What stimulates the dermis to produce a solitary fibrous papule is unknown, but the genetics of the three associated syndromes, particularly TSC, is well researched. TSC is a multisystem genetic disorder characterized by hamartoma formation in many organs, particularly the skin, brain, eyes, kidneys, and heart. This results in the classic triad of intellectual disability, seizures, and angiofibromas of the face.⁵,⁶ There are two tumor suppressor genes (TSC1 and TSC2) that are associated with the development of TSC.⁶ Although the mutations in TSC2 are more commonly spontaneous, they may be inherited from a parent in about 30% of patients, and it was calculated that any child with a TSC parent has a 50% chance of developing the condition.⁵ TSC1 encodes for hamartin, while TSC2 encodes for tuberin.⁶ Both of these molecules are physically associated in vivo, suggesting that they function in the same complex (hamartin-tuberin complex) rather than in separate pathways.²

When mutations occur in either of these genes, the function of this complex will be affected, resulting in abnormal hyperactivation of the mTOR pathway (the signal transduction pathway of the mammalian target of rapamycin), which would lead to the development of TSC.⁶ Compared to normal skin in the same individuals, abnormal mTOR pathway activation results in a 12-to 23-fold overexpression of epiregulin in areas of the skin harboring angiofibromas.⁷ Epiregulin is an epidermal growth factor that stimulates dermal/epidermal fibroblast proliferation so that they are produced at a faster rate.⁷ The vascular component of angiofibromas results from the increased expression of angiogenic factors such as vascular endothelial growth factor (VEGF).¹,⁵,⁶,⁷

MEN1 is a familial cancer syndrome with parathyroid, pancreatic, pituitary, and cutaneous findings and is caused by mutations of the MEN1 gene, which codes for the production of a protein called menin.⁸ The disease is most commonly inherited as an autosomal dominant trait in 80% of
cases, but it may also occur sporadically in the sporadic form of the disease.⁹

BHD syndrome is an uncommon autosomal dominant genetic condition first described in 1997 and is caused by a mutation of the BHD gene. Dermatologically, the syndrome is hallmarked by a triad of multiple trichodiscomas, fibrofolliculomas, or acrochordons, but solitary as well as multiple facial angiofibromas have also been reported.²,¹⁰ However, these characteristic cutaneous lesions are rarely reported in the eyelids.¹¹,¹² From a pathophysiological point of view, BHD syndrome is associated with abnormal activation of the mTOR pathway, but in contrast to TSC, suppression of the pathway rather than hyperactivation is observed. This finding is interesting and represents a paradigm shift in the understanding of the pathogenesis of genetic neoplastic diseases because there is a significant clinical overlap between BHD syndrome and TSC.³ This finding suggests that an abnormally high as well as an abnormally low level of activity within the same pathway can result in the same clinical phenotype.¹³

The solitary nonhereditary form of angiofibroma commonly involves the nose (fibrous papule) and has only been reported in the eyelids once,¹⁴ while the multiple nonhereditary type which commonly involves the penis has not been reported in the periocular region. The multiple hereditary type associated with tuberous sclerosis, and less commonly MEN1 and BHD syndrome, is the type that is more often observed in the periorbital region. Recent studies suggest that the frequency of TSC varies between 1/6000 and 1/10,000 live births.⁶,¹⁵ The prevalence of MEN1 is estimated to be between 1/10,000 and 1/100,000 individuals,¹⁶ while the incidence and prevalence of the BHD syndrome are unknown, but the consensus is that it is more common than was previously thought.¹¹

Angiofibromas often present as small skin-colored or reddish, waxy-looking, dome-shaped papules that may be single or multiple and may or may not have overlying telangiectatic vessels (Figure 49.1A-C).¹⁷ The multiple hereditary angiofibroma is the type most commonly encountered in the periocular region, but massive lesions are occasionally seen (Figure 49.1D). In patients with the TSC, the genetic disorder most commonly associated with angiofibromas, cutaneous lesions are found in 60% to 70% of patients, and angiofibromas are among the commonest types of skin lesions encountered in these patients. It is unusual to observe disease onset at birth, as it more commonly starts between the age of 3 and 10 years, but the condition usually exacerbates at puberty and then plateaus. TSC is characterized by the presence of bilateral (rarely, unilateral), firm, discrete, reddish-brown, pink, or skin-colored telangiectatic papules, which average in size between 1 and 3 mm in diameter or even larger, that are symmetrically distributed in the butterfly region of the face (cheeks and nasolabial folds), but similar lesions may be scattered in the lower eyelids (39% of TSC patients) as well as the chin.²,⁵,¹⁷,¹⁸ The lesions are numerous, conspicuous, and they may occasionally form a large cauliflower-like mass if they coalesce together.⁵ Eyelash poliosis may also be observed in TSC patients and may even be the presenting sign of the disease.¹⁸,¹⁹,²⁰