Dermatologic Manifestations of Tuberous Sclerosis



Tuberous sclerosis is a genetic disorder affecting cellular differentiation and proliferation, which results in hamartoma formation in many organs (eg, skin, brain, eye, kidney, heart).

Von Recklinghausen first described tuberous sclerosis in 1862. In 1880, Désiré-Magloire Bourneville coined the term sclerose tubereuse, from which the name of the disease has evolved. Sherlock coined the term epiloia, encompassing the clinical triad of epilepsy, low intelligence, and adenoma sebaceum. The term tuberous sclerosis complex (TSC) is now widely used, emphasizing the variegated nature of its manifestations; most current reports refer to the condition as tuberous sclerosis complex.


The inheritance is autosomal dominant, while up to 50-70% of cases of tuberous sclerosis have been attributed to new mutations. This high percentage of mutations may be reduced after careful examination and detailed investigation of apparently healthy parents, who on closer inspection may have disease features.[1]

Two genetic loci for tuberous sclerosis have been identified so far. The first gene maps to chromosome 9, specifically 9q34 (TSC1); the second gene maps to chromosome 16, specifically 16p13 (TSC2).[2, 3, 4, 5] Tuberin, the protein gene product of TSC2, was the first of the affected proteins to be isolated. Tuberin shows a small region of homologic identity to the catalytic domain of the Rap 1 guanosine triphosphatase (GTPase) activity protein (Rap 1 GAP). Rap 1 is a member of a group of proteins involved in the regulation of cell proliferation and differentiation. Loss of tuberin activity is thought to lead to activation of Rap 1 in tumors. Hamartin, the TSC1 second gene product, has been isolated and may function as a tumor suppressor.[6] Hamartin and tuberin heterodimerize and inhibit mTOR, the mammalian target of rapamycin.[7]

Interestingly, hamartin and tuberin have been shown to have coiled coil domains that interact with each other. Hamartin and tuberin are thought to act synergistically to regulate cellular growth and differentiation.[8, 9] The deregulation in organogenesis results in tumors, which may affect any organ in the body. Most of the tumors represent hamartomas and, in many organs, resemble embryonic cells, suggesting that the defect occurs at an early stage in life. A very small proportion of families exist whose genetic localization has not been determined.

Mammalian target of rapamycin

Mammalian target of rapamycin (mTOR) is a key player in pathways involved for cellular growth, proliferation, and survival via a cytoplasmic serine/threonine kinase .In cells that lack either TSC1 or TSC2, mTOR activity is increased many-fold, and this would cause uninhibited growth and subsequent hamartomas in various organs. mTOR inhibitors, which have already been used in some cancers, could play a role in tumor lysis or shrinkage owing to the above pathways being altered.



The frequency of tuberous sclerosis worldwide is 1 case in 5,800-30,000 persons.


No racial predilection has been noted for tuberous sclerosis.


No sex predilection has been noted for tuberous sclerosis.


Most tuberous sclerosis patients are diagnosed between ages 2 and 6 years. Cardiac and cortical tubers develop at infancy, while skin lesions are seen in more than 90% of patients at all ages. The ash-leaf macule can be present at birth, while the facial angiofibroma and ungual fibromas can develop in late adolescence. Wand et al report a case of tuberous sclerosis first diagnosed in a military pilot at age 22 years.[10]


Tuberous sclerosis shows a wide variety of clinical expressions. Some individuals are severely affected, while others have very few features. Forme frustes are common. An accurate estimation of the course in an individual with tuberous sclerosis depends on the extent of involvement. About a quarter of severely affected infants are thought to die before age 10 years, and 75% die before age 25 years; however, the prognosis for the individual diagnosed late in life with few cutaneous signs depends on the associated internal tumors.


Most individuals with tuberous sclerosis present with parental concern about small raised tumors on the child's face. (In most cases, the parent draws the attention to the cutaneous stigmata.)

Some tuberous sclerosis cases are detected in child health clinics as whitish spots.

Children with late-onset tuberous sclerosis and individuals with few skin signs may remain undetected until adolescence.

Dental pitting and fibromas may be noticed by the parents or an astute dentist.

Clinical manifestations have a varied penetrance, adding to the delay in diagnosis.

Physical Examination

The criteria for diagnosing tuberous sclerosis complex have been revised from the previous recommendations.[11, 12]

Diagnostic criteria

The International Tuberous Sclerosis Complex Consensus Conference updated the diagnostic criteria that were set in 1998,[13] and the updated criteria are described in the Table below. The guidelines for management and surveillance have also been updated. Genetic testing can also be done, and the criteria for the diagnosis are described below.

Table. Clinical Criteria for Diagnosing Tuberous Sclerosis Complex

View Table

See Table

Definite diagnosis is two major features or one major feature with 2 or more minor features.

Possible diagnosis is either one major feature or 2 or more minor features.

Genetic criteria

The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definite diagnosis of tuberous sclerosis complex. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 protein (eg, out-of-frame insertion or deletion or nonsense mutation), prevents protein synthesis (eg, large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment. Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria and are not sufficient to make a definite diagnosis of tuberous sclerosis complex.

Note that approximately 15% of individuals with tuberous sclerosis complex have no mutation identified by conventional genetic testing, and a normal result does not exclude tuberous sclerosis complex or have any effect on the use of clinical diagnostic criteria to diagnose tuberous sclerosis complex.[13]

Clinical features

Major features of tuberous sclerosis are as follows:

The minor features of tuberous sclerosis are as follows:

Skin lesions

Skin lesions[14] are found in 70-80% of cases of tuberous sclerosis.

The characteristic lesions are angiofibromas, previously known by a misnomer, adenoma sebaceum. These are pink or skin-colored telangiectatic papules commonly observed in the nasolabial folds and on the cheeks and chin. They usually appear in children younger than 10 years and increase in size and number until adolescence, remaining unchanged thereafter. Other areas in which they may be observed include in and around nails (ungual fibromas), scalp, and forehead, in the latter location reaching sizes up to several centimeters. In the oral mucosa, they may be observed in the lips, dorsa of tongue, and palate. Dental pitting occurs in about 90% of patients. A hand lens examination aids detection of these pits, which are less obvious in deciduous teeth.

Periungual fibromas (Koenen tumors) are smooth, firm, flesh-colored papules emerging from the nail folds. They can be the only manifestation in some individuals. These are noted around puberty and may increase in frequency as the patient ages.

Shagreen patches are flesh-colored soft plaques that are frequently found in the lumbosacral area but may occur anywhere on the trunk. The surface may be pebbly (resembling pigskin or untanned leather) with prominent follicular openings. They are usually noticed during the first decade.

White macules are ovoid, hypopigmented, ash leaf–shaped macules that can be found on the trunks or limbs. The configuration resembles the leaves of the European mountain ash tree. White macules offer an excellent opportunity for early diagnosis because they may be found at birth or early infancy. The use of Wood lamp accentuates these macules. The color, even though described as white, lacks the depigmented white appearance of vitiligo. A careful examination is necessary before making any firm diagnosis because hypopigmented macules may be a normal finding in newborn babies. One suggestion is that 3 or more white macules at birth should alert the clinician regarding the possibility of tuberous sclerosis.

Confetti lesions are hypopigmented macules on the extremities and are one of the minor criteria.

Other skin signs include guttate leukoderma, café-au-lait macules, and poliosis.

Neurologic findings of tuberous sclerosis

The tuberosclerotic nodules of glial proliferation occur in the cerebral cortex, basal ganglia, and ventricular walls but are rare in the cerebellum, medulla, or spinal cord. Rarely, hydrocephalus may result from obstruction of the foramen of Monro.

Subependymal giant cell astrocytomas also may be present, and serial imaging scans are recommended to monitor if growth occurs.

The number of tubers in the cortex and subcortex appears to correlate with the clinical severity of tuberous sclerosis disease, as measured by the ease of control of seizures, the appearance of developmental milestones, and school performance.

Epilepsy occurs in 80-90% of all patients, with a positive correlation with subnormal intelligence.[15] Epilepsy requires treatment, preferably with monotherapy. Carbamazepine and sodium valproate are traditionally used in the initial treatment. Vigabatrin, an irreversible inhibitor of GABA transaminase, is reported to be more effective for infantile spasms in tuberous sclerosis complex. Lamotrigine is also used as adjunctive therapy for partial seizures in adults. In many cases, resection of the tuber may result in better control of epilepsy.

Mental retardation is observed in 60-70% of cases; however, if mental development is normal throughout childhood, subsequent worsening is uncommon.

Other features noted include schizophrenia, autistic behavior, and attention-deficit hyperactivity disorder.

The cognitive impairment in tuberous sclerosis complex is related to age of seizure onset.

Ocular findings of tuberous sclerosis

Ocular findings of tuberous sclerosis[14] include hypopigmented spots in the iris, equivalent to the ash-leaf macule in the skin. Retinal phakomas are observed as whitish-gray nodular lumps with a lump of mulberries appearance.[16] These represent hamartomas characterized by proliferation of astrocytes. Every patient with tuberous sclerosis complex should have a thorough ophthalmologic examination at the time of diagnosis.

Tuberous sclerosis findings in other organs

Cardiac rhabdomyomas are observed in over 50% of infants. They may be detected prenatally by fetal echocardiography and are the commonest cardiac abnormality detected in utero. Up to 50-60% of patients with tuberous sclerosis complex have cardiac disease, mainly rhabdomyomas. These may cause mechanical problems because of their size or because of the defects in the conducting system caused by their infiltrating nature. Rhabdomyomas usually undergo spontaneous resolution in the first few years of life in about 80% of patients, even though residual areas of histologically abnormal myocardium may persist.

Aneurysms of thoracic and abdominal aortas have also been observed rarely.

Renal involvement is usually manifested by angiomyolipomas. Angiomyolipomas are benign tumors of vessels and are seen in up to 75% of patients. Spontaneous bleeding may be fatal, and these tumors are best treated by embolization.[17] Other features may include renal cysts, polycystic kidneys, and renal carcinoma.

Pulmonary changes include lymphangiomatosis with cyst formation. This may be progressive and result in dyspnea, cor pulmonale, recurrent pneumothorax, and respiratory failure.

Gastrointestinal tumors may be associated. Microhamartomatous polyps are present in the rectum in 75% of cases. Hepatic hamartomas have also been reported.

The bones may show areas of cyst formation, periosteal new bone growth, and areas of sclerosis.

Other abnormalities noted include pituitary adrenal dysfunction, thyroid disorders, premature puberty, diffuse cutaneous reticulohistiocytosis, and gigantism.

Imaging Studies

Evaluation of newly diagnosed tuberous sclerosis patients should include a personal and family history and a clinical examination, including funduscopy, cranial imaging (eg, MRI, nonenhanced CT scanning), renal ultrasonography, and echocardiography in infants.

Computed cranial tomography scanning and MRI are performed not only in suspect cases but also in patients whose diagnosis is obvious. Do not use scan results to predict the neurologic outcome of an individual patient. New MRI techniques such as FLAIR (fluid attenuated inversion recovery) help identify small tubers, which may not be detected with other imaging techniques.[18]

If tubers are present, serial imaging scans are essential to evaluate for growth of the tumor.

EEG is useful when the initial presentation includes epileptic seizures. EEG is not required in children who do not have epilepsy.

Renal ultrasonography is used to evaluate children and older patients in particular for renal tumors.

ECG is a baseline study essential to detect any cardiac arrhythmias. Wolff-Parkinson-White syndrome seems to be the most common arrhythmia in patients with tuberous sclerosis complex (TSC).

Echocardiography is recommended for patients of any age with symptoms of cardio rhabdomyoma. Because most symptoms occur in neonates, older children do not need to have an echocardiogram, unless it is to confirm a previous dubious diagnosis.

Neurodevelopmental testing as age-appropriate screening for behavioral and neurodevelopmental dysfunction at the time of diagnosis is essential. Periodically reassess children with abnormal test results. Newly diagnosed adults with normal social and cognitive function (as demonstrated by educational and career achievements) may not require formal testing. Frequent assessment is probably not warranted in such individuals.

Consensus guidelines have been published to help in the assessment of cognitive and behavioral problems in persons with tuberous sclerosis complex. Refer to the Tuberous Sclerosis Association for the guidelines.

Molecular diagnosis using DNA-based testing is not yet routinely available but in the future could be developed and would help to identify patients at increased or decreased risk for particular complications.

Ongoing evaluation

Annual or at least biannual MRI can be performed until age 21 years. At that point, any single tumors identified may need closer monitoring.

The frequency of EEG depends upon the clinical features and the treatment response of epilepsy. Consider EEG in the evaluation of a patient with unexplained decline of behavioral or cognitive function, in whom epileptic seizures are suspected.

Neurodevelopmental testing should take into account various features of tuberous sclerosis complex, including mental retardation, which is the most common, and other features, which are learning disabilities, autism, and attentional deficit. Repeat assessment around the time that a child enters school and then reassess periodically in response to educational and behavioral concerns.

Renal ultrasonography is recommended annually. Patients who have large renal lesions or lesions that have grown substantially should have more frequent follow-up examinations.

ECG is indicated in persons with arrhythmias or unexplained loss of consciousness. Repeat echocardiography is not required in asymptomatic patients. Any suggestion of cardiac dysfunction may merit investigations.

Pulmonary function testing is reserved for patients with pulmonary dysfunction and may be performed annually. Women should undergo chest CT scanning at least once on reaching adulthood.

Evaluation of family members

In a family with only one child affected, evaluation of parents is more important than siblings or relatives.

Cranial CT scanning is more likely to detect lesions of tuberous sclerosis as a screening tool; MRI often detects lesions that are not as specific to tuberous sclerosis complex. MRI is the first choice; however, if the scan results are negative and the diagnosis is uncertain, then CT scanning may be performed.

Renal lesions occur in about 80% of patients, making renal ultrasonography an important screening test.

Echocardiography is not recommended unless compelling cardiac symptoms persuade otherwise because cardiac rhabdomyomas commonly disappear by adulthood.

Although molecular diagnosis is not yet commercially available, identifying some patients with tuberous sclerosis complex who do not fulfill clinical diagnostic criteria should soon be feasible.

Histologic Findings

Angiofibromas show atrophic sebaceous glands with dermal fibrosis and dilation of some of the capillaries. The fibrosis occasionally has a glial appearance because of the large size and stellate shape of the fibroblasts. Elastic tissue is absent in the angiofibromas.

The ungual fibromas show mainly fibrosis, rarely capillary dilation.

The shagreen patches show increased dense sclerotic mass of broad collagenous bundles. Normal collagen bundles may sometimes be arranged in an interwoven pattern. The elastic tissue is reduced.

The hypopigmented ash-leaf macule shows normal melanocyte numbers with decreased pigmentation. Electron microscopy shows smaller melanosomes with defective melanization.

Medical Care

A multidisciplinary team approach is useful to address the many organ systems that may be affected by tuberous sclerosis. Periodic monitoring is necessary, ranging from 1-3 years, depending on the internal tumors and their manifestations. Treatment plans should be determined on an individual basis.

Sirolimus and everolimus have now become approved treatments for this condition. In a 2016 study, sirolimus (Rapamycin) was used in a 1% formulation applied twice daily continuously.[19] The authors found good improvement when started at an earlier age. Irritation was the main adverse effect.

Recommendations for epilepsy include the following:

Solid renal lesions with a low fat content on ultrasound should be carefully investigated by an expert.

Recommendations for assessment of renal disease include the following:

Investigate for pervasive developmental disorders at age 2 years (eg, Childhood Autism Test [CHAT]) and again at school entry (ie, age 4-5 y). Perform an Alzheimer's Disease Information Questionnaire (ADIQ) if developmental delay is suspected.

Screening for psychiatric and behavioral disturbances may require testing at school entry and again at age 7 years, at secondary school transition, and during mid adolescence (age 15 y). Refer the patient to a mental health specialist as required.

If developmental delay is suspected, assess the patient's intellectual and cognitive profile at key stages in order to identify problems early and act accordingly (age 2-3 y, age 7-8 y). Access the need to place children and adults with learning disabilities and neuropsychological impairments in the care of specialists; also assess the need to refer patients to a community learning disabilities team.[21]

Infantile spasms may be treated and relapses may be less with high dose vigabatrin. This can be given long term to prevent relapses.[22]

Surgical Care

The facial angiofibromas cause the most psychological distress for patients and benefit from laser treatment. The argon and pulsed-dye lasers are more effective on vascular lesions, while the carbon dioxide laser is effective in lesions with increased fibrous content. Either laser or diathermy can remove ungual fibromas.


Assess whether any of the following is needed:

Investigate family members, when indicated, including a family history, a clinical examination (including skin evaluation with UV light), funduscopy, brain CT scanning or MRI, and genetic counseling.

Long-Term Monitoring

Neurodevelopmental testing as age-appropriate screening for behavioral and neurodevelopmental dysfunction at the time of tuberous sclerosis diagnosis is essential. Reassess children with abnormal test results periodically. Repeat assessment around the time that a child enters school and then reassess periodically in response to educational and behavioral concerns.

Guideline Summary

Comprehensive guidelines have been issued for cases that are newly diagnosed and for cases that have been under follow-up. These updated guidelines based on a consensus conference of a multidisciplinary panel have helped to streamline diagnosis and management of patients.[23]


Rabindranath Nambi, MD, Consulting Staff, Department of Dermatology, Dudley Group of Hospitals, UK

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Eleanor E Sahn, MD, Director, Division of Pediatric Dermatology, Associate Professor, Departments of Dermatology and Pediatrics, Medical University of South Carolina

Disclosure: Nothing to disclose.


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Facial angiofibromas in a young man with tuberous sclerosis complex.

Dysplastic periungual fibroma involving the great toe in a patient with tuberous sclerosis.

Facial angiofibromas in a young man with tuberous sclerosis complex.

Dysplastic periungual fibroma involving the great toe in a patient with tuberous sclerosis.

Major Features Minor Features
Hypomelanotic macules (≥3, at least 5 mm in diameter)Confetti skin lesions
Angiofibromas (≥3) or fibrous cephalic plaqueDental enamel pits (>3)
Ungual fibromas (≥2)Intraoral fibromas (≥2)
Shagreen patchRetinal achromatic patch
Multiple retinal hamartomasMultiple renal cysts
Cortical dysplasiasaNonrenal hamartomas
Subependymal nodules 
Subependymal giant cell astrocytoma 
Cardiac rhabdomyoma 
Lymphangioleiomyomatosis (LAM) plus 
Angiomyolipomas (≥2)b 
a Includes tubers and cerebral white matter radial migration lines.

b A combination of the two major clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis.