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TUBEROUS SCLEROSIS

Background
Medical Management Considerations
References
Resources for Families
Advisory Committee
Publication Information

Learning Points

  • Recognize that Tuberous Sclerosis (TS) is a genetic neurocutaneous disorder with highly variable presentations, a broad clinical spectrum, and multi-organ involvement.
  • Confirm that TS is an autosomal dominant disorder with variable penetrance (two-thirds of cases are sporadic, while one-third are familial).
  • Restate the occurrence of TS (1:6,000 births) and acknowledge that if a parent has the TS gene, there is a 50% chance that each child will inherit the disorder.
  • List five characteristic features of TS; e.g.,
    • Seizures (80-90%)
    • Hypopigmented areas, especially on trunk and extremities (87%)
    • Mental retardation (45-60%)
    • Renal angiomyolipomas (60-80%) and cysts
    • Facial angiofibromas (previously known as “adenoma sebaceum”) appearing at age 4-5
  • Delineate three conditions commonly associated with TS; e.g.,
    • Epilepsy – often resistant to medication
    • Psychiatric and behavioral disorders
    • Learning disabilities
  • Acknowledge that clinical expression of TS varies so that recognition and diagnosis may not be possible until well after birth
  • List four ongoing medical management considerations for TS; e.g.,
    • Review and document clinical features periodically, watching for changes
    • Refer to dermatologist as needed
    • Obtain brain CT or MRI when clinically indicated
    • Refer for biopsies and pathological evaluation of lesions as needed
  • Refer families to appropriate resources on Tuberous Sclerosis

BACKGROUND
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Description and Cause

Tuberous Sclerosis (TS) is a genetic neurocutaneous disorder with highly variable presentations, a broad clinical spectrum, and multi-organ involvement. It is characterized by cutaneous lesions and benign tumor formation in any organ – especially the brain, skin, kidney, eyes, and heart. Other possible affected areas include the lung, viscera, liver, ovary, pancreas, bone, teeth, and nails.

Tuberous Sclerosis is an autosomal dominant disorder with variable penetrance; two-thirds of cases are sporadic, while one-third are familial. TS is caused by defects or mutations in 2 different genes, TSC1 on chromosome and TSC2 on chromosome 16. TSC1 (hamartin) is a tumor suppressor. TSC2 (tuberin) regulates metasolic cell pathways and is also a tumor suppressor. Only one of the genes needs to be affectd for TS to be present.

Occurrence

  • 1:6,000 births
  • If a parent has the TS gene, there is a 50% chance that each child will inherit the disorder.

Characteristic Features

  • Seizures (80-90%)
  • Hypopigmented areas, especially on trunk and extremities (87%)
  • Calcified subependymal and/or periventricular nodules on CT scan
  • Developmental Delay
  • Facial angiofibromas (previously known as “adenoma sebaceum”) appearing at age 4-5
  • Periungual and subungual fibromas in adolescents and adults
  • Shagreen patches (leathery, pebble skin areas usually on lower back)
  • Forehead plagues rasied, discolored areas, unique to TS)
  • Renal angiomyolipomas (60-80%) and cysts
  • Retinal hamartomas (50%)
  • Mental retardation (45-60%)
  • Cardiac rhabdomyomas in  50% of infants
  • Cysts on liver, ovary, or pancreas (rare)
  • Dental pits; gum fibromas
  • Infantile spasms

Common Associations

  • Epilepsy – often resistant to medication
  • Psychiatric and behavioral disorders
  • Learning disabilities
  • Attention Deficit and Hyperactivity Disorder
  • Autism
  • Renal carcinoma
  • High blood pressure
  • Pulmonary dysfunction (recurrent pneumothorax, dyspnea, pulmonary failure)

MEDICAL MANAGEMENT CONSIDERATIONS
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Note: These considerations are in addition to the normal medical care provided to an individual without Tuberous Sclerosis. Most recommendations can be addressed through clinical examination by the primary care provider, although referral to a neurologist is usually necessary for the management of seizures.

Diagnosis

Diagnosis is not difficult in patients with obvious clinical manifestations. However, diagnostic tools may be required in those individuals who have subtle findings or mild forms of the disorder. In these cases, consider ultrasonography, MRI, CT, and histological confirmation. Wood’s lamp examination may be helpful to delineate characteristic hypopigmented lesions.

Upon Diagnosis

Clinical expression varies so that recognition and diagnosis may not be possible until well after birth. In any case, the following should be performed as soon as diagnosis is confirmed:

  • Perform complete physical and neurological exam to detect congenital anomalies
  • Examine entire body with Wood’s lamp to view hypomelanotic macules
  • Assess family medical history
  • Use MRI or CT scan to detect brain lesions
  • Refer to cardiologist to detect cardiac rhabdomyomas and arrhythmia
  • Obtain renal ultrasound, CT, or MRI
  • Refer for ophthalmologic evaluation
  • Provide genetic counseling, including discussion of recurrence risk
  • Refer to early intervention programs (if under age 3) and Tuberous Sclerosis/disability support groups
  • Discuss possibility of SSI enrollment

Ongoing (all ages)

  • Review and document clinical features periodically, watching for changes
  • Refer to dermatologist as needed
  • Obtain brain CT or MRI when clinically indicated
  • Refer for biopsies and pathological evaluation of lesions as needed
  • Use computerized tomography, sonography, or renal scintigraphy to differentiate angiomyolipomas from renal cell carcinoma
  • Monitor for seizures; prescribe standard anticonvulsant medications and consider referral to neurologist if seizures occur  [Return to the index for a complete document on Epilepsy]
  • Consider epilepsy surgery or vagal nerve implant for refractory seizures
  • Consider surgical excision of tumors when appropriate
  • Monitor blood pressure

Childhood (1 to 13 years)

  • Monitor for facial angiofibromas beginning around age 4 or 5
  • Monitor renal function using serum BUN or creatinine every 3 years; refer for renal ultrasound or CT when necessary
  • Recommend and arrange for dental care
  • Refer for speech and language therapy evaluation as needed
  • Refer for psychiatric/behavioral evaluation as needed
  • Refer for physical and/or occupational therapy evaluation as needed
  • Monitor school progress
  • Refer to early intervention program (if under age 3) or to special education program (if over age 3) as appropriate

Adolescence and Adulthood (13 years and over)

  • Monitor for periungual and subungual fibromas
  • Obtain chest X-ray, CT, or MRI in females at puberty to detect pulmonary signs
  • Discuss possibility of surgically removing facial angiofibromas or peri- and subungual fibromas (by dermabrasion or laser removal)
  • Discuss long-term employment and living arrangements as needed

REFERENCES
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Peer-reviewed Journal Articles/Academies

Avellino, A.M. et al. (1997). Surgical Management and Seizure Outcome in Patients with Tuberous Sclerosis. Journal of Neurosurgery, 87(3), 391-396.

Bongers, V. et al. (1997). The Value of Renal Scintigraphy in the Conservative Management of a Patient with Tuberous Sclerosis. Clinical Nuclear Medicine, 22(3), 176-178.

Roach, E.S., Gomez, M.R., Northrup, H. (1998). Tuberous Sclerosis Complex Consensus Conference: Revised Clinical Diagnostic Criteria. Journal of Child Neurology, 13, 624-628.

Seri, S. et al. (1998). Frontal Lobe Epilepsy Associated with Tuberous Sclerosis: Electroencephalographic- Magnetic Resonance Imaging Fusion. Journal of Child Neurology, 13(1), 33-38.

Zvulunov, A. et al. (1995). Neurocutaneous Syndromes Associated with Pigmentary Skin Lesions. Journal of the American Academy of Dermatology, 32(6), 915-935.

Special Interest Groups/Other Publications

Capute, A.J., Accardo, P.J. (1996). Developmental Disabilities in Infancy and Childhood vol. I: Neurodevelopmental Diagnosis and Treatment. Baltimore: Paul H. Brookes.

Capute, A.J., Accardo, P.J. (1996). Developmental Disabilities in Infancy and Childhood vol II: The Spectrum of Developmental Disabilities. Baltimore: Paul H. Brookes.

Harlan, D.J., Lowder, D. (1999). Tuberous Sclerosis Complex. In: Griffith’s 5 Minute Clinical Consult. Ed: Dambro, Mark R. Baltimore: Lippincott Williams & Wilkins, pp. 1108-1109.

May, P.B. (2006). Tuberous Sclerosis (Developmental Medicine Clinic syllabus). UMD New Jersey, Robert Wood Johnson Medical School. Retrieved May 18, 2006.

Clinical Manifestations of Tuberous Sclerosis.(2006). Tuberous Sclerosis Alliance. Retrieved May 18, 2006.

RESOURCES FOR FAMILIES
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American Academy of Dermatology
888-462-DERM

Autism Society of America
800-328-8476

California Department of Developmental Services
916-654-1690

California Regional Centers
915-654-1958

Epilepsy Foundation of America
800-332-1000

Exceptional Parent Magazine
800-247-8080

March of Dimes Birth Defects Foundation
914-428-7100

National Tuberous Sclerosis Association, Inc.
800-225-NTSA

ADVISORY COMMITTEE
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Theodore A. Kastner, M.D., M.S.
Felice Weber Parisi, M.D., M.P.H.
Richard J. Brouette, M.D., F.A.A.F.P., D.A.B.F.P.
Romie H. Holland, M.D.
Jaime D. Mejlszenkier, M.D., F.A.A.N
Joan M. Reese, M.D., M.P.H.

PUBLICATION INFORMATION
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This document does not provide advice regarding medical diagnosis or treatment for any individual case, and any opinions or statements contained in this document are not intended to serve as a standard of medical care. Physicians are encouraged to view the considerations presented in this document in light of evolving scientific information. This document is not intended for use by the layperson. Reproduction of this document may be done with proper credit given to California Department of Developmental Services.