Tuberous Sclerosis

Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the TSC genes causes excessive tumor-like growths in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). The diagnosis is made on clinical suspicion and confirmed by genetic testing. Management entails a multidisciplinary approach that targets monitoring and treatment of the various manifestations of the disorder. mTOR inhibitors such as sirolimus and everolimus are used to treat severe manifestations.

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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.

Clinical Presentation

Dermatologic features (95%)

  • Ash leaf spots:
    • Hypopigmented macules (> 5 mm)
    • Located on trunks/extremities
    • Present from birth
    • ≥ 3 usually the earliest sign of tuberous sclerosis complex (TSC)
  • Shagreen patches:
    • Flesh-colored nodules
    • Irregularly shaped, thickened skin (leather-like)
    • Usually located on the lower back
  • Angiofibroma:
    • Red spots or small cutaneous bumps
    • Appear around 3–5 years of age and increase over time
    • Butterfly pattern on the face (malar region)
    • Ungual fibromas: smooth, firm, flesh-colored lumps that emerge from the nail folds.
  • Confetti lesions:
    • Hypopigmented macules (< 3 mm)
    • Multiple
    • Dispersed throughout the body

CNS features (70%)

  • Cortical tubers
  • Glioneuronal hamartoma
  • Subependymal giant-cell astrocytomas (SEGAs)
  • Subependymal nodules
  • Present with:
    • Epilepsy
    • Infantile spasm
    • Cognitive impairment
    • Behavioral issues
    • Symptoms of increased cranial pressure:
      • Headache
      • Vomiting
      • Diplopia

Cardiopulmonary features (40%)

  • Cardiac rhabdomyomas: maybe detected in utero
  • Coarctation of the aorta
  • Lymphangioleiomyomatosis (LAM) of the lung (similar to diffuse pulmonary fibrosis): present with dyspnea or pneumothorax

Renal features

  • Angiomyolipomas 
  • Renal cysts
  • Present with:
    • Hemorrhage
    • Flank pain
    • Hematuria
    • Tender abdominal mass

Ophthalmic features (30%)

  • Retinal hamartoma
  • Retinal achromic patches (hypopigmented spots)
Major diagnostic features of TSC

Major diagnostic features of tuberous sclerosis complex (TSC; indicated in bold type)
LAM: lymphangioleiomyomatosis
PEComa: tumor showing perivascular epithelioid cell differentiation
SEGA: subependymal giant-cell astrocytoma

Image: “The clinical manifestations of TSC and LAM are diverse and affect multiple organs and tissues” by Delaney SP, Julian LM, Stanford WL. License: CC BY 4.0

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. 

References

  1. Crino, P.B., Nathanson, K.L., Henske, E.P. (2006). The tuberous sclerosis complex. N Engl J Med 355:1345–1356. https://doi.org/10.1056/NEJMra055323
  2. Webb, D.W., Clarke, A., Fryer, A., Osborne, J.P. (1996). The cutaneous features of tuberous sclerosis: a population study. Br J Dermatol 135:1–5. https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2133.1996.d01-923.x
  3. Datta, A.N., Hahn, C.D., Sahin, M. (2008). Clinical presentation and diagnosis of tuberous sclerosis complex in infancy. J Child Neurol 23:268–273. https://doi.org/10.1177/0883073807309250
  4. Krueger, D.A., Northrup, H., International Tuberous Sclerosis Complex Consensus Group. (2013). Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:255–265. https://doi.org/10.1016/j.pediatrneurol.2013.08.002
  5. Zamora, E.A., Aeddula, N.R. (2021). Tuberous sclerosis. In: StatPearls. Retrieved August 18, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK538492/

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