Coexistence of Acne Inversa with Psoriasis and Dowling-Degos Disease Harboring Impaired PSENEN-Notch Signaling
Acne inversa (AI), also known as hidradenitis suppurativa, is a chronic recurrent inflammatory skin disease characterized by deep painful nodules and abscesses that lead to scarring, primarily in intertriginous areas. Familial AI has been linked to loss-of-function mutations in the gamma-secretase (GS) genes. Gamma-secretase is a transmembrane protease composed of four essential protein subunits: one catalytic presenilin subunit (PSEN) and three cofactor subunits (nicastrin [NCSTN], presenilin enhancer 2 [PSENEN], and anterior pharynx defective 1). Gamma-secretase is involved in the cleavage of various type I membrane proteins, including amyloid precursor protein and Notch proteins. PSENEN directly binds to PSEN and is required for its autocatalytic cleavage and protease activity. To date, six mutations have been reported in PSENEN, all of which result in frameshift truncations and altered protein products, predominantly leading to haploinsufficiency.
Psoriasis is a genetically-determined proliferative and inflammatory disorder resulting from complex interactions between aberrant keratinocyte proliferation and differentiation, and a T-lymphocyte-mediated immune process. Dowling-Degos disease (DDD) is a rare autosomal dominant disorder characterized by progressive reticulate hyperpigmentation and small dark-brown hyperkeratotic papules, mainly affecting flexural areas. This report describes a three-generation Chinese Han family with coexisting AI, psoriasis, and DDD, highlighting the role of impaired PSENEN-Notch signaling in these conditions.
The proband, a 20-year-old male, presented with a 4-year history of relapsing multiple separated comedones, inflammatory papules, pustules, painful nodules, and cysts, particularly located on the nape, upper back, and buttocks. One year after the initial manifestations, he developed an itchy eruption characterized by scattered erythematous papules and macules with silvery-white lamellar scales, mainly on the scalp and extremities. Histopathological examination of an inflammatory nodule from the buttocks revealed destruction of pilosebaceous follicles with surrounding marked fibrosis, while a scaly papule from the forearm showed regular acanthosis, confluent parakeratosis, hypogranulosis, and the formation of a Munro microabscess. Based on these findings, the patient was diagnosed with concomitant AI (Hurley stage I) and psoriasis.
The proband’s 48-year-old mother had similar but more severe inflammatory AI lesions with hypertrophic scars involving the nape, upper trunk, axillae, groins, and buttocks since puberty (Hurley stage II). She also exhibited extensive comedones, pitted scars, and macular or reticulate hyperpigmentation located at flexural areas and the face, reminiscent of DDD. Other family members manifested either AI lesions or AI-DDD lesions with varying severity, revealing an autosomal dominant inheritance pattern.
The study was approved by the Institutional Ethical Review Boards of the Union Hospital of Fujian Medical University. After obtaining informed consent, the entire coding regions and proximal flanking intronic sequences of the GS genes in the family were analyzed by Sanger sequencing. A heterozygous frameshift c.66delG mutation in exon 3 of the PSENEN gene was detected in the proband and his mother. This mutation segregated with affected family members and was not observed in 100 control individuals. The mutation resulted in a premature termination codon (p.F23LfsX46), which was previously reported.
To further investigate the impact of the mutation, mRNA was extracted from peripheral lymphocytes of five AI patients in the family and five normal non-consanguineous controls. The relative PSENEN-Notch signaling molecule mRNA levels were detected by real-time quantitative polymerase chain reaction. Compared with the controls, the patients exhibited significant reductions in PSENEN mRNA expression, indicating that the mutant was subjected to nonsense-mediated decay and resulted in loss-of-function. Additionally, Notch molecules, including Notch1–3 and the target gene HES1, were significantly suppressed in the patients, signifying that PSENEN haploinsufficiency contributed to deficiency in Notch signaling activity.
The coexistence of AI and psoriasis in this case was likely not coincidental. A recent study revealed that 28 of 440 AI patients manifested concomitant psoriasis vulgaris (6.4%). Interestingly, hyperkeratosis and psoriasiform hyperplasia of the interfollicular epidermis with subepidermal inflammatory infiltrates are often observed in AI, resembling those evident in psoriasis. PSENEN is involved in the intracellular cleavage of Notch proteins, which is necessary for the activation of Notch signaling. Inherited or acquired impairment of Notch signaling is hypothesized to be the primary pathogenic event in AI. Within the epidermis, Notch signaling is involved in epidermal cell differentiation, hair follicular terminal differentiation, and epidermal proliferation. Consistent with its role in hindering proliferation and promoting differentiation of keratinocytes, expression of Notch signaling is also decreased in psoriasis, characterized by hyperproliferation and disturbed differentiation of keratinocytes. Moreover, tumor necrosis factor-alpha and interleukin-12/23 inhibitors have demonstrated utility in AI, suggesting that the inflammation cascade is implicated in its pathogenesis, similar to psoriasis. Notch signaling is also a significant regulator of T-lymphocyte-mediated immune responses because it serves as a feedback repressor of over-activated natural immunity. Impaired Notch signaling may cause excessive proinflammatory macrophage cytokine expression (tumor necrosis factor-alpha, interleukin-1beta, interleukin-23), thereby triggering Th17-mediated immune responses.
Several cases of co-manifestation of AI-DDD with PSENEN mutations have been described, suggesting the possible existence of a common pathogenetic mechanism. Indeed, the two entities share important clinical and histopathological features, including onset during puberty, flexural location, and follicular involvement. Only heterozygous mutations in PSENEN gave rise to pigmentation abnormalities, including DDD, while the other two identified AI genes, PSEN1 and NCSTN, were not mentioned. The Notch pathway has an integral role in skin homeostasis by mediating melanocyte proliferation and differentiation, and orchestrating interactions between melanocytes and keratinocytes. It is intriguing that PSENEN knockdown in zebrafish led to the development of aberrant pigmentation, resembling the DDD phenotype. Similar compromised PSENEN-Notch signaling was observed in keratinocytes from patients with AI-DDD and isolated AI in a recent study. Taken together, these findings imply that PSENEN mutations in AI may predispose patients to the occurrence and development of DDD through disrupted Notch signaling.
This report demonstrates three different phenotypes in one AI family: AI, AI-DDD, and AI-psoriasis. It further suggests that diminished expression of PSENEN-Notch molecules may induce dysfunction of Notch signaling and be the unifying molecular mechanism underlying the significant phenotypic heterogeneity in this AI family.
The authors are most grateful to all members of the acne inversa family for taking part in their study. This work was supported by grants from the National Natural Science Foundation of China, the Natural Science Foundation of Fujian Province, Fujian Provincial Health Technology Project, and the Opening Foundation of Research Platform of Fujian University of Traditional Chinese Medicine.
doi.org/10.1097/CM9.0000000000001040
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