Elsevier

The Lancet

Volume 372, Issue 9639, 23–29 August 2008, Pages 657-668
The Lancet

Seminar
Tuberous sclerosis

https://doi.org/10.1016/S0140-6736(08)61279-9Get rights and content

Summary

Tuberous sclerosis is a genetic multisystem disorder characterised by widespread hamartomas in several organs, including the brain, heart, skin, eyes, kidney, lung, and liver. The affected genes are TSC1 and TSC2, encoding hamartin and tuberin respectively. The hamartin–tuberin complex inhibits the mammalian-target-of-rapamycin pathway, which controls cell growth and proliferation. Variations in the distribution, number, size, and location of lesions cause the clinical syndrome to vary, even between relatives. Most features of tuberous sclerosis become evident only in childhood after 3 years of age, limiting their usefulness for early diagnosis. Identification of patients at risk for severe manifestations is crucial. Increasing understanding of the molecular abnormalities caused by tuberous sclerosis may enable improved management of this disease.

Introduction

Tuberous sclerosis is a genetic, variably expressed, multisystem disorder that can cause circumscribed, benign, non-invasive lesions in any organ.1, 2 The term tuberous sclerosis of the cerebral convolutions was used more than a century ago to describe the distinctive findings at autopsy in some patients with seizures and mental subnormality. The term tuberous describes the potato-like consistency of gyri with hypertrophic sclerosis.3 The wide range of organs affected by the disease4 implies an important role for TSC1 and TSC2 genes, encoding hamartin and tuberin, in the regulation of cell proliferation and differentiation.

In a series of patients reported by the Mayo Clinic (Rochester, MN, USA), more than 90% had skin lesions, about 90% had symptoms of cerebral pathology, 70–90% had renal abnormalities, and about 50% had retinal hamartomas5 (figure 1). Tuberous sclerosis is a protean disease: the random distribution, number, size, and location of lesions cause varied clinical manifestations. Some lesions, such as renal angiomyolipomas, do not occur until a certain age; by contrast, cardiac rhabdomyomas appear in the fetus, and almost always regress spontaneously in infancy.6 The frequency of most clinical signs in the prenatal period is unknown. Few data are available for the rate of clinical signs that need imaging examinations (ie, subependymal nodules, retinal hamartomas) in young children.

Major and minor criteria exist to diagnose tuberous sclerosis (panel). The diagnosis is made when two major features, or one major and two minor ones, can be shown. Sometimes, an antenatal diagnosis can be made based on fetal ultrasound and MRI, which show cardiac and brain lesions. Most patients are diagnosed in infancy or early childhood, making early therapeutic interventions and treatments possible.7

Population-based studies in UK reported a frequency of 1 in 12 000 to 1 in 14 000 in children under 10 years of age.8 However, improved methods of ascertainment have identified individuals who are not severely affected by tuberous sclerosis, increasing the estimates of its frequency.9 The disorder has a birth rate of 1 in 6000.10

Tuberous sclerosis is an autosomal dominant disorder, although two-thirds of patients have sporadic mutations. The genes in which abnormalities are found are called TSC1 and TSC2. Both genes have been studied by multigenerational linkage analysis.11, 12 TSC1 is located at position 9q34, and encodes a transcript of 8·6 kb, containing 23 exons and encompassing 55 kb of DNA.13 TSC2 is located at position 16p13.3, and encodes a transcript of 5·5 kb, containing 41 exons and encompassing 40 kb of DNA.14 Table 1 shows features of these genes. 307 allelic variants of TSC1 and 1061 of TSC2 have been reported so far.

Recent studies, carried out on small families, indicated that mutations of TSC1 account for 15–30% of the families.15, 16 In preponderance of mutations of TSC2 is even higher in sporadic cases, where mutations of TSC1 are found in 10–20% of families.15, 17, 18, 19, 20 More severe disease in cases with new mutations of TSC2 would reduce the chance of these people having a family.21

Mutational studies have shown no hotspots (ie, preferred sites of mutation) in these genes. Large deletions or rearrangements are present in TSC2 more frequently than in TSC1.22 In 2–3% of patients, large genomic deletions in TSC2 also affect the adjacent gene, polycystic kidney disease type 1 (PKD1).23 Missense mutations are more common in TSC2 than in TSC1, and tend to cluster in the GTPase-activating protein (GAP) binding domains.24

The overall mutation detection rate in patients with tuberous sclerosis is around 85–90%, even when new implemented diagnostic techniques are used (eg, multiplex ligation-dependent probe amplification).22 Therefore, mutations are not identified in 10–15% of patients.20 The low detection rate could be due to: (1) methods (eg, denaturing high-pressure liquid chromatography and direct sequencing) that are not sensitive enough; (2) mutations in intronic and promoter regions, which might disrupt gene expression, and be missed by most mutation screening methods: (3) difficulty of detecting mutations by any conventional method in patients with diagnostic features of tuberous sclerosis and low rate of mosaicism for either TSC1 or TSC2 mutations;25 and (4) additional causative loci that could account for a few patients with tuberous sclerosis.

After the discovery of TSC1 and TSC2 and their encoded proteins (hamartin and tuberin), several downstream protein cascades that might be affected by the pathogenesis of the disease, such as the pathway of mammalian target of rapamycin (mTOR), have been identified.26, 27, 28 mTOR is stimulated by Ras homologue enriched in brain (RHEB), a small G protein of the Ras family. RHEB is active when bound to GTP. Tuberin and hamartin form an intracellular complex which activates GTPase, reducing stimulation of mTOR.29, 30, 31 mTOR detects signals of nutrient availability, hypoxia, or growth factor stimulation32, 33 (figure 2), and is part of many cell processes, such as cell-cycle progression, transcription and translation control, and nutrient uptake. It phosphorylates, among other proteins, S6K1 and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). S6K1 is a kinase that activates ribosomal subunit protein S6, leading to ribosome recruitment and protein translation. 4E-BP1 inhibits activity of eukaryotic translation initiation factor 4E (eIF4E) and, when phosphorylated by mTOR, releases eIF4E from its control.34 Tuberin and hamartin also bind, independently of the tuberin–hamartin complex, to several other proteins; however, the physiological relevance of these interactions is unclear35 (figure 3).

Inactivation of both alleles of TSC1 or TSC2 is needed for tumour development. Loss of heterozygosity is frequent in renal angiomyolipomas, less in subependymal giant-cell astrocytomas, and almost absent in cortical tubers.36, 37 Haploinsufficiency—ie, minor signalling or biochemical effects due to the presence of only one functional gene, manufacturing 50% of the usual quantity of protein—might contribute to the pathological effects of tuberous sclerosis in some organs. According to Knudson's theory, the second hit is caused by a somatic, independent mutation: somatic, second-hit mutations of TSC1 or TSC2, detectable by loss-of-heterozygosity analysis, might synergise with first-hit, systemic mutations of TSC1 or TSC2, to cause complete loss of TSC1–TSC2 function. Identification of loss of heterozygosity at different markers in an astrocytoma and angiomyolipoma from the same patient suggested the multifocal origin of a second-hit mutation.38 By contrast, identical somatic mutations of TSC2 have been described in abnormal lung and kidney cells, but not in healthy cells, of patients with sporadic lymphangiomyomatosis and renal angiomyolipoma. The hypothesis of benign metastasis has been proposed to explain this phenomenon: perhaps benign cells with mutations in TSC1 or TSC2 could travel to the lungs from renal angiomyolipomas.39, 40 This hypothesis is supported by the finding that TSC2-deficient smooth-muscle cells have higher migration potential than normal cells in vitro, and most patients with tuberous-sclerosis-associated pulmonary lymphangioleiomyomatosis have large, potentially metastatogenic renal angiomyolipomas. Understanding the role of hamartin and tuberin in cell adhesion and migration through ezrin–radixin–moesin proteins, and small GTP-binding protein Rho, might expand the knowledge of benign metastasis.41, 42

Individuals with the same genotype can have different clinical phenotypes. Wide variation in the extent and severity of clinical manifestations, even within the same family, shows that no strict correlation exists between a mutation and its clinical outcome.43 Individuals with mutations in TSC2 have on the whole more severe symptoms than those with mutations in TSC1:15, 16, 18, 19, 20, 44, 45 specifically, more frequent and severe epilepsy, mental retardation (moderate and severe), cortical tubers, renal angiomyolipomas, retinal hamartomas, and advanced facial angiofibromas.15 However, some missense mutations in TSC2 might cause a mild clinical phenotype.46, 47, 48, 49

Patients with no evident mutations have, on average, milder manifestations than patients with mutations in TSC2 and sometimes even milder than those with mutations in TSC1. Mosaicism is a possible explanation for this finding in sporadic patients. In familial cases, the possibility of a distinct mutational spectrum, or mutations in an unknown gene, should be considered.15 The reported association between a high-expression allele of the gene encoding interferon gamma and a low frequency of renal angiomyolipomas in patients with mutations in TSC2 suggests that modifier genes might have important effects on the phenotype.50

About 85% of children and adolescents with tuberous sclerosis have CNS complications, including epilepsy, cognitive impairment, challenging behavioural problems, and autism.51

Progress in structural and functional imaging has led to further characterisation of brain lesions, such as cortical tubers, subependymal nodules, subependymal giant-cell tumours, and white matter abnormalities.52, 53 Intracranial aneurysms, especially implicating the internal carotid artery, have also been seen in tuberous sclerosis.54 Widespread anatomical abnormalities of grey and white matter structure have been noted, even in patients with average intelligence.55

Cortical tubers are characterised by proliferation of glial and neuronal cells, and loss of the six-layered structure of the cortex. Tubers are variable in size and multiple in number, and can be detected by fetal MRI as early as 26 weeks of gestation56, 57 (figure 4). The most prominent abnormal cell types in tubers are large dysplastic neurons, giant cells, and bizarrely shaped astrocytes. Dysplastic neurons have disrupted radial orientation in the cortex and abnormal dendritic arborisation, showing γ-aminobutyric acid (GABA)-transporter defect and low GABAergic inhibition.58 Subependymal nodules are hamartomas, typically seen in the subependymal wall of the lateral ventricles. Some nodules protrude into the ventricular cavity. Subependymal nodules develop during fetal life, are present in most patients with tuberous sclerosis, and are usually asymptomatic (figure 5).

Nodules bigger than 5 mm, which are located near the foramen of Monro, not calcified, and enhanced by gadolinium, have a high probability of evolving into a subependymal giant-cell tumour, particularly in familial cases of tuberous sclerosis59 (figure 5). Transformation of a subependymal nodule into a subependymal giant-cell tumour is usually a gradual process, of which the highest rate is in the first two decades of life.60 Growth over 12 months has rarely been reported.59 Subependymal giant-cell tumours are slow-growing tumours and of mixed glioneuronal lineage, and are the most common brain tumours in patients with tuberous sclerosis, occurring in about 10% of cases.59, 60, 61, 62 Growth of these lesions at the foramen of Monro can block circulation of the cerebrospinal fluid, leading to progressive lateral ventricular dilatation and increased intracranial pressure.60

Neonatal subependymal giant-cell tumours are extremely rare; however, large subependymal giant-cell tumours have been identified in utero at 19 weeks of gestation.63

Epilepsy associated with tuberous sclerosis generally begins during the first year of life and, in most patients, in the first few months. Focal seizures precede, coexist with, or evolve into infantile spasms. Focal or multifocal epileptiform abnormalities might be present when an EEG is done between the neonatal period and the development of spasms (figure 6). During non-rapid eye movement (REM) sleep, multifocal and focal EEG abnormalities tend to generalise.64 Several children who have partial seizures or spasms at onset later develop intractable seizures with multifocal EEG abnormalities, which are associated with bilateral and synchronous slow spike–wave complexes.65, 66 Epileptogenic foci can shift from one epileptogenic tuber to another during the course of the disease due to maturational phenomena; different regions can become epileptogenic over time.67 However, in many patients one localisation is consistently present, especially in the fronto–temporal regions, in a topographic relation with a major tuber.51, 68

Epileptogenesis in tuberous sclerosis is caused by diminished neuronal inhibition, secondary to molecular changes of GABA receptors in giant cells and dysplastic neurons, and enhanced excitation, which is secondary to molecular changes of glutamate receptors in dyplastic neurons.69 The deficiency of GABAergic interneurons might explain the early onset and severity of seizures in tuberous sclerosis.70, 71 Impaired extracellular potassium uptake by astrocytes contributes to neuronal hyperexcitability and epileptogenesis in a mouse model.72 The importance of the GABA inhibitory system in tuberous sclerosis has been confirmed by studies of vigabatrin, an inhibitor of GABA transaminase, which can stop spasms in up to 95% of infants affected by tuberous sclerosis.73, 74, 75 Prompt seizure control is crucial, and could prevent the development of an epileptic encephalopathy.76 Treatment with vigabatrin seems to prevent spread of paroxysmal activity outside the cortical dysplasia.77 A clinical response is often present after one or two doses. In our experience, low doses (50 mg/kg, once daily) are rapidly effective in infants, if the treatment is started shortly after onset of focal seizures or spasms.78

The risk of visual-field loss caused by vigabatrin progressively rises with increased duration of treatment and mean dose.78, 79 Therefore, administration of low doses of vigabatrin for brief periods minimises the chance of ophthalmological toxicity.80 Several techniques, including electroretinography (ERG), electro-oculography (EOG), multifocal electroretinography (mfERG), and ocular coherence tomography are used to identify possible retinal damage in children treated with vigabatrin.79, 81, 82, 83

Tuberous sclerosis has a striking variability of neurocognitive manifestations and psychopathological features.84 In the same family, some individuals can be impaired and have severe autism and challenging behaviours, whereas others lead normal lives.85 A bimodal distribution of intelligent quotient (IQ) exists between a population of severely disabled patients (mean IQ=30–40) and a population of less severely disabled patients (mean IQ=93).86 About 30% of individuals with tuberous sclerosis are profoundly impaired, and show little or no new improvements. More than 50% of individuals with tuberous sclerosis have average intelligence (IQ>70),86 but might be prone to specific cognitive deficits of memory, attention, or executive skills.76, 85, 87, 88 Most important variables associated with poor cognitive outcome include a history of refractory seizures, mutations of TSC2, and the presence of cortical tubers in certain regions.89 Data of monozygotic twins indicate that non-genetic factors also cause differences in neurological and psychiatric outcome.90 Individuals with learning disabilities usually have a history of early-onset seizures, which often present as infantile spasms.86 Seizure onset during early stages of brain development can be temporally associated with autistic regression.91, 92 Frequency of autism in infants with tuberous sclerosis might be significantly higher than frequency of cardiac or renal abnormalities, for which screening is routinely done.93 Children with cognitive impairment are significantly more likely to have an autistic spectrum disorder and attention deficit hyperactivity disorder.84 Seizure-related sleep disorders, such as prolonged sleep latency and night waking, are routinely seen.94

Hypomelanotic macules are the most common dermatological manifestation, being present in 90–98% of patients with tuberous sclerosis (figure 7).95, 96 The hypopigmented macules are best seen under ultraviolet light (Wood's lamp) particularly on the trunk and buttocks.

Hypomelanotic macules can be the only skin lesions in infants: if the child also has focal seizures or infantile spasms, a diagnosis of tuberous sclerosis should be considered. Bilateral facial angiofibromas are hamartomatous nodules of vascular and connective tissue, with a butterfly pattern over the malar eminences and nasal labial folds of the face (figure 7). Their frequency is about 80% in children with tuberous sclerosis who are older than 5 years of age.97 They generally appear in children of 3–4 years of age, giving a ruddy appearance to the cheeks, which become rougher and cobblestoned thereafter. Rarely, these lesions are unilateral: in such cases, they might represent a segmental form of tuberous sclerosis.98

Another common dermatological feature of tuberous sclerosis is the shagreen patch (figure 7). These patches are connective tissue naevi, generally located on the lumbosacral flank; they can also be scattered across the trunk or thighs. The frequency of these lesions rises with age. Webb and colleagues97 showed that these lesions are present in 54% of children with tuberous sclerosis who are older than 5 years of age, and are usually evident by 10 years of age, typically with an irregular border, a raised, roughened surface, and a generally pigmented skin over the lesion. Molluscum fibrosum pendulum is common on the neck, groins, axillae, and near flexory surfaces of limbs, especially in adults.99

The forehead fibrous plaque is a yellow–brown or flesh-coloured patch of raised skin of variable size and shape, with a diameter from a few millimetres to several centimetres. These lesions are found in around 36% of people with tuberous sclerosis. They are classified histologically as angiofibromas, although the vascular component is not pronounced. In some children, forehead fibrous plaques develop in the neonatal period, and are the first skin lesions of tuberous sclerosis.

Ungual fibromas, also called Koenen tumours, are connective tissue hamartomas close to or underneath nail beds. They are generally more common on toes than on fingers, and develop at 15–29 years and are more common in women than in men. When present at the base of the nail, they can produce a groove. They can be induced by nail-bed trauma.

Dental abnormalities (dental pits) are seen in 90% of patients with tuberous sclerosis, but only in 9% of the general population.100

Cardiac rhabdomyomas are the main feature of the disease in the fetus and newborn baby. 96% of infants with cardiac rhabdomyomas will ultimately be diagnosed with tuberous sclerosis.101 Although patients typically have several, these tumours are rarely symptomatic. Nonetheless, they can manifest prenatally as arrhythmia, non-immune hydrops, or death. These tumours are usually 3–25 mm in diameter, are most commonly located within the ventricles, and within the walls more often than the septum (figure 7). In a small percentage of patients, supraventricular tachycardia, secondary to a ventricular pre-excitation syndrome such as Wolff–Parkinson–White syndrome, can be associated with these septal lesions. Large lesions can obstruct cardiac outflow or cause cardio-embolic disease.101 However, lesions usually recede over time, with complete regression in childhood.102

Renal complications are the most frequent cause of tuberous-sclerosis-related death.103 Multiple, bilateral angiomyolipomas are found in about 70–90% of adult patients, and are more often symptomatic in women.104, 105 Their frequency is lower in children than in adults, but up to 16% of patients below the age of 2 years can be affected.95 These tumours consist of abnormal blood vessels, smooth muscle, and adipose tissue. They tend to grow slowly. However, ultrasonography may reveal dramatic progression of tumour size (3–4 cm every 2 years) in adolescents.106 Spontaneous bleeding is the most common complication in patients with tumours larger than 4 cm in diameter. Surgical resection should be nephron-sparing, to preserve renal function, and done only if clinically suggested. If tumours are more than 4 cm in diameter, the preferred method of treatment is tumour embolisation,107, 108, 109 which can be used as a prophylactic treatment. The procedure is especially recommended in patients with centrally located tumours, when surgery is likely to cause loss of function of the kidney.110 Angiogenesis inhibitors could have a role in preventing the development of renal angiomyolipomas, and could improve the prognosis for patients with tuberous sclerosis.111

As well as angiomyolipomas, patients with tuberous sclerosis develop renal cysts and renal-cell carcinomas. Renal cysts are usually asymptomatic, unless they are in patients with contiguous deletions in TSC2 and PKD1. In these individuals, cysts can be large and multiple, leading to end-stage renal failure by early adult life.23 Renal-cell carcinoma is seen in 2–3% of patients with tuberous sclerosis. This carcinoma is usually diagnosed during childhood, but symptoms appear only after many years.112, 113, 114 Smooth-muscle cell carcinomas usually stain for cytokeratin and are negative for HMB45, which is a marker of renal angiomyolipomas.

Retinal hamartomas are present in about 40–50% of people with tuberous sclerosis. They can be found at any age (figure 7);115 they have been described in small children and even newborn babies.116

Different morphological types of hamartomas exist. The most common type is a subtle, flat, smooth-surfaced, salmon-coloured, semitransparent, circular or oval lesion, on the superficial part of the retina, usually near or at the posterior pole. The second most common type is an easily recognised, opaque, white, elevated, multinodular, calcified lesion that is frequently described as resembling a mulberry. The third most common type of lesion contains features of the other two, being calcified and nodular centrally, but having a semitranslucent, smooth, and salmon-coloured perimeter.117 Progression from a flat to an elevated shape of lesion has been reported.118

Lesions referred to as mulberry are seen in about 50% of patients with tuberous sclerosis, and are frequently bilateral.117 They are composed of glial and astrocytic fibres, and can be evident by 2 years of age. Unless these lesions affect the macula or optic nerve, they are typically asymptomatic. Sometimes, an achromic patch is seen on the retina, similar to the hypopigmented macules on the skin.

Pulmonary lymphangiomyomatosis is characterised by alveolar smooth-muscle proliferation, and cystic destruction of lung parenchyma. No study has yet defined the frequency of the disease symptomatically within the general population, but it probably affects 1–3% of people with tuberous sclerosis.119

Pulmonary lymphangiomyomatosis is usually generalised and progressive, extremely difficult to treat, and with a poor prognosis. This disease predominantly affects premenopausal women and is exceptionally rare in men (figure 7).120, 121, 122 The onset in childhood has been rarely reported.119 First manifestations are shortness of breath, lung collapse, coughing, and chest pain. Pulmonary lymphangiomyomatosis can take place as an isolated form (sporadic) or as a pulmonary manifestation of tuberous sclerosis (tuberous-sclerosis-associated). Most tuberous-sclerosis-associated cases are caused by mutations in TSC2; few are caused by mutations in TSC1.123, 124 Sporadic pulmonary lymphangiomyomatosis typically results from two somatic mutations in TSC2.124, 125

Renal angiomyolipomas are present in 32% of patients with sporadic pulmonary lymphangiomyomatosis and in 93% of patients with tuberous-sclerosis-associated pulmonary lymphangiomyomatosis:126 renal tumours might be a source of metastatic cells.39 Pulmonary lymphangiomyomatosis is present almost exclusively in women: perhaps oestrogens regulate cell-signalling pathways of tuberous sclerosis (figure 2) and migration of TSC2-deficient cells. In-vitro studies have shown that the carboxy terminal of TSC2 interacts with the oestrogen receptor α, and functions as a transcriptional corepressor of the receptor.127

Hepatic multiple, bilateral angiomyolipomas have been reported in patients with tuberous sclerosis only rarely, perhaps because they are usually asymptomatic. In two ultrasonographic studies of individuals with tuberous sclerosis, the proportion of patients who had hepatic angiomyolipomas was 24% and 16%.128, 129 These angiomyolipomas are more common in adults (23–45%) than in children, and more frequent in women than in men.130 Renal angiomyolipomas usually precede development of hepatic angiomyolipomas in patients with tuberous sclerosis. Hepatic angiomyolipomas grow more slowly than renal angiomyolipomas, and do not cause death.131

Section snippets

Diagnosis and management

At the onset of tuberous sclerosis, diagnostic studies are commonly done, to confirm the presence of the disease or to find the cause of symptoms. When symptoms suggesting tuberous sclerosis arise, brain MRI is usually done.7 EEG is useful when the initial presentation includes seizures; children or adolescents who have never had seizures generally do not need to have an EEG. The diagnosis of tuberous sclerosis is made before the onset of seizures in an increasing group of newborn babies and

Future developments

At present, the management of tuberous sclerosis is symptomatic. However, the discovery of mTOR pathway upregulation in tuberous-sclerosis-associated tumours presents new possibilities for treatment strategies.149 Interferon gamma and interferon alpha interact with mTOR, leading to deactivation of the translational repressor 4E-BP1, which could be beneficial for the treatment of tuberous sclerosis.150

Sirolimus makes the dysregulated mTOR pathway return to normal in cells that lack TSC1 or TSC2.

Search strategy and selection criteria

Information in this Seminar is mainly based on peer-reviewed medical publications from 1985 to 2007 (PubMed). Selection criteria are the novelty and importance of studies, and their relevance to general medical doctors and paediatricians. Search terms included “tuberous sclerosis”, “clinical features”, “molecular genetics”, “medical and surgical treatment”, and “sirolimus”. Only articles published in English were reviewed. All articles were read by the authors, and references were

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