Mutations in the γ-Secretase Genes NCSTN , PSENEN , and PSEN1 Underlie Rare Forms of Hidradenitis Suppurativa (Acne Inversa)

Pink, Andrew E.; Simpson, Michael A.; Desai, Nemesha; Dafou, Dimitra; Hills, Alison; Mortimer, Peter; Smith, Catherine; Trembath, Richard C.; Barker, Jonathan

doi:10.1038/jid.2012.162

Cited by 135 publications

(152 citation statements)

References 9 publications

(17 reference statements)

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“…At the same time, the importance of genetic factors is highlighted by studies showing that 30%–40% of HS patients reported a family history of HS 5,14,15. Moreover, familial forms of HS following an autosomal dominant pattern of inheritance with 100% penetrance have been described in different populations, being linked to mutations in subunits of the gamma-secretase proteins (up to 5% of HS cases) 16–18…”

Section: Etiology and Pathogenesismentioning

confidence: 99%

Hidradenitis suppurativa: from pathogenesis to diagnosis and treatment

Napolitano¹,

Megna²,

Тимощук³

et al. 2017

CCID

173

164

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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily affecting apocrine gland-rich areas of the body and presenting with painful nodules, abscesses, sinus tracts, and scarring. HS is a multifactorial disease in which genetic and environmental factors play a key role. The primary defect in HS pathophysiology involves follicular occlusion of the folliculopilosebaceous unit, followed by follicular rupture, and immune responses (perifollicular lympho-histiocytic inflammation), finally leading to the development of clinical HS lesions. HS has a destructive impact on the patient’s quality of life, being a very challenging disease. Available treatments are limited, mostly off-label and with high variability in the reported efficacy. Fortunately, a monoclonal antibody against tumor necrosis factor alpha has been recently approved for treatment of moderate to severe HS, offering patients a promising new option. This review focuses on the main features of HS, including epidemiology, clinical aspects, pathogenesis, severity classifications, comorbidities, and currently available treatments.

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Section: Etiology and Pathogenesismentioning

confidence: 99%

Hidradenitis suppurativa: from pathogenesis to diagnosis and treatment

Napolitano¹,

Megna²,

Тимощук³

et al. 2017

CCID

173

164

View full text Add to dashboard Cite

show abstract

“…Mutations in the γ-secretase genes NCSTN, PSENEN , and PSEN1 impairing the Notch signaling in hair follicles have been found in some HS patients (Pink et al, 2012). TNF-α, IL-1β, and IL-10 levels were frequently increased in HS lesions (van der Zee et al, 2011).…”

Section: Skin Diseases With Il-1 Involvementmentioning

confidence: 99%

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

2017

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In 2002, intracellular protein complexes known as the inflammasomes were discovered and were shown to have a crucial role in the sensing of intracellular pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Activation of the inflammasomes results in the processing and subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18. Several autoinflammatory disorders such as cryopyrin-associated periodic syndromes and Familial Mediterranean Fever have been associated with mutations of genes encoding inflammasome components. Moreover, the importance of IL-1 has been reported for an increasing number of autoinflammatory skin diseases including but not limited to deficiency of IL-1 receptor antagonist, mevalonate kinase deficiency and PAPA syndrome. Recent findings have revealed that excessive IL-1 release induced by harmful stimuli likely contributes to the pathogenesis of common dermatological diseases such as acne vulgaris or seborrheic dermatitis. A key pathogenic feature of these diseases is IL-1β-induced neutrophil recruitment to the skin. IL-1β blockade may therefore represent a promising therapeutic approach. Several case reports and clinical trials have demonstrated the efficacy of IL-1 inhibition in the treatment of these skin disorders. Next to the recombinant IL-1 receptor antagonist (IL-1Ra) Anakinra and the soluble decoy Rilonacept, the anti-IL-1α monoclonal antibody MABp1 and anti-IL-1β Canakinumab but also Gevokizumab, LY2189102 and P2D7KK, offer valid alternatives to target IL-1. Although less thoroughly investigated, an involvement of IL-18 in the development of cutaneous inflammatory disorders is also suspected. The present review describes the role of IL-1 in diseases with skin involvement and gives an overview of the relevant studies discussing the therapeutic potential of modulating the secretion and activity of IL-1 and IL-18 in such diseases.

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“…[3,8,15,26,27]. The importance of genetic factors is highlighted by studies showing that 30-40% of HS patients reported a family history of HS [28,29] as well as 5% of HS patients presenting with a familial form with mutations in subunits of the γ-secretase proteins [30,31]. Originally, when first described, HS was thought to be a disease of the apocrine gland because it most commonly occurs in apocrine gland-rich intertriginous areas.…”

Section: Pathogenesismentioning

confidence: 99%

Medical and Surgical Treatment of Hidradenitis Suppurativa: A Review

Scuderi

Monfrecola

Dessy

et al. 2017

Skin Appendage Disord

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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease presenting with painful nodules, abscesses, sinus tracts, and scarring primarily affecting apocrine gland-rich intertriginous areas. HS prevalence ranges from 0.05 to 1%. The central pathogenic event in HS is believed to be the occlusion of the upper part of the folliculopilosebaceous unit, leading to the rupture of the sebofollicular canal with the consequent development of perifollicular lymphohistiocytic inflammation. The HS treatment choices are influenced by disease severity and its individual subjective impact, involving both medical and surgical interventions. However, given the chronic nature of HS, its destructive impact on social, working, and daily life of patients, its management is often frustrating for both the patient and physician. Hence, prompt and effective management strategies are urgently needed and a multidisciplinary approach is advocated. Therefore, in this article, we highlighted the main features of HS (clinical aspects, epidemiology, pathogenesis, diagnostic criteria, classifications, comorbidities, and treatments), so that awareness of this disease might be heightened in primary care physicians and surgeons, who may be the first health care providers to see patients with this disease owing to its characteristic clinical presentation (inflammatory nodules, abscesses, sinus tract, etc.).

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Mutations in the γ-Secretase Genes NCSTN , PSENEN , and PSEN1 Underlie Rare Forms of Hidradenitis Suppurativa (Acne Inversa)

Cited by 135 publications

References 9 publications

Hidradenitis suppurativa: from pathogenesis to diagnosis and treatment

Hidradenitis suppurativa: from pathogenesis to diagnosis and treatment

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

Medical and Surgical Treatment of Hidradenitis Suppurativa: A Review

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