BASICS

DESCRIPTION

Tuberous sclerosis (TS) is a rare multisystem syndrome with a classic triad of findings including: Infantile seizures, adenoma sebaceum of facial skin, and mental retardation.

EPIDEMIOLOGY

Incidence

10–16 per 100,000 live births

Prevalence

7–12 per 100,000

RISK FACTORS

Family history

Genetics

Autosomal dominant

GENERAL PREVENTION

Genetic counseling

PATHOPHYSIOLOGY

Hamartin (gene: TSC1) and tuberin (gene: TSC2) on chromosome 9, act as a single unit in the mTOR signaling pathway controlling cell division and growth. Defects in these genes lead to unregulated hamartomatous growth in multiple body sites.

ETIOLOGY

Many different mutations have been identified in both the TSC1 and TSC2 genes.

COMMONLY ASSOCIATED CONDITIONS

None

DIAGNOSIS

HISTORY

• Careful family history and physical exam of family members

• Infantile seizures/spasms

– Usually last a few seconds and involve rapid nodding of the head and myoclonic spasms of the limbs

• Facial adenomatous rash

• Developmental delay

PHYSICAL EXAM

• Skin

– Facial adenoma sebaceum

– Ash-leaf spots (using a Wood’s lamp)

– Subungual fibromas

– Café-au-lait spots (rare)

• Eye

– Optic disc or peripheral retinal astrocytic hamartomas

– Hypopigmented lesions

– Coloboma (rare)

– Papilledema (in cases of hydrocephalus)

– Rarely: Vitreous hemorrhage, retinal neovascularization, retinal exudation or detachment, and vitreous seeding

• Oral cavity

– Pitting of enamel

– Gingival fibromas

• Pulmonary

– Abnormal lung sounds

– Evidence of pneumothorax

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Basic metabolic panel: Look specifically at renal function

• Urinalysis: Look for hematuria

Imaging

Initial approach

• MRI/CT (MRI is preferred)

– Periventricular calcified subependymal nodules

• Echocardiogram

– Cardiac rhabdomyoma

• Renal ultrasound

– Renal angiomyolipoma

– Polycystic kidney disease, renal cell carcinoma (rare)

• Chest X-ray/CT

– Parenchymal and subpleural cystic changes, pneumothorax

• Skeletal X-ray

– Sclerotic areas with focal calcification involving the skull and spine

– Cysts in the phalanges of the hands and feet

Follow-up & special considerations

Routine surveillance for new tumors, or growth of existing tumors

Diagnostic Procedures/Other

• No reliable genetic testing available

• Patient is categorized as definite, probable, or suspect for TS on the basis of constellation of findings

– Definite: 2 major features or 1 major feature plus 2 minor features

– Probable: 1 major plus 1 minor feature

– Suspect: 1 major feature or 2 or more minor features

• Major features

– Facial angiofibromas

– Ungual fibromas

– Ash-leaf spots

– Shagreen’s patch

– Multiple retinal astrocytic hamartomas

– Cortical brain tuber

– Subependymal brain nodule

– Subependymal giant cell astrocytoma

– Cardiac rhabdomyoma

– Lymphangioleiomyomatosis of the lungs

– Renal angiomyolipoma

• Minor features

– Pitting of dental enamel

– Gingival fibromas

– Nonrenal hamartoma (liver, spleen, etc.)

– Rectal hamartoma polyps

– Bone cysts

– Brain white matter “migration tracts”

– Retinal hypopigmented patch

– Multiple renal cysts

– “Confetti” skin lesions

Pathological Findings

• CNS: Astrocytic hamartoma—large, well-differentiated, astrocytes with calcium

• Skin: Adenoma sebaceum—benign angiofibroma

• Skin: Ash-leaf spot: Amelanotic nevus

• Retina: Astrocytic hamartoma

– Endophytic: in the nerve fiber layer

– Exophytic: In the subretinal space

– Can slowly enlarge, and rarely exude fluid causing retinal detachment or vitreous seeding (simulating retinoblastoma)

– Composed of large pleomorphic astrocytes with focal calcification

• Renal: Angiomyolipoma—composed of HMB-45+ spindle cells; can occur in the renal medulla, cortex, or capsule

• Pulmonary: Lymphangioleiomyomatosis consists of a proliferation of HMB-45+ smooth muscle-like cells growing along the walls of airways and blood vessels.

DIFFERENTIAL DIAGNOSIS

• Differential diagnosis of a retinal astrocytic hamartoma

– Retinoblastoma

– Optic disc drusen

– Retinal astrocytoma (solitary lesion, identical to retinal lesions of TS. Lesions in TS are often multiple)

– Coats’ disease

– Toxocariasis

– Myelinated nerve fiber layer

TREATMENT

MEDICATION

First Line

• Drugs to control symptoms

• Anti-epileptics for seizure control

Second Line

Rapamycin has been used (Experimental) in mice to reduce learning deficits in TS.

ADDITIONAL TREATMENT

General Measures

Routine surveillance for new tumors, or growth of existing tumors

Issues for Referral

• Pediatrics and Genetics for diagnosis and family counseling

• Neurology for seizures and CNS involvement

• Cardiology for rhabdomyoma

• Nephrology, if kidney involvement is severe

• Pulmonary, if lung involvement is severe

• Ophthalmology/retina examination to look for astrocytic hamartomas, often crucial for diagnosis

Additional Therapies

Genetic counseling for patient and family

SURGERY/OTHER PROCEDURES

• Neurosurgery for obstructive hydrocephalus

• Renal transplant for end-stage renal failure

• Lung transplant (rare) for severe lung involvement

• Pars plana vitrectomy (rare) for vitreous hemorrhage or retinal detachment

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Routine surveillance for new tumors or growth of existing tumors

Patient Monitoring

• Monitor for changes in mental status or seizure control

• Monitor for changes in lung function

DIET

No special diet

PATIENT EDUCATION

• Tuberous Sclerosis Alliance

– www.tsalliance.org/

PROGNOSIS

Life expectancy can be normal

COMPLICATIONS

• Cardiac rhabdomyomas can cause obstructive heart failure or arrhythmia, usually in infancy

• Renal failure can be progressive and require renal transplant

• Pulmonary involvement can be progressive

– Can present with pneumothorax

– Severe lymphangioleiomyomatosis of the lungs is more common in females

• Neurologic complications include hydrocephalus, severe mental retardation, and (rarely) status epilepticus

• Ocular complications are rare but can include visual field defects, vitreous hemorrhage, and retinal detachment

ADDITIONAL READING

• Roach ES, Smith M, Huttenlocher P, et al. Diagnostic criteria: Tuberous sclerosis complex, Report of the diagnostic criteria committee of the National Tuberous Sclerosis Association. J Child Neurol 1992;7:22–24.

• Rowley SA, O’Callaghan FJ, Osborne JP. Ophthalmic manifestations of tuberous sclerosis: A population-based study. Br J Ophthalmol 2001;85:420–423.

• Williams R, Taylor D. Tuberous sclerosis. Surv Ophthalmol 1985;30:143–153.

CODES

ICD9

• 362.89 Other retinal disorders

• 759.5 Tuberous sclerosis

• 759.6 Other congenital hamartoses, not elsewhere classified

CLINICAL PEARLS

• Hypopigmented macules (“Ash-leaf spots”), best seen with a Wood’s lamp, are often the only finding of TS present at birth.

• Cardiac rhabdomyomas enlarge during late gestation and early infancy and tend to regress thereafter.

• Retinal astrocytic hamartoma, found in ∼50% of TS patients, can occur as a solitary lesion in normal patients, but can be multiple and bilateral in TS.

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