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
Table 140-1 Diagnostic Criteria for Tuberous Sclerosis Complex (TSC) ||Download (.pdf)
Table 140-1 Diagnostic Criteria for Tuberous Sclerosis Complex (TSC)
- Facial angiofibromas or forehead plaque
- Nontraumatic ungual or periungual fibromas
- Hypomelanotic macules (three or more)
- Shagreen patch (connective tissue nevus)
- Multiple retinal nodular hamartomas
- Cortical tubera
- Subependymal nodule
- Subependymal giant cell astrocytomas
- Cardiac rhabdomyoma, single or multiple
- Renal angiomyolipomasb
- Multiple randomly distributed pits in dental enamel
- Hamartomatous rectal polypsc
- Bone cysts
- Cerebral white matter migration linesa,d,e
- Gingival fibromas
- Nonrenal hamartomac
- Retinal achromic patch
- Confetti skin lesions
- Multiple renal cystsc
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 (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 ash-leaf macules on the lower leg of a child with tuberous sclerosis complex.
A. Hypomelanotic macules on the lateral chest of an adult with tuberous sclerosis complex. The macules may be easily overlooked. B. Wood's lamp accentuates the macules.
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
Confetti-like hypopigmented macules on the lower leg of an adult with tuberous sclerosis complex.
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
Multiple facial angiofibromas on the nose, cheeks, and chin, with relative sparing of the upper lip as commonly observed in tuberous sclerosis complex.
Angiofibromas are often larger in the alar grooves and may become less erythematous over time, as in this adult with tuberous sclerosis complex.
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
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
The forehead fibrous plaque in tuberous sclerosis complex is often pink-red and has a bumpy surface and irregular outline.
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
The shagreen patch in tuberous sclerosis complex is a firm, bumpy plaque that is usually located on the lower back.
The shagreen patch may consist of grouped, dermal papules that are minimally elevated above the skin.
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
Multiple periungual and subungual fibromas on the toes in a patient with tuberous sclerosis complex.
A periungual fibroma emanating from the proximal nail fold in tuberous sclerosis complex causes a longitudinal groove in the nail.
Subungual fibromas may disrupt the normal nail anatomy in tuberous sclerosis complex, causing distal onycholysis.
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
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
Molluscum fibrosum pendulum, another name for multiple skin tags in tuberous sclerosis complex, is observed on the neck in this patient.
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
Multiple dental enamel pits are seen in nearly all patients with tuberous sclerosis complex.
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
Multiple gingival fibromas and dental pits in this adult with tuberous sclerosis complex.
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.
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
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
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
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
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.
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.
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