Hidradenitis suppurativa (HS) is a severe chronic inflammatory disorder characterized by recurrent painful deep-seated nodules with a predilection to the apocrine-bearing areas of skin. A minority of cases of HS are due to mutations in the γ-secretase complex. Contention exists surrounding the pathogenicity of sequence variants and their effects upon Notch signalling. This systematic review was registered with PROSPERO (CRD42016041425) and was conducted in line with the PRISMA statement. Eligibility criteria for this review included published case reports, case series and reviews that identified sequence variants or protein or functional studies from patients with HS. Sixty-two articles were identified reporting a total of 41 sequence variants - heterozygous missense (nine), splice site (nine), insertion resulting in frameshift (one), premature termination codon (19) and promoter region PSTPIP1 (three) - with 18 associated protein or functional studies. The American College of Medical Genetics and Genomics standards and guidelines on the interpretation of sequence variants were applied to each identified variant to assess evidence for pathogenicity. Twenty-three variants were assessed as likely pathogenic, 17 of uncertain significance and one benign. The large number of variants of 'uncertain significance' is largely due to the variable number of functional studies. Four studies used Notch as a proxy for γ-secretase function, with conclusions of nonpathogenicity based on the assumption of Notch signalling as the sole pathogenic process. The role of Notch-independent signalling mechanisms requires further research. Limitations to this study include identification of variants of Mendelian inheritance and not complex polygenic traits.

SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a rare inflammatory condition describing the combination of skin, bone, and joint manifestations that has a heterogeneous presentation. We report a case of severe SAPHO syndrome in association with hidradenitis suppurativa and pyoderma gangrenosum in a 27-year-old male. The patient had an initial migratory arthritis affecting the knees, ankles, metacarpophalangeal joints, proximal interphalangeal joints, wrists, shoulder, and lower back, which progressed to a persistent arthritis and swelling at the sternum, shoulders, wrists, hands, feet, and lower back. Radiographic changes were consistent with the diagnosis of SAPHO syndrome. Serum proinflammatory cytokine levels were significantly elevated and improved substantially after 3 months of therapy. Rationale for therapy in this patient was the observation that tumor necrosis alpha antagonists have been successfully used in SAPHO syndrome, and since arthropathy was so prominent in our patient, we elected to use adalimumab combined with methotrexate.

Hidradenitis suppurativa is a chronic, painful, autoinflammatory condition resulting in nodules, abscesses and sinus tracts. We present an evidence-based review providing new understanding of the pathogenesis of hidradenitis suppurativa and associated comorbidities. By the nature of their speciality, dermatologists are uniquely positioned to investigate and treat patients with this condition. Data collected from a subspecialty hidradenitis suppurativa clinic (N = 106) and experiences thereof are discussed in this review.

Summary of general pathogenic mechanismsHidradenitis Suppurativa is a chronic inflammatory condition manifesting in recurrent painful deep-seated nodules and abscesses with variable phenotypic presentations (1). Melnik and Plewig eloquently describe the concept of HS as an autoinflammatory disease with dysregulation of the gamma-secretase/Notch pathway (2); however, recent studies have identified 'typical' and 'atypical' HS subtypes with differing morphology (nodules, comedones), lesion distribution (axillary, submammary and gluteal) and comorbidity prevalence (1). The pathogenic hypothesis proposed by Melnik and Plewig (2) as well as reports of inconsistent responses to systemic therapies (3,4) has led to suggestions that variable phenotypic presentations are suggestive of heterogeneous pathogenic inflammatory dysregulation within the gamma-secretase/ Notch pathway paradigm (5). The complex interaction between metabolic syndrome and HSPascoe and Kimball describe the complex yet 'established link' between metabolic syndrome and HS (6). Comorbidities including insulin resistance, glucose intolerance (7), dysregulated adipokine levels (8) (indirectly measured via BMI) (9) and bacterial superinfection (10) are all possible modulators of disease activity. These associations, however, have not taken into account the heterogeneity of HS presentations and ensuing confounding relationships. The point prevalence of HS is quoted at 18% amongst bariatric surgery patients (11) with an odds ratio for metabolic syndrome of 3.89 (95% CI 1.90-7.98) for a hospital HS cohort (12). However, analysis by Canoui-Poitrine et al.(1) shows statistically significant variation in BMI between 'subtypes' of HS, discrepancies which may confound existing results. Miller et al. (12), adjusting for BMI, revealed significant correlation between decreased HDL/elevated TG levels and HS in this cohort, suggesting an underlying metabolic disturbance independent of BMI. The role of adipose tissue as a dynamic endocrinological organ across all BMI ranges in HS requires further investigation (7). HS occurs in individuals with normal BMI (11), with 52.6% of individuals in Canoui-Poitrine's analysis of BMI 25 or lower (1). The rates of metabolic derangements in this 'atypical' subtype are less well defined than their 'typical' counterparts. Hence, treatment focused on metabolic comorbidities may be appropriate in 'typical' HS but their utility is as yet unclear in 'atypical' subtypes.

Hidradenitis suppurativa is a chronic, painful, autoinflammatory condition resulting in nodules, abscesses and sinus tracts. We present an evidence-based review providing new understanding of the pathogenesis of hidradenitis suppurativa and associated comorbidities. By the nature of their speciality, dermatologists are uniquely positioned to investigate and treat patients.

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