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 autosomaldominant 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.

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Medical ImageryMoth-eaten alopecia in secondary syphilis A young man presented to the hospital with a 1-month history of multiple patches of alopecia over the scalp and erythematous macules with scales on his palmoplantar and genital area. He recalled an unsafe sexual behavior 3 months ago. Physical examination revealed multiple irregular, poorly defined, nonscarring patches of alopecia with moth-eaten appearance over the occipital and temporal scalp ( Figure 1A). Numbers of erythematous macules with prominent desquamation scattered on both palms and soles. Erythema with fine scales was found on the genitals.The patient was clinically ascertained to have secondary syphilis, which was further confirmed by a positive result of Treponema pallidum haemagglutination assay (TPHA) test and a rapid plasma reagin (RPR) titer of 1:64. The patient received an intramuscular injection of 2.4 MIU of benzathine penicillin G, and the lesions resolved completely with regrowth of hair at 3-month follow-up ( Figure 1B).Alopecia is relatively uncommon in the clinical spectrum of secondary syphilis and is regarded as a specific immune response to the spirochete antigens in hair follicles. The "moth-eaten" alopecia is the most commonpattern and is considered pathognomonic for secondary syphilis (Costa et al., 2018). The syphilitic alopecia typically resolves with routine antibiotic therapy in 8-12 weeks (Piraccini et al., 2015). Figure 1. Temporal aspect of the scalp of the patient. (A) Clinical photograph of the patient before initial treatment, presenting with multiple patches of alopecia on the scalp; (B) The hair regrew completely at 3-month follow-up.

Background  Mendelian disorders of cornification (MeDOC) are a group of heterogeneous genodermatoses with different genetic bases. The pathogenesis of a substantial group of MeDOC remains to be elucidated. Objectives  To identify a new causative gene and the pathogenesis of a previously undescribed autosomal-dominant cornification disorder. Methods  Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants. As the variants were located around the signal peptide (SP) cleavage site of a kallikrein-related peptidase, SP cleavage, subcellular localization and extracellular secretion of the variants were evaluated in eukaryotic overexpression systems by Western blotting or immunocytochemistry. Then the trypsin-like and chymotrypsin-like proteolytic activity of the peptidase and degradation of its catalytic substrate were assayed using the patients’ stratum corneum (SC) samples. The morphology of the lamellar bodies and corneodesmosomes (CDs) in the patients’ SC was ultrastructurally examined. A mouse model harbouring the equivalent variant was constructed and evaluated histologically. Results  We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma. KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC. In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant. Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients’ SC samples. Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients’ SC, indicating delayed skin desquamation. Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation. Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype. Conclusions  We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation. Our findings highlight the essential role of KLKs in maintaining homeostasis of skin keratinization and desquamation.

Becker’s nevus (BN) is a cutaneous hamartoma which is characterized by circumscribed hyperpigmentation with hypertrichosis. Recent studies have revealed that BN patients harbored postzygotic ACTB mutations, which were restricted to arrector pili muscle lineage. We screened for ACTB mutations in 20 Chinese patients with BN and found that recurrent mutations (c.C439A or c.C439T) in ACTB were detected in the majority of BN patients. However, more than 20% of the patients were negative for ACTB mutations, suggesting a possible genetic heterogeneity in Becker’s nevus. Interestingly, these mutations were also detected in dermal tissues outside the arrector pili muscle. We further performed genotype–phenotype correlation analysis, which revealed that lesions above the waistline, including the trunk above the anterior superior spine level, upper limbs and face, or covering more than 1% BSA were more likely to be positive for ACTB mutations. Altogether, our results provide further evidence of postzygotic ACTB mutations in BN patients and suggest a possible genotype–phenotype correlation of BN.