AUTHOR AND EDITOR INFORMATION

Section 1 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

INTRODUCTION

Section 2 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Background

Tuberous sclerosis is a genetic disorder affecting cellular differentiation and proliferation, which results in hamartoma formation in many organs (eg, skin, brain, eye, kidney, heart).

Von Recklinghausen first described tuberous sclerosis in 1862. Bourneville coined the term sclerose tubereuse, from which the name of the disease has evolved. Sherlock coined the term epiloia, encompassing the clinical triad of epilepsy, low intelligence, and adenoma sebaceum. The term tuberous sclerosis complex (TSC) is now widely used, emphasizing the variegated nature of its manifestations.

Pathophysiology

The inheritance is autosomal dominant, while up to 50-70% of cases have been attributed to new mutations. This high percentage of mutations may be reduced after careful examination and detailed investigation of apparently healthy parents, who on closer inspection may have disease features.

Two genetic loci have been identified so far. The first gene maps to chromosome 9, specifically 9q34 (TSC1); the second gene maps to chromosome 16, specifically 16p13 (TSC2). Tuberin, the protein gene product of TSC2, was the first of the affected proteins to be isolated. Tuberin shows a small region of homologic identity to the catalytic domain of the Rap 1 guanosine triphosphatase (GTPase) activity protein (Rap 1 GAP). Rap 1 is a member of a group of proteins involved in the regulation of cell proliferation and differentiation. Loss of tuberin activity is thought to lead to activation of Rap 1 in tumors. Hamartin, the TSC1 second gene product, has recently been isolated and may function as a tumor suppressor. Hamartin and tuberin heterodimerize and inhibit mTOR, the mammalian target of rapamycin.

Interestingly, hamartin and tuberin have been shown to have coiled coil domains that interact with each other. Hamartin and tuberin are thought to act synergistically to regulate cellular growth and differentiation. The deregulation in organogenesis results in tumors, which may affect any organ in the body. Most of the tumors represent hamartomas and, in many organs, resemble embryonic cells, suggesting that the defect occurs at an early stage in life. A small proportion of families exist whose genetic localization has not been determined.

Frequency

United States

The frequency in the United States is 1 case in 5,800-30,000 persons.

International

International frequency is the same as US frequency.

Mortality/Morbidity

Tuberous sclerosis shows a wide variety of clinical expressions. Some individuals are severely affected, while others have very few features. Forme frustes are common. An accurate estimation of the course in an individual depends on the extent of involvement. About a quarter of severely affected infants are thought to die before age 10 years, and 75% die before age 25 years; however, the prognosis for the individual diagnosed late in life with few cutaneous signs depends on the associated internal tumors.

Race

No racial predilection has been noted.

Sex

No sex predilection has been noted.

Age

Most patients are diagnosed between ages 2 and 6 years. Cardiac and cortical tubers develop at infancy, while skin lesions are seen in more than 90% of patients at all ages. The ash-leaf macule can be present at birth, while the facial angiofibroma and ungual fibromas can develop in late adolescence.

CLINICAL

Section 3 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

History

• Most individuals present with parental concern about small raised tumors on the child's face. (In most cases, the parent draws the attention to the cutaneous stigmata.)
• Some cases are detected in child health clinics as whitish spots.
• Children with late onset and individuals with few skin signs may remain undetected until adolescence.
• Dental pitting and fibromas may be noticed by the parents or an astute dentist.
• Clinical manifestations have a varied penetrance, adding to the delay in diagnosis.

Physical

The criteria for diagnosing TSC have recently been revised. The features have been divided into major features and minor features.

• Major features
• • Facial angiofibromas or forehead plaque
  • Nontraumatic ungual or periungual fibromas
  • Hypomelanotic macules (>3)
  • Shagreen patch (connective tissue nevus)
  • Multiple retinal nodular hamartomas
  • Cortical tuber
  • Subependymal nodule
  • Subependymal giant cell astrocytoma
  • Cardiac rhabdomyoma, single or multiple
  • Lymphangiomyomatosis
  • Renal angiomyolipoma
• Minor features
• • Multiple randomly distributed pits in dental enamel
  • Hamartomatous rectal polyps
  • Bone cysts
  • Cerebral white matter radial migration lines
  • Gingival fibromas
  • Nonrenal hamartoma
  • Retinal achromic patch
  • Confetti skin lesions
  • Multiple renal cysts
• Diagnosis
• • Definite tuberous sclerosis complex is diagnosed by the presence of either 2 major features or 1 major feature plus 2 minor features.
  • Probable tuberous sclerosis complex is indicated by 1 major feature plus 1 minor feature.
  • Possible tuberous sclerosis complex is indicated by either 1 major feature or 2 or more minor features.
• Skin lesions (found in 70-80% of cases)
• • The characteristic lesions are angiofibromas, previously known by a misnomer, adenoma sebaceum. These are pink or skin-colored telangiectatic papules commonly observed in the nasolabial folds and on the cheeks and chin. They usually appear in children younger than 10 years and increase in size and number until adolescence, remaining unchanged thereafter. Other areas in which they may be observed include in and around nails (ungual fibromas), scalp, and forehead, in the latter location reaching sizes up to several centimeters. In the oral mucosa, they may be observed in the lips, dorsa of tongue, and palate. Dental pitting occurs in about 90% of patients. A hand lens examination aids detection of these pits, which are less obvious in deciduous teeth.
  • Periungual fibromas (Koenen tumors) are smooth, firm, flesh-colored papules emerging from the nail folds. They can be the only manifestation in some individuals. These are noted around puberty and may increase in frequency as the patient ages.
  • Shagreen patches are flesh-colored soft plaques that are frequently found in the lumbosacral area but may occur anywhere on the trunk. The surface may be pebbly (resembling pigskin or untanned leather) with prominent follicular openings. They are usually noticed during the first decade.
  • White macules are ovoid, hypopigmented, ash leaf–shaped macules that can be found on the trunks or limbs. White macules offer an excellent opportunity for early diagnosis because they may be found at birth or early infancy. The use of Wood lamp accentuates these macules. The color, even though described as white, lacks the depigmented white appearance of vitiligo. A careful examination is necessary before making any firm diagnosis because hypopigmented macules may be a normal finding in newborn babies. One suggestion is that 3 or more white macules at birth should alert the clinician regarding the possibility of tuberous sclerosis.
  • Other skin signs include guttate leukoderma, café-au-lait macules, and poliosis.
• Neurologic findings
• • The tuberosclerotic nodules of glial proliferation occur in the cerebral cortex, basal ganglia, and ventricular walls but are rare in the cerebellum, medulla, or spinal cord. Rarely, hydrocephalus may result from obstruction of the foramen of Monro.
  • Subependymal giant cell astrocytomas also may be present, and serial imaging scans are recommended to monitor if growth occurs.
  • The number of tubers in the cortex and subcortex appears to correlate with the clinical severity of disease, as measured by the ease of control of seizures, the appearance of developmental milestones, and school performance.
  • Epilepsy occurs in 80-90% of all patients, with a positive correlation with subnormal intelligence. Epilepsy requires treatment, preferably with monotherapy. Carbamazepine and sodium valproate are traditionally used in the initial treatment. Vigabatrin, an irreversible inhibitor of GABA transaminase, is reported to be more effective for infantile spasms in TSC. Lamotrigine is also used as adjunctive therapy for partial seizures in adults. In many cases, resection of the tuber may result in better control of epilepsy.
  • Mental retardation is observed in 60-70% of cases; however, if mental development is normal throughout childhood, subsequent worsening is uncommon.
  • Other features noted include schizophrenia, autistic behavior, and attention-deficit hyperactivity disorder.
• Ocular findings: Ocular involvement includes hypopigmented spots in the iris, equivalent to the ash-leaf macule in the skin. Retinal phakomas are observed as whitish-gray nodular lumps with a lump of mulberries appearance. These represent hamartomas characterized by proliferation of astrocytes. Every patient with TSC should have a thorough ophthalmologic examination at the time of diagnosis.
• Findings in other organs
• • Cardiac rhabdomyomas are observed in over 50% of infants. They may be detected prenatally by fetal echocardiography and are the commonest cardiac abnormality detected in utero. Up to 50-60% of patients with TSC have cardiac disease, mainly rhabdomyomas. These may cause mechanical problems because of their size or because of the defects in the conducting system caused by their infiltrating nature. Rhabdomyomas usually undergo spontaneous resolution in the first few years of life in about 80% of patients, even though residual areas of histologically abnormal myocardium may persist.
  • Aneurysms of thoracic and abdominal aortas have also been observed rarely.
  • Renal involvement is usually manifested by angiomyolipomas. Angiomyolipomas are benign tumors of vessels and are seen in up to 75% of patients. Spontaneous bleeding may be fatal, and these tumors are best treated by embolization. Other features may include renal cysts, polycystic kidneys, and renal carcinoma.
  • Pulmonary changes include lymphangiomatosis with cyst formation. This may be progressive and result in dyspnea, cor pulmonale, recurrent pneumothorax, and respiratory failure.
  • Gastrointestinal tumors may be associated. Microhamartomatous polyps are present in the rectum in 75% of cases. Hepatic hamartomas have also been reported.
  • The bones may show areas of cyst formation, periosteal new bone growth, and areas of sclerosis.
  • Other abnormalities noted include pituitary adrenal dysfunction, thyroid disorders, premature puberty, diffuse cutaneous reticulohistiocytosis, and gigantism.

DIFFERENTIALS

Section 4 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Other Problems to be Considered

Angiofibromas (differentiate from acne vulgaris by telangiectasia, absence of comedones and pustules, and a relatively asymptomatic nature)
Shagreen patch (must be differentiated from connective tissue nevi)
Hypopigmented spots (may need to be differentiated from nevus anemicus, nevus achromicus, and early vitiligo)

WORKUP

Section 5 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Imaging Studies

• Evaluation of newly diagnosed patients should include a personal and family history and a clinical examination, including funduscopy, cranial imaging (eg, MRI, nonenhanced CT scanning), renal ultrasonography, and echocardiography in infants.
• • Computed cranial tomography scanning and MRI are performed not only in suspect cases but also in patients whose diagnosis is obvious. Do not use scan results to predict the neurologic outcome of an individual patient. New MRI techniques such as FLAIR (fluid attenuated inversion recovery) help identify small tubers, which may not be detected with other imaging techniques.
  • If tubers are present, serial imaging scans are essential to evaluate for growth of the tumor.
  • EEG is useful when the initial presentation includes epileptic seizures. EEG is not required in children who do not have epilepsy.
  • Renal ultrasonography is used to evaluate children and older patients in particular for renal tumors.
  • ECG is a baseline study essential to detect any cardiac arrhythmias. Wolff-Parkinson-White syndrome seems to be the most common arrhythmia in patients with TSC.
  • Echocardiography is recommended for patients of any age with symptoms of cardio rhabdomyoma. Because most symptoms occur in neonates, older children do not need to have an echocardiogram, unless it is to confirm a previous dubious diagnosis.
  • Neurodevelopmental testing as age-appropriate screening for behavioral and neurodevelopmental dysfunction at the time of diagnosis is essential. Periodically reassess children with abnormal test results. Newly diagnosed adults with normal social and cognitive function (as demonstrated by educational and career achievements) may not require formal testing. Frequent assessment is probably not warranted in such individuals.
  • Recently, consensus guidelines have been published to help in the assessment of cognitive and behavioral problems in persons with TSC. Refer to the Tuberous Sclerosis Association for the guidelines.
  • Molecular diagnosis using DNA-based testing is not yet routinely available but in the future could be developed and would help to identify patients at increased or decreased risk for particular complications.
• Ongoing evaluation
• • Annual or at least biannual MRI can be performed until age 21 years. At that point, any single tumors identified may need closer monitoring.
  • The frequency of EEG depends upon the clinical features and the treatment response of epilepsy. Consider EEG in the evaluation of a patient with unexplained decline of behavioral or cognitive function, in whom epileptic seizures are suspected.
  • Neurodevelopmental testing should take into account various features of TSC, including mental retardation, which is the most common, and other features, which are learning disabilities, autism, and attentional deficit. Repeat assessment around the time that a child enters school and then reassess periodically in response to educational and behavioral concerns.
  • Renal ultrasonography is recommended annually. Patients who have large renal lesions or lesions that have grown substantially should have more frequent follow-up examinations.
  • ECG is indicated in persons with arrhythmias or unexplained loss of consciousness. Repeat echocardiography is not required in asymptomatic patients. Any suggestion of cardiac dysfunction may merit investigations.
  • Pulmonary function testing is reserved for patients with pulmonary dysfunction and may be performed annually. Women should undergo chest CT scanning at least once on reaching adulthood.
• Evaluation of family members: In a family with only one child affected, evaluation of parents is more important than siblings or relatives.
• • Cranial CT scanning is more likely to detect lesions of tuberous sclerosis as a screening tool; MRI often detects lesions that are not as specific to TSC. MRI is the first choice; however, if the scan results are negative and the diagnosis is uncertain, then CT scanning may be performed.
  • Renal lesions occur in about 80% of patients, making renal ultrasonography an important screening test.
  • Echocardiography is not recommended unless compelling cardiac symptoms persuade otherwise because cardiac rhabdomyomas commonly disappear by adulthood.
  • Although molecular diagnosis is not yet commercially available, identifying some patients with TSC who do not fulfill clinical diagnostic criteria should soon be feasible.

Histologic Findings

Angiofibromas show atrophic sebaceous glands with dermal fibrosis and dilation of some of the capillaries. The fibrosis occasionally has a glial appearance because of the large size and stellate shape of the fibroblasts. Elastic tissue is absent in the angiofibromas.

The ungual fibromas show mainly fibrosis, rarely capillary dilation.

The shagreen patches show increased dense sclerotic mass of broad collagenous bundles. Normal collagen bundles may sometimes be arranged in an interwoven pattern. The elastic tissue is reduced.

The hypopigmented ash-leaf macule shows normal melanocyte numbers with decreased pigmentation. Electron microscopy shows smaller melanosomes with defective melanization.

TREATMENT

Section 6 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Medical Care

A multidisciplinary team approach is useful to address the many organ systems that may be affected. Periodic monitoring is necessary, ranging from 1-3 years, depending on the internal tumors and their manifestations. Treatment plans should be determined on an individual basis.

Recently, sirolimus has shown promise in regression of both subependymal giant cell astrocytomas and renal angiomyolipomas.

• Recommendations for epilepsy include the following:
  • Review current antiepileptic medications.
  • For new and unexplained behavior problems, mood changes, sleep disturbance, or nonconvulsive status, perform urgent brain scanning (MRI preferred to CT scanning) if symptoms and signs suggest raised intracranial pressure or if focal neurological symptoms or signs are present; perform EEG if applicable.
• Solid renal lesions with a low fat content on ultrasound should be carefully investigated by an expert
• Recommendations for assessment of renal disease include the following:
  • Measure blood pressure annually.
  • Test renal function (eg, urea, electrolyte, and plasma creatinine levels) regularly in adults and children with polycystic kidney disease.
  • Perform renal ultrasonography and repeat annually if a lesion has been documented or if otherwise indicated.
  • Refer the patient to a specialist clinic if frank hematuria occurs or if treatment of the renal lesion is being contemplated.
• Investigate for pervasive developmental disorders at age 2 years (eg, Childhood Autism Test [CHAT]) and again at school entry (ie, age 4-5 y). Perform an Alzheimer's Disease Information Questionnaire (ADIQ) if developmental delay is suspected.
• Screening for psychiatric and behavioral disturbances may require testing at school entry and again at age 7 years, at secondary school transition, and during mid adolescence (age 15 y). Refer the patient to a mental health specialist as required.
• If developmental delay is suspected, assess the patient's intellectual and cognitive profile at key stages in order to identify problems early and act accordingly (age 2-3 y, age 7-8 y). Access the need to place children and adults with learning disabilities and neuropsychological impairments in the care of specialists; also assess the need to refer patients to a community learning disabilities team (The Tuberous Sclerosis Association, 2002).

Surgical Care

The facial angiofibromas cause the most psychological distress for patients and benefit from laser treatment.

• The argon and pulsed-dye lasers are more effective on vascular lesions, while the carbon dioxide laser is effective in lesions with increased fibrous content.
• Either laser or diathermy can remove ungual fibromas.

Consultations

• Assess whether any of the following is needed:
• • Special education (with appropriate documentation)
  • Further vocational training or new work placement (refer to the local disablement resettlement officer if required)
  • Social care options (eg, supported or sheltered employment, daycare, supported leisure activities, supported/staffed sheltered housing, residential care)
• Investigate family members, when indicated, including a family history, a clinical examination (including skin evaluation with UV light), funduscopy, brain CT scanning or MRI, and genetic counseling.

FOLLOW-UP

Section 7 of 8  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

Further Outpatient Care

• Neurodevelopmental testing as age-appropriate screening for behavioral and neurodevelopmental dysfunction at the time of diagnosis is essential. Reassess children with abnormal test results periodically. Repeat assessment around the time that a child enters school and then reassess periodically in response to educational and behavioral concerns.

REFERENCES

Section 8 of 8

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• References

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• Tuberous Sclerosis Association. Clinical guidelines for the care of patients with Tuberous Sclerosis Complex. Available at: http://www.tuberous-sclerosis.org. Birmingham, England; April, 2002.
• Williams JM, Racadio JM, Johnson ND, et al. Embolization of renal angiomyolipomata in patients with tuberous sclerosiscomplex. Am J Kidney Dis. Jan 2006;47(1):95-102. [Medline].
• van Slegtenhorst M, Nellist M, Nagelkerken B, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet. Jun 1998;7(6):1053-7. [Medline].

Article Last Updated: Mar 19, 2007