The deregulation of NOTCH pathway, inflammatory cytokines, and keratinization genes in two Dowling-Degos disease patients with hidradenitis suppurativa.

Dowling-Degos disease (DDD) is a rare autosomal-dominant genodermatosis and it has been associated with hidradenitis suppurativa (HS). Deregulation of NOTCH pathway has been linked to the development of HS in DDD context (DDD-HS). However, molecular alterations in DDD-HS, including altered gene expression of NOTCH and downstream effectors that are involved in the follicular differentiation and inflammatory response, are poorly defined. We report two cases of patients diagnosed with DDD-HS, one of those, under Adalimumab treatment. Our results have shown downregulation of NOTCH1/NCSTN pathway, distinct molecular profiles of inflammatory cytokines (IL23A and TNF), and a novel aberrant upregulation of genes involved in the cornified envelope (CE) formation (SPRR1B, SPRR2D, SPRR3, and IVL) in paired HS lesions of two DDD patients.

Histopathologic findings characteristic of CARD14-associated papulosquamous eruption.

BACKGROUND: Pathogenic mutations in caspase recruitment domain-containing protein 14 (CARD14) lead to CARD14-associated papulosquamous eruption, which shares clinicopathologic findings with psoriasis and pityriasis rubra pilaris. We aimed to describe distinguishing histopathologic features of CARD14-associated papulosquamous eruption. METHODS: This retrospective study examined the histopathologic features of specimens from patients with confirmed CARD14-associated papulosquamous eruption and adult patients with plaque psoriasis and pityriasis rubra pilaris. RESULTS: Lesional skin biopsies from patients with CARD14-associated papulosquamous eruption consistently showed alternating checkerboard parakeratosis and orthokeratosis, acanthosis without acantholysis, and dilated vessels in the dermal papillae, with some cases also showing follicular plugging. CONCLUSION: CARD14-associated papulosquamous eruption has a range of findings, with a predominance of features typically associated with pityriasis rubra pilaris.

Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations.

Protein O-fucosyltransferase-1 (POFUT1), which transfers fucose residues to acceptor sites on serine and threonine residues of epidermal growth factor-like repeats of recipient proteins, is essential for Notch signal transduction in mammals. Here, we examine the consequences of POFUT1 loss on the oncogenic signaling associated with certain leukemia-associated mutations of human Notch1, report the structures of human POFUT1 in free and GDP-fucose bound states, and assess the effects of Dowling-Degos mutations on human POFUT1 function. CRISPR-mediated knockout of POFUT1 in U2OS cells suppresses both normal Notch1 signaling, and the ligand-independent signaling associated with leukemogenic mutations of Notch1. Normal and oncogenic signaling are rescued by wild-type POFUT1 but rescue is impaired by an active-site R240A mutation. The overall structure of the human enzyme closely resembles that of the Caenorhabditis elegans protein, with an overall backbone RMSD of 0.93 Å, despite primary sequence identity of only 39% in the mature protein. GDP-fucose binding to the human enzyme induces limited backbone conformational movement, though the side chains of R43 and D244 reorient to make direct contact with the fucose moiety in the complex. The reported Dowling-Degos mutations of POFUT1, except for M262T, fail to rescue Notch1 signaling efficiently in the CRISPR-engineered POFUT1-/- background. Together, these studies identify POFUT1 as a potential target for cancers driven by Notch1 mutations and provide a structural roadmap for its inhibition.

Fibroelastolytic papulosis: histopathologic confirmation of disease spectrum variants in a single case.

Fibroelastolytic papulosis is a rare, acquired fibroelastolytic disorder that presents clinically as white-to-yellow papules and plaques most commonly occurring on the neck of elderly patients. The term fibroelastolytic papulosis encompasses two closely related conditions previously described as pseudoxanthoma elasticum-like papillary dermal elastolysis (PDE) and white fibrous papulosis of the neck (WFPN). Here we present a case of a 78-year-old white female with a several-year history of numerous, asymptomatic 2-3 mm yellowish, non-follicular papules distributed symmetrically over the posterior neck, axillae, arm and antecubital fossae. Histopathologic examination revealed thickened and clumped elastotic fibers admixed with thick, sclerotic appearing collagen bundles in the mid and deep reticular dermis. Rare melanophages, loss of vertically oriented elastic fibers and scattered elastotic globes were noted in the papillary dermis. Based on the shared clinicopathologic features showed in this case, strong consideration should be made for the additional inclusion of papillary dermal elastosis as existing along the disease continuum of fibroelastolytic papulosis. This occurrence of fibroelastolytic papulosis shows unique histopathologic findings of pseudoxanthoma elasticum-like PDE, papillary dermal elastosis and WFPN, further supporting the theory that these entities exist as variants along the fibroelastolytic papulosis spectrum.

Clear Cell Papulosis: Report of a Case With Unique Clinical and Histologic Findings.

Clear cell papulosis is a rare, self-limited, benign disease of early childhood, characterized by white macules and flat papules over the milk line. Histopathologically, it is characterized by scattered clear cells throughout the basal and/or suprabasal epidermal layers, which-as clear cells of Toker of the nipple do-typically express cytokeratin 7. They also exhibit other markers expected for adenoid differentiation, such as low-molecular weight cytokeratins, carcinoembryonic antigen, epithelial membrane antigen, and mucin. The age of onset, distribution of lesions, histopathology, and its benign behavior nature help to exclude clinically similar conditions, either benign or malignant. The authors report a case of clear cell papulosis in a 7-year-old Brazilian girl in whom lesions were observed on the legs and histologically formed by solid and adenoid aggregates of clear cells, in a similar fashion than clear fetal cells of Toker.

Expression of REIC/Dkk-3 in normal and hyperproliferative epidermis.

Dickkopf (Dkk) family members are known as Wnt modulators involved in the development, cell growth/differentiation and cancer. REIC/Dkk-3, which does not interfere with Wnt signalling, has been proposed to be a tumor suppressor gene, but its physiological function has remained unclear. In this study, we analysed the expression of REIC/Dkk-3 in normal interfollicular epidermis (IFE) and hyperproliferative epidermis. REIC/Dkk-3 was expressed in human and mouse IFE, being localized at the interface of upper spinous layer and granular layer. Skin cancer cell lines lost REIC/Dkk-3 expression as reported previously. When we analysed patient samples, REIC/Dkk-3 expression was down-regulated in the hyperproliferative epidermis including skin cancers and non-cancerous proliferative diseases. REIC/Dkk-3 expression was also suppressed in the regenerative and inflammative epidermis of model mice. These findings will certainly contribute to the extension of studies on REIC/Dkk-3.

Long-term follow-up study of clear cell papulosis.

BACKGROUND: Clear cell papulosis (CCP) was described as a new entity in 1987. Since then, only case reports or small case series have appeared in the literature and the long-term outcome of CCP remains unknown. OBJECTIVES: The aim of this study was to review cases of CCP diagnosed at our institution and to investigate their outcome. METHODS: Nineteen patients given a diagnosis of CCP more than 6 years previously were identified. Their medical records and histopathologic findings were reviewed. RESULTS: With a median follow-up duration of 11.5 years, regression of skin lesions was observed in 85.7% of patients. Persistence of skin lesions 11.5 years after diagnosis was confirmed histopathologically in one case, with a reduction in clear cell density. LIMITATIONS: Retrospective nature of the study is a limitation. CONCLUSION: No treatment is necessary for CCP because the skin lesions are asymptomatic and most patients experience at least partial regression.

Drug-induced papuloerythroderma: analysis of T-cell populations and a literature review.

Papuloerythroderma of Ofuji is characterized by coalescent solid papules that spare the skin folds. Although cutaneous lymphomas and internal malignancies are known associated conditions, the causative agents are unclear in most cases. A number of recent reports have documente d that drugs can induce papuloerythroderma. We review ed the reported cases and our own cases of drug-induc ed papulo erythroderma, together with our data from lympho cyte transformation tests and T-cell subsets of peri pheral blood. All of the 9 patients were male, and the causative drugs were various. Provocation tests were positive in all 6 patients examined. Whereas drug patch tests were negative in all 5 cases tested, the patients' peripheral blood lymphocytes responded well to the culprit drug in 4 of 5 patients tested. The patients had higher percentages of circulating CCR4+CD4+ T helper (Th) 2 cells than CXCR3+CD4+ Th1 cells. Drug-induced papuloerythroderma seems to be mediated by Th2 cells reacting with the causative drug.

In situ expression of corticotropin-releasing hormone (CRH) and proopiomelanocortin (POMC) genes in human skin.

Systemic stresses induce corticotropin-releasing hormone (CRH) expression in hypothalamus. CRH is released to the pituitary gland, where it stimulates proopiomelanocortin (POMC) production acting via the CRH receptor (CRH-R). CRH and POMC peptides are also detected in sites outside of the central nervous system (CNS), such as the skin. However, it has not been elucidated whether these peptides detected in the skin are derived from CNS or are produced locally. Using immunohistochemical and in situ reverse-transcription (RT)-PCR techniques, we demonstrated coexpression of CRH and POMC mRNAs in the epidermis and pilosebaceous units of the human skin. This coexpression was confirmed by the combination of laser-capture microdissection (LCM) with RT-PCR, analyzing mRNA expressions in captured sebaceous cells. Immunoreactivities and expressions of CRH and POMC mRNAs were strong in inflammatory lesions, melanocytic nevus, seborrheic keratosis, and also in the periphery of the benign tumor. These findings suggest that CRH and POMC peptides are produced locally in the skin and are regulated by inflammatory cells as well as by autocrine mechanisms. The skin may have "a local stress response system," whose activity is mediated by CRH and POMC peptides, in an equivalent to hypothalamus-pituitary adrenal axis.

Pruritic papular eruption associated with HIV-etiopathogenesis evaluated by clinical, immunohistochemical, and ultrastructural analysis.

Pruritic Papular Eruption with Human Immunodeficiency Virus infection (PPE-HIV) is characterized by symmetrically distributed papules with pruritus in the skin of patients suffering advanced HIV infection. Although known since 1985, the etiology of this symptomatic dermatitis is unclear. We set out to characterize the phenotype of the infiltrating cells and the cytokine profile in the lesions, as an attempt to contribute to determining its etiopathogenesis. Clinical data and histological, immunohistochemical, and ultrastructural features of skin biopsies from 20 HIV patients with PPE were studied. The histopathological aspects, cell immunophenotypes, and cytokine expressions in the lesions where quantified and compared to perilesional skin, and to those in the clinically normal skin of HIV patients without PPE-HIV (n=11) and those in normal skin samples from HIV negative individuals (n=10). PPE-HIV occurred mainly in HIV patients with mean CD4+ counts of 124.6 +/- 104 lymphocytes/mm3. Furthermore, their eosinophil counts were significantly increased. The skin lesions were characterized by a predominantly perivascular dermal lymphohistiocytic inflammatory infiltrate. Langerhans cells were normally distributed in the epidermis and seen among the cellular components of dermal infiltrates. The density of CD8+ lymphocytes was elevated and the density of CD4+ cells was reduced in dermal infiltrates. Interleukin 5 was the predominant cytokine in the lesions. Electron microscopic analysis didn't disclose HIV or other infectious agents in the lesions. These results refute the hypothesis of an infectious etiology of PPE-HIV. CD8+ lymphocytes and Langerhans cells seem to have roles in the pathogenesis of PPE-HIV. The increased frequency of IL5 was associated with abundant eosinophils in the lesions, suggesting a type Th2 response in this dermatitis.

No evidence of KSHV/HHV-8 in mycosis fungoides or associated disorders.

The recently discovered human virus known as Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) has been associated with body-cavity-based lymphomas in AIDS patients. It is most closely related to two other herpesviruses, the Epstein-Barr virus and herpesvirus saimiri, which are known to be associated with lymphomas in humans and nonhuman primates, respectively. To determine whether KSHV/HHV-8 is involved in the pathogenesis of mycosis fungoides (MF) and related disorders, we used a genomic PCR assay followed by confirmatory Southern blot analysis with a nested oligonucleotide probe to analyze cases for the presence of this virus. The specimens studied included fresh-frozen lesional tissues obtained from 16 patients with MF, seven with lymphomatoid papulosis, seven with primary cutaneous CD30+ large cell lymphoma of T-cell lineage, and five with Hodgkin's disease. Two T-cell tumor lines were also studied: MT4 (derived from a patient with adult T-cell leukemia/lymphoma) and Jurkat (derived from a patient with T-cell acute lymphoblastic leukemia). All cases were uniformly negative for KSHV/HHV-8, whereas Kaposi's sarcoma-positive controls and human beta-globin DNA integrity controls were appropriately positive. These findings provide strong evidence against a role for KSHV/HHV-8 in the pathogenesis of MF or associated lymphoproliferative disorders.

Tenascin-C expression in papulosquamous disorders other than psoriasis in pediatric patients: an epiphenomenon?

BACKGROUND: Tenascin-C is a large extracellular matrix protein that is expressed in the basal membrane zone during embryonic development, tissue repair, and oncogenesis. In vitro studies suggest that proliferating epithelium induces the production of tenascin-C by mesenchymal cells. OBJECTIVE: Our goal was to compare the expression of tenascin-C in psoriasis with other papulosquamous disorders of the skin in pediatric patients. METHODS: The study was conducted on skin biopsy samples of 37 patients with psoriasis or other papulosquamous disorders. Of the 37 skin biopsy samples, 17 (45.9%) were diagnosed as psoriasis and 20 (54.1%) were diagnosed as other papulosquamous disorders histopathologically, and the expression of tenascin-C was evaluated immunohistochemically. RESULTS: Tenascin-C expression was seen in the dermis of lesional tissues or epidermal keratinocytes in 1 (5.8%) of the 17 biopsy samples diagnosed as psoriasis and 15 (75.0%) of the 20 biopsy samples diagnosed as other papulosquamous disorders (p  =  .001). CONCLUSION: Tenascin-C expression was not found to be a staining characteristic of psoriasis lesions. But the significant staining intensity of the tenascin-C expression in other papulosquamous disorders suggests that tenascin-C expression might be an epiphenomenon in the papulosquamous disorders other than psoriasis immunohistochemically.

Epithelioid fibrous papule - a new variant.

Fibrous papules (FPs) are common benign lesions occurring most frequently on the nose. Multiple variants have been described, including classic, hypercellular, clear cell, pigmented, pleomorphic, inflammatory and granular FPs. We describe a group of FPs with characteristics that do not easily fit into any of the above categories, with diffuse sheets of distinctive epithelioid cells, causing potential diagnostic confusion. Immunoperoxidase stains show that the cells of this 'epithelioid fibrous papule' are reactive for procollagen, and are negative for NKI/C3, unlike previously described clear cell variants.

Colloid milium of the upper eyelid margins: a rare presentation.

AIM: To report a rare presentation of colloid milium occurring only on the upper eyelid margins. DESIGN: Interventional case report. METHODS: (1) Slit-lamp examination of eyelids and eyes and clinical examination including the face and a general physical examination; (2) photography of the lesions on the lids; and (3) excision biopsy and histopathologic examination. MAIN OUTCOME MEASURES: Histologic examination confirmed the clinical diagnosis. RESULTS: Clinical examination and histopathologic findings revealed the cysts to be colloid milium. CONCLUSIONS: Colloid milium can involve upper eyelids in isolation, sparing the lower eyelids and facial skin. Such rare presentations should be kept in mind while examining similar lesions.

Clear cell papulosis of the skin.

Clear cell papulosis is a new entity first described in 1987. To date, six patients have been reported: all were young Taiwanese children. The disease is characterized clinically by multiple small, whitish maculopapules distributed along the milk line and by the presence of large, benign pagetoid cells in the epidermis resembling the clear cell of the nipple. The significance of this entity lies in its potential histogenetic link with Paget's disease of the skin. We report four new Taiwanese patients, three girls and one boy, aged between 21 months and 4 years. Two were sisters. Small hypopigmented macules first appeared on the pubis. They were eventually distributed bilaterally along the milk line but were most numerous in the public area. The disease may easily be overlooked when the macules are tiny or few in number and thus display no clear milk-line distribution, or when they occur in white-skinned individuals. Histologically, solitary large clear cells with large, round pale nuclei were detected in the basal layer of the hypomelaninized epidermis. The numbers of clear cells varied on haematoxylin and eosin staining and were only small in two patients. The cytoplasm of the clear cells was decorated by antikeratin AE1 and anticarcinoembryonic antigen antibodies. AE1 was the best marker of the clear cell. Some of the AE1-positive cells were tadpole-like in shape and were situated well above the basal layer. Ultrastructurally, large clumps of disintegrated or vacuolated mucin granules were present in the cytoplasm of the clear cells. The melanocytes appeared normal; the suprabasal keratinocytes were essentially devoid of melanosomes. The pathological findings in the present study support the hypothesis that these clear cells are an aberrant derivative of sweat gland cells in the epidermis and are potentially the precursor cells giving rise to mammary and extramammary Paget's disease. The differential diagnosis includes chicken pox scars, idiopathic guttate hypomelanosis, hypomelanotic tinea versicolor, anetoderma and early, hypopigmented lesions of Paget's disease.

Transepidermal elimination of urate-like crystals: a new perforating disorder?

We report two men who developed a transient perforating disorder characterized by transepidermal elimination of negatively birefringent needle-shaped crystals similar to monosodium urate. This striking clinical presentation has not previously been described and we propose that it be added to the group of diseases known as the primary perforating disorders.