Reply to: ‘‘Hidradenitis suppurativa: Epidemiology, clinical presentation, and pathogenesis”

To the Editor: We recently read with great interest the article: “Hidradenitis suppurativa: Epidemiology, clinical presentation, and pathogenesis.”1Goldburg S.R. Strober B.E. Payette M.J. Hidradenitis suppurativa: epidemiology, clinical presentation, and pathogenesis.J Am Acad Dermatol. 2020; 82: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar In this CME activity, the authors describe with detail the current data on the epidemiology and pathogenesis of hidradenitis suppurativa (HS) as well as the clinical characteristics of the disease. Of particular interest is the section on familial HS and its underlying genetics. Indeed, some forms of HS are familial in which genetic mutations have been identified. As mentioned by the authors, the genes that have been implicated include NCSTN, PSEN1, and PSENEN (presenilin enhancer-2).1Goldburg S.R. Strober B.E. Payette M.J. Hidradenitis suppurativa: epidemiology, clinical presentation, and pathogenesis.J Am Acad Dermatol. 2020; 82: 1045-1058Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar The protein products of these genes comprise the γ-secretase transmembrane complex, which functions to cleave intracellular Notch receptors, leading to activation of Notch signaling.2Li W. Xu H. He Y. Lin L. Li C. Comorbidities or different entities? Phenotype variability associated with PSENEN mutations.Br J Dermatol. 2019; 180: 221-222Crossref PubMed Scopus (6) Google Scholar,3Ralser D.J. Basmanav F.B. Tafazzoli A. et al.Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (50) Google Scholar Although crucial for developmental processes, Notch signaling, in the skin, is thought to mediate melanocyte-keratinocyte interaction and thus regulating the delicate balance between their proliferation and differentiation. Here, we would like to complement and expand on the information provided in the article by highlighting an important association that dermatologists need to be aware of between HS and Dowling-Degos disease (DDD), especially among carriers of the PSENEN gene mutation.2Li W. Xu H. He Y. Lin L. Li C. Comorbidities or different entities? Phenotype variability associated with PSENEN mutations.Br J Dermatol. 2019; 180: 221-222Crossref PubMed Scopus (6) Google Scholar,3Ralser D.J. Basmanav F.B. Tafazzoli A. et al.Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (50) Google Scholar DDD is an autosomal dominant genodermatosis characterized by progressive reticular hyperpigmentation and small, dark-brown hyperkeratotic papules on the trunk, face, flexures, and extremities. On histology, DDD typically exhibits epidermal downgrowth of rete ridges with increased pigmentation at the tips.2Li W. Xu H. He Y. Lin L. Li C. Comorbidities or different entities? Phenotype variability associated with PSENEN mutations.Br J Dermatol. 2019; 180: 221-222Crossref PubMed Scopus (6) Google Scholar, 3Ralser D.J. Basmanav F.B. Tafazzoli A. et al.Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (50) Google Scholar, 4Weber L.A. Kantor G.R. Bergfeld W.F. Reticulate pigmented anomaly of the flexures (Dowling-Degos disease): a case report associated with hidradenitis suppurativa and squamous cell carcinoma.Cutis. 1990; 45: 446-450PubMed Google Scholar The presence of the HS-DDD overlap has been well described in the literature. The first reports of DDD coexisting with HS date back to the 1990s.2Li W. Xu H. He Y. Lin L. Li C. Comorbidities or different entities? Phenotype variability associated with PSENEN mutations.Br J Dermatol. 2019; 180: 221-222Crossref PubMed Scopus (6) Google Scholar, 3Ralser D.J. Basmanav F.B. Tafazzoli A. et al.Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (50) Google Scholar, 4Weber L.A. Kantor G.R. Bergfeld W.F. Reticulate pigmented anomaly of the flexures (Dowling-Degos disease): a case report associated with hidradenitis suppurativa and squamous cell carcinoma.Cutis. 1990; 45: 446-450PubMed Google Scholar, 5Agut-Busquet E. Romaní J. Ribera M. Luelmo J. Hidradenitis suppurativa of the nape: description of an atypical phenotype related to severe early-onset disease in men.J Dermatol. 2019; 46: 149-153Crossref PubMed Scopus (9) Google Scholar Since then, this association has become more evident, especially with the identification of underlying PSENEN mutations in most of these patients.2Li W. Xu H. He Y. Lin L. Li C. Comorbidities or different entities? Phenotype variability associated with PSENEN mutations.Br J Dermatol. 2019; 180: 221-222Crossref PubMed Scopus (6) Google Scholar,3Ralser D.J. Basmanav F.B. Tafazzoli A. et al.Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (50) Google Scholar Current evidence suggests that PSENEN mutation carriers may manifest 3 different phenotypes: HS alone, DDD alone, and, importantly, HS and DDD together.2Li W. Xu H. He Y. Lin L. Li C. Comorbidities or different entities? Phenotype variability associated with PSENEN mutations.Br J Dermatol. 2019; 180: 221-222Crossref PubMed Scopus (6) Google Scholar,3Ralser D.J. Basmanav F.B. Tafazzoli A. et al.Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (50) Google Scholar Some have even suggested that increased HS susceptibility exists in PSENEN mutation carriers with the DDD subphenotype, especially patients with history of nicotine abuse or obesity.3Ralser D.J. Basmanav F.B. Tafazzoli A. et al.Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (50) Google Scholar In those patients, follicular hyperkeratosis was demonstrated on microscopy in body areas with reticulate hyperpigmentation, suggesting that this histopathologic feature may serve as a potential marker to identify individuals with DDD with HS susceptibility.3Ralser D.J. Basmanav F.B. Tafazzoli A. et al.Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (50) Google Scholar A recent study also demonstrated that patients with HS with atypical nape involvement had a significantly higher prevalence of DDD, suggesting that patients with both HS and DDD commonly present with atypical HS.5Agut-Busquet E. Romaní J. Ribera M. Luelmo J. Hidradenitis suppurativa of the nape: description of an atypical phenotype related to severe early-onset disease in men.J Dermatol. 2019; 46: 149-153Crossref PubMed Scopus (9) Google Scholar Increased awareness of this disease overlap is important for diagnosis and treatment. Both conditions may affect the flexures but are treated differently. Recognizing that HS and DDD may coexist in the same patient will allow dermatologists to be on alert for diagnosing and treating both conditions concomitantly and appropriately. Hidradenitis suppurativa: Epidemiology, clinical presentation, and pathogenesisJournal of the American Academy of DermatologyVol. 82Issue 5PreviewHidradenitis suppurativa (HS) is an inflammatory disorder that is characterized by chronic deep-seated nodules, abscesses, fistulae, sinus tracts, and scars in the axilla, inguinal area, submammary folds, and perianal area. This disfiguring condition is accompanied by pain, embarrassment, and a significantly decreased quality of life. Although the mechanism of HS has not been entirely elucidated, lesion formation is believed to center around follicular hyperkeratosis within the pilosebaceous–apocrine unit. Full-Text PDF