eMedicine Specialties > Neurology > Pediatric Neurology

Tuberous Sclerosis

Author: David Neal Franz, MD, Professor, Departments of Pediatrics and Neurology, University of Cincinnati College of Medicine; Director, Tuberous Sclerosis Clinic, Cincinnati Children's Hospital Medical Center
Coauthor(s): Tracy A Glauser, MD, Professor, Departments of Pediatrics and Neurology, University of Cincinnati College of Medicine, Children's Comprehensive Epilepsy Program, Children's Hospital Medical Center of Cincinnati
Contributor Information and Disclosures

Updated: Feb 14, 2007

Introduction

Background

In 1880, Bourneville first described the cerebral manifestations of this disorder, applying the term "sclerose tubereuse" to indicate the superficial resemblance of the lesions to a potato. In 1908 Vogt set forth the triad of intractable epilepsy, mental retardation, and adenoma sebaceum; this description (until relatively recently) represented the hallmark of tuberous sclerosis complex (TSC) to most clinicians. Unfortunately, this concept led many primary care physicians and even neurologists to conclude, incorrectly, that a diagnosis of TSC predestines a child to crippling, lifelong neurological and psychological morbidity.

TSC is now known to be a genetic disorder affecting cellular differentiation, proliferation, and migration early in development, resulting in a variety of hamartomatous lesions that may affect virtually every organ system of the body. Less than one third of affected persons fit the classic constellation of symptoms.

Pathophysiology

The TSC2 gene was identified in 1993, and its protein product has been named tuberin. Tuberin has GTPase-activating properties and seems to function as a tumor suppressor. The highest levels of tuberin are found in adult human brain, heart, and kidney; tuberin also has been localized to arterioles of kidney, skin, and heart, as well as to pyramidal neurons and cerebellar Purkinje cells. Its exact function, particularly during neurogenesis, remains unknown. Individual tubers are thought to arise developmentally when mutated neural progenitor cells in the subependymal germinal matrix give rise to abnormally migrating daughter cells that in turn produce tubers. The tubers may undergo cystic degeneration or calcification, or exhibit contrast enhancement on neuroimaging, but these features do not necessarily imply malignant transformation.

Hamartin, the TSC1 product, was identified in 1997 and also may function as a tumor suppressor. Rather than having completely separate functions, both hamartin and tuberin have been shown to have "coiled-coil" domains that interact with each other. Hamartin and tuberin form a complex in this fashion that serves to inhibit the protein complex mTOR (mammalian target of rapamycin) via the GTPase-activating protein Rheb (see Image 21). mTOR was so named because of its ability to bind to the immunosuppressant drug rapamycin (sirolimus, Rapamune) before its function was known. mTOR functions, among other things, as a sort of master switch for cellular anabolism versus catabolism, and it has important regulatory functions for cell growth, cell volume, and protein synthesis. It is also regulated by a wide variety of other factors including insulin and amino acids, and mTOR is highly conserved among a wide range of species, from yeast, to Drosophila, to mammals.

The function of the tuberous sclerosis gene products, hamartin and tuberin, has become increasingly evident over the past several years. Together, they form a tumor suppressor complex, which through the GTPase activating function of tuberin, drives the small GTPase termed Ras homolog enhanced in the brain (Rheb) into the inactive GDP-bound state. Rheb in the GTP bound, active state is a positive effector of the mammalian target of rapamycin (mTOR). mTOR is an evolutionarily conserved protein kinase, which is expressed from fungi to human. Results over the last 10 years have shown that mTOR serves as a major effector of cell growth as opposed to cell proliferation.

Mutations in either hamartin or tuberin drive Rheb into the GTP-bound state, which results in constitutive mTOR signaling. mTOR appears to mediate many of its effects on cell growth through the phosphorylation of the ribosomal protein S6 kinases (S6Ks) and the repressors of protein synthesis initiation factor eIF4E, the 4EBPs. The S6Ks act to increase cell growth and protein synthesis, whereas the 4EBPs serve to inhibit these processes. mTOR interacts with the S6Ks and the 4EBPs through an associated protein, Raptor. When mTOR is constitutively activated through mutations in either hamartin or tuberin this results in the hamartomatous lesions of tuberous sclerosis in the brain, kidneys, heart, lungs, and other organs.

Rapamycin is capable of inducing regression of renal angiomyolipomas in animal models of TSC, and this effect appears to be enhanced by interferon-gamma, whose receptors are up-regulated by overactivity of mTOR. This pathway may be excessively active in other human malignancies as well as in TSC. These observations raise the possibility of new therapeutic interventions for this disorder. Trials of rapamycin for renal angiomyolipomas in humans with TSC are nearing completion at the authors' center and in Munich, Germany. A multicenter trial of rapamycin for angiomyolipomas is to begin soon, as is a trial for lymphangioleiomyomatosis (LAM).

The high incidence of sporadic TSC, coupled with a probable "second hit" phenomenon, seems a likely explanation for the marked phenotypic variability observed. In the second hit hypothesis, affected individuals inherit or acquire via mutation a flawed copy of one of the TSC genes. Clinical signs and/or symptoms do not emerge unless the other, normal allele also receives a "second hit," resulting in both copies being abnormal. This allows considerable potential for diversity, not only among various deletions and mutations between 2 genetic loci, but also with regard to possible interactions between protein products of varying functionality arising from different mutations on each allele.

Further complicating the high spontaneous mutation rate is the observation that parents of an affected child, who themselves show no sign of TSC, nonetheless have an increased risk (approximately 2% overall) of having additional affected children. This is thought to result from parental mosaicism for one of the TSC genes limited to cells of their germ line (ie, gonadal tissues). True failure of penetrance of the TSC genes is believed to be rare.

Recent research has identified phenotypic differences as they may relate to particular genotypes. Linkage studies initially suggested a roughly equal distribution of TSC1 and TSC2 mutations among affected individuals. However, subsequent mutational analysis has shown TSC2 mutations to be present in 80-90% of affected individuals, while TSC1 mutations are present in 10-20%. The TSC2 gene is contiguous with the gene producing polycystic kidney disease (PKD1). Individuals with features of both TSC and polycystic kidney disease (as opposed to simple renal cysts) likely have deletions spanning both genes.

Jones et al found a higher incidence of "mental handicap" in persons with TSC2 mutations than in those with TSC1 mutations. They identified mental handicap retrospectively in relatively broad terms: developmental quotient less than 70, inability to attend regular school without supplementary assistance, institutionalization, requiring assistance with daily activities, etc.

Dabora et al recently described genotypic and phenotypic features in 224 persons with TSC. A TSC2 genetic abnormality was found to be associated consistently with more severe clinical disease regardless of organ system. Although prominent phenotypic variability was still the rule, patients with TSC2 abnormalities were more apt to have higher tuber counts, refractory seizures, autism, larger angiomyolipomata (AML) and/or cardiac rhabdomyomata, and more severe cutaneous lesions. This suggests that, while tuberin and hamartin have similar functions, tuberin plays a more critical role in regulation of cellular differentiation. While TSC2 mutations are more apt to be associated with severe clinical phenotypes, they predominate in all forms of the disease, mild and severe, familial and sporadic. Spontaneous mutations are also much more likely to reflect TSC2 disease. Suggestions that TSC1 disease is more likely familial than sporadic appear to be incorrect.

Frequency

United States

Birth incidence is 1 case per 6,000 population, with a prevalence of 1 case per 10,000 population.

Factors that hamper accurate assessment of incidence and prevalence include underrecognition of less severe phenotypes, high spontaneous mutation rate (approximately two thirds), marked variability of symptoms (even within specific kindreds of affected individuals), and reluctance of asymptomatic parents and relatives to undergo diagnostic testing related to concerns of uninsurability and social stigma.

International

As in the United States

Mortality/Morbidity

• Complications of neurological involvement are the most common causes of mortality and morbidity. These are due chiefly to intractable epilepsy, status epilepticus, and subependymal giant cell astrocytoma (SEGA) with associated hydrocephalus.
• Renal complications are the next most frequent cause of morbidity and death. These usually arise from an enlarging AML, resulting in retroperitoneal hemorrhage. End-stage renal disease can occur, as a result of either destruction of normal renal parenchyma by an enlarging AML or polycystic kidney disease.
• Less common are cardiac arrhythmias (which can present with sudden, unexplained death), congestive heart failure, and end-stage lung disease. Cardiac involvement is maximal in infants and exhibits spontaneous regression as the child grows older. Pulmonary disease occurs predominantly in women in the third and fourth decades of life.

Race

TSC affects all races without a clear-cut predominance.

Sex

TSC affects both sexes equally. Some studies have suggested that males are more likely to suffer neurological morbidity, but this has not been demonstrated conclusively.

Age

TSC can present at any age.

• In infants and children, it usually is identified as a cause of epilepsy, autism, or cardiac failure.
• Older persons may present with renal failure or pulmonary or cutaneous manifestations in the absence of prominent, or any, neurological symptoms.
• Various organ systems are affected maximally at different points in life.
  • Cardiac involvement occurs during the intrauterine or neonatal period.
  • Rhabdomyomas tend to regress over time.
  • Epilepsy, autism, and developmental delays manifest themselves from infancy to adolescence.
  • Polycystic kidney disease usually is apparent in infancy or early childhood.
  • AMLs may develop at any time from childhood into adult life.
  • Lymphangiomyomatosis typically presents in the third or fourth decade of life.

Clinical

History

• As with all of medical practice, recognizing a disease, let alone managing it appropriately, is impossible unless its diagnosis is first considered in a particular patient. While this may seem self-evident, in fact most physicians are only dimly, if at all, aware of TSC. This awareness usually extends only to the Vogt triad or to individuals with severe neurological morbidity. As many as 50% of people with TSC have normal intelligence, and increasingly the diagnosis is being newly made in adults with renal, cutaneous, or pulmonary manifestations.
• History should focus upon identification of specific signs and symptoms suggestive of or consistent with TSC. Particular symptoms occur at various points in the life span, and this serves as a framework for history taking.
  • Cardiac involvement is maximal in prenatal life or infancy.
  • Seizures, autism, and developmental delays present in infancy or childhood. Seizures are often not intractable, and many adult patients may no longer suffer from them or require anticonvulsants. Many will have been told that they had febrile convulsions or an age-related epilepsy syndrome.
  • Cutaneous manifestations such as ash leaf macules are often present from birth but frequently are unrecognized. More obvious lesions such as angiofibromas or shagreen patches usually appear in childhood to early adolescence.
  • Renal lesions can present as hypertension and renal failure in the case of polycystic kidney disease, usually in infancy or early childhood. AMLs manifest as flank pain, hematuria/retroperitoneal hemorrhage, or abdominal masses from childhood throughout adult life.
  • Pulmonary involvement typically occurs in the second or third decade, with dyspnea, pneumothorax, or chylothorax. It often is misdiagnosed as emphysema, particularly in those with a history of smoking.
  • Persons with dental involvement may have had their teeth sealed or bonded for pitting, or a gingival fibroma resected.
• Family history should center on identification of one or more of these manifestations in first- or second-degree relatives. Specific questioning is often necessary, as TSC lesions often are ascribed to other causes, eg, pulmonary involvement as emphysema, renal lesions as "atypical Wilms tumors," etc.
• Comprehensive diagnostic criteria were set out first by Dr. Manuel R. Gomez; they now exist in revised form as set forth in a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association (USA).
  • Major features
    • Facial angiofibromas or forehead plaque
    • Nontraumatic ungual or periungual fibroma
    • Hypomelanotic macules (>3)
    • Shagreen patch (connective tissue nevus)
    • Multiple retinal nodular hamartoma
    • Cortical tuber: When cerebellar cortical dysplasia and cerebral white matter migration tracts occur together, they should be counted as one rather than two features of tuberous sclerosis.
    • Subependymal nodule
    • Subependymal giant cell astrocytoma
    • Cardiac rhabdomyoma, single or multiple
    • Lymphangioleiomyomatosis: When both lymphangioleiomyomatosis (LAM) and renal AMLs are present, other features of tuberous sclerosis should be present before a definite diagnosis is assigned. As many as 60% of women with sporadic LAM (and not TSC) may have a renal or other AMLs.
    • Renal AML: When both LAM and renal AMLs are present, other features of tuberous sclerosis should be present before a definite diagnosis is assigned (see previous remarks).
  • Minor features
    • Multiple randomly distributed pits in dental enamel
    • Hamartomatous rectal polyps: Histologic confirmation is suggested.
    • Bone cysts: Radiographic confirmation is sufficient.
    • Cerebral white matter radial migration lines: Radiographic confirmation is sufficient. One panel member felt strongly that 3 or more radial migration lines should constitute a major sign.
    • Gingival fibromas
    • Nonrenal hamartoma: Histologic confirmation is suggested.
    • Retinal achromic patch
    • "Confetti" skin lesions
    • Multiple renal cysts:
  • Diagnostic criteria
    • Definite TSC - Either two major features or one major feature plus two minor features
    • Probable TSC - One major plus one minor feature
    • Possible TSC - Either one major feature or two or more minor features
• Molecular genetic testing is now commercially available in the United States through Athena Diagnositics and at other centers. Testing through Athena was recently extended to include screening for large deletions and other types of mutations, which will improve their diagnostic yield.
  • Under optimal circumstances, genetic testing identifies mutations in up to 75-80% of affected individuals. Therefore, a negative genetic diagnostic test result does not exclude a diagnosis of tuberous sclerosis.
  • Diagnosis should be possible in most cases using established clinical criteria. Molecular genetic testing is useful in uncertain or questionable cases, for prenatal diagnosis, and for screening family members of an affected individual. The utility of molecular diagnostic testing is limited by the cost (approximately $3100 for an index case and $300 for confirmatory testing in family members), which is often not covered by private insurance carriers. Patient assistance programs may be available through various laboratories.

Physical

• Physical findings can vary greatly since TSC can affect different organ systems in different ways at different times of the patient's life. Neurological and dermatological abnormalities are the most common physical findings, since brain and skin pathology occurs in as many as 90-95 % of affected individuals.
• Neurological findings
  • Abnormal neurological findings result from the location, size, and growth of tubers and the presence of subependymal nodules (SENs) and SEGAs.
  • Tubers are noted most commonly in the cerebrum, without clear predilection for any particular lobe. They occur in the cerebellum as well, where they may be apparent only on microscopic examination. Rarely, they have been noted in the brain stem and spinal cord.
    • The number, size, and location of tubers can vary widely from patient to patient.
    • Depending on the location of tubers, neurological findings can include abnormalities in cognition (either global delays or specific location-related deficits like language delays), cranial nerves, focal motor/sensory/reflexes abnormalities, cerebellar dysfunction, or gait abnormalities.
  • SENs are noted about the wall of the lateral ventricles and may be either discrete or roughly confluent areas of firm, rounded hypertrophic tissue. SENs may occur anywhere along the ventricular surface, but most commonly occur at the caudothalamic groove in the vicinity of the foramen of Monro (see Image 1).
  • The generally benign SENs can degenerate into SEGAs in 5-10 % of cases. SEGAs can grow, often in an extremely indolent fashion, resulting in ventricular obstruction and hydrocephalus. Since this process occurs very gradually, patients may have marked hydrocephalus when they finally become symptomatic (see Image 2). In this situation, blindness or other permanent neurological deficit commonly ensues despite prompt neurosurgical intervention.
• Skin findings
  • The best-known cutaneous manifestation of TSC is adenoma sebaceum, which often does not appear until late childhood or early adolescence. This lesion is an angiofibroma (ie, cutaneous hamartoma) and is not related to excessive sebum or acne. Flat, reddish macular lesions develop first, which can be mistaken for freckles early on. They become increasingly erythematous and papulonodular over time, occasionally with a friable surface that may bleed easily. Facial angiofibromas typically are noted first in childhood and exhibit progression during puberty and adolescence (see Image 3). Adenoma sebaceum may be disfiguring.
  • Other skin lesions consist of hypomelanotic (ie, ash leaf) macules, periungual or gingival fibromas (see Images 4-5, and thickened, firm areas of subcutaneous tissue, often at the lower back (shagreen patch) or forehead and face (fibrous plaques).
  • Hypomelanotic macules are usually round or oval in shape and vary in size from a few mm to as much as 5 cm in length (see Image 6). Sometimes they have an irregular, reticulated appearance, as if white confetti paper had been strewn over the skin (confetti lesions). When the scalp is involved, an area of poliosis can result. They may be present at birth, or not show up until later in life. They vary widely in location and number from person to person. The number or size of the macules is not an essential feature of diagnosis. Hypomelanotic macules are a nonspecific finding and are not of themselves pathognomonic of TSC. Nonetheless finding more than 4 or 5 in a person who does not have the disease is common.
  • Fibromas may occur in other locations. When present in the lumbar region they have been called a "shagreen patch." The overlying skin may have an orange hue. They occasionally itch or are associated with dysesthesia, leading patients to wonder if "it is pinching a nerve." Shagreen patches are confined, however, to the subcutaneous tissue and are associated with dysraphism, osseous lesions, or mass effects on neural structures.
    • Fibromas can occur in the periungual regions, gingivae, or potentially anywhere in cutaneous or mucosal tissues. The underlying tissue may be hypertrophic/hamartomatous.
    • Symptoms can result from local irritation, such as that created by shoes, dentures, shaving, and disruption of the nail bed.
• Cardiac findings
  • Cardiac involvement is usually maximal at birth or early in life; it may be the presenting sign of TSC, particularly in early infancy. Fifty to sixty percent of individuals with TSC have evidence of cardiac disease, mostly rhabdomyomas. Conversely, anywhere from 50-85% of infants with isolated cardiac rhabdomyomas are said to later show definite evidence of TSC.
  • Rhabdomyomas are benign tumors that may be focal or diffuse and infiltrating in character. They produce symptoms primarily through outflow tract obstruction or by interfering with valvular function (see Images 7-8). Diffuse rhabdomyomas also may result in decreased contractility and cardiomyopathy (see Image 9). In such cases surgical treatment, inotropic support, and related measures may be necessary.
  • Rhabdomyomas develop during intrauterine life (usually between weeks 22 and 26 of gestation) and can result in non-immune hydrops fetalis and fetal death. The majority of cases, however, are clinically asymptomatic.
  • The lesions typically undergo spontaneous regression in the first few years of life, although residual areas of histologically abnormal myocardium may persist. These lesions can involve the cardiac conducting system and thereby may predispose an affected individual to ventricular pre-excitation or other arrhythmias not only in infancy, but also later in life. Such residual areas can be inapparent on echocardiography, yet still produce arrhythmia. This may have an underappreciated significance, as persons with TSC often require antiepileptic or psychotropic drugs that also may affect cardiac conduction.
• Ophthalmic findings
  • At least 50% of patients have ocular abnormalities; some studies have reported prevalence as high as 80%.
  • These lesions are in fact retinal astrocytomas that tend to become calcified over time. They appear as rounded, nodular, or lobulated areas on funduscopic examination, becoming whitish in color as they calcify.
  • They tend to be indolent and rarely produce symptoms or require intervention.
  • Visual acuity generally is unaffected, unless the retinal fovea is involved.
  • Hypopigmented areas of retina, iris, and even eyelashes have been reported. These are analogous to hypomelanotic macules of the skin.
• Lung findings
  • Symptomatic pulmonary involvement occurs almost exclusively in adult women, generally aged 30 or older. It was long thought to be distinctly uncommon, affecting 1% or fewer of women with TSC. However, recent prospective and retrospective studies have found cystic pulmonary abnormalities in as many as 40% of women with TSC. Women with large AMLs (>4-6 cm in diameter) appear to be at higher risk.
  • Symptomatic pulmonary disease in men, and even in children, with TSC has been reported anecdotally. The true incidence of pulmonary abnormalities in these populations is not known, although it is certainly less than in adult women.
  • Three forms have been described: multifocal micronodular pneumocyte hyperplasia (MMPH), pulmonary cysts, and LAM.
    • MMPH consists of hyperplasia of type II pneumocytes, seen as nodular densities on chest CT scan. This condition occurs with equal frequency in men and women with TSC and does not produce clinical symptoms.
    • Pulmonary cysts may be single or multiple (see Image 10). Solitary lesions may remain clinically silent or rupture, with resultant pneumothorax producing acute dyspnea and hemoptysis. Multiple cystic lesions may result in respiratory insufficiency or even pulmonary hypertension with cor pulmonale (usually in the case of LAM).
    • LAM is rather more insidious: interstitial fibrosing alveolitis develops with progressive restrictive lung disease. It also occurs, although less frequently, in women who do not have TSC (incidence of sporadic LAM, approximately 1 per 100,000). About 60% of women with sporadic LAM also have renal AMLs, but not other characteristics of TSC (see Image 11). Smooth muscle cells undergo abnormal proliferation with secondary compromise of bronchioles, venules, and lymphatic structures. Slowly, normal pulmonary elasticity is lost, with resultant decrease in vital capacity and increase in residual volume. Pulmonary hypertension, cor pulmonale, and worsening hypoxia/hypercapnia eventually supervene. When LAM is suspected clinically, high-resolution CT of the chest is the most sensitive diagnostic modality.
    • Owing to the overwhelming predominance of LAM in women, some believe that estrogen accelerates the progression of the condition. Some patients have been treated with hormonal therapy (ie, progesterone) to counteract the estrogen effect, although this has not been proven conclusively to be of benefit. Bronchodilators are helpful in selected cases.
    • LAM is inexorably progressive and ultimately results in death unless lung transplantation is undertaken. Interestingly, LAM occasionally has recurred in transplanted lungs. This raised the possibility that, rather than being a primary pulmonary disorder, LAM is caused by a circulating factor, or perhaps metastatic cells. Henske et al demonstrated that in fact metastatic cells from AMLs or leiomyomas are present in the lungs of women with LAM, regardless of whether they have TSC, and almost certainly cause the disorder (see Image 11). These cells frequently have abnormalities of either TSC1 or TSC2, which produce the characteristic smooth muscle hypertrophy and destruction of normal lung.
• Renal findings
  • Renal manifestations of TSC are the second most common clinical feature. Four types of lesions can occur: autosomal dominant polycystic kidney disease, isolated renal cyst(s), AMLs, and renal cell carcinoma.
  • Polycystic kidney disease occurs in 2-3% of persons with TSC, and usually presents early in life with hypertension, hematuria, or renal failure. As noted, this occurs as the result of a genetic abnormality affecting both the TSC2 gene and the PKD1 gene adjacent to it. Individuals with polycystic kidney disease have relatively little functional renal tissue, and ultimately require renal transplantation. They are highly susceptible to complications of urinary tract infection (UTI) or nephrolithiasis, which can produce acute renal failure. This should be borne in mind when using therapies that predispose to UTI or kidney stones, such as steroids, topiramate, zonisamide, or the ketogenic diet.
  • Renal cysts (as opposed to polycystic kidney disease) are found in 20% of males and 10% of females with TSC. They are rarely if ever symptomatic. Simple renal cysts often occur with AMLs, and this combination should suggest the diagnosis of TSC. Sometimes multiple renal cysts can be confused with true polycystic kidney disease. The presence of significant symptoms such as hypertension or failure to thrive, as well as the absence of associated AMLs, strongly suggest the latter diagnosis.
  • AMLs are noted in as many as 80% of persons with TSC. They also can occur as isolated lesions in persons without TSC.
    • As suggested by their name, they consist of abnormal smooth muscle, fat, and blood vessels, each present in varying degrees.
    • Patients tend to have either multiple small AMLs studding the surface of the kidney or one or more larger lesions. These larger lesions are more apt to be symptomatic, particularly when greater than 4-6 cm in their largest diameter. They often produce nonspecific complaints such as flank pain.
    • Of rather more concern is potentially life-threatening retroperitoneal hemorrhage from rupture of dysplastic, aneurysmal blood vessels. These hemorrhages also can destroy adjacent normal renal parenchyma or produce abdominal distention and obstruction by mass effects.
    • Some studies suggest that as many as 75% of AMLs will increase in size over time (see Image 11). Exactly when intervention is warranted is somewhat controversial. Very large AMLs (>6-8 cm in diameter) are likely to progress and often result in hemorrhage, particularly if prominent abnormal vasculature is present. AMLs with fewer dysplastic vessels may have a smaller risk of catastrophic hemorrhage but can present problems from their sheer size.
    • MRI and MR angiography are often helpful in planning therapy (see Images 12-13).
    • Because of their often exuberant blood supply, standard surgical resection can result in excessive bleeding, with nephrectomy being the end result.
    • When feasible, selective embolization is the preferred intervention. This procedure typically is able to spare functional renal tissue, directly addresses the chief risk of retroperitoneal hemorrhage, and has a substantially lower rate of morbidity than standard surgery. Some patients experience "postembolization syndrome" consisting of fever, flank pain, and malaise as the embolized lesion becomes necrotic. This usually can be prevented by pretreatment with steroids.
  • Renal cell carcinoma appears to occur more frequently in persons with TSC than in the general population, although the exact nature of this is unclear. In one series, 5 of 403 patients with TSC were found to have histologic evidence of a renal cell carcinoma. Nonetheless, a large AML is much more common in this population. A rapidly expanding renal mass in the absence of hemorrhage is suggestive of the diagnosis. MRI of the abdomen can be useful in differentiating a large AML from a true malignancy.
• Dental findings
  • Pitting of the dental enamel is invariably present in the permanent teeth of patients with TSC, particularly larger numbers of pits (>14). They are seen in the primary (deciduous) teeth of 30% of affected children.
    • They rarely produce symptoms.
    • This sign has led to interest in counting dental pits as an inexpensive bedside screening procedure. Smaller numbers ( <6) of dental pits may occur in as many as 10% of healthy controls. However, accurate assessment of dental pits may be possible only after staining the teeth, and by a dentist or person trained to look for them (see Image 5, Image 14). These factors have limited the utility of this feature of TSC for diagnosis.
  • Gingival fibromas occur in 70% of adults with TSC, in 50% of children with mixed dentition (both primary and permanent teeth), and in only 3% of children with only primary teeth (see Image 5, Image 14).
    • These may produce local irritation or interfere with dental alignment, and they require surgical resection in selected cases.
    • Isolated gingival fibromas can occur in persons who do not have TSC. However, gingival fibroma(s) in association with large numbers (>10) of dental pits is highly suggestive of TSC and should prompt further diagnostic evaluation.
• Other organ systems
  • Hamartomas and polyposis of stomach, intestine, and colon may occur. These almost never cause significant symptoms, although gastrointestinal hamartomas occasionally may bleed, leading to positive tests for fecal occult blood. Blood loss is almost always minimal, and rarely if ever results in anemia or clinical symptoms.
  • Hepatic cysts and AMLs (hepatic, not renal), typically asymptomatic and nonprogressive, have been reported in as many as 24% of patients with TSC, with a marked female predominance (female-to-male ratio 5:1).
  • Sclerotic and hypertrophic lesions of bone may be found incidentally on radiography performed for other indications. Occasionally they may be palpable, or associated with nonspecific, vague, aching pains. Osseous lesions rarely if ever produce serious difficulty, and they require only symptomatic treatment, if any at all. Some patients develop neurogenic scoliosis resulting from asymmetric weakness or intractable partial seizure activity. In these cases, typically a "dominant" tuber is present contralateral to the scoliosis or the supratentorial tuber burden is asymmetrical. These individuals may require standard orthopedic management if the curvature is severe.
  • A small number of patients with TSC may develop arterial aneurysms. Aneurysms have been reported intracranially, as well as in the aorta and axillary arteries (see Image 15).
  • Like lung disease, gastrointestinal and osseous abnormalities are seen primarily in adults, in whom they may be the presenting manifestations of TSC. Recognition of the true nature of these lesions is important, as adult-oriented practitioners are generally unaware of the broad spectrum of TSC. Pulmonary, renal, gastrointestinal, and bone findings may be mistaken for emphysema, neoplasia, or other disorders, and inappropriate measures undertaken.

Causes

See Pathophysiology.

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