Acquired Ichthyosis Revealing Lymphocytic Colitis.

A 69-year-old patient with no personal or family history of ichthyosis consulted our dermatology department for diffused cutaneous xerosis with intense pruritus evolving for 3 weeks. Physical examination revealed diffused ichthyosis of large polygonal fine scales on the skin without erythema (Figure 1). The lesions spared the face. Examination of the mucous membranes, hair, and nails revealed no abnormalities. There was no fever or adenomegaly. A skin biopsy revealed an orthokeratotic hyperkeratosis with thinning of granular layer (Figure 2). The initial diagnosis of acquired ichthyosis was maintained. The patient also reported a change in bowel habits since 2 weeks with watery, non-bloody diarrhea and mild steatorrhea. His laboratory investigations presented low serum vitamin B12 level, mild anemia, hypoalbuminemia, and fecal leukocytes; however, antinuclear antibodies, perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), rheumatoid factor, and complement components C3 and C4 were normal. A colonoscopy performed was also normal without any abnormalities. Colon biopsies revealed histologic aspects of lymphocytic colitis with more than 20% increase in lymphocytes in the surface epithelium of colorectal mucosa. Laboratory investigations excluded neoplasia, hemopathies, or autoimmune-associated diseases. The patient was treated with salazopyrin with a remarkable lessening of diarrhea and cutaneous manifestations within 4 weeks (Figure 3).

Kidney Disease Symptoms before and after Kidney Transplantation.

BACKGROUND AND OBJECTIVES: Patients with kidney failure report a high symptom burden, which likely increases while on dialysis due to physical and mental stressors and decreases after kidney transplantation due to restoration of kidney function. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We leveraged a two-center prospective study of 1298 kidney transplant candidates and 521 recipients (May 2014 to March 2020). Symptom scores (0-100) at evaluation and admission for transplantation were calculated using the Kidney Disease Quality of Life Short-Form Survey, where lower scores represent greater burden, and burden was categorized as very high: 0.0-71.0; high: 71.1-81.0; medium: 81.1-91.0; and low: 91.1-100.0. We estimated adjusted waitlist mortality risk (competing risks regression), change in symptoms between evaluation and transplantation (n=190), and post-transplantation symptom score trajectories (mixed effects models). RESULTS: At evaluation, candidates reported being moderately to extremely bothered by fatigue (32%), xeroderma (27%), muscle soreness (26%), and pruritus (25%); 16% reported high and 21% reported very high symptom burden. Candidates with very high symptom burden were at greater waitlist mortality risk (adjusted subdistribution hazard ratio, 1.67; 95% confidence interval, 1.06 to 2.62). By transplantation, 34% experienced an increased symptom burden, whereas 42% remained unchanged. The estimated overall symptom score was 82.3 points at transplantation and 90.6 points at 3 months (10% improvement); the score increased 2.75 points per month (95% confidence interval, 2.38 to 3.13) from 0 to 3 months, and plateaued (-0.06 points per month; 95% confidence interval, -0.30 to 0.18) from 3 to 12 months post-transplantation. There were early (first 3 months) improvements in nine of 11 symptoms; pruritus (23% improvement) and fatigue (21% improvement) had the greatest improvements. CONCLUSIONS: Among candidates, very high symptom burden was associated with waitlist mortality, but for those surviving and undergoing kidney transplantation, symptoms improved.

Cutaneous manifestations in an Italian military COVID hub.

BACKGROUND: The outbreak of the pandemic Coronavirus disease 2019 (COVID-19), caused by a novel coronavirus named Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2), affecting a high number of patients in Italy, forced a great number of doctors, even dermatologists, to work in the first lines in the dedicated departments. We analyzed the features and the incidence of dermatological issues emerged during the hospitalization due to COVID-19 and absent before. METHODS: All the SARS-CoV-2 positive patients hospitalized in Celio Military Hospital - COVID hub no-intensive care wards from March 16, 2020 until May 4, 2020 were evaluated by dermatologists several times during the hospital stay. RESULTS: Ninety-six patients (15 civilians and 81 Italian servicepeople) were enrolled: 34 (35.4%) patients developed cutaneous manifestations; 15 (16.0%) suffered from skin dryness; 5 (5.2%) irritant contact dermatitis; 4 (4.2%) seborrheic dermatitis; 4 (4.2%) morbilliform rashes; 3 (3.1%) petechial rashes and 3 (3.1%) widespread hives. CONCLUSIONS: A deeper knowledge of cutaneous manifestations in military and civilian hospitalized COVID-19 patients could suggest more effective treatments to win the battle against SARS-CoV-2.

Clinical, etiopathogenic, and therapeutic aspects of KID syndrome.

Keratitis-ichthyosis-deafness (KID syndrome) is a syndromes ichthyoses that is clinically and genetically heterogeneous requiring early and long-term multidisciplinary monitoring of affected individuals. A review of the clinical, etiopathogenic and therapeutic aspects is presented of this rare congenital ectodermal disorder.

Transient acantholytic dermatosis in a patient with prostate cancer.

Transient acantholytic dermatosis (TAD) is a relatively common entity that has been also noted to occur in patients with cancer. Herein, we describe a case of transient acantholytic dermatosis occurring in a patient with a history of prostate cancer status post radiation, now being treated with combination therapy with pembrolizumab and carboplatin-pemetrexed for advanced lung adenocarcinoma. Our case emphasizes the importance of being cognizant of TAD and its associations, particularly in cancer patients.

Biotinidase deficiency in a newborn.

INTRODUCTION: Biotinidase deficiency is an inherited disorder of biotin metabolism that is untreated may present within the first few month of life. OBJECTIVE: We report the exceptional observation of a biotinidase deficiency in Morocco. The rarity of this pathology, its age of onset, its mode of revelation and the lack of treatment in Morocco make the particularity of this observation. OBSERVATION: A newborn child born from a 24-year-old mother, followed by an estimated pregnancy of 37 weeks of amenorrhea according to the Farr score (morphological maturation score used for the dating of the pregnancy term). The infant presented at 7 days of life with a cutaneous-mucous eruption with icithiosic dry erythroderma of interest to the trunk, the face, the scalp associated with alopecia and depilation of the eyebrow. The biotinoidase deficiency was confirmed by its low serum concentration at 49 nka / l. The newborn died at 20 days of life before starting the specific treatment. CONCLUSION: Biotinidase deficiency is a rare condition requiring early screening and rapid management. The delay in diagnosis and the unavailability of treatment in Morocco can have fatal consequences.

Grover disease: review of subtypes with a focus on management options.

Grover disease (GD) is a benign eruption that causes a papulovesicular rash on the trunk and proximal extremities. It often resolves spontaneously but can follow a more chronic and fluctuating course that may last several years. Although the etiology remains unknown, several associated triggers have been identified including heat and sweating, cool and dry air, renal failure, malignancy, and the initiation of several drugs. Since the disease tends to resolve on its own, management is aimed at disease prevention and symptomatic relief. First-line therapy includes topical steroids and vitamin D analogues with adjuvant antihistamines. In more severe cases that are refractory to less aggressive therapy, systemic corticosteroids, retinoids, and phototherapy may lead to successful resolution. Novel therapies are few and have little evidence but involve innovative use of light therapy and immune modulators. Herein, we review the literature and new trends of GD with a focus on established and novel treatments.

Grover's Disease in a Kidney Transplant Recipient.

Dear Editor, It is not unusual for patients with renal insufficiency to develop skin pathologies. There are reports in the literature of increased incidence of calciphylaxis, pruritus, perforating dermatoses, and porphyria cutanea tarda in this patient population (1). Although it is quite rare, Grover's disease (GD) has been reported in several patients with renal insufficiency, but only once in a renal transplant recipient (2). The disease follows three patterns: persistently pruritic, transient eruptive, or a chronic asymptomatic course (3). Common risk factors concomitant with disease prevalence are immunosuppression, HIV, hemodialysis, viral and bacterial infections, malignancies, and other skin pathologies like contact and atopic dermatitis (4). A 60-year-old woman had a family history of polycystic kidney disease and was subsequently diagnosed in 1997. The patient had concomitant hepatic involvement and a stable aneurysm of the anterior cerebral artery. Consequently, the patient preemptively received a kidney transplant in 2015. The immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, and prednisone with basiliximab induction. In 2017, a biopsy of the right thigh demonstrated squamous cell carcinoma in situ measuring 1×1cm in size. The lesion was treated with surgical excision. The patient also exhibited an erythematous brown macule with undefined borders on the left side of the nose with a size of 12 mm; it was later determined to be actinic keratosis. The lesion was treated successfully with cryotherapy. During this period, a fever prompted a PCR for BK virus DNA which showed a substantial amount of copies, measuring 28,850 copies/mL in urine and 98 copies/mL in blood. The mycophenolate dose was reduced, and tacrolimus trough concentration was maintained at between 3 and 5 µg/L. In 2018 the patient presented with multiple pruritic erythematous papules located on the trunk. Upon histological biopsy, there was dominant suprabasal acantholysis with numerous cells separating from the epithelium. Furthermore, there was a moderate amount of mononuclear infiltrate in the upper portion of the dermis and sparse suprabasal clefts (Figure 1). Clinical presentation and histologic examination were consistent with Grover's disease. The patient was treated topically with betamethasone cream twice daily for four weeks. The skin changes persisted for only a few weeks. The pathophysiological mechanism causing GD is still unknown. It is usually only a transient skin condition that lasts no more than a few weeks, but there have been more chronic cases lasting for years, particularly in patients on hemodialysis (5). The lesions commonly affect the chest area but may spread to diffusely envelope the body as erythematous papules, pustules, lichenoid lesions, or vesicles (2). Grover characterized 4 different subtypes based on the pathohistological findings as Darier-like (the most common), pemphigus vulgaris-like, Hailey-Hailey-like, or spongiotic subtype (3). The histological patterns are not exclusive to one patient and may even be found concomitantly in a single lesion. The condition is definitively diagnosed through histology, showing distinctive acantholysis along the epidermis with dyskeratosis that is described as "corps ronds" and "grains" (3). Grover's disease is more prevalent in middle-aged Caucasian men than any other group, with a 1.6-2.1 gender ratio (6). It was originally thought that the disease was caused by dysfunctional eccrine sweat glands, as the ailment was more common in patients that had increased perspiration either due to environmental heat, fever, or extensive bedrest. This idea was reinforced by histological evidence of atrophied sweat glands in uremic patients with renal insufficiency (7). Moreover, a case series and case report described remissions of GD in their patients on hemodialysis that received a renal transplant (5,8). However, subsequent studies have not supported an association with sweat dysfunction and disease development, while others have only managed to attribute sweat gland dysfunction as the primary trigger in 20-30% of cases (9). Conversely, cold dry air and xerosis cutis is thought to trigger the disease because it is four times more likely to be diagnosed in the winter months (10). Ultraviolet radiation has been identified as an exacerbating factor for GD, which could have been the trigger for onset of disease in our patient as demonstrated by her squamous cell carcinoma and actinic keratosis (11). Despite immunosuppression being a risk factor for GD, as shown by its association in patients with HIV, bone marrow transplantation, hemodialysis, and hematological malignancies, GD has been reported only once in the literature after a renal transplant (2,4). As our case, that patient developed GD a few years after transplant without an obvious trigger and the lesions appeared as red papules that were disseminated over the anterior thorax. Their patient's cutaneous lesion resolved spontaneously after 2 weeks and never returned in the 2.5-year follow-up period. Their patient has had two renal allografts over a 20 year timespan, while ours had had her graft for only two years. The immunosuppressive regimen was slightly different: cyclosporine, azathioprine, and methylprednisolone versus our combination of tacrolimus, mycophenolate mofetil, and prednisone. Grover's disease can be treated conservatively by avoiding risk factors such as UV light and sweating as well as and applying moisturizing emollients which may cause the lesion to resolve spontaneously. Medical therapy consists of topic corticosteroids, topical vitamin D analogues, oral retinoids, and oral corticosteroids, PUVA, and methotrexate for resistant cases (6,12). When a patient exhibits pruritic papules of the skin, GD should be considered in differential diagnosis, especially in kidney transplant patients and those on hemodialysis. While the condition is rare, increased recognition in this patient population will allow for studies to further characterize this poorly understood disease.

Study of the Mechanism Underlying the Onset of Diabetic Xeroderma Focusing on an Aquaporin-3 in a Streptozotocin-Induced Diabetic Mouse Model.

Xeroderma is a frequent complication in diabetic patients. In this study, we investigated the mechanism underlying the onset of diabetic xeroderma, focusing on aquaporin-3 (AQP3), which plays an important role in water transport in the skin. Dermal water content in diabetic mice was significantly lower than that in control mice. The expression level of AQP3 in the skin was significantly lower in diabetic mice than in control mice. One week after streptozotocin (STZ) treatment, despite their increased blood glucose levels, mice showed no changes in the expression levels of AQP3, Bmal1, Clock, and D site-binding protein (Dbp) in the skin and 8-hydroxydeoxyguanosine (8-OHdG) in the urine. In contrast, two weeks after STZ treatment, mice showed increases in the blood glucose level, decreases in AQP3, Bmal1, Clock, and Dbp levels, and increases in the urinary levels of 8-OHdG. The results of this study suggest that skin AQP3 expression decreases in diabetes, which may limit water transport from the vessel side to the corneum side, causing dry skin. In addition, in diabetic mice, increased oxidative stress triggered decreases in the expression levels of Bmal1 and Clock in the skin, thereby inhibiting the transcription of Aqp3 by Dbp, which resulted in decreased AQP3 expression.

Inherited ichthyoses: molecular causes of the disease in Czech patients.

Inherited ichthyoses belong to a large and heterogeneous group of mendelian disorders of cornification, and can be distinguished by the quality and distribution of scaling and hyperkeratosis, by other dermatologic and extracutaneous involvement, and by inheritance. We present the genetic analysis results of probands with X-linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis, and a patient with Netherton syndrome. Genetic diagnostics was complemented by in silico missense variant analysis based on 3D protein structures and commonly used prediction programs to compare the yields of these two approaches to each other. This analysis revealed various structural defects in proteins coded by mutated genes while no defects were associated with known polymorphisms. Two patients with pathogenic variants in the ABCA12 gene have a premature termination codon mutation on one allele and a silent variant on the second. The silent variants c.69G > A and c.4977G > A are localised in the last nucleotide of exon 1 and exon 32, respectively, and probably affect mRNA splicing. The phenotype of both patients is very severe, including a picture harlequin foetus after birth; later (at 3 and 6 years of age, respectively) ectropin, eclabion, generalised large polygonal scaling and erythema.

Italian translation, cultural adaptation, and pilot testing of a questionnaire to assess family burden in inherited ichthyoses.

BACKGROUND: Inherited ichthyoses are rare disorders characterized by generalized skin scaling. Among them, autosomal recessive congenital ichthyoses (ARCI) form a major subgroup presenting lifelong and severely disabling cutaneous and extracutaneous features and symptoms for which no curative treatment is available. Management relies on daily time-consuming and distressing topical medications. Disease manifestations, symptoms, and daily care affect not only the patient self-perception, but also different dimensions of patient and family life. To date, there is only a French validated ichthyosis-specific questionnaire, "Family Burden in Ichthyosis" (FBI), for the evaluation of family disease burden. It addresses economical aspects, daily life, familial and personal relationships, work, and psychological impact. The aim of our study was to develop an Italian translation of the French FBI questionnaire and to pilot-test it in ARCI patients. METHODS: The guidelines for cross-cultural adaptation of health-related quality of life measures were followed. Specifically, two independent forward translations were produced, followed by a reconciliation step by a multidisciplinary expert committee and back-translation. Revision of the original text and all translations was performed by the expert committee leading to a final version, which was pilot-tested by cognitive debriefing on 10 caregivers whose comments were evaluated by the committee. RESULTS: The translation and reconciliation process led to minor changes in five items in order to clarify the questions in relation to the possible answers or to obtain semantic/idiomatic/cultural equivalence of the Italian version with the French one. The cognitive debriefing process resulted into further minor wording modifications in four items to describe more precisely the disease impact according to parents' comments. The FBI developer approved the final Italian FBI version. CONCLUSIONS: The Italian version of the FBI generated in the present study is a useful instrument to measure the impact of ichthyosis on family daily life, education and working activities, psychological implications, and the disease economic load. The questionnaire will be further validated through a multicenter Italian study on burden of ARCI. A validated Italian questionnaire is a valuable tool for future clinical trials. In addition, it can be used to rapidly identify family distressing situations, which require attention and prompt intervention.

Chanarin-Dorfman syndrome.

Chanarin Dorfman syndrome is a multisystem, very rare, autosomal recessive lipid storage disorder, characterized by the accumulation of lipid vacuoles in neutrophils, and was first described by Dorfman in 1974. Due to a mutation in the ABHD5 gene of the short arm of chromosome 3, lipid is stored in the granulocytes at various sites in the human body, such as the muscle, liver, eye, ear, central nervous system, and bone marrow. Clinically, the disease is presented with ichthyosis, hearing loss, hepatomegaly, splenomegaly, cirrhosis, cataract, keratopathy, myopathy, and mental retardation. A 38-year-old male patient was referred to our Internal Medicine Clinic for consultation with laboratory findings as follows: high aspartate aminotransferase (AST; 203 U/L), alanine aminotransferase (ALT; 151 U/L), gamma-glutamyl transferase (GGT; 167 U/L), creatine kinase (CK; 1127 U/L) levels and low platelet levels (108000). After ultrasonography and gastroscopy, the patient was diagnosed with liver cirrhosis. Bilateral mixed-type hearing loss on audial tests and bilateral punctuate keratopathy, ectropion, and cataract in the left eye on ophthalmological tests were found. For the definitive diagnosis of Chanarin Dorfman syndrome, peripheral blood was examined, which revealed lipid accumulation in the neutrophils (Jordan's anomaly). We emphasize that if a patient has unusual findings, such as ichthyosis, hearing loss, hepatomegaly, splenomegaly, cirrhosis, cataract, keratopathy, myopathy, and mental retardation, the possibility of Chanarin Dorfman syndrome should be considered.

Xerosis cutis and associated co-factors in women with prurigo nodularis

Abstract: Background: Current data regarding the associated factors of prurigo nodularis are still uncertain, except for atopic predisposition. Objectives: The purposes of this study were to (1) determine the frequencies of xerosis and other accompanying diseases of female patients with prurigo nodularis; (2) compare the demographic, clinical and accompanying disease characteristics by grouping these patients according to whether they have associated xerosis (who were subsequently subgrouped as atopic or non-atopic) or not. Methods: In this retrospective descriptive study, 80 females with PN were categorized according to the accompanying diseases (dermatological, systemic, neurological, psychogenic, mixed, or undetermined origin). Results: A total of 45 associated co-factors including dermatological in 63 (78.8%), systemic in 57 (71.3%), psychological in 33 (41.3%) and neurological co-factors in 14 (17.5%) of all patients with prurigo nodularis were detected. Xerosis was observed in 48 (60%) patients (non-atopic co-factors in 66.7% of them). The ratio of patients with mixed co-factors, dermatological+systemic co-factors and dermatological+systemic+psychological co-factors were found to be significantly higher in patients with xerosis compared to those without xerosis. Study limitations: Our study has certain limitations such as the absence of an age-matched control group, absence of follow-up data and the fact that the diagnosis of xerosis has not been based on objective methods. Conclusions: Xerosis has been identified in more than half of the patients with PN and it has been determined that in most patients xerosis is associated especially with diabetes mellitus and other conditions related to prurigo nodularis.

Roles of aberrant hemichannel activities due to mutant connexin26 in the pathogenesis of KID syndrome.

Germline missense mutations in GJB2 encoding connexin (Cx) 26 have been found in keratitis, ichthyosis and deafness (KID) syndrome. We explored the effects of three mouse Cx26 mutants (Cx26-G12R, -G45E and -D50N) corresponding to KID syndrome-causative human mutants on hemichannel activities leading to cell death and the expression of immune response-associated genes. We analyzed the 3D images of cells expressing wild-type (WT) or mutant Cx26 molecules to demonstrate clearly the intracellular localization of Cx26 mutants and hemichannel formation. High extracellular Ca2+ conditions lead to the closure of gap junction hemichannels in Cx26-G12R or Cx26-G45E expressing cells, resulting in prohibition of the Cx26 mutant-induced cell death. Fluorescent dye uptake assays revealed that cells with Cx26-D50N had aberrantly high hemichannel activities, which were abolished by a hemichannel blocker, carbenoxolone and 18α-Glycyrrhetinic acid. These results further support the idea that abnormal hemichannel activities play important roles in the pathogenesis of KID syndrome. Furthermore, we revealed that the expressions of IL15, CCL5, IL1A, IL23R and TLR5 are down-regulated in keratinocytes expressing Cx26-D50N, suggesting that immune deficiency in KID syndrome expressing Cx26-D50N might be associated not only with skin barrier defects, but also with the down-regulated expression of immune response-related genes.