Tuberous Sclerosis Complex (Bourneville Disease, Bourneville Phakomatosis)

Are You Confident of the Diagnosis?

  • What you should be alert for in the history

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic condition characterized by hypomelanotic macules (Figure 1), hamartomas, and intellectual disability in 50% of those affected, as well as infantile spasms and/or seizure disorder in approximately 80% of affected individuals.

Figure 1.

Hypomelanotic macules.

Hamartomas occur most commonly in the brain, skin, kidneys, retina, lung, and heart, although any organ may be affected. A past medical history of infantile spasms, seizure disorder and/or intellectual disability in someone with hypomelanotic macules should raise suspicion of TSC. Additional past medical history suspicious for TSC includes tumor in the heart (cardiac rhabdomyomas) as an infant or child that have since resolved, cysts or tumors of the kidneys, benign brain tumors (cortical tubers, subependymal nodules), or a history of brain surgery to remove a tumor (subependymal giant cell tumor), as well as autistic-like behaviors.

  • Characteristic findings on physical examination

Multiple hypomelanotic macules/patches are present in greater than 90% of individuals with TSC, while approximately 1% of the general population has two or fewer hypomelanotic lesions. Generally present at birth or developing in early childhood, hypomelanotic macules/patches may be solitary lesions dispersed throughout the body or they can occur as a grouping of 1-3 mm macules referred to as “confetti” lesions. When hypomelanotic macules occur on the scalp, eyebrows, or eyelashes, the hair over the hypomelanotic area may be white (poliosis) (Figure 2). Hypomelanotic macules can be easily identified with the use of an ultraviolet Wood’s lamp in a darkened room; this can be particularly helpful when examining lighter-skinned individuals.

Figure 2.


Multiple facial angiofibromas are present in approximately 50-90% of individuals with TSC (Figure 3). Angiofibromas typically develop in late childhood or adolescence. These appear as papules, located primarily in the central portion of the face, ranging in color from pink to brown, depending upon the skin pigmentation of the affected individual. Angiofibromas grow during childhood and adolescence, but are generally stable in size during adulthood. Multiple angiofibromas may coalesce in the nasolabial folds. Angiofibromas are quite vascular and may bleed with minimal trauma.

Figure 3.


Fibrous facial plaques are connective tissue nevi present in 20-40% of individuals with TSC. These lesions have also been called “forehead” plaques, as the forehead is the most common cutaneous location. Fibrous facial plaques present as single or multiple raised rubbery lesions of the face, neck, and/or scalp, and range in color from lightly pigmented to pink, to darkly-pigmented (Figure 4). These plaques may be present at birth or develop during childhood.

Figure 4.

Fibrous facial plaques.

Shagreen patches are single or multiple connective tissue nevi present in 20-80% of individuals with TSC. These patches may be flesh-colored or more darkly-pigmented than the surrounding skin. Shagreen patches are plaques with an irregular surface, typically located in the lumbosacral area. These cutaneous markers for TSC may be present at birth, but most commonly develop during childhood.

Ungual fibromas are present in 20%-90% of individuals with TSC (Figure 5). These periungual or ungual papules develop during late childhood or adulthood. The ungual fibromas of TSC can be distinguished from traumatic ungual fibromas in that those associated with TSC are typically multiple and not associated with trauma, while traumatic ungual fibromas are typically singular and, as the name suggests, often present with history of trauma to the area. Fibromas may be periungual (arising from under the proximal nail fold) or subungual (arising from beneath the nail plate). Either rounded and flesh-colored or, alternatively, ungual fibromas may have a hyperkeratotic tip resembling a nail.

Gingival fibromas and dental pits Figure 6, Figure 7) may be present on physical examination as well.

Figure 5.

Periungual fibromas.

Figure 6.

Gingival fibromas.

Figure 7.

Dental pits.

  • Expected results of diagnostic studies


– Histopathology of hypomelanotic macules: a paucity of melanosomes, which are decreased in size and melanization. Melanocytes themselves are normal in number, but have poorly developed dendritic processes.

– Histopathology of facial angiofibromas: elevated lesions with a proliferation of stellate spindle-shaped, or multinucleated fibroblasts in a collagenous stroma. The collagen fibers are oriented perpendicularly to the epidermis and concentrically around follicles and dilated vessels.

– Histopathology of fibrous facial plaques: thick layers of sclerotic collagen, arranged concentrically around atrophic pilosebaceous glands. Unlike angiofibromas, fibrous facial plaques do not show proliferation and dilation of capillaries.

– Histopathology of the shagreen patch: dense, sclerotic bundles of collagen in the dermis, generally with reduced amounts of elastic tissue.

– Histopathology of the ungual and periungual fibromas: dermal proliferation of stellate fibroblasts, similar to angiofibromas, but with overlapping hyperkeratosis and occasionally with capillary dilation.


Mutations of two genes, TSC1 and TSC2, are known to cause TSC. Most mutations in TSC1 and TSC2 can be detected with gene sequencing; however, sequencing techniques are not able to detect large deletions and duplications, therefore if gene sequencing for TSC1 and TSC2 is negative, deletion/duplication testing for TSC1 and TSC2 is recommended. A mutation in TSC1 or TSC2 is discovered in approximately 80% of individuals with TSC; in the remaining 20% no mutation can be identified. Individuals who have no mutation identified may have mutations in TSC1 or TSC2 that cannot be detected with current testing technology or there may be additional, as yet unidentified genes, mutations of which cause TSC.

The diagnosis of TSC is based on specific major and minor diagnostic clinical features, as outlined in the Clinical Consensus statement first published in 1998 and most recently revised in 2004. A definite diagnosis of TSC is made when an individual has two major features or one major feature and two minor features. A probable diagnosis of TSC is made when an individual has one major feature and one minor feature. A possible diagnosis of TSC is made when an individual has one major feature or two or more minor features.

Major diagnostic features of TSC include:

– Facial angiofibromas

– Fibrous facial plaques

– Nontraumatic ungual or periungual fibromas

– Three or more hypomelanotic macules

– Shagreen patch

– Multiple retinal nodular hamartomas

– Cortical tuber

– Subependymal nodule

– Subependymal giant cell astrocytoma

– Cardiac rhabdomyoma (single or multiple)

– Lymphangioleiomyomatosis

– Renal angiomyolipoma

Minor diagnostic features of TSC include:

– Multiple randomly distributed pits in dental enamel

– Histologically confirmed hamartomatous rectal polyps

– Bone cysts

– Cerebral white matter radial migration lines

– Gingival fibromas

– Histologically confirmed nonrenal hamartomas

– Retinal achromic patch

– “Confetti” skin lesions

– Multiple renal cysts

Imaging studies (brain magnetic resonance imaging (MRI), renal MRI, and echocardiogram) should be obtained in order to evaluate the extent of disease in an individual who is found to have a mutation in TSC1 or TSC2. Imaging studies are needed to make a clinical diagnosis of TSC in an individual who has features of TSC, but in whom no mutation has been identified.

Characteristic findings in individuals with TSC include:

– Subependymal nodules, cortical tubers, and/or subependymal giant cell tumor, with or without hydrocephalus in the brain, are all detectable by MRI.

– Epithelial cysts or angiomyolipomas are detectable by renal MRI. Renal MRI should be performed when an individual is suspected to have TSC or as an initial evaluation in individuals with mutations in TSC1 or TSC2. Renal oncocytomas, renal cell carcinoma, and malignant transformation of angiomyolipomas may also occur in TSC-affected individuals.

– Single or multiple intracardiac masses consistent with rhabdomyomas are detectable by echocardiogram.

– Renal cysts and/or masses consistent with angiomyolipoma (which can be mistaken for renal carcinoma on ultrasound examination) are observed on ultrasound examination of the kidneys.

– Lymphangioleiomyomatosis (LAM), which appears on chest x-ray as diffuse coarse reticular opacities with normal to increased lung volumes. The imaging modality of choice for evaluation of possible LAM is a high-resolution chest computed tomography (CT).

– Uniform thin-walled cysts, distributed throughout the lung as revealed by high resolution chest CT in individuals with LAM.

Additional studies:

– Electrocardiography (ECG/EKG) may reveal arrhythmias.

– Electroencephalography (EEG) may indicate the presence of infantile spasms or seizures.

– Ophthalmologic examination, used to aid in diagnosis, may reveal retinal achromic patches or multiple retinal hamartomas.

– Neurodevelopmental and behavioral evaluation (should be obtained at the time of initial diagnosis and regularly thereafter).

  • Diagnosis confirmation

Differential diagnosis of TSC:

The differential diagnosis of TSC includes Birt-Hogg-Dubé syndrome, linear sebaceous nevus syndrome (also known as Schimmelpenning-Feuerstein-Mims syndrome), seizure disorder, or any syndrome of which seizures are a major characteristic, as well as a condition characterized by isolated LAM and renal angiomyolipomas, but no additional findings of TSC.

Birt-Hogg-Dubé syndrome is an autosomal dominant disorder caused by mutations in the FLCN gene, characterized by cutaneous manifestations, including angiofibromas, fibrofolliculomas, trichodiscomas, arocordons, collagenomas, pulmonary manifestations (pneumothorax), and renal cell carcinoma. This disorder may be distinguished from TSC in that the cutaneous manifestations of Birt-Hogg-Dubé do not include hypomelanotic macules, renal tumors do not include angiomyolipomas, and other manifestations of TSC (e.g., cortical tubers) are absent. Molecular genetic testing is available for both Birt-Hogg-Dubé syndrome and TSC.

Linear sebaceous nevus syndrome is an oculocutaneous syndrome characterized by central nervous system abnormalities that include intellectual disabilities and seizure disorder, and ophthalmologic abnormalities that include coloboma and skeletal anomalies. Individuals with TSC who have a seizure disorder typically have cortical tubers present on brain imaging which would not be present in individuals with linear sebaceous nevus syndrome.

The characteristic ocular abnormalities of TSC are retinal hamartomas and retinal achromic patches; coloboma is not a feature of TSC. Additionally, the other characteristic skin lesions, brain lesions, and renal findings of TSC are not present in linear sebaceous nevus syndrome.

Some individuals with isolated LAM may have renal angiomyolipomas, but do not have TSC. Given this, individuals who have LAM and renal angiomyolipomas (which are both major clinical features) must have additional major or minor clinical diagnostic features of TSC in order to be given a diagnosis of TSC.

Differential diagnosis of specific dermatologic manifestations of TSC:

The differential diagnosis of the hypomelanotic macules of TSC includes nevus anemicus, nevus depigmentosus, piebaldism, vitiligo, Vogt-Koyanagi-Harada syndrome, and Waardenburg syndrome.

– Nevus anemicus is a pharmacologic vascular abnormality that can be distinguished from a hypomelanotic macule with the placement of a glass slide on the border of the lesion. When pressure is applied, the border of the nevus anemicus will disappear, while a hypomelanotic macule will remain.

– Nevus depigmentosus occurs in the general population and is characterized by a light-colored macule on the skin that is present from birth. While the histology of a nevus depigmentosus is similar to the hypomelanotic macules of TSC, the lesions of the nevus depigmentosus are generally solitary, whereas individuals with TSC typically have multiple hypopigmented macules.

– Piebaldism is a rare autosomal dominant condition characterized by a white forelock with depigmentation of the surrounding skin, as well as areas of depigmentation on the body. Unlike the hypopigmented lesions of TSC, the lesions of piebaldism are depigmented, lacking melanocytes.

– Similarly, vitiligo is characterized by a lack of melanocytes, resulting in depigmentation rather than hypopigmentation, as is seen in TSC. Vitiligo is characterized by patches of depigmentation throughout the body that change in size and shape over time.

– Vogt-Koyanagi-Harada syndrome is characterized by bilateral granulomatous uveitis with poliosis and vitiligo. Uveitis is not a characteristic of TSC. Vogt-Koyanagi-Harada syndrome is rare during infancy and childhood.

– Waardenburg syndrome (Types I-IV) is also characterized by a white or hypopigmented forelock, varying degrees of hearing impairment, and depigmentation or hypopigmentation of the skin. Hearing impairment is not a characteristic feature of TSC.

In addition to TSC, facial angiofibromas may occur in multiple endocrine neoplasia type 1 (MEN1), Birt-Hogg-Dubé syndrome, or as a solitary lesion in the general population. Facial angiofibromas may be mistaken for acne vulgaris, acne rosacea, or multiple trichoepithelioma, although these lesions are easily distinguished with histopathology if there is uncertainty of diagnosis based on the physical examination.

– MEN1 is an autosomal dominant tumor predisposition syndrome caused by mutations in the MEN1 gene that may present with nonendocrine or endocrine tumors, including parathyroid tumors, pituitary tumors, well-differentiated endocrine tumors of the gastro-entero-pancreatic tract, carcinoid tumors, and adrenocorticoid tumors. Angiofibromas are one manifestation of the nonendocrine tumors associated with MEN1. Endocrine tumors are not associated with TSC. Additionally, individuals with TSC will frequently have additional clinical findings to support the diagnosis (cortical tubers, hypomelanotic macules, etc.).

– Birt-Hogg-Dube (see previous description)

The differential diagnosis of the fibrous facial plaques of TSC includes nevus sebaceous:

– Nevus sebaceous is a congenital lesion that typically occurs on the scalp, although this cutaneous plaque may occur on the face. The nevus sebaceous is characteristically yellowish in color, with alopecia at the site of the lesion due to the replacement of the follicular appendages with sebaceous glands. Individuals with linear sebaceous nevus syndrome may have intellectual disabilities and seizure disorder, making differentiation from TSC more difficult. The fibrous facial plaques of TSC may occur on the scalp, but are not always associated with alopecia, as are nevi sebaceous.

Individuals with TSC who have a seizure disorder typically have cortical tubers present on brain imaging that would not be present in individuals with linear sebaceousnevus syndrome. Additionally, the other characteristic skin lesions and renal findings of TSC are not present in linear sebaceous nevus syndrome.

The differential diagnosis of the shagreen patch of TSC includes several syndromes associated with connective tissue nevi including MEN1, Birt-Hogg-Dubé syndrome, Buschke-Ollendorff syndrome, Cowden syndrome, familial cutaneous collagenoma, or eruptive collagenoma, as well as an isolated collagenoma.

– The connective tissue nevi (collagenomas) associated with MEN1 occur on the proximal extremities as well as the trunk, unlike the shagreen patch of TSC, which is typically located on the lower back.

– The connective tissue nevi (collagenomas) associated with Birt-Hogg-Dubé syndrome can rarely resemble the shagreen patch of TSC. Differentiation between Birt-Hogg-Dubé syndrome and TSC can be made based on the presence of other characteristic features of TSC, keeping in mind that individuals with Birt-Hogg-Dubé may also have facial angiofibromas and renal tumors (although not renal angiomyolipomas).

– Buschke-Ollendorff syndrome is an autosomal dominant disorder caused by mutations in the LEMD3 gene and characterized by the presence of disseminated connective tissue nevi (elastomas or collagenomas) and osteopoikilosis. Plaques associated with Buschke-Ollendorff syndrome may occur anywhere on the body, unlike the shagreen patches of TSC, which typically occur on the lower back. Osteopoikilosis is not associated with TSC.

– Cowden syndrome is an autosomal dominant condition caused by mutations in the PTEN gene that has characteristic cutaneous lesions (multiple hamartomas, tricholemmomas) and confers an increased risk for breast, thyroid, and endometrial cancers. The connective tissue nevi (collagenomas) of Cowden syndrome occur in multiple areas of the body, rather than on the lower back as do the shagreen patches of TSC. Cowden syndrome and TSC can be easily distinguished based on other clinical characteristics (e.g. hypomelanotic macules, cortical tubers, renal angiomyolipomas in TSC).

– Familial cutaneous collagenoma, eruptive collagenoma, and isolated collagenoma do not exhibit other characteristic features of TSC (cortical tuber, renal angiomyolipomas, etc.).

Who is at Risk for Developing this Disease?

Tuberous sclerosis complex is an autosomal dominant disorder. With each pregnancy, individuals with TSC have a 50% chance of passing on TSC to their children. One-third of individuals with TSC have inherited it from a parent, while the remaining two-thirds have TSC as the result of a new (de novo) mutation in the TSC1 or TSC2 gene. TSC is seen with similar frequency (~1/10,000) in all races and ethnicities.

What is the Cause of the Disease?

  • Etiology

Tuberous sclerosis complex is caused by mutations in one of two known tumor suppressor genes, TSC1 and TSC2, located on chromosomes 9q34 and 16p13.3, respectively. Twenty percent of TSC is caused by mutations in TSC1, 60% is due to mutations in TSC2, and in the remaining 20%, no mutation is identified.

Knudson’s two-hit hypothesis has been used to explain many of the lesions of TSC. Individuals with TSC are born with one mutated copy of either the TSC1 gene or the TSC2 gene in every cell of their body. A somatic mutation, or a “second hit” may then occur in a tissue, causing loss of all TSC1 or TSC2 tumor suppressor function in that cell, leading to overgrowth.

Not all of the lesions of TSC can be explained using Knudson’s two-hit hypothesis, as the cortical tubers and a significant portion of the cardiac rhabdomyomas of TSC have not been shown to exhibit loss of the normal functioning allele (also called loss of heterozygosity). This suggests that at least some manifestations of TSC are due to other factors such as haploinsufficiency (i.e. a single functioning copy of the TSC1 or TSC2 gene in every cell is not sufficient to prevent disease) or modifier genes.

  • Pathophysiology

TSC1 and TSC2 function as tumor suppressor genes. TSC1 encodes the protein hamartin while TSC2 encodes the protein tuberin. Together, hamartin and tuberin form a functional complex, referred to as the TSC1/TSC2 complex. The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase important for regulation of cell growth, proliferation, and motility, protein synthesis and transcription.

One activator of mTOR is Rheb (Ras homolog enriched in brain). The normal function of the TSC1/TSC2 complex is to inhibit Rheb so that it is unable to activate mTOR, thereby limiting cell growth and proliferation. Mutations in TSC1 or TSC2 can lead to improper (or lack of) function of the TSC1/TSC2 complex, releasing the inhibition of mTOR via TSC1/TSC2 complex inhibition of Rheb, and leading to cell overgrowth and proliferation.

Systemic Implications and Complications

Central nervous system manifestations of TSC (including behavioral and neuropsychiatric) contribute to the majority of the morbidity and mortality of the disease and include subependymal nodules, cortical tubers, subependymal giant cell tumors, infantile spasms, seizures, intellectual disability, learning disabilities, autism, and attention deficit hyperactivity disorder.

Subependymal nodules are present in 90% of individuals with TSC. These are benign asymptomatic lesions lining the ventricles that may calcify. Subependymal nodules are a major clinical feature that can be quite useful in the diagnosis of TSC. These lesions can be detected by either brain MRI or CT, although MRI is the preferred imaging modality.

Cortical tubers are present in 70% of individuals with TSC, and are a major contributing factor to the presence of seizures, which occur in 80% of individuals with TSC. Like subependymal nodules, they can be detected by either brain MRI or CT, but MRI is preferred because the lesions can be better defined with MRI.

First-line treatment for individuals with TSC who have infantile spasms or seizures is vigabatrin. For cases in which seizure control may not be adequately obtained with vigabatrin or other anti-epileptic medications, surgical intervention may be necessary in order to remove a seizure focus. Early control of seizures through medical or surgical means is ideal, and likely to lead to a more favorable overall outcome for the patient. Brain MRI should be performed every 1 to 3 years, or more frequently, as dictated by the individual needs of the patient. EEG should be performed as clinically indicated (i.e., in individuals with suspected or known seizures).

Subependymal giant cell tumors (also referred to as subependymal giant cell astrocytomas or SEGAs) are thought to develop from subependymal nodules and occur in approximately 5%-15% of individuals with TSC. Like subependymal nodules and cortical tubers, subependymal giant cell tumors are not malignant tumors; however, they have a predilection for the foramen of Monro and can cause obstruction of CSF flow within the ventricles, leading to obstructive hydrocephalus if they become too large.

They are slow-growing tumors that typically occur in individuals with TSC younger than 20 years of age, although they can occasionally present in adulthood as well. On brain MRI they appear as an intraventricular mass, most often near the foramen of Monro.

Until recently, the only treatment option for individuals with symptomatic subependymal giant cell tumors was surgery; however, in October 2010 the United States Food and Drug Administration (FDA) approved the use of everolimus (Afinitor, Novartis) as treatment for subependymal giant cell tumors in adults and children over the age of 3 years. Everolimus is an analog of rapamycin (sirolimus). Like sirolimus, everolimus inhibits mTOR, thereby decreasing cell growth and proliferation, such as in the case of subependymal giant cell tumor growth.

After the initial diagnosis of TSC is made, formal cognitive and behavioral testing should be performed to obtain the baseline level of the individual. Follow-up testing is recommended during the first year of life, second year of life, between age 3 years and entry to preschool, again at age 6-8 years, age 9-12 years, age 13-16 years, age 18 years, and thereafter on a regular basis throughout adulthood. Formal cognitive and behavioral testing should also be obtained at any time there is a change in behavior.

Ophthalmologic manifestations of TSC include retinal achromic patches or multiple retinal hamartomas (“mulberry lesions”). Ophthalmological examination should be performed in individuals being evaluated for possible TSC. Even though these lesions are typically asymptomatic, they are useful for clinical diagnosis of TSC.

Renal manifestations of TSC include epithelial cysts and angiomyolipomas. Less commonly, renal oncocytomas, renal cell carcinoma, and malignant transformation of angiomyolipomas may also occur. Renal manifestations are the second leading cause of morbidity and mortality in individuals with TSC, after the neurologic manifestations. Initial evaluation of individuals with suspected TSC includes renal MRI.

Previously, the initial imaging modality for the kidneys was renal ultrasound because of its ease of use and low cost; however, more recent studies recommend MRI, given the higher quality of the image obtained and lack of radiation that is associated with CT.

Angiomyolipomas are the most common renal lesions in individuals with TSC. They are hamartomatous lesions present in 70% of individuals with TSC, composed of vascular (angio), smooth muscle (myo), and fat (lipo) tissues. Angiomyolipomas are PEComas (perivascular epitheliod cell-oma), mensenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells.

Typically, renal angiomyolipomas appear in childhood and continue to grow slowly as the patients enter adulthood. When angiomyolipomas reach 4cm in size, there is an increased risk of spontaneous hemorrhage. Treatment of angiomyolipomas with embolization may allow sparing of functional renal tissue and protect the kidney from damage caused by hemorrhage, or replacement/damage of renal parenchymal tissue caused by overgrowth of angiomyolipomas.

Renal epithelial cysts are seen in 20%-30% of individuals with TSC, making them the second most common renal manifestation of TSC. They may be single or multiple, and like angiomyolipomas, they typically present in childhood. Rare individuals with TSC have a contiguous gene deletion syndrome in which there is a deletion of part or all of both the TSC2 gene and the PKD1 gene (mutations of PKD1 cause autosomal dominant polycystic kidney disease), as these two genes are located next to one another on chromosome 16. These individuals have both polycystic kidney disease and TSC and, understandably, their renal prognosis is much less favorable than that of individuals who have TSC.

Renal oncocytomas and malignant transformation of angiomyolipomas occur in less than 1% of individuals with TSC. Renal cell carcinoma is not extremely common in individuals with TSC but it does occur more frequently than in the general population and at a younger age, affecting approximately 3% of individuals with TSC.

Cardiac and vascular manifestations of TSC include rhabdomyomas, arrhythmias, and arterial aneurysms. Cardiac rhabdomyomas are the earliest identifiable hamartomas of TSC. These occur in approximately 50-70% of individuals with TSC, and are most frequently detected prenatally or in the neonatal period. While the tumors themselves are benign, they may cause inflow or outflow obstruction, cardiac arrhythmias, or impair ventricular function and lead to congestive heart failure in 2-5% of individuals with TSC. Replacement of ventricular cardiac muscle by tumor tissue can lead to cardiomyopathy as well in up to 4% of individuals with TSC.

Despite these possible complications, the overwhelming majority of cardiac rhabdomyomas in individuals with TSC spontaneously regress, and in most cases, there is no need for surgical intervention. Occasionally, cardiac rhabdomyomas occur de novo at puberty, or persist from infancy, and present with increasing size at puberty. As in the neonatal period, intervention is only required in cases of cardiac compromise; the vast majority of cardiac rhabdomyomas are asymptomatic. Of note, ACTH, which can be used to treat infantile spasms, has been found to lead to an increase in the size of cardiac rhabdomyomas and, consequently, is contraindicated in individuals with TSC who have cardiac rhabdomyomas.

Cardiac arrhythmias sometimes occur in individuals with TSC, with or without associated cardiac rhabdomyomas, and are treated with anti-arrhythmic medications.

Some individuals with TSC develop arterial aneurysms, including abdominal or thoracic aortic aneurysms, as well as carotid and cerebral arterial aneurysms. These findings can occur in adults or children. Approximately twenty cases of aortic arterial aneurysms have been reported in the literature to date, although the actual incidence of arterial aneurysms in individuals with TSC is unknown.

Aortic aneurysms have been found in infants with TSC as young as 4.5 months of age, while the mean age of aortic aneurysms is 5 years. Some authors recommend screening for aortic aneurysms concurrent with renal imaging, as aortic aneurysms may progress rapidly and are associated with up to a 40% mortality.

Pulmonary manifestations of TSC include LAM and multifocal micronodular pneumocyte hyperplasia (MMPH).

LAM, like angiomyolipomas, is a PEComa. LAM occurs in 1-6% of individuals with TSC, typically in women between the ages of 20 and 40 years. Pulmonary CT shows diffuse interstitial changes, with infiltrates and cystic changes. Individuals with LAM at are increased risk of pneumothorax and chylothorax; some may progress to respiratory failure and death. Women with TSC should undergo pulmonary CT to identify possible LAM at age 18 years, and as clinically indicated thereafter.

MMPH occurs in males and females, with a significant female predominance, and is characterized by multiple nodular proliferation of type II pneumocytes. This condition can occur in individuals with or without LAM. Fewer than fifty cases have been reported in the literature.

Miscellaneous manifestations of TSC include extrarenal angiomyolipomas, dental pits, bone cysts, and rectal polyps.

Extrarenal angiomyolipomas have been seen in the liver, pancreas, and other organs, and are generally asymptomatic. Dental pits of the deciduous or permanent teeth are present in over 90% of individuals with TSC. Bone cysts and rectal hamartomatous polyps may be present in individuals with TSC as well, and are typically asymptomatic.

Treatment Options


Medical options:

– Topical: No FDA-approved topical treatment currently available. Clinical trials underway with topical rapamycin (sirolimus) show very promising results.

– Systemic: No FDA-approved systemic medical treatment currently available.

Surgical options:

– Laser surgery

– Shave excision and dermabrasion to the reticular layer of the dermis, followed by grafting of cultured autologous epithelium

– Cryosurgery

– Curettage

– Chemical peeling

– Excision

– Electrodessication

– Timed electrosurgery


Medical options:

Currently no FDA-approved topical or systemic treatment options

Surgical options:

– Excision

– Limited ablation with CO2 laser in defocused mode


Medical options:

Currently no FDA-approved topical or systemic treatment options

Surgical options:

Periungual fibromas:

– Excision

– CO2 laser ablation


– Excision


Medical options:

Currently no FDA-approved topical or systemic treatment options

Surgical options:

– Shaving with dermatome or combined wide excision with skin grafting

Optimal Therapeutic Approach for this Disease

There are multiple clinics throughout the country specializing in the multidisciplinary treatment of individuals with TSC. These TSC clinics are staffed with neurologists, neurosurgeons, geneticists, dermatologists, cardiologists, nephrologists, pulmonologists, ophthalmologists, psychiatrists, and developmental specialists with experience treating individuals with TSC. A list of these clinics can be accessed through the TS Alliance website at:

The dermatological manifestations of TSC most amenable to treatment include angiofibromas, fibrous facial plaques, and ungual fibromas. Angiofibromas and fibrous facial plaques may cause significant emotional and psychological distress in individuals with TSC. For this reason, it is extremely important to treat these lesions in individuals who are likely to receive psychological benefit.

Complications of angiofibromas, fibrous facial plaques, and ungual fibromas may include bleeding, chronic irritation, and infection. Angiofibromas can occasionally become so large that blockage of nasal passages occurs or vision is restricted and the corresponding skin lesions should be treated accordingly.


Laser treatment

Flat and red lesions in children under 4 years of age can be treated with a vascular laser, while raised and red lesions in older children and adults requires the use of both CO2 and vascular lasers. Children should be treated before starting school and prior to puberty. Raised and normopigmented lesions may be seen in both children and adults; these may be treated with the CO2 laser.


Dermabrasion is an effective treatment when angiofibromas affect large areas of the face.

Surgical excision

Surgical excision is only appropriate for removal of single or few angiofibromas because of the significant potential for scarring.


Surgical excision

Surgical excision is effective for small forehead and cheek plaques, as well as scalp plaques. Close scalp excisions with direct approximation or rotation-advancement flaps. Excellent cosmetic results may be obtained for small forehead plaques excised in a horizontal orientation. Small cheek plaques should be excised so that the resulting scar will follow the natural lines of the face. The CO2 laser can be used for small cheek plaques, but the final results are generally poor.

Limited ablation

Limited ablation of larger forehead plaques using the CO2 laser in a defocused mode can achieve acceptable results, although recurrence is common after debulking and flattening of a plaque with the CO2 laser. The full thickness of the dermis must not be ablated as this will leave the patient with significant unacceptable scarring.

A vascular laser may be effective for treatment of the red/pink color of fibrous facial plaques.


Periungual fibromas can be excised with a scalpel or ablated with a CO2 laser after exposing the lesion with a longitudinal incision over the lesion to the base and dissecting proximally to the base of the fibroma.

Subungual fibromas may be treated by carefully removing the nail plate, surgically excising the lesion and, if possible, replacing the nail plate.

Treatment for non-dermatological manifestations of TSC includes:

CNS, behavioral, neuropsychiatric manifestations

– Individuals with infantile spasms and seizures should be referred to a neurologist with experience treating individuals with TSC. Typical first-line treatment for infantile spasms and seizures in individuals with TSC is vigabatrin. Additional treatments for seizures include other anti-epileptic medications, placement of a vagal nerve stimulator, and neurosurgery to remove a seizure focus.

– Behavioral and neuropsychiatric manifestations of TSC should be treated as in any other individual, utilizing the expertise of psychiatrists as well as developmental pediatricians for children with TSC, based on the needs of the individual. Treatment options include pharmacotherapy, behavioral therapy, and psychotherapy.

– Options for treatment of subependymal giant cell tumors include pharmacotherapy with everolimus (Afinitor, Novartis), recently approved by the FDA in October 2010, as well as surgical intervention. The choice of therapy should be tailored to the individual patient, taking into account size of the tumor, degree of hydrocephalus, immune status, overall health status including anesthesia risk, and other factors. Treatment should be initiated under the care of a neurologist and neurosurgeon with experience treating individuals with TSC.

Renal manifestations of TSC

– Embolism of renal angiomyolipomas greater than 4cm in size, or those that have hemorrhaged

– Dialysis and/or renal transplant for end-stage kidney disease

– Pharmacological management of hypertension

Cardiac manifestations of TSC

– Resection of cardiac rhabdomyomas causing inflow or outflow tract obstruction, pharmacologic treatment of congestive heart failure, and pharmacological treatment of arrhythmias, as necessary and tailored to the individual patient.

Patient Management

Ideally, whenever possible, individuals with TSC should be evaluated and managed by a multidisciplinary team with expertise in the evaluation and ongoing management of individuals with TSC. The initial diagnostic evaluation is most frequently completed by a medical geneticist or neurologist.

Other specialists important for the evaluation and management of individuals with TSC include ophthalmologists for diagnosis of retinal hamartomas or achromic patches, dermatologists for diagnosis and treatment of angiofibromas, fibrous facial plaques and ungual fibromas, nephrologists for monitoring and treatment of renal manifestations, cardiologists when cardiac rhabdomyomas or arrhythmias are present, pulmonologists for individuals with LAM or MMPH, psychiatrists and developmental pediatricians for the neuropsychiatric manifestations of TSC.

Brain MRI should be performed every 1-3 years during childhood, and on regular basis in adults, as well as when indicated clinically. Brain MRI may be performed less frequently in adults without seizure disorder, as the risk of subependymal giant cell tumor is highest in childhood and early adolescence.

Electroencephalography should be performed as clinically indicated in individuals with known or suspected seizures.

Echocardiography should be performed in all individuals with suspected or newly diagnosed TSC. Subsequent echocardiography should be performed in individuals with cardiac rhabdomyomas every 6 months to 1 year, until the tumor shrinks or the size stabilizes. Electrocardiography should be performed at initial diagnosis and subsequently as clinically indicated.

Renal MRI should be performed in all individuals with suspected or newly diagnosed TSC. Renal MRI should be obtained every 3 years until adolescence, and every 1 to 3 years thereafter, in adolescents and adults without renal angiomyolipomas. In individuals with angiomyolipomas, renal MRI should be obtained every 6 months to 1 year, until the tumor shrinks or stabilizes and more frequently if clinically indicated.

Dermatologic evaluation should be performed in all individuals with suspected or newly diagnosed TSC, and thereafter as clinically indicated for the treatment of angiofibromas, fibrous facial plaques, and ungual fibromas.

High-resolution pulmonary CT should be obtained in all women with TSC at age 18, or at initial diagnosis of TSC in women older than 18 years, and as clinically indicated thereafter.

Formal cognitive and behavioral testing should be performed at the time of initial diagnosis of TSC, and subsequently between birth and 12 months, 13 to 35 months, 36 months to school entry, 6 to 8 years, 9 to 12 years, 13 to 16 years, 18 years, and regularly thereafter during adulthood to monitor for the development of psychiatric problems or changes in existing cognitive and behavioral difficulties. Formal cognitive and behavioral testing should also be obtained at any time when there is a change in typical behavior.

Unusual Clinical Scenarios to Consider in Patient Management

TSC is an autosomal dominant disorder, and affected individuals have a 50% chance of passing on the condition to their children with each pregnancy. Two-thirds of TSC is due to de novo (new) mutations, while one-third of TSC is inherited; however, unaffected parents of a child with TSC have a 1%-3% chance of having another child with TSC. This residual risk is due to the possibility of germline mosaicism, in which a parent may have a disease-causing mutation present in their germline (cells that develop into gametes) but not present in their somatic cells (body cells that do not develop into gametes); such a mutation would not be detectable by routine genetic testing performed on peripheral blood leukocytes.

What is the Evidence?

Chernoff, KA, Schaffer, JV. “Cutaneous and ocular manifestations of neurocutaneous syndromes”. Clin Dermatol.. vol. 34. 2016 Mar-Apr. pp. 183-204. (A recent review that discusses recent insights into disease pathogenesis and implications regarding future treatment targets.)

de Vries, P, Humphrey, A, McCartney, D, Prather, P, Bolton, P, Hunt, A. “Consensus clinical guidelilnes for the assessment of cognitive and behavioural problems in tuberous sclerosis”. Eur Child Adolesc Psychiatry. vol. 14. 2005 Jul. pp. 183-90. (A summary of a consensus conference convened in 2003 in Cambridge [UK], the goal of which was to produce guidelines for cognitive and behavioral assessments of individuals with TSC based on evidence from research in the field. An earlier consensus conference in 1998 had established clinical guidelines for the diagnosis and assessment of individuals with TSC. The purpose of the 2003 consensus conference was to expand upon the 1998 recommendations, with a specific focus on the cognitive and behavioral aspects of TSC.
An expert panel composed of child and adolescent psychiatrists, neuropsychologists, clinical and research psychologists, pediatric neurologists, special needs educators, other researchers familiar with clinical issues in TSC, individuals with TSC, as well as parents and caregivers of individuals with TSC formed the recommendations set forth in this publication.)

“Identification and characterization of the tuberous sclerosis gene on chromosome 16”. Cell. vol. 75. 1993 Dec 31. pp. 1305-15. (Publication describing the identification of the TSC2 gene on chromosome 16.)

Northrup, H, Au, KS. Tuberous sclerosis complex. May 7, 2009. (Overview of TSC, describing the natural history of TSC with specific clinical features, diganostic criteria, molecular genetics and testing, genotype-phenotype correlations, differential diagnosis, evaluation, surveillance, and therapies for TSC.)

Hyman, MH, Whittemore, VH. “National Institutes of Health consensus conference: tuberous sclerosis complex”. Arch Neurol. vol. 57. 2000 May. pp. 662-5. (National Institues of Health-sponsored consensus panel in 1998 providing recommendations on revised diagnostic criteria, surveillance protocols, and areas for future research for TSC.)

Inoki, K, Li, Y, Xu, T, Guan, KL. “Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling”. Genes Dev. vol. 16. 2003 Aug 1. pp. 1829-34. (Further delineation of the pathological mechanism of TSC caused by mutations in either TSC1 or TSC2.)

Kwiatkowski, DJ, Whittemore, VH, Thiele, EA. Tuberous sclerosis complex: genes, clinical features, and therapeutics. 2010. (Book with in-depth descriptions of the clinical features of TSC, molecular genetics, current treatment options, and many other aspects of TSC.)

Misago, N, Kimura, T, Narisawa, Y. “Fibrofolliculoma/trichodiscoma and fibrous papule (perifollicular fibroma/angiofibroma): a revaluation of the histopathological and immunohistochemical features”. J Cutan Pathol. vol. 36. 2009 Sep. pp. 943-51. (Description of the histopathological and immunohistochemical features of angiofibromas seen in TSC.)

Roach, ES, Sparagana, SP. “Diagnosis of tuberous sclerosis complex”. J Child Neurol. vol. 19. 2004 Sep. pp. 643-9. (A review of the clinical features of TSC, revised diagnostic criteria, and recent developments confirmatory diagnosis.)

(A United States advocacy and support organization dedicated to finding a cure for TSC, while improving the lives of those affected.)

van Slegtenhorst, M, de Hoogt, R, Hermans, C, Nellist, M, Janssen, B, Verhoef, S. “Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34”. Science. vol. 277. 1997 Aug 8. pp. 805-8. (Publication describing the identification of the TSC1 gene on chromosome 9.)

Wataya-Kaneda, M, Nakamura, A, Tanaka, M, Hayashi, M, Matsumoto, S, Yamamoto, K, Katayama, I. “Efficacy and Safety of Topical Sirolimus Therapy for Facial Angiofibromas in the Tuberous Sclerosis Complex: A Randomized Clinical Trial”. JAMA Dermatol.. 2016 Nov 12. (Data from this randomized double-blind placebo-controlled study support the conclusion that topical sirolimus is safe and effective for treating facial angiofibromas. The optimal concentration was 0.2% gel.)