A hair disorder can be difficult to define, but patients are typically motivated to seek treatment when their hair growth patterns are significantly different from their cultural group or when growth patterns change significantly. The causes of hair disorders are many and varied, but fundamentally the disorder is a consequence of aberrant alterations of normal hair biology. The potential trigger factors for hair disorders can be attributed to inflammation, genetics, the environment, or hormones, of which the relative contributions vary for different diagnoses, between individuals, and over time. This article discusses the causal mechanisms for the disordered hair follicle.
Key Points
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A hair follicle disorder can be defined as when the characteristics of hair growth fall outside the commonly accepted parameters for a particular group, whether identified by gender, age, ethnicity, and/or culture.
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A patient’s perception of a hair disorder is determined by differences in “hair coverage” relative to the prior hair growth pattern and/or the growth patterns of others in the patient’s cultural group.
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A dermatologist’s perception of a hair disorder is determined by objective measurements of hair follicle density per unit area of skin and average terminal hair fiber thickness.
Introduction: What is a hair follicle disorder?
Hair disorders are not directly life threatening, although they can be a symptom of a more serious condition. A hair disorder may indicate significant threats to life from shedding as a result of toxin exposure, through tumor-secreting hormonal imbalances, to extensive inflammation as occurs with systemic lupus erythematosus. Fundamentally, however, a hair disorder is any condition in which the visible hair coverage over the skin falls outside of normal hair growth parameters. The definition of “normal hair growth” varies with gender, ethnicity, age, and, often, the particular opinion of the individual concerned.
For most people, “normal” scalp hair coverage requires a certain density of terminal hair follicles over the frontal, temporal, auricular, midscalp, vertex, and occipital scalp. Of course, there may be considerable variability in tolerance. The exact geographic limits of terminal scalp hair coverage can differ with ethnicity; the hairline for some East Asian-Indians can be notably more forward on the temples than that for persons of other ethnicities, for example. The nature of the coverage also varies, with a relatively lower density of terminal hair follicles but larger average size of individual hair fibers in persons of Far East Asian ethnicities. Culture also plays a significant role in defining acceptable scalp hair coverage.
There is greater challenge in defining “normal” when it comes to facial hair and body hair. The definition of normal beard growth is highly variable between ethnicities, ranging from mostly full beard growth capacity in Middle East populations to no almost beard growth in Native North Americans. Even within ethnic groups, beard growth capacity can be variable as with North European whites. What is normal also varies with gender; beard growth is normal for men but a disorder when it occurs in women. Terminal, pigmented body hair again varies with ethnicity; Mediterranean people typically have more extensive body hair growth, whereas Far East Asian people may have relatively little body hair. Cultural opinion strongly modifies the definition of normal body hair growth parameters. Concerns related to body hair are mostly limited to those in North America and Far East Asia, although this anxiety is spreading to other ethnic groups. Notably, though, the impact of cultural influence is variable; for example, British and Finnish women regard male body hair growth as desirable, whereas North American women find it unattractive.
Consequently, whether a hair disorder is identified depends in part on the genetic and cultural background of the individual concerned. A hair follicle disorder is probably best defined as when the characteristics of hair growth fall outside the commonly accepted parameters for a particular group, whether defined by gender, age, ethnicity, and/or culture. Rectifying hair disorders, whether perceived or real, has become a global industry. The changeable definition of a hair disorder can also determine whether treatment comes from the cosmetic sector or from medical health care systems. For example, laser hair removal can be regarded as entirely cosmetic, or it may be considered a medical treatment when hypertrichosis can be given a specific diagnostic label. Defining a hair disorder can be challenging.
Introduction: What is a hair follicle disorder?
Hair disorders are not directly life threatening, although they can be a symptom of a more serious condition. A hair disorder may indicate significant threats to life from shedding as a result of toxin exposure, through tumor-secreting hormonal imbalances, to extensive inflammation as occurs with systemic lupus erythematosus. Fundamentally, however, a hair disorder is any condition in which the visible hair coverage over the skin falls outside of normal hair growth parameters. The definition of “normal hair growth” varies with gender, ethnicity, age, and, often, the particular opinion of the individual concerned.
For most people, “normal” scalp hair coverage requires a certain density of terminal hair follicles over the frontal, temporal, auricular, midscalp, vertex, and occipital scalp. Of course, there may be considerable variability in tolerance. The exact geographic limits of terminal scalp hair coverage can differ with ethnicity; the hairline for some East Asian-Indians can be notably more forward on the temples than that for persons of other ethnicities, for example. The nature of the coverage also varies, with a relatively lower density of terminal hair follicles but larger average size of individual hair fibers in persons of Far East Asian ethnicities. Culture also plays a significant role in defining acceptable scalp hair coverage.
There is greater challenge in defining “normal” when it comes to facial hair and body hair. The definition of normal beard growth is highly variable between ethnicities, ranging from mostly full beard growth capacity in Middle East populations to no almost beard growth in Native North Americans. Even within ethnic groups, beard growth capacity can be variable as with North European whites. What is normal also varies with gender; beard growth is normal for men but a disorder when it occurs in women. Terminal, pigmented body hair again varies with ethnicity; Mediterranean people typically have more extensive body hair growth, whereas Far East Asian people may have relatively little body hair. Cultural opinion strongly modifies the definition of normal body hair growth parameters. Concerns related to body hair are mostly limited to those in North America and Far East Asia, although this anxiety is spreading to other ethnic groups. Notably, though, the impact of cultural influence is variable; for example, British and Finnish women regard male body hair growth as desirable, whereas North American women find it unattractive.
Consequently, whether a hair disorder is identified depends in part on the genetic and cultural background of the individual concerned. A hair follicle disorder is probably best defined as when the characteristics of hair growth fall outside the commonly accepted parameters for a particular group, whether defined by gender, age, ethnicity, and/or culture. Rectifying hair disorders, whether perceived or real, has become a global industry. The changeable definition of a hair disorder can also determine whether treatment comes from the cosmetic sector or from medical health care systems. For example, laser hair removal can be regarded as entirely cosmetic, or it may be considered a medical treatment when hypertrichosis can be given a specific diagnostic label. Defining a hair disorder can be challenging.
Contribution of hair biology to hair disorders
The Patient’s Point of View
Whether a patient perceives he or she has a hair disorder is often determined by changes in “hair coverage,” usually on the scalp but also on the body. A significant increase or decrease in terminal hair, relative to the prior hair growth pattern or the growth patterns of other people in the same cultural group, can motivate the search for treatment. The definition of hair coverage for a patient is often different from the definition used by dermatologists and other professionals. For a patient, hair coverage is the total amount of hair present, something professionals might describe as total hair mass. A patient’s understanding of normal hair coverage typically involves a synthesis of the numbers of hairs, hair thickness, hair length, and hair style.
The Dermatologist’s Point of View
For a dermatologist, hair coverage is the combination of hair follicle density per unit area of skin with average hair fiber thickness. A higher density of follicles producing terminal hair fibers gives better coverage; the same density of hair follicles but producing thicker hair fibers also increases coverage. Improvements in both terminal hair density and average hair diameter work synergistically. Hair coverage is a fully quantitative, objective metric that is examined in trichograms, phototrichograms, and, most recently, digital trichogram image techniques. The length of hair is not considered in trichograms, but it can play a role in semi-uantitative analyses when global hair coverage is evaluated. Potentially, hair length can interfere with global analysis; an individual with the same hair density and same average hair fiber diameter might seem to have better overall scalp coverage if the hair is allowed to grow. To avoid this issue in clinical trials, participants are usually expected to have their hair cut in a similar style and length before each global evaluation and to avoid styling products. For the dermatologist, then, normal hair coverage is strictly determined by biologic parameters.
Hair Follicle Embryogenesis
The nature of hair follicle formation and growth is described in detail elsewhere. The development and differentiation of hair follicles during embryogenesis is classically divided into 8 stages characterized by distinct morphologies. Extensive research has examined hair follicle embryogenesis and its control, although understanding of the biologic mechanisms involved is quite limited. It is known to require a complex sequence of autocrine, paracrine, and endocrine signals to occur both within and between the epithelium and dermis. How these factors interact with each other, their relative significance, the degree of redundancy in the signaling system, and how these signals determine hair follicle distribution and subsequent growth cycle characteristics are still not well understood. However, it is clear that multiple signaling pathways are required for the correct development and geographic distribution of hair follicle formation through the skin. Consequently, perturbations in hair follicle embryogenesis can produce a hair disorder.
Hair Follicle (Fiber) Density
Outside of experimental induction– or injury-mediated hair follicle formation (neogenesis) and cases in which neogenesis may occur naturally in nonhuman species, embryogenesis determines the total number of hair follicles an individual has for the duration of life. Each human typically has 2 million hair follicles across the body. Disorders involving increases in hair follicle number or abnormally increased local density are not found in humans, except perhaps in rare cases involving neogenesis in hyperplastic skin lesions and clustering of follicles in tufted hair folliculitis. However, a failure of embryogenesis can lead to an abnormally low density of hair follicle formation (hypotrichosis), whether in general or in specific body regions. More common is a normal density of hair follicle formation, which is then adversely impacted later in life by an insult yielding a significant reduction in hair follicle number. Plainly, a considerable change in the density of hair follicles per unit area of skin can underlie the development of a hair disorder ( Fig. 1 ).
Hair Follicle (Fiber) Size
Hair follicles (fibers) of adults are classified into 3 different groups and size is a key feature that determines their categorization. Most human hair follicles produce short, fine, nonpigmented vellus hairs. In contrast, eyebrow, eyelash, and scalp follicles produce much bigger, slowly cycling, usually pigmented terminal hairs from birth. Follicles retain a degree of plasticity with respect to the type of hair produced and they can transform from vellus into terminal hair production, and vice versa. Hair follicles progressing through a transition in size are defined by some as producing intermediate hairs. Essentially, they are neither full terminal hairs nor full vellus hairs and are observed as terminal hair follicles miniaturize or vellus hair follicles enlarge ( Fig. 2 ). Hair follicle size, and so the size of the hair fiber the follicle produces, potentially has a great impact on hair coverage ( Fig. 3 ). A terminal to vellus scalp hair follicle switch (miniaturization) can be seen with the development of androgenetic alopecia (AGA), chronic alopecia areata (AA), or chronic telogen effluvium (TE), for example. Conversely, a vellus to terminal body hair follicle switch is seen with hirsutism and hypertichoses.
Hair Fiber Growth Rate
It can be a surprise for patients when they learn that the rate of hair growth does not make a very significant contribution to the development of their hair disorder. In the minds of many, a fast rate of hair growth tends to be associated with hypertrichosis, whereas alopecia is associated with a slow hair growth rate. There is some truth to this relationship; the rate of hair growth does slow in the development of AGA, whereas vellus hair follicles that switch to terminal hair follicles speed up their growth rate. However, compared with hair follicle size and density, the rate of hair growth provides little toward overall hair coverage as defined in the dermatology clinic. A cluster of hair follicles with slow fiber growth provide the same coverage as a cluster with the same density and size producing hair fiber unusually rapidly; if the patient is willing to wait for the hair to grow. Rate of hair growth is usually only a significant issue when a patient is impatient.
Contribution of the hair cycle to hair disorders
Hair Growth Cycle
The nature of hair follicle growth cycles is described in detail elsewhere. There are 3 main phases of the hair follicle cycle: an active growth phase called anagen; catagen when the hair follicle regresses; and telogen, when the hair follicle is largely quiescent ( Fig. 4 ). How long each phase takes partly depends on the type of hair follicle involved and its geographic location. For someone defined as “normal,” roughly 85% of scalp hair follicles are in anagen and 15% are in telogen, although these values can change with ethnicity. Anagen in normal terminal scalp follicles may last from 2 to 6 years, whereas telogen may take about 3 months and catagen about 3 weeks. Potentially, significant changes to the normal hair cycle can elicit a hair disorder.
Hair Follicle Anagen Growth Phase
The duration of anagen is a major determinant of the maximal hair length, along with the rate of hair growth. For example, the anagen phase of eyebrow hair follicles is only 70 days. In addition, the rate of growth is only 0.1 mm/d for eyebrow hair versus around 0.3 mm/d for scalp hair. The net result is a much reduced opportunity for long eyebrow hair to grow. Consequently, eyebrows grow to a certain length and apparently stop, whereas scalp hair can grow much longer. This differential in the time duration of anagen is part of what is known as the hair cycle clock (see later). An increase in the duration of anagen does not alter hair fiber density over the scalp; instead, it determines to what length the hair can grow. A patient tends to value hair length; longer hair can be cosmetically styled to cover areas affected by alopecia, for example.
Hair Follicle Telogen Phase
In and of its self, an increase in the duration of telogen does not alter hair fiber coverage over the scalp. Rather, the longer the time period of telogen, the larger is the window of opportunity for shedding of the telogen club hair to take place. Prolongation of the telogen phase in scalp hair follicles can result in alopecia development as shedding progressively occurs. Telogen hair fibers continue to be shed, but with the failure of the follicles to enter a new anagen phase, new hair fiber is not produced to replace the old shed fibers. This is the most common mechanism by which alopecia may develop, whether describing a distinct alopecic patch or a diffuse thinning. Such a situation can be observed in AGA or TE, for example. Mouse models can provide a demonstration of alopecia development as a result of shedding occurrence before the onset of renewed anagen. Mice with a targeted mutation of the telomerase RNA component have a decreased percentage of hair follicles in anagen, an increased percentage in telogen, and a progressive alopecia as shedding of telogen hair is apparently normal.
Hair Cycle Clock
Under normal physiologic conditions, each hair follicle will continue to cycle throughout life. These cycles are regulated by specific changes in the local signaling milieu, based on changes in expression of hormones, cytokines, and their respective receptors, as well as transcription factors, enzymes, antagonist binding proteins, and epigenetic events. These components may act in endocrine, paracrine, or autocrine manners with positive and negative feedback loops. What determines the clock mechanism and the duration of anagen in individual hair follicles is not known, although many hypotheses have been suggested.
Changes may occur to the hair cycle clock that contribute to the development of alopecias and, to a lesser extent, to hypertrichoses. A prolongation of the anagen growth phase duration (or, alternatively, a delay in the onset of catagen) may be a component of hypertrichosis, yielding excessively long hair. Conversely, a reduction in the anagen growth duration (premature induction of catagen) results in the growth of very short hair fibers as a result of the brief growth phase. This can sometimes be observed in patients with AA, for example. The impact of hair cycle clock changes is most noticeable in animal models. In Angora mice, in which a mutation in Fgf5 increases the duration of anagen, the fur is up to 50% longer than normal, producing a more fluffy appearance. In contrast, truncated anagen growth in mice transgenic for the Wingless-related MMTV integration site 3 (Wnt3) yields very short, stubble-like hair growth. A similar density of hair follicles is maintained in both situations.
Hair Follicle Exogen Event
The term “exogen” essentially describes telogen club hair fiber shedding from an individual hair follicle. Previously, hair fiber shedding was believed to be passive, but recent research suggests that shedding is an active and highly controlled process. Exogen is a moveable event in the main anagen-catagen-telogen cycle (see Fig. 4 ). The duration of anagen on its own does not alter the density of hair fiber present. Instead, a combination of anagen duration and a lack of exogen shedding allows for increased numbers of hair fibers to be present in the same hair follicle (old telogen club hairs plus new growing anagen hairs). Similarly, an increased duration of telogen alone also does not alter hair fiber coverage. The longer the time period of telogen, the larger is the window of opportunity for exogen shedding of the telogen club hair to take place. Alternatively, the duration of telogen may be normal but the exogen event is premature, leading to thin hair and alopecia. A good example is the Msx2 mutant mouse model in which waves of anagen hair growth and telogen rest occur but the exogen event is premature. The result is a mouse with bands of fur apparently migrating over bald skin.
Hair Follicle Kenogen Event
Typically, exogen and shedding of an old hair fiber occur as the follicle is in early anagen actively producing a new hair fiber. However, as noted, exogen can occur when a hair follicle is still in telogen before the onset of renewed anagen (see Fig. 4 ). When this occurs the hair follicle may remain empty of hair fiber for a period of time, in a state termed “kenogen.” Not surprisingly then, how long a club hair fiber is retained, and when it is shed in relation to the production of a new hair fiber, helps to determine hair coverage. Kenogen can be observed in healthy scalp skin, but the frequency and duration are significantly greater in individuals with alopecias. With more club hair fibers expelled from hair follicles still in a telogen state, so the numbers of kenogen follicles increase; the net result is bald skin.
Dystrophic Anagen Growth Phase
As noted, kenogen hair follicles devoid of visible hair fiber are most commonly in a prolonged telogen state. However, kenogen hair follicles can also be in an early anagen phase before the emergence of a new hair fiber from the skin surface or in a dystrophic anagen state. A dystrophic anagen state is when the follicle is active but unable to produce a healthy fiber. Such a situation can be observed in anagen effluvium or AA, for example. The external insult stops the follicles from successfully forming a recognizable hair fiber.
All of these biologic components can contribute to the development of a hair disorder with different combinations relevant to different disorders.
Causal factors of hair disorders
The authors have attempted to review the basic mechanisms behind hair disorders, but this does not address events that cause a hair disorder to occur. The potential trigger factors for hair disorders are many and varied but can be attributed to one or more categories: inflammation, genetics, the environment, and hormones ( Fig. 5 ). In most instances, factors from one of these categories predominate in the development of the hair disorder, but factors in other categories may also contribute ( Fig. 6 ). In different individuals with the same condition, the relative contributions of different factors promoting the hair disorder may vary. In addition, the key factors important in promoting the hair disorder may change over time.
Inflammation
Inflammation and Hair Loss
Hair loss promoted by some form of inflammatory insult is not unusual. The inflammation may be specific for the hair follicle or nonspecific. For example, skin inflammation associated with lupus erythematosus may induce a diffuse alopecia in regions of inflamed skin. In this situation, the inflammatory infiltrate is not specifically targeting hair follicles, but because of the general inflammatory effect, hair follicles in the vicinity are adversely affected. Nonspecific inflammation may be a primary promoter of a hair disorder or it may operate in combination with other influential factors. For example, scalp inflammation can be variably associated with AGA. When present, the inflammation may further exacerbate the alopecia. Many forms of nonspecific skin inflammation may promote a degree of alopecia, but in some cases, nonspecific inflammation can also promote hair growth. For example, local injury or irritation can lead to a stimulation of anagen and local increases in terminal hair growth. From ancient times, physical and chemical skin irritation techniques have been used to promote hair growth.
Although nonspecific inflammation can promote a hair disorder, inflammatory hair loss disorders can involve an infiltrate targeted to the affected hair follicles. It is worth noting that the target of interest for the inflammatory cells can be exogenous. The hair canal is a known reservoir of bacteria, fungi, viruses, and even parasitic organisms like demodex folliculorum. When exogenous stimulators are involved, the inflammatory hair loss condition is usually treatable by removing the antigenic challenge. However, more typically, endogenous hair follicle–specific targets are of interest to inflammatory cells, as occurs with AA or scarring alopecia. These conditions have been studied in some detail, and for both it has been hypothesized that hair follicle–expressed antigens are inappropriately stimulating the immune system.
Hair Follicles and Immune Privilege
Hair follicles, similar to other organs like the testis and the anterior chamber of the eye, are believed to be immune-privileged (IP) sites where immune cell activity is limited. IP sites are characterized by downregulation of major histocompatibility complex (MHC)-I complexes, increase in immunosuppressive cytokines, and constitutive expression of cell surface immune regulatory factors such as Fas ligand. Active IP may be especially important during normal hair follicle cycling when apoptosis takes place during the catagen (regressing) phase of the cycle. Activation of the immune system by the antigens released from hair follicles during this phase needs to be avoided. The loss of IP is involved in many (auto)-immune diseases such as multiple sclerosis, autoimmune uveitis, fetal rejection, mumps orchitis, and autoimmune chronic active hepatitis. Potentially, when the hair follicle is unable to maintain IP, immune cells are able to infiltrate into the hair follicle and be activated by the hair follicle–specific self-antigens. Activated immune cells express various inflammatory cytokines and proapoptotic molecules that could interfere with hair follicle integrity and may result in hair loss.
AA: An Inflammation-Mediated Hair Loss Disorder
AA is one of the most common forms of autoimmune disease associated with hair follicle. It is characterized by nonscarring, inflammatory patches of hair loss that can progress into alopecia totalis and alopecia universalis. From immunohistologic analysis of AA lesions in both humans and rodent models, there is an increase in CD8 + cytotoxic lymphocytes infiltrating into the hair follicle, whereas CD4 + cells localize around the hair follicle. In association with the infiltration is increased expression of MHC class I and II and possibly a loss of IP supporting factors. This could be a sign of collapsed hair follicle IP, allowing lymphocyte infiltration. In response to endogenous inciting antigens, the lymphocytes may disrupt the normal hair growth cycle and/or induce apoptosis in the follicular cells via cytokines and other molecules. When depleting CD4 + or CD8 + cells in rodent models, there is a significant improvement in AA and hair regrowth. Conversely, transfer of AA-activated CD8 + cells into healthy recipients induces localized AA at site of injection, whereas CD4 + cells alone eventually promote systemic hair loss, suggesting CD4 + cells promote AA by “helping” CD8 + cells. The basic inflammatory mechanism of AA has been confirmed by many research groups; however, the exact antigen(s) that trigger the onset of AA are still not yet elucidated.
Role of genetics
Although it is clear that inflammation is the driving force behind the development of AA, genetics also play a role (see Fig. 6 ). It has been found that monozygotic twins have similar times of onset and patterns of AA and some patients have a family history of AA. These are strong indications that AA is heritable in at least some cases. The genetic composition of a person may affect the expression of self-antigens, which can increase the chance of immune cells targeting and killing hair follicle cells. It has been found that in patients with AA that there is an aberrant expression of specific MHC antigens that likely promote antigen-specific immune cell activation. Mouse and human genomewide screening studies have suggested several more non-HLA gene alleles that may confer AA susceptibility.
Role of hormones and the environment
Although genotype may control the relative susceptibility of each individual, environmental inputs are probably important for the onset of AA (see Fig. 6 ). The behavior of hair follicle immune responses can be modified by environmental factors. In AA, cytomegalovirus has been implicated, as well as hepatitis B vaccination, although conflicting data are presented in different studies. In a mouse model, diet can modify AA susceptibility, and testosterone can increase resistance to AA. Elevated corticotrophin-releasing hormone in AA mice may lead to a dysregulated immune system. The abnormal corticotrophin-releasing hormone and hypothalamic-pituitary-adrenal axis activity in AA could also potentiate an autoimmune response. These observations highlight the complexity of AA progression; more than one factor combined with genetic predispositions may be required for the dysregulation of immune response and the onset of hair loss. The development of AA involves input from multiple factors and certain thresholds must be reached before clinically significant changes can be observed.
Cicatricial Alopecia: An Inflammation-Mediated Hair Loss Disorder
Targeted inflammation around the upper, permanent portion of the hair follicle can lead to its destruction, as seen in primary cicatricial (scarring) alopecias. Permanent hair follicle loss results in decreased or completely absent hair follicle density in affected areas. In some scarring alopecias, there is a neutrophil infiltrate, and in others there is a mixed infiltrate of lymphocytes and neutrophils. In the case of lichen planopilaris, Langerhans cells and CD4 + and CD8 + lymphocytes infiltrate the upper permanent follicular epithelium. Some hypothesize that a loss of IP in the hair follicle bulge region and, therefore, destruction of bulge stem cells are what lead to the permanent hair loss observed in scarring alopecia. Stronger expression of MHC Class I and II and β 2 -microglobulin are observed in the bulge region of hair follicles in cicatricial alopecia–affected skin compared with uninvolved skin. It is unclear whether the inflammation is the initiating event, causing hair follicle disruption, or a secondary event responding to an unidentified hair follicle abnormality. Additionally, it is unknown whether the inflammatory target antigen is from hair follicle cells or from an external source.
Role of genetics, hormones, and the environment
It is unclear how the different subtypes of primary scarring alopecias are activated and progress, but genetics, hormones, and the environment may play a role in some cases (see Fig. 6 ). A down-regulation of lipid metabolism genes, such as PPARγ , have been observed in advance of inflammation suggesting that lipid metabolic issues appear earlier than inflammatory problems in lichen planopilaris. Knockout of PPARγ in bulge cells of mice render them more susceptible to the development of scarring alopecia. Potentially, then, the genetics of lipid metabolism may help determine susceptibility to some forms of scarring alopecia. In lichen planopilaris, postulated stimuli include exposure to quinacrine, vaccinations, or gold. In folliculitis decalvans, Staphylococcus aureus infection has been proposed as an antigenic stimulus and antimicrobial treatment can be effective in some cases. A case of tick-borne lymphadenopathy was followed by development of cicatricial alopecia. In frontal fibrosing alopecia, estrogens may increase susceptibility to its development. As with AA, scarring alopecias may be inflammatory cell driven, but genetics, hormones, and environmental components may help determine the course of the disease.
Genetics
Genetics and Hair Loss
Congenital disorders of hair growth are almost always genetic. The environment, hormones, and inflammation may contribute, but the impact of gene-mediated activity predominates (see Fig. 6 ). Fundamentally, a congenital hypertrichosis or congenital alopecia is caused by incorrect or incomplete embryogenic formation of hair follicles. Because hair coverage is defined by hair follicle density, size, and growth cycle, genetic modifications to these parameters can result in congenital hair growth disorders.
Genetics and Hair Follicle Density
The most obvious genetic modification of embryogenesis possible is a reduction in the number of hair follicles formed per unit area of skin. This defect may be localized, as with aplasia cutis congenita or triangular alopecia, when local skin and hair follicles are incompletely formed or follicles fail to achieve terminal size. Alternatively, a genetic defect may affect the entire skin and be apparent from birth. As examples, EDA gene mutations cause anhidrotic ectodermal dysplasia (ED) and EDA receptor gene mutations cause hypohydrotic ED. These syndromes involve a much decreased density of hair follicles, as well as teeth and sweat glands. All these epidermal appendages have similar mechanisms of embryogenic development and so can be similarly affected by the same gene mutation.
Genetics and Hair Follicle Growth Cycle
In other genetic hair loss conditions, hair follicle formation may be normal at first, but with time the hair follicles fail to fully regenerate as part of the normal hair growth cycle. In congenital atrichia, the recessive hairless ( hr ) gene encodes for a transcription factor that is defective. The hair follicles form and progress through their first full cycle as normal. However, during catagen, the mesenchymal dermal papilla and dermal sheath cells fail to maintain close association with the epithelial cells as the follicle regresses. As the cells separate and can no longer communicate with each other, the follicles fail to regenerate and enter a new anagen phase. Similarly with Marie Unna hereditary hypotrichosis, the hair follicles may initially form and grow hair but fail to survive and successfully enter subsequent hair growth cycles. The late-onset, patterned destruction of hair follicles in Marie Unna hypotrichosis makes this condition unique as a genetic hair loss condition. These and other hair growth disorders involve mutations in genes (usually just one gene) that are functionally significant for cohesive hair follicle structure maintenance throughout the hair growth cycle.
Genetics and Hair Follicle Size
Congenital hypertrichosis is not determined by the number and distribution of hair follicles but instead by whether the hair follicles are terminal or vellus size in a geographic region of skin. Embryos are covered from head to toe by a more or less uniform coat of long fine unpigmented lanugo hair. Shortly before full-term, the scalp hairs progress into terminal hairs while the remaining body hair follicles involute and become vellus hairs. As a result, terminal hair follicle distribution is mostly restricted to the scalp at birth. When terminal hair follicles form beyond these limits on the face and elsewhere in the place of vellus hair follicles, the consequence may be diagnosed as congenital hypertrichosis. Hair growth cycle duration can play a role in some hypertrichoses. In congenital hypertrichosis lanuginosa the duration of anagen is prolonged beyond the norm in vellus hair follicles, the net result being long, fine, unpigmented hair growth. Again, the density of hair follicles has not been altered.
Genetics, the Environment, Hormones, and Inflammation
Of course, genetic hair loss disorders can be modulated and even mediated by factors in the environment, hormonal activity, and inflammatory cell action (see Fig. 6 ). AA may be an inflammatory cell–mediated disease, but the environment and genetics can play a role for at least some patients. Similarly, AGA (see later) has a strong genetic component. Even with TE, generally accepted as a condition that develops in response to environmental insults, genes may play a role in determining an individual’s level of susceptibility to the development of hair loss in response to the insult.
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