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Disorders of Pigmentation
Published in Ayşe Serap Karadağ, Lawrence Charles Parish, Jordan V. Wang, Roxburgh's Common Skin Diseases, 2022
Michael Joseph Lavery, Charles Cathcart, Hasan Aksoy
Melanin is derived from phenylalanine and passes through several steps before forming pheomelanin, eumelanin, or neuromelanin (Figure 25.1). Pheomelanin produces yellow-red pigment, and eumelanin produces brown-black pigment. The process of determining which pigment is produced is controlled by the melanocortin-1 receptor (MC1R). A loss of function in this receptor leads to increased production of pheomelanin and can increase the risk of melanoma from ultra-violet radiation. Genetic variations in the MC1R gene have been identified in malignant melanoma and oculocutaneous albinism.
Disorders of pigmentation
Published in Rashmi Sarkar, Anupam Das, Sumit Sethi, Concise Dermatology, 2021
It has to be determined whether the pigmentation is due to melanin or some other pigment (Table 19.2). Generalized melanin hyperpigmentation is seen in Addison’s disease due to destruction of the adrenal cortex from tuberculosis, autoimmune influences, metastases, or amyloidosis. Pigmentation is marked in the flexures, sites of trauma, scars, and sun-exposed areas, but the mucosae and nails are also hyperpigmented. The pigmentation is mediated via activation of the melanocortin-1 receptor. The diagnosis is supported by hypotension, hyponatraemia, and extreme weakness. The hyperpigmentation is due to an excess of pituitary peptides resulting from the lack of adrenal steroids. After bilateral adrenalectomy, pigmentation may be extreme (Nelson’s syndrome). This is associated with an enlarged pituitary gland, elevated fasting plasma ACTH level, and neurologic symptoms. Pheochromocytoma is characterized by Addisonian pigmentation due to ectopic ACTH and MSH production. Carcinoid syndrome manifests with diffuse hyperpigmentation due to an MSH-secreting tumor; along with pellagroid dermatitis.
Newer Agents for Topical Treatment
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Devinder Mohan Thappa, Malathi Munisamy
Alpha-melanocyte−stimulating hormone agonistic analog: Afamelanotide, a potent and longer lasting synthetic α-MSH analog, is a potentially effective treatment for vitiligo which is available as a monthly 16-mg subcutaneous implant. It targets the key pathway of melanogenesis by binding to melanocortin-1 receptor (MC1R) and stimulates pigmentation and increases proliferation of melanocytes. Since MC1R is not expressed by melanocyte stem cells, afamelanotide has no effect on the differentiation of melanocyte stem cells. Hence afamelanotide needs to be combined with phototherapy for increased efficacy, as phototherapy induces melanoblast differentiation, proliferation, and eumelanogenesis and thus combination therapy would increase the speed and extent of repigmentation. Afamelanotide causes potent tanning, causing a major concern in fair-skinned individuals, as it results in sharp color contrast. Hence the best results were obtained in dark-skinned individuals [3,6,18].
Emerging drugs for the treatment of scleroderma: a review of recent phase 2 and 3 trials
Published in Expert Opinion on Emerging Drugs, 2020
David Roofeh, Alain Lescoat, Dinesh Khanna
Non-canonical and canonical TGF-β signaling plays a central role in fibrosis and despite disappointing results of Riociguat, other drugs targeting these pathways need to be tested in SSc, alone or in combination. Pirfenidone down-regulates smad3 dependent- and Akt-dependent TGF-β signaling in primary human lung fibroblasts [93] and is endorsed for the management of idiopathic pulmonary fibrosis. The multicenter randomized placebo-controlled Scleroderma Lung Study III will evaluate the benefit of pirfenidone as add-on to a background therapy of MMF (NCT03221257). Selected TGF-β targeting by fresolimumab, an engineered human monoclonal Ig that neutralizes the three major isoforms of TGF-β, namely, β1, β2, and β3, has shown promising results on mRSS in explorative studies although its effects still need to be explored in RCTs [94]. A Phase 1b trial targeting TGF-β1 and β3 (due to potential toxicity associated with targeting β2) showed benefits on skin score and was well tolerated [95]. MT-7117 is a novel orally administered, small molecule, which acts as an agonist of melanocortin-1 receptor (MC1R). MC1R is activated by α-melanocyte-stimulating hormone which can be locally synthesized in response to sunlight exposure. In a bleomycin skin model, treatment with MCIR agonist reduced skin fibrosis and collagen content [96].
Evolution of approaches to identify melanoma missing heritability
Published in Expert Review of Molecular Diagnostics, 2020
Sanger sequencing has also allowed the association of polymorphisms in the Melanocortin 1 Receptor (MC1R) gene, which confer the red hair phenotype in an autosomal dominant or recessive manner depending on the variant, and the occurrence of melanoma [24]. This gene, which encodes for the α melanocyte-stimulating hormone (α-MSH) and is highly polymorphic in the Caucasian population, confer a moderate risk of melanoma with mechanisms that are likely not limited to the resulting skin color [25]. In fact, the association of specific MC1R variants and melanoma in dark-skinned individuals, as well as studies on preclinical models [26,27] support the hypothesis that the pheomelanin that accumulates due to specific MC1R variants may act as a carcinogen, even without high UV exposure.
Association between sensory processing and dental fear among female undergraduates in Japan
Published in Acta Odontologica Scandinavica, 2019
Mika Ogawa, Nozomu Harano, Kentaro Ono, Yukiyo Shigeyama-Tada, Tomoko Hamasaki, Seiji Watanabe
Difference in sensory processing may have a role in the development and maintenance of dental fear as a biological and genetic factor. Genetic contributions to the development/maintenance of dental fear are reported. Dental fear is shown to be heritable and related to the fear of pain [21,22,57]. Variation in the melanocortin-1 receptor gene, which is associated with red hair colour and lower sensitivity to local anaesthesia, has been identified as a predictor of dental fear [57]. Because sensory processing is based on genetic factors [26], it is conjectured to play a role in genetic and biological predispositions to dental fear and leads to fear conditioning and/or cognitive and personality vulnerability (Figure 2).