Dermatologic Manifestations of Tuberous Sclerosis Clinical Presentation

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