Pink papules on the fingers and toes

The diagnosis of tuberous sclerosis complex (TSC) can be readily made in the patient described in this case based simply on his cutaneous findings. TSC is a genetic neurocutaneous syndrome that is manifested by the development of hamartomas in multiple...

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The diagnosis of tuberous sclerosis complex (TSC) can be readily made in the patient described in this case based simply on his cutaneous findings. TSC is a genetic neurocutaneous syndrome that is manifested by the development of hamartomas in multiple organs, particularly the skin, brain, retina, lungs, kidneys, and heart.^1,2

The diagnostic criteria for TSC were revised at the 2012 TSC Consensus Conference.² The clinical criteria are divided into two categories: major features and minor features.² The major clinical criteria include hypomelanotic macules, facial angiofibromas or fibrous cephalic plaque, ungual fibromas, shagreen patch, retinal nodular hamartomas, cortical dysplasias, subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangiomyomatosis, and renal angiomyolipoma.

Minor features include confetti skin lesions, dental enamel pits, intraoral fibromas, retinal achromic patch, renal cysts, and nonrenal hamartomas.² A definitive diagnosis of TSC can be made when a patient has two major features, or has one major and two minor features, or has an identified genetic mutation, regardless of clinical features.²

The man in this case exhibited several of the major cutaneous features of TSC: The digital lesions he complained about were ungual fibromas; the papules on his face were angiofibromas; the textured plaque was a shagreen patch; and of the hypopigmented patches, the larger finger-shaped lesion was identified as an “ash leaf macule.”

This ash leaf macule, often present at birth, occurs in more than 90% of patients with TSC and is best visualized with a Wood’s lamp. Angiofibromas, also referred to as adenoma sebaceum, affect approximately 75% of patients with TSC but typically do not develop until after age 2 years. The shagreen patch is a connective-tissue hamartoma with an orange-peel-like texture and usually develops in the first decade of life. Although present in 50% of patients with TSC, the shagreen patch can be seen alone or in other syndromes as well.^1,2

Ungual fibromas are also referred to as Koenen tumors.¹ Present in approximately 20% of all patients with TSC, these fibromas typically begin around puberty, grow in number and size throughout life,^1,2 and can be found in up to 80% of older adult patients.² Lesions are more common on toes than on fingers,1 and women more commonly affected than men.³

Although characteristic skin lesions of TSC were reported as early as 1835, the facial lesions were not called adenoma sebaceum until 1890.⁴ Von Recklinghausen was first to note brain involvement in 1862,^1,2 yet, Bourneville is credited with naming the syndrome in 1880 by describing the pathology of the cortex as “sclérose tubéreuse des circonvolutions cérébrales.”^1,4 At the beginning of the 20th century, a relationship between the cutaneous and cerebral manifestations was realized when Vogt described the triad of epilepsy, developmental delay, and angiofibroma.^1,4 Epidemiologic data have subsequently revealed that this triad occurs in only 29% of patients and that 6% of individuals have none of these entities.¹ A complete description of the clinical findings of TSC was not published until 1979.⁴ The genetic abnormalities were eventually discovered in the 1990s.¹

A mutation in one of two genes—TSC1 on chromosome 9 or TSC2 on chromosome 16—can result in the development of TSC. ¹ TSC1 and TSC2 encode for hamartin and tuberin, respectively, which interact to form a tumor suppressor heterodimer that inhibits the mammalian target of rapamycin (mTOR), an important regulator of cell proliferation.¹ A defect in either protein prevents the inhibition of mTOR, allowing unregulated cellular proliferation.

TSC occurs in approximately 1 in 10,000 live births. Although the condition has an autosomal dominant inheritance, two-thirds of cases are sporadic.¹ Sporadic cases are more likely to be associated with a TSC2 defect and have more severe disease.¹ Multiple alleles of TSC1 and TSC2 exist, possibly explaining the widely variable clinical presentations of TSC.¹ Before genetic testing was commercially available, the definitive diagnosis of TSC was delayed until an average age of 5 years because of the paucity of clinical criteria.¹

The differential diagnosis of a Koenen tumor comprises a variety of subungual or periungual growths, including a pyogenic granuloma, verruca vulgaris, keratoacanthoma, subungal exostosis, and acquired periungual fibrokeratoma.

In contrast to Koenen tumors, acquired periungual fibrokeratomas more commonly appear on the fingers than on the toes and frequently develop following trauma.^5,6 Interestingly, the authors from one study suggested the non-random distribution of ungual fibromas in TSC is evidence that trauma may have a role in their development as well.⁷ However, when a multitude of lesions are present, the diagnosis is more likely TSC; two or more lesions must be present in order to qualify as a major diagnostic feature for TSC.²

Histology can further help distinguish an acquired periungual fibrokeratoma from a Koenen tumor.⁶ Whereas both conditions can be characterized by abundant dermal collagen with capillaries and an acanthotic and hyerkeratotic epidermis, the presence of atypical stellate fibroblasts distinguishes Koenen tumors from acquired periungual fibrokeratomas.^3,5-7

Treatment of TSC is site-specific and symptom-specific. Surgical excision is currently the therapeutic mainstay for ungual fibromas, but there is a high recurrence rate.^5,8 Other modes of removal and destruction have been tried. Berlin et al. reported a successful cosmetic and therapeutic outcome in one patient treated with a continuous CO2 laser, with no recurrence at 11 months.⁸ Another study showed superior conservation of the proximal nail fold and nail plate integrity through shave excision of multiple lesions with subsequent phenolization, reporting no recurrence at six months.⁹

A new agent may have promise for patients with TSC. Sirolimus (Rapamune), also known as rapamycin, is a medication commonly used in the solid-organ transplant recipient. An inhibitor of mTOR, sirolumus is being investigated as a treatment option for various hamartomas of TSC.^1,10 Initial reports suggest that topical sirolimus may be effective for facial angiofibromas.¹⁰

The use of sirolimus was discussed with the patient in this case. Unfortunately the man’s insurance would not cover the cost, and he opted for surgical removal of the most symptomatic lesions instead. The man was also referred to a primary-care clinician for evaluation for other stigmata of TSC.

Ms. Braswell is a third-year student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Dr. Nunley is a professor of dermatology.