Genetics and Gene Auto-Inflammatory
Synopsis of Study: Both familial (hereditary) and sporadic (acquired, non- hereditary) cases of HS have been reported. It is thought that approximately 33% of HS cases are familial. Genetic variants of HS are heterogeneous, with several mutations identified throughout the genome, lacking a consistent genotype to phenotype correlation 39– 41. One study of 53 Chinese patients hypothesized to have familial HS were found to have a unique phenotype consisting of an increased male prevalence, earlier onset, and more severe disease involving atypical regions such as the neck and back 42. Because of the phenotypic variance in HS, Canoui-Poitrine et al. attempted to develop distinct phenotype-based subtypes of the disease, including axillary-mammary, follicular, and gluteal types. However, genetic analyses have not yet correlated with this grouping technique 43. Additionally, the specific phenotype “hidradenitis suppurativa fulminans” has been proposed to describe a specific, severe presentation of the disease 40. Phenotypic categorization will assist in future studies and determining a greater understanding of the varying presentations and genetics of this disease.
Some cases of HS are associated with syndromes, including pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) syndrome, related to mutations in proline-serine-threonine-phosphatase protein 1 (PSTPIP1). This gene is involved in the regulation of the inflammasome complex, a series of proteins and signaling pathways the body utilizes in response to inflammation-inducing stimuli 44. Another similar syndrome, pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) syndrome, is also associated with PSTPIP1 gene mutations 45. Similarly, synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome has been associated with cases of HS. These relationships between HS and other auto-inflammatory diseases have bolstered the theory that HS may be auto-inflammatory in nature 46.
There is also evidence to support a relationship between familial HS and loss-of-function mutations in γ-secretase proteins, such as presenilin-1, presenilin enhancer-2, anterior pharynx defective 1, and nicastrin (NCSTN). These mutations were noted in variants of HS involving atypical regions such as the thighs and trunk 7, 47. The protease γ-secretase plays a role in the regulation of the canonical Notch signaling pathway, which is relevant to HS because Notch functions in the development of hair follicles, and as an immunomodulator in T-cell-mediated cellular immune responses. Inherited or acquired alterations in Notch signaling may play a pivotal role in HS disease pathogenesis 48. Cigarette smoking has been shown to decrease the activity of the Notch signaling pathway, further strengthening this association. Of note, having one of the above mutations does not guarantee disease development or progression 49.
Further, Xiao et al. analyzed the gene encoding NCSTN ( NCSTN) in a human keratinocyte cell line and found that NCSTN knockdown cells exhibited impaired γ-secretase activity, leading to more rapid proliferation and a greater proportion of cells in the S-phase of the cell cycle. This study bolstered the theory that a deficiency in the NCSTN gene in familial forms of HS may play a role in abnormal keratinocyte growth and proliferation 50. Interestingly, Duchatelet et al. discovered a NCSTN mutation in a patient with PASH syndrome, interrelating genetic and auto-inflammatory hypotheses of the pathogenesis of HS 51.
Finally, a retrospective study by Deckers et al. evaluated trends in early onset HS, defined as disease onset before age 13. A family history of HS was a significant factor in the diagnosis of early onset HS as well as more widespread disease. There were no reported differences in comorbidities in patients with early onset disease compared to controls with normal-onset HS 52.
The referees who approved this portion article are:
Geoffrey David Cains, Department of Dermatology, University of New South Wales, Sydney, Australia
No competing interests were disclosed.
Christopher Sayed, Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; UNC Dermatology and Skin Cancer Center, Chapel Hill, NC, USA
Competing interests: Christopher Sayed has held roles with Abbvie Inc. as a speaker, Advisory Board Member and co-investigator.
Robert Micheletti, Department of Dermatology and Department of Medicine, University of Pennsylvania, Philadelphia, USA
No competing interests were disclosed.
Version 1. F1000Res. 2017; 6: 1272.
Published online 2017 Jul 28. doi: 10.12688/f1000research.11337.1
Mallory K Smith,1 Cynthia L Nicholson,2 Angela Parks-Miller,2 and Iltefat H Hamzavia,2
1Wayne State University School of Medicine, Detroit, MI, USA
2Henry Ford Hospital Department of Dermatology, Detroit, MI, USA
Mallory Smith and Cynthia Nicholson drafted and wrote the article. Angela Miller contributed expertise for the “Psychosocial impact” section, and Iltefat Hamzavi contributed expertise on disease management. All authors were involved in the manuscript revisions and agreed on the final submission.