Acquired scalp alopecia. Part I: A review

In this two-part series we review the acquired scalp alopecias. A broad spectrum of diseases result in alopecia. In this first part we provide a framework for the assessment and diagnosis of scalp hair loss, and begin covering the individual conditions. The non-scarring alopecias covered include effluvium, androgenetic alopecia, alopecia areata, trichotillomania, and loose anagen syndrome. The scarring alopecias cause permanent pilosebaceous follicle loss; the lymphocyte-associated scarring alopecia described encompasses lichen planopilaris, discoid lupus erythematosus, pseudopelade, and follicular mucinosis. Part II will cover the neutrophil-associated and infiltrative processes causing scarring alopecia followed by the medical management of alopecia. There is particular reference to newly described conditions and progress in the understanding of older conditions. More recently characterized conditions include the loose anagen syndrome, chronic telogen effluvium, and the frontal fibrosing variant of lichen planopilaris.     

Antibodies to hair follicles in alopecia areata

Although alopecia areata is suspected to be an autoimmune disease, no direct evidence of an altered immune response to components of the hair follicle has been reported. We studied whether antibodies to normal human anagen scalp hair follicles are present in individuals with alopecia areata. Thirty-nine alopecia areata sera and 27 control sera were tested by Western immunoblotting for antibodies to 6 M urea-extractable proteins of normal anagen scalp hair follicles. At serum diluted 1:80, all alopecia areata subjects (100%), but only 44% of control individuals, had antibodies directed to one or more antigens of approximately 57, 52, 50, 47, or 44 kD. The incidence of antibodies to individual hair follicle antigens in alopecia areata was up to seven times more frequent than in control sera and their level up to 13 times greater and was statistically significant for all five antigens. Tissue specificity analysis indicated that these antigens were selectively expressed in hair follicles. These findings indicate that individuals with alopecia areata have abnormal antibodies directed to hair follicle antigens, and support the hypothesis that alopecia areata is an autoimmune disease.     

Different populations of melanocytes are present in hair follicles and epidermis

Melanocytes in human skin reside both in the epidermis and in the matrix and outer root sheath of anagen hair follicles. Comparative study of melanocytes in these different locations has been difficult as hair follicle melanocytes could not be cultured . In this study we used a recently described method of growing hair follicle melanocytes to characterize and compare hair follicle and epidermal melanocytes in the scalp of the same individual. Three morphologically and antigenically distinct types of melanocytes were observed in primary culture. These included (1) moderately pigmented and polydendritic melanocytes derived from epidermis; (2) small, bipolar, amelanotic melanocytes; and (3) large, intensely pigmented melanocytes; the latter two were derived from hair follicles. The three sub-populations of cells all reacted with melanocyte-specific monoclonal antibody. Epidermal and amelanotic hair follicle melanocytes proliferated well in culture, whereas the intensely pigmented hair follicle melanocytes did not. Amelanotic hair follicle melanocytes differed from epidermal melanocytes in being less differentiated, and they expressed less mature melanosome antigens. In addition, hair follicle melanocytes expressed some antigens associated with alopecia areata, but not antigens associated with vitiligo, whereas the reverse was true for epidermal melanocytes. Thus antigenically different populations of melanocytes are present in epidermis and hair follicle. This could account for the preferential destruction of hair follicle melanocytes in alopecia areata and of epidermal melanocytes in vitiligo.     

Growth factors and cytokines in hair follicle development and cycling: recent insights from animal models and the potentials for clinical therapy

Hair growth disorders, particularly those that lead to hair loss (alopecia), are common and frequently cause significant mental anguish in affected individuals. The mechanisms underlying the majority of these disorders are unknown. However, insights into the specific molecular mechanisms of hair follicle development and cycling have recently been made using animal models, particularly mice that over- or underexpress a specific gene for a growth factor or cytokine. Other animal models have demonstrated that certain growth factors and cytokines can prevent much of the alopecia caused by cancer chemotherapeutic agents. These animal models have confirmed the importance of growth factors and cytokines in hair follicle development and cycling, and have formed the foundation for potential clinical therapy of hair growth disorders, particularly alopecia. Nevertheless, important questions concerning their efficacy, safety and delivery will need to be answered before successful clinical therapy of any hair growth disorder becomes a reality.     

Evaluation and surveillance of blood pressure during pregnancy

BACKGROUND: Women generally regard their hair loss as socially unacceptable and go to great measures to conceal their problem. In some cases, the negative self-image brought about by hair loss may be the basis of psychiatric illness. The purpose of this study was to evaluate a 2% topical minoxidil solution (Rogaine/Regaine, The Upjohn Co, Kalamazoo, Mich) for the treatment of female androgenetic alopecia. A 32-week, double-blind, placebo-controlled trial was conducted in 11 US centers. Three hundred eight women with androgenetic alopecia were enrolled. Two hundred fifty-six of these women completed the trial. A refined photographic technique was used to objectively determine the number of nonvellus hairs regrown. RESULTS: After 32 weeks of treatment, the number of nonvellus hairs in a 1-cm2 evaluation site was increased by an average of 23 hairs in the 2% minoxidil group and by an average of 11 hairs in the placebo group. The 95% confidence interval for the difference in mean hair count change between the treatment groups was 5.9 to 17.5 hairs. The investigators determined that 13% in the minoxidil-treated group had moderate growth and 50% had minimal growth. This compared with 6% and 33%, respectively, in the placebo-treated group. Similarly, 60% of the patients in the 2% minoxidil group reported that they had new hair growth (20% moderate, 40% minimal) compared with 40% (7% moderate, 33% minimal) of the patients in the placebo group. No evaluations of dense hair growth were reported for either treatment group. No clinically significant changes in vital signs were observed and no serious or unexpected medical events were reported. CONCLUSIONS: Topical minoxidil was significantly more effective than placebo in the treatment of female androgenetic alopecia.     

Dominant inheritance of optic pits

We report a patient with concurrent chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and alopecia universalis. A dramatic improvement in strength accompanied the administration of prednisone, although no regrowth of hair was noted. CIDP and alopecia universalis are two relatively rare autoimmune disorders. The simultaneous occurrence of these disorders suggests a common pathogenetic mechanism, including the possibility of shared antigens between peripheral nerve myelin and the hair follicle.     

Androgenetic alopecia in men and women: an overview of cause and treatment

Hair loss is a cause of anxiety and distress in both men and women. New understanding of the causes of androgenetic alopecia is leading to potential new medical therapies. Pathophysiology, clinical presentations, diagnosis, current and future treatments are discussed.     

Leptomeningeal angiomatosis accompanied by hair follicle nevus

A 5-day-old male infant with leptomeningeal angiomatosis accompanied by hair follicle nevus and congenital alopecia is reported. Admitted for frequent left hemiconvulsions, he had three small papular lesions around his right eye and ipsilateral alopecia from the frontal to parietal areas. Histopathological examination of the papular lesions revealed crowding of hair follicles. There were no other skin lesions and no ophthalmic abnormalities. Ictal EEG showed a theta burst in the right parietal area. Computed tomography of the brain revealed cerebral atrophy and a slightly high intensity lesion in the right parietal and occipital lobes with calcification. Gyriform enhancement was demonstrated by contrast MRI in these areas. The pathogenesis is discussed. This case may represent a previously unknown neurocutaneous syndrome.     

Hearing loss due to the mitochondrial A1555G mutation in Italian families

A 68-year old woman presented with a frontal fibrosing alopecia and lesions of the buccal mucous membranes typical for lichen planus. Postmenopausal frontal fibrosing alopecia (PFFA) has recently been described by Kossard as a distinct entity characterized by progressive recession of the frontotemporal and parietal hair margins leading to permanent alopecia in the form of a symmetrical band-like area of scanning in postmenopausal women. The histology (perifollicular lymphocytic infiltration and fibrosis, increase of apoptosis of hair follicle keratinocytes) is indistinguishable from that of lichen planopilaris. The localization and age- and sex-related characteristics of PFFA are not sufficient to delineate it as a discrete entity from lichen planopilaris. Our observation of oral lichen planus in a postmenopausal woman with frontal fibrosing alopecia points to the possibility that PFFA actually may represent a variant of lichen planopilaris with a predilection for the frontotemporal hairline. Other variants of lichen planopilaris include multifocal lichen planopilaris, disseminated lichen planopilaris (Lassueur-Graham-Little syndrome), lichenoid pseudopelade, and any combination of these ("mixed type"). An effective therapy of PFFA is not known. Also, treatment of lichen planopilaris forms in which fibrosis predominates over inflammation is similarly problematic, but the natural course of these diseases seems to be self-limited.     

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.     

Surveying the counselling needs of families with disablement in the United Arab Emirates

We have previously described spontaneous but reversible hair loss that clinically and histologically resembles human alopecia areata in a colony of C3H/HeJ mice. Alopecia areata in humans is associated with antibodies to hair follicles. This study was conducted to determine whether C3H/HeJ mice with hair loss have a similar abnormal antibody response to hair follicles. Eighteen C3H/HeJ mice with alopecia, 12 unaffected littermates, and 15 control mice were examined for circulating antibodies to C3H/HeJ anagen hair follicles by indirect immunofluorescence and against extracts of isolated C3H/HeJ and human anagen hair follicles by immunoblotting. Using both procedures, antibodies to anagen hair follicles were present in all C3H/HeJ mice with alopecia but in none of the control mice. The antibodies were also present in some unaffected C3H/HeJ littermates but were absent in mice of an unrelated strain with inflammatory skin disease and alopecia, indicating that their appearance did not result from the hair loss. These antibodies reacted to hair follicle-specific antigens of 40-60 kDa present in murine and human anagen hair follicles. These antigens were also reactive with human alopecia areata antibodies. Some of the antibodies in both C3H/HeJ mice and humans with alopecia areata reacted to antigens of 44 and 46 kDa, which were identified as hair follicle-specific keratins. This study indicates that C3H/HeJ mice with hair loss have circulating antibodies to hair follicles similar to those present in humans with alopecia areata. These findings confirm that these mice are an appropriate model for human alopecia areata and support the hypothesis that alopecia areata results from an abnormal autoimmune response to hair follicles.     

Analysis of apoptosis during hair follicle regression (catagen)

Keratinocyte apoptosis is a central element in the regulation of hair follicle regression (catagen), yet the exact location and the control of follicular keratinocyte apoptosis remain obscure. To generate an "apoptomap" of the hair follicle, we have studied selected apoptosis-associated parameters in the C57BL/6 mouse model for hair research during normal and pharmacologically manipulated, pathological catagen development. As assessed by terminal deoxynucleotide transferase dUTP fluorescein nick end-labeling (TUNEL) stain, apoptotic cells not only appeared in the regressing proximal follicle epithelium but, surprisingly, were also seen in the central inner root sheath, in the bulge/isthmus region, and in the secondary germ, but never in the dermal papilla. These apoptosis hot spots during catagen development correlated largely with a down-regulation of the Bcl-2/Bax ratio but only poorly with the expression patterns of interleukin-1beta converting enzyme, p55TNFR, and Fas/Apo-1 immunoreactivity. Instead, a higher correlation was found with p75NTR expression. During cyclophosphamide-induced follicle dystrophy and alopecia, massive keratinocyte apoptosis occurred in the entire proximal hair bulb, except in the dermal papilla, despite a strong up-regulation of Bax and p75NTR immunoreactivity. Selected receptors of the tumor necrosis factor/nerve growth factor family and members of the Bcl-2 family may also play a key role in the control of follicular keratinocyte apoptosis in situ.     

Finasteride: a review of its use in male pattern hair loss

The 5alpha-reductase inhibitor finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT), the androgen responsible for male pattern hair loss (androgenetic alopecia) in genetically predisposed men. Results of phase III clinical studies in 1879 men have shown that oral finasteride 1 mg/day promotes hair growth and prevents further hair loss in a significant proportion of men with male pattern hair loss. Evidence suggests that the improvement in hair count reported after 1 year is maintained during 2 years' treatment. In men with vertex hair loss, global photographs showed improvement in hair growth in 48% of finasteride recipients at 1 year and in 66% at 2 years compared with 7% of placebo recipients at each time point. Furthermore, hair counts in these men showed that 83% of finasteride versus 28% of placebo recipients had no further hair loss compared with baseline after 2 years. The clinical efficacy of oral finasteride has not yet been compared with that of topical minoxidil, the only other drug used clinically in patients with male pattern hair loss. Therapeutic dosages of finasteride are generally well tolerated. In phase III studies, 7.7% of patients receiving finasteride 1 mg/day compared with 7.0% of those receiving placebo reported treatment-related adverse events. The overall incidence of sexual function disorders, comprising decreased libido, ejaculation disorder and erectile dysfunction, was significantly greater in finasteride than placebo recipients (3.8 vs 2.1%). All sexual adverse events were reversed on discontinuation of therapy and many resolved in patients who continued therapy. No other drug-related events were reported with an incidence > or =1% in patients receiving finasteride. Most events were of mild to moderate severity. Oral finasteride is contraindicated in pregnant women because of the risk of hypospadias in male fetuses. CONCLUSIONS: Oral finasteride promotes scalp hair growth and prevents further hair loss in a significant proportion of men with male pattern hair loss. With its generally good tolerability profile, finasteride is a new approach to the management of this condition, for which treatment options are few. Its role relative to topical minoxidil has yet to be determined.     

Induction of hair growth in ear wounds by cultured dermal papilla cells

In the adult hair follicle the dermal papilla plays a crucial role in the dermal-epidermal interactions that control hair production and events of the growth cycle. It has previously been shown that cultured cells from rat vibrissa follicle dermal papillae can stimulate hair growth when implanted into amputated follicles. This study investigated the effects of implanting low-passage cultured papilla cells into small incisional wounds in the rat ear pinna. The groups of fibers that emerged from wound sites were much larger than local hairs, and often had vibrissa-type characteristics. Later-passage papilla cells or cultured skin fibroblasts failed to elicit the same response. Histology revealed that big follicles were formed when papilla cells were trapped between the cut edges of the epidermis. Abnormally large follicles were seen at wound sites many months post-operatively. Independent of epidermal influence, cultured papilla cells in the wound dermis formed rounded papilla-like aggregates that also persisted until biopsy. A previously described method of wrapping papilla cells in glabrous epidermis was less successful in percentage terms but resulted in the production of one very large vibrissa-type follicle and fiber. These results further illustrate that the inductive powers and developmental information retained by cultured dermal papilla cells parallel the properties of their embryonic precursors; the findings may have implications for human hair growth.     

Hair diseases

A few common causes of hair loss account for the vast majority of cases. A well-directed history and simple physical examination is often sufficient to make a diagnosis. Laboratory testing is often unnecessary. A scalp biopsy can be useful, but only if processed and interpreted correctly. Androgenetic alopecia, alopecia areata, senescent alopecia, telogen effluvium, traction alopecia, trichotillomania, and cosmetic hair damage are common causes of non-scarring alopecia. Discoid lupus erythematosus, lichen planopilaris, and central, centrifugal scarring alopecia are the most common forms of scarring hair loss.     

Incorporation of adhesion peptides into nonadhesive hydrogels useful for tissue resurfacing

The recessive patchwork (pwk) mutation in mice is associated with a unique hair follicle phenotype. Mice homozygous for patchwork exhibit a variegated coat containing a mixture of white and fully pigmented hairs, but no partially pigmented hairs. We have investigated the etiology of this mutation. We report here that the white hairs result from the lack of melanocytes in the follicle. As indicated by the coat color pattern of patchwork<-->albino chimeras, the target cell for the patchwork mutation is the melanocyte and/or its precursor. Examination of these chimeras also suggested that patchwork does not act in a cell-autonomous manner. The colonization of the skin by melanoblasts in patchwork embryos was studied using a lacZ transgene. Melanoblasts die by apoptosis in hair follicles from homozygous pwk/pwk fetuses starting at embryonic day 18.5, indicating that patchwork acts from this stage. The combination of pwk and KitW-ei, a mutation responsible for a reduced number of melanoblasts in the hair follicle, suggested that pwk gene product is necessary for low numbers of melanoblasts to survive and differentiate in the hair follicle from embryonic day 18.5 onward. We conclude that the pigmented hairs on the coat of pwk/pwk mice may be attributed to a community effect among melanoblasts in the hair follicle at the end of embryogenesis.     

TNF-alpha induces apoptosis in rat fetal brown adipocytes in primary culture

The balding (bal) mutation of the mouse is an autosomal recessive mutation that causes alopecia and immunologic anomalies. A new allele was identified by allelism testing after using an interspecific backcross to localize the mutation to the centromeric end of mouse chromosome 18. We investigated the skin and hair histologic lesions of two alleles (bal(J) and bal(Pas)) at this locus and analyzed the expression of several keratinocyte markers and the production of autoantibodies by immunofluorescence on frozen skin sections. The lesions observed included separation of the inner and outer root sheath in anagen follicles resulting in the hair fiber being very easily plucked from the follicle. Vesicles on the ventral tongue, mucocutaneous junction of the eyelid, foot pads, and rarely in skin were also evident. Separation occurred between the basal and suprabasilar cells forming an empty cleft, resembling that observed in human pemphigus vulgaris. Immunofluorescence studies did not reveal the presence of tissue-bound or circulating autoantibodies. Expression of keratinocyte markers in hair follicles was normal. Keratin 6-positive cells were found on either side of the follicular separation suggesting a molecular defect in adhesion molecules between the inner layer of the outer root sheath cells to layers on either sides. This hypothesis has been confirmed by another group who demonstrated that the bal(J) mutation is due to the insertion of a thymidine in the desmoglein 3 gene, resulting in a premature stop codon.     

Investigation of the actions and antagonist activity of some polyamine analogues in vivo

Complete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development.