Chapter 140. Tuberous Sclerosis Complex

The incidence of tuberous sclerosis complex (TSC) is as high as 1 in 6,000 live births.1,2 It occurs with equal frequency in males and females and in different races and ethnicities. Hereditary transmission is evident in approximately one-third of patients. Sporadic disease occurs in about two-thirds of patients, and this is attributed to de novo mutations.3

TSC is caused by mutations in a tumor suppressor gene, either TSC1 or TSC2.3 Mutations in TSC2 are observed in about three-fourths of patients, and even more commonly in de novo cases.4,5 Patients with mutations in TSC2 tend to exhibit a more severe phenotype.4–7

TSC1 maps to chromosome band 9q34. The 8.6-kb full-length transcript encodes a protein called hamartin or TSC1.8 TSC2 maps to chromosome band 16p13.3. The 5.5-kb transcript encodes a protein called tuberin or TSC2.9 Immediately adjacent to TSC2 on chromosome 16 is PKD1, the gene mutated in polycystic kidney disease. Some patients with TSC have severe, early-onset renal cystic disease, and most of these patients have a contiguous deletion of TSC2 and PKD1.10

Typical of mutations in tumor suppressor genes, the mutations observed in patients with TSC are inactivating mutations located anywhere along the sequence of TSC1 or TSC2. Consistent with Knudson's two-hit hypothesis, most TSC tumors show a second somatic mutation that inactivates the wild-type allele.11,12 TSC1 and TSC2 form a complex that inhibits signaling through the mammalian target of rapamycin (mTOR) pathway (Fig. 140-1). Loss of TSC1/TSC2 function leads to increased mTOR signaling and increased cell growth. Rapamycin is a drug that inhibits mTOR and may be useful for the treatment of internal tumors in TSC.13

Clinical Criteria

The diagnosis of TSC is based on clinical criteria categorized as major or minor features (Table 140-1).14,15 Cutaneous and oral lesions comprise 4 of 11 major features and 3 of 9 minor features. Major features are thought to have a high degree of specificity for TSC, whereas minor features are less specific or substantiated. No single feature is present in all patients, and no feature is specific for TSC. Genetic testing can be offered and may be important in particular situations (see Section “Molecular Diagnosis”).15

History

The medical and family history taking should include questions about seizures, learning disability, behavioral disorders, visual problems, and tumors of the brain, heart, kidneys, lungs, and skin. Determining the ages of onset of skin lesions and their subsequent changes may assist in discriminating TSC skin lesions from similar-appearing non-TSC skin lesions. Many TSC skin lesions are not present at birth, but appear later at ages typical for the lesion.16 For example, infants show multiple hypomelanotic macules but not angiofibromas or ungual fibromas. Adults may have multiple angiofibromas and ungual fibromas, but hypomelanotic macules may have faded or disappeared.

Cutaneous and Oral Lesions

Hypomelanotic Macules

Hypomelanotic macules (Fig. 140-2) are observed in over 90% of children with TSC.4,17–21 They are often present at birth or appear within the first few years of life and may fade or disappear in adulthood. The ultraviolet light of a Wood's lamp is used to improve detection, especially in lightly pigmented individuals22 (Fig. 140-3).

Hypomelanotic macules typically measure 0.5–3.0 cm in diameter. They are off-white and not completely depigmented as in vitiligo.23 Some are oval at one end and taper to a point at the other. Such lesions are called ash-leaf spots because of their resemblance to the leaf of the European mountain ash.24 They number from 1 to over 20. They can be located anywhere on the body but tend to occur most often on the trunk and buttocks. When located on the scalp, they cause poliosis.17

Three or more hypopigmented macules constitutes a major feature for the diagnosis of tuberous sclerosis. One or two, and in rare individuals up to three, hypomelanotic macules occur in 4.7% of the general population.25 A less common type of hypopigmentation is the “confetti” skin lesion (Fig. 140-4), which is considered a minor feature for diagnosis. It typically occurs on the legs below the knees or on the forearms, and consists of multiple hypopigmented macules 2–3 mm in diameter.17,24

Facial Angiofibromas

Angiofibromas appear at 2–5 years of age and eventually affect 75% to 90% of patients.4,17,20,21 These 1–3 mm in diameter pink to red papules have a smooth surface (Fig. 140-5). They may be hyperpigmented, especially in individuals with darker pigmentation. They occur on the central face and are often concentrated in the alar grooves (see eFig. 140-5.1), extending symmetrically onto the cheeks and to the nose, nasal opening, and chin, with relative sparing of the upper lip and lateral face. Sometimes lesions occur on the forehead, scalp, or eyelids. They may number from 1 to over 100. Lesions may coalesce to form large nodules, especially in the alar grooves.17,20,22 Angiofibromas are unilateral in rare cases and may indicate a segmental or mosaic defect.26–29

The development of papules may be preceded by mild erythema that is intensified by emotion or heat. During puberty, angiofibromas may grow in size and number. During adulthood they tend to be stable in size, but redness may gradually diminish.22

Angiofibromas must be multiple to be counted as a major feature. A solitary angiofibroma is clinically and histologically indistinguishable from the fibrous papule that occurs sporadically as a single lesion in the general population.30 Multiple angiofibromas are also observed in multiple endocrine neoplasia type 1,31–33 and as an unusual finding in Birt–Hogg–Dubé syndrome.34

Fibrous Facial Plaque

The forehead plaque may be congenital or show gradual development over years.17,35 It is present in 20% to 40% of patients.4,17,20 It is an irregular, soft to firm, connective tissue nevus with the color of the normal surrounding skin, red, or hyperpigmented in darkly pigmented individuals (Fig. 140-6). The plaque can also be found on the scalp, cheeks, and elsewhere on the face and is therefore sometimes referred to as a fibrous facial plaque. The forehead plaque is grouped together with angiofibromas as a major feature for diagnosis.14

Shagreen Patch

The shagreen patch is observed in approximately 50% of patients.4,17,20,21 It may be present in infancy but usually becomes apparent later. It is a firm or rubbery irregular plaque ranging in size from 1 to 10 cm (Fig. 140-7). The surface may appear bumpy with coalescing papules and nodules, or the patch may have the surface appearance of an orange peel. The color may be that of the surrounding skin, or it may be slightly pink or brown. There may be scattered smaller oval papules with or without a larger plaque (see eFig. 140-7.1). The most common locations are on the lower back and buttocks; the patch is found less commonly on the thighs.22

Ungual Fibromas

Ungual fibromas, also known as Koenen's tumors, usually appear after the first decade and eventually affect up to 88% of adults with TSC.20 They are more common on the toes than on the fingers.36

Ungual fibromas measure 1 mm to 1 cm in diameter. They arise from under the proximal nail fold (periungual fibromas) and under the nail plate (subungual fibromas). Periungual fibromas are red papules and nodules that are firm, pointed, and hyperkeratotic, or soft and rounded (Fig. 140-8). They press on the nail matrix and cause a longitudinal groove, and sometimes a groove forms without an evident papule20,36 (see eFig. 140-8.1). Subungual fibromas can be seen through the nail plate as red or white oval lesions or as red papules emerging from the distal nail plate, causing distal subungual onycholysis (see eFig. 140-8.2). In addition to ungual fibromas, TSC patients may develop “red comets” (subungual red streaks), splinter hemorrhages, and longitudinal leukonychia.36

Presence of a nontraumatic ungual fibroma is a major feature for diagnosis of TSC.14 Solitary lesions (also termed acral or acquired digital fibrokeratomas) are also observed in the general population, especially after nail trauma.37 Multiple acral fibromas with a myxoid stroma were reported in one patient with familial retinoblastoma.38

Other Skin Lesions

Molluscum fibrosum pendulum (skin tags) is the name given to multiple fibroepithelial polyps in TSC. These range from soft pedunculated papules to larger firm pedunculated nodules located on the neck, axillae, trunk, and flexures (see eFig. 140-8.3). They can be skin colored or hyperpigmented.17 Skin tags are common in the general population, so these are not useful for diagnosis. Miliary fibromas are patches of multiple minute papules, usually on the neck or trunk that appear like “gooseflesh.”22 Pachydermodactyly is a benign thickening of the proximal fingers that has been observed in a few patients with TSC.36,39,40

Dental Pitting

Multiple pits of the dental enamel are observed in up to 100% of TSC patients.41–44 These pits can be tiny pinpoint lesions or larger crater-like lesions (see eFig. 140-8.4). They occur on both deciduous and permanent teeth. The identification of these lesions is enhanced by using a dental plaque stain. Dental pits can also be seen in the general population, albeit with lower prevalence and at lower numbers than in TSC.41 The presence of multiple dental pits is a minor feature for diagnosis.14

Oral Fibromas

Approximately 50% of TSC patients have oral fibromas20 (see eFig. 140-8.5). These sometimes occur in the first decade but are more common in adulthood.45 They are most common on the gingivae, but also occur on the buccal and labial mucosa, hard palate, and tongue.45 Some patients have diffuse gingival overgrowth. Gingival overgrowth is a common side effect of anticonvulsants, especially phenytoin and cyclosporine, but gingival overgrowth can be observed in TSC even in patients not treated with anticonvulsants or immunosuppressive agents.45,46 Gingival fibromas are a minor feature for diagnosis.14 Oral fibromas in the general population are typically single and form at sites of trauma, usually on the tongue or buccal mucosa.47

Related Physical Findings

Tuberous sclerosis can affect almost any organ. Only one-third of patients have the classic triad of seizures, mental retardation, and angiofibromas.

Brain

Cerebral lesions include cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. Cerebral lesions may manifest as seizures, cognitive disability, and behavioral disorders. Seizures occur in approximately 80% of patients, with onset common in the first 2 months and usual by the first 2 years of life. Seizures are most likely infantile spasms but can be all types except pure absence (classic petit mal).48 Seizures are controlled with antiepileptic drugs. A ketogenic diet can decrease seizures and mTOR inhibitors may also prove to be useful in reducing seizures.49,50 Epilepsy surgery may be required for seizures intractable to anticonvulsant therapy.51,52

Learning disability tends to occur in patients with seizures, but many children with seizures have no obvious neurologic impairment. The extent of mental disability ranges from mild to profound. Individuals with normal intelligence may have specific deficits in attention, executive control, and memory.53 Behavioral disorders include autism, attention deficit disorder, hyperactivity, aggressive behavior, impulsivity, anxiety, and sleep disorders.7,53,54

Subependymal giant cell astrocytomas occur in 6% to 14% of individuals with TSC. They may increase intracranial pressure and cause headache, vomiting, and bilateral papilledema.55

Heart

Cardiac rhabdomyomas are observed in 50% to 70% of infants with TSC.56 These neoplasms are often asymptomatic and spontaneously regress, but they may cause fetal hydrops and stillbirth or heart failure shortly after birth.57,58 Cardiac rhabdomyomas may cause dysrhythmias, commonly Wolff–Parkinson–White syndrome, noticed in utero or in the first year of life in TSC patients.57–59

Kidneys

Angiomyolipomas (AMLs) are observed in approximately 75% TSC patients over 10 years of age.56,60 Additional renal lesions include renal cysts and rarely renal cell carcinoma.61 Polycystic kidney disease is present in 2% to 3% of patients.56 Renal lesions can cause renal insufficiency, hypertension, and potentially fatal retroperitoneal hemorrhage. Patients may require selective embolization or partial nephrectomy.62–65

Lungs

Lung involvement in TSC includes lymphangioleiomyomatosis (LAM), multifocal micronodular pneumocyte hyperplasia, and clear cell tumors of the lung. LAM develops in females with TSC during the third or fourth decade of life. Radiographic evidence of LAM was observed in 26% to 40% of adult females with TSC, most of whom had subclinical disease.66 It may cause spontaneous pneumothorax, chylothorax, dyspnea, cough, and hemoptysis.67

Eyes

Retinal astrocytic hamartomas are observed in 44% to 87% of patients.68 The most common type is a slightly raised, smooth, translucent, gray, noncalcified circular or oval lesion with indistinct boundaries. Also common are elevated and opaque multinodular “mulberry” lesions that have calcified, glistening nodules. Retinal astrocytic hamartomas can be similar to retinal lesions in neurofibromatosis type 1 and may appear similar to retinoblastomas. Some patients have vision loss, but blindness is rare.69 In exceptional cases, enucleation has been required for enlarging retinal astocytomas.70 TSC patients may also have “punched out” depigmented retinal lesions, which were observed in 39 of 100 patients compared to 6 of 100 controls.68 Additional eye findings include angiofibromas of the eyelids, colobomas, strabismus, and sector iris depigmentation. Retinal astrocytic hamartomas are a major feature for the diagnosis of TSC.

Gastrointestinal Tract

Rectal polyps, usually asymptomatic, have been observed in 14 of 18 adults (78%) with TSC.71 Histologically, they are hamartomas and rarely adenomas. Polyps have also been observed in the upper gastrointestinal tract and colon of TSC patients.72,73 The presence of hamartomatous rectal polyps is a minor feature for TSC. Hepatic AMLs occur in TSC, typically in association with renal AMLs.74 They are more common in females than in males with TSC.

Other Organs

Benign tumors have been found in the spleen, thymus, and thyroid. TSC may also be associated with pituitary, parathyroid, and islet cell tumors.75 Arterial stenotic-occlusive disease and arterial aneurysms including aortic and intracranial aneurysms have been observed,76 Bone lesions in TSC are usually asymptomatic and may be sclerotic (calvaria, pelvis, vertebrae, ribs, and long bones)77 or cystic (phalanges).78 In unusual cases, there is localized overgrowth of a digit.36

Skin Histopathologic Findings

Hypomelanotic macules have normal numbers of melanocytes, in contrast to the lesions of vitiligo, in which melanocytes are absent. The melanocytes in hypomelanotic macules have poorly developed dendritic processes, and melanosomes are decreased in numbers, size, and melanization.23 Angiofibromas contain plump, spindle-shaped, or stellate fibroblastic cells in the dermis among increased numbers of dilated vessels (see eFig. 140-8.6). Collagen fibers are oriented in an onionskin pattern around follicles and vessels. The epidermis shows melanocytic hyperplasia and flattening of rete ridges. Periungual fibromas are similar, but with more extensive hyperkeratosis and a variable increase in vascularity (see eFig. 140-8.7). The shagreen patch has sclerotic bundles of collagen in the reticular dermis (see eFig. 140-8.8). Elastic fibers are typically reduced in amount.

Special Tests (Including Imaging Studies)

Besides dermatologic and ophthalmologic examination, the initial evaluation of a patient suspected to have TSC includes the following: (1) cranial computed tomography (CT) or cranial magnetic resonance imaging (MRI), (2) renal ultrasonography (or MRI or CT), and (3) electrocardiography.60 In addition, the following tests are recommended for subsets of patients. Electroencephalography is valuable if seizures are suspected and subsequently for seizure management. In children, standardized cognitive and behavioral assessments are indicated at the time of diagnosis, in response to changes in behavior or worsening performance, and at regular intervals tailored to the individual.53 In adult women, high-resolution chest CT is used to detect LAM. Echocardiography is indicated if the patient exhibits cardiac symptoms.60

After diagnosis, the patient should have periodic surveillance for the development of new lesions or changes in existing lesions. Cranial CT or MRI is recommended every 1–3 years in children. This may reveal the presence of a subependymal giant cell astrocytoma, which allows removal before it becomes locally invasive or causes symptoms. Similarly renal ultrasonography is recommended every 1–3 years, depending on clinical suspicion and results of previous examinations. If large or numerous renal tumors are present, renal CT or MRI should be performed. Echocardiography and chest CT are indicated for cardiac and pulmonary symptoms, respectively60

Screening of first-degree relatives of a TSC patient begins with examination of the skin, oral mucosa, teeth, and retina. Most affected family members will show TSC lesions with this approach, but additional imaging studies are recommended even in their absence.60 When results of the physical examination are negative, cranial CT is recommended over MRI because of its lower cost and the lower likelihood of detecting lesions unrelated to TSC. Renal ultrasonography is also recommended. Molecular diagnosis may be useful for individuals in families with a known genetic change.60

Molecular Diagnosis

Genetic testing may be useful to confirm diagnosis in individuals not meeting criteria for definite TSC.60 It can provide additional information for genetic counseling, and it can be used in prenatal diagnosis.15 Genetic testing may yield false-negative or inconclusive results. Extensive analysis of TSC1 and TSC2 fails to identify a mutation in approximately 15% of TSC patients.4,5 TSC1 and TSC2 are large genes, and mutations may occur anywhere along the sequence. Also, sequence analysis does not identify large deletions and must be supplemented by other methods of analysis.4,5,79 Mutation detection may also be hampered by somatic mosaicism.

Differential diagnoses for several major features of TSC are summarized in Boxes 140-1, 140-2, 140-3, and 140-4.

None of the skin lesions in TSC is prone to malignant degeneration, but the lesions can be a major cosmetic concern for the patient, causing social isolation and difficulties with self-esteem.80 Angiofibromas, facial plaques, and ungual fibromas can be painful or bleed spontaneously or in response to minor trauma. Ungual fibromas can cause nail dystrophy and eventual loss of the nail. Large facial lesions may obstruct vision or occlude the nasal passages.81

Individuals with tuberous sclerosis exhibit decreased overall survival compared with the general population. The causes of premature death include renal failure, intractable seizures, obstructive hydrocephalus, cardiac outflow obstruction, arrhythmia, respiratory failure, pneumothorax, and hemorrhage from an aneurysm or a tumor, especially AMLs.82,83 Fatal events may occur at any age. Brain and heart tumors may cause death in infancy, whereas lung and kidney tumors are more likely to cause premature death in adulthood. The prognosis for the individual patient depends on disease expressivity. Some individuals have a normal life span with few medical complications.

When an infant is newly diagnosed with TSC, a major aspect of care is answering questions and addressing the concerns of the family. Unfortunately, many parents report negative experiences because of physician insensitivity and the provision of inaccurate information and inadequate support.84 Patients should be promptly referred to other specialists and social services as needed, and genetic counseling should be offered. Families should be informed about organizations dedicated to TSC, such as the Tuberous Sclerosis Alliance (http://www.tsalliance.org).

Current treatments for TSC skin tumors are mostly surgical. Angiofibromas have been treated by excision, curettage, chemical peel, cryosurgery, dermabrasion, electrosurgery, and different types of laser procedure.81,85–89 Multiple sessions using several approaches may be required for optimal results. Potential complications of surgical treatments include infection, hypertrophic scarring, postinflammatory hyperpigmentation, and hypopigmentation. Treated angiofibromas tend to recur over a couple of years, and new lesions may form.81 Ungual fibromas are usually treated by excision, but these lesions also have a high recurrence rate. Hypomelanotic macules may be temporarily concealed using self-tanning lotions or makeup matched to the person's skin color. The shagreen patch is usually left untreated, but it can be excised. For further details regarding surgical approaches to TSC skin lesions, as well as preoperative and postoperative issues, consult reference nos. 22 and 81.

Clinical trials are in progress to test potential medical therapies for TSC tumors. Oral rapamycin caused regression of subependymal giant cell astrocytomas, decreased the size of renal AMLs, and improved pulmonary function in patients with LAM.13,90 Several patients showed improvement in angiofibromas while on oral rapamycin,91,92 but the potential for serious side effects is likely to limit systemic use of rapamycin for these benign skin lesions, especially in children. Application of a topical form of rapamycin has recently been shown in a single case to diminish the size and numbers of angiofibromas while reducing the risks of systemic administration93 and maintaining efficacy against TSC skin lesions, but surgical approaches continue to be the mainstay of treatment until appropriate studies are done.

It is not unusual for a child with TSC to be born to parents who do not carry the diagnosis of TSC. This may represent a de novo mutation, parental mosaicism, or it may indicate that one parent has a very mild form of TSC that has escaped detection. Both parents should be carefully screened as described earlier. If one parent has TSC, there is a 50% chance that subsequent children will inherit the mutation.

If neither parent has TSC, it is possible that there is alternate paternity or undisclosed adoption. Another possibility is that one parent is mosaic for a mutation in TSC1 or TSC2.94,95 This has profound implications for genetic counseling. Whereas it would be extremely unlikely for parents of a child with a de novo mutation to have another affected child, germ-line mosaicism in one parent greatly increases the risk of having another child with TSC. An estimate of the overall risk that apparently unaffected parents will have a second child with TSC is approximately 2%.15

Prenatal testing can be performed on cells obtained by chorionic villus sampling or amniocentesis.15,96,97 It is also possible to use high-resolution ultrasonography and ultrafast MRI to examine for TSC tumors in the fetus, but the sensitivity of these tests is unknown.15,98–101 It should be emphasized that TSC is highly variable, even within a family, and that genetic testing does not predict disease severity in offspring. Also, this brief summary does not detail many issues surrounding genetic testing that require utmost thought and sensitivity and consultation with genetics professionals.