BACKGROUNDAndrogenetic alopecia, often referred to as male pattern baldness, stands as the most prevalent form of alopecia. It is primarily characterized by a progressive reduction in hair diameter, length, and pigmentation.1 This process is driven by the influence of androgens, specifically dihydrotestosterone (DHT), in individuals genetically predisposed to this condition. The manifestation of androgenetic alopecia typically centers on the frontal and vertex regions of the scalp, while interestingly, the occipital area is usually spared from its effects.2 This localized pattern of hair loss can create distinctive patterns, such as receding hairlines and balding crowns, that are recognizable hallmarks of this condition. Beyond its mere physical impact, androgenetic alopecia exerts a profound influence on the psychological and emotional well-being of those affected. Hair is not merely a biological feature; it often carries a significant part of an individual’s identity and self-esteem.3 Consequently, the hair loss experienced in androgenetic alopecia can result in feelings of diminished self-confidence and self-image.CASE REPORTWe report the case of a 35-year-old man without comorbidities. The patient comes to the attention of the dermatologist complaining a progressive hair loss over the past 2 years. The patient reports that, at first, the hair loss was evidenced by the presence of hair on the pillow when he woke up and later, he noticed increased hair loss while showering. He initially attributed the fall to a period of work stress and did not give importance to it. However, progressive thinning in the fronto-parietal and vertex region led him to pay more attention to the problem, until he decided to book a dermatological examination with the intention of undergoing a hair transplant. At the dermatological examination, the patient presented a clinical picture compatible with androgenetic alopecia with involvement of the frontal and vertex region assessable as grade V, according to the Hamilton-Norwood scale4 (Figure 1A). Pull Test was positive and trichoscopy showed miniaturization of hair in androgen-dependent areas and hair reduction per pilo-sebaceous unit. The patient reported that hair loss had a strong impact on quality of life and personal, work, and relationship habits. In relation to the strong functional and esthetic impact of the problem, before deciding to undergo hair transplantation, the dermatologist proposed a conservative therapy: topical minoxidil 5% two times daily, oral finasteride 1 mg daily and topical application of a gel containing three oligopeptides mimicking growth factors, caffeine and taurine, and an iron chelating complex, one time per week. The patient underwent monthly follow-ups, and at 6 months after the start of the therapy, the results were striking: increased thickness of the shaft at the fronto-parietal and vertex levels and increased hair density per pilo-sebaceous unit were observed (Figure 1D). The patient was satisfied by the treatment and decided to postpone the transplantation.DISCUSSIONMale androgenetic alopecia is the most common cause of hair loss and has a strong impact on the quality of life of patients suffering from it. Currently, there are several treatments approved by the US FDA that have proven efficacy such as oral finasteride and topical minoxidil. On the other hand, some pioneering studies have demonstrated the efficacy of drugs such as dutasteride, topical finasteride, and/or oral minoxidil. Good emerging alternatives also include nondrug therapies such as platelet-rich plasma or laser therapy with wavelengths between 630 and 660 nm. In addition, studies on topical androgen receptor antagonists and topical cetirizine have provided promising results5. Recently, very promising data have been reported regarding the topical use of growth factor mimetic oligopeptides6, caffeine7, and taurine8 in individuals with androgenetic alopecia and/or telogen effluvium. Specifically, weekly use of a gel containing three growth factor mimicking oligopeptides, caffeine and taurine, and an iron chelating complex (GFmgel) has been shown to be particularly effective in subjects with androgenetic alopecia when used in combination with anti-hair loss medications such as topical minoxidil and oral finasteride9. In the case described, the patient applied a gel containing three growth factors mimicking oligopeptides, caffeine and taurine, and an iron chelating complex (GFmgel) in combination with dual therapy with minoxidil and finasteride. The patient, who initially expressed the will to undergo hair transplantation, was incredibly satisfied with the result achieved with conservative therapy six months later. Although our patient showed an excellent outcome, further real-world studies are needed to confirm the effectiveness of the combination of drug therapy and topical gel containing oligopeptides mimicking growth factors for the treatment of androgenetic alopecia.Figure 1Clinical presentation at baseline visit (Figure 1A); after 2 months (Figure 1B), after 4 months (Figure 1C) and after 6 months of therapy (Figure 1D).References:Piraccini BM, Alessandrini A. Androgenetic alopecia. G Ital Dermatol Venereol. 2014 Feb;149(1):15-24.Lolli F, Pallotti F, Rossi A et al. Androgenetic alopecia: a review. Endocrine. 2017 Jul;57(1):9-17. doi: 10.1007/s12020-017-1280-y. Epub 2017 Mar 28. PMID: 28349362.Huang CH, Fu Y, Chi CC. Health-Related Quality of Life, Depression, and Self-esteem in Patients With Androgenetic Alopecia: A Systematic Review and Meta-analysis. JAMA Dermatol. 2021 Aug 1;157(8):963-970.Rossi A, Ferranti M, Magri F et al. Clinical and Trichoscopic Graded Live Visual Scale for Androgenetic Alopecia. Dermatol Pract Concept. 2022 Apr 1;12(2):e2022078.Saceda-Corralo D, Domínguez-Santas M, Vañó-Galván S et al. What’s New in Therapy for Male Androgenetic Alopecia? Am J Clin Dermatol. 2023 Jan;24(1):15-24.Shome D, Kapoor R, Surana M et al. Neo® hair growth factor formulation for the treatment of hair loss in Covid-19-induced persistent Telogen Effluvium-A prospective, clinical, single-blind study. J Cosmet Dermatol. 2022 Jan;21(1):16-23. doi: 10.1111/jocd.14626. Epub 2021 Dec 7.Völker JM, Koch N, Becker M et al. Caffeine and Its Pharmacological Benefits in the Management of Androgenetic Alopecia: A Review. Skin Pharmacol Physiol. 2020;33(3):93-109.Kim H, Chang H, Lee DH. Simulative evaluation of taurine against alopecia caused by stress in Caenorhabditis elegans. Adv Exp Med Biol. 2013; 776:267-76.Lazzari, Tiziana & Milani, Massimo. (2019). Efficacy of Autologous Platelet-Rich Plasma alone or in Combination with a Lotion Containing Growth-Factor like Polypeptides and Taurine in the Treatment of Androgenic Alopecia: A Randomized, Prospective, AssessorBlinded Trial. Journal of Clinical & Experimental Dermatology Research.

Title: Novel Variant c.7795-1G>A of COL7A1 Gene in a 12-month-old Female Child with Recessive Dystrophic Epidermolysis BullosaType of article: Case ReportAuthors: Francesca CAROPPO1,2, Fortunato CASSALIA1, Anna BELLONI FORTINA1,2Affiliations:Dermatology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.Pediatric Dermatology Regional Center, Department of Women and Children’s Health, University of Padua, Padua, Italy, ERN Skin, ItalyCorresponding Author: Francesca Caroppo, MD Unit of Dermatology, Department of Medicine University of Padova, Italy Via Vincenzo Gallucci 4, 35121, Padova, Italy e-mail:[email protected]: Dystrophic Epidermolysis Bullosa, DEB, Epidermolysis Bullosa, EB, Congenital diseases, genetic diseases, mutation, rare skin diseasesWord count: 664Tables: NoneFigure: 2References: 9Patient Consent Written informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy.Conflicts of interest: NoneAcknowledgements: NoneAuthor Contributions: All authors contributed to designing and conducting the work, drafting, and revising the manuscript and approved the final version for submission.

Title: Sirolimus-induced DRESS syndrome in a stem cell transplant patient.Authors: Fortunato CASSALIA1, Alice SPILLER1, Roberto SALMASO1, Francesca CAROPPO1,2, Anna BELLONI FORTINA1,2Affiliations:Dermatology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy.Pediatric Dermatology Unit, Department of Women and Children’s Health, University of Padua, Padua, Italy.Corresponding Author: Francesca Caroppo, MD Unit of Dermatology, Department of Medicine University of Padova, Italy Via Vincenzo Gallucci 4, 35121, Padova, Italy e-mail: [email protected]:Word count: 1329Tables: NoneFigure: 3References: 9Conflicts of interest: NoneAcknowledgements: NoneAuthor Contributions: All authors contributed to designing and conducting the work, drafting, and revising the manuscript and approved the final version for submission.ABSTRACTBACKGROUND: We present a case of sirolimus-induced DRESS syndrome in a stem cell transplant patient. Sirolimus is an immunosuppressive drug that inhibits the mTOR pathway. It is commonly used in organ transplants to prevent rejection. While no sirolimus-induced DRESS cases have been reported, allergic reactions with everolimus, a similar drug, have been documented. DRESS syndrome is a severe drug reaction characterized by fever, rash, and organ involvement. Diagnosis is based on clinical findings and laboratory tests. Early recognition, discontinuation of the drug, and supportive care are crucial in managing DRESS syndrome, often involving systemic corticosteroids.CASE REPORT A 24-year-old man who had undergone haplo-TESE transplantation for acute lymphatic leukaemia presented with diffuse itchy eczematous lesions. Initially diagnosed as atopic dermatitis, he received topical steroid therapy and NB-UVB phototherapy, but his condition worsened. Two months later, he returned to the emergency department with eczematous patches, xerosis, fever, chills, and generalized edema. His medical history included relapses of leukaemia, acute cutaneous graft-versus-host disease (GVHD), and Evans syndrome. He had been on sirolimus immunosuppressive therapy before the onset of symptoms. A skin biopsy revealed spongiotic dermatitis with dermal eosinophils, suggestive of drug reaction or atopic reaction. Based on the severity of the symptoms and histological findings, the patient was diagnosed with sirolimus-induced DRESS syndrome. Sirolimus was discontinued, and oral steroid therapy was initiated, leading to significant improvement. At the one-month follow-up, the patient was symptom-free and had lost the gained weight.CONCLUSION Although no cases of sirolimus-induced DRESS syndrome have been reported, allergic reactions with eosinophilia induced by everolimus have been documented. And since sirolimus and everolimus, both mTOR inhibitors, share a common mechanism of action, therapeutic indications, pharmacokinetics, adverse effects and drug interactions, it cannot be ruled out that sirolimus may trigger DRESS syndrome in patients with risk factors. In our case, the patient’s history characterized by stem cell transplantation and multiple immunosuppressive therapies may have contributed to the development of DRESS syndrome after beginning sirolimus therapy. This case may be the first evidence of sirolimus-induced DRESS syndrome in a stem cell transplant patient and highlights how early diagnosis, discontinuation of the culprit drug and appropriate management are crucial for a favourable outcome.BACKGROUND We present a case of sirolimus-induced DRESS syndrome1in a stem cell transplant patient. Sirolimus, also known as rapamycin, is an immunosuppressive and antiproliferative drug that inhibits the mammalian target of rapamycin (mTOR) pathway2. It has a wide range of clinical applications and has been extensively studied in various fields of medicine. Sirolimus is commonly used in solid organ transplants to prevent acute rejection and improve transplant survival with the advantage of reducing the nephrotoxicity associated with calcineurin inhibitors3. Although no cases of sirolimus-induced DRESS syndrome have been reported, allergic reactions with eosinophilia induced by everolimus, a similar drug of the mTOR inhibitor family, have been documented. In particular, cases of drug reaction with eosinophilia and systemic symptoms (DRESS) caused by an everolimus-eluting stent have been reported4. DRESS syndrome, also known as drug-induced hypersensitivity syndrome (DIHS), is a severe adverse drug reaction characterized by fever, skin rash, multi-organ involvement and eosinophilia. The pathogenesis of the DRESS syndrome remains unclear, involving a complex interaction between drug metabolism, immune dysregulation and genetic factors. Skin manifestations vary from maculopapular eruptions to severe exfoliative dermatitis, while organ involvement often involves the liver, kidneys, lungs and haematological system. Other systemic symptoms may include lymphadenopathy, myocarditis and interstitial nephritis. The diagnosis of DRESS syndrome is based on the recently validated RegiSCAR score5 which considers clinical findings, temporal relationship with drug exposure and blood tests. Early recognition and discontinuation of the involved drug are crucial for the management of DRESS syndrome. Supportive care and careful monitoring of organ function are essential, while symptomatic treatment aims to improve symptoms. Systemic corticosteroids are often administered to suppress the immune response6.CASE REPORTA 24-year-old boy, who had previously undergone haplo-TESE transplantation (transplantation of haploidentical haematopoietic stem cells for acute lymphatic leukaemia, presented to the dermatology outpatient clinic for the onset of a diffuse eruption with itchy eczematous lesions. The initial clinical presentation was diagnosed as atopic dermatitis and topical steroid therapy was recommended. In the following days, due to the lack of clinical response and the worsening of the skin eruption, about two months later the patient returned to the emergency department complaining of diffuse xerosis mixed with eczematous, itchy, finely scaling patches. In addition, the patient complained of fever and chills and significant and consistent oedema all over his body. He also reported a weight gain of 9 kg in the last month and eosinophilia >20% with leukopenia (Figure 1). The medical history revealed that the patient was diagnosed with acute lymphatic leukaemia in 2003 and underwent treatment according to the AIEOP LLA 2000 protocol (Prednisone, Vincristine, Daunorubicin, L-asparaginase, methotrexate, 6-Mercaptopurine, Cyclophosphamide, Cytarabine, Dexamethasone). In 2015, the patient developed a relapse for which he was treated according to the AIEOP protocol BFM 2009 concluded in 2017 (Prednisone, Vincristine, Daunorubicin, L-asparaginase, methotrexate, 6-Mercaptopurine, Cyclophosphamide, Cytarabine, Dexamethasone). However, in 2018, the patient developed a new relapse and therefore underwent haplo-TESE stem cell transplantation. Unfortunately, in 2019, the patient suffered an acute cutaneous GVHD for which he underwent treatment with oral cyclosporine in combination with tacrolimus that led to a rapid improvement of the skin manifestations. Unfortunately, in 2020 he was diagnosed with Evans syndrome and was treated with oral steroids; once the acute phase was over, the patient started immunosuppressive therapy with sirolimus 2 mg/die. Given the history and the severity of the clinical picture, the patient was hospitalized and a skin biopsy with histological examination was performed. The result of the histological examination revealed a hyperkeratosis with focally confluent spongiosis and irregular acanthosis of the epidermide. The underlying superficial dermis shows a modest infiltrate of lymphocytes, plasma cells and eosinophils, the latter also observed in the deep dermis. Specific histochemical stains did not reveal the presence of mucins and fungi (Alcial Blue and PAS) while immunohistochemical reactions for T and B lymphocytes excluded the clinical hypothesis of GVHD. The morphological picture depicts a spongiotic dermatitis with a discrete presence of dermal eosinophils suggesting the possibility of drug reaction vs. atopic reaction (Figure 2). Considering the clinical picture and the histological examination, the diagnosis of DRESS syndrome induced by sirolimus was made7. The drug was withdrawn and scaled-up oral steroid therapy was instituted, after 3 weeks of therapy the patient ceased taking the oral steroid. At the follow-up visit after one month the oedema was in remission, the patient no longer complained of any symptoms and had lost the previously accumulated kg (Figure 3).DISCUSSION The case described presents a 24-year-old boy with a complex medical history, including a previous diagnosis of acute lymphatic leukaemia and subsequent relapses, which required intensive treatments such as stem cell transplantation and immunosuppressive therapy. The patient presented to the dermatology outpatient clinic with diffuse itchy eczematous lesions, initially diagnosed as atopic dermatitis. Despite topical steroid therapy, the patient’s condition worsened with dry, itchy patches mixed with xerosis concomitant with fever, swelling, weight gain and abnormal blood results. Skin biopsy ruled out the diagnosis of graft-versus-host disease (GVHD). Based on the clinical presentation, histological findings and history of sirolimus therapy, the diagnosis of sirolimus-induced DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome was made. Sirolimus was discontinued and the patient started oral steroid therapy, which was gradually reduced and finally discontinued. After three weeks of treatment, the patient’s symptoms improved, including remission of oedema, and at the one-month follow-up visit the patient was asymptomatic and had lost the weight gained during the illness. DRESS syndrome is a severe form of drug reaction in which skin manifestations and systemic involvement are associated. The onset time is usually longer than in other delayed skin reactions, on average 6-8 weeks after the introduction of the responsible drug. It is a severe idiosyncratic T-cell mediated reaction, classified as a type Vb and sometimes IVc delayed hypersensitivity reaction. DRESS is presumed to result from a complex interaction between drug exposure (such as vaccines or biological drugs), genetic predisposition and/or viral reactivation, and the development of this serious clinical condition would appear to be the result of the cumulative effect of aligned risks1. Early recognition and discontinuation of the culprit drug are crucial for the management of DRESS syndrome. Systemic corticosteroids are often used to suppress the inflammatory response and supportive care is provided for any organ involvement6. Although no cases of sirolimus-induced DRESS syndrome are reported in the literature, allergic reactions with eosinophilia induced by everolimus have been described. In particular, cases of drug reaction with eosinophilia and systemic symptom syndrome caused by an everolimus-eluting stent have been reported4. Sirolimus and everolimus both belong to the class of drugs called mTOR inhibitors and share several features8, including: (1) Mechanism of action: Sirolimus and everolimus act by inhibiting the mammalian target of rapamycin (mTOR); (2) therapeutic indications: both are used in immunosuppressive therapy to prevent organ rejection in transplant patients. (3) Pharmacokinetics: both are administered orally and are rapidly absorbed. They have a large volume of distribution and are extensively metabolised in the liver. (4) Adverse effects: They have common adverse effects including immunosuppression, which may increase the risk of infection, delay wound healing and altered response to vaccines. Other potential side effects include hyperlipidaemia (elevated blood lipid levels), peripheral oedema, gastrointestinal disorders, and metabolic abnormalities; (5) drug interactions: both drugs are metabolised by cytochrome P450 enzymes, which may lead to potential drug interactions with other drugs that act on these enzymes9. It is important to consider these interactions when prescribing or administering these drugs. In our case, the patient’s history of previous intensive treatments, stem cell transplantation and immunosuppressive therapies may have contributed to immune system dysregulation and the onset of DRESS syndrome following the initiation of sirolimus therapy. Timely diagnosis, discontinuation of the drug and appropriate management led to the resolution of symptoms and general improvement of the patient’s condition. The case emphasizes the importance of careful monitoring and consideration of potential adverse drug reactions in patients undergoing complex treatment regimes. This case could be the first evidence of DRESS syndrome induced by sirolimus in a stem cell transplant patient.FIGURE 1 Eczematous, itchy, finely scaling patches and significant and consistent oedema.FIGURE 2 Flap of skin with hyperkeratosis, focally confluent spongiosis and irregular acanthosis of the epider-mide. Modest infiltrate of lymphocytes, plasma cells and eosinophils, in the deep dermis.FIGURE 3 One month after withdrawal of SirolimusREFERENCESRamirez, G. A., Ripa, M., Burastero, S., et al . (2023). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Focus on the Pathophysiological and Diagnostic Role of Viruses. Microorganisms, 11(2), 346.https://doi.org/10.3390/microorganisms11020346Mao, B., Zhang, Q., Ma, L., et al. (2022). Overview of Research into mTOR Inhibitors. Molecules (Basel, Switzerland), 27(16), 5295.https://doi.org/10.3390/molecules27165295Hahn, D., Hodson, E. M., Hamiwka, L. A., et al. (2019). Target of rapamycin inhibitors (TOR-I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients. The Cochrane database of systematic reviews, 12(12), CD004290.https://doi.org/10.1002/14651858.CD004290.pub3Bianchi, L., Caraffini, S., & Lisi, P. (2014). Drug reaction with eosinophilia and systemic symptoms syndrome caused by an everolimus-eluting stent. International journal of dermatology, 53(4), e286–e288.https://doi.org/10.1111/ijd.12112Kardaun, S. H., Sekula, P., Valeyrie-Allanore, L., et al (2013). Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. The British journal of dermatology, 169(5), 1071–1080. https://doi.org/10.1111/bjd.12501Calle, A. M., Aguirre, N., Ardila, et al. (2023). DRESS syndrome: A literature review and treatment algorithm. The World Allergy Organization journal, 16(3), 100673. https://doi.org/10.1016/j.waojou.2022.100673Jindal, R., Chugh, R., Chauhan, P., et al (2022). Histopathological Characterization of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Comparison with Maculopapular Drug Rash (MPDR). Indian dermatology online journal, 13(1), 32–39.https://doi.org/10.4103/idoj.idoj_452_21Yan, X., Huang, S., Yang, Y., et al (2022). Sirolimus or Everolimus Improves Survival After Liver Transplantation for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Granata, S., Dalla Gassa, A., Carraro, A., et al (2016). Sirolimus and Everolimus Pathway: Reviewing Candidate Genes Influencing Their Intracellular Effects. International journal of molecular sciences, 17(5), 735. https://doi.org/10.3390/ijms17050735

KEY CLINICAL MESSAGEWe present the case of a child developing widespread vesicle-bullous lesions during an acute and symptomatic Epstein-Barr Virus infection. Antibody serology, biopsy and direct immunofluorescence allowed the diagnosis of a paraviral bullous eruption. To our knowledge, this is the first report of bullous eruption following Epstein-Barr virus infection in childhood.