Tuberous sclerosis complex (TSC) is a dominantly inherited, multisystemic, genetic disorder involving the development of hamartias and hamartomas in multiple organ systems. The diagnosis of TSC and further evaluation of at-risk persons involve careful examination of the skin, heart, eyes, brain, and kidneys. Presenting features may be in any or all of these organs and the prognosis can be difficult to predict, with variability ranging from mild disease manifesting only as skin findings and asymptomatic brain lesions, to a more severe course involving seizures, mental retardation and extensive renal disease. An accurate diagnosis allows for the timely referral of affected individuals to the appropriate specialists to determine if other, unseen symptoms exist. However, many individuals and families with TSC report that their diagnosis came after much delay or uncertainty. Despite being one of the more common single gene disorders seen in children and adults (most recent estimates of incidence are one out of every 5,800 livebirths¹), its diagnosis often eludes physicians striving to care for their patients. Genetic testing may now aid in making a diagnosis of TSC; direct sequencing is able to determine the causative mutation in either the TSC1 or TSC2 gene in approximately 80% of cases.² The following review discusses the diagnosis and features of TSC, the importance of coordinating further evaluations for your patients and their family members, and the role that genetic testing will play in TSC diagnosis and management.

There are no known pathognomonic signs for TSC; no single clinical feature is unique to the condition. In addition, many features known to be present in TSC such as seizures and mental retardation are common in the general population, and should not be considered when diagnosing TSC. A constellation of features is therefore necessary, with more specific features contributing more heavily to the diagnosis, and an increasing number of features making the clinical suspicion of TSC more likely.

In July of 1998, a consensus conference was convened by the Tuberous Sclerosis Alliance with the purpose of evaluating and revising the clinical diagnostic criteria that had been previously established in 1992. The recommendations made by the assembled experts were published in the December 1998 issue of the Journal of Child Neurology³ and provide the most specific clinical criteria for making a diagnosis of TSC.

A diagnosis is considered definite when a patient has either two "Major Features" of TSC or one "Major Feature" and two "Minor Features" (Table 1). The clinician should consider TSC probable when the patient has one "Major Feature" and one "Minor Feature," while a possible diagnosis results from the presence of either one "Major Feature" or two or more "Minor Features."

Table 1 - Diagnostic Criteria for Tuberous Sclerosis Complex

Despite the availability of diagnostic criteria, making a diagnosis of TSC can be difficult given the age-dependent presentation of many of its symptoms. For example, newborns identified with a cardiac rhabdomyoma have a greater than 50% risk of having TSC,⁴ but absolute diagnosis can be difficult, as an apparent second symptom such as hypomelanotic macules or retinal hamartomas may not appear until infancy. Another factor limiting the accurate diagnosis of TSC is the prevalence of many of the diagnostic criteria as isolated findings in the general population. The presence of a single hypomelanotic macule, for example, has been reported in about five percent of the general population.⁵ This report and others led the 1998 consensus conference attendees to agree that three or more macules must be present before they are called a symptom of TSC. The decision renders the macules a more specific finding, but can, in some cases, limit the ability to confirm a diagnosis of TSC in a newborn until three or more macules have developed.

In cases with an uncertain diagnosis, the clinician needs to consider further testing and determine whether imaging studies are warranted. While there are reports of diagnosing TSC in one-week-old infants via cranial computed tomography (CT)⁶, most infants undergoing such evaluations present with seizure activity as an indication for imaging. In the case of a newborn or infant with a questionable diagnosis and the absence of seizure activity, many parents and physicians may feel uncomfortable subjecting the child to CT or cranial magnetic resonance imaging (MRI) studies. A consultation with a neurologist familiar with the diagnosis of TSC should be coordinated to discuss the benefits, risks and limitations of imaging procedures, thereby enabling the family to make an informed decision regarding further testing.

When the clinical criteria for TSC diagnosis were developed, genetic testing was still limited in its scope. Today, genetic testing for TSC mutations is more readily available. Previous studies indicate that direct sequencing of the TSC1 and TSC2 genes will detect approximately 80% of the causative mutations in persons with definite diagnoses.² While the sensitivity of the genetic testing for TSC mutations is not yet determined in persons with probable or possible diagnoses, preliminary experience indicates that it may, in a proportion of cases, enable rapid diagnosis in the newborn period.⁷ Given the highly penetrant nature of TSC mutations and the specificity of genetic testing for single gene disorders, a positive genetic test should be considered diagnostic of TSC. The availability of clinical DNA test makes TSC diagnosis more rapid and precise, possibly preventing the need for repeated, oftentimes inconclusive clinical evaluations that are both complicated and expensive.

Clinical features of TSC are most commonly seen in the skin, eyes, central nervous system, kidneys, heart, and the lungs. Additional features have been reported in gums and teeth, bones, and most other major organs. Table 2 briefly describes some of the more commonly reported symptoms, typical ages of onset, and their reported prevalence in TSC.

Table 2 - TSC Symptoms, with Onset and Prevalence in TSC Patients

Because TSC affects multiple internal as well as external organs, diagnostic studies are warranted on all persons with a new diagnosis of TSC, regardless of their outward manifestations of the disease. For example, published recommendations for diagnostic and follow up evaluations suggest baseline brain imaging using either CT or cranial MRI modalities regardless of the presence of neurological symptoms.²² This suggestion is largely due to the possibility of identifying a subependymal giant cell astrocytoma (SEGA), a tumor that has an increased growth potential over subependymal nodules (SEN), therefore requiring more extensive follow up.

In order to ensure comprehensive care, referrals to a variety of specialists familiar with TSC should be coordinated. If possible, a referral to a multidisciplinary clinic specializing in TSC is ideal, as the center will likely house all necessary specialists, including a neurologist, geneticist, ophthalmologist, and a cardiologist. Further recommended examinations are listed in the Table 3 below, and include referrals for neurodevelopmental assessment, given the high risk of mental retardation, learning delay and behavioral problems in individuals with TSC. Continued evaluation (Table 3) is suggested throughout the life of the TSC patient, as many features may not present until later in the child’s life or the tumors may grow in size.

Table 3 - Diagnostic and Surveillance Screening in TSC

The clinician making the diagnosis of TSC will be responsible for assuring that other, at-risk family members are also evaluated for the features of the condition. TSC is an autosomal dominant genetic disorder, and while all persons with TSC are thought to have symptoms, the presentation of their symptoms can be highly variable. A determination of whether or not the parents and siblings of a diagnosed child are affected is important to the provision of later genetic counseling (see Genetics of TSC and the Role of Genetic Testing), thereby making an accurate diagnosis necessary. There is some debate as to which evaluations are necessary when testing the parents of a newly diagnosed child. The consensus is that a thorough physical examination conducted by a physician familiar with TSC will detect the majority of affected individuals.²³ The evaluation should include a skin examination with a Wood’s lamp (ultraviolet light) and a retinal examination through dilated pupils. Further evaluation via diagnostic imaging techniques can be ordered, but rarely yields a diagnosis in adults who have no outward physical feature of TSC.²³ A molecular genetic test for TSC is now commercially available, and can help in confirming a clinical diagnosis, particularly in children, where many clinical symptoms may not yet be present due to the variable age of onset of many symptoms.

The pathologic manifestations of TSC can cause variable symptoms based on the size and the location of the hamartomas. Therefore, a variety of management considerations are necessary. Table 4 describes the various treatment considerations for each of the features.

Table 4. Management Considerations for TSC Clinical Features

TSC is inherited as an autosomal dominant genetic condition. Individuals with TSC have a 50% chance of passing their condition on to each of their children. Many dominant genetic disorders occur for the first time in a family due to a new mutation. Approximately 67% of TSC diagnoses²³ fall into this category. The ability to differentiate between an inherited versus new occurrence of TSC sometimes relies on a thorough evaluation of the family members of an affected child (see Management of Patients with TSC above).

Despite the medical community’s best efforts to provide genetic counseling to persons with TSC and their families, other genetic factors may complicate matters. In some cases, apparently unaffected parents of a child with TSC can go on to have another affected child, despite assurances that they, themselves, are not affected. The term germline mosaicism describes the phenomenon when an individual has cells in their germline (ovum or sperm cells) that carry a genetic mutation, despite the absence of detectable clinical symptoms of the condition. Germline mosaicism is known to occur in TSC.²⁴ Given the complicated nature of TSC genetics, immediate family members of all persons affected with TSC should receive a referral to a genetic counselor or medical geneticist to discuss their unique genetic risk to either develop TSC or have a child with TSC.

Two causative genes, TSC1 and TSC2, have been discovered. Research into the roles these genes and their protein products play in the human body are ongoing, but the two genes are thought to work together, possibly to regulate the growth of cells. When a person has TSC, they are thought to have a mutation in either the TSC1 or TSC2 gene. There are no known cases of an individual having a mutation in both genes. There are no definite genotype/phenotype correlations yet for TSC, however, preliminary evidence suggests that mutations in TSC2 tend to produce more symptoms, with increased severity, than mutations in TSC1.²⁵ Further studies are needed to clarify this issue. In the future it may be possible to prescribe specific courses of treatment and evaluation may be suggested based on the knowledge of an individual’s mutational status.

A positive genetic test allows the patient, their family, and their physician to know the exact disease-causing mutation. This information may be desired for a number of reasons. In some cases, the identification of a TSC1 or TSC2 mutation will enable the physician to make a definite diagnosis of TSC in a child who may not have yet developed enough symptoms for a clinical diagnosis. While a negative DNA test result cannot rule out a diagnosis of TSC, a positive one does confirm the diagnosis. In other cases, a child may have a definite diagnosis, and the parents may want to know their, as well as their other children’s, TSC status without undergoing extensive diagnostic evaluations. After identifying the TSC mutation in the affected child, other at-risk family members can easily be tested to determine whether they are also affected. In addition, the availability of DNA mutation results makes reproductive planning options and prenatal testing available (currently offered on a research basis only),²⁶ if desired by the family.

Tuberous sclerosis is a multisystemic disorder; it can be difficult to diagnose; it has an unpredictable course; and is subject to a number of complicated genetic phenomena. Given the prevalence of TSC, it is likely that most health care providers will come into contact with a number of affected individuals in the course of their practice. Many individuals with TSC, particularly those with milder cases not involving seizures, report a long history of questioning physicians regarding their TSC-related symptoms prior to the receipt of their ultimate diagnosis. Health care providers, particularly those working in neurology, pediatrics, nephrology, dermatology, and cardiology will benefit from becoming familiar with the more common outward manifestations of TSC, as familiarity will enable appropriate referrals and more rapid, accurate diagnoses for affected individuals.

Upon diagnosing TSC, it is recommended that providers, recognizing that the manifestations of this disorder could occur in a variety of organ systems, should refer TSC-related care to a multidisciplinary clinic or a variety of specialists. Given the unpredictability of symptoms and the complicated genetic nature of TSC, all affected individuals and their immediate family should be referred for genetic counseling with a medical geneticist or genetic counselor. Genetic testing will play a major role in clarifying diagnoses, accurately diagnosing family members of affected individuals and allowing families to make use of reproductive testing options, when desired.

1 2 3 4 5 Your understanding of the disease or condition How you will diagnose patients with this disorder How you will explain the disease or condition to patients and their families None of the above Breaking news in genetics Dementias Epilepsy Mitochondrial disorders Movement disorders Multiple sclerosis Neuromuscular disorders Pediatric disorders

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