A 6-year-old patient presents with lesions on his forehead and face. His mother reports he has a history of seizures.
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Tuberous sclerosis (TS) is a rare autosomal dominant genetic disease characterized by seizures, mental retardation and skin findings, including hypopigmented macules, facial angiofibromas and fibrous plaques.
The mutations occur in TSC1 and TSC2 genes, which code for the proteins hamartin and tuberin, respectively. Although it’s an autosomal dominant disorder, up to 75% of cases are due to new spontaneous mutations. Other important clinical manifestations of TS include gingival fibromas, dental enamel pits and hamartomas, which can be found in the eye, brain, kidneys, heart and lungs.
Cutaneous lesions are often the initial clinical feature. As a result, dermatologists routinely assist in the diagnosis of TS. Hypopigmented macules affect 90% to 100% of TS patients, and are present at birth or within the first few months of life.
Facial angiofibromas are red-to-pink papules with a smooth surface, symmetrically distributed over the centrofacial areas that spare the upper lips. They start to appear at age 2 years, and affect approximately 80% of patients with TS by adolescence.
Fibrous plaques of the forehead, present in about 20% of TS cases, are yellow-to-brown or skin-colored plaques of variable size and shape, usually located on the forehead or scalp. They are common at any age and can be seen at birth.
A shagreen patch, a form of collagenoma present in 40% to 50% of TS cases, is a slightly elevated patch or plaque that typically begins to develop around 2 years of age. The rough surface resembles an orange peel and occurs in the lumbosacral area.
Periungual fibromas affect approximately 30% to 60% of patients with TS, begin to develop later in childhood and continue to form throughout adulthood. These commonly occur around the toenails, more so than the fingernails, and can lead to nail plate distortion without a visible tumor.
This patient exhibited the fibrous plaque on the forehead and angiofibromas on the nose and cheeks characteristic of TS.
Tuberous sclerosis diagnosis is broken into three categories:
- Possible TS – presence of one major feature or two or more minor features
- Probable TS – presence of one major plus one minor feature
- Definite TS – presence of either two major features or one major feature accompanied by two minor features
Major features include:
- Facial angiofibromas or forehead plaque
- Ungual or periungual fibroma
- More than three hypomelanotic macules
- Shagreen patch
- Multiple retinal nodular hamartomas
- Cortical tuber
- Subependymal nodule
- Subependymal giant cell astrocytoma
- Single or multiple cardiac rhabdomyoma
- Renal angiomyolipoma
Minor Features are as follows:
- Multiple randomly distributed pits in dental enamel
- Hamartomatous rectal polyps
- Bone cysts
- Cerebral white matter migration lines
- Gingival fibromas
- Non-renal hamartomas
- Retinal achromic patch
- “Confetti” skin lesions
- Multiple renal cysts
Treatment & Prognosis
There is no cure for TS, but there are treatments for many of its symptoms. Antiepileptic drugs can control seizures, psychiatric medications are used for behavior problems and intervention programs can help individuals with special needs and developmental issues.
Sirolimus, as well as its derivative everolimus, are mTOR inhibitors that can be used to treat subependymal giant cell astrocytoma (SEGA) brain tumors and renal angiomyolipomas. Surgery may be needed due to complications from tubers or SEGA, and hemorrhage from angiomyolipomas.
Respiratory insufficiency due to lymphangioleiomyomatosis (LAM) can be treated with supplemental oxygen therapy or lung transplantation, if severe.
Because TSC is a lifelong condition, individuals need to be monitored regularly to make sure they are receiving appropriate screening and treatment. Neurodevelopmental and behavioral evaluations are performed for newly diagnosed patients and as needed for educational/behavioral concerns for follow-up patients.
Other exams that are done include ophthalmologic examination as needed, cranial CT and MRI every one to three years during childhood and adolescence.
If a patient has a history of seizures consider electroencephalography. For those with cardiac symptoms, ECG abnormalities, and/or age <5 years, electrocardiogram or echocardiogram can be performed. Renal ultrasound can detect polycystic kidney disease and angiomyolipomas every one to three years, if there is no history of renal lesions, or twice yearly if there are known angiomyolipomas. Adult women should undergo chest computed tomography to screen for LAM, and thereafter if they develop pulmonary symptoms.
The prognosis for individuals with TS is variable and depends on the severity of symptoms. Individuals with mild symptoms usually do well and have a normal life expectancy, whereas those with severe symptoms may develop severe mental retardation and persistent epilepsy.
Regardless of severity, all individuals with TS are at risk for life-threatening conditions related to brain tumors, kidney lesions or LAM. Hence, continued monitoring by a physician experienced with TS is important. With appropriate medical care, most individuals with the disorder can look forward to normal life expectancy.
Nelly Song, BS, is a senior medical student at the University of Texas Medical School in Houston.
Adam Rees, MD, is a graduate of the University of California Los Angeles School of Medicine and a resident in the Department of Dermatology at Baylor College of Medicine also in Houston.
- Bolognia J, Jorizzo JL, Schaffer JV. “Chapter 110: Cysts.” Dermatology. St. Louis: Mosby/Elsevier, 2008.
- National Institute of Neurological Disorders and Stroke. “Tuberous Sclerosis Fact Sheet.” Available at: www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm
- Hake S. “Cutaneous Manifestations of Tuberous.” Ochsner J. 2010; 10(3): 200-204.