A 10 month old girl presents to the emergency room for tonic-clonic seizures lasting a few minutes. This baby girl is a product of a normal pregnancy and was delivered full-term by normal spontaneous vaginal delivery. There were no postnatal complications and this infant was discharged from the hospital at 48 hours of life. Her history is significant for jerking movements (onset at 5 months of age) described as sudden flexion of the neck, arms, and legs onto the trunk preceded by a cry. Her parents were not too worried about this behavior since the child would return back to normal and they attributed it to colic or "gas". There was no history of fever, coughing, vomiting or diarrhea. She has been gaining weight appropriately and eating normally. She is on solid foods and formula, which the parents prepare correctly. Her immunizations are up to date. She is on no medications and her development has been normal. She is able to sit up, crawl, cruise with both hands, and combines syllables.
Her family history is also unremarkable in that there is no history of seizures, mental retardation, or consanguinity.
Exam: VS T 37.0, P 100, R 26, BP 90/60, O2 sat 100% on RA, weight 9.0 kg (50%ile), length 73 cm (50%tile), HC 44.5 cm (50%tile). She is alert and active in no distress. She is not toxic. She tracks well. She has good bonding with mother. She has multiple small 1-2 cm oval, irregular hypopigmented macules on her trunk and extremities. HEENT is normal. Her neck is supple without lymphadenopathy. Heart, lungs and abdomen are normal. Neuro: She has no facial asymmetry. She moves all her extremities well. There are no focal deficits. She does not exhibit cortical thumbing or scissoring of her lower extremities. She tracks well. She has good head control and is able to support herself on her legs.
In the ER, her work-up includes a head CT scan revealing cortical tubers in the cerebral cortex and multiple subependymal nodules in the lateral ventricles. She is admitted to the floor where an EEG shows "hypsarrhythmia". An echocardiogram and a renal ultrasound are also done showing tumors in both the heart and kidneys. A diagnosis of tuberous sclerosis is made. She is started on ACTH, unfortunately her condition fails to improve and she continues to have intractable seizures in addition to being mentally retarded.
Tuberous sclerosis was probably first described by Friedrich Daniel von Recklinghausen in 1862, when he presented a baby who died "after taking a few breaths". She had pathological findings of tumors bulging from the heart, which Dr. Recklinghausen named "myomata" and described in few words, the brain having "a great number of scleroses." Then in 1880, Désiré-Magloire Bourneville first described the brain of a diseased individual in greater detail, and used the term "tuberous sclerosis of the cerebral convolutions" because of the gross nodular appearance of the brain tumors resembling tubers, or roots of a plant (1).
Over a century later, we know much more about tuberous sclerosis complex (TSC). It is one of the neurocutaneous syndromes because it is thought that TSC is due to a defect in differentiation of the primitive ectoderm, which gives rise to the nervous system and skin. Therefore, it is in the same family of disorders, which includes neurofibromatosis, Sturge-Weber disease, von Hippel-Lindau disease, ataxia telangiectasia, linear nevus syndrome, hypomelanosis of Ito, and incontinentia pigmenti (2). It was also thought to be similar to neurofibromatosis and von Hippel-Lindau disease as being one of the phakomatoses, which is derived from the Greek word phakos, meaning "spot." This "spot" refers to a congenital grouping of nevus cells that is found in several organs and has the potential of enlarging and forming a tumor by cellular proliferation.
TSC is inherited as an autosomal dominant trait like neurofibromatosis; however, at least half of the cases are due to new mutations. The estimated frequency is 1 in 6000, and there is no racial predilection; therefore, we have seen several of these patients in Hawaii. There have been two genes implicated in TSC discovered so far, called TSC1 and TSC2 which are located on chromosomes 9q34 and 16p13 respectively. The TSC1 gene encodes for a protein called hamartin and the TSC2 gene encodes for tuberin. Although these two gene products have been discovered, the diagnosis of TSC is a clinical one and is not dependent on a blood test yet. The complicating feature of TSC is its wide clinical expression. Therefore, one patient could be asymptomatic while another patient could have seizures and severe mental retardation. Although variable expression is a feature of TS, it is doubtful that there is incomplete penetrance, meaning that a person with an autosomal dominant gene defect does not show any signs of the disease (3). This makes genetic counseling very difficult since one cannot predict what the phenotypic expression of the offspring will be, even though the chances of an individual having TSC is 50% given that one of the parents have the dominant allele. Also, because of the variable expression of this disease, it is imperative that in obtaining a family history, one asks if there is a history of mental retardation; seizures; obstructive hydrocephalus; brain or cardiac tumors; cardiac dysrhythmias at an early age; stillbirths (especially with hydrops); kidney, lung, or bone cysts; pulmonary failure; spontaneous pneumothorax; renal angiomyolipomas or failure; fibromatous growths around or under the nails or on gums; enamel pits; retinal phakomas; skin lesions such as hypopigmented macules, facial angiofibroma and shagreen patches; poliosis (premature white hair) or canities (white hairs) of the scalp, lashes, or brows; and iris depigmentation, in addition to recognizing that these signs can be mistaken for vitiligo, refractory acne, or autosomal dominant polycystic kidney disease. However, family history is often insufficient; therefore, family members should be examined for hypopigmented macules (with a Wood's lamp) and brain anomalies by computed tomography. Because of the possibility for other tumors, ophthalmologic examination, renal radiographic studies, chest radiography, and echocardiogram are often ordered.
TSC is classified as a neurocutaneous syndrome meaning that its manifestations include neurologic and dermatologic features. Vogt proposed a diagnostic triad for TSC in 1908 being mental retardation, seizures, and adenoma sebaceum; however, because of the variable clinical expression, this triad of symptoms may not be present all together, and is therefore not used. Tuberous sclerosis is a multiorgan disease and does not only include the brain pathology; therefore, "tuberous sclerosis complex" may be a better term for this disease (4).
The diagnosis of TSC is still made clinically and as mentioned previously, the identification of TSC1 and TSC2 and their gene products have not changed the way it is diagnosed. The Consensus Conference on TSC by the National Tuberous Sclerosis Association in 1998 categorized major and minor diagnostic features (listed below) for the diagnosis of the tuberous sclerosis complex. A definitive diagnosis of TSC is made by either 2 major features, or 1 major and 2 minor features. Probable TSC is made by 1 major plus 1 minor feature. And possible TSC is made by either 1 major feature or 2 or more minor features (4).
Major Features
1. Facial angiofibromas or forehead plaques
2. Nontraumatic ungual or periungual fibroma
3. Hypomelanotic macules (more than 3)
4. Shagreen patch (connective tissue nevus)
5. Multiple retinal nodular hamartomas
6. Cortical tuber
7. Subependymal nodule
8. Subependymal giant cell astrocytoma
9. Cardiac rhabdomyoma, single or multiple
10. Lymphangiomyomatosis
11. Renal angiomyolipoma
Minor Features
1. Multiple randomly distributed pits in dental enamel
2. Hamartomatous rectal polyps
3. Bone cysts
4. Cerebral white matter radial migration lines
5. Gingival fibromas
6. Nonrenal hamartomas
7. Retinal achromic (pale, without color) patch
8. "Confetti" skin lesions
9. Multiple renal cysts
TSC can sometimes present during the first year of life with infantile spasms. In two studies, infantile spasms were the presenting complaint in 69% of patients. Infantile spasms usually begin between the ages of 4 and 8 months, and present with brief symmetrical contractions of the neck, trunk, and extremities, which can either be in flexion or extension, or both. Clusters of seizures may last for minutes with a brief period occurring between each seizure, and may be preceded or followed by a cry. Because of this, the spasms are sometimes mistaken for colic. The spasms have a tendency to occur when the infant is drowsy or upon awakening. Infantile spasms have a very unique pattern on EEG, called hypsarrhythmia, which consists of chaotic, high-voltage, bilateral, asynchronous, slow-wave activity (5).
Perhaps more characteristic of TSC is the development of other types of seizures. The seizures are thought to be due to the cortical tubers or its surrounding cortex that occur in the brain of these patients, although they can sometimes be secondary to cerebral cortex next to a subependymal giant cell astrocytoma. Seizures are the presenting symptom in about 90% of patients with this disease, most of who are children. Although they can occur at all ages, they usually occur in the first year of life. The most common seizure types, besides infantile spasms, are partial simple, partial complex, and partial with secondary generalization (6).
Given that TSC involves hamartomatosis, a condition in which benign tumors form from dysplastic cells that multiply excessively, imaging is extremely important. Because of the CNS manifestations, CT and MRI are essential in the evaluation of a patient suspecting of having TSC, especially if signs of cerebral involvement are present. Cortical tubers, which are most characteristic of TSC, are primarily located in the cerebral cortex and underlying white matter, and are called hamartias, or groups of dysplastic cells that do not grow more rapidly than the other normal cells. They are sometimes calcified, often multiple, and hypomyelinated. Two hamartomatous brain lesions are subependymal nodules and subependymal giant cell tumors. Subependymal nodules are growths that are usually on the outer walls of the lateral ventricles, nearly always next to or within the caudate nucleus. They are generally less than 1 cm and may calcify. They are found in about 80% of patients, and are the single most diagnostic feature by CT scan of TSC. Another unique brain lesion is the subependymal giant cell tumor. These tumors usually lie adjacent to the foramen of Monro and are histologically identical to the subependymal nodules. The difference between the giant cell astrocytomas and subependymal nodules is the propensity for growth in the former. Because of its location, there is a propensity of these tumors to cause hydrocephalus from obstructing the flow of CSF through these foramina (7).
After seizures, mental retardation and other psychiatric problems are also commonly seen in tuberous sclerosis patients. Patients who have never had seizures, infrequent seizures, or seizures after 4 years of age, will most likely have normal intelligence and development. Behavioral and psychiatric problems that are seen in TSC includes ADHD, sleep problems, childhood schizophrenia, and autism.
Ash leaf spots are irregular, hypopigmented macules resembling the leaves of the ash tree (also similar to Hawaiian maile leaves) (8). These lesions occur in the majority of patients with TSC and are often seen at birth, although they can appear months or years later. They appear on the trunk and extremities, number anywhere from 3 to 4, to more than 100, and are usually 1.0 cm or larger. At times, numerous tiny macules are grouped together, resembling confetti, and are usually located in the distal parts of the extremities. Although ash leaf spots appear at birth and may last throughout life, they can become less obvious with time and disappear. These hypomelanotic macules are best seen with a Wood's lamp or ultraviolet light, since melanin absorbs light in the wavelength of 360 nm, making the macules that are deficient in melanin stand out (9).
Adenoma sebaceum or facial angiofibroma is a pathognomonic finding in TSC and was found in over 80% of patients over 5 years of age in one study. They are tiny red or pink papules with a glistening surface found bilaterally over the cheeks, chin, and nasolabial folds in a butterfly fashion. Larger angiofibromas can occur on the scalp or forehead, and appear as large, flesh-colored plaques that can be soft and doughy to hard. These lesions persist for life.
Another characteristic dermatologic manifestation is the shagreen patch. The word shagreen comes from the French words, peau chagrinee, which mean, "skin with the appearance of untanned leather." This lesion usually appears after the first decade of life and persists throughout life. They are usually found in the lumbosacral area, but sometimes are located elsewhere on the trunk. They are yellowish brown or pink in color, feel like pigskin or an orange peel, and can be few millimeters to over 10 cm in size. They are the second only to ash leaf spots as being the most common lesion in TSC that is found in the trunk.
Ungual fibromas, another characteristic sign of TSC, are flesh colored, or red papules or nodules found on the finger or toe nail bed, with the toes being more common than the fingers, ranging from 1 to 10 mm in size. These fibromas occur more commonly in females, grow back when removed, and appear during or after puberty.
For ophthalmologic lesions, the most common retinal hamartoma is the noncalcified tumor, which appears as a smooth, salmon-gray colored, circular lesion with indistinct borders. These tumors are usually located superficially to a retinal artery and are found in over half of patients with eye involvement. The second type of retinal tumor is the calcified mulberry tumor. Despite the lesions that can occur in the eye, blindness is rare, except in cases where the tumor involves the fovea or optic nerves (10).
Another common tumor is the cardiac rhabdomyoma, which can occur in about 50% of patients. These tumors can occur in any of the four chambers, although it is most commonly located in the left ventricle. Echocardiography is an essential component in the work-up of these individuals (11).
Renal involvement occurs in about 80% of patients with TSC. The lesions include angiomyolipomas, cysts, and renal cell carcinomas. Angiomyolipomas are localized proliferations of blood vessels, smooth muscle and fat. They can be associated with chronic renal failure, with the risk increased if there are also cysts. Cysts can develop in infancy and usually present with severe hypertension due to a mass effect of the cyst into the renal vessels (12).
The differential diagnosis of tuberous sclerosis complex is dependent on the presenting symptom, which in most cases are seizures. There are many causes of seizures, however, it is important to note whether any neurocutaneous stigmata such as ash leaf spots or cafe au lait spots are present since they will be clues that neurocutaneous syndromes like tuberous sclerosis or neurofibromatosis may be the cause. Therefore, a careful skin examination is essential in the evaluation of seizures.
There are many manifestations and degrees of severity of tuberous sclerosis; therefore, management should be aimed at treatment and evaluation of the symptoms. Patients with seizures should have an imaging test such as CT, and an EEG performed to look for anatomical abnormalities or abnormal EEG patterns such as "hypsarrhythmia". If tuberous sclerosis is suspected, the patient should also have an echocardiogram and renal ultrasound or CT done since the chances for cardiac and renal tumors are high. A good funduscopic examination is essential to determine the presence of retinal hamartomas.
The treatment of seizures is difficult because these seizures are often refractory to antiepileptic drugs. The best drug we have available for infantile spasms (also called hypsarrhythmia seizures) in the United States is intramuscular ACTH, however, the drug of choice is vigabatrin because it is safer and more effective. Vigabatrin is an anticonvulsant which inhibits GABA transaminase, which breaks down GABA (an inhibitory neurotransmitter) (13). However, the U.S. Food and Drug Administration has been reluctant to approve it because of its risk of psychosis (about 1-2%), clefts in the myelin sheath of peripheral nerves seen in rodents, and case reports of permanent peripheral vision loss. ACTH can lead to hypertension and other side effects of corticosteroids, such as osteoporosis, weight gain, Cushingoid appearance, avascular necrosis of the femoral head, etc.
Genetic counseling is very important in the management of TSC. A good family history should be obtained in addition to examining the family members for any signs and stigmata of TSC. Since it is autosomal dominant, the chances that an offspring will have this disorder is 50%; however, given the phenotypic variability of this disease, predicting the outcome of the couple's future children can be difficult. For example, because less than 50% of individuals with tuberous sclerosis will have mental retardation, the couple should be told that their offspring will have about a 25% chance of being mentally retarded. Other alternatives for having children should also be discussed; those being adoption, artificial insemination with donor sperm, and in vitro fertilization with a donor egg. If there is a negative family history and sporadic disease is likely, then the chances for future offspring having the disease is probably less than 2%, although one of the parents could still carry the gene and not thought of having the disease since its expression may be very mild. Prenatal diagnosis may be possible as early as 22 to 25 weeks by detecting the presence of cardiac or brain tumors; however, this is not always possible. If it is known that this family has a TSC1 or TSC2 gene mutation, then it may be possible to detect this mutation in the fetus through chorionic villus sampling.
The outcome of tuberous sclerosis complex is variable, depending on the severity of the disease. Some individuals may have a normal lifespan and not know that they have the disease, whereas, others could succumb to a lifetime of intractable seizures, mental retardation, or the development of other hamartomas throughout their adult life leading to new problems.
I would like to thank Dr. Robert Bart for reviewing this chapter and his useful comments and suggestions.
Questions
1. How is tuberous sclerosis complex inherited?
2. What percentage of TSC is sporadic (due to new mutations)?
3. Name three dermatological features of TSC. At what ages do each of these lesions occur?
4. What is the treatment of choice for infantile spasms that is approved by the FDA?
5. What is the EEG pattern of infantile spasms?
6. If a patient is diagnosed with TSC by computed tomography of the brain, what other tests must be done in the work-up?
References
1. Gomez MR. Chapter 1 - History of Tuberous Sclerosis Complex. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 3-9.
2. Haslam, Robert. Chapter 605-Neurocutaneous Syndromes. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1835-1839.
3. Michels VV. Chapter 21 - Genetic Counseling. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 313-323.
4. Gomez MR. Chapter 2 - Definition and Criteria for Diagnosis. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 10-23.
5. Haslam R. Chapter 602 - Seizures in Childhood. In: Behrman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1813-1829.
6. Gomez MR. Chapter 4 - Natural History of Cerebral Tuberous Sclerosis. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 29-46.
7. Carlson BA, Houser OW, Gomez MR. Chapter 8 - Brain Imaging in the Tuberous Sclerosis Complex. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 85-100.
8. Bart RD. Personal communication, April 30, 2001.
9. Rogers RS, O'Connor WJ. Chapter 11 - Dermatologic Manifestations. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 160-180.
10. Robertson DM. Chapter 10 - Ophthalmic Findings. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 145-159.
11. Mair DD, Edwards WD, Seward JB. Chapter 13 - Cardiac Manifestations. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 194-206.
12. Bjornsson J, Henske EP, Bernstein J. Chapter 12 - Renal Manifestations. In: Gomez MR, Samson JR, Whittemore VH (eds). Tuberous Sclerosis Complex, third edition. 1999, New York: Oxford University Press, pp. 181-193.
13. Menkes JH, Sankar R. Chapter 12 - Paroxysmal Disorders. In: Menkes JH (ed). Textbook of Child Neurology, fifth edition. 1995, Baltimore: Williams & Wilkins, p. 761.
Answers to questions
1. Autosomal dominant.
2. 50%.
3. Ash leaf spots (birth), adenoma sebaceum or facial angiofibroma (5 years old), shagreen patch (after 10 years old).
4. ACTH.
5. Hypsarrhythmia.
6. Echocardiogram and renal ultrasound.