Tuberous Sclerosis

Overview

Epidemiology

• Prevalence: 1 in 6000–10,000 newborns in the United States
• Men and women are equally affected.

Etiology

• Autosomal dominant inheritance
• Loss-of-function mutation in the:
  • TSC1 gene (25% of cases):
    • Located on chromosome 9 (long arm)
    • Encodes hamartin → tumor-suppressor protein
  • TSC2 gene (75% of cases):
    • Located on chromosome 16 (short arm)
    • Encodes tuberin → tumor-suppressor protein
• Spontaneous mutations in 80% of cases

Pathophysiology

• Pathology occurs when the physiologic basis of cellular quiescence is disrupted.
• 2-hit hypothesis:
  • Tumor suppressor:
    • The tumor-suppressor proteins ensure that the cell remains in the resting phase of a cell cycle.
    • Loss of function → inhibitory signal is lifted → cells spend less time in G1 phase
  • mTOR pathway:
    • A posttranslational modification that results in up-regulation of cell cycle.
    • Normally controlled by the tuberin–hamartin complex
    • Loss of the complex results in continuous up-regulation and growth of cells.

Diagnosis

No single clinical presentation of TSC is considered diagnostic. 

• Detailed history and physical
• Thorough full-body skin examination is crucial.
• Imaging studies to rule out cardiac or renal manifestations:
  • Ultrasonography
  • CT
  • MRI 
• Diagnostic criteria for TSC: 
  • 2 major clinical features OR
  • 1 major and ≥ 2 minor clinical features
• Probable TSC:
  • 1 major clinical feature OR
  • ≥ 2 minor clinical features

Diagnostic criteria for TSC

• Genetic criteria: presence of TSC1 or TSC2 mutation
• Clinical criteria:
  • Major features:
    • Ash leaf spots
    • Shagreen patch
    • Angiofibroma
    • Ungual fibroma
    • Multiple retinal hamartomas
    • CNS features
    • Cardiac rhabdomyoma
    • Lymphangioleiomyomatosis (LAM)
    • Angiomyolipoma
  • Minor features:
    • Dental enamel pits
    • Intraoral fibromas
    • Retinal achromic patches
    • Multiple renal cysts
    • Nonrenal hamartoma

Management

• A multidisciplinary approach aims to monitor and treat clinical manifestations of the disease.
• Counseling regarding genetic testing and mode of inheritance must be discussed.

CNS manifestations

• Epilepsy:
  • Educate parents on infantile spasm.
  • EEG done routinely
  • Treatment of spasms/seizures:
    • Vigabatrin for infantile spasms
    • Antiepileptics
    • Surgical tumor resection for treatment-resistant cases
• Tumors:
  • MRI done every 1–3 years
  • Treatment:
    • Surgical resection
    • mTOR inhibitor: everolimus
• Neuropsychiatric:
  • Monitor skills and mood at each visit.
  • Intervene with support and early intervention as needed.

Cardiac manifestations

• Asymptomatic cases: 
  • ECG and ECG are done at baseline and every 3 years until regression of rhabdomyoma occurs.
• Symptomatic cases:
  • Need closer assessments, especially of conduction pathways, using ambulatory ECG tests.

Renal manifestations

• Abdominal MRI done every 3 years
• GFR and blood pressure monitoring yearly
• Treatment:
  • Angiomyolipoma:
    • Artery embolization
    • mTOR inhibitor
    • Surgical resection
  • Renal cysts: manage hypertension

Skin manifestations

• Annual detailed skin exam
• Counseling regarding sun protection 
• Counseling against use of over-the-counter treatments
• Treat disfiguring lesions using laser therapy

Eyes and dental manifestations

• Complete eye exam annually.
• Dental checkups annually

Respiratory manifestations

• Counseling against smoking and the use of estrogen in women
• High-resolution CT done every 5–10 years (more frequently if cysts are detected)
• Treatment:
  • mTOR inhibitors: sirolimus (1st-line), everolimus
  • Lung transplantation

Differential Diagnosis

• Vitiligo: most common depigmenting disorder; caused by the destruction of melanocytes. The etiology of vitiligo is unknown, but genetic and autoimmune factors may play a role. Presentation is with hypopigmented or depigmented macules or patches. The ash leaf spots and confetti spots may initially be confused with the hypopigmentation noted in vitiligo. However, the mucosa is spared in TSC, and the lesions are not usually found around the skin covering the joints. Vitiligo doesn’t present with epilepsy or hamartoma. 
• Multiple endocrine neoplasia (MEN): autosomal dominant inherited conditions characterized by ≥ 2 hormone-producing tumors involving endocrine organs. MEN1 may present with angiofibroma in a similar malar, butterfly pattern as seen in TSC; however, other endocrine abnormalities, especially involvement of the parathyroid gland is not noted in TSC and can differentiate the 2 conditions.
• Epilepsy: chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition such as tuberous sclerosis. Clinical presentation correlates to the classification of the epileptic disorder. Diagnosis is confirmed with EEG. Some epileptic disorders resolve over time, but many require lifelong antiepileptic medication for management; in some refractory cases, surgical procedures may be needed.