Noncicatrizing alopecias; with special reference to alopecia areata

Since the epochal work of Hamilton there has been general acceptance of the causal relationship of the male sex hormone, age and familial inheritance in development of male pattern baldness. Some of the medicaments used in recent years may cause a diffuse loss of scalp hair. Alopecia that accompanies disease states is probably due to generalized toxemia and disturbances in metabolism. Sometimes male pattern baldness occurs in physiologic states, as exemplified by diffuse hair loss occasionally in the postpartum period. Alopecia areata deserves a critical appraisal, since it may be evidence of underlying neuropsychotic states that need psychiatric diagnosis and treatment. The development of alopecia totalis or universalis in 50 per cent of the prepuberal cases of alopecia areata is of real significance, especially since so very few patients recover their normal scalp hair. The conclusions reached by the authors of two articles reporting on 368 cases of alopecia areata, alopecia totalis and alopecia universalis that the evidence is overwhelming against the malfunction of the endocrine glands as the cause of alopecia areata must be considered real contributions to our understanding of this condition.A few conditions simulate alopecia areata. Probably the ones which are seen most often are trichotillomania and patchy baldness caused by agents used in hair waving and straightening. Our findings in 22 cases of alopecia areata of a persistent inflammatory perivascular and perifollicular infiltrate, massive plugging of the ostia, disappearance of robust hair follicles and diminution in total number of hair follicles and sometimes fibrosis are not necessarily diagnostic of alopecia areata but seem to be very definitely characteristic. Treatment for alopecia areata is of little avail. At this time we do not recommend the general use of the corticosteroids despite the improvement of scalp appearance in the majority of instances in which the systemic administration of these hormones have been employed.     

Genetic disorders associated with severe alopecia in children: a report of two unusual cases and a review

Moderate to severe alopecia in children may be due to a genetic disorder. This paper reviews the heritable causes of alopecia in children and gives a detailed account of two affected unrelated children. One has alopecia universalis while the other has alopecia postulated to be due to a new disorder of genetic etiology. The article concludes that for purposes of genetic counseling and prognosis it is crucial that a correct diagnosis be made.     

NONCICATRIZING ALOPECIAS—With Special Reference to Alopecia Areata

Since the epochal work of Hamilton there has been general acceptance of the causal relationship of the male sex hormone, age and familial inheritance in development of male pattern baldness.Some of the medicaments used in recent years may cause a diffuse loss of scalp hair. Alopecia that accompanies disease states is probably due to generalized toxemia and disturbances in metabolism. Sometimes male pattern baldness occurs in physiologic states, as exemplified by diffuse hair loss occasionally in the postpartum period.Alopecia areata deserves a critical appraisal, since it may be evidence of underlying neuropsychotic states that need psychiatric diagnosis and treatment. The development of alopecia totalis or universalis in 50 per cent of the prepuberal cases of alopecia areata is of real significance, especially since so very few patients recover their normal scalp hair.The conclusions reached by the authors of two articles reporting on 368 cases of alopecia areata, alopecia totalis and alopecia universalis that the evidence is overwhelming against the malfunction of the endocrine glands as the cause of alopecia areata must be considered real contributions to our understanding of this condition.A few conditions simulate alopecia areata. Probably the ones which are seen most often are trichotillomania and patchy baldness caused by agents used in hair waving and straightening.Our findings in 22 cases of alopecia areata of a persistent inflammatory perivascular and perifollicular infiltrate, massive plugging of the ostia, disappearance of robust hair follicles and diminution in total number of hair follicles and sometimes fibrosis are not necessarily diagnostic of alopecia areata but seem to be very definitely characteristic.Treatment for alopecia areata is of little avail. At this time we do not recommend the general use of the corticosteroids despite the improvement of scalp appearance in the majority of instances in which the systemic administration of these hormones have been employed.     

Genetic control of alopecia in sheep

A hypothesis is suggested which turns down the opinion that alopecia or pathological wool shedding in sheep is due to some pathological processes or disease. We suppose that this trait is controlled by a gene of natural wool shedding inherited from sheep far ancestors, and we propose to designate the recessive alopecia gene as Alp3 and its dominant allele, a wool alopecia resistance gene, as AlpA. Alopecia will only be revealed in homozygotic Alpa/Alpa state, due to recessivity of alopecia gene, but heterozygotic AlpA/Alpa and homozygotic AlpA/AlpA sheep will have a normal wool coat. A new polymorphic trait is supposed to exist which is conditioned by simultaneous presence of two genetic alleles in a sheep population with descrete phenotypic manifestation.     

Topical minoxidil in the treatment of alopecia areata.

A modified double blind crossover study was performed to assess the effect of 1% topical minoxidil as compared with placebo in 30 patients with alopecia areata and alopecia totalis. The active preparation produced a highly significant incidence of hair regrowth. A cosmetically acceptable response was noted in 16 patients. No side effects were seen. The study confirmed that topical minoxidil will induce new hair growth in alopecia areata but that it is less likely to do so in more severe and extensive disease. Furthermore, patients with alopecia universalis and totalis may not respond at all. Nevertheless, as compared with other drugs minoxidil applied topically is relatively non-toxic, is easy to use, and has no systemic or local side effects.     

Methods of hair loss evaluation in patients with endocrine disorders

Hair loss may accompany several endocrine disorders, including hypopituitarism, hypothyreosis, hyperthyreosis, hypoparathyroidism, diabetes mellitus, growth hormone deficiency, hyperprolactinaemia, polycystic ovary syndrome, SAHA syndrome, congenital adrenal hyperplasia, Cushing syndrome, or virilising tumours. Most patients with endocrine disorders present with diffuse non-scarring alopecia, such as anagen effluvium, telogen effluvium or androgenetic alopecia. Focal non-scarring alopecia, such as alopecia areata coexisting with autoimmune thyroiditis, is less frequent and scarring alopecia is a rare finding in patients with endocrine abnormalities. In some cases an endocrine disorder may be suspected based on dermatological findings during hair loss evaluation. Classic methods of hair evaluation include hair weighing, pull test, wash test, the trichogram, and histopathological examination. Newly developed non-invasive diagnostic techniques include the phototrichogram, trichoscan, trichoscopy, and reflectance confocal microscopy.     

Coat condition, housing condition and measurement of faecal cortisol metabolites--a non-invasive study about alopecia in captive rhesus macaques (Macaca mulatta)

BACKGROUND: Previous studies have characterized alopecia in captive rhesus macaques (Macaca mulatta) by a mixed partial to complete alopecia in a bilateral symmetric pattern. METHODS: In this study, coat condition assessments were related to exogenous and endogenous factors in captive rhesus macaques under different housing conditions in order to identify disturbances in environmental factors controlling or influencing hair growth. Additionally, the degree of alopecia was investigated in relation to adrenal endocrine function as an indicator of social stress using faecal glucocorticoid measurements. RESULTS: Hair loss was found to vary with season and sex, was most pronounced in adult females during the winter and spring months. Generally, infants were not affected, but alopecia developed during adolescence. However, the housing system, available enclosure space and variations in group size and composition also appeared to influence coat condition. Levels of immunoreactive cortisol metabolites (11-oxoetiocholanolone) in faeces were significantly negatively correlated with alopecia, suggesting a relationship between hypothalamic-pituitary-adrenal (HPA) axis activity and hair loss in captive rhesus macaques. CONCLUSIONS: Although the present study demonstrates the influence of the HPA axis on coat condition, it is not known if hair loss is caused by abnormal behaviour or hormonal imbalances of the HPA axis itself. Our data suggest that alopecia in rhesus macaques is a highly complex multicausal disorder.     

Interleukin 1 protects from cytosine arabinoside-induced alopecia in the rat model

Protection from cytosine arabinoside-induced alopecia by ImuVert has recently been reported in a rat model. ImuVert, a biologic response modifier, is capable of activating mononuclear cells causing release of various cytokines. In the present study, using the young rat model, recombinant human IL 1 beta produced excellent protection from cytosine arabinoside-induced alopecia. Mouse recombinant tumor necrosis factor gave definite but modest protection whereas human tumor necrosis factor gave none. It is concluded that the protection from alopecia by ImuVert is mediated by cytokines, primarily IL 1.     

Fatty acid supplements improve hair coat condition in rhesus macaques

As captive rhesus macaques often exhibit hair loss, alopecia was quantified and behavior was recorded before, during, and after fatty acid supplementation in six macaques. Fatty acid treatment was associated with a decrease in alopecia and in self‐grooming behavior. Therefore, fatty acids may be a viable treatment for alopecia in some captive primates.     

Alopecia in Rhesus macaques correlates with immunophenotypic alterations in dermal inflammatory infiltrates consistent with hypersensitivity etiology

Background Although alopecia is a commonly recognized problem affecting many captive Rhesus macaque colonies, there is no consensus as to the underlying etiology or appropriate course of management. Methods We performed skin biopsies to assess underlying pathology in alopecic Rhesus macaques and performed immunohistochemical and metachromatic staining of these biopsies to assess the cellular infiltrates. Results Alopecia is associated with superficial dermal perivascular mononuclear cell infiltrates and skin pathology consistent with chronic hypersensitivity dermatitis. The inflammation is primarily composed of CD4+ cells admixed with histiocytes and mast cells. Inflammation is correlated with degree of alopecia. Further analysis in different groups of macaques revealed that animals born outdoors or infected with lung mites had reduced dermal inflammatory cell infiltrates and a lower incidence of alopecia. Conclusions These findings support a hypothesis that an altered housing status resulting in decreased pathogen burden in Rhesus macaque colonies may contribute to dermal immunophenotypic alterations and subsequent development of dermatitis with resultant alopecia.     

Evaluation of the CTSL2 Gene as a Candidate Gene For Alopecia X in Pomeranians and Keeshonden

Alopecia X is a noninflammatory, progressive, bilateral symmetric alopecia in dogs. The disease is mainly found in Nordic breeds. The breed predisposition and a strong familial accumulation suggest a hereditary background. We analyzed the cathepsin L2 gene (CTSL2) as a candidate for alopecia X. The comparative sequencing of 14 affected and 18 control animals revealed ten polymorphisms; however, none of these polymorphisms affected the coding sequence. Haplotype analysis did not reveal an association of one particular CTSL2 haplotype with the disease phenotype; therefore, we conclude that the CTSL2 gene is probably not the causative gene for alopecia X.     

Evaluation of the CTSL2 gene as a candidate gene for alopecia X in Pomeranians and Keeshonden

Alopecia X is a noninflammatory, progressive, bilateral symmetric alopecia in dogs. The disease is mainly found in Nordic breeds. The breed predisposition and a strong familial accumulation suggest a hereditary background. We analyzed the cathepsin L2 gene (CTSL2) as a candidate for alopecia X. The comparative sequencing of 14 affected and 18 control animals revealed ten polymorphisms; however, none of these polymorphisms affected the coding sequence. Haplotype analysis did not reveal an association of one particular CTSL2 haplotype with the disease phenotype; therefore, we conclude that the CTSL2 gene is probably not the causative gene for alopecia X.     

Role for the Epidermal Growth Factor Receptor in Chemotherapy-Induced Alopecia

Treatment of cancer patients with chemotherapeutics like cyclophosphamide often causes alopecia as a result of premature and aberrant catagen. Because the epidermal growth factor receptor (EGFR) signals anagen hair follicles to enter catagen, we hypothesized that EGFR signaling may be involved in cyclophosphamide-induced alopecia. To test this hypothesis, skin-targeted Egfr mutant mice were generated by crossing floxed Egfr and Keratin 14 promoter-driven Cre recombinase mice. Cyclophosphamide treatment of control mice resulted in alopecia while Egfr mutant skin was resistant to cyclophosphamide-induced alopecia. Egfr mutant skin entered catagen normally, as indicated by dermal papilla condensation and decreased follicular proliferation, but did not progress to telogen as did Egfr wild type follicles. Egfr mutant follicles responded with less proliferation, apoptosis, and fewer p53-positive cells after cyclophosphamide. Treatment of control mice with the EGFR inhibitors erlotinib or gefitinib similarly suppressed alopecia and catagen progression by cyclophosphamide. Secondary analysis of clinical trials utilizing EGFR-targeted therapies and alopecia-inducing chemotherapy also revealed evidence for involvement of EGFR in chemotherapy-induced alopecia. Taken together, our results demonstrated the involvement of EGFR signaling in chemotherapy-induced alopecia, which will help in the design of novel therapeutic regimens to minimize chemotherapy-induced alopecia.     

Autoimmune hair loss induced by alloantigen in C57BL/6 mice

Exponentially growing Meth-A cells expressing H-2K(d).D (d) antigen were found to induce alopecia when injected intraperitoneally into normal C57BL/6 mice, which express the H-2K(b).D (b) antigen. However, the capacity to induce alopecia disappeared when Meth-A cells were treated with K252a, which inhibits protein kinases. Histologically, skin in affected areas showed dense mononuclear cell infiltration and a focal foreign-body giant-cell reaction in hair follicles. The subtyping of lymphocytes in peripheral blood demonstrated a significant difference between normal mice and Meth-A cell-injected mice. To further examine the mechanism by which the alloantigen induces alopecia, lymphocytes isolated from the peripheral blood of normal C57BL/6 mice were cultured in medium containing Meth-A cell homogenate, phytohemagglutinin (PHA) and recombinant mouse interleukin-2 (rm IL-2), and intravenously injected into normal C57BL/6 mice. The adoptive transfer of the lymphocytes induced alopecia in a similar way. These findings suggest that the protein kinase-modulated alloantigen induces alopecia by disturbing the immunological homeostasis, and that lymphokine-activated killer cells play an important role in induction of alopecia by cross-reacting with hair follicles.     

Epidermal Cadm1 expression promotes autoimmune alopecia via enhanced T cell adhesion and cytotoxicity

Autoimmune alopecia is characterized by an extensive epidermal T cell infiltrate that mediates hair follicle destruction. We have investigated the role of cell adhesion molecule 1 (Cadm1; Necl2) in this disease. Cadm1 is expressed by epidermal cells and mediates heterotypic adhesion to lymphocytes expressing class 1-restricted T cell-associated molecule (CRTAM). Using a murine autoimmune alopecia model, we observed an increase in early-activated cytotoxic (CD8-restricted, CRTAM-expressing) T cells, which preferentially associated with hair follicle keratinocytes expressing Cadm1. Coculture with Cadm1-transduced MHC-matched APCs stimulated alopecic lymph node cells to release IL-2 and IFN-γ. Overexpression of Cadm1 in cultured human keratinocytes did not promote cytokine secretion, but led to increased adhesion of alopecic cytotoxic T cells and enhanced T cell cytotoxicity in an MHC-independent manner. Epidermal overexpression of Cadm1 in transgenic mice led to increased autoimmune alopecia susceptibility relative to nontransgenic littermate controls. Our findings reveal that Cadm1 expression in the hair follicle plays a role in autoimmune alopecia.     

Systemic corticosteroids in alopecia totalis

Two cases of alopecia totalis are presented and some observations made on the course and treatment of the disorder. The stimulus for extensive alopecia areata appears to occur for short periods in at least some cases and may, therefore, be amenable to shorter courses of systemic corticosteroids than was formerly thought possible. Discontinuing systemic therapy does not always result in a rapid recurrence of totalis and bouts of alopecia partialis which may follow its discontinuance may be managed by more conservative means. In addition, areas resistant to 30 mg. of prednisone per day may respond to topical and intralesional therapy even while prednisone is being reduced considerably below this level.     

A gene for universal congenital alopecia maps to chromosome 8p21-22.

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.     

Antioxidants and lipid peroxidation status in the blood of patients with alopecia

The aim of this research was to determine levels in blood of vitamin E, beta-carotene, lipid peroxidation as thiobarbituric-acid reactive substances (TBARS) and reduced glutathione (GSH) and activity of glutathione peroxidase (GSH-Px) in patients with alopecia. Studies were carried out on 37 patients with alopecia and 34 healthy age-matched controls. Red blood cell (RBC) and plasma samples from healthy and patient subjects were taken. Beta-cartotene levels (P<0. 001) in plasma and levels of GSH (P>0.05) and the activity of GSH-Px (P<0.05, P<0.01) in both plasma and RBC samples were significantly lower in patients with alopecia than in controls, whereas TBARS levels in plasma (P<0.05) and RBC (P<0.001) samples were significantly higher in patients with alopecia than in controls. However, vitamin E levels in plasma did not differ statistically. Although being far from conclusive, these results provide some evidence for a potential role of increased lipid peroxidation and decreased antioxidants in alopecia.     

The we gene is a modifier of the wal gene in mice

Interaction of gene wellhaarig (we) with genes waved alopecia (wal) and hairless (hr) was studied in mice. The mutant gene we is responsible for the development of a specific waved coat in homozygotes. Homozygous mice carrying mutant gene wal also have a wavy coat, though a partial alopecia develops with time in these animals. In homozygotes for the hr gene, hair loss is observed beginning from the age of ten days. A series of crosses we/we and wal/wal yielded animals with we/+wal/wal and we/we wal/wal genotypes. In mice we/+wal/wal carrying gene we at a single dose, alopecia is accelerated significantly as compared to the single-dose homozygotes +/+wal/wal. In we/we wal/wal mice, alopecia starts earlier than in we/+wal/wal mice; by the age of one month, the double homozygotes are almost hairless except for small body areas covered with a sparse coat. In addition, curliness of the first-generation hair in mice we/we wal/wal is much more expressed than in +/+wal/wal and we/we+/+ mice. The obtained evidence suggests that the we gene is a modifier of the wal gene because the former enhances the effects of the wal gene, which is confirmed by the earlier onset of alopecia and progression of the latter in mice having the we/+wal/wal genotype and especially in we/we wal/wal animals. The we/we hr/+ mice do not differ in coat from we/we+/+ mice; in both cases, the coat is wavy. The coat of double homozygotes we/we hr/hr, is similar to that of we/we+/+ mice until ten days of age, when the signs of alopecia appear. By the age of 21 days, mice we/we hr/hr have lost their coat completely like mice +/+ hr/hr. Hence, the we gene is a modifier of the wal gene though it does not interact with hr gene during the coat formation.     

Age-related diffuse chronic telogen effluvium- type alopecia in female squirrel monkeys (Saimiri boliviensis boliviensis)

We investigated the diffuse alopecia affecting some female squirrel monkeys (Saimiri boliviensis boliviensis) housed in a breeding facility. We randomly selected 100 female and 10 male animals and performed a complete physical exam and a hair assessment on all animals; blood tests, trichograms, hair density; and skin biopsies in representative cases; and a dominance behavioral assessment of 50 animals. Hair coat was normal in 35 female monkeys and all 10 male animals. Of the 65 females with diffuse alopecia, 17 had mild, 22 moderate, and 26 severe hair loss. The alopecia group had a mean age of 9.6 +/- 0.6 years, whereas that of the normal group was 4.7 +/- 0.6 years (P < 0.05). The parity in the alopecia group was 4.2 +/- 0.6 but 2.0 +/- 0.6 (P < 0.05) in the normal group. There were no statistically significant differences in body weight, hemoglobin, blood urea nitrogen, serum glucose, liver aspartate aminotransaminase, or free thyroxine. The trichogram demonstrated 20.8% +/- 1.6% (mean +/- standard error) of telogen hairs in the alopecia group compared with 9.5% +/- 2.8% of the control group (P < 0.05). The hair density in the alopecia group was 52.8 +/- 4.1/cm2 and 79.6 +/- 14.3/cm2 in the control group. Skin biopsies in affected monkeys demonstrated increased telogen follicles, with no fibrosis or inflammation. There were no statistically significant differences in the dominance behavioral analysis. The findings are consistent with chronic telogen effluvium (CTE). A number of organic, behavioral, and dominance-related stress causes of CTE were excluded. CTE appears to be predominantly age-related in this population. CTE in female squirrel monkeys may serve as an animal model for human diffuse alopecia.