Diagnosis and management of longitudinal erythronychia: A clinical review by an expert panel.

Longitudinal erythronychia (LE) is defined as a longitudinal red band of the nail(s) and is classified as localized (involvement of 1 nail) or polydactylous (involvement of more than 1 nail). The differential diagnosis is distinct for these classifications. The etiologies of localized longitudinal erythronychia are most frequently benign subungual neoplasms and less often malignancies. Polydactylous longitudinal erythronychia is typically secondary to regional or systemic diseases, including lichen planus and Darier disease. LE is a common but underrecognized clinical finding. Increased dermatologist awareness of the clinical characteristics and differential diagnosis for LE is necessary given the possibility for malignancy and associated systemic disease. In this clinical review, the clinical features, differential diagnosis, evaluation, and management of LE are described.

Bacterial Skin Dysbiosis in Darier Disease.

INTRODUCTION: Darier disease is a rare inherited disease with dominant skin manifestations including keratotic papules and plaques on sebaceous and flexural areas. Secondary infection of skin lesions is common, and Staphylococcus aureus commonly colonizes these lesions. The aim of the study was to characterize the bacterial microbiome of cutaneous Darier lesions compared to normal-looking skin and disease severity. METHODS: All patients with a history of Darier followed up at Emek Medical Center were invited to participate in the study. Patients that did not use antibiotics in the past month and signed informed consent had four skin sites sampled with swabs: scalp, chest, axilla, and palm. All samples were analyzed for bacterial microbiome using 16S rDNA sequencing. RESULTS: Two hundred and eighty microbiome samples obtained from lesional and non-lesional skin of the scalp, chest, axilla, and palm of 42 Darier patients were included in the analysis. The most abundant bacterial genera across all skin sites were Propionibacterium, Corynebacterium, Paracoccus, Micrococcus, and Anaerococcus. Scalp and chest lesions featured a distinct microbiome configuration that was mainly driven by an overabundance of Staphylococci species. Patients with more severe disease exhibited microbiome alterations in the chest, axilla, and palm compared with patients with only mild disease, driven by Peptoniphilus and Moryella genera in scalp and palmar lesions, respectively. CONCLUSION: Staphylococci were significantly associated with Darier lesions and drove Darier-associated dysbiosis. Severity of the disease was associated with two other bacterial genera. Whether these associations also hold a causative role and may serve as a therapeutic target remains to be determined and requires further investigation.

Clinical spectrum of patients diagnosed with childhood mastocytosis: a retrospective single center experience.

Summary: Background. Pediatric cutaneous mastocytosis patients diagnosed and followed up by our specialist were enrolled in this study, and clinical and laboratory evaluations were retrospectively analyzed from patients' archived files. Methods. Patients, who applied to the Division of Pediatric Allergy And Immunology Unit of a University Training and Research Hospital between 01.01.2010 and 28.04.2021, were enrolled in this study. Results. Of the 33 patients included in the study, 11 (33.3%) were female and 22 (67.7%) were male. The median age of onset of the patient's complaints was 7 (0-60) months. The median age at diagnosis was 11 (2-64) months. Their complaints' median regression age was 54 (6-192) months. Resistant clinical findings were followed in 13 (39.4%) patients. Itching, redness, gastrointestinal symptoms, and maculopapular eruption were the most common complaints. The rashes were mostly polymorphic and larger than 1 cm. Heat was the most common trigger. Darier's sign was positive in 97% of the patients. Antihistamines were the most commonly used drug for prophylaxis and treatment. The autoinjector prescription rate was 24.2%. Conclusions. Quality of life was mildly affected in 48,5% of the patients based on the CDLQI scores. Thus, patients should be followed up through adolescence for the development of systemic signs and symptoms.

[MACULOPAPULAR CUTANEOUS MASTOCYTOSIS HARBORING A KIT MUTATION (ASP419DEL): A CASE REPORT].

A 2-year-old, male patient presented with an 18-month history of scattered, brown macules and nodules up to 2 cm in size on his trunk and extremities. These macules were accompanied by pruritus and were positive for Darier's sign. A skin biopsy of a brown macule on the left thigh revealed a dense accumulation of CD117-positive, round or oval cells with amphophilic cytoplasm within the upper to middle dermis. The patient was otherwise healthy and had normal laboratory and imaging test results. Sequence analysis of genomic DNA from a skin biopsy demonstrated the presence of an Asp419del mutation in exon 8 of the KIT gene. Based on these findings, maculopapular cutaneous mastocytosis (MPCM) was diagnosed. The patient received H 1-antihistamine. Although the pruritus resolved, the brown macules remained for one year after the initial treatment. To the best of our knowledge, only three cases of cutaneous mastocytosis (CM) with an Asp419del mutation, including the present case, have been reported in the Japanese literature to date; moreover, while the previous two cases were of DCM, the present case was the first instance of MPCM. Normally, the symptoms of childhood-onset MPCM are dormant until puberty. However, a recent study reported that many MPCM patients may experience persistent or exacerbated symptoms. The present study therefore evaluated 53 Japanese cases of childhood onset MPCM with a KIT gene mutation and discussed the patients' clinical outcomes.

Keratosis follicularis (Darier disease) - clinical characteristics and treatment - a review and update.

Darier disease is one of the most common genodermatoses. Although Darier disease was described in 1886, targeted therapies remain unknown. Current literature lacks specific guidelines for treatment of Darier disease. Treatment remains symptomatic and may be challenging for dermatologists. The aim of this article is to present clinical characteristics and treatment options. In a mild form of the disease with a small number of skin lesions, the symptoms can be reduced by the use of topical medications. Oral retinoids, alternatively doxycycline, seem to be beneficial in extensive and persistent lesions unresponsive to local treatment. In limited, hypertrophic forms, surgical methods, laser therapy and photodynamic therapy could be used.

Impaired calcium signalling and neuropsychiatric disorders in Darier disease: An exploratory review.

Darier (Darier-White) disease (DD) is an autosomal dominant skin disorder caused by pathogenic mutations in the ATP2A2 gene which encodes a calcium ATPase in the sarco-endoplasmic reticulum (SERCA2). Defects in the SERCA2 protein lead to an impairment of cellular calcium homeostasis, which in turn, triggers cell death pathways. There is a high prevalence of neuropsychiatric disorders in patients affected by this condition, namely intellectual disability, bipolar disorder, schizophrenia, and suicidality. Though these associations have been well-documented over the years, little has been discussed or investigated regarding the pathophysiological mechanisms. The goal of this article is to review the literature related to the most commonly associated neuropsychiatric disorders found in patients with DD, highlight the pathophysiological mechanisms underlying each condition, and examine potential interventions that may be of interest for future development. A literature search was performed using PubMed to access and review relevant articles published in the last 40 years. Keywords searched included Darier disease neuropsychiatric, Darier disease pathophysiology, SERCA2 central nervous system, SERCA 2 skin, ATP2A2 central nervous system, ATP2A2 skin, sphingosine-1-phosphate signalling skin, sphingosine-1-phosphate signalling central nervous system, P2X7 receptor skin, and P2X7 receptor central nervous system. Our search resulted in 2692 articles, of which 61 articles were ultimately included in this review.

Whole-transcriptome sequencing identifies postzygotic ATP2A2 mutations in a patient misdiagnosed with herpes zoster, confirming the diagnosis of very late-onset segmental Darier disease.

An 82-year-old female patient presented with a recent onset of painful skin lesions in unilateral distribution on the abdominal area following the lines of Blaschko; the initial diagnosis of Varicella-Zoster infection was made. However, because the individual lesions appeared as hyperkeratotic papules and were unresponsive to antiviral therapy, a skin biopsy was performed, which revealed hyperkeratosis, suprabasal acantholysis and dyskeratosis with corps ronds and grains, consistent with acantholytic dyskeratotic acanthoma. Since this entity has been associated with Darier disease, whole-transcriptome sequencing by RNA-Seq was performed on RNA isolated from a lesion and from adjacent normal appearing skin, and a recently developed bioinformatics pipeline that can identify both genomic sequence variants and the presence of any of 926 viruses was applied. Two pathogenic missense mutations in the ATP2A2 gene were identified in the lesional but not in normal appearing skin, and no evidence of Varicella-Zoster infection was obtained. These findings confirm the diagnosis of segmental Darier disease due to postzygotic mutations in the ATP2A2 gene, and attest to the power of a novel single-step application of RNA-Seq in providing correct diagnosis in this rare genodermatosis.

Therapeutic Options for the Treatment of Darier's Disease: A Comprehensive Review of the Literature.

Darier's disease (also known as keratosis follicularis or dyskeratosis follicularis) is an autosomal dominant inherited disorder which manifests as hyperkeratotic greasy papules in the first or second decade of life. Aside from symptom management and behavioral modifications to avoid triggers, there are currently no validated treatments for Darier's disease (DD). However, a variety of treatments have been proposed in the literature including retinoids, steroids, vitamin D analogs, photodynamic therapy, and surgical excision. The purpose of this review article is to identify therapeutic options for treating DD and to outline the evidence underlying these interventions. A search was conducted in Medline for English language articles from inception to July 4, 2020. Our search identified a total of 474 nonduplicate studies, which were screened by title and abstract. Of these, 155 full text articles were screened against inclusion/exclusion criteria, and 113 studies were included in our review. We identified Grade B evidence for the following treatments of DD: oral acitretin, oral isotretinoin, systemic Vitamin A, topical tretinoin, topical isotretinoin, topical adapalene gel, topical 5-flououracil, topical calciptriol and tacalcitol (with sunscreen), grenz ray radiation, and x-ray radiation. All other evidence for treatments of DD consisted of case reports or case series, which is considered grade C evidence. Considering the quality and quantity of evidence, clinicians may consider initiating a trial of select topical or oral retinoids first in patients with localized or generalized DD, respectively.

Darier Disease with Psoriasis.

Darier disease is an autosomal dominant disorder with dark crusty patches and is classified as hereditary acantholytic dermatosis. Keratotic papules and crust are often present on the scalp, forehead, chest, back, upper arms, elbows, groin, and behind the ears, predominantly in seborrheic areas. A 48-year-old male patient presented skin lesions with pruritus on the trunk and both upper and lower extremities. He first noticed the lesion 15 years before. On physical examination, there were multiple erythematous papules with crust on the trunk and red-brown colored keratotic plaque on both extremities. The suspected histopathological diagnosis was psoriasis vulgaris. The patient's skin lesions and pruritus were significantly improved after the psoriasis treatment. While continuing psoriasis treatment, the patient showed sudden worsening of the skin lesions on the scalp, abdomen, and fingernails (V-shaped nicks) with pruritus. Punch biopsy was performed on the abdominal lesion again and the final diagnosis was Darier disease. The patient was then treated using alitretinoin while maintaining the use of guselkumab for psoriasis. There are only a few cases that we found in which patients with Darier disease also had psoriasis. We report this rare case of Darier disease with psoriasis and propose that an additional biopsy might be necessary for accurate diagnosis and proper treatment.

Patients with Darier Disease Exhibit Cognitive Impairment while Patients with Hailey-Hailey Disease Do Not: An Experimental, Matched Case-control Study.

Darier disease and Hailey-Hailey disease are severe, monogenetic dermatological disorders with mutations affecting all cells, making them liable to exhibit extra-dermal symptoms. The aim of this study is to assess broad cognitive function in individuals with these diseases, using an experimental, case-control set-up comparing cognition in patients with that in healthy controls matched for age, sex and level of education. Cognition was assessed with the Cambridge Neuropsycho-logical Test Automated Battery. Patients with Darier disease (n = 29) performed significantly poorer on 5 of the 10 key cognitive measurements, while patients with Hailey-Hailey disease (n = 25) did not perform differently from controls. The main conclusion is that patients with Darier disease exhibit significant impairment in cognitive function, which reinforces the view that Darier disease should be regarded as a disorder affecting multiple organs, and should therefore be given medical consideration, and possibly treat-ment, as such.

Darier Disease - A Multi-organ Condition?

Darier disease is a severe, rare autosomal dominant inherited skin condition caused by mutations in the ATP2A2 gene encoding sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 in the endoplasmic reticulum. Since sarcoendoplasmic reticulum Ca2+-ATPase isoform 2 is expressed in most tissues, and intracellular calcium homeostasis is of fundamental importance, it is conceivable that other organs besides the skin may be involved in Darier disease. This review focusses on the association of Darier disease with other organ dysfunctions and diseases, emphasizing their common molecular pathology. In conclusion, Darier disease should be considered a systemic condition that requires systemic and disease mechanism targeted treatments.

Subcutaneous sarcoidosis: A case series of 19 patients.

Subcutaneous sarcoidosis is a rare variant of this disease, whose relationship with systemic disease is still controversial. Our objective was to describe the clinical characteristics of a series of patients with subcutaneous sarcoidosis and to investigate the relationship between these skin lesions and the disease's activity, severity, and prognosis. Nineteen patients with biopsy-confirmed subcutaneous sarcoidosis between 2009 and 2019 were selected. Mean age at diagnosis was 53 years. Lung involvement was detected in 10 patients (52.6%), mainly in stages I and II. Only two patients (10.5%) had additional systemic signs and five patients (26%) suffered from other autoimmune diseases simultaneously. Six patients (31.6%) had elevated angiotensin-converting enzyme levels (mean level 174.5 U/L). Eight patients (42%) received treatment, mainly systemic corticosteroids, and all patients except for one had a favorable clinical outcome. Subcutaneous sarcoidosis is frequently associated with a mild form of systemic disease, and the prognosis seems favorable regardless of treatment. Sarcoid nodules could be an early finding of systemic disease, allowing for less invasive procedures for histological confirmation.

An Update on the Cutaneous Manifestations of Darier Disease.

BACKGROUND: Knowledge about the clinical features of Darier disease, an orphan autosomal-dominant genetic disorder, is sparse and has been evaluated only in few studies. OBJECTIVES: To investigate the clinical features of a large group of patients with Darier disease, and to explore for associations between disease characteristics and severity of the disease. METHODS: Seventy-six individuals with Darier disease were evaluated utilizing a structured questionnaire-based interview, a physical examination, and a retrospective assessment of their medical records. RESULTS: The most frequent locations of lesions were hands (99%) and fingernails (93%). Wart-like lesions on the hands were more visible after soaking them in water for 5 minutes, we therefore named this phenomenon the "wet hand sign". Oral involvement was found in 43% of patients, while 48% of women and 16% of men showed genital lesions. Patients with severe Darier disease had a tenfold greater risk of developing genital lesions than those with mild disease (P = .01). Most patients (88%) in our study exhibited a combination of the four types of the disease patterns of distribution (flexural, seborrheic, nevoid, and acral). CONCLUSIONS: Documentation of disease on the hands and fingernails provides a highly sensitive means to aid in the diagnosis of Darier disease. It is important to evaluate mucosal lesions including genital and oral mucosa.

Regional Differences in the Permeability Barrier of the Skin-Implications in Acantholytic Skin Diseases.

The chemical milieu, microbiota composition, and immune activity show prominent differences in distinct healthy skin areas. The objective of the current study was to compare the major permeability barrier components (stratum corneum and tight junction (TJ)), investigate the distribution of (corneo)desmosomes and TJs, and measure barrier function in healthy sebaceous gland-rich (SGR), apocrine gland-rich (AGR), and gland-poor (GP) skin regions. Molecules involved in cornified envelope (CE) formation, desquamation, and (corneo)desmosome and TJ organization were investigated at the mRNA and protein levels using qRT-PCR and immunohistochemistry. The distribution of junction structures was visualized using confocal microscopy. Transepidermal water loss (TEWL) functional measurements were also performed. CE intracellular structural components were similarly expressed in gland-rich (SGR and AGR) and GP areas. In contrast, significantly lower extracellular protein levels of (corneo)desmosomes (DSG1 and CDSN) and TJs (OCLN and CLDN1) were detected in SGR/AGR areas compared to GP areas. In parallel, kallikrein proteases were significantly higher in gland-rich regions. Moreover, gland-rich areas were characterized by prominently disorganized junction structures ((corneo)desmosomes and TJs) and significantly higher TEWL levels compared to GP skin, which exhibited a regular distribution of junction structures. According to our findings, the permeability barrier of our skin is not uniform. Gland-rich areas are characterized by weaker permeability barrier features compared with GP regions. These findings have important clinical relevance and may explain the preferred localization of acantholytic skin diseases on gland-rich skin regions (e.g., Pemphigus foliaceus, Darier's disease, and Hailey-Hailey disease).

[Case report: Epigastric dermatofibroma reconstruction by reverse abdominoplasty with umbilic transposition]. / Cas clinique : reconstruction par abdominoplastie inversée et transposition ombilicale d'un dermatofibrosarcome épigastrique.

Dermatofibrosarcoma is the most common cutaneous sarcoma. Its surgical management is a technical challenge due to the high amount of substance loss. We explain a new technique of abdominal wall reconstruction by a reverse abdominoplasty with umbilical transposition. This new surgical technique allowed, in one time, the excision and the abdominal wall reconstruction. Functional and esthetic results are really satisfactory.

A case of severe refractory Darier's disease of the feet in which management with carbon dioxide (CO2) laser therapy demonstrated superior outcomes to surgical excision.

Darier's disease is a rare genodermatosis typically characterized by scaly or crusted papules. Usual management comprises topical and oral treatments, however medical therapy may be inadequate in cases of severe disease. For these patients, further treatment options may include the use of carbon dioxide (CO2) laser therapy or surgical excision with skin grafting. We describe a unique situation in which both CO2 laser therapy and surgical excision were trialed in comparable areas within a single patient. Superior outcomes over a 7-year follow up period have been seen with the use of CO2 laser therapy.

[Cutaneous plasmacytosis with Darier's sign in a woman of European origin]. / Plasmocytose cutanée avec signe de Darier chez une femme d'ascendance européenne.

INTRODUCTION: Cutaneous plasmacytosis is a rare skin condition first described in 1976 and it is seen mainly in patients of Asian descent. Patients usually present with multiple reddish-brown macules and nodules chiefly on the trunk and face, with clusters of well-differentiated plasma cells in the dermis. The aetiopathogenesis and nosological features of this entity remain obscure. We report herein a case of cutaneous plasmacytosis in a European middle-aged woman with presence of Darier's sign. PATIENTS AND METHODS: A 56-year-old woman of European descent presented with asymptomatic hyperpigmented patches affecting the dorsal aspect of her trunk for at least two years. Darier's sign was present in some episodes. Cutaneous biopsy showed a moderately dense interstitial and perivascular infiltrate containing numerous well-differentiated mature plasma cells affecting the entire dermal surface. Kappa and lambda immunochemistry demonstrated polyclonal plasma cell infiltrates with absence of light-chain restriction. Immunohistochemical examination was negative for HHV-8 and Treponema pallidum spirochetes. Laboratory findings revealed hypergammaglobulinaemia with no monoclonal bands being detected on immunofixation. A diagnosis of cutaneous plasmacytosis was made. In the absence of systemic involvement initial management consisted of clinical surveillance. DISCUSSION: The characteristic clinico-pathological features of CP allowed diagnosis of this skin condition in our patient, although it is very rarely reported in patients of European descent. The main differential diagnoses were ruled out, namely plasmacytic infiltrates related to infections and marginal B-cell lymphoma.

[Pediatric cutaneous mastocytosis]. / Cas clinique : La mastocytose cutanée pédiatrique.

Mastocytosis are orphan diseases characterized by the accumulation of mast cells in one or more organs. A distinction is made between systemic forms (10 %) and pure cutaneous forms (90 %), the latter being mainly pediatric and generally having a spontaneously favourable prognosis. In the absence of a systemic sign, the diagnostic criteria for cutaneous mastocytosis are Darier's sign, in principle, pathognomonic, as well as skin histology confirming mast cell infiltration. The treatment is essentially preventive (avoidance of factors triggering degranulation) and symptomatic (antihistamine agents).

Les mastocytoses sont des maladies orphelines caractérisées par l'accumulation de mastocytes dans un ou plusieurs organes. On distingue les formes systémiques (10 %) des formes cutanées pures (90 %). Ces dernières sont principalement pédiatriques et ont, généralement, un pronostic spontanément favorable. En cas d'absence de signe d'appel systémique, les critères de diagnostic de mastocytose cutanée sont le signe de Darier, en principe, pathognomonique ainsi que l'histologie cutanée affirmant l'infiltration mastocytaire. Le traitement est essentiellement préventif (éviction des facteurs déclenchant la dégranulation) et symptomatique (médicaments antihistaminiques).

ER-to-Golgi blockade of nascent desmosomal cadherins in SERCA2-inhibited keratinocytes: Implications for Darier's disease.

Darier's disease (DD) is an autosomal dominantly inherited skin disorder caused by mutations in sarco/endoplasmic reticulum Ca2+ -ATPase 2 (SERCA2), a Ca2+ pump that transports Ca2+ from the cytosol to the endoplasmic reticulum (ER). Loss of desmosomes and keratinocyte cohesion is a characteristic feature of DD. Desmosomal cadherins (DC) are Ca2+ -dependent transmembrane adhesion proteins of desmosomes, which are mislocalized in the lesional but not perilesional skin of DD. We show here that inhibition of SERCA2 by 2 distinct inhibitors results in accumulation of DC precursors in keratinocytes, indicating ER-to-Golgi transport of nascent DC is blocked. Partial loss of SERCA2 by siRNA has no such effect, implicating that haploinsufficiency is not sufficient to affect nascent DC maturation. However, a synergistic effect is revealed between SERCA2 siRNA and an ineffective dose of SERCA2 inhibitor, and between an agonist of the ER Ca2+ release channel and SERCA2 inhibitor. These results suggest that reduction of ER Ca2+ below a critical level causes ER retention of nascent DC. Moreover, colocalization of DC with ER calnexin is detected in SERCA2-inhibited keratinocytes and DD epidermis. Collectively, our data demonstrate that loss of SERCA2 impairs ER-to-Golgi transport of nascent DC, which may contribute to DD pathogenesis.