TUBEROUS SCLEROSIS

By Gary M. White, MD

Tuberous sclerosis; adenoma sebaceum Multiple facial angiofibromas--the old term being adenoma sebaceum.


Tuberous sclerosis (TS) is a neurocutaneous disorder that is characterized by skin lesions, mental retardation, and seizures. TS is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin respectively. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation. About one-third of cases are familial with AD inheritance. The remaining two-thirds are sporadic (the patient is born with a new mutation).

See also ash leaf macule, Koenen's tumor and shagreen patch.

Age of Onset

Feature Age of Onset
Ash leaf macule Majority present at birth but may appear at 1-2 months of age.
Facial angiofibromas May start as early as 2 years of age. Usually apparent by 3-4 years of age
Koenen's tumor Late childhood
Shagreen patch Sometime in the first decade of life.

Workup for the patient with multiple facial angiofibromas

Multiple facial angiofibromas can no longer be considered pathognomonic for tuberous sclerosis. They occur in approximately half of patients with MEN 1. They may also occur as an isolated finding [Am J Med Genet A. 2010].

Clinical

The first manifestation of TS typically is the ash leaf spot which appears as a hypopigmented (but not depigmented) spot on the young child. The majority are present at birth, but they may occur by one or two months of age. Eighty percent to 95% of patients with TS develop ash leaf spots.

In the preteen years, multiple papules develop on the face--the new term being angiofibromas (old term being adenoma sebaceum). It may be confused initially with acne. Eighty percent of TS patients develop facial angiofibromas which may start as early as two years of age. They are usually evident to some degree by 3-4 years of age.

The shagreen patch is a skin-colored leathery plaque with prominent follicular openings resembling orange peel, usually located in the lumbosacral area.

The forehead plaque presents as a slowly growing, firm, elevated and yellow-brown to skin-colored plaque on the forehead with similar histopathology as facial angiofibromas. Various reviews have found them in 2.5-55.5% of patients with TS.

Periungual fibromas, AKA Koenen's tumor, start appearing in late childhood as firm, smooth, flesh-colored tumors arising in the periungual area. They may cause a variety of nail dystrophies.

Other cutaneous findings that may occur in TS include café au lait macules, molluscum fibrosum pendulum, a forehead fibrous plaque, nevus anemicus, [JAMA Derm 2016;152;217 ]and confetti-like hypopigmented macules. Widespread angiokeratomas have been reported in TS [BJD 1996;135;280]. Dental enamel pits may occur.

Folliculocystic and collagen hamartoma is a newly lesion associated with TS characterized by abundant collagen deposition, concentric perifollicular fibrosis, and keratin-filled infundibular cysts that are visible on histopathological examination. It has however, been reported unassociated with TS [Ann Dermatol. 2015 Oct;27(5):593-6].

Systemic Associations

Seizures occur in over 90% of children with TS--75% occurring in the first year of life. Other systemic manifestations include tooth pits, cardiac rhabdomyomas, seizures, cortical or cerebral tubers, CNS tumors (e.g., giant cell astrocytoma, ependymoma, meningioma), pulmonary lymphangiomyomatosis, renal angiomyolipomas, renal cysts, and retinal astrocytomas.

Patients with TS may present early in childhood with supraventricular tachycardia or other arrhythmias secondary to cardiac rhabdomyomas. All infants diagnosed with TS should have an electrocardiogram. Sudden death may rarely occur in TS and one study found the main factors to be cardiac arrhythmia, epilepsy, and intratumoral hemorrhage with additional complications including cardiac outflow obstruction, obstructive hydrocephalus, aneurysm rupture, and spontaneous pneumothorax.

Treatment

Treatment should be multidisciplinary involving pediatric neurologists, nephrologists, and cardiologists as indicated. All infants with TS should have an EKG to exclude Wolff-Parkinson-White syndrome. Referral to a nephrologist is important because of the frequent association with renal angiomyolipomas, renal cysts, and occasionally renal malignancy. Renal ultrasound is usually done initially and every 1-3 years. mTOR inhibitors (e.g., rapamycin, everolimus) are beneficial in various facets of TS, including subependymal giant cell astrocytomas, renal angiomyolipomas, and facial angiofibromas.

Facial Angiofibromas

Topical rapamycin (AKA sirolimus) has been shown effective for adenoma sebaceum [J Eur Acad Dermatol Venereol 2015;29:14-20]. A wide range of concentrations have been used, e.g., 0.003%-1%, given BID. Ointments, creams, and gels have been compounded, but the simplest is to give the standard oral solution (1 mg/ml) for use topically with the clear warning not to be taken internally. If irritation is a problem, Aquaphor or Vaseline may be applied once the solution dries. It appears that the earlier treatment is initiated, the better. Topical rapamycin is well tolerated with only infrequent local adverse side effects observed. In another study [JAMA Derm 2017;153;39] compared with placebo, twice-daily treatment with sirolimus gel for 12 weeks significantly decreased the size and redness of angiofibromas in all groups of patients receiving 0.2% sirolimus gel, as well as in children receiving gel with 0.1% or 0.05% sirolimus.

Topical everolimus has been investigated as well. Laser has also been used. Individual larger lesions may be shaved. In a case report [Pediatrics 2015;Aug 24], topical timolol 0.5% gel BID applied unilaterally for 2 weeks before and starting 5 days after laser ablative surgery markedly reduced erythema as well as the number and size of angiofibromas compared to the untreated side.

Oral rapamycin (sirolimus) when given for systemic conditions, most commonly lymphangioleiomyomatosis of the lungs, has been shown to reduce angiofibromas on the order of 25-50%. Shagreen patches and ungual fibromas respond less well. There was no loss of improvement in the angiofibromas after treatment cessation [JAAD 2015;73;802]. At the current time, oral rapamycin for cutaneous fibromas only (and not systemic manifestations) is not recommended.

Additional Pictures

Adenoma Sebaceum
Tuberous sclerosis: adenoma sebaceum Tuberous sclerosis; adenoma sebaceum

Ash Leaf Macules
Tuberous sclerosis with ash leaf macules Tuberous sclerosis with ash leaf macules

Koenen's Tumor
Tuberous sclerosis with a Koenen's tumor

Shagreen patch
Shagreen patch

Forehead Fibrous Plaque (First Courtesy O. Dale Collins, MD)
Forehead Fibrous Plaque Forehead Fibrous Plaque

References

Giant angiofibromas. JAAD December 2012 Volume 67, Issue 6, Pages 1319–1326

Folliculocystic and collagen hamartoma. J Am Acad Dermatology Volume 66, Issue 4, Pages 617–621, April 2012

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