Dermatologic Manifestations of Tuberous Sclerosis

Updated: Sep 24, 2021
Author: Rabindranath Nambi, MD; Chief Editor: Dirk M Elston, MD 



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 and tuberin heterodimerize and inhibit mammalian target of rapamycin (mTOR), the mammalian target of rapamycin.[6]

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.[7, 8] 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.

MicroRNA-34a has been shown to be highly overexpressed in cortical tubers during fetal and early postnatal brain development. miR-34a negatively regulates mTORC1 and may also contribute to abnormal corticogenesis in tuberous sclerosis complex (TSC).[9]

Experiments in human cell lines, mice, Drosophila, and Caenorhabditis elegans have shown that endonuclease G (ENDOG) plays a protective role against the development of TSC. ENDOG causes autophagy by suppressing mTOR signalling and activating the DNA damage response, offering an alternative pathogenesis.[10]

Building on the newer pathways for pathogenesis includes the E3 ubiquitin ligase Peli1 as an important regulator of T-cell metabolism and antitumor immunity. Peli1 regulates the activation of a metabolic kinase, mTORC1, through its interaction with mTORC1 inhibitory proteins TSC1 and TSC2. Peli1 causes nondegradative ubiquitination of TSC1 and promotes TSC1-TSC2 dimerization and TSC2 stabilization. Hence, Peli1 is regarded as a novel regulator of mTORC1 and downstream mTORC1-mediated actions on T-cell metabolism and antitumor activity.[11]

The mechanisms of cellular energy sensing and AMPK-mediated mTORC1 inhibition are not fully delineated. A newer candidate in the pathogenesis of TSC is RIPK1, which promotes mTORC1 inhibition during energetic stress. RIPK1 mediates between AMPK and TSC2 and causes TSC2 phosphorylation at Ser1387. Loss of RIPK1 results in high basal mTORC1 activity, leading to accumulation of RIPK3 and CASP8 and sensitization to cell death. RIPK1-deficient cells are unable to cope with energetic stress and are vulnerable to low glucose levels and metformin. These findings elaborate on the regulation of mTORC1 during energetic stress and interactions between prosurvival and prodeath pathways.[12]

Mouse models and clinical studies of TSC have supported the glial dysfunction theory in the pathophysiology of epilepsy and TSC-associated neuropsychiatric disorders (TAND).The role of astrocytes, microglia, and oligodendrocytes in the pathophysiology of epilepsy and TANDs in TSC has been analyzed. Targeting glia cells may be considered in developing novel treatments for the neurological manifestations of TSC.[13]

Studies have provided new evidence on the role of exosomes and noncoding RNA cargo (including miR-142-3p, miR-223-3p, and miR-21-5p ) in the neuroinflammatory cascade of epilepsy and may help in the development of novel biomarkers and therapeutic approaches for the treatment of drug-resistant epilepsy.[14]

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.[15]


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 (TSC) have been revised from the previous recommendations.[16, 17]

Diagnostic criteria

The International Tuberous Sclerosis Complex Consensus Conference updated the diagnostic criteria that were set in 1998,[18] 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 (Open Table in a new window)

Major Features

Minor Features

Hypomelanotic macules (≥3, at least 5 mm in diameter)

Confetti skin lesions

Angiofibromas (≥3) or fibrous cephalic plaque

Dental enamel pits (>3)

Ungual fibromas (≥2)

Intraoral fibromas (≥2)

Shagreen patch

Retinal achromatic patch

Multiple retinal hamartomas

Multiple renal cysts

Cortical dysplasiasa

Nonrenal 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.

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.[18]

Clinical features

Major features of tuberous sclerosis are as follows:

  • Facial angiofibromas or forehead plaque[18] (see the image below)

    Facial angiofibromas in a young man with tuberous Facial angiofibromas in a young man with tuberous sclerosis complex.
  • Nontraumatic ungual or periungual fibromas (see the image below)

    Dysplastic periungual fibroma involving the great Dysplastic periungual fibroma involving the great toe in a patient with tuberous sclerosis.
  • Hypomelanotic macules (≥3)

  • Shagreen patch (connective tissue nevus)

  • Multiple retinal nodular hamartomas

  • Cortical tuber

  • Subependymal nodule

  • Subependymal giant cell astrocytoma

  • Cardiac rhabdomyoma, single or multiple

  • Lymphangiomyomatosis

  • Renal angiomyolipoma

The minor features of tuberous sclerosis are as follows:

  • Multiple randomly distributed pits in dental enamel

  • Hamartomatous rectal polyps

  • Bone cysts

  • Cerebral white matter radial migration lines

  • Gingival fibromas

  • Nonrenal hamartoma

  • Retinal achromic patch

  • Confetti skin lesions

  • Multiple renal cysts

Skin lesions

Skin lesions[19] 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.

An entity described in 2021 as associated with TSC is the folliculocystic and collagen hamartoma (FCCH).[20] It is commonly seen on the head and neck. Clinical features include a solitary, well-circumscribed exophytic tumor covered with comedones and cystlike structures. Histopathology features include thickening of the collagen bundles in the dermis, concentric perifollicular and perivascular fibrosis, an increased number of dilated vessels, and keratin-filled cysts lined by the infundibular epithelium. Treatment is surgical excision.

Graying of hair in TSC is distinct from poliosis. Graying occurs later in childhood, is progressive, and is interspersed among pigmented hairs and not sharply demarcated.[21]

A report from 2021 described hypohidrosis in the macules of TSC and neurofibromatosis.[22]

A case report has shown the rare association of a TSC patient with cardiac rhabdomyoma, subependymal giant cell astrocytoma (SEGA), hypomelanotic macules, and juvenile xanthogranuloma.[23]

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.[24] 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.

The largest international cohort of patients with TSC has been documented in the TOSCA registry.[25] Seizures can occur in almost 84% patients, as early as age 2 years, with focal seizures (67.5%) being more common than infantile spasms (38.9%). The TSC2 mutation was associated with an increased incidence of infantile spasms (47.3%) compared with the TSC1 mutation (23%). GABAergic drugs were the preferred drug of choice for both focal seizures and infantile spasms. Focal seizures can occur at all ages, including an onset that precedes the emergence of infantile spasms. Proper seizure control can lower the rates of intellectual disabilities.

Hemimegalencephaly has been reported in a few cases of TSC.[26] It is associated with intractable epilepsy and severe developmental delay.

Ocular findings of tuberous sclerosis

Ocular findings of tuberous sclerosis[19] 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.[27] 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.

Pathogenic variants in the TSC2 gene can rarely result in an atypical, unilateral iris coloboma associated with localized areas of retinal dysembryogenesis.[28]

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.[29] 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.

A few cases of insulinoma have been reported in association with TSC.[30] The tumor can vary in size and location on the pancreas, causing hypoglycemia.

A 2021 TOSCA cohort study shows several rare associations in TSC patients.[31] The most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), and hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly noted in adults than in children (66.2% vs 22.7%), in females more than males (58.4% vs 41.6%; except for scoliosis: 48.9% vs 51.1%), and in those with TSC2 mutations more than TSC1 mutations (67% vs 21.1%; except for thyroid adenoma: 42.9% vs 57.1%). Among malignancies, the most common were renal cell carcinoma (47.7%), breast cancer (10.8%), and thyroid cancer (9.2%). Malignancies were commonly seen in adult patients, although 26.1% were reported in children and 63.1% in individuals younger than 40 years. Malignancy was commonly seen in association with TSC1 mutations.



Diagnostic Considerations

Consider the following:

  • Angiofibromas (differentiate from acne vulgaris by telangiectasia, absence of comedones and pustules, and a relatively asymptomatic nature)
  • Shagreen patch (must be differentiated from connective tissue nevi)
  • Hypopigmented spots (may need to be differentiated from nevus anemicus, nevus achromicus, and early vitiligo)

Differential Diagnoses



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.[32]

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.[33] The authors found good improvement when started at an earlier age. Irritation was the main adverse effect.

Recommendations for epilepsy include the following:

  • Review current antiepileptic medications.

  • For new and unexplained behavior problems, mood changes, sleep disturbance, or nonconvulsive status, perform urgent brain scanning (MRI preferred to CT scanning) if symptoms and signs suggest raised intracranial pressure or if focal neurological symptoms or signs are present; perform EEG if applicable.

  • Everolimus is an mTOR inhibitor that has been shown to reduce epileptic fits in over 55% of children treated. This has cytoreductive effects in subependymal giant cell astrocytoma and renal angiomyolipoma.

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:

  • Measure blood pressure annually.

  • Test renal function (eg, urea, electrolyte, and plasma creatinine levels) regularly in adults and children with polycystic kidney disease.

  • Perform renal ultrasonography and repeat annually if a lesion has been documented or if otherwise indicated.

  • Refer the patient to a specialist clinic if frank hematuria occurs or if treatment of the renal lesion is being contemplated.

  • mTOR inhibitors have changed the landscape of management, with the EXIST-2 study showing clear reduction in renal masses with everolimus 10 mg daily.[34] This appears to be well tolerated. There has been a rebound increase in a few patients upon cessation of the drug.

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.[35]

Infantile spasms may be treated and relapses may be less with high-dose vigabatrin. This can be given long term to prevent relapses.[36]

A 2020 double-blinded, randomized controlled trial has shown the superiority of topical rapamycin (0.1%) and calcitriol (0.0003%) combination compared with rapamycin monotherapy in the treatment of facial angiofibromas.[37] The combination resulted in a faster resolution of erythema, greater reduction in papule elevation, and better durability.

Calcitriol, the active form of vitamin D, has been shown to reduce the calcification in an in vitro model and was able to restore and rectify the defects in genes related to tuberous sclerosis complex (TSC).[38]

Studies on bumetanide therapy in TSC have shown marked improvement in all relevant behavioral domains, as was confirmed by parent questionnaires.[39] Bumetanide also has a favorable effect on hyperexcitability and sensory processing, thereby improving neuropsychiatric outcomes.

Experimental studies using rhabdomyosarcoma cells with ciclopirox olamine (CPX) have shown inhibition of mTORC1.[40] This inhibitory role contributed to its anticancer activity. CPX inhibition of mTORC1 was attributed to activation of AMP-activated protein kinase (AMPK)–TSC/raptor pathways.

Studies have identified macropinocytosis and phospholipid metabolism as novel mechanisms of metabolic homeostasis in mTORC1-hyperactive cells, which is targeted by ritanserin.[41] Hence, ritanserin may be a novel therapeutic strategy for use in mTORC1-hyperactive tumors, including pancreatic cancer.

Dysregulation of vitamin A–metabolizing enzymes has been observed in TSC gene mutations.[42] Retinoic acid normalizes RARβ levels and limits cell migration but only has a negligible effect on proliferation. The combination of retinoic acid with a reduced dosage of rapamycin has beneficial effects compared with a higher dosage of rapamycin monotherapy, as well as reducing the adverse effects of rapamycin.

Cutaneous delivery experiments using porcine skin have demonstrated that optimized micelle solutions and hydrogels (0.2%) were stable at 4°C for at least 6 and 3 months, respectively, and they increased sirolimus cutaneous bioavailability compared with the control (ointment 0.2%).[43]

mTOR inhibitors (rapamycin and its analogues ) are the preferred drug in the treatment of CNS lesions, with good efficacy and safety profile. A 2019 meta-analysis reported an increased incidence of stomatitis (grades 1 and 2) compared with earlier reported rates of upper respiratory tract infections and nasopharyngitis.[44]

A 2019 retrospective multicenter study has shown that mTOR inhibitor treatment with everolimus is safe for patients younger than 2 years.[45] Cardiac manifestations, subependymal giant cell astrocytoma size, and early epilepsy have shown the best response to everolimus.

Epilepsy in TSC can occur in 70-90% of children, with high degrees of resistance to conventional medication. EPISTOP was a multicenter clinical trial that proposed preventive antiepileptic therapy to modify the natural history.[46] Prophylactic vigabatrin therapy started after the first EEG abnormality was found to be safe and effective in reducing the severity of seizures.

A report from 2021 showed the effectiveness of cannabidiol in TSC-associated seizures.[47] The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage.

Topical sirolimus has proven to be an effective and safe option for the treatment of facial angiofibromas in tuberous sclerosis.[48]

A single session of carbon dioxide laser ablation has been shown to increase percutaneous delivery of topical rapamycin in the treatment of angiofibromas.[49]

Comparative studies have shown superior antitumor activity of the inosine-5'-monophosphate dehydrogenase (IMPDH) inhibitor mizoribine, compared with mycophenolate mofetil.[50] These results provide preclinical support for placing mizoribine over other IMPDH inhibitors as an alternative to mTOR inhibitors for the treatment of TSC-associated tumors and other tumors featuring uncontrolled mTORC1 activity.

Studies in knockout mice have shown that oral administration of solid lipid curcumin particle (SLCP), a novel curcumin formulation, activates AMPK activity and inhibits mTOR activity in the brain tissue of Tsc2+/- mice.[51] It was found to rectify the electrophysiological abnormality and memory loss in the mice.

Everolimus is generally well tolerated with very few cutaneous adverse effects. Case reports have shown the rare occurrence of a child developing erythema nodosum while undergoing everolimus therapy.[52]

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.

In the case of treatment-resistant seizures in TSC patients, surgery has been shown to improve quality of life and augment neurodevelopmental potential.[53] Novel diagnostic, ablative, and neuromodulatory techniques have been developed that may help patients who were previously considered inoperable.


Assess whether any of the following is needed:

  • Special education (with appropriate documentation)

  • Further vocational training or new work placement (refer to the local disablement resettlement officer if required)

  • Social care options (eg, supported or sheltered employment, daycare, supported leisure activities, supported/staffed sheltered housing, residential care)

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.

 A tuberous sclerosis associated neuropsychiatric disorders (TAND) checklist is currently used for quick screening of behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial manifestations in patients with tuberous sclerosis complex (TSC)—THE TAND CHECKLIST.[54]



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.[55]