Acne inversa (AI, OMIM #142690), also called hidradenitis suppurativa (HS), is a chronic, inflammatory, recurrent and debilitating skin follicular disease that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axilla, inguinal and anogenital regions. The estimated prevalence in Caucasian populations ranges from 0.1% to 1%1 but rarely reported in Chinese. About 35%–40% of AI patients have a familial history, which shows an autosomal-dominant inheritance pattern.2 In 2010, our group identified loss-of-function mutations in the NCSTN, PSENEN and PSEN1 genes in six Han Chinese families, thus first reported that haploinsufficiency of genes encoding γ-secretase components as the genetic basis for familial AI.3 To date, over 40 mutations in γ-secretase genes have been identified in familial AI patients from different populations, according to the Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/). In this letter, we reported two novel mutations in NCSTN and PSENEN in two Chinese AI families. Patient 1 is a 25-year-old male presented with recurrent inflammatory papules, painful nodules, pustules, cysts and scars on the back of neck, axillae, back, upper chest, forearms and buttocks for 6 years (Figure 1A–F). With these clinical features, a diagnosis of acne inversa was made. He had been treated with isotretinoin without significant improvement. He has no positive family history. After the written informed consent was obtained, an in-house panel-based targeted next-generation sequencing revealed a novel frame shift mutation c.1555dupA in NCSTN in patient 1 (Figure 1G). NCSTN encoding nicastrin, a glycoprotein acting as a γ-secretase complex stabilizer,4 is the most commonly mutated gene reported in familial AI. This mutation generated a premature termination codon (p.T519NfsX9), which was predicted to cause loss of function of NSCTN thereby causing the disease. In family 2, there were 1 male and 4 female patients (Figure 1H). The proband (III 4) was a 25-year-old female presented with recurrent inflammatory papules, pustules and painful nodules at the age of 11 years. Other patients in this family had similar clinical manifestations and fulfilled the diagnostic criteria of AI (Figure 1I–P). All patients had normal intellectual ability and no neuropsychiatric disorder and behaviour problems. By targeted sequencing, a heterozygous nonsense mutation, c.13C>T p.R3X, was identified in PSENEN, which was never reported before. Sanger sequencing confirmed this mutation in the proband and showed that her affected sister also carried the same mutation. PSENEN encodes presenilin enhancer protein 2 (PEN2), a member of the γ-secretase enzyme complex, in which loss-of-function mutations have been reported to cause familial AI. The nonsense mutation p.R3X was classified as “pathogenic” according to the ACMG/AMP 2015 guideline5 and should be responsible for the disease in this family. In conclusion, herein, we reported two novel mutations of γ-secretase genes in two Chinese families with AI, which expanded the mutation spectrum of γ-secretase genes underlying AI. The study was supported by the National Key Research and Development Programme of China [2016YFC0905100 to XZ], the CAMS Innovation Fund for Medical Sciences (CIFMS) [2016-I2 M-1-002 to XZ], the National Natural Science Foundation of China (NSFC) [81788101 and 81230015 to XZ] and the Natural Science Foundation of Beijing [7172167 to D-LM]. The authors wish to acknowledge the constructive comments and contributions of Wei Liu, Department of Dermatology, Peking Union Medical College Hospital, Jia-Wei Liu, Department of Dermatology, Peking Union Medical College Hospital, and Rong-Rong Wang, McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and Chinese Academy of Medical Sciences & Peking Union Medical College. None declared. In the study, Y.T.Q. and M.X. are the co-first authors. D.L.M. and X.Z. are the co-corresponding authors and revised the manuscript and supervised the study. Y.T.Q. and D.L.M. cared for the patients. M.X. and K.Q.L. performed the next-generation sequencing and contributed to the interpretation of the results. Y.T.Q. and M.X. wrote the initial draft. All authors participated in the design of the study, clinical assessment and genomics research. All the authors take responsibility for acquisition, analysis and interpretation of the data. All authors have read and approved the final manuscript.
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Aug 25, 2024
Sana Rashid + 6
Open Access