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Introduction: Actinic keratosis (AK) is a common precancerous skin lesion that arises on chronically UV-exposed skin and can progress to keratinocyte carcinoma. Objective: The aim of this study is to compare efficacy, safety, local skin reaction, time to wound closure, and patient preference of imiquimod (IMQ) 3.75% vs 5-fluorouracil (5-FU) 4% cream treatment for AKs. Methods: Two symmetrical contralateral areas of approximately 25 cm2 harboring a similar (≥5) number of AKs were selected and randomly assigned to IMQ 3.75% or 5- FU 4% cream treatment. The total number of AKs for each patient, was evaluated at baseline (T0) and 90 days after the end of treatments (T1). Local skin reaction (LSR) score was registered the day after the end of both treatments. Complete remission rate of lesions, cosmetic outcome, and patient preference of treatment were assessed after 90 days (T1). Results: The mean variation (ΔT0-T1) of AKs was not significantly different in patients treated with IMQ 3.75% and 5-FU 4% (p=0.35). The mean LSR was not significantly different for patients treated with IMQ 3.75% and 5-FU 4% (p=0.63). No difference in cosmetic outcome was observed in the 2 groups. Patient preference was equally distributed between the treatments. The mean time to wound closure after the end of the treatment was similar after IMQ 3.75% as compared to 5-FU 4% (p=0.83). Conclusions: This study reports a non-superiority of efficacy, tolerability, wound-healing time, and cosmetic outcome of topical IMQ 3.75% treatment compared to topical 5-FU 4% treatment in AK management.

Epidermolysis bullosa (EB) refers to a group of inherited disorders characterized by skin and mucous membrane fragility. This report presents the case of a 61-year-old Italian male with a localized variant of junctional epidermolysis bullosa (JEB) linked to the R795X mutation in the COL17A1 gene. The patient presented with bullous lesions, erosions, scars, and pigmentary changes on the pretibial areas and dystrophic nails. Genetic analysis confirmed the presence of the COL17A1 variant p.Arg795Ter (R795X) mutation, establishing a rare, localized variant of JEB. This case underscores the criticality of early and accurate diagnosis in the management of rare genetic disorders, as misdiagnosis can lead to ineffective treatments.

Aim: Abrocitinib is a JAK-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis (AD). We conducted a 16-week multicenter retrospective study to assess the short-term effectiveness and safety of abrocitinib in patients with moderate-to-severe AD.Our retrospective study included 85 adult patients from 14 Italian Dermatology Units affected by moderate-to-severe AD treated with abrocitinib 100/200 mg.Methods: Effectiveness of abrocitinib at weeks 4 and 16 was assessed by using the Eczema Area and Severity Index (EASI), the Investigator Global Assessment (IGA), the peak pruritus and sleep- Numerical Rating Scale (PP-NRS and S-NRS, respectively).Results: At week 16, improvement of at least 90% in EASI (EASI90) and IGA 0/1 was observed in 49.4% and 61.2% of patients, respectively. A reduction of at least 4 points in PP-NRS and S-NRS compared with baseline was achieved by 70.6% of patients for both endpoints. No significant safety reports were observed during the study period. Naïve patients had better rates of EASI 90 compared to patients who previously failed dupilumab.Conclusion: Our data confirm the effectiveness of abrocitinib in a real-world setting with better clinical responses at weeks 4 and 16, compared with Phase-III clinical trials. Longer analyses are required to further establish the safety profile of abrocitinib.

This study analyzed data from hospitals located in three regions of Ethiopia: Addis Ababa, Northeastern Ethiopia, and Southern Ethiopia. The research aims to investigate the prevalence and contributing factors associated with skin diseases in these regions. Skin disorders represent a significant health concern in these areas, though their epidemiology differs markedly from that observed in Western countries. We collected data from 6,449 patients, considering factors like education, income, cultural habits, and access to healthcare. Patients in Southern Ethiopia generally had higher Body mass indexes and incomes and were closer to dermatology centers. The findings indicate that infectious diseases and pruritic dermatoses are the most prevalent skin conditions in all regions. The study highlights the significant impact of socio-economic status on skin health, with higher education correlating with a lower incidence of infectious diseases and sebaceous gland disorders. Overcrowding was associated with a higher occurrence of infectious diseases, emphasizing the importance of hygiene and sanitary conditions. Additionally, the distance from a patient’s residence to the hospital influenced the duration of the disease, stressing the need for better accessibility to healthcare services. In conclusion, this research offers important insights into the spectrum of skin diseases in Ethiopia, emphasizing the role of socio-economic factors and the critical need for improved healthcare access and education.

Introduction: Pemphigus, an autoimmune disorder, significantly impacts the quality of life for those affected. Objective: This study examines the sleep quality in patients with pemphigus, a domain for which the existing literature provides limited data without a focused analysis. Methods: A total of 156 individuals, 52 in the case and 104 in the control group, completed several questionnaires (PSQI, GHQ12, and ABQOL). Disease severity was evaluated using the PDAI scale. Results: The case group exhibited significantly higher levels of psychological distress, reflected in GHQ12 scores (p=0.00), and notably poorer sleep quality compared to controls across various parameters (sleep latency [SL], disturbances [SDi], medication [SM], daytime sleep dysfunction [DSD]), and the global PSQI score (GS)] (p=0.00)]. Significant correlations were observed between PDAI scores and sleep duration (SDu) (p=0.01), SM (p=0.03), SL (p=0.03), and GS (p=0.00). An association was found between the equivalent steroid intake and SDu (p=0.00) as well as GS (p=0.02). No statistically significant correlation emerged between disease duration and PSQI scores. Our findings indicated a correlation between poor sleep quality and cutaneous rather than mucosal manifestations (p=0.01). Pemphigus affects sleep quality. Severe disease showed heightened SDi, correlating with higher steroid doses, and in the chronic phase, the impact seems to be more influenced by the pro-inflammatory stage of the disease. Patients with cutaneous pemphigus exhibit reduced sleep quality compared to those with oral pemphigus. Conclusion: Understanding that pemphigus worsens sleep quality can be beneficial for the holistic management of individuals with this condition.

Keratinocyte-derived skin cancers comprise basal cell carcinoma, squamous cell carcinoma, its precursor actinic keratosis, and Bowen’s disease. Historically, this group of neoplasms has been subsumed under the term non-melanoma skin cancer. However, the term non-melanoma skin cancer can be misleading and lacks precision. Therefore, more precise and reasonable terminology, valuing the relevance of keratinocyte-derived cancer, appears pertinent to meet its clinical and scientific significance. A group of experienced dermato-oncologists initiated a consensus approach to promote the use of the term “keratinocyte cancer” instead of “non-melanoma skin cancer” when referring to carcinomas and their precursors that are derived from keratinocytes. The vote among members of the consensus group indicated unanimous agreement on the consistent use of the term “keratinocyte cancer” instead of “non-melanoma skin cancer”. International delegates also voted in favour of the revised terminology. The more precise and, by means of etiopathogenesis, correct term “keratinocyte cancer” should be consistently used for malignancies originated from keratinocytes. This is expected to have a positive impact on patient–physician communication and gives better justice to this important group of keratinocyte-derived cancers.

Abstract Several comprehensive and updated guidelines are available on the management of psoriasis with systemic treatments. However, there is a lack of updates in recommendations and guidelines on topical treatments, particularly regarding the latest evidence and developments in treatment formulations. Consequently, a comprehensive literature review on this topic, considering the continuous evolution of knowledge and evaluation of the relevance of the available literature evidence, represents a current need to improve the topical management of psoriasis. This study critically appraises the available literature on all topical treatments of psoriasis from the past 20 years to address some relevant issues, such as the vehicle associated with the highest effectiveness, the best vehicle for improving patient adherence, and the best strategy in terms of efficacy and safety for long-term treatment. The greater effectiveness of the foam formulation was demonstrated for calcipotriene/betamethasone dipropionate (Cal/BD) administration compared with the gel and ointment. Without a direct comparison, matching-adjusted indirect comparison analyses support the superiority of the foam versus the cream overall. In addition, the reduced treatment period required by the Cal/BD foam (4 weeks) may favor this formulation over cream (8 weeks). The literature evidence, supported by a broad clinical experience, reported high rates of acceptability and adherence for the foam vehicle. A growing consensus is shared among dermatologists sustaining the proactive approach as the best option for the long-term topical treatment of psoriasis in adults. The Cal/BD foam is the only treatment for which the approved label allows biweekly maintenance use (proactive management), thus representing the first option for long-term topical treatment.

Cutaneous syncytial myoepithelioma (CSM) is a rare type of cutaneous neoplasm that typically presents as a solitary and well-circumscribed nodule on the skin. It predominantly occurs on the upper and lower extremities of adult patients. Immunohistochemically, CSM is characterized by the co-expression of smooth muscle and epithelial markers. Fluorescence in situ hybridization (FISH) targeting the EWSR1 gene rearrangement is an important diagnostic tool for CSM. In our case report, we found the focal positivity for CD34, which has never been previously observed; this was mostly confined to a central area of the neoplasm.

Abstract Methyl aminolevulinate (MAL) is a topical compound approved for use with photodynamic therapy (PDT) for the treatment of actinic keratosis (AK) and field cancerization in certain countries. There exists a high burden of disease for patients with AK: repeated treatments are required, there is a known risk of progression to keratinocyte carcinoma, and cosmetic appearance is affected. Delivery of PDT using MAL is a flexible treatment strategy available in many forms; red light, daylight, or artificial daylight can be used for illumination, all of which result in high AK clearance rates and low recurrence. MAL-PDT protocols continue to evolve to further improve adherence and treatment outcomes. Here, we used PubMed to search MEDLINE to identify guidelines, consensus recommendations, and studies describing the use of MAL for the treatment of AK. The aim of this targeted review is to consider various MAL-PDT treatment strategies on the basis of published literature, with a focus on personalizing treatment for the heterogeneous AK population.

BackgroundSince the early 1990s, Ultraviolet (UV) A1 phototherapy has been described as an effective and safe treatment of a multitude of skin disorders. However, after 30 years, its use has remained limited to few dermatological centers.ObjectiveTo analyze the changes over the years and the current position of UVA1 phototherapy through a Real-World Evidence (RWE) study at a single tertiary referral center.MethodsWe reviewed the medical files of 740 patients treated between 1998 and 2022. Treatment results were collected, efficacy was assessed by a grading scale and acute adverse effects were registered.ResultsWe treated patients with 26 different diseases. We registered marked improvement (MI) or complete remission (CR) in 42.8% of patients with morphea, 50% with Urticaria Pigmentosa, 40.7% with Granuloma annulare and 85.7% with skin sarcoidosis. Good results were obtained also in the treatment of chronic Graft Versus Host Disease (GVHD), Eosinophilic Fasciitis, Sclero-atrophic Lichen, skin manifestations of systemic lupus erythematosus and psoriasis of HIV+ patients. Systemic Sclerosis, Romberg’s Syndrome, Bushke’s Scleredema, Nephrogenic Fibrosing Dermopathy, REM Syndrome, Follicular Mucinosis, Pretibial Myxedema, Scleromyxedema, pemphigus foliaceus, chronic cutaneous lupus erythematosus, erythroderma of Netherton Syndrome and Necrobiosis Lipoidica were no or poorly responsive. In clinical indications where UVA1 was used as a second line phototherapy after narrow-band (NB)-UVB, we saw good MI or CR rates in Mycosis Fungoides (57% of patients), Atopic Dermatitis (33.9%), Pitiryasis Lichenoides chronica (50%), Pityriasis Lichenoides et varioliformis acute (75%) and Lymphomatod Papulosis (62.5%). Short-term adverse events were uncommon and mild.ConclusionOver the past decade, the annual number of treated patients has progressively declined for several reasons. Firstly, UVA1 phototherapy has taken a backseat to the cheaper and more practical NB-UVB phototherapy, which has proven effective for common indications. Secondly, the emergence of new, safe, and effective drugs for conditions such as atopic dermatitis, GVHD, and connective tissue disorders. Finally, our research has shown that UVA1 therapy is often ineffective or minimally effective for some rare diseases, contrary to previous case reports and small case series. Nonetheless, UVA1 continues to be a valuable treatment option for patients with specific skin disorders.

We present a case of erythropoietic protoporphyria (EPP) in a 21-year-old man who sought medical attention in April 2022 due to diffuse edema and erythema of the hands, which he had been experiencing since childhood and occurring shortly after sun exposure. The patient's medical history revealed a partial deletion of the long arm of chromosome 18. Based on the patient's medical background and clinical symptoms, we conducted various tests, including measuring total erythrocyte protoporphyrin levels and evaluating the fluorometric emission peak of plasma porphyrins using a spectrofluorometer. Additionally, a genetic analysis revealed a complete deletion of the FECH gene on one allele and the presence of an intronic variant on the other allele, identified as c.315–48T>C (IVS3–48T>C) and classified as a susceptibility polymorphism. In June 2022, the patient underwent an Afamelanotide implant, which resulted in an improvement in his clinical condition.

Most patients with psoriasis present with localized mild-to-moderate disease. In this case, the application of topical treatments in the first-line setting is recommended in most cases.Among different topical options, the fixed-dose combination of betamethasone dipropionate (BD) and vitamin D analogue (Cal) aerosol foam (Enstilar®, Leo Pharma) is approved as first-line topical therapy for the treatment of psoriasis in USA and the EU, due to its high efficacy and its favorable administration scheme.The PSO-LONG was the first trial to report on the long-term efficacy and safety of the Cal/DB foam treatment for the proactive management of psoriasis and now, the indications of Cal/BD foam included its use in the psoriasis maintenance treatment. However, the precise role of this treatment and the potential therapeutic schemes in the long-term management of psoriasis need further clarification.This Position Paper, authored by a group of Italian Expert Dermatologists, critically discusses the long-term management of psoriasis with Cal/BD foam in clinical practice. In particular, the biological rationale in the proactive treatment with Cal/BD foam and current evidence regarding this therapeutic approach are presented, along with its application also in patients with moderate-to-severe disease, difficult-to-treat lesions, or within combination regimens. In addition, strategies to improve adherence to long-term treatment of psoriasis are discussed,

Actinic keratoses are pre-malignant skin lesions that require personalized care, a lack of which may result in poor treatment adherence and suboptimal outcomes. Current guidance on personalizing care is limited, notably in terms of tailoring treatment to individual patient priorities and goals and supporting shared decision-making between healthcare professionals and patients. The aim of the Personalizing Actinic Keratosis Treatment panel, comprised of 12 dermatologists, was to identify current unmet needs in care and, using a modified Delphi approach, develop recommendations to support personalized, long-term management of actinic keratoses lesions. Panellists generated recommendations by voting on consensus statements. Voting was blinded and consensus was defined as ≥ 75% voting ’agree’ or ’strongly agree’. Statements that reached consensus were used to develop a clinical tool, of which, the goal was to improve understanding of disease chronicity, and the need for long-term, repeated treatment cycles. The tool highlights key decision stages across the patient journey and captures the panellist’s ratings of treatment options for attributes prioritized by patients. The expert recommendations and the clinical tool can be used to facilitate patient-centric management of actinic keratoses in daily practice, encompassing patient priorities and goals to set realistic treatment expectations and improve care outcomes.

Abstract Introduction Keratinocyte tumors (KT) are frequently observed. Surgery is the treatment gold standard. In some cases, a surgical approach might not be the best option. Radiotherapy (RT) and systemic treatments can frequently cause side effects or be contraindicated. Intralesional methotrexate (MTX) can be a conservative yet effective alternative. We decided to evaluate the effectiveness and safety of intralesional chemotherapy with MTX for the treatment of squamous cell carcinoma (SCC), keratoacanthoma (KA), and basal cell carcinoma (BCC). Methods All patients had a histologically confirmed diagnosis of BCC, SCC, or KA and no indication to surgery or RT. MTX was injected subcutaneously proceeding from the periphery of the lesion toward the center. Different protocols in terms of dose, frequency, and length of treatment were used to compare them. Treatment efficacy was evaluated in terms of tumor size reduction. Patients were divided into three groups: responders (improvement of more than 50%), partial responders (< 50%), and non-responders (no improvement or worsening). All data were analyzed using the chi-squared test (χ 2). Results Thirty-five patients were included. Twenty-one patients suffered from SCC, 12 from KA, and 2 from BCC. KA showed a higher response rate than SCC and BCC. For AK, 92% of patients had a complete resolution; 8% were partial responders. For SCC, 47.6% of cases were responders and 14.3% partial responders, while 38% non-responders. All BCCs showed no improvement. A treatment protocol of weekly injections, performed for 4 to 6 weeks, was the most efficient. Doses of 25 mg/ml per session seemed to be most effective. About one third of our patients developed side effects with mild anemia being the most frequent. Conclusions For selected cases, intralesional MTX can be a safe and effective option for the treatment of KT, especially in case of KA and, to a lesser extent, SCC.

Abstract Graham Little-Piccardi-Lassueur syndrome (GLPLS) is a rare variant of lichen planopilaris, characterized by a triad of clinical signs including follicular spinous papules on the body area, scarring alopecia of the scalp and non-scarring alopecia of the groin and/or axilla. To date, fewer than 50 cases have been described in the literature. We first report a case of GLPLS investigated with non-invasive techniques such as dermoscopy and in vivo reflectance confocal microscopy (RCM) and successfully treated with narrowband-UVB (NB-UVB) phototherapy.

A variety of non-filtering agents have been introduced to enhance sunscreen photoprotection. Most of those agents have only weak erythema protective properties but may be valuable and beneficial in supporting protection against other effects of UV radiation, such as photoimmunosuppression, skin aging, and carcinogenesis, as well as photodermatoses. The question arises how to measure and evaluate this efficacy since standard SPF testing is not appropriate. In this perspective, we aim to provide a position statement regarding the actual value of SPF and UVA-PF to measure photoprotection. We argue whether new or additional parameters and scales can be used to better indicate the protection conferred by these products against the detrimental effects of natural/artificial, UV/visible light beyond sunburn, including DNA damage, photoimmunosuppression and pigmentation, and the potential benefits of the addition of other ingredients beyond traditional inorganic and organic filters to existing sunscreens. Also, we debate the overall usefulness of adding novel parameters that measure photoprotection to reach two tiers of users, that is, the general public and the medical community; and how this can be communicated to convey the presence of additional beneficial effects deriving from non-filtering agents, e.g., biological extracts. Finally, we provide a perspective on new challenges stemming from environmental factors, focusing on the role of the skin microbiome and the role of air pollutants and resulting needs for photoprotection.

Abstract We report a rare case of a newborn male affected by incontinentia pigmenti, Klinefelter syndrome, and aplasia cutis congenita, who developed severe cutaneous, neurological, and ophthalmological manifestations. Genetic analysis showed the presence of the common mutation of NEMO (exon 4–10 deletion), Klinefelter syndrome karyotype (47 XXY), and random X inactivation. This is in accordance with the severity of involvement of the affected tissues (skin, central nervous system, and retina). Indeed, the patient developed typical skin lesions all over the body, except the head. Equally, multiple lesions diffusely involving both the cortical grey matter and subcortical white matter of the cerebellum and cerebral hemispheres were observed. Discussing current knowledge about the etiopathogenesis of skin and brain lesions in incontinentia pigmenti, our case seems to support the proapoptotic origin of central nervous system involvement. Possibly, incontinentia pigmenti patients suffer an impaired protection against apoptosis at the level of cerebral endothelial cells of small vessels, leading to vascular damage and subsequent ischemic brain lesions.

Photodermatoses are characterized by the development of skin eruptions following exposure to ultraviolet radiation or visible light. We report here the clinical findings and results of laboratory investigations and phototesting of 6 patients who experience debilitating and excruciating pain after sun exposure (“sun pain”) in the absence of any skin eruption. Phototesting with sub-erythemal doses of ultraviolet A radiation triggered localized pain in 4 patients. At follow-up, 3 female patients were found to have developed fibromyalgia, 2 male patients experienced a major depressive disorder, and another male patient had a conversion disorder. One patient also developed allodynia to tactile stimuli and one developed allodynia to thermal and tactile stimuli. Psychiatric conditions should be taken into consideration in patients presenting with excruciating and debilitating pain on exposure to ultraviolet radiation, but with absence of skin eruption. Further research is needed to evaluate whether it represents a type of allodynia triggered by exposure to ultraviolet radiation.

Basosquamous carcinoma is a rare clinical entity, which comprises 1.7–2.7% of all skin carcinomas. It is described as a basal cell carcinoma with features of squamous differentiation. To date, studies of the epidemiology of basosquamous carcinoma have been few and small in size. We report here the most extensive series of basosquamous carcinomas published to date, highlighting the differences between basosquamous carcinoma and other keratinizing tumours. Patients undergoing surgical excision for keratinizing tumours were enrolled in this study. Age, sex and tumour characteristics were recorded. A total of 1,519 squamous cell carcinomas, 288 basosquamous carcinomas and 4,235 basal cell carcinomas were collected. Basosquamous features were compared with those of basal cell and squamous cell carcinomas. For basosquamous carcinomas, 70.5% were located on the head and neck, particularly on the nose, forehead and cheeks, and represented almost 10% of the keratinizing tumours on the ears. Significant differences were found between basosquamous carcinoma and basal cell or squamous cell carcinomas. Basosquamous carcinoma should be considered a distinct type of keratinizing tumour with different anatomical, sex and age distributions.

Background: Although GPs are usually the first port of call for patients with psoriasis, there is a lack of consistent and up-to-date clinical recommendations for interventions for patients with mild-to-moderate disease. Aim: To provide practical recommendations for GPs to optimise psoriasis treatment with topical therapies in four key areas: patient identification; treatment decision making with topical theory; topical treatment outcomes; and optimising patient adherence. Design & setting: A consensus-seeking programme (modified-Delphi approach) was undertaken to assess the literature and develop recommendations for GPs, based on evidence and expert opinion. Method: Three dermatologists compiled 47 questions that were subsequently ranked and refined according to clinical relevance or importance using an online survey. Thereafter, 19 dermatologists from different European countries developed statements and clinical recommendations for the top seven ranked topical treatment and GP-relevant questions based on literature research and clinical experience. The final recommendations were based on 100% agreement among a final panel of seven experts. Results: The clinical effectiveness, fast onset of action, tolerability, cosmetic acceptability, and practicability of topical therapy, in addition to good physician—patient communication, are important for optimising patient adherence and maximising efficacy. Topical treatments combining corticosteroids and vitamin D analogues (administered as fixed combination) are well-established first-line treatments in mild-to-moderate psoriasis. Conclusion: Simple but detailed practical guidance is provided, which is formed from evidence and expert clinical recommendations, to assist GPs with the optimal use of topical agents based on efficacy, tolerability, disease severity, site of psoriasis, patient lifestyle and preferences, and intended duration of treatment.

Abstract Background Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations. In the 2017 EDS nosology, minimal criteria (general and gene-specific) for a clinical suspicion of spEDS have been proposed, but molecular analysis is required to reach a definite diagnosis. The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity and/or its complications. To date only 7 patients with β4GALT7-deficiency (spEDS-B4GALT7) have been described and their clinical data suggested that, in addition to short stature and muscle hypotonia, radioulnar synostosis, hypermetropia, and delayed cognitive development might be a hallmark of this specific type of spEDS. Additional 22 patients affected with an overlapping phenotype, i.e., Larsen of Reunion Island syndrome, all carrying a homozygous B4GALT7 mutation, are also recognized. Results Herein, we report on a 30-year-old Moroccan woman who fitted the minimal criteria to suspect spEDS, but lacked radioulnar synostosis and intellectual disability and presented with neurosensorial hearing loss and limb edema of lymphatic origin. Sanger sequencing of B4GALT7 was performed since the evaluation of the spEDS gene-specific minor criteria suggested this specific subtype. Mutational screening revealed the homozygous c.829G>T, p.Glu277* pathogenetic variant leading to aberrant splicing. Conclusions Our findings expand both the clinical and mutational spectrum of this ultrarare connective tissue disorder. The comparison of the patient’s features with those of the other spEDS and Larsen of Reunion Island syndrome patients reported up to now offers future perspectives for spEDS nosology and clinical research in this field.

Sun exposure is the main risk factor for cutaneous malignant melanoma (CMM). However, the UV-related pathogenetic mechanisms leading to CMM are far to be fully elucidated. In this paper we will focus on what we still don't fully know about the relationship between UVR and CMM. In particular, we will discuss: the action spectrum of human CMM, how different modalities of exposure (continuous/ intermittent; erythemal/ suberythemal) relate to different CMM variants, the preferential UVR induced DNA mutations observed in different CMM variants, the role of UV-related and UV-unrelated genetic damages in the same melanoma cells. Moreover, we will debate the importance of UVA induced oxidative and anaerobic damages to DNA and other cell structures and the role of melanins, of modulation of innate and acquired immunity, of vitamin D and of chronic exposure to phototoxic drugs and other xenobiotics. A better understanding of these issues will help developing more effective preventative strategies and new therapeutic approaches.

Mutations in B3GALT6, encoding the galactosyltransferase II (GalT-II) involved in the synthesis of the glycosaminoglycan (GAG) linkage region of proteoglycans (PGs), have recently been associated with a spectrum of connective tissue disorders, including spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) and Ehlers–Danlos-like syndrome. Here, we report on two sisters compound heterozygous for two novel B3GALT6 mutations that presented with severe short stature and progressive kyphoscoliosis, joint hypermobility and laxity, hyperextensible skin, platyspondyly, short ilia, and elbow malalignment. Microarray-based transcriptome analysis revealed the differential expression of several genes encoding extracellular matrix (ECM) structural components, including COMP, SPP1, COL5A1, and COL15A1, enzymes involved in GAG synthesis and in ECM remodeling, such as CSGALNACT1, CHPF, LOXL3, and STEAP4, signaling transduction molecules of the TGFβ/BMP pathway, i.e., GDF6, GDF15, and BMPER, and transcription factors of the HOX and LIM families implicated in skeletal and limb development. Immunofluorescence analyses confirmed the down-regulated expression of some of these genes, in particular of the cartilage oligomeric matrix protein and osteopontin, encoded by COMP and SPP1, respectively, and showed the predominant reduction and disassembly of the heparan sulfate specific GAGs, as well as of the PG perlecan and type III and V collagens. The key role of GalT-II in GAG synthesis and the crucial biological functions of PGs are consistent with the perturbation of many physiological functions that are critical for the correct architecture and homeostasis of various connective tissues, including skin, bone, cartilage, tendons, and ligaments, and generates the wide phenotypic spectrum of GalT-II-deficient patients.

Photodynamic therapy (PDT) with methyl-aminolevulinate (MAL) is an approved non-invasive treatment option for actinic keratoses (AKs). In vivo reflectance confocal microscopy (RCM) is a non-invasive tool for real-time imaging of epidermis and superficial dermis in vivo that has been previously reported to facilitate the in vivo evaluation of skin lesions, including AKs. The aim of this study was to investigate the use of in vivo RCM in evaluating AKs response to MAL-PDT. For this reason a total of 10 biopsy-proven AKs were treated by MAL-PDT, according to standard PDT protocol for AKs. RCM investigation was performed before and after PDT and RCM-guided punch biopsies was taken at 3 months in all patients for histopathologic examination. At 3 months follow-up, complete clinical response was observed by clinical examination in 9 out of 10 lesions and a partial clinical response in 1 lesion. In vivo RCM detected two residual AKs in subclinical form, missed by clinical examination. Histological analysis confirmed these results. In vivo RCM may be a new alternative tool for the non-invasive diagnosis of AKs and evaluation of AKs response to non-invasive treatments, as MAL-PDT, improving the ability of dermatologists to diagnose AKs even in subclinical stage.