Dermato-Endocrinology

As you all are aware, this journal has been launched to help developing and to serve as a speaking tube for the rapidly growing and exciting field of dermato-endocrinology that has been underestimated for much too long. A few decades ago, the generally accepted views on the function of the skin indicated a more passive role as a border against the environment. However, in recent years we have learned that, besides other important functions, the skin represents a fascinating, unique and important endocrine organ that may act in an autocrine or paracrine fashion. Consequently, our knowledge about the function and importance of the skin as an endocrine organ has greatly increased during the last decades. Correlatives for many of the classical endocrine pathways, including parathyroid hormone-, thyroid hormone- and vitamin D pathways have now also been found in the skin. The articles in this issue of Dermato-Endocrinology reflect the importance of the cutaneous endocrine system not only for a broad variety of common skin diseases but also for internal medicine and other medical disciplines.

In the first paper, Moan et al.1 report time trends and latitude dependence of uveal and cutaneous malignant melanoma induced by solar radiation. They evaluated the role of solar radiation in uveal melanoma etiology by studying the time and latitude dependency of the incidence rates of this melanoma type in comparison with those of cutaneous malignant melanoma (CMM). They found a marked north-south gradient of the incidence rates of CMM in Norway, with three times higher rates in the south than in the north. In contrast, no such gradient was found for uveal melanoma. They concluded that their data generally support the assumption that uveal melanomas are not generated by ultraviolet (UV) radiation and that solar UV, via its role in vitamin D photosynthesis, may have a protective effect.

In the following review, Sabine Fimmel and Christos C. Zouboulis2 investigate comorbidities of hidradenitis suppurativa (acne inversa). Comorbidities of hidradenitis suppurativa (acne inversa) were reviewed by extracting original and review publications included in MEDLINE, EMBASE and COCHRANE libraries using the terms “hidradenitis,” “Verneuil” and “acne inversa.” They found that follicular occlusion disorders, inflammatory bowel diseases, especially Crohn disease, spondylarthropathy, other hyperergic diseases, genetic keratin disorders associated with follicular occlusion and squamous cell carcinoma were the most common hidradenitis suppurativa comorbid diseases. They concluded that a first classification of these major comorbidities and their possible genetic background reveals a list of chromosome loci and genes, which could be hidradenitis suppurativa candidates. Interestingly, most of these diseases belong to the group of auto-inflammatory disorders, where Th17 cell cytokines seem to play a central role.

The short communication from Nakamura et al.3 reports a case with acute onset disseminated superficial porokeratosis associated with exacerbation of diabetes mellitus due to development of anti-insulin antibodies. The development of disseminated superficial porokeratosis is occasionally observed in association with renal transplant, autoimmune diseases, and various hematological disorders, suggesting that a certain immunosuppression may trigger a wide-spread abnormal keratinization. Interestingly, the authors here report for the first time a case of sudden onset disseminated superficial porokeratosis associated with an exacerbation of diabetes mellitus due to an anti-insulin antibody formation.

The following paper of Schlumpf et al.4 summarizes conclusions drawn concerning fundamental questions to sun protection during a continuous education symposium at the University of Zürich entitled “Vitamin D, immune system and sun protection.” Since exposure to sunlight is a main factor in the development of non-melanoma skin cancer and because there are associations between malignant melanoma and short-term intense ultraviolet (UV) exposure, particularly burning in childhood, strict protection from UV-radiation is recommended in many skin cancer prevention campaigns. However, it is well known that up to 90% of all requisite vitamin-D has to be formed within the skin through the action of the sun—a serious problem, for a connection between vitamin-D deficiency, demonstrated in epidemiological studies, and various types of cancer and other diseases has been confirmed. A UVB-triggered autonomous vitamin D synthesis pathway has recently been described in skin, producing the active Vitamin D metabolite calcitriol. This cutaneous vitamin D pathway is unique. Keratinocytes and dendritic cells can convert vitamin D to the biologically active vitamin D metabolite calcitriol. Interestingly, cutaneous T cells activated in the presence of calcitriol express the chemokine receptor CCR10, attracting them to the chemokine CCL27 that keratinocytes express selectively in the epidermis. As a consequence, T cells migrate from dermal layers of the skin to the epidermis under UV radiation. Thus, calcitriol has endocrine roles beyond its calciotropic action, including cell growth and cancer prevention. Strict sun protection procedures to prevent skin cancer may induce the risk of vitamin-D deficiency. As there is evidence that the protective effect of less intense solar radiation can outweight its mutagenic effect, balanced approaches to sun protection should be sought.

Schmaltz et al.5 explain in their article the skin manifestations in Tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant inherited disease that belongs to the group of hereditary fever syndromes, that are also named hereditary auto-inflammatory syndromes. TRAPS is characterized by a variety of naturally occurring mutations in a TNF receptor (TNFR), that affect the soluble TNFRSF1A gene in the 12p13 region. In some patients, the pathogenesis of TRAPS involves defective TNFRSF1A shedding from cell membranes in response to varying stimuli. TRAPS is characterized by the periodic occurrence of a broad variety of different clinical symptoms that represent an acute-phase response, including fever and pain in the joints, abdomen, muscles, skin, or eyes, with broad variations across patients. In many cases, skin involvement is present that may include migratory patches, skin rashes, erysepela-like erythema, edematous plaques, urticaria, periorbital edema, and/or conjunctivitis. The histology of skin lesions in TRAPS is nonspecific, in general a perivascular dermal infiltrate of lymphocytes and monocytes can be found. Cutaneous findings are of particular importance in TRAPS: they have been shown to give direction to the diagnosis of TRAPS and in most cases their treatment is challenging. As the incidence of TRAPS is very low, no prospective randomized controlled trials and only a few studies with case numbers up to twenty-five patients have been published. No guidelines for TRAPS treatment have been established so far. This review summarizes our present knowledge about pathogenesis, clinical outcome and treatment options of skin manifestations in TRAPS.

Grant and Boucher6 discuss in their review whether Hill's criteria for causality in a biological system are satisfied for vitamin D and periodontal disease. They report that there is mounting evidence that periodontal disease (PD) is linked to low serum 25-hydroxyvitamin D [25(OH)D] concentrations in addition to recognized risk factors like diet and smoking. The authors explain that evidence for strength of association, consistency, cohesion and ‘dose-effects’ (biological ‘gradients’) include strong inverse correlations between serum 25(OH) and both PD cross-sectionally and that PD is consistently more prevalent in darker vs. lighter skinned people and increases at higher latitudes with analogy for gingivitis and for disorders associated with PD whose risks increase with hypovitaminosis D. Evidence for plausibility includes that vitamin D increases calcium absorption and protects bone strength; induces formation of cathelicidin and other defensins that combat bacterial infection; reduces tissue production of destructive matrix metalloproteinases actively associated with PD and that prevalence of PD varies with common vitamin D receptor polymorphisms. Experimental evidence from limited supplementation studies (using calcium and vitamin D) shows that supplementation reduces tooth loss. Thus, existing evidence for hypovitaminosis D as a risk factor for PD to date meets Hill's criteria for causality in a biological system. The authors conclude that further experimental evidence for effectiveness and temporality, preferably from randomized controlled trials of vitamin D supplementation (adjusting for other PD risk factors including diet and smoking to reduce confounding) are necessary to confirm causality. If this hypothesis can be confirmed, dentists and periodontists could perform a valuable service to their patients by discussing the importance of adequate vitamin D status and on how to avoid deficiency.

In the following paper, Mascitelli et al.7 comment on whether there is a connection between the widespread use of statins and the epidemic of nonmelanoma skin cancer. They hypothesize that some of the mechanisms involved in the “epidemic” of nonmelanoma skin cancer might also be due to widespread use of cholesterol lowering statin drugs.

Last but not least, Kyo et al.8 report their clinical findings in an adolescent girl presenting with an axillary accessory breast associated with galactorrhea. Interestingly, the galactorrhea ceased after surgical removal of the accessory breast.

In summary, the articles in this issue reflect many of the interesting facettes of Dermato-Endocrinology and the importance of the cutaneous endocrine system not only for a broad variety of common skin diseases but also for internal medicine and other medical disciplines.