TUBEROUS SCLEROSIS
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| TUBEROUS SCLEROSIS |
Tuberous sclerosis (Bourneville’s syndrome) is a multisystem disease that often manifests with cutaneous findings. It is inherited in an autosomal dominant manner and is directly caused by a defect in one of two genes, TSC1 or TSC2, usually due to a spontaneous mutation. TSC1 has been shown to encode the hamartin protein, whereas TSC2 gene encodes the tuberin protein. The skin, central nervous system (CNS), cardiovascular, respiratory, visual, and musculoskeletal systems are affected. This genodermatosis has an extremely variable phenotype. At one extreme is the severely disabled and mentally delayed individual with severe seizure disorders; at the other end of the spectrum is the individual with mild skin disease and unappreciable CNS disease.
Clinical Findings: The incidence of tuberous sclerosis is approximately 1 in 15,000, and the disease affects all races and genders equally. Infants and young children may present with primary CNS disease with the onset of seizures. All children with new-onset seizures should be evaluated for the cutaneous findings of tuberous sclerosis; if these are located, the child should be further evaluated for the possibility of this diagnosis. Mental delay may be noticeable, because the child may not meet normal developmental milestones. Other brain anomalies have been reported to occur in tuberous sclerosis, including astrocytomas, hydrocephalus, cortical tubers, and subependymal tumors. Cardiac rhabdomyomas may manifest with a murmur and are best evaluated with the use of an echocardiogram. The lungs are rarely involved with lymphangiomyomatosis. Cutaneous findings are often the earliest findings of the disease, even before the onset of CNS disease. The “ash leaf” macule is the first cutaneous finding; it is represented by a hypopigmented to depigmented macule in the shape of an ash leaf. Other hypopigmented macules are prominent components of tuberous sclerosis and include “confetti” macules and polygonal hypopigmented macules. The isolated finding of a hypopigmented macule in infants should make one consider and evaluate for the diagnosis of tuberous sclerosis. Approximately 0.25% of normal newborns have a hypopigmented macule with no other evidence of tuberous sclerosis.
Connective
tissue nevi are frequently seen in this disease and can manifest as small
plaques or dermal nodules. These nevi have been termed “shagreen patches.” Skin
biopsies are required to diagnose a connective tissue nevus. Koenen tumors, a
type of periungual fibroma, are a feature of the disease and can be seen on a
solitary digit or on multiple digits of the hands and feet. Café-au-lait
macules are occasionally seen. At puberty or slightly before, the presence of
facial angiofibromas may become noticeable. These facial tumors tend to
increase in size and number over time. They cause significant morbidity and
psychological harm to the affected individual. These angiofibromas have been
given the name adenoma sebaceum, and in some cases they are the initial
sign of the disease. They are frequently misdiagnosed as early acne, and only
after lack of response to therapy or referral to a dermatologist are they
accurately identified. These facial growths cause significant disfigurement,
and many individuals seek therapy to lessen the appearance of these tumors.
Pathogenesis: When defective, hamartin and tuberin have been shown
to cause tuberous sclerosis. They are both tumor suppressor proteins that
function by interacting with a G protein. This interaction inhibits the
so-called mammalian target of rapamycin (mTOR) signaling pathway. When
these proteins are mutated, the inhibition is removed, and the mTOR pathway is
allowed to signal uncontrolled. This leads to unregulated cell division and the
production of various tumors. Treatment: Therapy needs to be
individualized for each patient. Those with seizure disorders and CNS tumors
require the expertise of a neurologist or neurosurgeon or both. Antiseizure
medications are frequently required for prolonged periods. Routine
ophthalmological examinations should be recommended to evaluate for the
possibility of retinal astrocytic hamartomas (phakomas). Facial angiofibromas
can be surgically removed by many means. Laser vaporization and more
traditional surgical methods have been used to remove or lessen the appearance
of these tumors. No therapy is required for the hypopigmented macules or the
connective tissue nevi. All patients should be monitored routinely by their
pediatrician for evaluation of developmental milestones and physical examinations.
