Tuberous Sclerosis

Tuberous sclerosis or tuberous sclerosis complex (TSC) is a rare, multi-system genetic disease that causes benign tumours to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral problems, skin abnormalities, lung and kidney disease. TSC is caused by mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively. These proteins act as tumour growth suppressors, agents that regulate cell proliferation and differentiation.

The name, composed of the Latin tuber (swelling) and the Greek skleros (hard), refers to the pathological finding of thick, firm and pale gyri, called "tubers," in the brains of patients postmortem. These tubers were first described by Désiré-Magloire Bourneville in 1880; the cortical manifestations may sometimes still be known by the eponym Bourneville's disease.

Signs and symptoms

The physical manifestations of tuberous sclerosis are due to the formation of hamartia (malformed tissue such as the cortical tubers), hamartomas (benign growths such as facial angiofibroma and subependymal nodules) and, very rarely, cancerous hamartoblastomas. The effect of these on the brain leads to neurological symptoms such as seizures, developmental delay and behavioral problems.

Central nervous system

About 50% of people with TSC have learning difficulties ranging from mild to significant, and studies have reported that between 25% and 61% of affected individuals meet the diagnostic criteria for autism, with an even higher proportion showing features of a broader pervasive developmental disorder. A 2008 study reported self-injurious behavior in 10% of people with TSC. Other conditions, such as ADHD, aggression, behavioral outbursts and OCD can also occur. Lower IQ is associated with more brain involvement on MRI.

Three type of brain tumours may be associated with TSC: i. Giant cell astrocytoma: (grows and blocks the CSF flow leading to dilatation of ventricles causing headache and vomiting) ii. Cortical tubers: after which the disease is named. iii. Sub-ependymal nodules: form in the walls of ventricles.

Classic intracranial manifestations of tuberous sclerosis include subependymal nodules and cortical/subcortical tubers.

The tubers are typically triangular in configuration, with the apex pointed towards the ventricles, and are thought to represent foci of abnormal neuronal migration. The T2 signal abnormalities may subside in adulthood, but will still be visible on histopathological analysis. On magnetic resonance imaging, TSC patients can exhibit other signs consistent with abnormal neuron migration (radial white matter tracts hyperintense on T2WI, heterotopic gray matter).

Subependymal nodules are composed of abnormal, swollen glial cells and bizarre multinucleated cells which are indeterminate for glial or neuronal origin. There is no interposed neural tissue. These nodules have a tendency to calcify as the patient ages. A nodule that markedly enhances and enlarges over time should be considered suspicious for transformation into a subependymal giant cell astrocytoma (SEGA). A SEGA typically develops in the region of the foramen of Monro, in which case it is at risk of developing an obstructive hydrocephalus.

A variable degree of ventricular enlargement, either obstructive (e.g. by a subependymal nodule in the region of the foramen of Monroe) or idiopathic in nature.

Kidneys

Between 60 and 80% of TSC patients have benign tumors (once thought hamartomatous, but now considered true neoplasms) of the kidneys called angiomyolipomas (AML) frequently causing hematuria. These tumors are composed of vascular tissue (angio–), smooth muscle (–myo–), and fat (–lipoma). Although benign, an AML larger than 4 cm is at risk for a potentially catastrophic hemorrhage either spontaneously or with minimal trauma. AMLs are found in about 1 in 300 people without TSC. However those are usually solitary, whereas in TSC they are commonly multiple and bilateral.

Approximately 20-30% of people with TSC will have renal cysts, causing few problems. However, 2% may also have autosomal dominant polycystic kidney disease.

Very rare (< 1%) problems include renal cell carcinoma and oncocytomas (benign adenomatous hamartoma).

Lungs

Patients with TSC can develop progressive replacement of the lung parenchyma with multiple cysts. This process is identical to another disease called lymphangioleiomyomatosis (LAM). Recent genetic analysis has shown that the proliferative bronchiolar smooth muscle in tuberous sclerosis-related LAM is monoclonal metastasis from a coexisting renal angiomyolipoma. There have been cases of TSC-related LAM recurring following lung transplant.

Heart

Rhabdomyomas are benign tumors of striated muscle. A cardiac rhabdomyoma can be discovered using echocardiography in approximately 50% of people with TSC. However the incidence in the newborn may be as high as 90% and in adults as low as 20%. These tumors grow during the second half of pregnancy and regress after birth. Many will disappear entirely. Alternatively, the tumor size remains constant as the heart grows, which has much the same effect.

Problems due to rhabdomyomas include obstruction, arrhythmia and a murmur. Such complications occur almost exclusively during pregnancy or within the child's first year.

Prenatal ultrasound, performed by an obstetric sonographer specializing in cardiology, can detect a rhabdomyoma after 20 weeks. This rare tumour is a strong indicator of TSC in the child, especially if there is a family history of TSC.

Skin

Some form of dermatological sign will be present in 96% of individuals with TSC. Most cause no problems but are helpful in diagnosis. Some cases may cause disfigurement, necessitating treatment. The most common skin abnormalities include:

• Facial angiofibromas ("adenoma sebaceum"): A rash of reddish spots or bumps, which appear on the nose and cheeks in a butterfly distribution. They consist of blood vessels and fibrous tissue. This socially embarrassing rash starts to appear during childhood and can be removed using dermabrasion or laser treatment.
• Ungual or subungual fibromas: Also known as Koenen's tumors, these are small fleshy tumors that grow around and under the toenails or fingernails and may need to be surgically removed if they enlarge or cause bleeding. These are very rare in childhood but common by middle age.
• Hypomelanic macules ("ash leaf spots"): White or lighter patches of skin that may appear anywhere on the body and are caused by a lack of melanin. These are usually the only visible sign of TSC at birth. In fair-skinned individuals a Wood's lamp (ultraviolet light) may be required to see them.
• Forehead plaques: Raised, discolored areas on the forehead.
• Shagreen patches: Areas of thick leathery skin that are dimpled like an orange peel, usually found on the lower back or nape of the neck.

Other skin features are not unique to individuals with TSC, including molluscum fibrosum or skin tags, which typically occur across the back of the neck and shoulders, café au lait spots or flat brown marks, and poliosis, a tuft or patch of white hair on the scalp or eyelids.

Eyes

Retinal lesions, called astrocytic hamartomas (or "phakomas"), which appear as a greyish or yellowish-white lesion in the back of the globe on the ophthalmic examination. Astrocytic hamartomas can calcify, and in is in the differential diagnosis of a calcified globe mass on a CT scan.

Non-retinal lesions associated with TSC include:

• Coloboma
• Angiofibromas of the eyelids
• Papilledema (related to hydrocephalus)

Variability

Individuals with tuberous sclerosis may experience none or all of the clinical signs discussed above.

Diagnosis

There are no pathognomonic clinical signs for tuberous sclerosis. Many signs are present in individuals who are healthy (although rarely), or who have another disease. A combination of signs, classified as major or minor, is required in order to establish a clinical diagnosis.

In infants, the first clue is often the presence of seizures, delayed development or white patches on the skin. A full clinical diagnosis involves

• Taking a personal and family history.
• Examining the skin under a Wood's lamp (hypomelanotic macules), the fingers and toes (ungual fibroma), the face (angiofibromas) and the mouth (dental pits and gingival fibromas).
• Cranial imaging with non enhanced CT or, preferably, MRI (cortical tubers and subependymal nodules).
• Renal ultrasound (angiomyolipoma or cysts).
• An echocardiogram in infants (rhabdomyoma).
• Fundoscopy (retinal nodular hamartomas or achromic patch).

The various signs are then marked against the diagnostic criteria to produce a level of diagnostic certainty:

• Definite – Either two major features or one major feature plus two minor features.
• Probable – One major plus one minor feature.
• Suspect – Either one major feature or two or more minor features.

Due to the wide variety of mutations leading to TSC, there are no simple genetic tests available to identify new cases. Nor are there any biochemical markers for the gene defects. However, once a person has been clinically diagnosed, the genetic mutation can usually be found. The search is time-consuming and has a 15% failure rate, which is thought to be due to somatic mosaicism. If successful, this information can be used to identify affected family members, including prenatal diagnosis. As of 2006, preimplantation diagnosis is not widely available.

Management

Drug therapy for some of the manifestations of TSC is currently in the developmental stage. For example, a 2008 study found that treatment with rapamycin rescued learning and memory deficits in a mouse model of tuberous sclerosis. Community TSC is a distributed computing project to find drugs to treat TSC. The patients usually have relapse of symptoms in the clinical course. Unless any vital function is affected, life expectancy is good. Majority of patients will require some medications to control symptoms, e.g., anti-epileptics to control seizures.

Prognosis

The prognosis for individuals with TSC depends on the severity of symptoms, which range from mild skin abnormalities to varying degrees of learning disabilities and epilepsy to severe mental retardation, uncontrollable seizures, and kidney failure. Those individuals with mild symptoms generally do well and live long productive lives, while individuals with the more severe form may have serious disabilities. However, with appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.

Leading causes of death include renal disease, brain tumour, lymphangiomyomatosis of the lung, and status epilepticus or bronchopneumonia in those with severe mental handicap. Cardiac failure due to rhabdomyomas is a risk in the fetus or neonate, but is rarely a problem subsequently. Kidney complications such as angiomyolipoma (AML) and cysts are common, and more frequent in females than males and in TSC2 than TSC1. Renal cell carcinoma is uncommon. Lymphangioleiomyomatosis (LAM) is only a risk for females with AMLs. In the brain, the subependymal nodules occasionally degenerate to subependymal giant cell astrocytomas (SEGA). These may block the circulation of cerebrospinal fluid around the brain, leading to hydrocephalus.

Detection of the disease should prompt one for genetic counselling. It is also important to know that even though the disease does not have a cure, symptoms can be treated symptomatically. Hence, awareness regarding different organ manifestations of tuberous sclerosis is important.