eMedicine Specialties > Dermatology > Pediatric Diseases

Tuberous Sclerosis

Author: Rabindranath Nambi, MD, DD, DipNB, Consulting Staff, Department of Dermatology, Dudley Group of Hospitals, UK
Contributor Information and Disclosures

Updated: Aug 13, 2009

Introduction

Background

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. 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.

Pathophysiology

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.

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).¹ 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.² Hamartin and tuberin heterodimerize and inhibit mTOR, the mammalian target of rapamycin.³

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.^4,5 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 small proportion of families exist whose genetic localization has not been determined.

Frequency

United States

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

International

International frequency for tuberous sclerosis is the same as US frequency.

Mortality/Morbidity

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.

Race

No racial predilection has been noted for tuberous sclerosis.

Sex

No sex predilection has been noted for tuberous sclerosis.

Age

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.⁶

Clinical

History

• 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

The criteria for diagnosing tuberous sclerosis complex have been revised.^7,8 The features have been divided into major features and minor features.

• Major features of tuberous sclerosis
  • Facial angiofibromas or forehead plaque⁹
  • Nontraumatic ungual or periungual fibromas
  • 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
• Minor features of tuberous sclerosis
  • 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
• Diagnosis of tuberous sclerosis
  • Definite tuberous sclerosis complex is diagnosed by the presence of either 2 major features or 1 major feature plus 2 minor features.
  • Probable tuberous sclerosis complex is indicated by 1 major feature plus 1 minor feature.
  • Possible tuberous sclerosis complex is indicated by either 1 major feature or 2 or more minor features.
• Skin lesions (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. 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.
  • 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.¹⁰ 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.
• Ocular findings of tuberous sclerosis: Ocular involvement includes 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.¹¹ 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.¹² 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.
• Related clinical guideline summaries
  • American Academy of Neurology and the Child Neurology Society - Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society¹³
  • American Academy of Neurology, American Epilepsy Society, and the American Association of Neurological Surgeons - Practice parameter: temporal lobe and localized neocortical resections for epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons^14,15

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