Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous condition characterized by a predisposition to hamartomas in the brain, heart, kidney, skin, eye, and other organs. TSC is the second most common neurogenetic tumor syndrome affecting approximately 1 in 5500 to 10,000 live births, making it less common than neurofibromatosis (NF) 1 but more common than NF2. There is no racial, ethnic, or sex predilection. , Neurologic and neuro-oncologic manifestations feature prominently. The majority of patients experience seizures, many have refractory epilepsy, and neuroimaging reveals cortical tubers which are the hallmark of the disease along with subependymal nodules and, in some cases, subependymal giant cell astrocytomas (SEGAs). Any organ can be affected with common extra-nervous system manifestations including renal angiomyolipomas (AMLs), pulmonary lymphangioleiomyomatosis (LAM), cardiac rhabdomyomas, facial angiofibromas, and neurocognitive or neuropsychiatric symptoms (e.g., TSC-associated neuropsychiatric disorder, TAND).
Genetics
TSC is a genetic syndrome that results from mutation in one of two TSC tumor suppressor genes, TSC1 or TSC2 . Much of the genetic principles underlying other tumor suppressor syndromes reviewed in prior chapters (e.g., NF1 and NF2) also apply to TSC. Inheritance follows an autosomal dominant pattern; however, de novo mutations occur in up to 70% of patients, meaning that these affected individuals harbor a new germline mutation without a prior family history. TSC1 encodes the protein hamartin which is located on chromosome 9q34. TSC2 encodes the protein tubulin on chromosome 16p13. Original estimates suggested an equal prevalence of TSC1 and TSC2 ; however, recent reports suggest that this may only be true for familial inherited cases. There is complete penetrance, meaning that all patients with a TSC genotype will express phenotypic manifestations. There is variable expressivity, meaning that symptoms vary from individual to individual and the severity of disease in one family member cannot be used to predict disease burden in another.
Pathophysiology
TSC is a tumor suppressor syndrome that results from abnormal signaling within the mammalian target of rapamycin (mTOR) pathway. In the cell, hamartin and tuberin heterodimerize and act as a tumor suppressor GTPase of Rheb. Dephosphorylation of Rheb-GTP to Rheb-GDP inhibits the activation of mTOR complex 1 (mTORC1) and may also independently inactivate mTORC2. The end result is reduced mTORC activity. In the diseased state, loss of hamartin-tuberin function leads to increased mTORC activity, which promotes cell proliferation, growth, and hamartoma formation. Like most other tumor suppressor syndromes, tumors form according to Knudson’s two-hit hypothesis. An inactivating germline mutation causes a “first hit,” which increases susceptibility to a “second” somatic loss of heterozygosity, which results in tumor formation and many of the major manifestations of this syndrome ( Table 17.1 ). In addition, one functioning TSC allele is, in many cases, insufficient to maintain normal cell function, a process termed haploinsufficiency, and may contribute to many of the minor manifestations of the disease.
| Major features | Hypomelanotic macules (e.g., Ash leaf spots ) |
|
| Angiofibromas or fibrous cephalic plaque |
| |
| Ungual fibromas |
| |
| Shagreen patch | ||
| Retinal hamartomas |
| |
| Cortical tubers (or other cortical dysplasias, i.e., whiter matter radial migration lines) | ||
| Subependymal nodules | ||
| Cardiac rhabdomyoma | ||
| Pulmonary lymphangioleiomyoma (LAM) a | ||
| Angiomyolipomas a |
| |
| Minor features | Confetti Lesions | |
| Dental enamel pits |
| |
| Intraoral fibromas |
| |
| Retinal achromatic patch | ||
| Multiple renal cysts | ||
| Nonretinal hamartoma |
a If LAM and angiomyolipomas co-occur, they count as one major feature, not two.
Like NF1 and NF2, which were reviewed in the previous chapter, the diagnosis of TSC is made by clinical criteria that have been established by consensus conference. In this chapter, we first review the clinical criteria that are most frequently used to establish a diagnosis of TSC for pediatric and adult patients ( Cases 17.1 and 17.2 ). The following cases review common neurological manifestations including seizures and neuroimaging findings ( Cases 17.3 and 17.4 ). The last case reviews the diagnosis and management of the renal AMLs ( Case 17.5 ). This is followed by a general discussion of other common manifestations and a discussion of clinically relevant take-home points for TSC patients undergoing targeted therapy with mTOR inhibition.
Clinical cases
Case. A patient is referred after a prenatal diagnosis of TSC based on the presence of cardiac rhabdomyomas and postnatal MRI Brain with multiple subependymal nodules including at the bilateral foramen of Munro, cortical tubers, and radial migration lines. The mother and brother also have TSC. The patient was brought to the emergency room at age 2 months due to parental concern for infantile spasms and evidence of multiple hypopigmented macules consistent with Ash leaf spots. He was evaluated with continuous EEG and did not have infantile spasms or hypsarrhythmia. He was sent home without treatment. Given that her other son had infantile spasms, the mother remained vigilant and returned at 5 months old for similar concerns. Continuous EEG was consistent with infantile spasms, and the patient was started on hormonal (steroid) therapy. Although it was partially effective, he still had spasm clusters. When changed to vigabatrin, he had a remarkable response and was spasm free. He was weaned off and did not have return of spasms or other seizures.
Teaching Points. This case highlights (1) the clinical diagnostic criteria used to establish a diagnosis of TSC, and (2) common cutaneous manifestations used to establish a TSC diagnosis. Guidelines for making a diagnosis of TSC were first published in 1998 and revised by the International Tuberous Sclerosis Complex Consensus Conference in 2012. The criteria can be divided into major and minor manifestations of the disease, with the following being required to establish the diagnosis ( Table 17.1 ):
- 1.
Definitive TSC diagnosis:
- a.
Two major criteria OR
- b.
One major criteria and two or more minor criteria
- a.
- 2.
Possible TSC diagnosis:
- a.
One major criteria OR
- b.
Two or more minor criteria
- a.
Principles of TSC Diagnosis. One of the earliest manifestations of TSC are cardiac rhabdomyomas, which can be detected with prenatal ultrasound screening. Seizures may begin during infancy and often initially manifest as infantile spasms, though multiple seizure types are not uncommon including generalized tonic-clonic, tonic, clonic, atonic, and others. Cutaneous findings are present in approximately 90% of TSC patients. The first cutaneous sign is often hypopigmented macules called Ash leaf spots ( Fig. 17.1A ), which are first apparent in infancy. These and the major cutaneous findings reviewed below should be assessed in all children presenting with a new diagnosis of infantile spasms.
Hypomelanotic macules : These lesions look like an Ash leaf, often with a rounded appearance on one side and tapering to a sharp edge on the contralateral side. They are the most common cutaneous finding in TSC and occur in 90% of affected patients compared with only 1–4% of healthy children. The presence of three or more hypopigmented lesions >5 mm in diameter is one of the most specific diagnostic findings and should strongly suggest a diagnosis of TSC. A woods lamp examination may be useful in accentuating the appearance of these macules, particularly in individuals with light-colored skin. Though TSC is one of the more common conditions characterized by Ash leaf macules, other conditions can mimic TSC, including MEN-1, Birt-Hogg Dube syndrome, acne vulgaris, trichoepitheliomas, idiopathic guttate hypomelanosis, and congenital hypopigmented macules, and should be considered in patients without other TSC manifestations.
Shagreen patch: Shagreen patches are collagenoma-like lesions that typically occur in the lumbosacral region often with an “orange peel” appearance that may by hypopigmented, hyperpigmented, or skin-colored. A shagreen patch is the second most common cutaneous finding estimated to be present in up to 50% of TSC patients in the first decade of life. In patients who present with multiple hypopigmented macules (e.g., Ash leaf spots), a detailed skin examination should be performed to evaluate for the presence of a shagreen patch, fibrous cephalic plaque, or confetti lesions (see below).
Angiofibromas: Angiofibromas are facial cutaneous lesions occurring in the malar region across the nasal bridge, nasolabial folds, forehead, chin, and cheek ( Fig. 17.1E ). , They are rarely present at birth, often develop during the first decade of life, and can increase in number during adolescence and even into adulthood. Ungual fibromas are identical lesions that occur in the periungual and subungual nailfold regions ( Fig. 17.1D ). Intraoral fibromas are similar in appearance and are located in the gingiva, buccal mucosa, labial mucosa, or tongue, and may be seen in 20–70% of TSC patients ( Fig. 17.1C ). , One or two fibromas are common in the general healthy population; however, three or more is rare and fulfills a major diagnostic criterion. Topical mTOR inhibitors have shown benefit for angiofibroma, fibrous plaques, and hypomelanotic macules.
Fibrous cephalic plaque: Fibrous cephalic plaques are a variant of facial angiofibromas that occur on the forehead, scalp, and face. They have the appearance of a firm, yellow or brown slow-growing lesion on the forehead and are found in 20–36% of TSC patients.
Clinical Pearls
- 1.
Cutaneous findings are present in approximately 90% of TSC patients.
- 2.
The first cutaneous sign is often hypopigmented macules called Ash leaf spots which are first apparent in infancy.
Case 17.2a. A 27-year-old female presented for new evaluation of long-standing TSC with a history of intractable seizures, aggressive behavior, mood irritability, and developmental delay (e.g., nonverbal). She was diagnosed with TSC around 18 months of age due to new-onset seizures and the presence of cortical tubers on neuroimaging. Genetic testing was not performed and she developed intractable epilepsy with multiple seizures types, including generalized tonic-clonic, and stereotyped laughing episodes followed by behavioral arrest previously treated with rufinamide, brivaracetam, and topiramate and currently taking clobazam and valproic acid. At the time of her first referral evaluation, her mother was found to have multiple facial angiofibromas ( Fig. 17.1E ), subtle neurocognitive complaints, two periungual fibromas, and shagreen patch consistent with a diagnosis of TSC.
Case 17.2b. A 41-year-old female presented for new evaluation of TSC. She was diagnosed 5 years ago when she had a brain MRI for evaluation of migrainous headaches. Her imaging had shown two small cortically based hyperintensities consistent with cortical tubers. She had no prior history of seizures or genetic testing. Skin examination showed mild facial angiofibromas and periungual fibromas. Further imaging revealed an asymptomatic renal AML measuring 3.3 cm in greatest dimension.
Teaching Points. A new diagnosis of TSC in an adult patient is uncommon. The majority of patients will develop recognizable manifestations sufficient to establish a diagnosis in childhood. However, these adult cases underscore the benefit of recognizing the clinical features of TSC even in adult patients who do not carry a known diagnosis. Several important TSC findings manifest later in life including pulmonary LAM, which occurs more commonly in adult women. In one study, nearly half of adult-diagnosed TSC patients presented with symptoms of LAM, all of whom were women. Clinicians should be aware that, although adult-onset presentations are less common, such diagnoses when made are important for patient counseling and surveillance imaging.
Principles of TSC Diagnosis. Clinical examination is critical to establishing a TSC diagnosis and should not be replaced with genetic testing alone. Identification of a pathogenic mutation in TSC1 or TSC2 from blood or biopsy of normal tissue is sufficient to establish a definitive diagnosis of TSC. However, it is important to note that between 10% and 25% of patients who fulfill the clinical criteria for TSC will have no identified mutation on genetic testing.
Minor cutaneous manifestations include the following ( Table 17.1 ) , :
Confetti lesions: These hypomelanotic lesions are smaller in size to Ash leaf spots and often appear in groups or clusters ( Fig. 17.1B ). They are common in the first decade of life and can help contribute to the diagnosis of TSC, fulfilling a minor diagnosis criterion.
Oral lesions: Other than the intraoral fibroma, the most common oral lesion is dental enamel pitting. This is present in virtually all people with TSC but may also occur in between 7% and 70% of healthy persons and thus may be less helpful in isolation to establish a possible clinical diagnosis of TSC but are important to monitor. , Current guidelines recommend dental examinations every 6 months ( Table 17.2 ).
| Dental | Dental examination (e.g., oral fibroma and dental enamel pits) | Every 6 months (same as general population) |
|---|---|---|
| Neuropsychiatric | Screen for behavior problems and intellectual disability (i.e., TSC-associated neuropsychiatric disorder, TAND) | Annually |
| Comprehensive neuropsychiatric screening | Once during following age ranges (years): 0–3, 3–6, 6–9, 12–16, 18–25 | |
| Neurological | EEG (for interictal epileptiform activity or subclinical seizures) | At time of diagnosis 24-hour monitoring as needed after suspected seizure activity, behavioral change, or positive comprehensive neuropsychiatric screening |
| Brain MRI with and without contrast (for cortical tubers, subependymal nodules, and SEGA) | At time of diagnosis; repeat every 1–3 years until age 25 years | |
| Cardiovascular | Echocardiogram (for rhabdomyoma) | At time of diagnosis if less than 3 years old; repeat for asymptomatic lesions every 1–3 years until regression Referral to cardiology if symptomatic |
| EKG (for arrhythmia) | At time of diagnosis | |
| Blood pressure monitoring | Annually | |
| Pulmonary | High resolution CT scan 6-minute walk test, pulmonary function testing (for Lymphangioleiomyomatosis) | At time of diagnosis if symptomatic or if a woman >18 years old Repeat every 5–10 years if asymptomatic Repeat every 2–3 years if symptomatic |
| Renal | Abdominal MRI (renal ultrasound or CT abdomen, less sensitive); for angiomyolipoma and renal cysts | At time of diagnosis Repeat every 1–3 years |
| Glomerular filtration rate | Annually | |
| Dermatologic | Complete skin examination (for hypomelanotic macules, shagreen patches, angiofibromas, fibrous cephalic plaques, confetti lesions, etc.) | At time of diagnosis and annually |
| Ophthalmologic | Dilated fundoscopic examination (for retinal hamartomas or eye lesion) | At time of diagnosis Annually if known lesion |
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