▶Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with highly variable features.
▶Tuberous sclerosis complex is caused by mutations in 2 genes: TSC1 on chromosome 9 (encoding hamartin) and TSC2 on chromosome 16 (encoding tuberin).
▶The disorder is transmitted as an autosomal-dominant trait with high penetrance but markedly variable expressivity; two-thirds of cases represent new mutations.
Tuberous sclerosis complex involves abnormalities of the following systems:
▶Skin
■Hypomelanotic macules (ie, ash leaf macules): present at birth or soon thereafter; occur in 87% to 100% of patients (Figure 88.1)
■Facial angiofibromas (ie, adenoma sebaceum)
– Erythematous papules located in the nasolabial folds, nose, cheeks, or chin (Figure 88.2)
– Appear between 2 and 6 years of age; occur in 47% to 90% of patients
■Shagreen patches: plaques with a peau d’orange texture usually observed in the lumbosacral region (Figure 88.3); occur in 20% to 80% of patients
■Fibrous facial plaques: connective tissue nevi that may be present at birth
■Periungual fibromas: usually appear after puberty; observed in 17% to 80% of patients (Figure 88.4)
▶Brain: subependymal nodules (90%), seizures (80%), cortical tubers (70%), intellectual disability/developmental delay (50%), autism spectrum disorder (16%–61%)
▶Kidney: angiomyolipomas (70%), cysts
▶Heart: rhabdomyomas (47%–67%), arrhythmias
▶Eye: astrocytic hamartoma of the retina, optic disc, or both (up to 50% of patients)
▶Lungs: lymphangiomyomatosis (LAM) (30% of women)
Look-alikes
The constellation of clinical findings suggests the diagnosis of TSC and excludes other disorders. The differential diagnosis of hypopigmented macules and angiofibromas is presented here; however, in each of the conditions listed, other features of TSC would be absent.
Disorder | Differentiating Features |
Hypopigmented Macules | |
•Acquired disorder. •Affected areas exhibit complete pigment loss (ie, depigmentation), not hypopigmentation. •Predilection for elbows, knees, ankles, hips, fingers, and periorificial regions. •Tends to occur in symmetric fashion. | |
•Acquired disorder. •Poorly defined areas of macular hypopigmentation often with associated scale; most commonly involves the face. •Atopic history common. | |
•Acquired disorder. •Seen mainly in postpubertal individuals. •Well-defined hypopigmented macules and patches located on the trunk, proximal arms, or neck. •Lesions often have associated fine scale and may be pruritic. | |
Pigmentary mosaicism– nevus depigmentosus type | •Present at birth but may not become noticeable for months to years. •Hypopigmentation with a shaggy border. •Usually occurs unilaterally and respects the midline. •Typically larger than a hypopigmented macule. •Geographic or segmental distribution common. |
Pigmentary mosaicism– hypomelanosis of Ito type | •Present at birth but may not become noticeable for months to years. •Hypopigmentation that follows the Blaschko lines (ie, lines representing patterns of embryonic cell migration from the neural crest); presents as streaky lines on the extremities and whorls on the trunk. |
•Congenital absence of pigmentation localized to one area. •Associated poliosis (depigmentation of hair) may be present when involving face/scalp. •Rare associations with other abnormalities (eg, Waardenburg syndrome). | |
•Congenital area of pallor (may resemble hypopigmentation) resulting from diminished vascular flow to the affected region. •Diascopy (compressing the lesion with a glass slide) will cause blanching of surrounding normal skin, causing border of the lesion to disappear. | |
Angiofibromas | |
•Often appears later than angiofibromas. •Comedones (ie, blackheads and whiteheads) and pustules usually present. •Involvement of forehead, chest, shoulders, and back common. •Early acne usually limited to T-zone (ie, forehead, middle face/chin, nose). | |
•Usually translucent papules that may have a central umbilication. •Usually not symmetrically distributed and may be present at other (non-facial) sites. | |
•Typically exhibits small pustules and acneiform papules. •Erythema and scaling may be present, especially in nasolabial folds. •Concentrated in perioral, perirhinal, and periorbital regions. | |
•Small, rough-feeling (sandpaper-like), skin-colored or erythematous papules. •Keratin plug or hair emerging from follicular orifice may be observed or palpated. •Often located at other non-facial sites as well (eg, upper arms, thighs, buttocks). | |
▶Definite TSC requires the presence of 2 major features or 1 major and 2 or more minor features.
▶Possible TSC requires the presence of 1 major feature or 2 or more minor features.
▶Mutation analysis is available for diagnostic confirmation and prenatal diagnosis.
Major Features
▶3 or more hypomelanotic macules (at least 5 mm in diameter)
▶Facial angiofibromas (≥3) or forehead plaque
▶Periungual fibromas (≥2)
▶Shagreen patch (connective tissue nevus)
▶Multiple retinal hamartomas
▶Cortical dysplasias (includes tubers and cerebral white matter radial migration lines)
▶Subependymal nodules
▶Subependymal giant cell astrocytoma
▶Cardiac rhabdomyoma
▶Lymphangiomyomatosis
▶Angiomyolipoma (≥2)
Minor Features
▶“Confetti” hypopigmented macules
▶Dental enamel pits (≥3)
▶Intraoral fibromas (≥2)
▶Retinal achromic patch
▶Multiple renal cysts
▶Nonrenal hamartoma
▶Prompt diagnosis, treatment of the seizure disorder, surveillance for additional features and complications, and genetic counseling form the fundamental approach to management.
▶Multidisciplinary care is vital; subspecialties that may be involved in TSC patient care include genetics, neurology, ophthalmology, dermatology, nephrology, cardiology, oncology, pulmonology, orthopedic surgery, and dentistry.
▶Essential studies if considering the diagnosis include brain magnetic resonance imaging (MRI), neurodevelopmental testing, ophthalmologic evaluation, electrocardiography, echocardiography, and abdominal MRI (preferred over renal ultrasonography).
▶Several clinical trials are underway investigating the use of topical or systemic inhibitors of mammalian target of rapamycin (mTOR) for various manifestations of TSC.
■Everolimus has been approved for use in the treatment of subependymal giant cell astrocytoma associated with TSC.
■mTOR inhibitors are used to treat growing renal angiomyolipoma and severe lung disease caused by LAM.
■Topical mTOR inhibitors (especially sirolimus [rapamycin]) are being used to treat facial angiofibromas.
Treating Associated Conditions
▶Complete evaluation, as noted previously, should identify most of the associated problems; these should be managed appropriately.
▶Brain MRI should be repeated every 1 to 3 years in asymptomatic individuals younger than 25 years to monitor for subependymal giant cell astrocytoma.
▶Abdominal MRI (preferred over renal ultrasonography) should be performed every 1 to 3 years to monitor for angiomyolipoma and renal cystic disease.
▶Chest computed tomography should be performed if pulmonary symptoms are present (particularly in adult women to assess for pulmonary LAM).
Prognosis depends on
▶The extent of neurologic involvement and the development of central nervous system complications (Central nervous system tumors are the leading cause of morbidity and mortality.)
▶Complications in other organ systems
■Renal: second leading cause of early death in patients who have TSC
■Cardiovascular: rhabdomyomas (often regress spontaneously), cardiac arrhythmias
■Pulmonary: pulmonary LAM (usually affects adult women)
▶Presence of brain, cardiac, renal, or pulmonary tumors.
▶Consider referral for neurodevelopmental testing.
▶National Institute of Neurological Disorders and Stroke: Provides information about tuberous sclerosis and links to organizations providing support.
▶Tuberous Sclerosis Alliance: Provides support and information (in English and Spanish) for affected patients and their families. The organization also maintains a list of TSC clinics in the United States.
▶Tuberous Sclerosis Association: A site in the United Kingdom that provides information for patients and medical providers.