Handbook of Genetic Counseling/Tuberous Sclerosis-2

Tuberous Sclerosis

What is Tuberous Sclerosis?

• Referred to both as tuberous sclerosis (TS) and tuberous sclerosis complex (TSC). The term TSC is used in scientific literature to distinguish tuberous sclerosis from Tourette's syndrome.
• Autosomal dominant disorder that causes benign tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs
• The disease affects some people severely, while others are so mildly affected that it often goes undiagnosed
• The clinical symptoms of TSC vary greatly and may often not appear until later in life
• Some people with TSC experience developmental delay, mental retardation and autism.
• Many people with TSC are living independent, healthy lives
• There are presently no cures and there is no way to predict how severely or mildly an individual may be affected by TSC
• There can be complications in some organs such as the kidneys and brain that can lead to severe difficulties and even death if left untreated.
• To reduce these dangers, people with TSC should be monitored throughout their life by their physician for potential complications.
• Most people with TSC will live an average life span.

Who is affected?

• Prevalence of TSC is unknown, but its incidence is estimated to be 1 in 6,000 live births. This means approximately 50,000 individuals in the United States and more than 1 million worldwide have TSC
• It occurs in both sexes and in all races and ethnic groups

The tumors are not cancerous!

• The tumors resulting from tuberous sclerosis are benign, but may still cause problems.
• Tumors that grow in the brain can block the flow of cerebral spinal fluid in the spaces (ventricles) in the brain. This can lead to behavior changes, nausea, headaches or a number of other symptoms.
• In the heart, the tumors are usually at their largest at birth, and then decrease in size as the individual gets older. These heart tumors, called cardiac rhabdomyomas, can cause problems at birth if they are blocking the flow of blood or causing severe arrhythmia problems.
• The tumors in the eyes are not as common, but can present problems if they grow and block too much of the retina.
• The tumors in the kidney (renal angiomyolipoma) can become so large they eventually take over all of the normal kidney function. In the past, the patient was left until they developed kidney failure. Today, doctors are more aggressive and remove individual tumors before they get too large and compromise healthy kidney tissue. Very rarely (less than 2 percent of) individuals with TSC develop malignant (cancerous) kidney tumors.

Inheritance and Recurrence Risks

• Approximately 33 percent, or one-third, of people with TSC inherit it from a parent who also has TSC
• A parent who is affected has a 50% or 1 in 2 chance of having an affected child
• In the remaining 66 percent, or two-thirds of people with TSC, neither parent shows any symptoms or signs of TSC. It appears that one of the normal genes from either parent changes to the abnormal form, leading to a new (or sporadic) occurrence of TSC in the child
• Normally, these parents do not have another child with TSC because the mutation was sporadic, not inherited
• However, some families have more than one child with TS, even though neither parent showed symptoms or findings of TSC. This is due to germline mosaicism
• Germline mosaicism is relatively rare, and this explanation does not apply to most families with a sporadically affected child.
• However, due to germline mosaicism recurrence risk are quoted to be 1 to 3 percent
• There is no simple way to determine whether an unaffected parent of a child with TSC has germline mosaicism.

Genes responsible

• Two genes have been identified that can cause tuberous sclerosis.
• Only one of the genes needs to be affected for tuberous sclerosis to be present.
• The TSC1 gene is located on chromosome 9 and is called the hamartin gene.
• The other gene, TSC2, is located on chromosome 16 and is called the tuberin gene.
• The functions of hamartin and tuberin are not fully understood.
• Hamartin and tuberin have been shown to form heterodimers, suggesting that these two proteins may act in concert to regulate cell proliferation
• Both the TSC1 and TSC2 genes are believed to suppress tumor growth in the body.
• When either of these genes is defective, tumors are not suppressed and tuberous sclerosis results.
• The genes also play a role in the early fetal development of the brain and skin.
• The genes (TSC1 and TSC2) are involved in approximately 70 percent of TSC diagnoses.
• It is still unclear where the mutation lies in the remaining 30 percent of people tested.

Penetrance

• The penetrance of TSC, after careful, detailed evaluation of each person known to carry a TS mutation, is now thought to be 100%.
• Rare cases of seeming non-penetrance have been reported; however, molecular studies have resolved these cases, revealing two different sporadic TSC mutations in one family and the existence of germline mosaicism in others

Variable expressivity

• The variability in expression exists because TSC is autosomal dominant at the level of the organism but recessive at the cellular level. (There is an element of chance involved)
• Both the TSC1 and TSC2 genes have properties consistent with tumor suppressor genes functioning according to Knudson's "two hit"
• The clinical variability occurs secondary to the random nature of the second "hit" in individuals carrying a germline mutation.

Genotype-Phenotype Correlations

• The TSC1 and TSC2 phenotypes have been considered to be identical.
• The phenotype is different in cases of a contiguous gene syndrome involving large gene deletions and rearrangements of both the TSC2 gene and the PKD1 gene on 16p13
• One study found a greater risk of renal malignancy in patients with TSC2 and patients with TSC2 mutations have been found to have a higher frequency of mental
• Genotype and phenotype correlation studies provide statistical support of a milder phenotype in patients with a TSC1 mutation.
• A decreased proportion of individuals with TSC1 among sporadic cases of TSC has been reported. This might represent a true biologic phenomenon or decreased ascertainment of individuals with sporadic TSC1 because of a somewhat less severe phenotype.

Diagnosis and testing

• The diagnosis of TSC is based on clinical findings (see clinical diagnosis in the category below)
• Molecular testing is presently available on a research basis only
• It is available on a clinical basis only to those families with a known TSC1 or TSC2 mutation identified through previous research studies.
• Development of clinically available DNA analyses of the TSC1 and TSC2 genes has been hampered by the large size of the two genes, the large number of disease-causing mutations, and the high rate of somatic mosaicism (10-25%)

Prenatal Testing

• DNA-based diagnostic testing is possible for pregnancies at 50% risk in a family with a known TSC1 or TSC2 gene mutation previously identified through a research study and confirmed in a clinical laboratory
• DNA extracted from cells obtained from chorionic villus sampling (CVS) at about 10–12 weeks' gestation* or amniocentesis at 16–19 weeks' gestation can be analyzed for the known familial disease-causing mutations.
• For other families, high-resolution ultrasound examination for tumors is available, but its sensitivity is unknown.
• The risk for TSC is 50% in a fetus without a known prior increased risk for TSC, in which cardiac lesions consistent with rhabdomyoma are identified on ultrasound examination. Mutation analysis is currently not clinically available to further evaluate a fetus with this prenatal finding.

Clinical Diagnosis

• The diagnostic criteria for tuberous sclerosis complex (TSC) were revised at the Tuberous Sclerosis Complex Consensus *Conference, July 1998
• Definite TSC: Either two major features or one major feature plus two minor features
• Probable TSC: One major feature plus one minor feature
• Possible TSC: Either one major feature or two or more minor features

Major Features

• Facial angiofibromas or forehead plaque
• Non-traumatic ungual or periungual fibromas
• Hypomelanotic macules (three or more)
• Shagreen patch (connective tissue nevus)
• Multiple retinal nodular hamartomas
• Cortical tuber 1
• Subependymal nodule
• Subependymal giant cell astrocytoma
• Cardiac rhabdomyoma, single or multiple
• Lymphangiomyomatosis 2
• Renal angiomyolipoma 2

Minor Features

• Multiple randomly-distributed pits in dental enamel
• Hamartomatous rectal polyps
• Bone cysts
• Cerebral white matter radial migration lines 1
• Gingival fibromas
• Nonrenal hamartoma
• Retinal achromic patch
• "Confetti" skin lesions
• Multiple renal cysts
  • When cerebral cortical dysplasia and cerebral white matter migration tracts occur together, they are counted as one rather than two features of TSC.
  • When both lymphangiomyomatosis and renal angiomyolipomas are present, other features of tuberous sclerosis must be present before TSC is diagnosed.

Clinical Manifestations

• We still cannot predict the severity of physical symptoms in a person with a new diagnosis of TSC.
• A person can have TSC and have very few or mild symptoms, while a family member with TSC can have more severe or extensive

symptoms

• In most individuals, the disease affects only some of these organs.
• The severity of TSC can range from mild skin abnormalities to, in severe cases, mental retardation or renal failure.
• Many TSC manifestations also develop later in life.
• Most individuals who are mildly affected by TSC lead active and productive lives

HEART INVOLVEMENT

Manifestations

• Echocardiogram can show rhabdomyomas, the most common primary cardiac tumor of tuberous sclerosis complex (TSC) in infancy and childhood.
• The incidence of these tumors in TSC has been reported to vary from 47 percent to 67 percent.
• Childhood tumor regression is the rule. In other words, in most cases, cardiac tumors are their largest at birth and may shrink or disappear as the individuals grow older.
• A second peak in the incidence of these tumors may occur during puberty.
• If cardiac outflow obstruction does not occur at birth, the patient is unlikely to have health problems from these tumors later.

Treatment

• Cardiac rhabdomyomas are more likely to be the cause of heart failure in a newborn infant or young child than in an adult with TSC.
• Most rhabdomyomas of the heart are asymptomatic, but they should be treated by an experienced cardiologist if an arrhythmia or other cardiac problem is present.
• Cardiac arrhythmias infrequently have developed in children just after starting carbamazepine (Tegretol), used for the treatment of epilepsy. Reports have also shown a significant increase in the size of cardiac rhabdomyomas in infants with TSC with infantile spasms who are treated with adrenocorticotropic hormone (ACTH). Therefore, echocardiograms and EKG baseline measurements should be obtained before initiating these treatments.

BRAIN INVOLVEMENT

• CNS tumors lead to the most morbidity and mortality in TSC
• Brain and Neurologic Function: Several types of brain lesions are seen in individuals with TS; some people will have all the lesions, whereas others will have no brain involvement at all.
• Cortical tubers (from which TSC is named)
  • Occur in 70% of patients
  • thought of as a "birth defect" on the brain
  • small areas in the cortex (the outer layer of the brain) that do not develop normally
  • It is thought that the presence of cortical tubers, which disrupts the normal "wiring" of the brain, is what causes seizures in individuals with TSC.
• Subependymal nodules
  • occur in 90% of patients
  • develop near the walls of the cerebral ventricles (the cavities in the brain that contain cerebrospinal fluid)
  • Typically, these nodules accumulate calcium within the first few months or years of life.
  • Because of this calcification, they can be easily detected with a computed tomography (CT) scan.
  • The subependymal nodules are not directly responsible for neurological problems.
• Subependymal giant cell astrocytomas (SEGAs).
  • occur in 6-15% of all patients
  • Typically, SEGAs do not occur in very young children, and the chance for their growth decreases after age 20.
  • Medicine can be given to treat it
  • If a giant cell astrocytoma grows large enough, it can block the flow of fluid inside the ventricles of the brain, can result in significant morbidity and mortality, the tumor will have to be removed and/or the ventricles shunted to relieve fluid buildup and pressure.
    • Symptoms include vomiting, nausea, and headaches as well as changes in appetite, behavior, and mood.
    • These symptoms may or may not signal growth of a tumor, but they do signify that there may be a problem and that the child should be seen by a physician.

Brain imaging should be done at the time of diagnosis to get a baseline image and then every 1 to 3 years afterwards. A brain scan can sometimes show growth of a tumor even before symptoms develop.

EPILEPSY/SEIZURE DISORDERS

• Seizures occur in 60 percent to 90 percent of individuals diagnosed with TSC
• They are often the first symptom of TSC.
• Early in life, the seizures may consist only of brief head nodding or staring, or they may be more generalized, with spasms of the limbs and flexion and extension of the head and trunk.
• In older children and young adults, the seizures sometimes occur less often or cease.
• If seizures are suspected, an electroencephalogram (EEG) is usually conducted.
• Seizure control in a child with TSC is important.
• There appears to be a direct relationship among the age of the child at the onset of seizures; their frequency, duration, and severity; and the degree of mental handicap.
• Antiepileptic drugs (AEDs), properly administered, may control the seizures completely, although in some people the seizures return or cannot be controlled.
• Some children with TSC have "infantile spasms." During this type of seizure, the child brings his legs up to his chest in a repeated motion.
• Infantile spasms can sometimes be eliminated by the use of adrenocorticotropic hormone (ACTH), a hormone from the pituitary gland that stimulates the adrenal glands to produce cortisone. This medication is not used for long periods of time because of adverse side effects.
• Valproic acid (Depakene) has also been used to treat infantile spasms.

COGNITIVE, PSYCHIATRIC AND BEHAVIORAL INVOLVEMENT

• The behavior of a child with TS can often be the most difficult and trying problem for parents and family.
• Aggression, sudden rage, hyperactivity, attention deficit, acting out, obsessive-compulsive behavior, repetitive behaviors, staying in their "own world," being nonverbal even at an age when most children are speaking, and other autistic behaviors have all occurred in children with TSC.
• At least 50% of patients have developmental delay or mental retardation
• Some children with TSC, usually those who have a mental disability, are also diagnosed with autism.
• There appears to be a connection between TSC and autism that is not understood, and active research is exploring this link
• Occasionally, individuals with TSC are also diagnosed with schizophrenia, bipolar disease (manic depression), depression, or other psychiatric disorders.

Manifestations

• lymphangioleiomyomatosis (LAM) - pulmonary cystic disease
  • estimated to occur in 1-6% of cases
  • primarily affects women between the ages of 20 and 40 years
• The first symptoms of lung involvement in an individual with TSC may be shortness of breath after mild exercise, spontaneous pneumothorax, or coughing.
• Progression to pulmonary failure may develop, but not usually until the third or fourth decade of life, if at all.
• Pulmonary involvement in TSC can be severe, and some individuals will require lung transplantation.

Diagnostic screening and follow-up

• Recent studies have shown that many women with TSC have minor, asymptomatic lung involvement.
• The Consensus Conference Panel on Lung Involvement recommended that female patients should have a chest CT scan (not an x-ray) sometime before age 18 or at the time of diagnosis for women older than 18.
• A CT scan of the lung is superior to an X-ray because the early signs of lung involvement may easily be missed on an X-ray.
• If pulmonary involvement is noted, the individual should be monitored closely and should have repeated chest CT scans as needed.

Treatment

• Pulmonary involvement in TSC can be severe, even fatal.
• Recently, tamoxifen and progesterone have been used to treat pulmonary TSC with encouraging results.
• Any individual with TSC with lung involvement should see a pulmonologist who is knowledgeable about LAM.
• National Institutes of Health is also conducting clinical research of LAM
• Call the Tuberous Sclerosis Alliance or the LAM Foundation for more information.

KIDNEY INVOLVEMENT

• The second leading cause of early death (27.5%) in patients with TSC is renal disease
• In a recent study, an estimated 80% of children with TSC were found to have an identifiable renal lesion by the mean age of 10.5 years

Manifestations

• TSC can present itself as five different lesions in the kidneys:
  • benign angiomyolipomas-(occurring in 70 percent to 80 percent of adults and older children with TSC)
    • Renal angiomyolipomas-made up of vascular tissue (angio), smooth muscle (myo), and fat (lipoma)
    • They are benign hamartomas.
    • These hamartomas are well circumscribed groups of cells that multiply excessively, growing as benign tumors that may or may not cause symptoms.
    • The prevalence of TSC-related renal angiomyolipomas increases with age, and in adults bilateral tumors or multiple tumors in one kidney are common.
    • Angiomyolipomas begin in childhood in many individuals with TSC, but they usually grow very slowly and may not be problematic until young adulthood.
    • Individuals with TSC should have their kidneys imaged at the time of diagnosis and then regularly throughout their lives.
    • Accurate noninvasive ultrasound, CT, or MRI diagnosis of these benign lesions is highly dependent on their fat content
    • It can sometimes be difficult to tell the difference between a small or low-fat-content angiomyolipoma and a malignant tumor.
    • When tumors become larger than 4 cm, bleeding of the angiomyolipoma, the primary complication of this lesion, increases in frequency.
    • Pain may also become a significant problem with angiomyolipomas.
  • Cysts (occurring in 20% of patients)
    • TSC renal cysts are commonly multiple and bilateral.
    • They are the second most frequently occurring kidney manifestation of TSC.
    • Single or multiple renal cysts occur less often in individuals with TSC than do angiomyolipomas, but they may appear earlier.
    • Some cysts may collapse and disappear.
    • One important research finding was the discovery of the TSC2 gene in close proximity to the gene for polycystic kidney disease (PKD1) on chromosome 16.
    • A small group of individuals with TS have a large segment of chromosome 16 deleted, which means that both the TSC2 and PKD1 genes are removed.
  • malignant angiomyolipoma (<1%)
    • Malignant angiomyolipomas should be removed as soon as possible after their detection.
  • oncocytoma (benign adenomatous hamartoma) (<1%)
    • Oncocytomas are benign tumors only occasionally seen in individuals with TSC.
  • renal cell carcinoma (<1%)
    • rarely seen in individuals with TSC, but when these tumors are present, they often are multi-centric and bilateral.
    • These tumors should also be removed as soon as possible after their detection to prevent metastasis.

Diagnostic screening and follow-up

• Both renal angiomyolipomas and cysts are often asymptomatic and may not require treatment
• Both should be followed closely with imaging every 1 to 2 years because aggressive treatment can preserve kidney function with minimal trauma to the individual or the kidney.
• If the tumors are allowed to grow, they may lead to obstructive uropathy or displacement of much of the normal kidney tissue.
• There is also a significant risk of hemorrhage if the angiomyolipomas or cysts grow larger than 4 cm.
• Hematuria, back or abdominal pain, or internal hemorrhage may be the initial signs of kidney problems.

Treatment

• The renal lesions that appear in many individuals with TSC may remain stable and require no specific treatment.
• Renal tumors must sometimes be removed, however, if they grow rapidly, if there is an indication that they may be malignant (i.e., a solid tumor with little or no fat content), or to alleviate obstruction.
• With more frequent imaging of the kidneys and good clinical care, an individual with TSC should not have to lose an entire kidney or experience hemorrhaging from an angiomyolipoma.
• Early and aggressive treatment is much better for most individuals with TSC
• Unfortunately, some individuals with TSC who also have polycystic kidney disease will also have problems maintaining normal blood pressure levels.
• Their blood pressure usually can be controlled with medication early in the disease process; however, dialysis, and sometimes even renal transplantations, may eventually be necessary.
• Renal transplantation has been performed successfully in individuals with TSC; there does not appear to be a recurrence of angiomyolipomas in transplanted kidneys

SKIN INVOLVEMENT

• The skin is affected in virtually 100% of patients.
• Individuals with tuberous sclerosis complex (TSC) often see the disease manifested on the face, body and nails.
• In some cases, skin growths can become obtrusive but in most cases, the growths themselves are harmless.
• However manifestations such as facial angiofibromas can have a social impact and treatments are available.

Manifestations

• hypomelanotic macule
  • (87-100% of patients)
  • patches of skin lighter than the surrounding skin (can be any size or shape or may be the classic "ash-leaf" shape)
• shagreen patch-(20-80%)a patch of skin that is tough and dimpled like an orange peel
• periungual or subungual fibromas-(17-87%) fibrous growths that appear around the fingernails and toenails
• facial angiofibromas-(47-90%)
  • cause the most disfigurement
  • benign tumors of the face
  • may not be present at birth; do not usually appear until between the ages of 3 and 5 at the earliest
• Fibrous plaquessometimes appear on the forehead of individuals with TSC. There may also be fibrous, hairless scalp plaques surrounded by thin, white tufts of hair.
• Occasionally an individual with TSC coincidentally will have café au lait spots (areas of skin darker than the surrounding skin, but lighter and usually larger than a mole)
  • these skin lesions are not diagnostic of TSC.
  • A child with three or more or an adult with five or more café au lait spots may be diagnosed with neurofibromatosis

Diagnostic screening and follow-up treatment

• At the initial testing, the physician uses a Wood's lamp (an ultraviolet light) to better visualize the hypomelanotic macules-white patches on the skin that often are difficult to see, especially on infants and people with very pale skin.
• The entire body should be examined.
• The skin should be carefully examined for the other skin manifestations of TSC as well.

EYE INVOLVEMENT

Manifestations

• The appearance of retinal lesions varies from the classic mulberry lesions adjacent to the optic disk to the more common

plaque-like hamartoma.

• Retinal hamartomas
  • occasionally noted in individuals without other manifestations of TS and in individuals with other disorders.
  • although they are suggestive of TSC, single lesions are not diagnostic of TSC.
  • The frequency of retinal hamartomas in individuals with TSC has varied in reports from almost negligible to 87 percent of individuals (a difference probably reflecting the technique used and the expertise of the examiner)
• Although less common than the retinal hamartoma, a defect in the pigment of the iris has also been observed in some individuals with TSC.
• In addition, white depigmented patches, reminiscent of the hypopigmented macules on the skin, have also been observed on the retina of some individuals with TSC.

Diagnostic testing and follow-up

• Retinal lesions may be difficult to identify without pupillary dilation and indirect ophthalmoscopy, particularly difficult to examine in uncooperative children.
• Most retinal hamartomas remain dormant, although occasionally individuals with TSC have visual impairment resulting from a large hamartoma in the macular region.
• Instances of visual loss following retinal detachment, vitreous hemorrhage, or hamartoma enlargement are rare.

Treatment

• For the most part, treatment of the retinal lesions and repeated ophthalmologic examinations are unnecessary.
• Normal eye care should be maintained.

OTHER ORGAN INVOLVEMENT

• Cysts and tumors similar to those observed in the kidney sometimes appear in the liver, lung, pancreas, and other organs. These lesions are not usually seen until later in life and are rarely symptomatic.
• Bone cysts can also develop but usually do not cause problems until later in life.
• In addition, pits have been noted in both baby and adult teeth in over 90 percent of individuals with tuberous sclerosis complex (TSC), but their significance is not known.
• Rectal polyps have also been reported but do not appear to cause problems.

Initial Evaluation

• It is recommended that individuals suspected of having TSC have the following initial evaluation to establish the diagnosis and to identify potential complications for timely treatment. The evaluation and management plan described below was developed by the Clinical Issues Panel, Panel 1, at the Tuberous Sclerosis Consensus Conference in July, 1998
• Medical history, especially for features of TSC
• Family history, especially for features of TSC
• Physical examination with use of a Woods lamp (ultraviolet light) in a darkened room and special attention to dermatologic findings
• Cranial CT/MRI
• Renal ultrasonography
• Ophthalmologic examination
• Electrocardiography and echocardiography, if cardiac symptoms indicate
• Electroencephalography, if seizures are present
• Neurodevelopmental and behavioral evaluation
• Chest CT for adult females

Surveillance Screening in TSC

• At the time of diagnosis, many medical tests are performed. Patients

and parents should also be aware of routine testing that needs to be performed. Patients are advised to share this diagram with their physicians.

	"Asymptomatic" parent, child or first degree relative at time of diagnosis of affected individual	Suspected case or initial diagnostic evaluation
Fundoscopic Examination	+	+
Brain MRI	+b	+
Brain EEG	-	-f
Cardiac ECG and ECHO	-g	+
Renal MRI, CT or Ultrasound	+i	+
Dermatalogic screening	+	+
Neurodevelopmental Testing	-	+k
Pulmonary CT	-	-

FOR A CHILD

	Known case, no symptoms in referable organ	Known case, symptoms or findings previously documented
Fundoscopic Examination	-	+
Brain MRI	+c	+
Brain EEG	-	+e
Cardiac ECG and ECHO	-	+h
Renal MRI, CT or Ultrasound	+j	+h
Dermatalogic Screening	-	+e
Neurodevelopmental Testing	+l	+e
Pulmonary CT	-	+e

FOR AN ADULT

	Known case, no symptoms in referable organ	Known case, symptoms or findings previously documented
Fundoscopic Examination	-	+f
Brain MRI	+d	+e
Brain EEG	-	+e
Cardiac ECG and ECHO	-	+e
Renal MRI, CT or Ultrasound	+c	+h
Dermatalogic Screening	-	+e
Neurodevelopmental Testing	-	+e
Pulmonary CT	+m	+e

KEY

• MRI is magnetic resonance screening; EEG is electroencephalogram; ECG is electrocardiogram; ECHO is echocardiogram; and CT is computed tomography.
• + indicates screening recommended; - indicates screening not recommended
• b With negative physical examination results, CT is recommended.
• c Every 1 to 3 years.
• d Probably less frequently than in children.
• e As clinically indicated.
• f Unless seizures are suspected, this is generally not useful for diagnosis.
• g Unless needed for diagnosis.
• h Every 6 months to 1 year until involution or size stabilization occurs.
• i Ultrasound is generally recommended due to cost, although local imaging expertise may vary.
• j Every 3 years until adolescence.
• k Generally for children only.
• l Recommended for children at the time of beginning first grade.
• m For women at age 18.

References

• Roach, E.S., DiMario F.J., Kandt R.S., & Northrup H. (1998). Tuberous sclerosis consensus conference: Recommendations for diagnostic evaluation. Journal of Child Neurology, 14 (6), 401–407.
• Roach, E.S., Gomez M.R., & Northrup H. (1998). Tuberous sclerosis complex consensus conference: Revised clinical diagnostic criteria. Journal of Child Neurology, 13, 624–628.

Differential Diagnosis

• Many of the features of TSC are nonspecific and can be seen as isolated findings or as a feature of another disease.
• Depigmented patches have been reported to occur in up to 8 per 1000 newborns and in most cases have no medical significance.
• Other diseases that have hypopigmented macules as part of the phenotype include
  • Vitiligo
  • nevus depigmentus
  • nevus anemicus
  • piebaldism
  • Vogt-Koyanagi-Harada syndrome
• acne vulgaris, acne rosacea, or multiple trichoepithelioma can be mistaken for angiofibromas
• shagreen patchrd are rare but can be seen in families or sporadically
• Ungual fibromas can result from trauma but generally these are single lesions and their presence can be explained
• Renal cysts are seen in 1-2% of population, but not usually in people under 30 years of age
• Renal angiomyolipomas (AMLs) are rare tumors sometimes observed in individuals with no other medical problems. They show loss of heterozygosity TSC2.
• 50% of Infants with cardiac rhabdomyomas are affected with TSC and the others are an isolated finding

Psychosocial Issues

• Denial is a common reaction when a parent first learns of the diagnosis
• They may feel overwhelmed, sad, fearful, angry, guilty
• A survey of families associated with a TS support group in North Carolina

o Most parents reported that their concerns were initially ignored o It took a median of 3 physicians before a diagnosis established in children with infantile spasms o Infantile seizures were not diagnosed correctly in 40% of the TS patients

• The disfigurement caused by the tumors can lead to social isolation and self-esteem issues
• Stress and anxiety may persist due to health concerns

IDENTIFIED RESOURCES

• Tuberous Sclerosis Alliance

801 Roeder Road, Suite 750

Silver Spring, MD 20910

Phone: 800-225-6872; 301-562-9890

Fax: 301-562-9870

Email: ntsa@ntsa.org

www.tsalliance.org

• NCBI Genes and Disease Web page

www.ncbi.nlm.nih.gov/disease/TSC.html

• American Epilepsy Society

342 North Main Street

West Hartford, CT 06117-2507

Phone: 860-586-7505

Fax: 860-586-7550

Email: info@aesnet.org

www.aesnet.org

• Epilepsy Foundation of America

4351 Garden City Drive

Landover, MD 20785

Phone: 301-459-3700; 800-EFA-1000

Fax: 301-577-4941

Email: webmaster@efa.org

www.efa.org

• National Tuberous sclerosis Association

8181 Professional Place, Suite 110

Landover, Maryland

20785-2226

Tel -1800-225-6872

Email - ntsa@ntsa.org

References

• www.geneclinics.com Tuberous sclerosis complex
• www.tsalliance.org Tuberous Sclerosis Alliance
• Management of Genetic Syndromes. Cassidy, S.B. and Allanson, J.E.editors. Chapter____ written by_____ Mueller. Wiley-Liss Inc. 2001.

Notes

The information in this outline was last updated in 2001.