Faculty Bibliography

OBJECTIVES: Vitiligo commonly presents in children, with half of all cases developing before 20 years of age. Although studies have characterized differences between pediatric and adult vitiligo, little is known about vitiligo presenting in early childhood. The purpose of this study was to compare clinical features of early-onset (<3 years old) and later-onset (3-18 years old) childhood vitiligo. METHODS: This retrospective case series examined patients given a diagnosis of vitiligo in a pediatric dermatology practice at an academic medical center from 1990 to 2014. Characteristics of the early- and later-onset groups were compared by chi2 and t test for categorical and continuous variables, respectively. RESULTS: Of the 208 children in the study, 31 had early-onset and 177 had later-onset disease. Early-onset vitiligo was associated with higher percentages of body surface area involvement and increased rates of disease progression during an average 1.9 years of follow-up. There were no significant differences between the 2 groups in repigmentation, vitiligo type, halo nevi, gender ratio, or personal and family history of autoimmune diseases. LIMITATIONS: This was a retrospective, single-institution study. CONCLUSION: Patients given a diagnosis of vitiligo at younger ages tend to have more extensive and progressive disease.

Isotretinoin, the most effective therapy for severe acne, has engendered controversy. These controversies impact dermatologists' opinions of isotretinoin and prescription behaviors. This study was designed to characterize dermatologists' opinions of controversies surrounding isotretinoin, as well as counseling and prescribing practices. A 25-question survey was emailed to 7,013 dermatologists included in a proprietary database (MBD, Inc.) and anonymous responses were collected. 591 board-certified dermatologists participated. Thirty-seven percent of the responding dermatologists believe that isotretinoin may cause psychiatric disturbances. Dermatologists' opinions on this relationship did not significantly impact prescription practices in patients with history of depression (P=0.056) or in patients being treated with an antidepressant (P=0.118). A larger percentage of dermatologists surveyed believe there is a causal relationship between isotretinoin and psychiatric disturbances than isotretinoin and IBD. Of the surveyed dermatologists, 2.7% believe there is a causal association between isotretinoin and inflammatory bowel disease IBD. In addition, physicians with 20 or fewer years of experience, which included 50% of the responding dermatologists, were significantly less likely to have read the patient brochure (P=0.004), and more likely to prescribe isotretinoin to patients who had not failed systemic antibiotics (P =0.015). This questionnaire also may highlight a practice gap, as more recently trained dermatologists appear less likely to require failure of systemic antibiotics prior to initiating isotretinoin

J Drugs Dermatol 2015;14(2):184-189.

Importance: Hermansky-Pudlak syndrome (HPS) is a rare genodermatosis characterized by oculocutaneous albinism, platelet dysfunction, and in some patients, pulmonary fibrosis and granulomatous colitis. The granulomatous inflammation in the bowel of patients with HPS can be indistinguishable clinically and histologically from that of Crohn disease (CD); however, mucocutaneous granulomatous lesions have not been considered among the typical skin findings of HPS. Observations: We report a case of an albino woman in her 40s with a history of CD and pulmonary fibrosis who presented with ulcers, plaques, and nodules in the vulva, perineum, inguinal creases, and left axilla. These cutaneous findings had the typical clinical and histologic findings of metastatic cutaneous CD. However, she also had a genetically confirmed diagnosis of HPS. Conclusions and Relevance: It is unclear whether our patient's cutaneous findings were due to CD or secondary to HPS. This report reviews the features of HPS and CD, 2 entities characterized by a granulomatous inflammatory reaction pattern but with unique genetic and clinical features, and discusses the possible overlap between the 2 diagnoses.

Vitiligo is characterized by depigmented skin patches due to localized loss of melanocytes. The etiology of vitiligo is not fully understood, particularly the mechanisms that initially trigger depigmentation. Induction of oxidative stress is thought to be a common attribute of trigger events in vitiligo, while autoimmunity contributes to disease progression. In this study we sought to identify mechanisms that link disease triggers and the spread of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions, even when cultured in vitro, is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress caused by trigger events extends to the ER where redox reactions that facilitate protein folding are disrupted and that the subsequent accumulation of misfolded peptides activates the unfolded protein response (UPR). The UPR initially signals a reduction in global protein synthesis, while promoting expression of folding chaperones in order to restore homeostasis. Sustained UPR activation has been implicated in several autoimmune disorders and may play a role in vitiligo. We used 4-tertiary butyl phenol (4-TBP) and monobenzyl ether of hydroquinone (MBEH), phenols known to trigger occupational vitiligo, to study pathways that contribute to melanocyte loss. Expression of key UPR components was increased following exposure of human melanocytes to the phenols. In addition, we observed UPRmediated increases in pro-inflammatory interleukin-6 (IL6) and IL8, which have been shown to be increased in the skin of patients with vitiligo. We next investigated UPR-regulated pathways that may contribute to cytokine production and determined that cross-talk between the UPR and the nuclear factor-kappa B (NFkB) pathway contributes to the increase in expression of IL6 and IL8 following phenol exposure. Identification of the pathways that link exposure to vitiligoinducing triggers and onset of autoimmunity may allow for the development of more effective therapies for this disfiguring di!

Vitiligo is a common disorder characterized by progressive melanocyte death. Vitiligo can be induced in an occupational setting by exposure to vitiligo-inducing phenols (VIPs) such as 4 tert-butyl phenol (4TBP) and monobenzyl ether of hydroquinone (MBEH). These VIPs are believed to specifically target melanocytes due to their structural similarity to tyrosine and competition for binding to tyrosinase, the rate-limiting enzyme for melanin synthesis. By exposing normal melanocytes to VIPs and using microarray analysis and bioinformatics approaches for gene expression profiling, we identified key signaling pathways that are involved in the melanocyte response to VIP exposure. In particular, we hypothesized that exposure of primary human melanocytes to VIPs would result in oxidative stress that triggers antioxidant responses in order to protect melanocytes from cell death. Following melanocyte exposure to VIPs, HO-1 was upregulated (4TBP exposure: 5.49-fold; MBEH exposure: 25.98- fold). HO-1 is a direct target of Nrf2, a key regulator of the Nrf2- ARE antioxidant response. Activation of Nrf2 and its targets, HO- 1 and NQO1, was confirmed by conventional Western blot analysis and quantitative RT-PCR. We are now characterizing the mechanisms that regulate Nrf2 activation in response to VIPs. Additional antioxidants including SOD2 (4TBP: 10.5-fold; MBEH: 38.5-fold), peroxiredoxin 6 (4TBP: 2.44-fold; MBEH: 15.18-fold), and Nrf2 binding partners, MafK (4TBP: 2.12-fold; MBEH: 2.50- fold) and MafF (4TBP: 2.32-fold; MBEH: 3.16-fold) were also upregulated with VIP exposure and are being investigated further. Several studies have revealed dysfunctional antioxidant responses in melanocytes from patients with vitiligo, however the underlying mechanisms that reduce their efficacy are yet to be determined. We hypothesize that investigation of VIP-induced pathways may lead to the characterization of these mechanisms and provide opportunities for development of targeted therapeutics for the treatment of vitiligo