Faculty Bibliography

An 11-year-old girl with a history of diabetes mellitus type I and celiac disease presented with multiple, depressed patches of purple-brown skin on the right lower extremity and central back, with histopathologic features of early morphea. Though morphea may coexist with other autoimmune diseases, its presentation with both diabetes mellitus type I and celiac disease has not yet been described

Summary Accumulation of proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), comprising three signaling pathways initiated by Ire1, Perk and Atf6 respectively. Unfolded protein response activation was compared in chemically stressed murine wildtype melanocytes and mutant melanocytes that retain tyrosinase in the ER. Thapsigargin, an ER stressor, activated all pathways in wildtype melanocytes, triggering Caspase 12-mediated apoptosis at toxic doses. Albino melanocytes expressing mutant tyrosinase showed evidence of ER stress with increased Ire1 expression, but the downstream effector, Xbp1, was not activated even following thapsigargin treatment. Attenuation of Ire1 signaling was recapitulated in wildtype melanocytes treated with thapsigargin for 8 days, with diminished Xbp1 activation observed after 4 days. Atf6 was also activated in albino melanocytes, with no response to thapsigargin, while the Perk pathway was not activated and thapsigargin treatment elicited robust expression of the downstream effector CCAAT-enhancer-binding protein homologous protein. Thus, melanocytes adapt to ER stress by attenuating two UPR pathways

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) to enable cells to recover from ER stress. If the UPR fails to restore normal ER function, apoptosis is induced instead. We have demonstrated that melanocytes have the capacity to adapt to chronic ER stress and escape from UPR-induced cell death. Mutations in the pinkeyed dilution/oculocutaneous albinism type 2 (Oca2)-gene result in altered tyrosinase processing and trafficking in melanocytes, accompanied by accumulation of misfolded tyrosinase in the ER. Despite this chronic overload of ER-retained tyrosinase, Oca2-mutant melanocytes do not show diminished viability suggesting that they have adapted to the ER stress. The aim of this study is to elucidate the process of adaptation to ER stress in melanocytes. Differential protein expression between wildtype (melan-a) and Oca2-melanocytes (melan-p) was analyzed using microarray assays and Western blotting. Adaptation to chronic ER stress was studied by comparing wildtype murine melanocytes dosed with the ER stressor thapsigargin to Oca2-mutants. We observed increased Ire1 expression in Oca2-melanocytes compared to wildtype, indicating that this UPR pathway is activated. Prolonged Ire1 signaling after UPR activation in stressed cells has been found to promote cell survival. In addition, expression of proteins involved in the pro-apoptotic Perk pathway appears to be decreased in Oca2- melanocytes. However, Oca2-mutants also demonstrated up-regulation of Chop, which typically promotes cell death by down-regulating expression of anti-apoptotic Bcl-2. Remarkably, the pro-apoptotic effects of Chop expression appear to be mitigated by up-regulation of Bcl-2 expression. Furthermore, expression of pro-apoptotic proteins such as Bid and caspase 1 were down-regulated in Oca2-mutant melanocytes as compared to wildtype cells. Acute ER stress (0-24 h) in wildtype melanocytes activated all three UPR pathways, but Ire1 signaling was attenuated in chronically stressed cells (12 days), while Perk signaling was maintained. Cell viability did not change during this period. Thus, wildtype melanocytes adapted to chronic ER stress despite sustained activation of pro-apoptotic pathways. These results indicate that chronically stressed wildtype melanocytes and Oca2-mutant melanocytes adapt to ER stress by differential mechanisms. Melanocytes may thus adapt to ER-stress by multiple mechanisms, some of which may account for the increased drug resistance observed in melanocytes and melanoma

Background: Accumulation of immature proteins in the Endoplasmic Reticulum (ER) causes organelle stress that is counteracted by the unfolded protein stress response (UPR). Three pathways compose the UPR and are initiated when Ire1, Perk and Atf6 respectively, are released from heterodimers formed with the ER chaperone BiP. The UPR signals down-regulation of global translation and increased ER-chaperone expression. Ire1 is phosphorylated, activating its nuclease activity, which leads to splicing of the X-box binding protein 1 (Xbp1). The spliced RNA encodes a transcription factor that regulates expression of a subset of genes that comprise one arm of the UPR. Apoptosis is initiated if homeostasis is not re-established following UPR activation. The Ire1 pathway has recently been shown to play arole in the development of vitiligo, while the UPR has been implicated in keratinocyte response to UVB and in drug resistance in melanoma. We therefore investigated the melanocyte response to ER stress induced by chemical ER disruptors and by oxidative stress (the mechanism by which we propose UV exposure perturbs the melanocyte ER). Method: Wild-type mouse melanocytes were treated with thapsigargin, which disrupts the calcium balance in the ER causing UPR induction, and cells harvested at 6, 12 and 24 h. Western blot and microarray analyses were performed and data evaluated to identify pathways activated by thapsigargin treatment. In addition, melanocytes were dosed with compounds that induce oxidative stress. RNA was harvested and evaluated for activation of the UPR by Xbp-1 splicing. Results: IRE1 expression was upregulated within 6 h of treatment with thapsigargin, which promoted splicing of XBP1 mRNA and activation of its transcription factor activity. PERK and its downstream target CHOP were phosphorylated and HA-tagged ATF6 was cleaved within 6-12 h of treatment. Up-regulation of BiP and ER chaperones such as Ero1 and down-regulation of tyrosinase were also observed. In addition, several p53-related pathways were modulated in response to thapsigargin. Induction of oxidative stress was found to induce Xbp1 splicing. Conclusions: The UPR may play an important role in melanocyte response to stress, including response to oxidative stress induced by UV exposure. Dysfunction of this response may contribute to initiation and progression of vitiligo and drug resistance in melanoma

Summary Background Hair loss is an unwelcome event at any age, but it can be particularly distressing for adolescents and their families. While androgenetic alopecia (AGA) is the most common form of hair loss in adults, little is known about its prevalence, clinical features and response to treatments in the paediatric population. Objectives To better characterize the causes of alopecia in a paediatric population. Methods We performed a retrospective chart review to identify all patients with hair loss seen in an academic paediatric dermatology practice at New York University over a 12-year period to better characterize the causes of alopecia in this population. We review the clinical and histological features, natural progression and associated laboratory abnormalities of AGA in 57 paediatric patients. Results AGA was identified as the most frequent cause of hair loss in adolescents and the second most common diagnosis overall. The male to female ratio was 2 : 1 and the average age at initial presentation with AGA was 14.8 years. Adolescent girls had diffuse thinning or thinning at the crown, and boys frequently presented with female pattern hair loss. When biopsies were performed, perifollicular inflammation was a common finding. A family history of AGA was reported in 83% of patients. Laboratory evaluation for androgens revealed polycystic ovarian syndrome in three girls and late-onset congenital adrenal hyperplasia in one boy. Conclusions AGA is the most common form of hair loss in adolescents, and can be the presenting sign of an underlying endocrine disorder. An accurate and timely diagnosis is essential for appropriate medical and psychosocial intervention when warranted

OBJECTIVES: To better categorize the epidemiologic profile, clinical features, and disease associations of loose anagen hair syndrome (LAHS) compared with other forms of childhood alopecia. DESIGN: Retrospective survey. SETTING: Academic pediatric dermatology practice. Patients Three hundred seventy-four patients with alopecia referred from July 1, 1997, to June 31, 2007. MAIN OUTCOME MEASURES: Epidemiologic data for all forms of alopecia were ascertained, such as sex, age at onset, age at the time of evaluation, and clinical diagnosis. Patients with LAHS were further studied by the recording of family history, disease associations, hair-pull test or biopsy results, hair color, laboratory test result abnormalities, initial treatment, and involvement of eyelashes, eyebrows, and nails. RESULTS: Approximately 10% of all children with alopecia had LAHS. The mean age (95% confidence interval) at onset differed between patients with LAHS (2.8 [1.2-4.3] years) vs patients without LAHS (7.1 [6.6-7.7] years) (P < .001), with 3 years being the most common age at onset for patients with LAHS. All but 1 of 37 patients with LAHS were female. The most common symptom reported was thin, sparse hair. Family histories were significant for LAHS (n = 1) and for alopecia areata (n = 3). In 32 of 33 patients, trichograms showed typical loose anagen hairs. Two children had underlying genetic syndromes. No associated laboratory test result abnormalities were noted among patients who underwent testing. CONCLUSIONS: Loose anagen hair syndrome is a common nonscarring alopecia in young girls with a history of sparse or fine hair. Before ordering extensive blood testing in young girls with diffusely thin hair, it is important to perform a hair-pull test, as a trichogram can be instrumental in the confirmation of a diagnosis of LAHS