Faculty Bibliography

Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, the resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.

Introduction: Recent research on vitamin D has shown that the fat-soluble micronutrient has anti-microbial, anti-inflammatory, and anti-proliferative effects in cells and tissues. During wound healing, abnormal scarring may occur and lead to reduced mobility, disfigurement, and psychosocial concerns. The role of vitamin D in the pathogenesis and treatment of scarring has not been reviewed previously. Methods: A literature search was performed on PubMed to identify articles on vitamin D and keloid, hypertrophic, or burn scars. Results: Molecular, epidemiological, and human clinical studies are discussed. Overall, the evidence suggests lower levels of vitamin D precursors, the active metabolite, and receptor, are associated with increased risk of scar development and increased severity. Conclusions: Scars are challenging to treat, and patients are increasingly interested in non-invasive treatment options. Although few human clinical studies have been reported, vitamin D may be beneficial as an adjunct therapy to current treatment options. J Drugs Dermatol. 2020;19(7): doi:10.36849/JDD.2020.4986.

BACKGROUND:A systematic review failed to identify any systemic therapy used in alopecia areata (AA) where use is supported by robust evidence from high quality randomized controlled trials (RCTs). OBJECTIVE:To produce an international consensus statement on the use and utility of various treatments for AA. METHODS:Fifty hair experts from 5 continents were invited to participate in a 3 round Delphi process. Agreement >66% was considered consensus. RESULTS:In the first round, consensus was achieved in 22 of 423 (5%) questions. Following a face-to-face meeting in round 3, overall, consensus was achieved for only 130 (33%) treatment specific questions. There was greater consensus for intralesional treatment of AA 19 (68%) followed by topical treatment 25 (43%). Consensus was achieved in 45 (36%) questions pertaining to systemic therapies in AA. The categories with the least consensus were phototherapy and non-prescription therapies. LIMITATIONS/CONCLUSIONS:The study included a comprehensive list of systemic treatments for AA, but not all treatments used. CONCLUSION/CONCLUSIONS:Despite divergent opinions amongst experts, consensus was achieved on a number of pertinent questions. The concluding statement also highlights areas where expert consensus is lacking and where an international patient registry could enable further research.

Well-known causes of zinc deficiency, also referred to as acrodermatitis enteropathica (AE), include defects in intestinal zinc transporters and inadequate intake, but a rare cause of acquired zinc deficiency discussed here is an iatrogenic nutritional deficiency caused by parenteral nutrition administered without trace elements. While zinc-depleted parenteral nutrition causing dermatosis of acquired zinc deficiency was first reported in the 1990s, it is now again relevant due to a national vitamin and trace element shortage. A high index of suspicion may be necessary to diagnose zinc deficiency, particularly because early clinical findings are nonspecific. We present this case of acquired zinc deficiency in a patient admitted to a pediatric intensive care unit for respiratory distress and atypical pneumonia, who subsequently developed a severe bullous eruption due to iatrogenic zinc deficiency but was treated effectively with enteral and parenteral zinc supplementation, allowing for rapid re-epithelialization of previously denuded skin.

Interfollicular epidermal melanocytes are continually subjected to environmental challenges and activate protective stress responses for survival. Dysregulation of these responses may increase susceptibility to depigmentation typical of chemical leukoderma (depigmentation limited to site of exposure) and vitiligo (progressive depigmentation due to an autoimmune response). We delineated the response of melanocytes from normally pigmented individuals (NMs) to challenge with the chemotoxins monobenzone (MBEH) and 4-tertiary butyl phenol (4-TBP) and determined that the unfolded protein stress response (UPR) was activated following exposure. The UPR, a key survival pathway, is activated when the homeostasis of the Endoplasmic Reticulum (ER) is disrupted, for example by cellular oxidative stress induced by chemotoxin exposure. The UPR, which consists of three signal transduction pathways initiated by PERK, IRE1 or ATF6 respectively, promotes restoration of ER homeostasis and survival. In this study, we assessed the cytoprotective effect of the PERK arm of the UPR. PERK phosphorylates a number of proteins including the eukaryotic translation initiation factor, eIF2alpha. We treated melanocytes with the PERK kinase inhibitor GSK2606414 and confirmed efficacy by monitoring eIF2alpha phosphorylation, which was reduced after treatment. Melanocytes were then dosed with MBEH in the presence or absence of GSK2606414. The inhibitor sensitized melanocytes to MBEH (Cleaved/c-PARP observed with 250 muM MBEH + GSK2606414, compared to 400 muM MBEH + vehicle). To further investigate the role of PERK in melanocytes, we used a gene silencing (shRNA) approach to knockdown expression. An 88% decrease in viability (p < 0.0001) was observed 3 days post-infection (shPERK versus scrambled/shNT). Cultures were maintained for 14 days when viability was found to be improved (40% decrease in viability, p < 0.0001). Melanocytes that survived prolonged PERK downregulation adapted and could be maintained in culture (shPERKLT). Survival correlated with a paradoxical increase in phospho-eIF2alpha and reduced sensitivity to MBEH (c-PARP observed with 500 muM MBEH in shPERKLT versus 400 muM MBEH in shNT cells). Intriguingly, while eIF2alpha is not typically phosphorylated in unstressed cells, a fraction of eIF2alpha was phosphorylated in melanocytes at baseline. Thus PERK may play a role in determining melanocyte viability and sensitivity to chemotoxins

Vitiligo, an acquired depigmentation disorder, results from autoimmune targeting of melanocytes. Vitiligo can be triggered following exposure to phenols such as monobenzone (MBEH) and 4-tertiary butyl phenol (4-TBP). Melanocytes from individuals with idiopathic vitiligo (trigger is not known) are more sensitive to MBEH and 4-TBP. We hypothesized that stress response pathways activated following exposure to vitiligo triggers may be dysregulated in individuals who develop the disorder. We delineated the response of melanocytes from normally pigmented individuals (NMs) to challenge with MBEH and 4-TBP and identified two key survival pathways activated following exposure: the NRF2-regulated antioxidant response and the unfolded protein stress response (UPR). NRF2 knockdown sensitized NMs to MBEH (p < 0.0001), while NRF2 activation by knockdown of its repressor KEAP significantly decreased sensitivity (p < 0.0001). Similarly, inhibition of the PERK-eIF2alpha arm of the UPR with the chemical inhibitor GSK2606414 increased sensitivity to MBEH (cleaved PARP observed at 250 muM MBEH with GSK2606414 and 400 muM without). Activation of NRF2-regulated antioxidant responses and PERK-mediated phosphorylation of eIF2alpha following MBEH exposure was impaired in melanocytes from individuals who developed vitiligo. We have thus identified two stress response pathways that may be dysfunctional in vitiligo and contribute to the onset of depigmentation

PURPOSE/OBJECTIVE:Washing and over-the-counter cleansers are common interventions in acne vulgaris (AV), but the clinical evidence for their benefit is poorly understood. This systematic review presents clinical studies of washing and cleanser efficacy in acne vulgaris to guide treatment recommendations of dermatologists. MATERIALS AND METHODS/METHODS:We surveyed English-language articles indexed in MEDLINE (1951-March 2017) and EMBASE (1974-March 2017). Articles were required to be prospective studies of a single over-the-counter cleanser or washing intervention in AV with an objective AV outcome measurement published in a peer-reviewed journal. RESULTS AND CONCLUSIONS/CONCLUSIONS:Fourteen prospective studies representing 671 participants were included in this review. Modalities investigated included face washing frequency, true soap/syndet cleansing bars, antiseptic cleansers, alpha and beta-hydroxy (i.e. salicylic) acid cleansers, and several proprietary formulations. Given the low number of well-performed clinical studies of cleansers and washing, it is difficult to formulate reliable recommendations. We hope that our findings highlight the necessity of further investigation in this area.

Tinea incognito (TI) describes a common dermatophytosis with often atypical clinical features attributed to inappropriate use of topical immunomodulatory agents, usually corticosteroids. Given the high prevalence of TI and limited literature detailing this condition, we conducted a retrospective review of cases of pediatric dermatophytosis presenting to the Faculty Group Practice of the Ronald O. Perelman Department of Dermatology, New York University School of Medicine (New York, New York), between 2005 and 2016. Among microbiologically confirmed dermatophytosis cases, we found that even with prior treatment, TI often presented with classic features of tinea such as annularity and scale. The majority of cases were treated with oral antifungals, though some were treated with topical antifungals alone. This case series underscores the need to maintain a high clinical suspicion for TI.

Keratosis pilaris is a common skin disorder comprising less common variants and rare subtypes, including keratosis pilaris rubra, erythromelanosis follicularis faciei et colli, and the spectrum of keratosis pilaris atrophicans. Data, and critical analysis of existing data, are lacking, so the etiologies, pathogeneses, disease associations, and treatments of these clinical entities are poorly understood. The present article aims to fill this knowledge gap by reviewing literature in the PubMed, EMBASE, and CINAHL databases and providing a comprehensive, analytical summary of the clinical characteristics and pathophysiology of keratosis pilaris and its subtypes through the lens of disease associations, genetics, and pharmacologic etiologies. Histopathologic, genomic, and epidemiologic evidence points to keratosis pilaris as a primary disorder of the pilosebaceous unit as a result of inherited mutations or acquired disruptions in various biomolecular pathways. Recent data highlight aberrant Ras signaling as an important contributor to the pathophysiology of keratosis pilaris and its subtypes. We also evaluate data on treatments for keratosis pilaris and its subtypes, including topical, systemic, and energy-based therapies. The effectiveness of various types of lasers in treating keratosis pilaris and its subtypes deserves wider recognition.