• Information
  1. Epidemiology
  2. Etiology
  3. Pathogenesis
  4. Clinical Manifestations
  5. Associated Congenital Anomalies
  6. Diagnostic Criteria (Table 1)
  7. Diagnostic Evaluation
  8. Treatment
  9. Prognosis

A. Epidemiology

1. Incidence 1:50,000
2. Risk of mental retardation increases with the lower the age of onset of symptoms

B. Etiology

1. Autosomal dominant disease with variable expressivity
2. 50% of cases sporadic
3. Mutations in two distinct genes can cause tuberous sclerosis
   1. Tuberous sclerosis 1 gene (TSC1) located at chromosome (chr) 9q34
   2. TSC2 localized to chr 16p13
   3. TSC1 encodes hamartin (molecular weight 140K), found in centrosome
   4. TSC2 encodes tuberin, a transcription factor (200K) found in Golgi and nucelus
   5. Inactivation of both alleles of either TSC1 or TSC2 required for expression of phenotype
   6. TSC1 and TSC2 form a complex that regulate genes including Rheb and mTor
   7. Rheb is Ras homolog expressed in brain
   8. mTOR is mammalian target of rapamycin, a serine-threonine kinase
4. Family history present in 75% of familial cases
   1. Intelligence affected individuals may be normal
   2. Affected family members often have seizures
   3. Brain MRI will detect characteristic tubers

C. Pathogenesis

1. The tuberous sclerosis giant cell can develop as a glial or neuronal cell
2. May produce hamartomas, frank gliomas, or diffuse gliosis
3. Astrocyte overgrowth produces associated sclerosis
4. Calcified nodules projecting into ventricles appear as candle gutterings
5. Malignant change may transform a tuber into an astrocytoma

D. Clinical Manifestations

1. Neurologic
   1. Mental retardation
   2. Seizures
   3. Increased intracranial pressure (ICP)
   4. Dementia (diffuse-type)
2. Seizures
   1. May present as infantile spasms (very difficult to treat)
   2. Hypsarrhythmic electroencephalogram (EEG) pattern
   3. Later can be grand mal or focal Jacksonian type seizures
   4. May have associated autism
3. Increased ICP with hydrocephalus
   1. Obstruction of foramen of Monroe
   2. Malignant transformation
4. Dermatologic
   1. Under 3 years: Ash-leaf spots, Cafe-au-lait spots, Shagreen spot
   2. Older: adenosebaceum, telangiectasia, peri-ungal fibromas
   3. Adenoscebaceum occurs on face when sebaceous glands mature
5. Ash-leaf spots
   1. Flat hypopigmented patches
   2. Visible under Woods lamp
   3. Present in 0.2-0.3% of normal newborns
6. Shagreen spot
   1. Unevenly thickened raised skin area with orange-peel consistency
   2. Located in lumbrosacral region
7. Ophthalmologic
   1. Retinal hamartoma
   2. Benign retinal astrocyte proliferation
8. Retinal hamartoma
   1. Yellowish, multinodular cystic lesion arising from optic disk or retina
   2. Compared to appearance of unripe mulberry
9. Cardiac Rhabdomyomas
   1. Present in 50% of cases
   2. Rarely cause mechanical obstruction, heart failure or arrhythmia
   3. Typically regress spontaneously
10. Renal
    1. Kidney hamartomas
    2. Polycystic kidney disease

E. Associated Congenital Anomalies

1. Spina bifida
2. Hare lip
3. Agenesis of corpus collosum
4. Omphalocele
5. Splenic sinus histiocytosis

F. Diagnostic Criteria (Table 1, Ref [1])

1. Diagnosis
   1. Two major or one major and two minor criteria required for definitive diagnosis
   2. Probable diagnosis: one major and one minor criteria
   3. Possible diagnosis: one major or two minor criteria
2. Major Criteria
   1. Facial angiofibroma
   2. Ungual fibroma
   3. Shagreen patch
   4. Hypomelanotic macule
   5. Cortical tuber
   6. Subependymal nodule
   7. Subependymal giant-cell tumor
   8. Retinal hamartoma
   9. Cardiac rhabdomyoma
   10. Renal angiomyolipoma
   11. Lymphangiomyomatosis
3. Minor Criteria
   1. Multiple pits in dental enamel
   2. Hamartomatous rectal polyps
   3. Bone cysts
   4. Cerebral white-matter radial migration lines
   5. Gingival fibromas
   6. Retinal anatomic patch
   7. "Confetti" skin lesions (groups of small, lightly pigmented spots)
   8. Multiple renal cysts

G. Diagnostic Evaluation

1. Maintain a high level of suspicion with infantile spasms
2. Baseline studies include echocardiogram, abdominal ultrasound, and chest radiograph
3. Head CT showing characteristic intercranial calcifications
4. MRI better than CT for the following:
   1. Periventricular hamartomas
   2. White matter lesions
   3. Astrocytic tumors
   4. Hydrocephalus
5. EEG (electroencephalogram) for electrical pattern of associated seizures
6. Renal US or IVP to document associated renal abnormalities
7. Pathologic specimen
   1. Not necessary to make diagnosis
   2. Tuber consists of a proliferation of astrocytes
   3. Multinucleated giant cells seen

H. Treatment

1. Antiepileptic drugs for seizure disorder
2. Neurosurgical intervention for ICP

H. Prognosis

1. Depends on severity of seizure disorder and cognitive dysfunction
2. Death in ~75% by 25 years due to:
   1. A complication of the epilepsy
   2. An intercurrent infection
   3. Occasionally cardiac failure or pulmonary fibrosis

References

1. Crino PB, Nathanson KL, Henske EP. 2006. NEJM. 355(13):1345
2. Nelson, W. Textbook of Pediatrics. W.B. Saunders Company. (Philadelphia: 1996) 1707