- •Whole Exome Sequencing approach and novel bioinformatic pipeline has been adopted.
- •4 biological pathways are shared by all PASH and PAPASH patients.
- •All pathways are related to biological processes involving the skin.
- •The mainly impacted pathway is Vitamin D metabolism.
- •All patients show low Vitamin D serum levels and its supplementation is envisaged.
Diagnosis of pyoderma gangrenosum, acne and hidradenitis suppurativa (PASH) and pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) patients, in spite of recently identified genetic variations, is just clinical, since most patients do not share the same mutations, and the mutations themselves are not informative of the biological pathways commonly disrupted in these patients.
To reveal genetic changes more closely related to PASH and PAPASH etiopathogenesis, identifying novel common pathways involved in these diseases.
Cohort study on PASH (n = 4) and PAPASH (n = 1) patients conducted using whole exome sequencing (WES) approach and a novel bioinformatic pipeline aimed at discovering potentially candidate genes selected from density mutations and involved in pathways relevant to the disease.
WES results showed that patients presented 90 genes carrying mutations with deleterious and/or damage impact: 12 genes were in common among the 5 patients and bared 237 ns ExonVar (54 and 183 in homozygosis and heterozygosis, respectively). In the pathway enrichment analysis, only 10 genes were included, allowing us to retrieve 4 pathways shared by all patients: (1) Vitamin D metabolism, (2) keratinization, (3) formation of the cornified envelope and (4) steroid metabolism. Interestingly, all patients had vitamin D levels lower than normal, with a mean value of 10 ng/mL.
Our findings, through a novel strategy for analysing the genetic background of syndromic HS patients, suggested that vitamin D metabolism dysfunctions seem to be crucial in PASH and PAPASH pathogenesis. Based on low vitamin D serum levels, its supplementation is envisaged.
Abbreviations:PASH (pyoderma gangrenosum acne and hidradenitis suppurativa), PAPASH (pyoderma gangrenosum acne, pyogenic arthritis and hidradenitis suppurativa), HS (hidradenitis suppurativa), WES (whole exome sequencing), PG (pyoderma gangrenosum), PASS (pyoderma gangrenosum acne vulgaris, hidradenitis suppurativa and ankylosing spondylitis), IHS4 (International Hidradenitis Suppurativa Severity Score System), DLQI (dermatology life quality index), VAS (visual analogue scale), VDR (vitamin D receptor), DAMPs (damage-associated molecular patterns), ECM (extracellular matrix), MMPss (matrix metalloproteinases)
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Published online: May 21, 2020
Accepted: May 1, 2020
Received in revised form: April 10, 2020
Received: January 14, 2020
© 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.