complication.
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• Pulmonary
• Lymphangiomyomatosis.
• Rare, in adult female.
• Progressive emphysematous changes and lost of
  lung volume.
• Risk of spontaneous pneumothoraces.

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• Ophthalmic (50-80) -
• Mulberry Tumor
• Nodular astrocytoma of the retina on or about the
  optic nerve head.
• Refractile, yellowish, multinodular cystic
  lesions.
• Hamartomas (phakomas)
• Round or oval gray-yellow glial flat patches
  found centrally or peripherally.
• Unless near the macula the are not of clinical
  significance.

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• Other organs -
• Liver angiomas (25).
• Thyroid adenomas.
• Hamartomas in bone
• Rectal polyps (75), usually numerous and
  asymptomatic.

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Initial diagnostic studies

• Personal and family history
• Exam, including skin exam with UV light.
• Fundoscopy
• Cranial imaging (MRI or non-enhanced CT)
• Renal US
• Echocardiography in infant.

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Monitoring

• CNS - for behavior changes, convulsion, syncope
  imaging and EEG.
• Renal - BP, renal function, imaging (u/s).
• Cardiac - ECG if arrhythmia is suspected.
• Pulmonary - if indicated spirometry, chest
  x-ray, CT.
• Regular childhood hearing and vision f/u.
• Detailed developmental and psychiatric evaluation.

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References

• Gomez M R, Sampson J R, Whittemore V H. Tuberous
  Sclerosis Complex (3rd edition). Oxford
  University Press. 1999.
• Roach E S, Di Mario F J, Kandt R S, Northrup H.
  Tuberous Sclerosis Consensus Conference
  Recommendations for Diagnostic Evaluation. J
  Child Neurology 14 (1999) 401-407.
• Sparagana S P, Roach E S. Tuberous sclerosis
  complex. Curr Opin Neurol. 2000 13(2)115-9.
• Cheadle J P, Reeve M P, Sampson J R, Kwiatkowski
  D J. Molecular genetic advances in tuberous
  sclerosis. Hum Genet 2000 107(2)97-114.
• The Tuberous Sclerosis Association online site -
  www.tuberous-sclerosis.org