Tuberous Sclerosis Clinical Presentation

Updated: Aug 06, 2020
  • Author: David Neal Franz, MD; Chief Editor: George I Jallo, MD  more...
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As with all of medical practice, recognizing a disease, let alone managing it appropriately, is impossible unless its diagnosis is first considered in a particular patient. While this may seem self-evident, in fact most physicians are only dimly, if at all, aware of TSC. This awareness usually extends only to the Vogt triad or to individuals with severe neurological morbidity. As many as 50% of people with TSC have normal intelligence, and increasingly the diagnosis is being newly made in adults with renal, cutaneous, or pulmonary manifestations.

History should focus upon identification of specific signs and symptoms suggestive of or consistent with TSC. Particular symptoms occur at various points in the life span, and this serves as a framework for history taking.

  • Cardiac involvement is maximal in prenatal life or infancy.

  • Seizures, autism, and developmental delays present in infancy or childhood. Seizures are often not intractable, and many adult patients may no longer suffer from them or require anticonvulsants. Many will have been told that they had febrile convulsions or an age-related epilepsy syndrome.

  • Cutaneous manifestations such as ash leaf macules are often present from birth but frequently are unrecognized. More obvious lesions such as angiofibromas or shagreen patches usually appear in childhood to early adolescence.

  • Renal lesions can present as hypertension and renal failure in the case of polycystic kidney disease, usually in infancy or early childhood. AMLs manifest as flank pain, hematuria/retroperitoneal hemorrhage, or abdominal masses from childhood throughout adult life.

  • Pulmonary involvement typically occurs in the second or third decade, with dyspnea, pneumothorax, or chylothorax. It often is misdiagnosed as emphysema, particularly in those with a history of smoking.

  • Persons with dental involvement may have had their teeth sealed or bonded for pitting, or a gingival fibroma resected.

Family history should center on identification of one or more of these manifestations in first- or second-degree relatives. Specific questioning is often necessary, as TSC lesions often are ascribed to other causes, eg, pulmonary involvement as emphysema, renal lesions as "atypical Wilms tumors," etc.

Comprehensive diagnostic criteria were set out first by Dr. Manuel R. Gomez; they now exist in revised form as set forth in a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association (USA). [10]

Major features of TSC include the following:

  • Facial angiofibromas or forehead plaque

  • Nontraumatic ungual or periungual fibroma

  • Hypomelanotic macules (>3)

  • Shagreen patch (connective tissue nevus)

  • Multiple retinal nodular hamartoma

  • Cortical tuber: When cerebellar cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of tuberous sclerosis.

  • Subependymal nodule

  • Subependymal giant cell astrocytoma

  • Cardiac rhabdomyoma, single or multiple

  • Lymphangioleiomyomatosis: When both lymphangioleiomyomatosis (LAM) and renal AMLs are present, other features of tuberous sclerosis should be present before a definite diagnosis is assigned. As many as 60% of women with sporadic LAM (and not TSC) may have a renal or other AMLs.

  • Renal AML: When both LAM and renal AMLs are present, other features of tuberous sclerosis should be present before a definite diagnosis is assigned (see previous remarks).

Minor features of TSC include the following:

  • Multiple randomly distributed pits in dental enamel [11]

  • Hamartomatous rectal polyps: Histologic confirmation is suggested.

  • Bone cysts: Radiographic confirmation is sufficient.

  • Cerebral white matter radial migration lines: Radiographic confirmation is sufficient. One panel member felt strongly that 3 or more radial migration lines should constitute a major sign.

  • Gingival fibromas

  • Nonrenal hamartoma: Histologic confirmation is suggested.

  • Retinal achromic patch

  • "Confetti" skin lesions

  • Multiple renal cysts

The following are the diagnostic criteria for TSC:

  • Definite TSC - Two major features or one major feature plus two or more minor features

  • Possible TSC - Either one major feature or two or more minor features

Molecular genetic testing is now commercially available in the United States through several companies, including Athena Diagnostics, Ambry Genetics, GeneDX, and Invitae. Testing through Athena was extended to include screening for large deletions and other types of mutations, to improve their diagnostic yield.

  • Under optimal circumstances, genetic testing identifies mutations in up to 75-80% of affected individuals. Therefore, a negative genetic diagnostic test result does not exclude a diagnosis of tuberous sclerosis.

  • Diagnosis should be possible in most cases using established clinical criteria. Molecular genetic testing is useful in uncertain or questionable cases, for prenatal diagnosis, and for screening family members of an affected individual. The utility of molecular diagnostic testing is limited by the cost (approximate self-pay costs of $3300 to provide deletion analysis and DNA sequencing for TSC1 and TSC2 index cases, and $450 for confirmatory testing in family members). Costs are frequently not covered by private insurance carriers. Patient assistance programs may be available through various laboratories.



Physical findings can vary greatly since TSC can affect different organ systems in different ways at different times of the patient's life. Neurological and dermatological abnormalities are the most common physical findings, since brain and skin pathology occurs in as many as 90–95% of affected individuals.

Neurological findings

Abnormal neurological findings result from the location, size, and growth of tubers and the presence of subependymal nodules (SENs) and SEGAs.

Tubers are noted most commonly in the cerebrum, without clear predilection for any particular lobe. They occur in the cerebellum as well, where they may be apparent only on microscopic examination. Rarely, they have been noted in the brain stem and spinal cord.

  • The number, size, and location of tubers can vary widely from patient to patient.

  • Depending on the location of tubers, neurological findings can include abnormalities in cognition (either global delays or specific location-related deficits like language delays), cranial nerves, focal motor/sensory/reflexes abnormalities, cerebellar dysfunction, or gait abnormalities.

SENs are noted about the wall of the lateral ventricles and may be either discrete or roughly confluent areas of firm, rounded hypertrophic tissue. SENs may occur anywhere along the ventricular surface, but most commonly occur at the caudothalamic groove in the vicinity of the foramen of Monro.

Enhancing subependymal nodules, including a probab Enhancing subependymal nodules, including a probable giant cell astrocytoma in the region of the foramen of Monro. Subependymal nodules may increase in size over time from one scan to the next, and then stabilize. This lesion had not changed with serial imaging over 2 years. The patient remains asymptomatic and is monitored closely for any deterioration.

The generally benign SENs can degenerate into SEGAs in 5–10 % of cases. SEGAs can grow, often in an extremely indolent fashion, resulting in ventricular obstruction and hydrocephalus. Since this process occurs very gradually, patients may have marked hydrocephalus when they finally become symptomatic (see image below). In this situation, blindness or other permanent neurological deficit commonly ensues despite prompt neurosurgical intervention.

Hydrocephalus from a subependymal giant cell astro Hydrocephalus from a subependymal giant cell astrocytoma in a patient with tuberous sclerosis. The patient presented with acute blindness and ataxia.

Skin findings

The best-known cutaneous manifestation of TSC is adenoma sebaceum, which often does not appear until late childhood or early adolescence. This lesion is an angiofibroma (ie, cutaneous hamartoma) and is not related to excessive sebum or acne. Flat, reddish macular lesions develop first, which can be mistaken for freckles early on. They become increasingly erythematous and papulonodular over time, occasionally with a friable surface that may bleed easily. Facial angiofibromas typically are noted first in childhood and exhibit progression during puberty and adolescence (see image below). Adenoma sebaceum may be disfiguring.

Facial angiofibromas in a young man with tuberous Facial angiofibromas in a young man with tuberous sclerosis complex.

Other skin lesions consist of hypomelanotic (ie, ash leaf) macules, periungual or gingival fibromas (see images below), and thickened, firm areas of subcutaneous tissue, often at the lower back (shagreen patch) or forehead and face (fibrous plaques).

Dysplastic periungual fibroma involving the great Dysplastic periungual fibroma involving the great toe in a patient with tuberous sclerosis.
Gingival fibromas (see arrows) in a patient with t Gingival fibromas (see arrows) in a patient with tuberous sclerosis. A stain outlines dental pits and craters. Gingival hyperplasia from other causes (eg, phenytoin use) is more diffuse and usually not nodular/focal in nature.

Hypomelanotic macules are usually round or oval in shape and vary in size from a few mm to as much as 5 cm in length (see image below). Sometimes they have an irregular, reticulated appearance, as if white confetti paper had been strewn over the skin (confetti lesions). When the scalp is involved, an area of poliosis (ie, hypopigmented hair) can result. They may be present at birth, or not show up until later in life. They vary widely in location and number from person to person. The number or size of the macules is not an essential feature of diagnosis. Hypomelanotic macules are a nonspecific finding and are not of themselves pathognomonic of TSC. Nonetheless finding more than 4 or 5 in a person who does not have the disease is uncommon.

Typical ash leaf macules; the reddish, nodular are Typical ash leaf macules; the reddish, nodular area at the upper lumbar area is a shagreen patch.

Fibromas may occur in other locations. When present in the lumbar region they have been called a "shagreen patch." The overlying skin may have an orange hue. They occasionally itch or are associated with dysesthesia, leading patients to wonder if "it is pinching a nerve." Shagreen patches are confined, however, to the subcutaneous tissue and are not associated with dysraphism, osseous lesions, or mass effects on neural structures.

  • Fibromas can occur in the periungual regions, gingivae, or potentially anywhere in cutaneous or mucosal tissues. The underlying tissue may be hypertrophic/hamartomatous.

  • Symptoms can result from local irritation, such as that created by shoes, dentures, shaving, and disruption of the nail bed.

Cardiac findings

Cardiac involvement is usually maximal at birth or early in life; it may be the presenting sign of TSC, particularly in early infancy. Fifty to sixty percent of individuals with TSC have evidence of cardiac disease, mostly rhabdomyomas. Conversely, anywhere from 50-85% of infants with isolated cardiac rhabdomyomas are said to later show definite evidence of TSC.

Rhabdomyomas are benign tumors that may be focal or diffuse and infiltrating in character. They produce symptoms primarily through outflow tract obstruction or by interfering with valvular function (see images below). Diffuse rhabdomyomas also may result in decreased contractility and cardiomyopathy (see image below). In such cases surgical treatment, inotropic support, and related measures may be necessary.

Atrial rhabdomyoma as seen on cardiac CT scan in a Atrial rhabdomyoma as seen on cardiac CT scan in a patient with tuberous sclerosis.
Nonobstructive ventricular rhabdomyomas in a patie Nonobstructive ventricular rhabdomyomas in a patient with tuberous sclerosis.
Ventricular rhabdomyomas may diffusely infiltrate Ventricular rhabdomyomas may diffusely infiltrate the myocardium, as in this patient with tuberous sclerosis. The patient presented with cardiac failure and hydrops at birth. After a period of intensive supportive care and inotropic therapy, she now has essentially normal cardiac function and is on no medications.

Rhabdomyomas develop during intrauterine life (usually between weeks 22 and 26 of gestation) and can result in nonimmune hydrops fetalis and fetal death. The majority of cases, however, are clinically asymptomatic.

The lesions typically undergo spontaneous regression in the first few years of life, although residual areas of histologically abnormal myocardium may persist. These lesions can involve the cardiac conducting system and thereby may predispose an affected individual to ventricular pre-excitation or other arrhythmias not only in infancy, but also later in life. Such residual areas can be inapparent on echocardiography, yet still produce arrhythmia. This may have an underappreciated significance, as persons with TSC often require antiepileptic or psychotropic drugs that also may affect cardiac conduction.

Ophthalmic findings

At least 50% of patients have ocular abnormalities; some studies have reported prevalence as high as 80%.

These lesions are in fact retinal astrocytomas that tend to become calcified over time. They appear as rounded, nodular, or lobulated areas on funduscopic examination, becoming whitish in color as they calcify.

They tend to be indolent and rarely produce symptoms or require intervention.

Visual acuity generally is unaffected, unless the retinal fovea is involved.

Hypopigmented areas of retina, iris, and even eyelashes have been reported. These are analogous to hypomelanotic macules of the skin.

Lung findings

Symptomatic pulmonary involvement occurs almost exclusively in adult women, generally aged 30 or older. It was long thought to be distinctly uncommon, affecting 1% or fewer of women with TSC. However, recent prospective and retrospective studies have found cystic pulmonary abnormalities in as many as 40% of women with TSC. Women with large AMLs (>4-6 cm in diameter) appear to be at higher risk.

Symptomatic pulmonary disease in men, and even in children, with TSC has been reported anecdotally. The true incidence of pulmonary abnormalities in these populations is not known, although it is certainly less than in adult women.

Three forms have been described: multifocal micronodular pneumocyte hyperplasia (MMPH), pulmonary cysts, and LAM.

MMPH consists of hyperplasia of type II pneumocytes, seen as nodular densities on chest CT scan. This condition occurs with equal frequency in men and women with TSC and does not produce clinical symptoms.

Pulmonary cysts may be single or multiple (see image below). Solitary lesions may remain clinically silent or rupture, with resultant pneumothorax producing acute dyspnea and hemoptysis. Multiple cystic lesions may result in respiratory insufficiency or even pulmonary hypertension with cor pulmonale (usually in the case of LAM).

Multifocal pulmonary cysts characteristic of lymph Multifocal pulmonary cysts characteristic of lymphangiomyomatosis. As many as 40% of women with tuberous sclerosis have pulmonary cysts on chest CT scan.

LAM is rather more insidious: interstitial fibrosing alveolitis develops with progressive restrictive lung disease. It also occurs, although less frequently, in women who do not have TSC (incidence of sporadic LAM, approximately 1 per 100,000). About 60% of women with sporadic LAM also have renal AMLs, but not other characteristics of TSC (see image below). Smooth muscle cells undergo abnormal proliferation with secondary compromise of bronchioles, venules, and lymphatic structures. Slowly, normal pulmonary elasticity is lost, with resultant decrease in vital capacity and increase in residual volume. Pulmonary hypertension, cor pulmonale, and worsening hypoxia/hypercapnia eventually supervene. When LAM is suspected clinically, high-resolution CT of the chest is the most sensitive diagnostic modality.

Massive bilateral angiomyolipomas in a woman with Massive bilateral angiomyolipomas in a woman with tuberous sclerosis. She also has lymphangiomyomatosis.

Owing to the overwhelming predominance of LAM in women, some believe that estrogen accelerates the progression of the condition. Some patients have been treated with hormonal therapy (ie, progesterone) to counteract the estrogen effect, although this has not been proven conclusively to be of benefit. Bronchodilators are helpful in selected cases.

LAM is inexorably progressive and ultimately results in death unless lung transplantation is undertaken. [12] Interestingly, LAM occasionally has recurred in transplanted lungs. This raised the possibility that, rather than being a primary pulmonary disorder, LAM is caused by a circulating factor, or perhaps metastatic cells. Henske et al demonstrated that in fact metastatic cells from AMLs or leiomyomas are present in the lungs of women with LAM, regardless of whether they have TSC, and almost certainly cause the disorder (see image below). These cells frequently have abnormalities of either TSC1 or TSC2, which produce the characteristic smooth muscle hypertrophy and destruction of normal lung.

Massive bilateral angiomyolipomas in a woman with Massive bilateral angiomyolipomas in a woman with tuberous sclerosis. She also has lymphangiomyomatosis.

Renal findings

Renal manifestations of TSC are the second most common clinical feature. Four types of lesions can occur: autosomal dominant polycystic kidney disease, isolated renal cyst(s), AMLs, and renal cell carcinoma.

Polycystic kidney disease occurs in 2-3% of persons with TSC, and usually presents early in life with hypertension, hematuria, or renal failure. As noted, this occurs as the result of a genetic abnormality affecting both the TSC2 gene and the PKD1 gene adjacent to it. Individuals with polycystic kidney disease have relatively little functional renal tissue, and ultimately require renal transplantation. They are highly susceptible to complications of urinary tract infection (UTI) or nephrolithiasis, which can produce acute renal failure. This should be borne in mind when using therapies that predispose to UTI or kidney stones, such as steroids, topiramate, zonisamide, or the ketogenic diet.

Renal cysts (as opposed to polycystic kidney disease) are found in 20% of males and 10% of females with TSC. They are rarely if ever symptomatic. Simple renal cysts often occur with AMLs, and this combination should suggest the diagnosis of TSC. Sometimes multiple renal cysts can be confused with true polycystic kidney disease. The presence of significant symptoms such as hypertension or failure to thrive, as well as the absence of associated AMLs, strongly suggest the latter diagnosis.

AMLs are noted in as many as 80% of persons with TSC. They also can occur as isolated lesions in persons without TSC.

As suggested by their name, they consist of abnormal smooth muscle, fat, and blood vessels, each present in varying degrees.

Patients tend to have either multiple small AMLs studding the surface of the kidney or one or more larger lesions. These larger lesions are more apt to be symptomatic, particularly when greater than 4-6 cm in their largest diameter. They often produce nonspecific complaints such as flank pain.

Of rather more concern is potentially life-threatening retroperitoneal hemorrhage from rupture of dysplastic, aneurysmal blood vessels. These hemorrhages also can destroy adjacent normal renal parenchyma or produce abdominal distention and obstruction by mass effects.

Some studies suggest that as many as 75% of AMLs will increase in size over time (see image below). Exactly when intervention is warranted is somewhat controversial. Very large AMLs (>6-8 cm in diameter) are likely to progress and often result in hemorrhage, particularly if prominent abnormal vasculature is present. AMLs with fewer dysplastic vessels may have a smaller risk of catastrophic hemorrhage but can present problems from their sheer size.

Massive bilateral angiomyolipomas in a woman with Massive bilateral angiomyolipomas in a woman with tuberous sclerosis. She also has lymphangiomyomatosis.

MRI and MR angiography are often helpful in planning therapy (see following images).

Pre-embolization angiography of the patient with a Pre-embolization angiography of the patient with angiomyolipomas shown the previous image. Dysplastic arterial vessels are demonstrated.
Vessels to the angiomyolipoma shown in the previou Vessels to the angiomyolipoma shown in the previous image have been occluded with coils. This should produce regression of the lesion and prevention of hemorrhage. Functional intervening renal parenchyma is preserved.

Because of their often exuberant blood supply, standard surgical resection can result in excessive bleeding, with nephrectomy being the end result.

When feasible, selective embolization is the preferred intervention. This procedure typically is able to spare functional renal tissue, directly addresses the chief risk of retroperitoneal hemorrhage, and has a substantially lower rate of morbidity than standard surgery. Some patients experience "postembolization syndrome" consisting of fever, flank pain, and malaise as the embolized lesion becomes necrotic. This usually can be prevented by pretreatment with steroids.

Renal cell carcinoma appears to occur more frequently in persons with TSC than in the general population, although the exact nature of this is unclear. In one series, 5 of 403 patients with TSC were found to have histologic evidence of a renal cell carcinoma. Nonetheless, a large AML is much more common in this population. A rapidly expanding renal mass in the absence of hemorrhage is suggestive of the diagnosis. MRI of the abdomen can be useful in differentiating a large AML from a true malignancy.

Dental findings

Pitting of the dental enamel is invariably present in the permanent teeth of patients with TSC, particularly larger numbers of pits (>14). [1] They are seen in the primary (deciduous) teeth of 30% of affected children.

They rarely produce symptoms.

This sign has led to interest in counting dental pits as an inexpensive bedside screening procedure. Smaller numbers (< 6) of dental pits may occur in as many as 10% of healthy controls. However, accurate assessment of dental pits may be possible only after staining the teeth, and by a dentist or person trained to look for them (see images below). These factors have limited the utility of this feature of TSC for diagnosis.

Gingival fibromas (see arrows) in a patient with t Gingival fibromas (see arrows) in a patient with tuberous sclerosis. A stain outlines dental pits and craters. Gingival hyperplasia from other causes (eg, phenytoin use) is more diffuse and usually not nodular/focal in nature.
Enamel pitting in tuberous sclerosis. Pinpoint siz Enamel pitting in tuberous sclerosis. Pinpoint size pitting (A) and crater size pitting (B) are visible. Red dye is used to enhance recognition.

Gingival fibromas occur in 70% of adults with TSC, in 50% of children with mixed dentition (both primary and permanent teeth), and in only 3% of children with only primary teeth (see above images).

These may produce local irritation or interfere with dental alignment, and they require surgical resection in selected cases.

Isolated gingival fibromas can occur in persons who do not have TSC. However, gingival fibroma(s) in association with large numbers (>10) of dental pits is highly suggestive of TSC and should prompt further diagnostic evaluation.

Other organ systems

Hamartomas and polyposis of stomach, intestine, and colon may occur. These almost never cause significant symptoms, although gastrointestinal hamartomas occasionally may bleed, leading to positive tests for fecal occult blood. Blood loss is almost always minimal, and rarely if ever results in anemia or clinical symptoms.

Hepatic cysts and AMLs (hepatic, not renal), typically asymptomatic and nonprogressive, have been reported in as many as 24% of patients with TSC, with a marked female predominance (female-to-male ratio 5:1).

Sclerotic and hypertrophic lesions of bone may be found incidentally on radiography performed for other indications. Occasionally they may be palpable, or associated with nonspecific, vague, aching pains. Osseous lesions rarely if ever produce serious difficulty, and they require only symptomatic treatment, if any at all. Some patients develop neurogenic scoliosis resulting from asymmetric weakness or intractable partial seizure activity. In these cases, typically a "dominant" tuber is present contralateral to the scoliosis or the supratentorial tuber burden is asymmetrical. These individuals may require standard orthopedic management if the curvature is severe.

A small number of patients with TSC may develop arterial aneurysms. Aneurysms have been reported intracranially [13] , as well as in the aorta and axillary arteries (see following image).

Basilar artery aneurysm in a 2-year-old girl with Basilar artery aneurysm in a 2-year-old girl with tuberous sclerosis. The arrow shows the anterior aspect of the aneurysm where it abuts the clivus. The lesion was not present on MRI performed 11 months earlier.

Like lung disease, gastrointestinal and osseous abnormalities are seen primarily in adults, in whom they may be the presenting manifestations of TSC. Recognition of the true nature of these lesions is important, as adult-oriented practitioners are generally unaware of the broad spectrum of TSC. Pulmonary, renal, gastrointestinal, and bone findings may be mistaken for emphysema, neoplasia, or other disorders, and inappropriate measures undertaken.



See Pathophysiology.