Tangled Truths: Unraveling the Link Between Frontal Fibrosing Alopecia and Allergic Contact Dermatitis.

Frontal fibrosing alopecia (FFA) is an increasingly common diagnosis, especially in middle-aged women, and has garnered growing attention in the scientific literature. This variant of lichen planopilaris (LPP) is recognized as a progressive scarring alopecia affecting the frontal and temporal regions of the scalp as well as the eyebrows and occasionally other sites. Although its precise etiology remains elusive, various factors such as genetics, medications, hormonal influences, and environmental exposures-including specific chemicals present in sunscreens-have been implicated in its pathogenesis but without evidence of causality. The potential relationship between contact allergy and FFA has been explored, with some suggesting an increased prevalence of contact allergy among patients diagnosed with FFA. This article aims to explore the potential association between contact allergy and FFA, focusing on the current published literature and implicated allergens.

Methionine Dependence of Hair Maintenance in C57BL/6 Mice.

BACKGROUND/AIM: Hair-follicle keratinocytes contain high levels of cysteine, which is derived from methionine, rapidly proliferate, and form the hair shaft. The high proliferation rate of hair-follicle keratinocytes resembles that of aggressive cancer cells. In the present study, we determined the effect of a methionine-deficient diet on hair loss (alopecia) in mice with or without homocysteine supplementation. MATERIALS AND METHODS: Mice were fed a normal rodent diet (2020X, ENVIGO) (Group 1); a methionine-choline-deficient diet (TD.90262, ENVIGO) (Group 2); a methionine-choline-deficient diet with a 10 mg/kg/day supply of homocysteine administered by intra-peritoneal (i.p.) injection for 2 weeks (Group 3). In Group 2, mice were fed a methionine-choline-deficient diet for an additional 2 weeks but with 10 mg/kg/day of i.p. l-homocysteine and the mice were observed for two additional weeks. Subsequently, the mice were fed a standard diet that included methionine. Hair loss was monitored by photography. RESULTS: After 14 days, hair loss was observed in Group 2 mice on a methionine-restricted diet but not in Group 3 mice on the methionine-restricted diet which received i.p. homocysteine. In Group 2, at 2 weeks after methionine restriction, hair loss was not rescued by homocysteine supplementation. However, after restoration of methionine in the diet, hair growth resumed. Thus, after 2 weeks of methionine restriction, only methionine restored hair loss, not homocysteine. CONCLUSION: Hair maintenance requires methionine in the diet. Future experiments will determine the effects of methionine restriction on hair-follicle stem cells.

Pilose antler extract promotes hair growth in androgenic alopecia mice by promoting the initial anagen phase.

Androgenetic alopecia (AGA) is a prevalent disease in worldwide, local application or oral are often used to treat AGA, however, effective treatments for AGA are currently limited. In this work, we observed the promoting the initial anagen phase effect of pilose antler extract (PAE) on hair regeneration in AGA mice. We found that PAE accelerated hair growth and increased the degree of skin blackness by non-invasive in vivo methods including camera, optical coherence tomography and dermoscopy. Meanwhile, HE staining of sagittal and coronal skin sections revealed that PAE augmented the quantity and length of hair follicles, while also enhancing skin thickness and hair papilla diameter. Furthermore, PAE facilitated the shift of the growth cycle from the telogen to the anagen phase and expedited the proliferation of hair follicle stem cells and matrix cells in mice with AGA. This acceleration enabled the hair follicles to enter the growth phase at an earlier stage. PAE upregulated the expression of the sonic hedgehog (SHH), smoothened receptor, glioma-associated hemolog1 (GLI1), and downregulated the expression of bone morphogenetic protein 4 (BMP4), recombinant mothers against decapentaplegic homolog (Smad) 1 and 5 phosphorylation. This evidence suggests that PAE fosters hair growth and facilitates the transition of the growth cycle from the telogen to the anagen phase in AGA mice. This effect is achieved by enhancing the proliferation of follicle stem cells and matrix cells through the activation of the SHH/GLI pathway and suppression of the BMP/Smad pathway.

ANTXR1 deficiency promotes fibroblast senescence: implications for GAPO syndrome as a progeroid disorder.

ANTXR1 is one of two cell surface receptors mediating the uptake of the anthrax toxin into cells. Despite substantial research on its role in anthrax poisoning and a proposed function as a collagen receptor, ANTXR1's physiological functions remain largely undefined. Pathogenic variants in ANTXR1 lead to the rare GAPO syndrome, named for its four primary features: Growth retardation, Alopecia, Pseudoanodontia, and Optic atrophy. The disease is also associated with a complex range of other phenotypes impacting the cardiovascular, skeletal, pulmonary and nervous systems. Aberrant accumulation of extracellular matrix components and fibrosis are considered to be crucial components in the pathogenesis of GAPO syndrome, contributing to the shortened life expectancy of affected individuals. Nonetheless, the specific mechanisms connecting ANTXR1 deficiency to the clinical manifestations of GAPO syndrome are largely unexplored. In this study, we present evidence that ANTXR1 deficiency initiates a senescent phenotype in human fibroblasts, correlating with defects in nuclear architecture and actin dynamics. We provide novel insights into ANTXR1's physiological functions and propose GAPO syndrome to be reconsidered as a progeroid disorder highlighting an unexpected role for an integrin-like extracellular matrix receptor in human aging.

Transcriptome analysis of frontal fibrosis alopecia revealed involvement of immune cells and ferroptosis.

BACKGROUND: Frontal fibrosis alopecia (FFA) is a primary cicatricial alopecia and has received increasing attention in recent years. However, the pathogenesis of FFA has not been fully elucidated. METHODS AND RESULTS: Herein, we collected the transcriptome data of scalp lesions of seven patients with FFA and seven healthy controls. The differential expression analysis and weighted gene co-expression network analysis were conducted and we identified 458 differentially expressed genes (DEGs) in two key modules. Later, we performed functional enrichment analysis and functional modules identification, revealing the participation of immune response and fatty acid metabolism. Based on the results, we processed further studies. On the one hand, we analyzed the infiltrating immune cells of FFA through CIBERSORT algorithm, indicating the activation of M1 macrophage and CD8+ T cell. On the other hand, considering lipid metabolism of FFA and oxidative stress of hair follicle cells in alopecia, we explored the potential ferroptosis of FFA. By intersection of DEGs and ferroptosis-related genes from FerrDb database, 19 genes were identified and their expression was validated in an external dataset containing 36 FFA cases and 12 controls. Then, we used LASSO algorithms to construct a four-gene diagnostic model, which achieved an AUC of 0.924 in validation dataset. Additionally, the immune cells were found to be related to ferroptosis in FFA. CONCLUSION: Taken together, this study contributed to reveal the molecular mechanisms of FFA and is expected to inspire future research on treatment.

Clinical Characterization and Treatment Response of Folliculitis Decalvans Lichen Planopilaris Phenotypic Spectrum: A Unicentre Retrospective Series of 31 Patients.

Folliculitis decalvans and lichen planopilaris phenotypic spectrum has been described as a form of cicatricial alopecia. The aim of this study is to describe the clinical and trichoscopic features and therapeutic management of this condition in a series of patients. A retrospective observational unicentre study was designed including patients with folliculitis decalvans and lichen planopilaris phenotypic spectrum confirmed with biopsy. A total of 31 patients (20 females) were included. The most common presentation was an isolated plaque of alopecia (61.3%) in the vertex. Trichoscopy revealed hair tufting with perifollicular white scaling in all cases. The duration of the condition was the only factor associated with large plaques (grade III) of alopecia (p = 0.026). The mean time to transition from the classic presentation of folliculitis decalvans to folliculitis decalvans and lichen planopilaris phenotypic spectrum was 5.2 years. The most frequently used treatments were topical steroids (80.6%), intralesional steroids (64.5%) and topical antibiotics (32.3%). Nine clinical relapses were detected after a mean time of 18 months (range 12-23 months). Folliculitis decalvans and lichen planopilaris phenotypic spectrum is an infrequent, but probably underdiagnosed, cicatricial alopecia. Treatment with anti-inflammatory drugs used for lichen planopilaris may be an adequate approach.

Traditional Scraping (Gua Sha) Combined with Copper-Curcumin Nanoparticle Oleogel for Accurate and Multi-Effective Therapy of Androgenic Alopecia.

Androgenetic alopecia (AGA) is a prevalent systemic disease caused by diverse factors, for which effective treatments are currently limited. Herein, the oleogel (OG) containing copper-curcumin (CuR) nanoparticles is developed, designated as CuRG, which is also combined with traditional naturopathic scraping (Gua Sha, SCR) as a multifunctional therapy for AGA. With the assistance of lipophilic OG and SCR, CuR can efficaciously penetrate the epidermal and dermal regions where most hair follicles (HFs) reside, thereby releasing curcumin (CR) and copper ions (Cu2+) subcutaneously to facilitate hair regeneration. Concomitantly, the mechanical stimulation induced by SCR promotes the formation of new blood vessels, which is conducive to reshaping the microenvironment of HFs. This study validates that the combination of CuRG and SCR is capable of systematically interfering with different pathological processes, ranging from improvement of perifollicular microenvironment (oxidative stress and insufficient vascularization), regulation of inflammatory responses to degradation of androgen receptor, thus potentiating hair growth. Compared with minoxidil, a widely used clinical drug for AGA therapy, the designed synergistic system displays augmented hair regeneration in the AGA mouse model.

Divergent progression pathways in male androgenetic alopecia and female pattern hair loss: Trichoscopic perspectives.

BACKGROUND: Despite similarities in progressive miniaturization of hair follicles and transition of terminal hairs to vellus hairs, insufficient trichoscopic comparisons between male androgenetic alopecia (MAGA) and female pattern hair loss (FPHL) hinder our ability to select effective treatments. AIM: Our study aimed to explore gender-specific trichoscopic characteristics of MAGA and FPHL, while formulating hypotheses regarding the progression of these conditions across clinical stages. METHODS: We classified 126 male MAGA subjects using Hamilton-Norwood Classification and 57 FPHL subjects using adopted Sinclair Scale. Subsequently, we analyzed nine trichoscopic factors divided into three categories: hair-diameter related, hair-number per follicular unit related, and hair density related factors. RESULTS: Of the nine quantitative trichoscopic factors, hair-diameter and hair-number per follicular unit showed strong correlations with clinical stages in both genders. Hair density, a common trichoscopic factor for hair loss evaluation, weakly correlated with clinical stages in FPHL, but not at all in MAGA. In addition, MAGA was characterized by a progressive reduction in hair-diameter, followed by a reduction in hair-number per follicular unit. FPHL, on the contrary, showed the opposite progression. CONCLUSIONS: Trichoscopic factors vary with disease severity in a gender-specific manner. Our research highlights that MAGA and FPHL involve two distinct streams: hair-diameter decreasing by hair follicle miniaturization (Stream 1), and hair-number per follicular unit decreasing by hair follicle tri-lineage niche dysfunction (Stream 2). MAGA typically starts from Stream 1 to Stream 2, while FPHL starts from Stream 2. These diverse progression pathways underscore the importance of personalized treatment approaches.

Clinicopathologic and trichoscopic features of keratosis follicularis spinulosa decalvans: A case series study.

Keratosis follicularis spinulosa decalvans (KFSD) is a rare X-linked hereditary disorder characterized by the triad of follicular hyperkeratosis-photophobia-alopecia. The clinical heterogeneity makes the diagnosis difficult. To investigate the clinicopathologic and trichoscopic features of KFSD and to further clarify the essential requisites for the diagnosis, we conducted a retrospective study of patients with KFSD. The clinical information, histologic features, and trichoscopic findings were evaluated. Eight patients were from seven separate families. Two females were mother and daughter from the same family and the other six patients were male and represented sporadic cases. The average age of onset of alopecia was 21.25 years. Involvement of the scalp hairs leading to progressive scarring alopecia on the midline of the scalp with variable degrees of inflammation was the pathognomonic feature. It typically began after puberty. Vellus hair-associated follicular hyperkeratosis affected all of the patients. However, photophobia was not a constant feature. Histopathologic examination revealed disorders of the hair follicle with an acute-chronic inflammatory response. Follicular changes including fused infundibulum, the protrusion of the outer root sheath into the follicular canal, and a dilatation of the follicles at the isthmus level caused by the occlusion of keratin were observed. The trichoscopic features included perifollicular scaling, tufted hairs, and loss of follicular openings. In conclusion, terminal hair involvement, either scalp hairs, eyebrows, or eyelashes, and the hyperkeratosis of the follicle of vellus hairs is the diagnostic basis of KFSD. We hypothesize that follicular changes in histopathology are the primary event that trigger variable inflammation and further follicular destruction.

Dermoscopic findings and comparison of usefulness of longitudinal versus transversal sections in the histological diagnosis of alopecia X.

BACKGROUND: A combination of dermoscopic and histological findings may provide useful information for the diagnosis of hair follicle diseases. However, there are no studies on dermoscopic-histopathological correlations in dogs affected by alopecia X, and comparison of longitudinal versus transversal sectioning of skin biopsy specimens in the assessment of this hair loss disorder has not been thoroughly investigated. HYPOTHESIS/OBJECTIVES: The aim of this study was to correlate dermoscopic and histological features using both longitudinal and transversal sectioning of skin biopsy samples to gain additional information for the diagnosis of alopecia X. ANIMALS: Nineteen Pomeranian dogs affected by alopecia X and five healthy Pomeranians as controls. MATERIALS AND METHODS: Dermoscopic-histological correlation was performed within the diseased group, whereas histological comparisons against controls. The demographic and clinical characteristics also were related to the histological findings. RESULTS: The dermoscopic findings revealed scattered, thinned, short hairs mixed with amorphous keratoseborrhoeic-like material (follicular plugging), perifollicular and intrafollicular scaling, and hyperpigmentation varying from pinpoint black spots to a diffuse texture. Dermoscopic findings correlated with histological findings for selected qualitative and quantitative findings. The usefulness of transversal sections was demonstrated in accurately determining the hair follicular density and counts, growth arrest phases and in identifying mineralisation of hair follicle basement membrane when compared to the longitudinal. Conversely, no correlations between histological findings and demographic and clinical characteristics were detected. CONCLUSIONS AND CLINICAL RELEVANCE: These data provide evidence of the usefulness of dermoscopic evaluation as an accessory diagnostic tool and of transversal sections of skin biopsies as complementary to the diagnosis of alopecia X.

Chronic diffuse alopecia in women: a retrospective review of histopathologic diagnoses.

INTRODUCTION: The diseases causing chronic diffuse alopecia and having similar clinical findings, namely chronic telogen effluvium, androgenetic alopecia, and the alopecia with overlapping features, should be differentiated. Recently, diffuse variants of lichen planopilaris have been described with histopathologic features of lichen planopilaris but clinically presenting with diffuse hair loss mostly in an androgenetic pattern. OBJECTIVES: To determine the accurate diagnosis underlying chronic diffuse alopecia in women by evaluating histopathologic findings. PATIENTS AND METHODS: The study included 32 patients with diffuse and clinically noncicatricial alopecia for at least 6 months with no identifiable etiologic factor after general medical history, review of organ systems, and appropriate laboratory tests. Two 4 mm punch biopsies, one from vertex and the other from mid-occiput, were obtained and sectioned transversely. RESULTS: The median age was 30.5 years (range: 22-40 years), and the median duration of hair loss was 4 years (range: 1.5-10 years). The histopathologic diagnosis was androgenetic alopecia, chronic telogen effluvium, and overlapping alopecia in 13 (40.6%), three (9.4%), and four (12.5%) patients, respectively. In the remaining 12 (32.5%) patients, a lichenoid inflammatory reaction affecting the infundibulum and isthmus was noted, and the probable diagnosis of diffuse variant of lichen planopilaris was made. LIMITATIONS: The retrospective nature and the small sample size. CONCLUSION: When the clinical diagnosis is not straightforward and no etiologic factor is found, histopathologic examination is mandatory for the accurate diagnosis of the disorder leading to chronic diffuse alopecia in women.

Refractory alopecia areata with single hairs imitating frontal fibrosing alopecia: a prospective observational study.

BACKGROUND: Lonely hair sign is considered as a clue to the diagnosis of frontal fibrosing alopecia (FFA). OBJECTIVE: To report an undescribed variant of alopecia areata (AA) with which the patient developed single hairs and other features similar to FFA and to determine the underlying mechanism. METHODS: We conducted a prospective observational study in patients who presented with receding hairline and single hairs, evaluating the clinical, trichoscopic, and histological features and their correlation. Immunochemistry studies were performed to describe the microenvironment. RESULTS: Eighteen patients were enrolled in the study. Despite the similarity to FFA clinically, these patients showed different histopathology which revealed a normal number of pilosebaceous units, one anagen hair in one or more pilosebaceous units, and others in telogen stage, consistent with single hairs under the naked eye or under trichoscopy. The severity of the hair loss assessed by SALT was no more than 50, but the response to conventional therapy was poor. CONCLUSIONS: This study reports a unique variant of AA. The pathological basis is an increase in the telogen hair follicles, with one anagen hair in one or more pilosebaceous units. Minimal inflammation consisting of CD3+ T lymphocytes and mast cells was demonstrated in the microenvironment.

Linear alopecia in pediatrics: RCM and dermoscopy reveal diagnostic cues.

BACKGROUND: Alopecia areata (AA), trichotillomania (TM), nevus sebaceous (NS), and linear scleroderma en coup de sabre (LSCS) can all present with a patch of linear alopecia, making diagnosis challenging. The purpose of this study was to combine reflectance confocal microscopy (RCM) and dermoscopy in the diagnosis of these lesions in children. METHODS: A total of 36 patients with linear alopecia were enrolled, of whom 14 had AA, seven had TM, nine had NS, and six had LSCS. We evaluated the characteristics and distinguishing features of the four conditions using RCM and dermoscopy. RESULTS: The key to differential diagnosis was the dermal Hair follicle density in the dermis was decreased in AA, and the size and density of the follicular openings were normal in TM. In NS, the major features were petal-like and frogspawn-like structures. In LSCS, dermal papillary rings, sebaceous glands, and follicles were partially or completely missing, and abundant fibrous material was distributed in the dermis. Dermoscopy revealed alopecia, and all four conditions resulted in decreased hair density. AA patients exhibited yellow dots, black dots, and exclamation mark hairs. TM patients presented with irregularly broken hairs and blood spots. Both NS and LSCS patients exhibited an absence of follicular openings; NS patients demonstrated whitish and yellowish round structures, while an atrophic area with white patches, linear vessels, and no yellow or black dots was observed in LSCS patients CONCLUSION: RCM combined with dermoscopy can provide additional information on disease states and differentiate between AA, TM, NS, and LSCS.

A missense mutation in Lama3 causes androgen alopecia.

Hair loss disorders such as androgenetic alopecia have caused serious disturbances to normal human life. Animal models play an important role in exploring pathogenesis of disease and evaluating new therapies. NIH hairless mice are a spontaneous hairless mouse discovered and bred in our laboratory. In this study, we resequenced the genomes of NIH normal mice and NIH hairless mice and obtained 3,575,560 high-quality, plausible SNP loci and 995,475 InDels. The Euclidean distance algorithm was used to assess the association of SNP loci with the hairless phenotype, at a threshold of 0.62. Two regions of chromosome 18 having the highest association with the phenotype contained 345 genes with a total length of 13.98 Mb. The same algorithm was used to assess the association of InDels with the hairless phenotype at a threshold of 0.54 and revealed a region of 25.45 Mb in length, containing 518 genes. The mutation candidate gene Lama3 (NM_010680.2: c.652C>T; NP_034810.1: p. Arg217Cys) was selected based on the results of functional gene analysis and mutation prediction screening. Lama3 (R217C) mutant mice were further constructed using CRISPR/Cas9 technology, and the relationship between Lama3 point mutations and the hairless phenotype were clarified by phenotypic observation. The results showed that male Lama3 point mutation mice started to lose hair on the 80th day after birth, and the hair loss area gradually expanded over time. H&E staining of skin sections showed that the point mutation mice had increased sebaceous glands in the dermis and missing hair follicle structure (i.e., typical symptoms of androgenetic alopecia). This study is a good extension of the current body of knowledge about the function of Lama3, and the constructed Lama3 (R217C) mutant mice may be a good animal model for studying androgenetic alopecia.

Alopecia Areata: Current Treatments and New Directions.

Alopecia areata is an autoimmune hair loss disease that is non-scarring and is characterized by chronic inflammation at the hair follicle level. Clinically, patients' presentation varies from patchy, circumscribed scalp involvement to total body and scalp hair loss. Current management is guided by the degree of scalp and body involvement, with topical and intralesional steroid injections as primarily first-line for mild cases and broad immunosuppressants as the mainstay for more severe cases. Until recently, the limited number of blinded, randomized, placebo-controlled clinical trials for this disease had made establishing an evidence-based treatment paradigm challenging. However, growing insights into the pathogenesis of alopecia areata through blood and tissue analysis of human lesions have identified several promising targets for therapy. T-helper (Th) 1/interferon skewing has traditionally been described as the driver of disease; however, recent investigations suggest activation of additional immune mediators, including the Th2 pathway, interleukin (IL)-9, IL-23, and IL-32, as contributors to alopecia areata pathogenesis. The landscape of alopecia areata treatment has the potential to be transformed, as several novel targeted drugs are currently undergoing clinical trials. Given the recent US FDA approval of baricitinib and ritlecitinib, Janus kinase (JAK) inhibitors are a promising drug class for treating severe alopecia areata cases. This article will review the efficacy, safety, and tolerability of current treatments for alopecia areata, and will provide an overview of the emerging therapies that are leading the revolution in the management of this challenging disease.

Minimizing Bias in Alopecia Diagnosis in Skin of Color Patients.

Alopecia is one of the most common dermatologic conditions affecting black patients, with a significantly negative impact on quality of life.1,2 Timely and accurate diagnosis is therefore critical in order to reverse or halt progression of disease.3 Unfortunately, lack of representation of skin of color (SOC) patients in the current literature may contribute to misdiagnosis as providers may be unfamiliar with the clinical spectrum of alopecia presenting in darker scalps.4 Some scarring alopecia subtypes such as Central Centrifugal Cicatricial Alopecia (CCCA) are more prevalent in certain racial groups. However, focusing solely on patient demographics and gross clinical findings may obscure accurate diagnoses. To distinguish alopecia findings in Black patients, a dedicated approach using a combination of clinical exam findings and patient history, along with trichoscopy and biopsy, is essential to prevent misdiagnosis and improve clinical and diagnostic outcomes. We present three cases of alopecia in patients of color which the initial suspected clinical diagnosis did not correspond with trichoscopic and biopsy results. We challenge clinicians to reexamine their biases and fully evaluate patients of color with alopecia. An examination should include a thorough history, clinical examination, trichoscopy, and potentially a biopsy, particularly when findings do not correlate. Our cases highlight the challenges and disparities that exist in diagnosis of alopecia in Black patients. We emphasize the need for continued research regarding alopecia in skin of color and the importance of a complete workup for alopecia to improve diagnostic outcomes.Balazic E, Axler E, Nwankwo C, et al. Minimizing bias in alopecia diagnosis in skin of color patients. J Drugs Dermatol. 2023;22(7):703-705. doi:10.36849/JDD.7117.  .