David A. Whiting

Desmoglein 4 in Hair Follicle Differentiation and Epidermal Adhesion: Evidence from Inherited Hypotrichosis and Acquired Pemphigus Vulgaris

Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins, known as desmogleins and desmocollins. We identified a cadherin family member, desmoglein 4, which is expressed in the suprabasal epidermis and hair follicle. The essential role of desmoglein 4 in skin was established by identifying mutations in families with inherited hypotrichosis, as well as in the lanceolate hair mouse. We also show that DSG4 is an autoantigen in pemphigus vulgaris. Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. We provide evidence that desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.

Diagnostic and predictive value of horizontal sections of scalp biopsy specimens in male pattern androgenetic alopecia

BACKGROUND Vertical sections of small scalp biopsy specimens are often inadequate for the diagnosis of male pattern androgenetic alopecia (MPAA). Quantitative analysis of follicular structures in horizontal sections can provide more information. OBJECTIVES Our purpose was to establish better diagnostic criteria by comparing horizontal and vertical sections of scalp biopsy specimens from MPAA and normal control subjects and to determine the predictive value of horizontal sections, by relating counts of follicular structures in MPAA to subsequent hair regrowth from topical minoxidil therapy. METHODS Paired 4 mm punch biopsy specimens were taken from 22 normal control subjects and 106 patients with MPAA, for horizontal and vertical sectioning. In horizontal sections, hair bulbs, terminal anagen, catagen and telogen hairs, telogen germinal units, and vellus hairs were counted, as were follicular units and stelae. RESULTS The diagnosis of MPAA was confirmed by finding decreased terminal hairs and increased stelae and vellus hairs. The average horizontal section contained 22 terminal and 13 vellus hairs, a 1.7:1 ratio. Changes compatible with MPAA were found in most vertical and horizontal sections, but horizontal sections were required for follicular counts and showed terminal:vellus hair ratios diagnostic of MPAA in 67% of cases. Of 44 patients treated with topical minoxidil, five with less than 2 follicular structures/mm2 showed no hair regrowth, 32 with 2 to 4 follicular structures/mm2 showed regrowth in 72%, and seven with more than 4 follicular structures/mm2 showed regrowth in 86% of cases. In MPAA with no significant inflammation, regrowth occurred in 77% of cases, versus 55% in cases with significant inflammation. CONCLUSION Horizontal sections of scalp biopsy specimens in MPAA provide more diagnostic information than vertical sections and appear to have a predictive value for hair regrowth.

Chronic telogen effluvium : Increased scalp hair shedding in middle-aged women

BACKGROUND Diffuse loss of scalp hair is a common problem in middle-aged women. A segment of these cases represents idiopathic chronic telogen effluvium (CTE). OBJECTIVE The purpose was to establish distinctive clinical and pathologic criteria for the diagnosis of CTE to facilitate its differentiation from androgenetic alopecia (AGA) and systemic causes of chronic diffuse hair loss. METHODS A group of 355 patients (346 females, 9 males) with diffuse generalized thinning of scalp hair of unknown origin were classified as having CTE and were included in the study. Characteristically they presented with a history of hair loss with both increased shedding and thinning of abrupt onset and fluctuating course and showed diffuse thinning of hair all over the scalp, frequently accompanied by bitemporal recession. Two 4 mm punch biopsy specimens were taken mostly from the mid or posterior parietal scalp of these patients. The biopsies were performed at these same areas in 412 patients with AGA (193 male, 219 female). Similar paired biopsy specimens were also taken from 22 normal control subjects (13 males, nine females). Specimens were sectioned horizontally and vertically and were examined for terminal and velluslike (miniaturized) hairs, follicular stelae, follicular units, and perifollicular inflammation and fibrosis. RESULTS In horizontal sections of 4 mm punch biopsy specimens from patients with CTE the average number of hairs was 39, the terminal/velluslike hair ratio was 9:1, 89% of the terminal hairs were in anagen, and 11% were in telogen. In AGA these values were 35, 1.9:1, 83.2%, and 16.8%, respectively, and in normal control subjects 40, 7:1, 93.5%, and 6.5%, respectively. Significant degrees of inflammation and fibrosis were present in only 10% to 12% of cases of CTE and normal controls, but occurred in 37% of cases of AGA. CTE ran a prolonged and fluctuating course in many patients. CONCLUSION CTE, which usually affects 30- to 60-year-old women, starts abruptly with or without a recognizable initiating factor. It may be distinguished from classic acute telogen effluvium by its long fluctuating course and from AGA by its clinical and histologic findings.

The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia

BACKGROUND Data suggest that androgenetic alopecia is a process dependent on dihydrotestosterone (DHT) and type 2 5alpha-reductase. Finasteride is a type 2 5alpha-reductase inhibitor that has been shown to slow further hair loss and improve hair growth in men with androgenetic alopecia. OBJECTIVE We attempted to determine the effect of finasteride on scalp skin and serum androgens. METHODS Men with androgenetic alopecia (N = 249) underwent scalp biopsies before and after receiving 0.01, 0.05, 0.2, 1, or 5 mg daily of finasteride or placebo for 42 days. RESULTS Scalp skin DHT levels declined significantly by 13.0% with placebo and by 14.9%, 61.6%, 56. 5%, 64.1%, and 69.4% with 0.01, 0.05, 0.2, 1, and 5 mg doses of finasteride, respectively. Serum DHT levels declined significantly (P <.001) by 49.5%, 68.6%, 71.4%, and 72.2% in the 0.05, 0.2, 1, and 5 mg finasteride treatment groups, respectively. CONCLUSION In this study, doses of finasteride as low as 0.2 mg per day maximally decreased both scalp skin and serum DHT levels. These data support the rationale used to conduct clinical trials in men with male pattern hair loss at doses of finasteride between 0.2 and 5 mg.

Cicatricial alopecia: clinico-pathological findings and treatment

Cicatricial alopecia is the result of various diseases of the scalp. It is usually circumscribed but may be widespread. It presents as areas of hair loss in which the underlying scalp is scarred, sclerosed, or atrophic. In early stages, the underlying disease is usually diagnosable clinically and histologically, but in late stages, only scarring may be evident. The scarring is the result of the destruction and fibrosis of hair follicles. A recent hypothesis suggests that the primary pathology of many of the mechanistically obscure scarring alopecias occurs in the sebaceous gland. It is speculated that inadequate sebaceous gland function could lead to hair follicle destruction.1 The failure of affected follicles to regrow is thought to be because of destructive changes at the level of the insertion of the arrector pili muscle into the region of the follicular bulge.2 This is where the slow cycling hair follicle stem cells that are capable of initiating follicular renewal at the end of the resting phase of the hair cycle are located.3 Not all disorders classified under the term cicatricial or scarring alopecia have histological evidence of true scar formation in which elastic fibers are destroyed.4,5 For example, true scars differ from scleroderma, in which collagen fibers are thickened and hyalinized but connective tissue is not destroyed. Under the term “cicatricial alopecia” are included diseases in which there is true scarring because of the destruction of the hair follicle and others in which there is no true scar formation. The latter could better be called “permanent alopecia.” The hallmark of permanent alopecia is middermal hyalinization involving the follicular bulge. Follicular destruction in scarring alopecia may be primary or secondary.6,7 In primary scarring alopecia, the hair follicle itself is the principle target for destruction, with relative sparing of the intervening dermis. Causes of primary scarring alopecia include discoid lupus erythematosus, lichen planopilaris, pseudopelade, and folliculitis decalvans, and are listed in Table 1.7 Secondary scarring alopecia results from nonfollicular events that impinge upon and eventually destroy the follicle. The permanent follicular scarring is the result of the close proximity of the follicles to the primary pathological process. The scarring may be secondary to numerous congenital or nevoid disorders affecting the hair follicle such as nevus sebaceus.8 Destruction of hair follicles may also result from physical and chemical trauma or pathological changes in the dermis because of sclerosing diseases or granulomatous or neoplastic infiltrates. Causes of secondary scarring alopecia are shown in Table 2. Primary scarring alopecias are reviewed here. In many cases, extensive permanent damage is already present when patients are first seen, leaving little hope for regrowth with specific treatment; however, it should be possible to recognize and diagnose cases of scarring alopecia at an earlier stage in order to obtain better treatment outcomes. To gain further clinico-pathological data about cicatricial alopecia, 358 consecutive patients were studied, and horizontal and vertical sections of scalp biopsies were examined. Primary and secondary scarring alopecias were seen and salient details are given here.

The role of scalp dermoscopy in the diagnosis of alopecia areata incognita

BACKGROUND Alopecia areata incognita is a variety of alopecia areata characterized by acute diffuse shedding of telogen hairs without typical patches. OBJECTIVE We sought to report the clinical, pathological, and dermoscopic features of alopecia areata incognita. METHODS Seventy patients with alopecia areata incognita were evaluated clinically and with videodermoscopy during the period of 2002 to 2006. Pathology was performed in 50 patients. RESULTS The presence of numerous, diffuse, round or polycyclic yellow dots, different in size and uniform in color and distribution, was a typical dermoscopic feature in all patients. Short regrowing hairs were also present. The dermoscopic findings were correlated and supported by the histologic features of the scalp specimens. LIMITATIONS Scalp biopsy was performed only in 50 patients. CONCLUSION Videodermoscopy is a first step before performing a biopsy. It can help the clinician to find the right place to take the sample, but can also avoid unnecessary biopsies.

Finasteride increases anagen hair in men with androgenetic alopecia

Background The growth of scalp hair is a cyclical process of successive phases of growth (anagen) and rest (telogen). In previous clinical trials in men with androgenetic alopecia, treatment with finasteride increased scalp hair counts in a defined area (i.e. increased hair density). Objectives The current study used a phototrichogram methodology to assess the effect of finasteride on the phases of the hair growth cycle. Patients/Methods Two hundred and twelve men, age 18–40 years, with androgenetic alopecia were randomized to receive finasteride 1 mg daily or placebo for 48 weeks. At baseline and at 24 and 48 weeks, macrophotographs were taken to measure total and anagen hair count in a 1‐cm2 target area of the scalp. Results At baseline, mean total and anagen hair counts in the finasteride group were 200 and 124 hairs, respectively (% anagen = 62%) and the anagen to telogen ratio was 1·74 (geometric mean). In the placebo group, the respective values were 196 and 119 hairs (% anagen = 60%) and 1·57. At week 48, the finasteride group had a net improvement (mean ± SE) compared with placebo in total and anagen hair counts of 17·3 ± 2·5 hairs (8·3% ± 1·4%) and 27·0 ± 2·9 hairs (26% ± 3·1%), respectively (P < 0·001). Furthermore, treatment with finasteride resulted in a net improvement in the anagen to telogen ratio of 47% (P < 0·001). In this study, treatment with finasteride 1 mg day−1 for 48 weeks increased both total and anagen hair counts, and improved the anagen to telogen ratio. Conclusions These data provide direct evidence that finasteride 1 mg daily promotes the conversion of hairs into the anagen phase. These data support that finasteride treatment results in favourable effects on hair quality that contribute to the visible improvements in hair growth observed in treated patients.

Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss

BACKGROUND Androgenetic alopecia is a common condition of adult men. Finasteride, a type 2 5alpha-reductase inhibitor, decreases the formation of dihydrotestosterone from testosterone. OBJECTIVE Two separate clinical studies were conducted to establish the optimal dose of finasteride in men with this condition. METHODS Men from 18 to 36 years of age with moderate vertex male pattern hair loss received finasteride 5, 1, 0.2, or 0.01 mg/day or placebo based on random assignment. Efficacy was determined by scalp hair counts, patient self-assessment, investigator assessment, and assessment of clinical photographs. Safety was assessed by clinical and laboratory measurements and by analysis of adverse experiences. RESULTS Efficacy was demonstrated for all end points for finasteride at doses of 0.2 mg/day or higher, with 1 and 5 mg demonstrating similar efficacy that was superior to lower doses. Efficacy of the 0.01 mg dose was similar to placebo. No significant safety issues were identified in the trials. CONCLUSION Finasteride 1 mg/day is the optimal dose for the treatment of men with male pattern hair loss and was subsequently identified for further clinical development.

Human hair histogenesis for the mitochondrial DNA forensic scientist.

Analysis of mitochondrial DNA (mtDNA) sequence from human hairs has proven to be a valuable complement to traditional hair comparison microscopy in forensic cases when nuclear DNA typing is not possible. However, while much is known about the specialties of hair biology and mtDNA sequence analysis, there has been little correlation of individual information. Hair microscopy and hair embryogenesis are subjects that are sometimes unfamiliar to the forensic DNA scientist. The continual growth and replacement of human hairs involves complex cellular transformation and regeneration events. In turn, the analysis of mtDNA sequence data can involve complex questions of interpretation (e.g., heteroplasmy and the sequence variation it may cause within an individual, or between related individuals. In this paper we review the details of hair developmental histology, including the migration of mitochondria in the growing hair, and the related interpretation issues regarding the analysis of mtDNA data in hair. Macroscopic and microscopic hair specimen classifications are provided as a possible guide to help forensic scientists better associate mtDNA sequence heteroplasmy data with the physical characteristics of a hair. These same hair specimen classifications may also be useful when evaluating the relative success in sequencing different types and/or forms of human hairs. The ultimate goal of this review is to bring the hair microscopist and forensic DNA scientist closer together, as the use of mtDNA sequence analysis continues to expand.

Comparison of Alopecia areata in Human and Nonhuman Mammalian Species

Alopecia areata (AA) is a nonscarring form of inflammatory hair loss in humans. AA-like hair loss has also been observed in other species. In recent years the Dundee experimental bald rat and the C3H/HeJ mouse have been put forward as models for human AA. AA in all species presents with a wide range of clinical features from focal, locally extensive, diffuse hair loss, to near universal alopecia. Histologically, all species have dystrophic anagen stage hair follicles associated with a peri- and intrafollicular inflammatory cell infiltrate. Autoantibodies directed against anagen stage hair follicle structures are a consistent finding. Observations on AA pathogenesis suggest nonhuman species can provide excellent models for the human disease. Ultimately, animal models will be used to determine the genetic basis of AA, potential endogenous and/or environmental trigger(s), mechanism(s) of disease initiation and progression, and allow rapid evaluation of new and improved disease treatments.