Does anybody out there know about tuberous sclerosis?

Question

Obviously, I have read all the info I can from the 'net and elsewhere, but that's not the same as personal experience. My son, who has learning difficulties, seizures etc is being investigated for this.

Answer 1

Visit the TS alliance,

http://www.tsalliance.org

They have an outreach program, clinic references, diagnostic criteria, a wealth of information.

There is a project that uses home computers to find a cure for Tuberous Sclerosis. They also have a forum:

http://www.childhooddiseases.org

Answer 2

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Answer 3

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Answer 4

1

Answer 5

This is quite a lot of information from a neuro book. if you have some doubt please contact me at [e-mail]. i will try to clarify.

TUBEROUS SCLEROSIS

Tuberous sclerosis was first described by von Recklinghausen in 1863. In 1880, Bourneville coined the term sclérose tubéreuse for the potato-like lesions in the brain.
In 1890, Pringle described the facial nevi, or adenoma sebaceum. Vogt later emphasized the classic triad of seizures, mental retardation, and adenoma sebaceum.
Eponymically, tuberous sclerosis is called Pringle disease when there are only dermatologic findings, Bourneville disease when the nervous system is affected, and
West syndrome when skin lesions are associated with infantile spasms, hypsarrhythmia, and mental retardation. Tuberous sclerosis (MIM 191100) is a hereditarily determined progressive disorder characterized by the development in early life of hamartomas, malformations, and congenital tumors of the nervous system, skin, and viscera.

GENETICS AND INCIDENCE
Tuberous sclerosis is inherited as an autosomal-dominant trait, with a high incidence of sporadic cases and protean clinical expressivity. These features are attributed
to modifier genes, for which the homozygous condition results in a phenotypically normal individual despite the presence of the gene for tuberous sclerosis; when
heterozygous, the modifier gene results in a mildly affected patient. The defective gene has been mapped to chromosome 9q34 (TSC1) in some families and to chromosome 16p13.3 (TSC2) in others. Hamartin is the gene product for TSC1, and tuberin is the gene product for TSC2. Both are involved in the regulation of cell growth and are considered tumor suppressor genes. As in other hereditary tumor syndromes, a second somatic mutation may be involved in pathogenesis.
Incidence figures must be considered minimal because milder varieties are often unrecognized. Autopsy data gave an incidence of 1 in 10,000 people; clinical
surveys gave a prevalence between 1 in 10,000 and 1 in 170,000. Although all races are affected, the disease is thought to be uncommon in blacks, and there may be
a greater frequency in males.

PATHOLOGY AND PATHOGENESIS
The pathologic changes are widespread and include lesions in the nervous system, skin, bones, retina, kidney, lungs, and other viscera.
The brain is usually normal in size, but several or many hard nodules occur on the surface of the cortex. These nodules are smooth, round, or polygonal and project
slightly above the surface of the neighboring cortex. They are white, firm to the touch, and of various sizes. Some involve only a small portion of one convolution;
others encompass the convolutions of one whole lobe or a major portion of a hemisphere. In addition, there may be developmental anomalies of the cortical
convolutions in the form of pachygyria or microgyria. On sectioning of the hemispheres, sclerotic nodules may be found in the subcortical gray matter, the white
matter, and the basal ganglia. The lining of the lateral ventricles is frequently the site of numerous small nodules that project into the ventricular cavity ( candle
gutterings) (Fig. 102.1). Sclerotic nodules are less frequently found in the cerebellum. The brainstem and spinal cord are rarely involved.

Histologically, the nodules are characterized by a cluster of atypical glial cells in the center and giant cells in the periphery. Calcifications are relatively frequent. Other
features include heterotopia, vascular hyperplasia (sometimes with actual angiomatous malformations), disturbances in the cortical architecture, and, occasionally,
development of subependymal giant-cell astrocytomas. Intracranial giant aneurysm and arterial ectasia are uncommon findings.
The skin lesions are multiform and include the characteristic facial nevi ( adenoma sebaceum) and patches of skin fibrosis. The facial lesions are not adenomas of the
sebaceous glands but rather small hamartomas arising from nerve elements of the skin combined with hyperplasia of connective tissue and blood vessels . In late childhood, lesions similar to those on the face are found around or underneath the fingernails and toenails ( ungual fibroma). Circumscribed areas of
hypomelanosis or white nevi are common in tuberous sclerosis and are often found in infants. Although these depigmented nevi are less specific than the sebaceous
adenoma, they are of importance in raising suspicion for the diagnosis in infants with seizures. Histologically, the skin appears normal except for the loss of melanin,
but ultrastructural studies show that melanosomes are small and have reduced content of melanin.

The retinal lesions are small congenital tumors ( phakomas) composed of glia, ganglion cells, or fibroblasts. Glioma of the optic nerve has been reported.
Other lesions include cardiac rhabdomyoma; renal angiomyolipoma, renal cysts, and, rarely, renal carcinoma; cystic disease of the lungs and pulmonary
lymphangioleiomyomatosis; hepatic angiomas and hamartomas; skeletal abnormalities with localized areas of osteosclerosis in the calvarium, spine, pelvis, and
limbs; cystic defects involving the phalanges; and periosteal new bone formation confined to the metacarpals and metatarsals.

SYMPTOMS AND SIGNS
The cardinal features of tuberous sclerosis are skin lesions, convulsive seizures, and mental retardation. The disease is characterized by variability and expressivity
of the clinical manifestations.

CUTANEOUS SYMPTOMS
Depigmented or hypomelanotic macules are the earliest skin lesion . They are present at birth, persist through life, and may only be found with a
Wood's-lamp examination. The diagnosis is suggested if there are three or more macules measuring 1 cm or more in length. Numerous small macules sometimes
resemble confetti or depigmented freckles. Most macules are leaf-shaped, resembling the leaf of the European mountain ash tree and sometimes following a
dermatomal distribution. Facial adenoma sebaceum (facial angiofibroma) is never present at birth but is clinically evident in more than 90% of affected children by age
4 years. At first, the facial lesion is the size of a pinhead and red because of the angiomatous component. It is distributed symmetrically on the nose and cheeks in a
butterfly distribution. The lesions may involve the forehead and chin but rarely involve the upper lip. They gradually increase in size and become yellowish and
glistening. Shagreen patches, a connective tissue hamartoma, are also characteristic. Rarely present in infancy, the patches become evident after age 10. Usually
found in the lumbosacral region, shagreen plaques are yellowish-brown elevated plaques that have the texture of pig skin. Other skin lesions include café-au-lait
spots, small fibromas that may be tiny and resemble coarse goose flesh, and ungual fibromas that appear after puberty.

Neurologic Symptoms
Seizures and mental retardation indicate a diffuse encephalopathy. Infantile myoclonic spasms with or without hypsarrhythmia are the characteristic seizures of young
infants and, when associated with hypopigmented macules, are diagnostic of tuberous sclerosis. The older child or adult has generalized tonic-clonic or partial
complex seizures. There is a close relationship between the onset of seizures at a young age and mental retardation. Mental retardation rarely occurs without clinical
seizures, but intellect may be normal, despite seizures. Other than a delayed acquisition of developmental milestones, intellectual impairment, or nonspecific
language or coordinative deficiencies, a formal neurologic examination is typically nonfocal.
Ophthalmic Symptoms
Hamartomas of the retina or optic nerve are observed in about 50% of patients. Two types of retinal lesions are seen on funduscopic examination: (1) the easily
recognized calcified hamartoma near or at the disc with an elevated multinodular lesion that resembles mulberries, grains of tapioca, or salmon eggs ( Fig. 102.4); and
(2) the less distinct, relatively flat, smooth-surfaced, white or salmon-colored, circular or oval lesion located peripherally in the retina ( Fig. 102.5). Nonretinal lesions
may range from the specific depigmented lesion of the iris ( Fig. 102.6) to nonspecific, nonparalytic strabismus, optic atrophy, visual-field defects, or cataracts.

Visceral Symptoms
Renal lesions include hamartomas (angiomyolipomas) and renal cysts. Typically, both are multiple, bilateral, and usually innocuous and silent. Renal cell carcinoma is
a rare complication in the older child or adult. In one series, there was a 50% incidence of tuberous sclerosis in patients with cardiac rhabdomyoma. This cardiac
tumor may be symptomatic at any age, even infancy, and can result in death.
Pulmonary hamartomatous lesions consisting of multifocal alveolar hyperplasia associated with cystic lymphangioleiomyomatosis occur in fewer than 1% of patients.
These become symptomatic (often with a spontaneous pneumothorax) in the third or fourth decade and are progressive and often fatal. Sclerotic lesions of the
calvaria and cystic lesions of the metacarpals and phalanges are asymptomatic. Hamartomatous hemangiomas of the spleen and racemose angiomas of the liver are
rare and usually asymptomatic. Enamel pitting of the deciduous teeth may aid in diagnosis.

LABORATORY DATA
Unless renal lesions are present, routine laboratory studies are normal. Renal angiomyolipomas are usually asymptomatic and rarely cause gross hematuria, but they
may show albuminuria and microscopic hematuria. Sonography (Fig. 102.7), angiography, and computed tomography (CT) are often diagnostic. Multiple or diffuse
renal cysts may be associated with albuminuria or azotemia and hypertension. Intravenous pyelography is diagnostic.

Chest radiographs may reveal pulmonary lesions or rhabdomyoma with cardiomegaly. Electrocardiogram findings are variable, but the echocardiogram is diagnostic.
Skull radiographs usually reveal small calcifications within the substance of the cerebrum . Cerebrospinal fluid is normal, except when a large intracerebral
tumor is present. The electroencephalogram is often abnormal, especially in patients with clinical seizures. Abnormalities include slow-wave activity and epileptiform
discharges such as hypsarrhythmia, focal or multifocal spike or sharp-wave discharges, and generalized spike-and-wave discharges. CT is diagnostic when calcified
subependymal nodules encroach on the lateral ventricle (often in the region of the foramen of Monro); there may also be calcified cortical or cerebellar nodules . A few nodules appear isodense on CT and are better visualized on magnetic resonance imaging (MRI). Fluid-attenuated inversion recovery (FLAIR) MRI
images allow more accurate delineation of cortical and subcortical tubers. Calcified paraventricular and cortical lesions have been visualized shortly after birth. The
number of cortical tubers often correlates with the severity of cortical dysfunction. There is enough variation in clinical outcome that prognosis cannot be based on
cortical tuber count alone.

DIAGNOSIS
Clinical diagnosis is possible at most ages. In infancy, three or more characteristic depigmented cutaneous lesions suggest the diagnosis, and this is reinforced in the
presence of infantile myoclonic spasms. In the older child or adult, the diagnosis is made by the triad of tuberous sclerosis: facial adenoma sebaceum, epilepsy, and
mental retardation. Retinal or visceral lesions may be diagnostic. The disease, however, is noted for protean manifestations, and a family history may be invaluable in
establishing the diagnosis, which is often reinforced by CT or MRI evidence of calcified subependymal nodules.
The differential diagnosis includes other diseases that involve skin, nervous system, and retina. Neurofibromatous and encephalotrigeminal angiomatosis are
differentiated by the characteristic skin lesions of those disorders.
Multisystem involvement may result in difficulties in establishing a diagnosis of tuberous sclerosis. The National Tuberous Sclerosis Association has developed a
classification of diagnostic criteria ( Table 102.1). Prenatal diagnosis is not currently available.

COURSE AND PROGNOSIS
Mild or solely cutaneous involvement often follows a static course, whereas patients with the full-blown syndrome have a progressive course with increasing seizures
and dementia. The child with infantile myoclonic spasms is at great risk of later intellectual deficit. Brain tumor, status epilepticus, renal insufficiency, cardiac failure,
or progressive pulmonary impairment can lead to death.

TREATMENT
There is no specific treatment. The cutaneous lesions do not compromise function, but cosmetic surgery may be indicated for facial adenoma sebaceum or large
shagreen patches. Infantile myoclonic spasms previously responded to corticosteroid or corticotropin therapy, and currently vigabatrin is the drug of choice; focal and
generalized seizures are treated with anticonvulsants. Progressive cystic renal disease often responds to surgical decompression, but with renal failure, dialysis or
renal transplantation may be necessary. Intramural cardiac rhabdomyoma and complicating congestive heart failure are managed medically with cardiotonics,
diuretics, and salt restriction. Whole obstructive intracavity tumors and congestive heart failure require surgical extirpation of the tumor. Progressive pulmonary
involvement is an indication for respiratory therapy, but response is poor and most patients die a few years after the onset of this complication.