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Yi Zhao,1 Gang Wang,2 Wenqiong Ni,3 Zhiqiang Song,4 Kun Chen,5 Chunlei Zhang,6 Shoumin Zhang,7 Yangfeng Ding,8 Min Zheng,9 Yulin Shi,10 Zhimiao Lin,11 Xiaomin Liu,12 Xiaofei Zhang,13 Qintian Zhou,14 Kazi Deluwar Ahmed14 1Department of Dermatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 2Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China; 3Department of Dermatology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People’s Republic of China; 4Department of Dermatology, Southwest Hospital, The Third Military Medical University, Chongqing, People’s Republic of China; 5Institute of Dermatology, Chinese Academy of Medical Science and Peking Union Medical College, Nanjing, People’s Republic of China; 6Department of Dermatology, Peking University Third Hospital, Beijing, People’s Republic of China; 7Department of Dermatology, Henan Provincial People’s Hospital, Zhengzhou 450003, People’s Republic of China; 8Department of Dermatology, Shanghai Skin Disease Hospital, Shanghai, People’s Republic of China; 9Department of Dermatology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 10Department of Dermatology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine; Institute of Psoriasis, Tongji University School of Medicine, Shanghai, People’s Republic of China; 11Department of Dermatology and Venereology, Peking University First Hospital, Beijing, People’s Republic of China; 12Department of Dermatology, The University of Hong Kong–Shenzhen Hospital, Shenzhen, People’s Republic of China; 13Department of Clinical Epidemiology and Biostatistics, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China; 14Scientific Affairs and MSL Department, LEOPharma China, Shanghai, People’s Republic of ChinaCorrespondence: Yi ZhaoDepartment of Dermatology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Beijing 102218, People’s Republic of ChinaEmail zhaoyimd@tsinghua.edu.cnGang WangDepartment of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, People’s Republic of ChinaEmail xjwgang@fmmu.edu.cnObjective: We aimed to prospectively evaluate the visit adherence in mild to moderate psoriasis patients.Methods: Plaque psoriasis patients aged 18 or above who were prescribed with a two-component formula ointment were eligible for the study. The patients were randomly assigned to group A or B, and received management with or without planned patient-doctor communication via a mobile platform. The outpatient visit was scheduled at week 2, 8, 16, 28, 48, and 52. Visit adherence was evaluated as the visit rate of the patients.Results: Two hundred twenty-one patients were included. Generally, the visit adherence dropped over time during follow-up. The visit rates in group A were 5.2– 15.7% through the 52 weeks, and similar rates were found in group B (7.5– 17.0%, vs group A, P > 0.05). A negative binomial regression model showed that older age and higher BSA were correlated with more frequent visits.Conclusion: The visit adherence of mild to moderate psoriasis patients was very low in China. Proactive inquiries of the doctors via the mobile platform failed to improve the visit adherence of the patients.Keywords: psoriasis, visit adherence, topical treatment

Background CLOVES syndrome (OMIM# 612918) is a rare overgrowth disorder resulted from mosaic gain-of-function mutations in the PIK3CA gene. All the reported CLOVES-associated PIK3CA mutations are missense mutations affecting certain residues. We aim to investigate underlying mutation and its pathogenicity in a patient with CLOVES syndrome and to evaluate the inhibitory effects of the PI3K/AKT/mTOR pathway inhibitors. Results We performed whole-exome sequencing (WES) and Sanger sequencing to detect underlying somatic mutations in the skin lesion of the patient. Quantitative real-time PCR (qRT-PCR) was employed to evaluate the mRNA abundance of PIK3CA in the patient’s skin lesion. AKT phosphorylation level assessed by immunoblotting of lysates from transiently transfected cells was performed to evaluate the PIK3CA mutations and inhibitory effects of PI3K/AKT/mTOR pathway inhibitors. A somatic frameshift mutation c.3206_3207insG (p.X1069Trpfs*4) in PIK3CA was identified in the genomic DNA extracted from the vascular malformation sample of the patient. This mutation affects the canonical stop codon of PIK3CA (NM_006218.4) and is predicted to produce a prolonged protein with four additional residues. qRT-PCR demonstrated that the mRNA expression levels of the patient’s affected skin tissue were comparable compared to the normal control. In vitro studies revealed that p.X1069Trpfs*4 mutant exhibited increased AKT phosphorylation significantly to that of the wildtype, which could be inhibited by PI3K/AKT/mTOR pathway inhibitors. Conclusions We have identified the first frameshift mutation in PIK3CA that causes CLOVES syndrome, which was confirmed to overactive PI3K/AKT/mTOR pathway by transient transfection assays. We also provided more evidence of ARQ092 to be a potential therapeutic option for PROS in vitro.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.