A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in <i>PSENEN</i>

Pavlovsky, Mor; Sarig, Ofer; Eskin‐Schwartz, Marina; Malchin, Natalia; Bochner, Ron; Mohamad, Janan; Gat, Andrea; Peled, A.; Häfner, A.; Sprecher, Eli

doi:10.1111/bjd.16000

Cited by 49 publications

(59 citation statements)

References 38 publications

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“…Syndromic disease has the potential to become a third classification; however, further epidemiological evidence and clinical consensus is required to define the symptomatology sufficient for a syndromic phenotype diagnosis. It remains unclear whether a syndromic phenotype should remain restricted to PASH (pyoderma gangrenosum, acne and HS) and PAPASH (pyogenic arthritis, pyoderma gangrenosum, acne and HS) syndromes, or whether other autoimmune, inherited and autoinflammatory syndromes (familial Mediterranean fever, Crohn disease, Dowling‐Degos disease) should also be included under this heading.…”

Section: Discussionmentioning

confidence: 99%

Inter‐rater reliability of phenotypes and exploratory genotype–phenotype analysis in inherited hidradenitis suppurativa

et al. 2019

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Summary Background Genotype–phenotype correlation measures the correlation between the presence of a physical trait with a group of similar mutations but is dependent on reliable phenotyping. It can provide information on disease pathogenesis, future disease progression, severity or activity. Such indicators would be valuable in hidradenitis suppurativa (HS). Objectives To assess inter‐rater reliability (IRR) of HS clinical phenotypes and perform exploratory genotype–phenotype correlation in cases of HS with identified sequence variants. Methods Linkage disequilibrium between variants was assessed. Genotype–phenotype correlations were explored using Spearman correlation coefficients. IRR was calculated using Cohen's κ. Correlation between phenotype classifications was assessed using the χ2 statistic. Results Forty‐three sequence variants with clinical information were identified. Clinical phenotypes were classified as LC2 (n = 29; 67%), scarring folliculitis (n = 18; 42%), atypical (n = 38; 88%) and nodular (n = 26; 60%). LC1 phenotype was associated with regular (χ2 = 41·289, P < 0·001) and typical (χ2 = 29·013, P < 0·001) phenotypes. Cohen's κ was highest for van der Zee and Jemec (0·815), followed by Martorell‐Calatayud et al. (0·813), Naasan and Affleck (0·774) and Canoui‐Poitrine et al. (0·435) classifications. High linkage disequilibrium was seen between variants of Han Chinese pedigrees. No significant genotype–phenotype correlations were identified. Conclusions These findings may be influenced by selection, publication bias and the assumption that HS is a monogenic disorder. The poor IRR of existing phenotype measures suggests limited utility of existing measures. Further investigations into the correlation of clinical phenotypes with inflammatory biomarkers may aid in prognostic efforts for this disease. What's already known about this topic? Genotype–phenotype correlation can provide information regarding disease pathogenesis and predictions for future disease progression, severity or activity. The identification of such indicators in hidradenitis suppurativa (HS) would be valuable for patients and clinicians alike, given the lack of biomarkers or clinical predictors of disease. What does this study add? Sixty‐five sequence variants across 20 separate genes were identified. There was no significant correlation between phenotype classification in four separate classification schema and gene, mutation type or impact on Notch signalling. Utility of current phenotype measurements are limited. The lack of genotype–phenotype correlation in HS is suggestive that the underlying assumption of inherited HS as a monogenic disorder may need revision.

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Section: Discussionmentioning

confidence: 99%

Inter‐rater reliability of phenotypes and exploratory genotype–phenotype analysis in inherited hidradenitis suppurativa

et al. 2019

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“…Most reports involved Chinese hidradenitis suppurativa families, with most of the mutant genes identified in NCSTN . Table provides a summary of known specific mutations …”

Section: Mutations In γ‐Secretase Genes Present In Hidradenitis Suppumentioning

confidence: 99%

A gene dysfunction module reveals the underlying pathogenesis of hidradenitis suppurativa: An update

Jiang

Huang

et al. 2019

Aust J Dermatology

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Hidradenitis suppurativa is a chronic skin disease characterised by repeated skin abscesses with sinus tracts and scar formation. Currently, the aetiology and pathogenesis of hidradenitis suppurativa remain unclear. Genetic factors, immune disorders, hormonal abnormalities, skin‐microbial dysbiosis, smoking, obesity and mechanical friction all influence hidradenitis suppurativa pathogenesis. Moreover, hidradenitis suppurativa has a familial subset with autosomal dominant transmission proposed and is related to a mutation of γ‐secretase component genes. In this review, we analyse and summarise research progress regarding the relationship between the γ‐secretase gene dysfunction and the pathogenesis of hidradenitis suppurativa.

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“…The co‐occurrence of HS and DDD was first mentioned in 1990, and several further reports have followed. In this issue of the BJD , Pavlovsky et al . describe four more individuals with HS–DDD.…”

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confidence: 99%

“…Notch signalling has been implicated in differentiation of both interfollicular and follicular epithelium, the hair growth cycle, follicular cyst development, sebaceous gland differentiation and melanocyte homeostasis – a combination of downstream effects that begins to link the clinicopathological anomalies of both HS and DDD. To address the possibility of aberrant Notch, Pavlovsky et al . designed a Notch reporter assay and in the keratinocytes of their patient with HS–DDD they were able to show a reduction in Notch signalling (and in other associated Notch effector genes) that provides some rationale for the clinical collision of HS and DDD.…”

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Concurrent hidradenitis suppurativa and Dowling-Degos disease taken down a ‘Notch’

McGrath

2018

Br J Dermatol

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A phenotype combining hidradenitis suppurativa with Dowling-Degos disease caused by a founder mutation in PSENEN

Abstract: The present data confirm the genetic basis of the combined DDD-HS phenotype and suggest that Notch signalling may play a central role in the pathogenesis of this rare condition.

Cited by 49 publications

References 38 publications

Inter‐rater reliability of phenotypes and exploratory genotype–phenotype analysis in inherited hidradenitis suppurativa

Inter‐rater reliability of phenotypes and exploratory genotype–phenotype analysis in inherited hidradenitis suppurativa

A gene dysfunction module reveals the underlying pathogenesis of hidradenitis suppurativa: An update

Concurrent hidradenitis suppurativa and Dowling-Degos disease taken down a ‘Notch’

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