Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis.

Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.

Cutaneous Horn Presentation in Porokeratotic Eccrine Ostial and Dermal Duct Nevus. A Brief Review and Case Report.

ABSTRACT: Porokeratotic eccrine ostial and dermal duct nevus is a rare adnexal hamartoma characterized by the presence of a cornoid lamella exclusively overlying eccrine acrosyringia. Different clinical presentations have been reported in the literature. Here, we report a case of a 6-year-old girl diagnosed with porokeratotic eccrine ostial and dermal duct nevus confirmed by histopathologic study. Atypical lesions are described as whitish, warty-looking neoformations located in the anterolateral region of the right hip (cutaneous horn).

A possible role for second-hit postzygotic GJB2 mutation in porokeratotic eccrine ostial and dermal duct nevus.

Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare type of epidermal nevus involving the eccrine acrosyringia. It typically presents as asymptomatic linear keratotic papules and plaques along the lines of Blaschko and predominantly affects the extremities. This disease has recently been linked to somatic mutations within the GJB2 locus. Only four GJB2 mutations have been previously documented for PEODDN, and the underlying genetic basis remains inconclusive. Herein, we report an 18-year-old female with a hyperkeratotic plaque on the dorsa of the proximal interphalangeal joint of her right ring finger, as well as multiple small hyperkeratotic papules linearly distributed on the lateral sides of her fingers occurring since birth. Histopathological results revealed prominent parakeratotic cornoid lamella-like tiers at the opening of the eccrine secretory ducts. Whole-exome sequencing of the affected skin tissue revealed a heterozygous germline mutation and a postzygotic somatic mutation in GJB2. In summary, this study presents a case of PEODDN with compound heterozygous mutations in GJB2, which broadens the genetic spectrum of this disease entity and implies a possible role for second-hit mutations in the pathogenesis of PEODDN.

Disseminated superficial actinic porokeratosis following hydroxyurea treatment: A case report.

Porokeratosis encompass a group of acquired and familial, preneoplastic, keratinization disorders, clinically characterized by atrophic macules or patches with a peripheral keratotic rim, the cornoid lamella. Genetic background is recognized as crucial in its pathophysiology, while immunosuppression and ultraviolet radiation represent triggering factors. We report the case of a woman who developed disseminate superficial actinic porokeratosis following the intake of hydroxyurea for a polycythaemia vera. Clinical, dermoscopic and histopathology data are showed, and the role of drug as a second-hit mutation trigger is discussed.

Porokeratotic Variant of Lichen Planus.

A 44-year-old woman presented with mildly itchy, brownish-black plaques for the last 2 years. The lesions first appeared on the upper back, followed by involvement of the face and upper arms within 4-5 months. Individual lesions began as small papules that gradually evolved into small, annular, and barely palpable plaques. There were no systemic complaints, photosensitivity, or history of intake of prolonged medication. Cutaneous examination revealed multiple, well-demarcated, and hyperpigmented oval to round plaques on the photo-exposed area, including the face, bilaterally on arms, and upper trunk, measuring about 1 × 1-3 × 3 cm2 in size (Figures 1A and 1B). Dermatoscopic examination established rolled-out, thread, double-marginated border with central atrophy with a brownish reticular background. Multiple brownish to black globules and dark lacunae were also observed (Figures 1C and 1D). No Wickham's striae were viewed. Combination of clinical presentation with dermatoscopic findings indicated a provisional clinical diagnosis of disseminated superficial porokeratosis. Biopsy performed on the upper back revealed hyperkeratotic epidermis with mild lymphocytic exocytosis and spongiosis with pigmentary incontinence. The coronoid lamina was not revealed in any of the pathologic sections examined, including further deeper sections and in a repeat biopsy. Clinical morphology, dermatoscopic features, and pathology were considered compatible with the diagnosis of porokeratotic variant of lichen planus (LP). The patient was counseled and started on topical steroids (fluticasone). She is on regular follow-up.

Follicular Porokeratoma: Report of a New Variant of Porokeratoma (Porokeratotic Acanthoma) and Literature Review.

ABSTRACT: Porokeratoma is a rare type of epidermal acanthoma, of which 22 cases have been published in the literature. It is characterized by the presence of multiple cornoid lamellae embedded within a single verrucous or keratotic nodule. Despite this histologic feature being shared with porokeratosis, the etiopathogenesis of porokeratoma and its relationship with porokeratosis remain unclear. We report a new case of porokeratoma involving hair follicles, a finding that has been reported in only one of the previously published cases. Analogous to follicular porokeratosis, a form of porokeratosis involving hair follicles, we have termed this lesion "follicular porokeratoma." A review of all 23 published cases (including the present case) is also provided.

Eruptive superficial porokeratosis in a patient with nephrotic syndrome.

A 34-year-old female was referred to our department, complaining of multiple asymptomatic lesions that appeared two weeks previously. The patient had active nephritis with nephrotic syndrome and was treated with immunosuppressive therapies. Physical examination revealed multiple well-circumscribed rounds of flat brownish plaques with slightly elevated borders, some of which were covered by scales. The number of lesions was nine in total. Skin biopsy specimens showed dyskeratotic cells in the thinned epidermis with cornoid lamella, and the absence of a granular cell layer. The development of porokeratosis was considered to be related to immunosuppressive therapy or the activity of nephritis.

Treating linear porokeratosis with topical lovastatin/cholesterol cream.

Linear porokeratosis is a rare variant of porokeratosis that is characterized by unilateral lesions along the lines of Blaschko. Like all variants of porokeratosis, linear porokeratosis is characterized by the histopathologic finding of cornoid lamellae bracketing the lesion. The underlying pathophysiology involves a two-hit post-zygotic knockdown of genes involved in mevalonate biosynthesis in embryonic keratinocytes. Although there is currently no standard or effective treatment, therapies targeted to rescue this pathway and restore keratinocyte cholesterol availability are promising. Presented here is a patient with a rare, extensive case of linear porokeratosis treated with compounded 2% lovastatin/2% cholesterol cream leading to partial resolution of the plaques.