The microcomedone theory has been the cornerstone of comedogenesis.¹¹ Because comedones are central to the evolution of acne vulgaris, comedo lesions have been extensively studied in that setting, but it is not entirely implausible to propose that the pathogenetic events during comedogenesis are essentially the same, regardless of whether the final disease is seen with acne vulgaris or any of the other entities observed in the periocular region.¹¹ A comedo is essentially a disorder of the pilosebaceous unit, and this theory maintains that due to hormonal and other factors, the elemental step in comedogenesis is excessive production
of keratin.¹¹ The initial keratinizing process usually involves the superficial infundibular region of the hair follicle where follicular hyperkeratinization can plug the orifice. Those keratotic plugs later cause back pressure which may result in the development of cystic dilations, or secondary epidermal inclusion cysts in the “downstream portion of the follicle.”⁴,⁹ Of note these intrafollicular retention cysts are not just a collection of keratin, but also contain sebum and occasionally bacteria.⁴,¹¹

NC is an uncommon skin lesion characterized by the aggregation of dilated follicular orifices filled with keratinous material (comedones). There are approximately 200 reported cases in the literature, but the exact etiology is unknown.⁴,¹⁶ It is either categorized as a congenital hair follicle deformity (a hamartomatous malformation caused by an imperfect development of the folliculosebaceous unit) or as an epidermal nevus involving the hair follicle.⁴,⁶ Genetic evidence is more in favor of an adnexal hamartomatous origin because the somatic mutation that has been observed in association with NC occurs in the NEK9 gene, a gene that is believed to be involved in follicular homeostasis.⁶,¹³ The epithelial-lined invaginations which are destined to form mature terminal hairs and sebaceous glands are incapable of performing such a task, and instead accumulate a soft cornified ostial product resulting in a comedo-like plug.⁶,¹³,¹⁴ Abnormalities in FGFR2 signaling have also been implicated in comedogenesis in NC patients, as well as in the subsequent inflammation that frequently occurs with these lesions. Mouse models have demonstrated that FGFR2 is also necessary for skin and hair follicle homeostasis and in the regulation of cutaneous inflammation.¹³,¹⁷

Several theories have been put forward in trying to elucidate the etiology of FRS. Possible predisposing causes include extensive sun exposure and ultraviolet damage (UV-B, or UV-A₁), smoking, radiation therapy, and topical or systemic steroids.⁴,¹²

The exact pathogenesis of a dilated pore of Winer is controversial. Whether it represents a variant of an infundibular cyst that has ruptured with ensuing inflammation, followed by induction of scar tissue formation and fibrosis, or whether it is a true neoplasm (infundibuloma) remains to be determined.⁸,¹⁵ Nevertheless, the dilated pore of Winer is considered by some authorities to be an architecturally simpler, solitary form of NC, with a single, large dilated infundibulum filled with keratin.⁴,¹⁵

In patients with NC, half of the cases are congenital while the other half develops the disease before the age of 10 years. Acquired NC cases have rarely been reported in association with trauma, irritation, or systemic disease. Nevertheless, the clinical presentation of congenital NC may be delayed because of the benign nonprogressive nature of these lesions.²,⁴ On the other hand, FRS arises in middle-aged or elderly individuals.