Overview of tuberous sclerosis
Tuberous sclerosis is an autosomal dominant disease that involves multiple organ systems and is characterized by skin lesions, seizures, and mental retardation, with a combination of pharmacologic and surgical treatments in disseminated cases.
Definition
Tuberous sclerosis is a rare autosomal dominant disease involving multiple organ systems [1].
Typical clinical manifestations are skin damage, seizures, and mental retardation [2].
Tuberous sclerosis may also manifest as damage to other organs and tissues such as retina, teeth, heart, liver, kidney, and lungs.
Morbidity
The incidence is 1/10,000 to 1/6,000 in neonates and about 1/8,000 in adults [1].
Some of the clinical manifestations of tuberous sclerosis are gender and age related [1].
Rarely, facial hemangiofibromas and fingernail fibromas are seen in infancy.
Cardiac rhabdomyosarcomas rarely remain clinically symptomatic beyond the neonatal period.
Renal vascular smooth muscle lipomas can be detected by abdominal imaging in approximately 80% of patients over the age of 10 years, but clinical symptoms often do not appear until adolescence or adulthood.
Pulmonary symptoms tend to appear in adulthood and are significantly more common in females than in males, with approximately 80% of female patients presenting with pulmonary lymphangioleiomyomatosis by the age of 40 years.
Causes
Causes
Tuberous sclerosis is an autosomal dominant disorder.
Commonly mutated genes include the TSC1 gene on chromosome 9q34 and the TSC2 gene on chromosome 16p13.3, with TSC2 mutations being more common [3]. No causative gene is found in about 10% of patients.
Predisposing factors
The disease is hereditary with no clear predisposing factors.
Risk factors
The disease tends to develop in children and adolescents with a family history of the disease.
Pathogenesis
Rapamycin targeting protein (mTOR) exists in mammals and has the function of regulating gene transcription and protein synthesis, modulating cell cycle, apoptosis and autophagy. It plays an important regulatory role in cell metabolism, proliferation and cytoskeletal movement, and has anti-tumor effects [4-5].
The TSC gene belongs to oncogenes, and mutations in the TSC1 and TSC2 genes lead to overactivation of the targets of the rapamycin pathway and abnormal cell differentiation and proliferation, resulting in benign tumors such as subventricular nodules, cortical misshapen tumors, retinal misshapen tumors, and cardiac rhabdomyosarcomas or misshapen tumors.
The common types of TSC1 gene mutations are nonsense mutations and code-shifting mutations, while TSC2 gene mutations are mostly missense mutations, segment deletions or duplications.
Symptoms
The disease usually develops in infancy, childhood or adolescence, and in a few cases may also start in middle age, and is characterized by neurological and skin damage, but also retinal, oral, renal, pulmonary and cardiac lesions [6]. Compared with TSC1, TSC2 has a greater number of intracerebral nodules, more severe damage to various systems, and more prominent intellectual disability.
Neurologic damage
More than 80% of patients exhibit symptoms of epileptic seizures, which may manifest as infantile spasms in infancy, showing characteristic myoclonic seizures, and in children and adults, often as epileptic generalized tonic clonic seizures and complex partial seizures.
Myoclonic seizures are characterized by a sudden, rapid, forceful jerking of a part of the limb.
Generalized tonic clonic seizures are characterized by sudden loss of consciousness, sudden collapse, body stiffness, limb convulsions, which may be accompanied by screaming, eye rolling, purple lips, foaming at the mouth, tongue biting, urinary and fecal incontinence, etc., and then enter into clonic phase after tens of seconds, and then gradually regain consciousness in a few minutes, and the process of the seizure can not be recalled.
Complex partial seizures are characterized by impaired consciousness or impaired consciousness accompanied by repeated lip smacking, pouting, chewing, licking teeth, swallowing, repeated rubbing of hands, undressing, unbuttoning and other actions.
The younger the age at which the seizure occurs, the more likely the patient is to have mental retardation, diminished intelligence, accompanied by emotional instability, childish behavior, and impulsivity.
Epileptogenic foci are mostly located in or adjacent to focal dysplastic cortex, which is resistant to antiepileptic drugs, and most of them require surgical resection of the foci.
Skin damage
Depigmented spots, or leukoplakia, are the earliest skin changes, present at birth, distributed on the trunk and limbs, oval in shape, and ranging from a few millimeters to several centimeters.
Most children develop angiofibromas after the age of 4 years, mainly in the nasolabial folds, cheeks, and chin, which appear as a smooth, waxy, pink or light brown rash, known as facial sebaceous adenomas.
After the age of 10 years, some children may develop shark’s leather spots, which are slightly elevated above the normal skin, with localized thickening and roughness of the skin, and are grayish-brown or slightly brownish plaques.
Cardiac lesions
Cardiac rhabdomyomas are an early and common clinical manifestation of tuberous sclerosis and can be detected by fetal ultrasound at 20 to 30 weeks of gestation; multiple cardiac rhabdomyomas are almost 100% suggestive of tuberous sclerosis. It usually resolves within 3 years after birth, mostly within 1 year, without accompanying sequelae.
Heart failure or arrhythmias can be present if the tumor does not disappear and obstructs the large blood vessels or abnormal blood flow in the cardiac chambers, and occasionally cardiac rhabdomyomas have led to cerebral embolism in patients [7].
Pulmonary lesions
They manifest as exertional dyspnea, spontaneous pneumothorax, enlarged thoracic lymph nodes, cough and hemoptysis, and spontaneous pneumothorax may trigger acute pulmonary dysfunction.
Lesions in other parts of the body
Renal lesions: renal vascular smooth muscle tumors, renal cysts and rare renal cell carcinomas may occur.
Ocular lesions: Gray or yellow lens tumors may be seen in the retina or optic nerve. Most are benign and asymptomatic, but occasionally patients may experience acute vision loss following retinal detachment or vitreous hemorrhage.
Oral lesions: These include enamel pits and fibromas of the gingiva, buccal mucosa, and labial mucosa.
Others include perineural fibromas, and misshapen rectal polyps.
Consultation
Where to go
Depending on the appearance of the symptoms, different departments may be consulted.
Neurology
Neurology may be consulted if neurological symptoms such as epilepsy are present.
Neurosurgery
If epilepsy has not been treated conservatively by internal medicine and requires surgical treatment, you can consult the neurosurgery department.
Dermatology
If you have any of the above mentioned skin lesions, you may consult the Department of Dermatology.
Pediatrics
Patients with infants, children, and young children may consult the Department of Pediatrics.
Other Departments
In case of other organ damage, consult the appropriate department, such as stomatology, respiratory medicine and ophthalmology.
Preparation
Preparation for consultation: registration, preparation of documents, common problems
Tips for medical treatment
Family members should accompany you to the hospital to avoid inaccurate description of your medical history.
Preparation List
Symptom list
Pay special attention to the time of onset of symptoms, special manifestations, etc.
Is there any sudden loss of consciousness, sudden collapse?
Is there any hardening of the body, twitching of the limbs, accompanied by screaming and rolling of the eyes?
Are there purple lips, foaming at the mouth, tongue bite, incontinence, etc.?
Is there any repeated smacking, pouting, chewing, licking teeth, swallowing, rubbing hands, undressing, unbuttoning, etc.?
Is there a sudden cessation of ongoing activities, with something like a brief freeze?
Is there any involuntary rapid twitching of the eyelids or other parts of the body?
Is there any intellectual deterioration, emotional instability, childish behavior, impulsivity, etc.?
Are there any facial white spots, localized thickening and roughness of the skin and pink, grayish-brown or light brown rashes or plaques?
Has there been heart failure or arrhythmia since birth?
Is there exertional dyspnea, spontaneous pneumothorax, cough and hemoptysis?
Are there any intraoral enamel pits, intraoral gingival, buccal mucosal and labial mucosal fibromas?
List of medical history
Is there a family history of tuberous sclerosis?
Any past history of recurrent seizures and convulsions?
Checklist
Test results from the last six months, which can be brought to the doctor’s appointment
Electroencephalogram (EEG), electrocardiogram (ECG)
Chest CT, head CT, head MRI.
Cardiac ultrasound, liver and kidney ultrasound
Other tests: blood routine, liver and kidney function, etc.
Medication List
Medications used in the last 3 months, if available in boxes or packages, carry them to the doctor’s office
Antiepileptic drugs: aminocaproic acid, topiramate, lamotrigine, adrenocorticotropic hormone, prednisolone [8].
Target protein inhibitors of the rapamycin system: paromomycin, sirolimus, everolimus, etc.
Other medications recently being taken orally.
Diagnosis
Diagnosis is based on
Medical history.
Past history of recurrent seizures.
Family history of patients who may have similar clinical presentations or who have been diagnosed with tuberous sclerosis.
Symptoms
The disease usually develops in infancy, childhood, or adolescence, and in a few cases may begin in middle age.
Various types of seizures, mental retardation, and diminished intelligence are accompanied by emotional instability, childish behavior, and impulsivity.
Multiple pigmentation defects, skin lesions, angiofibromas, shark leather spots on the face, trunk and limbs.
A few patients may present with exertional dyspnea, spontaneous pneumothorax, cough and hemoptysis.
Fibromas are seen in the oral cavity in enamel pits and gingiva, buccal and labial mucosa.
Physical examination
The doctor may carefully examine the skin of the patient’s head and face for angiofibromas, etc.
The doctor may ask the patient to expose the skin of the trunk and limbs to check for skin depigmentation spots, etc.
The doctor may ask the patient to do some simple cognitive function tests to see if there are any developmental delays.
The doctor may examine the patient’s mouth for enamel pits and fibromas of the gums and oral mucosa.
Screening Tests
Laboratory Tests
These include routine blood tests, liver and kidney function, coagulation, and blood electrolyte measurements.
The purpose is to assess the physical condition, as well as to make a preoperative evaluation for any surgical treatment that may be required.
Electroencephalography
An electroencephalogram (EEG) may reveal abnormal electrical waves in and around the lesion area.
Video EEG or intermittent flash stimulation-induced EEG may also be done when the condition warrants.
Genetic testing
Genetic testing is important in the diagnosis of the disease.
Pathogenic mutations in the TSC1 or TSC2 genes can be detected by genetic testing to make a definitive diagnosis of tuberous sclerosis.
Sonography/Imaging
Cranial CT or cranial MRI can detect the presence of subventricular giant cell astrocytomas, nodules and calcifications in the cortex, as well as angiodysplastic tumors [9].
Cardiac ultrasound can detect cardiac rhabdomyomas, and liver and kidney ultrasound can detect renal cysts, angiomyolipomas, and liver lesions.
Precautions: CT has a certain degree of radiation, children and pregnant women need to be cautious of the examination; before MRI examination, if there are metal dentures, cardiac stents and other metal implants in the body, consult the doctor whether the examination can be carried out.
Electrocardiogram
Electrocardiogram (ECG) examination can find out whether there is any cardiac arrhythmia.
Diagnostic criteria
The disease is mainly based on the International Consensus Conference on Tuberous Sclerosis diagnostic criteria [10]:
Genetic diagnostic criteria
A definitive diagnosis of tuberous sclerosis can be made by genetic testing that reveals pathogenic mutations in the TSC1 or TSC2 genes.
Clinical diagnostic criteria
Main features
Pigment loss spots (≥3, diameter ≥5 mm).
Angiofibromas of the face (≥3) or fibrous plaques of the head.
Fingernail fibromas (≥2).
“Sharkskin-like spots.
Multiple retinal nodular malformations.
Cortical dysplasia (including cortical nodules and white matter radial migration lines).
Subventricular nodules.
Subventricular giant cell astrocytoma (SEGA).
Cardiac rhabdomyosarcoma.
Pulmonary lymphangioleiomyomatosis.
Renal vascular smooth muscle lipoma.
Secondary features:
Includes “blotchy” skin lesions.
Punctate depressions of enamel (>3).
Intraoral fibromas (≥2).
Retinal depigmentation spots.
Multiple bone cysts.
Non-renal malignant tumors.
Diagnostic level
Suspected tuberous sclerosis
Possession of 1 major feature, or 2 minor features.
Definitive tuberous sclerosis
Possession of 2 major features, or possession of l major feature and 2 minor features.
When only pulmonary lymphangioleiomyomatosis and renal angiomyolipoma are present as primary features, other features are needed to diagnose tuberous sclerosis.
Differential diagnosis
Vitiligo
Similarities: Vitiligo can also be characterized by loss of skin pigmentation, i.e., leukoplakia.
Differences: Nodular sclerosis is usually associated with seizures, mental retardation, and abnormalities seen on ancillary tests such as electroencephalogram, cranial CT or MRI.
Primary Epilepsy
Similarity: Primary epilepsy can also present with myoclonic seizures, generalized tonic clonic seizures and complex partial seizures, which require differential diagnosis.
Differences: In addition to seizures, tuberous sclerosis may present with multi-organ tissue lesions of the skin, heart, kidneys, and eyes.
Cardiac rhabdomyosarcoma
Similarities: Cardiac rhabdomyosarcoma is a rare primary tumor of the heart, whereas patients with tuberous sclerosis can also present with cardiac rhabdomyosarcoma and need to be differentiated.
Differences: Patients with tuberous sclerosis usually have symptoms such as white spots forming on the skin and seizures, while primary cardiac rhabdomyosarcoma does not have these symptoms.
Treatment
Aim of treatment: symptomatic treatment to improve the quality of life.
Principle of treatment: Combination of drug treatment and surgical treatment.
Drug therapy
Specific targeting drug paromomycin mechanism target protein mTOR inhibitor: everolimus, sirolimus, etc.
Antiepileptic drugs: aminocaproic acid, topiramate, lamotrigine, adrenocorticotropic hormone, prednisolone.
Surgery
Seizures for which medication is ineffective can be treated with surgery, including resection of focal cerebral cortical lesions, corpus callosotomy, and so on.
Surgical treatment is also feasible when subventricular giant cell astrocytoma of the brain causes obstructive hydrocephalus or has a significant occupying effect surgical resection of the tumor, and ventriculoperitoneal shunt.
Questions you may be concerned about
Can everolimus control complications of tuberous sclerosis?
Everolimus is used for the treatment of renal angiomyolipoma and cerebral subventricular giant cell astrocytoma associated with tuberous sclerosis.
Nodular sclerosis is an autosomal dominant disorder with multisystemic involvement, which is characterized by symptoms such as epilepsy, mental retardation, skin leukoplakia and facial angiofibromas. Patients may also develop pulmonary cysts and lymphatic smooth muscle tumors, hepatic and renal cysts and angiomyolipomas.
Everolimus is an antineoplastic drug that treats renal angiomyolipoma and cerebral subventricular giant cell astrocytoma associated with tuberous sclerosis.
Adverse reactions such as diarrhea, cough, stomatitis, infection, pharyngitis, fever, and fatigue may occur with everolimus. It should be contraindicated in people who are allergic to its components or in pregnant women.
The use of everolimus must be regulated under the supervision of a doctor.
Prognosis
Cure
At present, symptomatic treatment is the mainstay, and there is no complete cure for tuberous sclerosis. However, active treatment can substantially improve the quality of life of patients.
Prognostic factors
Prognosis is related to the time of diagnosis and treatment initiation. The earlier the diagnosis and treatment, the better the quality of life of the patient.
Hazards
Patients’ seizures and long-term oral antiepileptic drugs can affect intellectual development, reduce quality of life, and increase social and family economic burden.
Patients often have white spots and other lesions on the skin of the face, limbs and trunk, which affect their appearance and have a significant impact on their psychological development.
A few patients will suffer from heart, liver, kidney and lung lesions leading to liver, kidney and cardiopulmonary insufficiency.
Daily
Daily management
Dietary management
Balanced nutrition, with high quality protein, low fat, low salt, low oil and high fiber diet.
Avoid spicy and stimulating, too oily food, and do not overeat.
Life management
Patients often have epileptic seizures, sudden loss of consciousness and falls, which may easily lead to trauma, and need to strengthen protective measures to prevent head and limb trauma and fracture injuries caused by falls.
Take medication regularly and do not adjust or stop medication on your own.
Psychological support
Family members should guide the patient to correctly understand the disease and establish confidence in the treatment of the disease.
When the patient has obvious anxiety and depression, seek help from medical staff for psychological counseling.
Disease monitoring
Oral targeted drugs such as everolimus need to be monitored for adverse reactions such as stomatitis, infection and dyslipidemia.
Patients taking oral antiepileptic drugs need to be monitored regularly for blood counts, liver and kidney functions, and electroencephalograms.
Infants with a family history of the disease need to be monitored for mental retardation to detect the presence of the disease as early as possible.
Cranial MRI monitoring should be performed every 1 to 3 years in asymptomatic pediatric and adolescent patients for early detection of intracranial subventricular giant cell astrocytoma [7].
If an intracardiac rhabdomyosarcoma appears prenatally or in infancy, cardiac ultrasound should be performed every 1 to 3 years until the rhabdomyosarcoma is confirmed to have regressed [7].
Prevention.
The disease is hereditary and the main method of prevention is to avoid the birth of an affected child with the causative gene.
Genetic counseling and genetic testing are recommended for family members of diagnosed patients.
Family members of diagnosed patients should undergo prenatal diagnosis before having children.