Trichilemmal Cysts With Divergent Ductal Differentiation: A Series of 4 Cases.

ABSTRACT: Trichilemmal cysts are common clonal tumors with a predilection for the scalp. They are composed of an outer epithelial wall resembling the outer root sheath in the isthmus of the hair follicle and a central core of compact keratin. Sweat duct differentiation is exceptional with only one convincing case reported to date. Here, we sought to characterize the clinicopathological characteristics of sweat duct differentiation in trichilemmal cysts. We reviewed all cases of trichilemmal cyst diagnosed at our institution between 2008 and 2019. Ductal structures were found in 4 of 411 cases (0.97%). Subjects included 2 male and 2 female patients with a median age of 37.5 years (range 34-55). The ducts were lined by attenuated epithelial cells and immunoreactive for polyclonal carcinoembryonic antigen and cytokeratin 7. Ductal differentiation involved a median of 7.5% (range 1%-50%) of the cyst wall. All 4 cases were from the scalp and treated with local excision. No recurrence was identified with a median follow-up period of 1.5 years (range 1-12 years). In summary, sweat duct differentiation in trichilemmal cysts is rare but likely under recognized. Conceptually, we suggest it represents a type of divergent cellular differentiation within a clonal neoplasm rather than a retention cyst or hybrid cyst.

Mechanism of cell-intrinsic adaptation to Adams-Oliver Syndrome gene DOCK6 disruption highlights ubiquitin-like modifier ISG15 as a regulator of RHO GTPases.

DOCK6 is a RAC1/CDC42 guanine nucleotide exchange factor, however, little is known about its function and sub-cellular localization. DOCK6 regulates the balance between RAC1 and RHOA activity during cell adhesion and is important for CDC42-dependent mitotic chromosome alignment. Surprisingly, a cell intrinsic adaptation mechanism compensates for errors in these DOCK6 functions that arise as a consequence of prolonged DOCK6 depletion or complete removal in DOCK6 knockout cells. Down-regulation of the ubiquitin-like modifier ISG15 accounts for this adaptation. Strikingly, although most other DOCK family proteins are deployed on the plasma membrane, here we show that DOCK6 localizes to the endoplasmic reticulum (ER) in dependence of its DHR-1 domain. ER localization of DOCK6 opens up new insights into its functions.

Congenital diseases caused by defective O-glycosylation of Notch receptors.

The Notch signaling pathway is highly conserved and essential for animal development. It is required for cell differentiation, survival, and proliferation. Regulation of Notch signaling is a crucial process for human health. Ligands initiate a signal cascade by binding to Notch receptors expressed on a neighboring cell. Notch receptors interact with ligands through their epidermal growth factor-like repeats (EGF repeats). Most EGF repeats are modified by O-glycosylation with residues such as O-linked N-acetylglucosamine (O-GlcNAc), O-fucose, and O-glucose. These O-glycan modifications are important for Notch function. Defects in O-glycosylation affect Notch-ligand interaction, trafficking of Notch receptors, and Notch stability on the cell surface. Although the roles of each modification are not fully understood, O-fucose is essential for binding of Notch receptors to their ligands. We reported an EGF domain-specific O-GlcNAc transferase (EOGT) localized in the endoplasmic reticulum. Mutations in genes encoding EOGT or NOTCH1 cause Adams-Oliver syndrome. Dysregulation of Notch signaling because of defects or mutations in Notch receptors or Notch signal-regulating proteins, such as glycosyltransferases, induce a variety of congenital disorders. In this review, we discuss O-glycosylation of Notch receptors and congenital human diseases caused by defects in O-glycans on Notch receptors.

Management of clinical and subclinical actinic keratoses with histological and immunohistochemical assessments by confocal microscopy.

Reflectance confocal microscopy has been used to monitor treatment efficacy in non-melanoma skin cancer, but few studies have compared different therapies using the same confocal criteria. We compare a single score designed in previous study to evaluate confocal, histological, and immunohistochemical results obtained before and after two treatments of actinic keratosis (AK) and in field cancerisation area. Thirty volunteer male patients, aged >50-year old, with at least three clinically visible AKs on the bald scalp, were included in this study: 15 patients were submitted to 3% diclofenac therapy and 15 to 5% fluorouracil therapy. Confocal imaging was performed on a 5 × 5 cm skin area. In five patients of each group we performed cutaneous biopsies. Scaling, upper nucleated cells, and inflammatory cells showed a higher percentage reduction in field cancerisation, especially in diclofenac treatment group, while in AK inflammatory cells showed a greater percentage reduction in 5-fluorouracil treatment group. Both therapies are efficacious, but their effectiveness is different on the single parameters of the confocal, histology, immunohistochemically.

Inflammasome Activation Characterizes Lesional Skin of Folliculitis Decalvans.

Folliculitis decalvans (FD) is a chronic inflammatory disease leading to scarring alopecia with poorly defined pathogenesis. The aim of this study was to investigate the expression of markers associated with the activation of innate immune signals, such as inflammasome (NALP1 and NALP3), interleukin (IL)-1ß and IL-8 and type I interferon (MxA). A retrospective monocentric study was conducted and included 17 patients with FD with available biopsies. Disease activity (stable vs. active) was defined clinically and histologically. Immunostaining was performed using antibodies directed against NALP1, NALP3, IL-1ß, IL-8, and MxA on FD skin biopsies. Results were compared with normal controls and lichen planopilaris. Eleven patients had active disease and 6 had stable disease. NALP1, NALP3, and IL-1ß expression were significantly increased in hair follicles in FD compared with controls and lichen planopilaris. This study highlights the predominant immune signal associated with inflammasome activation in FD, suggesting the use of IL-1ß blockade in FD.

Adams-Oliver syndrome review of the literature: Refining the diagnostic phenotype.

The Adams-Oliver syndrome (AOS) is defined as aplasia cutis congenita (ACC) with transverse terminal limb defects (TTLD). Frequencies of associated anomalies are not well characterized. Six causative genes have been identified: ARHGAP31, DOCK6, EOGT, RBPJ, NOTCH1, and DLL4. We review 385 previously described individuals (139 non-familial and 246 familial probands and family members) and add clinical data on 13 previously unreported individuals with AOS. In addition to ACC and TTLD, the most commonly associated anomalies included a wide variety of central nervous system (CNS) anomalies and congenital heart defects each seen in 23%. CNS anomalies included structural anomalies, microcephaly, vascular defects, and vascular sequelae. CNS migration defects were common. Cutis marmorata telangiectasia congenita (CMTC) was found in 19% of the study population and other vascular anomalies were seen in 14%. Hemorrhage was listed as the cause of death for five of 25 deaths reported. A relatively large number of non-familial probands were reported to have hepatoportal sclerosis with portal hypertension and esophageal varices. Non-familial probands were more likely to have additional anomalies than were familial probands. The data reported herein provide a basis for refining the diagnostic features of AOS and suggest management recommendations for probands newly diagnosed with AOS. © 2017 Wiley Periodicals, Inc.

Low-dose oral isotretinoin for moderate to severe seborrhea and seborrheic dermatitis: a randomized comparative trial.

BACKGROUND: The efficacy of low-dose oral isotretinoin in the treatment of seborrhea and seborrheic dermatitis has been poorly investigated in randomized studies. OBJECTIVES: This study was designed to determine the efficacy and safety of low-dose oral isotretinoin in the treatment of moderate to severe seborrhea and seborrheic dermatitis on the scalp and/or face. METHODS: A randomized, comparative clinical trial, using two groups, was conducted over 6 months. Patients in Group ISO were treated with isotretinoin 10 mg every other day. In Group X, patients received antiseborrheic topical treatment. Patient opinion, investigator assessment, scalp pruritus, sebum production, and quality of life (QoL) comprised the efficacy outcomes. RESULTS: The intention-to-treat population comprised a total of 45 patients with mean ± standard deviation ages of 28.7 ± 5.8 years in Group ISO and 29.8 ± 6.5 years in Group X. The rate of sebum production significantly decreased in Group ISO. Patient opinion, investigator, and QoL assessments improved in both groups. CONCLUSIONS: Low-dose oral isotretinoin can be a therapeutic modality for moderate to severe seborrhea and seborrheic dermatitis.

Physiological and microbiological verification of the benefit of hair washing in patients with skin conditions of the scalp.

BACKGROUND: It is unclear whether hair washing is effective against scalp eruption and pruritus caused by seborrheic dermatitis or psoriasis vulgaris. AIMS: To assess whether a proper hair-washing regimen, including the use of antibacterial shampoo, can ameliorate scalp eruption symptoms and alter the composition of the scalp microflora. METHODS: Eighteen patients with seborrheic dermatitis or psoriasis vulgaris scalp eruptions were instructed in proper techniques of daily hair washing, rinsing, and shampooing, which they underwent for 12 weeks. They used control shampoo in weeks 1-4 and 9-12, and an antibacterial shampoo during weeks 5-8. At the start of the test period and at weeks 4, 8, and 12, we assessed scalp symptoms (erythema, scaling/desquamation, dryness, itchiness, and scratching scars); microbial DNA levels from lesion and nonlesion areas; and levels of interleukin (IL)-1α, IL-1ra, and total protein in the scalp's horny layer. RESULTS: Compared to baseline values, scaling/desquamation and itchiness improved significantly at weeks 8 and 12. Other observed skin symptoms also improved over time. Malassezia colonization levels in lesion and nonlesion areas decreased gradually; the decrease was significant at week 8 in lesion areas and at weeks 4 and 8 in nonlesion areas. Bacterial colonization levels also decreased gradually, achieving significance in lesion areas at week 4. Gradual decreases in IL-1ra/IL-1α level showed statistical significance at weeks 4 and 12, while the protein quantity significantly decreased at week 12. CONCLUSION: Proper hair washing improved scalp condition symptoms, and possibly the underlying etiology.

Special Stains and Immunohistochemical Stains in Hair Pathology.

BACKGROUND: Patterns in scalp biopsies can overlap, and distinction may be difficult. OBJECTIVE: To review the current knowledge about the usefulness of special stains and immunohistochemical stains (IHC) for the diagnosis of hair disorders. METHODS: The authors used the search engines PubMED, MEDLINE, and MeSH to retrieve articles on the application of special stains and IHC in hair pathology. RESULTS: The authors selected 65 relevant articles discussing the use of special stains and IHC markers in scalp biopsies, including case reports and original articles. No reviews on the subject were found. Although fungal stains, such as periodic acid-Schiff, are very helpful in the diagnosis of noninflammatory tinea capitis, they may be negative in kerion. Elastic stains may help to diagnose end-stage scarring alopecia on vertical sections. Stains for mucin may help to distinguish lupus erythematosus from lichen planopilaris. Lymphocytic markers may assist in the diagnosis of lymphoma-associated alopecia. CONCLUSIONS: On a practical level, there is no evidence to recommend the routine use of a stain or a panel of stains in hair pathology. No stain can distinguish between nonscarring and early scarring alopecia. Most IHC stains are currently limited to the experimental and research setting.

The Use of Anti-Keratin 903 Antibodies to Visualize Colloid Bodies and Diagnose Lichen Planopilaris.

Cytokeratins are a major component of colloid bodies that are essentially diagnostic of lichen planopilaris (LPP). Here, the authors assess the ability of the cytokeratin 903 antibody (CK-903) to stain colloid bodies and differentiate LPP from other histologically similar appearing primary cicatricial alopecias. A retrospective review of all specimens submitted to the dermatopathology department over a 2-year window identified 18 cases of LPP and 20 cases of histologically similar appearing entities (discoid lupus erythematosus or central centrifugal cicatricial alopecia) through a combination of H&E, elastic van gieson, and periodic acid-schiff stains. All 38 samples were then prospectively stained with CK-903. Colloid bodies were identifiable in 3 of the 18 LPP cases based on H&E alone but were seen in 9 of 18 cases when CK-903 was used. There were no cases where colloid bodies were seen on H&E but not subsequently identified with CK-903. Additionally, there was no CK-903 staining in any of the 20 cases of similar appearing entities except 1 case of discoid lupus erythematosus, which is known to occasionally show colloid bodies. The authors conclude that CK-903 is a useful adjunctive tool that will allow for a quicker, less costly, and more accurate diagnosis of LPP given its ability identify colloid bodies even in the setting of significant inflammation and fibrosis and its advantages over direct immunofluorescence of low cost, short preparation time, and lack of need for a specialized fluorescent microscope.

Fibroblast growth factor receptor signaling in kidney and lower urinary tract development.

Fibroblast growth factor receptors (FGFRs) and FGF ligands are highly expressed in the developing kidney and lower urinary tract. Several classic studies showed many effects of exogenous FGF ligands on embryonic renal tissues in vitro and in vivo. Another older landmark publication showed that mice with a dominant negative Fgfr fragment had severe renal dysplasia. Together, these studies revealed the importance of FGFR signaling in kidney and lower urinary tract development. With the advent of modern gene targeting techniques, including conditional knockout approaches, several publications have revealed critical roles for FGFR signaling in many lineages of the kidney and lower urinary tract at different stages of development. FGFR signaling has been shown to be critical for early metanephric mesenchymal patterning, Wolffian duct patterning including induction of the ureteric bud, ureteric bud branching morphogenesis, nephron progenitor survival and nephrogenesis, and bladder mesenchyme patterning. FGFRs pattern these tissues by interacting with many other growth factor signaling pathways. Moreover, the many genetic Fgfr and Fgf animal models have structural defects mimicking numerous congenital anomalies of the kidney and urinary tract seen in humans. Finally, many studies have shown how FGFR signaling is critical for kidney and lower urinary tract patterning in humans.

The role of oxidative damage in poor scalp health: ramifications to causality and associated hair growth.

The oxidative stress element of unhealthy scalp leads to compromised pre-emergent hair formation and poorly formed hair as it grows. Only cosmetic solutions can minimize the impact of unhealthy hair and to achieve healthy looking and feeling hair, the scalp health must be normalized first. The objectives of this research were to both investigate whether oxidative stress was a relevant aetiological element in scalp dandruff and seborrhoeic dermatitis and whether scalp condition affects the quality of hair that grows from it. Further, this research was designed to determine whether an effective anti-dandruff shampoo would repair and protect the scalp and pre-emergent hair from oxidative stress. This study demonstrated that oxidative stress is an aetiological element relevant to the dandruff condition and that a potentiated ZPT shampoo effectively improves scalp condition, including a reduction in oxidative stress. The compromised hair condition associated with dandruff is concomitantly improved when the scalp condition is improved. It appears that there is a direct link between hair quality and scalp health.

Evaluation of the Diagnostic Value of Plasmacytoid Dendritic Cells in Differentiating the Lymphocytic Cicatricial Alopecias.

BACKGROUND: Differentiating lymphocytic scarring alopecias may be difficult clinically as well as histopathologically. OBJECTIVE: To investigate plasmacytoid dendritic cell (PDC) presence and distribution patterns and their diagnostic value in differentiating scarring alopecias of lupus erythematosus (LE) from lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA). METHODS: Seventeen LE-associated alopecia, 20 LPP and 10 FFA cases were immunohistochemically tested for PDC presence/distribution and activity. RESULTS: LE-associated alopecia showed increased PDC content (≥10% PDCs in all cases and ≥50% in 94% of cases), PDC clusters (100% of cases), and deeper dermal and perieccrine distribution (100% of cases) with involvement of the dermoepidermal junction (DEJ, 94% of cases), while the majority of LPP and FFA had <10% PDC content that was mainly confined to the upper dermis surrounding the hair infundibulum with rare DEJ involvement and rare clustering. CONCLUSIONS: Specific PDC-related parameters may serve as a useful diagnostic adjunct in the differentiation between LE-associated alopecia versus LPP and FFA.

Oxidative stress in patients with scalp seborrheic dermatitis.

Seborrheic dermatitis (SD) is a common, chronic inflammatory skin disease that mainly affects the scalp. The objective of this study was to evaluate the activities of superoxide dismutase (SOD) and catalase (CAT) and the levels of malondialdehyde (MDA) in scraping samples of patients with scalp SD. Thirty consecutive patients with a diagnosis of scalp SD and thirty-one healthy volunteers were enrolled. The samples were obtained by scraping the skin surface of the scalp. SOD and CAT activities and MDA levels were measured in scraping samples by spectrophotometric method. SOD and CAT activities and MDA levels were significantly higher in patients than in controls (p<0.001 all). There was a positive correlation between the severity of the disease and itching scores (contingency coefficient = 0.671, p<0.001). Except for this correlation, there was no significant correlation among age, sex, duration and severity of the disease, itching scores, antioxidant enzymes and MDA levels in the patient group (p>0.05). Cutaneous oxidative stress in patients with SD may play an important role in the pathogenesis of the disease. Further clinical and laboratory evaluation of the oxidant/antioxidant system in patients with SD is warranted.

A comprehensive pathophysiology of dandruff and seborrheic dermatitis - towards a more precise definition of scalp health.

Despite an increasing knowledge of dandruff and seborrheic dermatitis (D/SD), the pathophysiological understanding is still incomplete but suggests a role of Malassezia yeasts in triggering inflammatory and hyper-proliferative epidermal responses. The objective of this report is to review published literature from in vivo studies of D/SD populations to provide a more complete description of overall scalp health. New biomolecular capabilities establish a depth of pathophysiological understanding not previously achievable with traditional means of investigation. Biomarkers representing inflammation, hyper-proliferation and barrier function are all perturbed by the D/SD condition and robustly respond to therapeutic resolution. These biomarkers can be sampled noninvasively, enabling their use in routine clinical evaluations as either surrogate endpoints or complementary ones to classical signs/symptoms to broaden the etiological learning.

Baseline sebum IL-1α is higher than expected in afro-textured hair: a risk factor for hair loss?

OBJECTIVE: To investigate changes in sebum cytokines in response to hair cosmetics. Design and setting A prospective study at a University hospital. METHODS: We used a novel method for scalp surface sebum collection (Sebutape(®)) on three visits, sequentially a week apart, to investigate changes in six cytokines in 36 healthy women before and after shampoo and compared various chemical treatments (ammonium thioglycolate, "lye" sodium hydroxide and "no-lye" guanidine hydroxide relaxers) performed by a professional hairdresser. RESULTS: Significant levels detected were IL-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1ra), which were higher in untreated scalp vs. forehead: P < 0.001. Baseline levels of scalp sebum IL-1α were 18 times higher than IL-1ra. The levels of IL-1α decreased uniformly after shampoo (visit 1) and various chemical treatments (both crown and vertex all P < 0.001 - visit 2) but increased on follow-up at visit 3. Decreases in IL-1ra mimicked IL-1α at the vertex [after shampoo (P = 0.018) and visit 3 (P = 0.014)], but not on the crown, a finding which may suggest site-specific scalp predisposition to inflammation. The ratio of IL-1ra/IL-1α increased in all groups after all chemical treatments and on follow-up (all P < 0.001) but was surprisingly not significantly different from natural hair that underwent shampoo. LIMITATIONS: A wider cytokine panel may reveal response differences in treatment groups. CONCLUSIONS: Baseline inflammatory scalp cytokines are higher than expected and reduce with shampooing. Scrutiny of the influence of hair moisturizer formulations and shampoo intervals and studies investigating pro-fibrotic cytokines are required. This may elucidate the predilection of afro-textured hair to scarring alopecia.

Scalp stratum corneum histamine levels: novel sampling method reveals association with itch resolution in dandruff/seborrhoeic dermatitis treatment.

Dandruff and seborrhoeic dermatitis are accompanied by bothersome itch. We have established a novel non-invasive methodology to sample histamine levels in the stratum corneum in order to facilitate an understanding of pruritogenesis in this condition. Histamine levels were assessed in two groups of subjects with dandruff before and after 3 weeks of treatment with a commercial potentiated zinc pyrithione shampoo. A comparative population without dandruff was also studied. Itch self-perception was quantified on a visual analogue scale. The histamine level in subjects with dandruff was more than twice that in those who did not have dandruff. Under conditions known to resolve flaking symptoms, the shampoo led to a reduction in histamine in subjects with dandruff to a level that was statistically indistinguishable from those who did not have dandruff. This reduction in histamine was accompanied by a highly significant reduction in the perception of itch intensity. These findings suggest an association between the subjective perception of itch in the scalp and the level of histamine in the skin.