Tuberous Sclerosis

Tuberous sclerosis (TS; Bourneville disease) is an autosomal dominant disorder characterized by typical skin lesions and the growth of hamartomatous tumors of the CNS and other organs.
The classic triad of TS includes the following:
- Adenoma sebaceum
- Epilepsy
- Mental retardation, although at least 50% of affected persons show no evidence of mental retardation
TS has an incidence of 1 per 6,000 births.

TS results from mutations in TSC1 or TSC2, which encode for hamartin and tuberin, respectively.
Hamartin and tuberin act together to regulate cell differentiation and proliferation. Defects in these gene products may result in the growth of multiple hamartomas in TS.
An estimated 70% of patients with TS have a new mutation.

Ash-leaf macules are hypopigmented, characteristically oval, and sometimes linear or “confetti-shaped” macular lesions that are the earliest clinical feature of TS (Fig. 11.6).
The so-called adenoma sebaceum (actually angiofibromas) are pink to reddish-brown, dome-shaped papules most commonly located on the nose, nasolabial folds, and cheeks (Fig. 11.7).
Periungual fibromas (Koenen tumors) are smooth, firm, skin-colored papules (Fig. 11.8).
The characteristic “shagreen patch” is a pebbly, skin-colored “peau d'orange” or “pigskin-like” dermal plaque (collagenoma) that has fine hypopigmentation resembling confetti and most often appears in the lumbosacral region.
A fibrous forehead plaque may occur on the forehead, face or scalp and is usually present from birth (Fig. 11.9).
Ash-leaf macules and the fibrous forehead plaque are usually present at birth.
Adenoma sebaceum may begin to develop in late childhood and adolescence.

Central Nervous System Lesions

Gliomatous brain tumors (tubers), which may calcify in 50% of patients
Seizure disorders in 70% to 80% of patients, with fewer than 50% showing evidence of mental retardation
Retinal and optic nerve gliomas

Other Findings

Renal involvement is common and is usually apparent in the first decade. Typically presents as renal hamartomas (angiomyolipomas) or less often as renal cysts.
Bone changes, mostly bone cyst formation and sclerosis, are also common in TS.
Cardiac rhabdomyomas of the atrium occur in 50% to 60% of patients but rarely cause cardiac obstructive disease and tend to regress spontaneously.
Less common clinical findings include retinal hamartomas (called phakomas), gastrointestinal tumors, and pulmonary lymphangioleiomyomatosis.
Pits in the tooth enamel are another marker of TS.

Outline
Central Nervous System Lesions
Other Findings

Diagnosis of TS requires the presence of two major or one major and two minor criteria:

Major Diagnostic Criteria

Minor Diagnostic Criteria

Multiple dental enamel pits
Hamartomatous rectal polyp
Bone cyst
Gingival fibroma
Nonrenal hamartoma
Retinal achromic patch
Confetti skin lesions: fine, hypopigmented macules (2 to 4 mm) that look as though they are “sprinkled” on the lower legs
Multiple renal cysts

Outline
Major Diagnostic Criteria
Minor Diagnostic Criteria

Laboratory Evaluation

Cranial MRI to identify cortical tubers
Posteroanterior and lateral skull films (for adults) to demonstrate calcifications of gliomas of the brain
Echocardiography to detect rhabdomyomas
Renal ultrasonograms to search for tumors
Skin biopsy of cutaneous lesions

Differential Diagnosis of Adenoma Sebaceum

Acneiform papules

Differential Diagnosis of Ash-Leaf Macules

Nevus depigmentosus (see Chapter 1: Birthmarks)

An ND is often difficult to distinguish from an ash-leaf macule.
NDs are well-demarcated hypopigmented patches often seen at birth or within the first years of life.
ND is usually a solitary lesion but occasionally multiple lesions or a segmental lesion is present.

Vitiligo

Depigmented patches variably sized, that will appear “chalk white” with Wood lamp examination.

Management

Prognosis of TS depends on the severity of the condition and the presence of neurologic involvement.
Parents should be educated about association and genetic basis of condition.
Patients should have close surveillance for development of seizures and mental retardation.
Patients with TS should also be monitored for the development of brain, cardiac, renal, bony, lung, or eye tumors.
Removal of cosmetically objectionable or disfiguring adenoma sebaceum by excision, electrocautery, dermabrasion, or laser resurfacing.
Rapamycin has shown promising results for the treatment of tumors associated with TS. The topical form is effective for facial angiofibromas (adenoma sebaceum).
Painful periungual fibromas can be removed surgically.
Genetic counseling of patients with TS and their families after computed tomographic scanning is performed on the parents and siblings of the affected patient (these studies have demonstrated CNS lesions in asymptomatic parents of TS patients).

Helpful Hints

In general, patients with mutations in TSC1 have a milder course.
Ash-leaf macules are hypopigmented not depigmented.
Families dealing with TS should be made aware of support networks including the Tuberous Sclerosis Alliance (www.tsalliance.org).