Section 15. Disorders of the Hair and Nails

Hair is found only in mammals, where during the course of evolution its primary roles were to serve as insulation and protection from the elements. However, in contemporary humans, hair's main purpose revolves around its profound role in social interactions. Loss of hair (alopecia) and excessive hair growth in unwanted areas (hirsutism and hypertrichosis) can lead to significant psychological and emotional distress that supports a multibillion-dollar pharmaceutical and cosmetic effort to reverse these conditions.

Fundamental understanding of hair growth and its controls is increasing and result in new treatments for alopecia.1,2 These advances resulted from the interest of developmental biologists and other investigators in the hair follicle as a model for a wide range of biologic processes. As each hair follicle cyclically regenerates, it recapitulates its initial development. Many growth factors and receptors important during hair follicle development also regulate hair follicle cycling.3–10 The hair follicle possesses keratinocyte and melanocyte stem cells (MSCs), nerves, and vasculature that are important in healthy and diseased skin.11–13 To appreciate this emerging information and to properly assess a patient with hair loss or excess hair (see Chapter 88), an understanding of the anatomy and development of the hair follicle is essential.

Morphologically, hair follicle development has been divided into eight consecutive stages, several of which are illustrated in Fig. 86-1. Each stage is characterized by unique expression patterns for growth factors and their receptors, growth factor antagonists, adhesion molecules, and intracellular signal transduction components.14–16 Promising advances in understanding the molecular mechanisms behind hair follicle development arose through the discovery that mammalian counterparts (homologs) of genes important for normal Drosophila (fruit fly) development also affect hair follicle development. Decapentaplegic [Dpp/bone morphogenetic protein (BMP)], Engrailed (en), Homeobox (hox), hedgehog/patched (hh/ptc), notch, wingless/armadillo (wg/wnt/catenin) genes are all critical for hair follicle and vertebrate development in general.17–19 These genes were all first discovered in Drosophila, thus, most of the names assigned to them describe the peculiar appearance (phenotype) of the flies carrying mutations in these genes.20

Follicle formation begins on the head, and then moves downward to the remainder of the body in utero. The first hairs formed are lanugo hairs, which are nonpigmented, soft, and fine. Lanugo hair is typically shed between the 32nd and 36th weeks, although approximately one-third of newborns still retain their lanugo hair for up to several weeks after birth.

Patterning genes, called homeobox genes, which are precisely organized in the genome so that they are expressed in strict temporal sequences and spatial patterns during development, likely are responsible for the nonrandom and symmetric distribution of hair follicles over the body.21,22 In adult mice, homeobox gene expression reappears in hair follicles and serves to maintain normal hair shaft production.6 Engrailed, a type of homeobox gene, is responsible for dorsal–ventral patterning, and mice lacking engrailed develop hair follicles on their footpads.23

Although hair follicles and hairs all share the same basic anatomy, their growth, size, shape, pigmentation, and other characteristics differ widely, based on body location and variation among individuals. Many of these characteristics are established during development but are then profoundly altered by hormonal influences later in life. We are beginning to understand the genes controlling hair length, curl and distribution because of elegant genetic studies on dogs. These studies reveal that fibroblast growth factor-5 (FGF-5), Keratin 71, and R-spondin 2 influence length, curl and distribution respectively.24 In humans, thicker hair found in Asians is associated with increased activity of ectodysplasin receptor (EDAR),25 the receptor of ectodysplasin (EDA) (see below).

The size of many types of follicles changes drastically several times throughout life. For example, lanugo hair follicles, which produce hair shafts several centimeters long, convert to vellus follicles that produce small hairs that protrude only slightly from the skin surface. Later in life, vellus follicles on the male beard enlarge into terminal follicles that generate thick, long hairs. On the scalp of genetically predisposed individuals, terminal follicles miniaturize and form effete, microscopic hairs.

Epithelial Placode or Primary Hair Germ

In the human fetus, hair follicles develop from small collections of cells, called epithelial placodes, which correspond to stage 1 of hair follicle development and first appear around 10 weeks’ gestation (see Fig. 86-1). The epithelial placode then expands to form the “primary hair germ” whose progeny eventually generate the entire epithelial portion of the hair follicle.26

The cells of the hair placode and germ express placental cadherin and become oriented vertically, losing their desmosomes, hemidesmosomes, and epithelial cadherin, which decreases their adhesion to their neighbors.27–29 Dermal cells beneath the hair placode form a cluster (or condensate), which later develops into the dermal papilla.30

Hair follicle formation depends on a series of mesenchymal/epithelial interactions.30 An initial signal arises in the mesenchyme (primitive dermis) and instructs the overlying epithelium to form an appendage, indicated by the appearance of regularly spaced placodes (see Fig. 86-1). The second signal arises from the epithelial placode and causes an aggregation of cells in the underlying mesenchyme that will eventually form the dermal papilla. Finally, a signal from this primitive dermal papilla initiates proliferation and differentiation of placode cells, ultimately leading to formation of a mature follicle. These reciprocal signals pass through the intervening basement membrane, which undergoes alterations in its morphology and chemical composition that may alter its ability to sequester growth factors and binding proteins, thus possibly modulating the epithelial/mesenchymal interactions.

Many of these regulatory molecules important for the formation of the hair follicle have been defined, but how they interact to generate hair follicles in an otherwise homogeneous epithelium is yet to be determined. In one model, the spacing and size of placodes are regulated by a dermal signal, which varies in character in different body regions. The dermal signal occurs uniformly within each body region and triggers the activation of promoters and repressors of follicle fate in the epithelium that then compete with one another, resulting in the establishment of a regular array of follicles.15,31 Differences in the levels of promoter and repressor activation could account for regional differences in the size and spacing of follicles. Consistent with this model, several positive and negative regulators of hair follicle fate are initially expressed uniformly in the epidermis and subsequently become localized to placodes.

One of the earliest molecular pathways that positively regulates hair follicle initiation is the WNT/β-catenin pathway. β-Catenin is the downstream mediator of WNT signaling. WNT proteins bind to receptors on the cell membrane and, through a series of signals, inhibit the degradation of cytoplasmic β-catenin. β-Catenin then translocates to the nucleus, forming a complex with the LEF/TCF family of transcription factors and resulting in expression of downstream genes.15,31 Activation of this β-catenin pathway appears necessary for establishing epithelial competence—a state in which the epithelial tissue has the potential to form a hair follicle. Normally, the β-catenin pathway is inactive in the adult epidermis, but by artificially activating β-catenin in epidermal basal cells of adult transgenic mice, hair follicles develop de novo.32 This remarkable finding could eventually have therapeutic implications, although constant activation of this pathway in the hair follicle also results in pilomatricomas and trichofolliculomas, two types of relatively rare cutaneous tumors.32,33

EDA, a molecule related to tumor necrosis factor, and its receptor (EDAR) also are part of another major pathway that stimulates early follicle development in both mice and humans.34 EDA gene mutations cause X-linked anhidrotic ectodermal dysplasia, a syndrome associated with decreased numbers of hair follicles, and defects of the teeth and sweat glands (see Chapter 142).35 The EDAR gene is mutated in autosomal recessive and dominant hypohidrotic ectodermal dysplasias, causing identical phenotypes to those resulting from EDA mutations. The mouse Edar gene is expressed ubiquitously in the epithelium before placode formation, and then becomes restricted to placodes, whereas the Eda gene is ubiquitously expressed even after placode formation.36 Mice with mutations in these genes have the same phenotype as humans with similar mutations, and mice overexpressing Eda in the epidermis show formation of the “fused” follicles due to the loss of proper spacing between neighboring hair placodes.37,38 Humans with more active EDAR genes have thicker hair.25

In contrast to EDA and EDAR, which promote hair follicle development, members of the BMP family inhibit follicle formation. Bmp2 is expressed diffusely in the ectoderm, but then localizes to the early placode and underlying mesenchyme, while Bmp4 is expressed in the early dermal condensate.39,40 BMP signaling inhibits placode formation, whereas neutralization of BMP activity by its antagonist Noggin promotes placode fate, at least in part via positive regulation of lymphoid enhancer factor 1 (Lef-1) expression.39,41–43 Mice lacking Noggin have fewer hair follicles than normal and retarded follicular development.43 The Notch pathway also appears to play a role in determining the follicular pattern. The Notch ligand Δ-1 is normally expressed in the mesenchyme underlying the placode44–46 and, when misexpressed in a small part of the epithelium, promotes and accelerates placode formation while suppressing placode formation in surrounding cells.44,47

Another secreted protein present in the follicular placode that plays a major role in epithelial-mesenchymal signaling is sonic hedgehog (Shh).48,49 Skin from mice lacking Shh have extremely effete hair follicles with poorly developed dermal papillae.50–52 Patched1 (Ptc1), the receptor for Shh, is expressed in the germ cells and the underlying dermal papilla, suggesting that Shh may have both autocrine and paracrine inductive properties necessary for hair germ and dermal papilla formation.53 Patched is the gene deficient in basal cell nevus syndrome (see Chapter 116).19

The Bulbous Peg or Hair Bud

In the next stage of development, the bulbous peg or hair bud (or stage 2 of hair follicle development, see Fig. 86-1) is formed by elongation of the hair germ into a cord of epithelial cells. The mesenchymal cells at the sides of the peg will develop into the fibrous sheath of the hair follicle, and those at the tip of the peg will develop into the dermal papilla. The deepest portion of the follicle peg forms a bulbous structure that surrounds the underlying mesenchymal cells destined to become the dermal papilla. These epithelial cells will become the matrix of the hair follicle, which gives rise to the hair shaft and inner root sheath. The outer root sheath forms two bulges on the side of the hair follicle forming an obtuse angle with the surface of the skin. The superficial bulge will develop into the sebaceous gland. The deeper bulge serves as the future site of epithelial stem cells that generate the new lower follicle during hair follicle cycling. The arrector pili muscle usually attaches in the bulge area, and contraction of the muscle causes a more vertical orientation of the hair shaft leading to “goose bumps.” In the axillae, anogenital region, areolae, periumbilical region, eyelids (the specialized glands of Moll), and external ear canals, a third bulge develops superficial to the sebaceous gland bud and gives rise to the apocrine gland.

As the hair follicle bulb appears during the bulbous peg stage, at least eight different cell layers constituting all of the components of the mature hair follicle are formed. Understanding which genes determine specific cell lineages within the follicle is an important question. GATA-3 is important in inner root sheath differentiation.54 Notch1, a membrane protein involved in determining cell fate through cell–cell interactions and intracellular signal transduction, and its ligands Serrate1 and Serrate2 are expressed in matrix cells destined to form the inner root sheath and hair shaft.46,55 Notch1 appears to control the phenotype of keratinocytes as they leave the bulb matrix and differentiate into specific cell types.56

Mature Hair Follicle

The central lumen where the hair shaft will emerge is formed by necrosis and cornification of epithelial cells in the infundibulum. As the hair shaft is produced, several signaling pathways are involved in the control of its differentiation. Wnt/β-catenin/Lef-1 signaling plays an important role in hair shaft formation, and ectopic expression of Wnt3 in the hair follicle outer root sheath causes hair shaft fragility.57,58 Hair shaft keratin genes contain binding sites for Lef-1,59 which translocates to the nucleus after activation of the WNT/β-catenin pathway. WNT signaling probably regulates expression of hair shaft keratin genes, because nearly all of these genes contain Lef-1 binding sites in their promoter regions.60

BMP signaling is also essential for proper differentiation of the inner root sheath and hair shaft, because conditional deletion of BMP receptor type 1A in keratinocytes results in profound alterations of the inner root sheath and hair shaft formation.61–63 Several other putative transcription factors control hair shaft differentiation, including HOXC13,6 a homeobox protein, and the WHN gene,64–66 which is mutated in nude mice and rarely in humans with hair, nail, and immune defects.67,68

This process of hair follicle formation is repeated in several waves, with the formation of secondary follicles alongside the initial follicle. The follicles are primarily clustered into groups of three and possess an oblique orientation with a similar angle to their neighbors.

Hair Types

After formation of the lanugo hair that is characteristic of the prenatal period, there are two major types of hair classified according to size (Table 86-1). Terminal hairs are typically greater than 60 μm in diameter, possess a central medulla, and can grow to well over 100 cm in length. The duration of the growing stage (anagen) determines the length of the hair. The hair bulb of terminal hairs in anagen is located in the subcutaneous fat. In contrast, vellus hairs are typically less than 30 μm in diameter, do not possess a medulla, and are less than 2 cm in length. The hair bulb of vellus hairs in anagen is located in the reticular dermis. Terminal hairs are found on the scalp, eyebrows, and eyelashes at birth. Vellus hairs are found elsewhere, and, at puberty, vellus hair follicles in the genitalia, axillae, trunk, and beard area in men transform into terminal hair follicles under the influence of sex hormones. Terminal hair follicles in the scalp convert to vellus-like or miniaturized hair follicles during androgenetic alopecia (see Chapter 88).1,69

The curvature of the hair varies greatly among different individuals and races, and ranges from straight to tightly curled. Curved hair shafts arise from curved hair follicles. The shape of the inner root sheath is thought to determine the shape of the hair. Curled hair in cross section is more elliptical or flattened in comparison with straight hair, which is more round. Several genes influencing hair shape have been identified. Mutations in the epidermal growth factor receptor (EGFR) pathway and in insulin-like growth factor binding protein 5 result in curly hair in mice.70,71

Microscopic Anatomy

The upper follicle consists of the infundibulum and the isthmus, and the lower follicle consists of the suprabulbar and the bulbar areas (Fig. 86-2).14,66 The upper follicle is permanent, but the lower follicle regenerates with each hair follicle cycle. The major compartments of the hair from outermost to innermost include the connective tissue sheath, the outer root sheath, the inner root sheath, the cuticle, the hair shaft cortex, and the hair shaft medulla, each characterized by distinct expression of the hair follicle-specific keratins (Table 86-2).72,73

Outer Root Sheath

The outer root sheath is continuous with the epidermis (see Fig. 86-2) at the infundibulum and continues down to the bulb. The cells of the outer root sheath change considerably throughout the follicle. The outer root sheath in the infundibulum resembles epidermis and forms a granular layer during its keratinization. In the isthmus, the outer root sheath cells keratinize in a trichilemmal fashion, lacking a granular layer. Trichilemmal keratinization occurs where the inner root sheath begins to slough. Desmoglein expression markedly changes here as well and trichilemmal or pilar cysts retain these characteristics.74 Keratinocytes in the outer root sheath form the bulge at the base of the isthmus (see Section “Hair Follicle Stem Cells”). These cells generally possess a higher nuclear to cytoplasmic ratio compared with other areas of the follicle. Moving downward, the outer root sheath cells become much larger and contain abundant glycogen in the suprabulbar follicle. In the bulb, the outer root sheath consists of only a single, flattened cell layer that can be traced to the base of the follicle.

Inner Root Sheath

The inner root sheath extends from the base of the bulb to the isthmus and contains four parts from outermost to innermost: companion layer, Henle layer, Huxley layer, and the inner root sheath cuticle. The companion layer (see Fig. 86-2) has been referred to as the innermost layer of the outer root sheath, but recent evidence indicates that it is more like inner root sheath than outer root sheath.75 The companion layer attaches to Henle layer and moves upward with the rest of the inner root sheath; thus, it provides a slippage plane between the outer root sheath, which is stationary, and the inner root sheath.76 The companion layer is prominent in some follicles (e.g., the beard) compared with others. The cells of the companion layer are flat compared to the cuboidal outer root sheath cells and express a type II cytokeratin, K6hf.75 Henle layer is one-cell-layer thick and is the first to develop keratohyalin granules and the first to keratinize. Huxley layer is two to four cell layers thick and keratinizes above Henle layer at the region known as Adamson fringe. Some cells within Huxley's layer protrude through Henle layer and attach directly to the companion layer. These cells are called Fluegelzellen or wing cells.77 The cells of the inner root sheath cuticle partially overlap, forming a “shingled roof” appearance, and they intertwine precisely with the cuticle cells of the hair shaft. This association between the two cuticles anchors the hair shaft tightly to the follicle. The inner root sheath, composed of hard keratins and associated proteins (see Table 86-2), is thought to dictate hair shape by funneling the hair shaft cells as they are produced. The transcription factor, GATA-3, is critical for inner root sheath differentiation and lineage. Mice lacking this gene fail to form an inner root sheath.54

Hair Shaft

The hair shaft (and inner root sheath) arises from rapidly proliferating matrix keratinocytes in the bulb, which have one of the highest rates of proliferation in the body. The cells of the future hair shaft are positioned at the apex of the dermal papilla and form the medulla, cortex, and hair shaft cuticle (see Fig. 86-2). Immediately above the matrix cells, hair shaft cells begin to express specific hair shaft keratins in the prekeratogenous zone. The differentiation of hair shaft cells in this zone is dependent on the Lef-1 transcription factor. Lef-1 binding sites are present in most hair keratin genes. BMP receptor type 1a is also critical for matrix cell differentiation into the hair shaft, because loss of this receptor prevents hair shaft differentiation.61–63

The hair shaft cuticle covers the hair, and its integrity and properties greatly impact the appearance of the hair. Once the hair exits the scalp, the cuticle endures weathering, and it is often completely lost at the distal ends of long hairs. Inside the cuticle, the cortex comprises the bulk of the shaft and contains melanin. The cortex is arranged in large cable-like structures called macrofibrils. These, in turn, possess microfibrils that are composed of intermediate filaments. The medulla sits at the center of larger hairs, and specific keratins expressed in this layer of cells (see Table 86-2) are under the control of androgens.78

Dermal Papilla

The dermal papilla (see Fig. 86-1) is a core of mesenchymally derived tissue enveloped by the matrix epithelium. It is comprised of fibroblasts, collagen bundles, a mucopolysaccharide-rich stroma, nerve fibers, and a single capillary loop. It is continuous with the perifollicular sheath (dermal sheath) of connective tissue that envelops the lower follicle.

Tissue recombination experiments have shown that the dermal papilla has powerful inductive properties, including the ability to induce hair follicle formation when transplanted below nonhair-bearing footpad epidermis.76,79 This shows that the tissue patterning established during the fetal period can be altered under appropriate conditions. In human follicle, the volume of the dermal papilla correlates with the number of matrix cells and the resulting size of the hair shaft.80 In mice, sizes of the hair bulb and hair diameter strongly depend of the proliferative activity of the matrix keratinocytes.81

Many soluble growth factors that appear to act in a paracrine manner on the overlying epithelial matrix cells originate from the dermal papilla. Specifically, keratinocyte growth factor (KGF) is produced by the anagen dermal papilla, and its receptor, FGF receptor 2 (FGFR2), is found predominantly in the matrix keratinocytes. Injections of KGF into nude mice produce striking hair growth at the site of injection,82 suggesting that KGF is perhaps necessary for hair growth and cycling. However, surprisingly, KGF knockout mice develop morphologically normal hair follicles that produce “rough” or “greasy” hair; thus, KGF's effects on hair follicle morphogenesis and cycling appear dispensable or replaceable by other growth factors with redundant functions.83

Hair Follicle Innervation

Myelinated sensory nerve fibers run parallel to hair follicles, surrounding them and forming a network.84 Smaller nerve fibers form an outer circular layer, which is concentrated around the bulge of terminal follicles and the bulb of vellus follicles. Several different types of nerve endings, including free nerve endings, lanceolate nerve endings, Merkel cells, and pilo-Ruffini corpuscles are found around hair follicles.85 Each nerve ending detects different forces and stimuli. Free nerve endings transmit pain, lanceolate nerve endings detect acceleration, Merkel cells sense pressure, and pilo-Ruffini structures detect tension. Perifollicular nerves contain neuromediators and neuropeptides, such as substance P or calcitonin gene-related peptide, that influence follicular keratinocytes and alter hair follicle cycling.86–90 Conversely, hair follicle keratinocytes produce neurotrophic factors that influence perifollicular nerves and stimulate their remodeling in hair cycle-dependent manner.90,91 Merkel cells that are considered neuroendocrine cells also produce neurotrophic factors, cytokines, or other regulatory molecules. Because Merkel cells are concentrated in the bulge area, some have postulated that these secreted factors may influence the cycling of the hair follicle.92

Perifollicular Sheath

The perifollicular sheath envelops the epithelial components of the hair follicle and consists of an inner basement membrane called the hyaline or vitreous (glassy) membrane and an outer connective tissue sheath. The basement membrane of the follicle is continuous with the interfollicular basement membrane. It is most prominent around the outer root sheath at the bulb in anagen hairs. During catagen, the basement membrane thickens and then disintegrates.

Surrounding the basement membrane is a connective tissue sheath comprised primarily of type III collagen. Around the upper follicle, there is a thin connective tissue sheath continuous with the surrounding papillary dermis and arranged longitudinally. Around the lower follicle, the connective tissue sheath is more prominent, with an inner layer of collagen fibers that encircle the follicle surrounded by a layer of longitudinally arranged collagen fibers.66

When transplanted under the skin, this perifollicular connective tissue has the remarkable ability to form a new dermal papilla and induce new hair follicle formation.93 Even when the connective tissue sheath is transplanted to another individual, these follicles survive without evidence of immunologic rejection.

Each individual hair follicle perpetually traverses through three stages: (1) growth (anagen), (2) involution (catagen), and (3) rest (telogen).12 The length of anagen determines the final length of the hair and thus varies according to body site; catagen and telogen duration vary to a lesser extent depending on site. Scalp hair has the longest anagen of 2 years to more than 8 years. Anagen duration in young males at other sites is shorter: legs, 5–7 months; arms, 1.5–3.0 months; eyelashes, 1–6 months; and fingers, 1–3 months. In contrast to most mammals, including mice and newborn humans, in the adult human the hairs of the scalp grow asynchronously. Approximately 90%–93% of scalp follicles are in anagen and the rest primarily in telogen.94 Applying these figures to the 100,000–150,000 hairs on the scalp indicates that approximately 10,000 scalp hairs are in telogen at any given time. However, because we lose only 50–100 hairs per day, this indicates that telogen is a heterogenous state. The follicles that are shedding their hair shaft are thus in “exogen,” which comprises approximately 1% of the telogen hair follicles (see Fig. 86-2 and below). Hair on the scalp grows at a rate of 0.37–0.44 mm/day or approximately 1 cm/month.

Hair Follicle Stem Cells

Because the lower portion of the follicle cyclically regenerates, hair follicle stem cells were thought to govern this growth. Historically, hair follicle stem cells were assumed to reside exclusively in the “secondary germ” (see Fig. 86-2), which is located at the base of the telogen hair follicle. It was thought that the secondary germ moved downward to the hair bulb during anagen and provided new cells for production of the hair. At the end of anagen, the secondary germ was thought to move upward with the dermal papilla during catagen to come to rest at the base of the telogen follicle. This scenario of stem cell movement during follicle cycling was brought into question when a population of long-lived presumptive stem cells was identified in an area of the follicle surrounding the telogen club hair.95 Subsequently, it was shown that the secondary germ is a transient structure that forms at the end of catagen from cells in the lower bulge.96 The concept that hair follicle stem cells are permanently located in the bulge has now been confirmed using lineage analysis, which showed that the bulge cells give rise to all epithelial layers of the hair follicle.11,97,98 In line with this, ablation of bulge cells results in destruction of the follicle.96 These findings support the notion that loss of hair follicle stem cells in the bulge leads to permanent or cicatricial types of alopecia (see Chapter 88).

Progress has been made in defining subsets of cells within the hair follicle that serve as different stem and progenitor populations. Markers that have been shown through genetic lineage analysis to contribute to the perpetual cycling of the hair follicle, include cytokeratin 15 and Lgr5.96,99 Lgr5, although sometimes touted as an exclusive marker of secondary germ cells, also marks bulge cells. Lgr6, a gene related to Lgr5, is expressed in an area above the bulge in the upper isthmus. The cells marked by Lgr6 migrate to the epidermis during homeostasis and after wounding.100 In addition to these markers, several others demonstrate the heterogeneity of the hair follicle epithelium.101

Are bulge cells the “ultimate” stem cells within the skin epithelium? For example, do they generate epidermis and sebaceous glands during homeostasis and after wounding? To answer these questions, lineage analysis and transgenic techniques were again used. As illustrated in Fig. 86-3, bulge cells do not normally move to the epidermis, but after full-thickness excision of the skin, bulge cell progeny migrate into the wound during reepithelialization.11,96 These cells comprise approximately 30% of the cells in the regenerated epidermis. The role of bulge cells in sebaceous gland maintenance is still not clear, but is under investigation.

Anagen

The formation of a new lower follicle and hair at anagen onset recapitulates folliculogenesis in the fetus. Anagen can be divided into seven stages: (1) stage I—growth of the dermal papilla and onset of mitotic activity in the germ-like overlying epithelium; (2) stage II—bulb matrix cells envelop the dermal papilla and begin differentiation, evolving bulb begins descent along the fibrous streamer; (3) stage III—bulb matrix cells show differentiation into all follicular components; (4) stage IV—matrix melanocytes reactivate; (5) stage V—hair shaft emerges and dislodges telogen hair; (6) stage VI—new hair shaft emerges from skin surface; and (7) stage VII—stable growth.102

During proliferation and migration of keratinocytes into the dermis to reform the new lower follicle, enzymes such as proteases and collagenases appear at the leading edge of the downgrowth, and growth factors and their receptors are upregulated similar to an epithelial wound.12 Pathways of keratinocyte differentiation that are seen in the epidermis during wound healing, such as expression of keratin 6, are activated. Mice lacking Stat3, a regulator of cell migration in the cutaneous epithelium, show defects in wound healing and a failure of hair follicles to enter anagen,103 thus further illustrating the similarity between wound healing and the early events of anagen. Remarkably, the dermal papilla in the midst of this degradative milieu survives and moves downward. Neurocutaneous and vascular networks are remodeled.91,95 Melanocytes proliferate and repopulate the new hair bulb.104 Finally, a burst of endothelial proliferation and angiogenesis in the dermal papilla marks the time point when the lower follicle is completely restored and is actively producing the new hair shaft.105

Catagen

The onset of catagen is marked by cessation of the mitotic activity of the matrix cells and by well-coordinated apoptosis in the cyclic portion of the hair follicle.12,106 Pigment production by melanocytes ceases before matrix cell proliferation stops, thus leading to a nonpigmented proximal end in the telogen club hair (see Fig. 86-2). Melanin is often found in the surrounding dermis and papilla where it is engulfed by macrophages. The perifollicular sheath collapses, and the vitreous or glassy membrane thickens. The lower follicle retracts upward with the dermal papilla. The perifollicular sheath forms a fibrous streamer comprised of fibroblasts, small blood vessels, and collagen.1 Eventually, the dermal papilla becomes situated immediately below the bulge at the lower portion of the isthmus.

During catagen, the largest follicles, on the scalp for example, shorten their length from 2- to 5-mm-long structures whose deepest portion, the bulb, extends down into the subcutaneous fat to truncated 0.25- to 0.5-mm follicles in telogen. As the basement membrane around the lower follicle thickens, the dermal papilla, protected from the surrounding apoptosis and destruction (perhaps because it expresses Bcl-2, an antiapoptotic factor12) condenses and begins to move upward to come to rest below the bulge during telogen. The migration of the dermal papilla from the subcutaneous fat to the dermis during catagen is necessary for continued follicle cycling. This is illustrated by the syndrome of atrichia with papules.107,108 These patients have mutations in either their hairless gene or in their vitamin D receptor gene, in which case they also have rickets. Mice with similar mutations have the hairless phenotype. We know from these mice that folliculogenesis is normal; however, when the follicles enter catagen for the first time, the lower portion of the follicle does not involute and contract properly, and the dermal papilla remains stranded in the subcutaneous fat.95 Although bulge cells are still present, no new anagen follicles ever form, presumably because the stem cells cannot interact with the dermal papilla.95

The study of mouse mutants has also resulted in several key findings that have increased our understanding of the molecular events at catagen onset. Specifically, Hebert et al3 discovered that mice lacking the Fgf5 gene have hair that is 50% longer than their wild-type litter mates, and that mutations in this gene are responsible for the angora phenotype that was described more than 30 years ago. Although these findings were rather unexpected, careful evaluation of Fgf5 expression throughout the normal hair cycle demonstrated that its expression was upregulated in the outer root sheath and hair matrix cells just before the onset of catagen, suggesting that Fgf5 may trigger catagen onset. Interestingly, the follicle still eventually entered catagen, even in the absence of FGF-5, suggesting redundancy in the FGF-5 pathway or an intrinsic finite proliferative capability of the matrix cells.95 Further studies also demonstrated that other FGF family members and their receptors are expressed during anagen, and probably also play a role in the hair follicle cycle.109 The hair phenotype of FGF-5-deficient mice is substantially reversed by ectopic expression of the antiapoptotic gene bcl-xLx in the outer root sheath, suggesting that regulation of cell survival in the outer root sheath may play a role in control of the hair growth cycle.110

Although it has been known for many years that exogenous EGF administered to sheep results in catagen induction,111 only through more recent transgenic and knockout studies in mice has the importance of the EGFR system in hair cycle regulation been realized.70,112 For example, knockout mice lacking transforming growth factor-α (TGF-α), the major ligand for EGFR, have abnormal hair follicle development and manifest the waved hair phenotype.4,5 When EGFR is functionally downregulated in the basal layer of the epidermis and hair follicle using a dominant negative transgenic strategy, the resulting hair is not only waved, but also longer than normal.70 The transition of the hair follicles from anagen to catagen is delayed in these mice. Hair follicles in mouse skin that completely lack EGFR also do not progress from anagen to telogen.112 Thus, EGFR and its ligand are required for normal hair follicle development and cycling. Given the complexity of the EGFR family, which includes four receptors (ErbB1–4) and at least six ligands, future studies are needed to clarify the role of individual family members in hair follicle cycling.113

In addition to FGF-5 and EGF, neurotrophins and TGF-β1 induce premature catagen. Neurotrophin-3 and brain-derived neurotrophic factor transgenic mice show premature catagen development, and brain-derived neurotrophic factor overexpression leads to the shortening of hair length by 15%, most likely via stimulation of proapoptotic signaling through p75 kDa neurotrophin receptor.114,115 TGF-β1 induces premature catagen in isolated human hair follicles and in mouse skin in vivo, and TGF-β1 knockout mice display delay in catagen onset.116–118

Telogen and Exogen

Once the involution of catagen is complete and a club hair is formed (see Fig. 86-2), the hair follicle prepares the hair for expulsion from the scalp. About 1% of telogen follicles are shed each day. Milner et al119 have proposed distinguishing hair shedding as a separate phase called exogen. Exogen is a highly controlled and timed event in mammals that shed on a seasonal basis. That exogen is an active stage is supported by Headington's description of one type of telogen effluvium he termed immediate telogen release.120 This type of hair loss can be seen soon after starting medications, such as minoxidil, or in response to rapid fluctuations in light/dark cycles. It consists of an increase in shedding of club hairs within weeks of the precipitating event (too soon to be caused by follicles prematurely entering telogen from anagen), suggesting that club hairs that are normally retained in the follicle can be actively shed. The heterogeneity of telogen is further supported by the work of Guarrera and Rebora,121 who followed individual hairs in situ using macrophotographs for more than 2 years and showed that several months could transpire between hair shedding and regrowth. This “lag period” is normally not present or is very short, but often lasts several months in patients with androgenetic alopecia.

Hair becomes pigmented as a result of a tightly coordinated program of melanin synthesis and transport from the hair bulb melanocytes to differentiating hair shaft keratinocytes.122–124 This process is strictly coupled to anagen and ceases during catagen and telogen. Numerous signaling molecules, structural proteins, enzymes, cofactors, and transcriptional regulators control hair pigmentation (Figs. 86-4 and 86-5).122,124,125

Hair Melanocyte Development

Melanoblasts can be identified in the epidermis of human embryos at 50 days of estimated gestational age before the onset of hair follicle morphogenesis.126–128 These follicular melanocytes originate in the neural crest and migrate first to the dermis and then epidermis.129 New data reveal that melanocytes in the skin arise from two sources: from neural crest cells migrating in the dorsolateral pathway and from Schwann cell progenitors located in cutaneous nerves.129a Commitment of neural crest cells to the melanocyte lineage is regulated by Pax3 and microphthalmia transcription factors (Mitf), which stimulate the expression of dopachrome tautomerase [or tyrosinase-related protein 2 (Trp2)], an enzyme involved in melanin biosynthesis that also functions as an early melanoblast marker.128 Subsequent steps of melanoblast development (migration into the dermis and epidermis) are controlled by signaling mechanisms activated through endothelin receptor type B and c-kit oncogene (c-kit) receptor, which are mutated in humans with Hirschprung disease and piebaldism, respectively, resulting in formation of unpigmented hairs129 (see also Chapter 72).

After entering the placode of the developing hair follicle, melanoblasts proliferate and become melanogenically active synchronously with the onset of hair fiber formation.130 Experimental and genetic data suggest that migration of melanoblasts into the hair follicle and their development toward melanogenically active forms depend on stem cell factor (SCF)/c-kit signaling. SCF is a ligand that binds to its receptor, c-kit. Pharmacologic blockade of c-kit during embryogenesis, as well as genetic ablation of SCF or c-kit in corresponding mouse mutants results in unpigmented hairs.131–133

Hair Follicle Melanocyte Stem Cells and Pigment-Producing Melanocytes

MSCs located in the hair follicle bulge generate progeny that repopulate the melanocytes in the new hair bulb formed at the onset of anagen.103,134 MSCs express Trp2, Bcl-2, Pax3, while other melanogenic enzymes (tyrosinase, Trp1) and signaling molecules (c-kit, endothelin receptor type B, SOX10, Mitf and Lef-1)135 are expressed at low levels. MSCs can be first detected in the bulge area during late stages of hair follicle morphogenesis and similarly to epithelial stem cells they are quiescent.134–136 TGF-β signaling plays an important role in controlling MSCs entering into a noncycling (dormant) state during hair follicle (HF) morphogenesis.137

Maintenance of MSCs during hair follicle cycling is controlled by TGF-β and Notch-signaling pathways. Notch signaling plays a crucial role in the survival of melanocyte stem cells and immature melanoblasts by preventing apoptosis.138 Crosstalk between the TGF-β pathway and Bcl2 is also important for maintenance of MSCs, and Bcl2 knockout mice show progressive hair graying due to their depletion.135–138 Bcl-2 plays a key role in maintenance of MSCs, and Bcl-2 knockout mice show progressive hair graying due to the depletion of MSCs.139–141 However, Bcl-2 deficiency may be compensated by overexpression of SCF, which rescues loss of MSCs in the hair follicle bulge of Bcl-2 knockout mice.135

Melanogenically active melanocytes are located in the hair bulb above the dermal papilla.104,124 These cells synthesize and transport melanin to hair shaft keratinocytes and express a full set of enzymes and other proteins involved in melanin biosynthesis including tyrosinase, Trp1, Trp2 (in mice), and pMel17 (in humans).105,135 Keratinocytes, as pigment recipient cells, produce Foxn1 and its target Fgf2 to identify themselves as the targets for pigment transfer.142

Hair Cycle-Dependent Changes in Melanocytes

Hair follicle melanocytes undergo substantial remodeling during hair follicle cycling.104,124 In telogen, hair follicle melanocytes are found in the bulge, secondary hair germ, and connective tissue.104 In humans, melanocytes in the telogen hair follicle do not express Trp1 or tyrosinase and do not proliferate. Melanocytes can be visualized by expression of pMel17.141 Some of these cells also express c-kit receptor, whereas others remain c-kit-negative and represent MSCs.104,134,135 TGF-β signaling is activated in MSCs when they reenter the quiescent noncycling state during the hair cycle and this process requires Bcl2 for cell survival.137

During early anagen, resting melanocytes proliferate, differentiate, and migrate within the hair follicle synchronously with regeneration of the hair follicle bulb. Hair follicle melanocytes are maximally proliferative during early and midanagen, and their transition to melanogenic competence is accompanied by the appearance of Trp1 and tyrosinase proteins.104,143 However, this process is stringently controlled, and Notch signaling is necessary to prevent differentiation of melanoblasts into pigment-producing melanocytes before they reach the hair bulb, as well as for their proper positioning in the hair matrix.144

Similar to embryonic and early postnatal development, SCF/c-kit signaling plays a critical role in repopulation of the bulb with pigment-producing melanocytes. C-kit is expressed on proliferating, differentiating, and melanogenically active melanocytes, whereas overexpression of SCF in the epidermis of transgenic mice significantly increases the number of hair follicle melanocytes and their proliferative activity.104 Similarly, administration of the ACK45 antibody blocking c-kit signaling dramatically reduces melanocyte number in anagen hair follicles, resulting in hair depigmentation.104 However, in the next hair cycle, the previously treated animals grow fully pigmented hairs with the normal number and distribution of melanocytes, suggesting that MSCs are not dependent on SCF/c-kit.104

During catagen, melanogenic activity in the follicular melanocytes abruptly ceases. Immunohistochemical and electron microscopic data suggest that some pigment-producing melanocytes located above the follicular papilla undergo apoptosis, while others drop into the dermal papilla of the follicle and migrate into the dermis.145,146

Molecular Control of Hair Color

Follicular melanocytes synthesize pigment via a cascade of enzymatic conversions of phenylalanine or tyrosine into brown–black eumelanin or yellow pheomelanin that requires melanogenic enzymes (tyrosinase, Trp1/2, γ-glutamyl transpeptidase, peroxidase) and essential cofactors, such as 6-tetrahydrobiopterin.122 The balance between black and yellow pigment synthesis (eumelanin and pheomelanin, respectively) is regulated by signaling through the melanocortin type 1 receptor (MC-1R) that has long been implicated in the control of hair color.147,148 (See Chapter 72.)

After binding to MC-1R, α melanocyte-stimulating hormone (α-MSH) stimulates adenylyl cyclase, resulting in elevation of intracellular cyclic adenosine monophosphate levels. This leads to increase of transcriptional activity of Mitf that stimulates synthesis of melanogenic enzymes (tyrosinase, Trp1/2) involved in eumelanin formation.149,150 Pheomelanin synthesis in the hair follicle melanocytes of mice occurs when MC-1R signaling is inhibited by Agouti signal protein (ASP) that competes with α-MSH in binding to MC-1R.148,149 In mice, ASP expression is positively regulated by BMP signaling, and transgenic mice overexpressing BMP antagonist Noggin show hair darkening.151 Although ASP is expressed in human skin, its role in human pigmentation remains unclear.150

Recent data also demonstrate existence of fully functional proopiomelanocortin/MC-1R system in human hair follicles: MC-1R is expressed by hair follicle melanocytes, whereas its ligands α-MSH and adrenocorticotropic hormone are able to promote proliferation, dentricity, and melanogenesis.152 Similar effects are seen with another proopiomelanocortin-derived peptide, β-endorphin that interacts with μ-opiate receptor expressed by hair follicle melanocytes.152 However, signaling through the μ-opiate receptor may regulate hair pigmentation via modulating the activity of protein kinase C-β, a known positive regulator of melanogenesis.153

Follicular melanocytes are sensitive to aging, which results in their premature loss and hair graying.154 In contrast to normally pigmented hair follicles, fewer melanocytes are found in the bulbs of gray hairs; however, these melanocytes still express tyrosinase, synthesize and transfer melanin to keratinocytes.146 In addition, a population of melanogenically inactive melanocytes (melanoblasts including stem cells) in the outer root sheath is markedly reduced in the follicles producing gray hairs compared to pigmented follicles (Commo et al, 2004). The fact that MSCs are damaged in hair follicles producing gray hairs was confirmed in mice by applying ionizing radiation, which triggered premature differentiation of MSCs in the follicular bulge into mature, pigment-producing melanocytes followed by their depletion and irreversible hair graying.155 Deficiency of ATM-kinase, a central transducer of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating its role in protecting MSCs from their premature differentiation.155

However, hair graying is also mediated by H2O2-induced oxidative damage in the entire hair follicle including the hair shaft, which does not exclusively affect follicle melanocytes, thus suggesting that accumulation of hydrogen peroxide in both keratinocytes and melanocytes is one of the critical factors that underlie biochemical changes in the follicular pigmentary unit of graying hairs.156

The hair follicle is formed as the result of a complex interplay of signals between epithelium and mesenchyme. The nature of these signals is just now being elucidated, with many molecular pathways important in development also playing roles in hair follicle formation. The product of this process is a miniature organ with distinctive vertical and concentric divisions. Both epithelial stem cells and MSCs in the follicle are important for the constant regeneration of the follicle.

Follicular keratosis refers to orthokeratosis involving the follicular ostium and infundibulum. Horny plugs protrude from the orifices, producing a rough sensation on palpation of the skin. It may be isolated [keratosis pilaris (KP)] or associated with other pathologic processes, including follicular inflammation, atrophy, scarring, and alopecia [keratosis pilaris atrophicans (KPA)]. These are reaction patterns that occur alone or as part of a wide variety of syndromes.

Typical KP is a common condition of keratotic follicular plugging with varying degrees of surrounding erythema. Sometimes, the erythema is so striking that it is the main complaint. The clinical expression of KP varies from subtle to conspicuous, which, along with possible racial differences, may explain the great range of reported prevalences, from 1% to 42%.1–4 It involves most commonly the extensor aspects of the upper arms (Fig. 87-1) and thighs as well as the face but may rarely be more extensive, extending to the distal limbs and the trunk. There seem to be two patterns. In early childhood, the face and arms are mainly affected and gradual improvement is seen in most cases by later childhood or adolescence. In the other pattern, the onset is in teenage years, and the extensor arms and legs are predominantly involved. It usually improves by the mid-20s. However, in both patterns, the condition may be persistent into later adult life.5 The histopathologic pattern in skin biopsy specimens is nonspecific, simply showing the follicular orifice distended by a keratin plug.

Treatment is usually with various keratolytics, from simple urea, lactic acid, or salicylic acid preparations to topical retinoids and tazarotene.6,7 These preparations may aggravate associated erythema, limiting their value.

Associations of Keratosis Pilaris

Clinical ichthyosis vulgaris (see Chapter 49) is associated with KP8; in one series KP was found in 74.3% of patients (Fig. 87-1).2 Other conditions in which KP is more prevalent or more prominent are atopic disorders, hypothyroidism, Cushing syndrome, insulin dependent diabetes, obesity or high body mass index, and Down syndrome.9 Follicular keratosis, which may simulate KP, can occur in several nutritional deficiencies, although vitamin A deficiency is most commonly cited (see Chapter 130).10

Erythromelanosis Follicularis Faciei et Colli

Erythromelanosis follicularis faciei et colli (EEFC) is a condition probably related to KP.11 The suffix “colli” refers to the neck. EEFC It is seen primarily in adolescents and young adults, most commonly in males. Well-demarcated erythema, hyperpigmentation, and follicular papules involve the preauricular and maxillary areas, usually in a symmetric distribution, with spread in some cases to the temples and sides of the neck and trunk. Atrophy is not a feature. Histopathology is nonspecific, demonstrating a variable degree of follicular hyperkeratosis, dilation of upper dermal vessels, some perivascular inflammatory infiltrate, and hyperpigmentation of the basal layer. There are few reports of EEFC in the literature, however it may be underreported.

Keratosis Pilaris Rubra

Although erythema is often present in typical KP, it is usually mild and limited to the perifollicular skin. When perifollicular erythema is more noticeable, the disorder has been called keratosis pilaris rubra (KPR) or less commonly keratosis follicularis rubra.12 These findings are usually limited to the cheeks, forehead, and neck (Fig. 87-2). Features that differentiate EFFC from KPR are a lack of reported involvement on the torso and the presence of hyperpigmentation. However the hyperpigmentation noted in EFFC may, at least in part, be related to skin pigmentation type, with darker skin types showing more evidence of hyperpigmentation. Thus it is likely that KPR and EFFC are variants of the same clinical spectrum.

The general term keratosis pilaris atrophicans is a group of rare genodermatoses in which the clinical hallmarks is follicular keratosis with variable degrees of inflammation, and secondary atrophic scarring and/or alopecia.13–15 Three distinct clinical entities that fall under the umbrella of keratosis pilaris atrophicans include ulerythema ophryogenes [UO or keratosis pilaris atrophicans faciei (KPAF)], atrophoderma vermiculatum, and keratosis follicularis spinulosa decalvans (KFSD).

Ulerythema Ophryogenes (Keratosis Pilaris Rubra Atrophicans Faciei)

The prefix ‘ophryo-’ refers to the eyebrow. UO is a form of KPA affecting particularly and initially the eyebrow areas, in some cases extending later to the cheeks and forehead.13 Scalp and eyelash hair is normal. The onset is within months of birth, with erythema and small keratotic follicular papules involving the lateral one-third of the eyebrows. It may slowly progress through childhood to involve more of the eyebrows and sometimes beyond, leading to alopecia (Fig. 87-3). Progression usually ceases after puberty but the sequelae are permanent. The condition is frequently associated with standard KP that may involve the arms and legs or may be more generalized. The term keratosis pilaris rubra atrophicans faciei is used interchangeably with UO, however some prefer this diagnosis for patients in whom the initial erythema starts on the cheeks as opposed to the eyebrows.

Most cases have followed an autosomal dominant inheritance pattern, with incomplete penetrance.13 Response to topical corticosteroids, topical retinoids, and keratolytics has been poor. There is one report of a good response to several months’ therapy with oral isotretinoin, with lessening of the horny plugs and the erythema.16 The improvement was maintained for some months after therapy had ceased. Some improvement in erythema was reported with the pulsed tunable dye laser at 585 nm, but the follicular plugging was unchanged.17

Syndromes Associated with Ulerythema Ophryogenes

UO has been reported in association with isolated woolly hair,18,19 Noonan syndrome,19,20 cardiofaciocutaneous (CFC) syndrome,21,22 Rubenstein–Taybi syndrome,23 Cornelia de Lange syndrome,24 and 18p deletion.25,26 CFC and Noonan syndrome have overlapping clinical features, and both have mutations in genes of the Ras pathways.27,28 In CFC, mutations have been described in BRAF, KRAS, MEK1, and MEK2 genes.27 Whereas in Noonan syndrome, there is primarily mutations of PTPN11, but also KRAS and SOS1 genes.29,30

Follicular keratosis in Noonan syndrome, if present, is usually limited to the face (Fig. 87-3B) and resembles UO with loss of eyebrow hairs.19,20 In CFC syndrome, follicular keratosis is often much more extensive, and there may be striking alopecia involving the scalp.22 The remaining scalp hair in CFC syndrome is brittle and curly.

Atrophoderma Vermiculatum (Folliculitis Ulerythematosa Reticulata)

AV is a form of KPA in which the cheeks are predominantly involved, with follicular plugs and pit-like depressions up to 1.5 mm in diameter and a background of erythema. Alopecia and follicular papules are not features of the condition,22,31 but sparse open and closed comedones and milia may be found.32 The depressions merge into each other, producing a “worm-eaten,” “honeycombed,” or reticular appearance (Fig. 87-4). Involvement of the forehead, arm, and leg, as well as the typical cheek area, has been described.14 However, in general, it is rare for the condition to involve the limbs, and eyebrow involvement does not occur. Standard KP of the extensor aspects of arms and legs is a common associated finding.31 Unlike the other KPA disorders in which the onset is in infancy, AV usually starts in childhood, between 5 and 12 years old, although later onset has been described14; the course is usually one of inexorable worsening. The condition is often sporadic but, in some cases, appears to be inherited as an autosomal dominant trait.33 Several more or less linear unilateral cases have been described,34 suggesting a possible mosaic form of the condition.35 However, it is possible that at least some of these cases may represent examples of nevus comedonicus.35

Histopathologic evaluation demonstrates atrophic pilosebaceous units with mild perifollicular and perivascular inflammation. The follicular orifices are dilated and filled with keratin plugs. Numerous dermal horn cysts may be found. There is perifollicular fibrosis and a decrease in elastic fibers in the dermis.31,36

Therapy is uniformly unsuccessful and has included topical steroids, topical retinoids, cryotherapy, and derm-abrasion. Favorable results have also been described with carbon dioxide laser in a case in which atrophy was prominent, and pulsed dye laser in a case with a marked erythematous component.32 Oral isotretinoin suppressed the inflammation in one patient.37

Syndromes Associated with Follicular Atrophoderma

Follicular atrophoderma occurs as a feature of several rare syndromes38–43 and in nevus comedonicus (Table 87-1).44 As such, these conditions may come into the differential diagnosis of atrophoderma vermiculatum.

Keratosis Follicularis Spinulosa Decalvans

The term KFSD was first used by Siemens in 1926 who described a scarring follicular condition in 20 members of a large family.45 The condition begins in infancy with noninflammatory, flesh-colored, spiny lesions affecting hair-bearing areas, especially the scalp (Fig. 87-5) and later eyebrows, eyelashes, and the dorsal of the hands and fingers. Sometimes, more proximal limbs and even the trunk become involved.45–47 An associated plantar keratoderma may occur, especially over the heels.15 By puberty, many of the follicular spines have disappeared and are replaced by atrophy. Scarring alopecia of scalp (see Fig. 87-5), eyebrows, and eyelashes becomes apparent in childhood and progresses till puberty. It is often patchy and is rarely total. Facial lanugo hair is absent, and axillary and pubic hair is often thinned.

Photophobia is seen in many patients, and punctate corneal epithelial defects have been seen in some.47 It is unclear whether there is a primary epithelial defect or whether the corneal changes occur as a result of irritation from distorted remnant lashes and keratotic plugs in eyelash follicles. There are rare reports of other ophthalmologic abnormalities, including cataract and retinal detachment.48

Biopsy specimens show follicular based hyperkeratosis, perifollicular and dermal inflammation, fibrosis, and distorted follicles at different stages of the condition.46 Family studies suggest an X-linked dominant inheritance pattern,45,47–49 with men often more severely affected than women. A mutation in the gene encoding spermidine/spermine N(1)-acetyltransferase (SSAT) has been noted in these patients and has been localized to Xp22.13-p22.2.50 However clinical heterogeneity is likely as there have been identification of pedigrees unlinked to this region as well as rare instances of male to male transmission suggesting an autosomal dominant form.51,52 In the differential diagnosis of KFSD is ichthyosis follicularis with alopecia and photophobia (IFAP) syndrome [see Section “Ichthyosis Follicularis, Alopecia (Atrichia), and Photophobia Syndrome”].53 However, features in KFSD not shared by IFAP are involvement of the fingers, late atrophy, and scarring of involved follicles, and the development in some patients of a red–brown telangiectatic pigmentation of cheeks and brows.

In general, treatment of KFSD is unsatisfactory; however, there are isolated reports of improvement in photophobia with oral vitamin A,47 as well as conflicting reports on the results of dapsone,51,54 and oral retinoids.46,55,56

Folliculitis Spinulosa Decalvans

A variant of KFSD has been called folliculitis spinulosa decalvans (acknowledging that this name may lead to confusion with the separate entity of folliculitis decalvans).15,57 This variant is characterized by persistent pustule formation, especially on the scalp. Unlike the typical variant of KFSD, there is more severe inflammation, and it is progressive, rather than stable or remitting after puberty. In addition, the inheritance appears to be autosomal dominant rather than X-linked recessive. Treatment response to isotretinoin has been unsuccessful.57

Apart from the conditions described in the preceding sections in association with UO, there are other conditions that have follicular keratosis as a significant feature (Table 87-2).

Monilethrix

(See Chapter 88)

Monilethrix is an autosomal dominant condition producing a beaded appearance of the hair.58 Mutations in the human basic hair trichocyte keratins K81, K83, and K86 (formerly hHb1, hHb3, and hHb6, respectively) have been reported.59–61 However, the failure to demonstrate these mutations in one family suggests the possibility of genetic heterogeneity.62 A striking follicular keratosis is associated in some pedigrees and may involve the scalp (Fig. 87-6), face, and limbs. Nail onychodystrophy or koilonychia are also variably reported. Genotype/phenotype correlation is not obvious in reported cases in which mutations have been identified.63,64 The clinical phenotype of autosomal recessive hypotrichosis resembles that of monilethrix. In these patients, there is a defect of the desmoglein 4 gene, which belongs to the desmosomal cadherin superfamily and is also expressed in the cortex of the hair follicle.65–67

Keratosis Pilaris and Hereditary Koilonychia

A family has been described with koilonychia and widespread KP, involving all areas of trunk and limbs. Affected family members also showed eyebrow involvement with alopecia, simulating UO/KPAF.68 The inheritance pattern appeared to be autosomal dominant. Unlike previous cases, there was no monilethrix in this pedigree.

Keratitis, Ichthyosis, and Deafness Syndrome

(See Chapter 49)

Widespread spiny follicular keratosis is a striking feature of keratitis, ichthyosis, and deafness syndrome, a connexin/gap-junction disorder. This autosomal dominant disorder is also characterized by alopecia of scalp, body, eyebrow, and eyelash hair, vascularizing keratitis, and a profound sensorineural hearing loss.69

Hereditary Mucoepithelial Dysplasia

The characteristic features of hereditary mucoepithelial dysplasia (HMD) are follicular keratosis, nonscarring alopecia with some coarse abnormal hairs remaining, fiery-red palatal and gingival mucosae, photophobia with demonstrable keratitis and corneal vascularization, and psoriasiform hyperkeratotic lesions in the perineal area and often also on the extensor limbs.70–72 The condition occurs in both sexes, and family studies suggest both autosomal dominant and autosomal recessive patterns of inheritance may be possible. Light microscopic evaluation of skin and mucosae shows dyskeratotic cells in the spinous layer, vacuolated basal cells, and lack of epithelial maturation.70,72 Electron microscopy shows paucity of desmosomes, cytoplasmic vacuolization, and presence of multilaminar bands and wheat sheaf-like collections of filamentous fibers in the cytoplasm, resembling gap-junction material, and suggesting a disorder of desmosomal or gap junction proteins.72 However, subsequent studies of several characteristic cases in one pedigree found normal expression of gap junction proteins (connexins 26, 32, and 43), desmosomal proteins (desmogleins 1 and 2, plakoglobin, desmoplakins I and II, and plakophilin 1), adherens junction proteins (β-catenin and E-cadherin), and cytoskeleton proteins (keratins, β-tubulin, vimentin, and actin).70 Genetic analysis in the studied family excluded the desmosomal cadherins in chromosome 18q12 as candidate genes and ruled out a mutation in connexin 26.70

Ichthyosis Follicularis, Alopecia (Atrichia), and Photophobia Syndrome

The association of ichthyosis follicularis, alopecia, and photophobia was first reported as a syndrome by McLeod in 1909,73 and for many years additional reported cases of what came to be designated IFAP syndrome occurred in males. Affected individuals demonstrate widespread, flesh-colored, spiny, follicular projections with minimal, if any, inflammation (except for inflammatory palmoplantar keratoderma with advancing age), severe alopecia, often total atrichia involving eyebrows and lashes as well as scalp hair, and severe photophobia, often with demonstrable corneal vascularization.53,74–76 The condition was postulated to be inherited as an X-linked recessive trait, which is supported by the report of the mother and sister of a male patient with classical features of IFAP syndrome having linear lesions of hyperkeratosis, hypohidrosis, and atrophy and a patchy scalp alopecia, distributed along Blaschko's lines.77 Recently, the gene defect has been mapped to Xp22.11-p22.13 and a missense mutation of the gene, MBTPS2, which codes for an intramembrane zinc metalloprotease, has been identified.78 This gene is essential for cholesterol homeostasis and endoplasmic reticulum stress response.

Patients may have only cutaneous features, but neurologic and skeletal anomalies and recurrent infections have occasionally been described.44,79–82 Atypical cases have included females with generalized involvement and transmission from mother to daughter83,84–86; psoriasiform patches,80,85,86 particularly involving the perineal area; and hypotrichosis rather than complete atrichia.86 Some patients with psoriasiform plaques lack the typical spiny follicular projections80,81 and may represent a different entity,76 or even a variant of HMD.86 In support of the latter is the ultrastructural finding of reduced numbers of desmosomes in one patient with IFAP and psoriatic lesions, analogous to what is seen in HMD.85 Patients with documented mutations in MBTPS2, have reportedly had spiny follicular projections during infancy, and the later progressive development of psoriasiform plaques. Treatment of IFAP is usually unsatisfactory, but there are reports of temporary flattening of the follicular keratotic papules and plaques and regrowth of eyelashes with oral acitretin.87,88

The importance of human hair in view of social communication and sexual attraction is enormous. Thus, diseases that lead to hair loss (alopecia), structural hair shaft defects or excessive hair growth on the body are often accompanied by diminished sense of personal well-being and self-esteem, leading to depressive moods and withdrawal from social interims.

In this chapter, we discuss the biologic basis and clinical presentation of hair growth disorders, give definitions (eTable 88-0.1), explain key management principles, and provide practical advice for diagnosis, therapy and patient management.

Two frequently applied terms of alopecia and effluvium need to be characterized. While effluvium typifies the process of hair shedding, alopecia characterizes the final result of this. Both terms are nonspecific; they do not give etiological information of the underlying hair loss (see eTable 88-0.1).

Disorders that result in alopecia can be grouped into diffuse, patterned and focal hair loss as well as into scarring (synonym: cicatricial) and nonscarring forms. Scarring forms are characterized by permanent destruction of hair follicular stem cell structure resulting in loss of hair producing capabilities. In contrast, in nonscarring alopecia the hair follicle is not ultimately destroyed and subsequent hair regrowth follows periods of hair shedding. In both, scarring and non scarring alopecia, distribution of hair loss can occur in a diffuse pattern over the whole scalp or be circumscribed, affecting only a few, more or less demarcated areas. Alopecia can also be due to improper or missing follicle development. These rare inherited hair abnormalities can be focal (e.g., aplasia cutis congenita, see Chapter 107) or diffuse (e.g., ectodermal dysplasia, see Chapter 142).

Hair growth disorders caused by structural hair shaft defects can be acquired or inherited. While acquired hair shaft defect are accompanied by increased hair breakage and are usually due to hair grooming practices, inherited hair shaft defects can be grouped into disorders with or without increased hair breakage. Acquired hair shaft disorders are reversible when trigger factors are stopped. Inherited hair shaft disorders cannot be cured, but tend to improve as the patient ages.

(See Chapter 86)

Clinically Relevant Hair Biology

History

A thorough patient history is critical for the development of an initial differential diagnosis and for the relationship with the patient. The patient should be asked about the duration and pattern of the hair problem. Was the problem present at birth, did it evolve gradually over time starting at a certain age or was there a rapid onset? A hair problem that is present at birth leads more to a genetic disorder; certain conditions are more common in children, such as tinea capitis, alopecia areata, or trichotillomania. For example, a rapid onset of hirsutism can lead to the diagnosis of an androgen-secreting tumor. A gradual thinning of fronto-parietal scalp hair fits more to the diagnosis of androgenetic alopecia (AGA) (see eTable 88-0.2). Patients with hair loss should be asked if the hair is shedding or thinning and if the hair is coming out “by the root” or if it is breaking off. A patient history includes the family history as well as questions about current and past medication, pregnancy, menses, menopause, thyroid function, diet, past and present health, surgeries, accidents, physical or emotional stress events and hair care practices.

Global Assessment and Imaging

The global examination of the scalp should first of all assess the overall pattern of the hair problem. It is important to determine density and distribution and if the hair loss is focal or global. Furthermore, the presence of scaling, erythema, erosions, crust or pustules and the presences or absence of follicular ostia should be noted. The clinical examination should also involve the nails, since some disorders, for example alopecia areata, lichen planopilaris (LPP), or ectodermal dysplasia can also affect finger and toe nails. Excessive body hair is oftentimes shaved or epilated. The extent of unwanted terminal hair growth can be evaluated by a patient self-assessment with the help of images (see Section “Hirsutism”).

Pull Test

The pull test is a useful ancillary, qualitative test for the assessment of the ongoing activity of hair loss. The examiner grasps approximately 50–60 hairs and tugs at them from proximal to distal end. Removal of six hairs indicates a positive pull test and active shedding. However, the test can be considered positive if three hairs can be pulled out in several different areas of the scalp. The proximal ends can be examined against a white (for dark hair) or black (for light hair) background. A blunt tip indicates hair breakage; a tapered tip can indicate regrowth or miniaturized hairs. The proximal end of the hair shafts may also be examined with a light microscope to determine, if the hairs break off (blunt ends) or came out as club hairs (telogen hair).

Biopsy

A scalp biopsy is necessary, particularly when confirming the diagnosis of scarring alopecia. A scalp biopsy should also be considered for the differential diagnosis of TE, diffuse alopecia areata and AGA. The following recommendations were developed at the consensus meeting on cicatricial alopecia in February 2001: one 4-mm punch biopsy including subcutaneous tissue should be taken from a clinically active area, processed for horizontal sections and stained with hematoxylin and eosin. Elastin (acid alcoholic orcein), mucin, and periodic acid-Schiff (PAS) stains may provide additional information. A second 4-mm punch biopsy from a clinically active disease affected area should be cut vertically into two equal pieces. One-half provides tissue for transversely cut routine histological sections; the other half can be used for direct immunofluorescence (DIF) studies.1,27 Usually only one biopsy from the affected area is necessary for the diagnosis of a nonscarring alopecia; the samples are preferably processed with horizontal sections.

Trichogram

This technique is a simple method of quantifying hair loss by comparing the proportion of anagen to catagen and telogen hairs. For accurate measurement, patients should avoid washing their hair 3–4 days prior the test. Also perms, dyes, or straightening of hair can alter results and have to be avoided at least 6 weeks prior. A group of about 25–50 hairs should be grasped with a needle holder close to the scalp and plucked sharply in the direction of the hair. The proximal ends of the hair shafts are place on a glass slide in a drop of water and covered with a cover slip. Alternatively, a solution of 1% dimethylcinnamaldehyde in 0.5 N hydrochloric acid can be used, which stains the anagen hairs red due to the presence of protein bound citrulline in the inner root sheath. The roots are than examined by light microscopy with 100-fold magnification. Ten to twenty percent of telogen hair can be regarded as normal (the percentage of anagen hairs is slightly higher in women and children compared to men); a telogen count over 35% is highly suspicious for a TE. By repeating the trichogram over a time period, a hair loss condition can be followed and treatment results can be measured28 (Fig. 88-1).

Investigation of plucked hairs for spores allows establishing the diagnosis of tinea capitis. In this case the hair should be mounted in 5% potassium hydroxide and gently heated.

Phototrichogram

Videodermoscopy

AGA or pattern hair loss is by far the most common type of hair loss in men and women. Male pattern hair loss (MPHL) (also known as male AGA, male balding) is an androgen-dependent, genetically determined trait. Female pattern hair loss (FPHL) (or female androgenetic alopecia) is believed to be the same entity. However, the requirement of androgens is less clear-cut than in men and the distribution of hair loss is generally different.35,36 In both, men and women, AGA is characterized by a progressive decline in the duration of anagen, an increase in the duration of telogen and miniaturization of scalp hair follicles.

Men

Estimates of the prevalence of AGA vary widely. Most men will develop some degree of recession of the hairline during their lifetime. A progression to at least type III (see Fig. 88-2) is seen in around 50% of men and women beyond 40 years of age.37–40,41 The risk of male pattern baldness depends on the family history in the father, the mother, or the maternal grandfather.42,43 Men whose father had hair loss were twice as likely to have hair loss as men whose father showed no hair loss.

Ethnic variation in the incidence of AGA has been reported. AGA seems to be four times less frequent in men of African ancestry,44 around three times less frequent in Korean men45 and approximately 1.5 times less frequent in men originating form China, Japan or Thailand.46,47

Women

FPHL is less common than MPHL but shows a similar age-related increase in frequency and severity. However, the condition can start as early as the prepubertal period both in men and women (Fig. 88-3). Around 40% of Caucasian women have developed some degree of FPHL at age 70.35,48 FPHL seems to be less frequent in Asian women.45

The underlying causes of patterned hair loss have yet to be determined. In men, MPHL appears to result from a combination of androgen hyperactivity, a genetic predisposition to hair loss-related sensitivity to androgen action as well as an androgen-independent genetic predisposition. For females, the condition known as female pattern hair loss (FPHL) may have a more complex etiology. However, androgen action combined with genetic sensitivity to those actions seems to play a dominant role in most cases, and indeed these factors may be present generally in FPHL.

In AGA, large, pigmented hairs, called terminal hairs, are gradually replaced by fine (nearly invisible) colorless vellus hairs.1,39 This transformation follows a progressive course with each hair cycle in the following manner. Scalp hair develops in three phases40,49: (1) a growth phase, or anagen, of approximately 2–6 years; (2) a short (2–3 weeks) phase, catagen, which actually represents the termination of anagen; and (3) transition to the telogen phase. A telogen hair does not grow and is shed from the follicle after about 12 weeks. The transition to catagen results in decreased levels of anagen-maintaining cytokines within the hair follicle. MPHL and FPHL exhibit a progressive decrease in anagen duration with each cycle, producing shorter, thinner hairs.38 Finally, the interval between late telogen hair shedding (exogen) and new hair growth with initiation of anagen increases, resulting in more follicles without hair and an apparent reduction in scalp hair density.37

The Role of Androgens in Male Pattern Hair Loss

The Role of Androgens in Female Pattern Hair Loss

Genetic Factors in Men

Genetic Factors in Women

Clinical Findings

The identification of AGA is usually not difficult if the alopecia occurs in a classical clinical pattern. In 1951, Hamilton produced the first grading scale for MPHL. The Hamilton scale ranges from type I to VIII. Whereas type I represents the prepubertal scalp with terminal hair growth on the forehead and all over the scalp, type II and III show gradual frontal mostly M-shaped recession of the hairline, type IV, V and VI show additional gradual thinning in the vertex area, type VII and VIII show a confluence of the balding areas and leave hair only around the back and the sides of the head.50,90 In 1975 Norwood modified the classification, and included variations on the middle grades III a, IV a and V a, that show a more prominent gradual receding of the middle portion of the frontal hairline and type III vertex which is characterized by a loss of hair mainly in the tonsure area and a frontotemporal recession which never exceeds that of type III.91 (Fig. 88-4). In 1977, Ludwig introduced a classification for pattern of AGA in women, characterized by a diffuse loss of hair on the crown and persistence of the frontal hairline.92 In 1994, Olsen noted that women with AGA did not necessarily present with diffuse hair loss over the entire top but rather may have increasing hair loss towards the front, called frontal accentuation or Christmas tree pattern (Fig. 88-5). Women can also show a male pattern of distribution, as well as men can show a more female pattern.1

A thorough scalp exam together with the patient history usually allows a definitive diagnosis.

Standardized global scalp photography, especially of the part area, is very helpful as a qualitative assessment of the progression of the hair loss and as therapy control. A pull test and a trichogram can give information on the ongoing activity of the condition. Videodermoscopy and phototrichogram techniques can be used for therapy control.

The diagnosis can be more difficult if the hair loss is more diffuse over the entire scalp or if it occurs together with other hair loss conditions such as TE, diffuse alopecia areata or mild forms of cicatricial alopecias. A scalp biopsy allows a definitive diagnosis, since it provides information on histological features, the number of terminal and vellus hair per area and the number of anagen and telogen hair.

In women, a laboratory test for ferritin and thyrotrophin-stimulating hormone (TSH) are recommended to rule out sources for and underlying TE. An extensive laboratory workup for androgens is not recommended for a routine visit. Women with irregular periods and/or other signs of androgen excess should be at least checked for free and total testosterone as well as DHEA-S. The best time for the blood work is in the morning of one of the days of her menstrual cycle. She also must be off the pill for at least one cycle.

Risk Factor and Association with Other Diseases

An increased risk of coronary heart disease and insulin resistance has been correlated for early vertex balding, especially in young men with hypertension, obesity, and dyslipidemia.93–95 Early vertex balding has also been correlated with an increased risk of prostate cancer.96,97

Differential Diagnosis

(Box 88-1)

Treatment

AGA is a progressive condition with a decrease in hair density of approximately 6% of hair fiber per year.40 However, increased shedding can occur periodically and the extent of hair loss depends on the genetic predisposition. Currently two pharmaceutical treatments are approved for the therapy of AGA in men: oral finasteride and topical minoxidil.

Minoxidil

Minoxidil is a biologic response modifier, which has been shown to halt AGA in many patients and regrow hair to a certain extent. Minoxidil, a piperidinopyrimidine derivative, was noted to cause hypertrichosis when administered orally as an antihypertensive. It is now used as a 2% and a 5% topical treatment in a lotion or foam preparation.

The mechanism of action is not fully understood. A direct effect on the hair follicle cells may be responsible for the effects of minoxidil. It has been shown to have a mitogenic effect on epidermal cells leading to prolonged survival time and induced increased proliferation of hair follicles in vitro.98–100 A possible mechanism of action involves a change in calcium homeostasis of cells, as minoxidil is converted to minoxidil sulfate, a potassium channel agonist. Increased potassium channel permeability leads to impaired entry of calcium into cells, thus decreasing epidermal growth factors and enhancing hair growth.101

Several clinical trial have shows the efficacy of topical minoxidil. An increase in hair counts probably reflects reversal of miniaturized hairs to thicker, more highly visible terminal hairs. Although studies have been performed on the vertex scalp, the drug also works on the frontal scalp, especially if hairs have not completely miniaturized to vellus-like hairs. Moderate to dense regrowth could be seen in up 30%–45% of patients.41 Some patients experience an increased shedding in the first 4–6 weeks of application. This positive sign seems to indicate anagen induction with earlier “molting” of telogen hairs from the follicles. The patient should be educated and prepared for this possible side effect to improve compliance. Observed side effects include contact dermatitis in 6.5% of patients and facial hypertrichosis in 3%–5% of women.102 Most patients do not have a true contact allergy to minoxidil but an irritation from propylene glycol. The 2% lotion with less propylene glycol, other vehicles with butylene glycol or the foam may then be used. To discriminate, which component causes the dermatitis, a patch test or testing the product on the volar forearm (repeated open application test) may be helpful.

Only minimal amounts of minoxidil are systemically absorbed and serum levels are too low to have hemodynamic effects in normotensive or hypertensive patients. Nevertheless, less than one in thousand patients may experience tachycardia and decreased blood pressure. Patients with hypotension or heart problems should be cautious and use the medication with approval from their cardiologist. The cardiac effects suggested in earlier studies could not definitely be linked to minoxidil and may be due to increased incidence of coronary artery disease in subsets of men with AGA.93

Topical minoxidil solution is used twice daily (1ml or 25 drops bid). It is also available in a 5% foam. If the hair has been shampooed, the hair and scalp should be at least towel-dry. The lotion or foam should stay on the scalp for at least 4 hours before the next shampoo. The patient should be informed that this is a lifelong treatment. It takes 4–6 months before the medication starts working and that the maximum effect can be expected after 1 year.

Finasteride

Finasteride is a synthetic azo-steroid that has been used for the treatment of AGA in men since 1997. It is a potent and highly sensitive selective 5α-reductase type-2 inhibitor.59 It binds irreversibly to the 5α-reductase isoenzyme 2 and inhibits the conversion of testosterone to DHT. Finasteride has a pharmacological half-life of around 8 hours. The administration of 1 mg finasteride daily reduces the concentration of DHT in scalp skin by 64%, serum DHT is reduced by 68%.59 The dose response curve is nonlinear and therefore higher doses do not lead to significantly increased suppression of DHT or greater clinical benefits.103 In placebo-controlled studies, a significant hair count increase in men with vertex alopecia or frontal AGA could be shown after 6 and 12 months.104,105 Finasteride stabilizes hair loss in 80% of patients with vertex hair loss and 70% of patients with frontal hair loss. The chance of mild to moderate regrowth is 61% on the vertex and 37% on the frontal scalp.106 After 24 months of continuous use, 66% of the patients experienced a certain amount of hair regrowth in the vertex area (approximately 10%–25% of the hair the patient lost previously).107 Most of the patient showed no further hair loss and only a few patients continued to lose hair. Continued use beyond 2 years does not promote continued hair regrowth. Instead the hair density stabilizes with the retention of the newly acquired hair.107 If successful, the treatment should be continued indefinitely because the balding process continues once treatment ceases.38 Finasteride was found to be well tolerated with side effects occurring in fewer than 2% of patients. The side effects included decreased libido in 1.8% of the recipients versus 1.3% in the placebo group, erectile dysfunction in 1.3% of the recipients versus 0.7% in the placebo group and decreased ejaculate volume in 0.8% of the recipients versus 0.4% in the placebo group.108,109 Finasteride 1 mg daily does not affect spermatogenesis or semen production in men aged 19–41 years of age.110 The effect on prostate volume and serum prostate specific antigen (PSA) in younger men was small and reversible after discontinuation of the drug.110 Finasteride can decrease PSA levels by 50% in older men.111 Therefore a baseline PSA should be taken in men over 40 and the family doctor should be advised to double the PSA value while patients are taking finasteride.106 Long term side effects of 1 mg finasteride daily are yet unknown. A placebo controlled study over 7 years carried out in 9,060 men 55 years of age or older, taking 5mg finasteride per day or placebo, showed that finasteride prevents or delays the appearance of prostate cancer, but a slightly higher risk of high-grade prostate cancer.

Finasteride is not approved for the use in women and its efficacy in FPHL is still controversial. A multicenter double-blind, placebo-controlled, randomized study of finasteride 1 mg/day in postmenopausal women with FPHL showed no differences in anagen:telogen ratio and the terminal hair:miniaturized hair ratio. However, Camacho et al reported hair regrowth using finasteride 2.5 mg/day in 41 women with FPHL and SAHA (seborrhea, acne, hirsutism, and alopecia).39,49

Dutasteride

Dutasteride is an inhibitor of type I and II 5α-reductase. It is approved at a dose of 0.5 mg daily for the treatment of symptomatic benign prostatic hyperplasia. Some studies have shown great efficacy in the treatment of MPHL and FPHL.112–115 However, dutasteride is not FDA approved for use in androgenetic alopecia. More studies are necessary for the evaluation of the safety profile of this drug.

Cyproterone Acetate

The antiandrogen cyproterone acetate (CPA) is a synthetic derivative of 17-hydroxyprogesterone. It acts as an AR antagonist with weak progestational and glucocorticoid activity.62 It also inhibits the steroidogenic enzyme 21-hydroxylase, reducing the production of aldosterone and to a lesser extent 3-β-hydroxysteroid dehydrogenase, both of which are needed to synthesize cortisol. CPA is available in Europe, Canada and South America. It is usually combined with ethinyl estradiol as a birth control pill. CPA is not approved by the FDA for the treatment of AGA. For the treatment of FPHL a regimen with 100 mg CPA daily on days 5–15 of the menstrual cycle and 50 μg of ethinyl estradiol on days 5–25 or 50 mg CPA daily on days 1–10 of the cycle and 35 μg of ethinyl estradiol on days 1–21 have been suggested.116 In a randomized 12 months clinical trial in 66 women, 33 women with FPHL used topical minoxidil 2% plus combined oral contraceptive whereas 33 women received CPA 52 mg daily plus ethinyl estradiol 35 μg for 20 days of the cycle. The later combination result in greater hair density in women with hyperandrogenism.117 Side effects from CPA are irregular menstrual cycles, weight gain, breast tenderness, loss of libido, depression, nausea. Since CPA is an antiandrogen, its use in men is obsolete, unless a gender change is desired.

Spironolactone

Spironolactone is a synthetic 17-lactone drug, which is a renal competitive aldosterone antagonist with a mild antiandrogenic effect by blocking the AR and preventing its interaction with DHT. The maximum androgen suppression is reached after 4–12 months; dosages of 200 mg daily are required. Spironolactone may have a preventative effect in FPHL and may reduce shedding in individuals without hyperandrogenism.118 However, Spironolactone is not approved by the FDA for the treatment of FPHL and, sd sn antiandrogen, should not be used in men. The main side effect is menstrual irregularities, which may be mitigated by decreasing the dose to 50–75 mg/day and adding oral contraceptives or after 2–3 months of therapy. Spironolactone is contraindicated in patients with renal insufficiency, hyperkalemia, pregnancy, abnormal uterine bleeding, and women with genetic predisposition of breast cancer.116,118

17α- and 17β-Estradiol

In Europe topical 17α- or 17β-estradiol are commercially available for the treatment of FPHL. Studies showed an increased in anagen and decreased telogen rates after topical treatment compared with placebo treatment.119 The underlying pathways of 17α-estradiol induced hair regrowth are unknown. Niiyama et al showed that 17α-estradiol is able to diminish the amount of DHT formed by human hair follicles after incubation with testosterone while increasing the concentration of weaker steroids.119,120 Recently, it has been shown that hair follicles in women with FPHL express more aromatase activity as compared to male hair follicles. Under the influence of 17α-estradiol, an increased conversion of testosterone to 17β-estradiol and androstenedione to estrone takes place in hair follicles derived from the occiput, which might explain the beneficial effects of estrogen treatment in FPHL. Woman who were taking aromatase inhibitors were shown to develop FPHL more rapidly.121 Another theory about the effectiveness of estradiol is the systemic induction of SHBG and therefore the reduction of free, bioavailable testosterone.63 Since estradiol is absorbed through the scalp skin, systemic side effects must be considered, and it cannot be used in men.

Low-Level Light Therapy

Laser sources have become very popular in medical and nonmedical areas. Manufacturers and suppliers often guarantee hair regrowth and various devices are available without prescription. The only FDA approved low-fluence laser light device is the Hair Max Laser Comb® (Lexington international, LLC, Boca Raton, FL, United States of America) (FDA approval as a medical device). Paradoxical hair growth has occurred in patients undergoing laser hair removal when relatively low energy fluences were used. The mechanism of action of this phenomenon is unknown. One theory suggests an increase in blood flow in the dermal papilla.122–124 Low-level laser light sources appear to be safe to use in the treatment of hair loss. More studies are necessary to understand the mechanism of action and to evaluate the efficacy of these devices.

Hair Restoration Surgery

Hair restoration is the most successful and permanent treatment for AGA in suitable candidates. It includes hair transplantation (HT) and, in skillful hands, scalp-reduction surgery. Suitable candidates for HT are those with reasonable expectations, a donor supply that is adequate to cosmetically improve the recipient area coverage and those without contraindications for surgery. The most dramatic change in cosmetic appearance is achieved in patients with stages Hamilton–Norwood VI and VII, and in patients with anterior accentuation of balding (subtypes IIIa and IVa, “Christmas tree pattern”).

With recent advancements in technique and combination with medical treatment, more patients may benefit from the surgical option. Larger numbers of smaller grafts are moved per session, and results have thus become very natural.125,126 It is possible and advisable to distribute small grafts in between preexisting hairs and thus account for future hair loss. Rational use of the donor area with strip harvesting or FU extraction makes several sessions possible in many patients if they experience progressive hair loss.

HT is based on the principle of donor dominance as shown by androgen-independent follicles retaining their properties when they are transplanted into androgen-dependent areas. The donor supply is limited by the area of the strip (size of the “safe zone,” scalp elasticity) and the density of donor hair.

HT is an outpatient procedure and may take up to 10 hours, depending on various factors, especially the number of grafts. Tumescence anesthesia is used for the donor and recipient areas, sometimes combined with nerve blocks. The most commonly used technique is strip harvesting. It allows for a relatively fast removal of large numbers of hairs leaving a fine line as a scar, which can be minimized with special harvesting and wound closure techniques. The strip is dissected into FUs (“families” of hairs growing together in one connective tissue sheath) under magnification these grafts are then carefully and strategically placed in the balding areas. The recipient side is prepared with small needles or spears, according to the size of the graft. A recent technique involves separately harvesting individual FUs using very small blunt punches (follicular unit extraction (FUE). This procedure is usually more time consuming but avoid a long scar in the occipital area. Follicular unit extraction is indicated in patients who desire to wear a very short hairstyle.

Wigs and Hairpieces

Scalp prostheses are practical for patients who are not candidates for hair restoration surgery, women with extensive hair loss and/or patients without satisfying improvement after using medical therapy. Wigs and hairpieces can provide excellent cosmetic results, especially when they are custom made. It is usually easier to overcome the reluctance to wear a scalp prosthesis if the hair piece blends in nicely with the preexisting hair and is comfortable to wear. Women tend to be less reluctant to wear a wig or hairpiece, especially if the patient is exposing her natural hairline (Figs. 88-6 and 88-7).

Genetic

Hypotrichosis Simplex

Hypotrichosis simplex is characterized by progressive global loss of scalp hair starting during childhood. This autosomal dominant disorder affects both sexes equally; eyebrows and body hair is unaffected by the condition. The pathogenesis is of hypotrichosis simplex is not fully understood. In two families with hypotrichosis simplex, a gene defect in the corneodesmosin gene (adhesin protein) was found84,127 (Fig. 88-8).

Reduced or Absent Hair Growth Associated with Ectodermal Dysplasia

A failure in normal follicle development in utero can results in a reduction or absence of hair follicles. These developmental disorders are often associated with ectodermal defects. These hereditary syndromes, most frequently show abnormalities of bones, central nervous system, teeth or eyes (see Chapter 142). The most common ectodermal dysplasia, hypohidrotic ectodermal dysplasia, which is characterized by sparse hair, abnormal teeth and reduced or absent sweating, is due to a mutation in the ectodysplasin signaling pathway.128 This pathway is involved in the early embryogenic formation of the hair follicle.129–131 Ectodermal dysplasias with hair disorders are discussed in Chapter 142.

Atrichia with Papular Lesions

Atrichia with papular lesions is an autosomal dominant hair disorder that presents in infancy. Hair is usually present at birth but alopecia develops within the first year of life. Several years after the development of alopecia, papular follicular cysts often appear.132 Mutations either in the hairless gene or the gene encoding the vitamin D receptor can lead to this phenotype. Hair follicle formation in utero appears to be normal, but massive apoptosis in the hair bulb during the first catagen phase leads to a separation of the dermal papilla from the base of the hair follicle and consequent failure to reenter anagen. The follicular epithelium than undergoes a cystic change. If universal hair loss occurs during the first month of life, atrichia with popular lesions and alopecia areata universalis should be considered as differential diagnosis. If universal alopecia is seen in the family, gene testing and genetic counseling should be considered.

Short Anagen Syndrome

The term short anagen hair syndrome applies to a poorly understood clinical presentation of short fine hair in children.87 The hair fails to grow long due to a shortened anagen phase. Hair density and hair shafts seem to be normal. The condition may improve after puberty. Short anagen hair can be inherited autosomal dominant or can occur sporadically.

Loose Anagen Syndrome

Loose anagen syndrome is characterized by an easy epilation of anagen hair. The hair appears to grow slowly and can be pulled out without pain. Hair density can appear normal or reduced and some children may display demarcated areas of incomplete alopecia. The typical patient with loose anagen hair syndrome is 2–5 years of age. The condition more frequently affects girls and hair is most often light blond. The hair loss tends to get better without any treatment once the child grows older. Microscopic examination of gently pulled hair can make the diagnosis; 80%–100% of the hairs are anagen hairs with a ruffled cuticle and no inner root sheath. However, the hair loss can cycle, and it may be hard to gather enough hair with a gentle pull, necessitating collection by the parent at home and later microscopic evaluation. Loose anagen hair syndrome can be familial, sporadic or associated with other developmental defects such as Noonan syndrome or hypohidrotic ectodermal hyperplasia.133 It is also seen in association with HIV.134 Hair shaft abnormalities, alopecia areata and trichotillomania have to be considered in the differential diagnosis. (See Fig. 88-9.)

Epidemiology

The second most common cause of hair loss in women after FPHL is TE. The latter presents as a nonpatterned increase in shedding of terminal hairs, diffusely over the entire scalp, and can produce an apparent thinning of hair in severe cases.135 While both genders can experience TE, attitudes toward hair loss result in a greater proportion of females who complain. TE can copresent with AGA, particularly in early-onset situations, and this can complicate diagnosis and treatment. TE differs from AGA in that it is not androgen-sensitive, does not appear to be inherited and, since it does not involve a terminal- to vellus-hair transition, does not decrease matrix cell volumes or hair shaft diameters.136 TE also tends to be related to external causes and is often reversed when the exogenous stimuli are removed.

Acute Telogen Effluvium

Etiology and Pathogenesis

The pathophysiology underlying TE is best characterized as a premature shift of hairs from the anagen (growth) phase into the catagen (resting) and telogen (terminal) phases. However, there are variants: anagen may be prolonged, or telogen may instead be shortened or prolonged. Which type of shift occurs depends on the stimulus producing the shift, with the main clinical difference being the latency of effluvial onset following the stimulus.

The hair loss that commonly occurs following pregnancy is generally seen 2 or 3 months postpartum, although some individuals can exhibit longer times to onset. While this is classic TE, the mechanism has been shown to involve a delayed transition from anagen to catagen/telogen, which results in a simultaneous shedding of large numbers of terminal hairs.137 This hair does eventually regrow; however, the returning hair may show changes in texture, color and curliness, and may not attain its previous length. As such, pregnancy (parturition or abortion) may in some cases produce permanent changes in anagen length.136

Other perturbations can produce TE, usually involving premature termination of the anagen phase. Some women experience transient TE 2–3 months after discontinuing or changing oral contraceptive medication; the delayed onset of TE in these cases distinguishes it from the anagen effluvium (AE) initiated by certain drugs (see below). In the 1970's, the popularity of fad “crash” diets resulted in many cases TE about 3 months after initiation of these spartan regimens, depending on the severity of weight loss. Sudden deprivation of amino acids and other dietary factors most likely produced the condition, and the hair tended to regrow following cessation of the diets.136 Surgical procedures, psychological traumas, and febrile illness have all been reported to produce TE events.

Drugs are widely reported to produce temporary hair loss. This is usually, but not necessarily, of the AE variety, since, depending on the causal agent, the time course and severity may suggest a diagnosis of TE to be appropriate. Agents producing TE include cimetidine, enalapril and captopril, imiquimod, metoprolol and propranolol,138–141 lithium,142 l-dopa143 trimethadione,144 and bromocriptine.145 The hair loss from administration of etretinate146 and isotretinoin are problems, more of the AE, as is hair loss that sometimes follows renal dialysis, possibly with hypervitaminosis A.136 Finally, hair loss occurring following environmental contamination or poisoning, for example with selenium, arsenic, thallium, mercury, and lead, displays an AE-like rapid onset, probably involving a cytotoxicity mechanism.

Clinical Findings

TE is characterized by a fairly sudden onset of massive shedding. Anagen hairs are prematurely shifted into telogen hairs and the normal anagen/telogen ratio of 90:10 can switch to 70:10. Women often present with the “bag sign”: bringing in bags with hair that they have collected every day or over a couple of days (Fig. 88-10). More than 300 telogen hairs can be shed every day. The global examination of the scalp may show a reduction in hair density especially in the temporal area. The pull test is usually positive (3 or more hairs can be pulled out on different parts of the scalp). A trichogram or phototrichogram can be use to quantify the amount of telogen hair. A scalp biopsy may be helpful to distinguish the condition from diffuse alopecia areata or AGA.

Chronic Telogen Effluvium

Etiology and Pathogenesis

Chronic Telogen Effluvium (CTE) was first proposed in 1996 as a means of distinguishing the abrupt-onset, short-acting type TE, usually caused be exogenous triggers or parturition, from a more durable condition (CTE) that may not be so clearly related to any external event.147

A few conditions have been proposed to be underlying stimuli for CTE. While “crash” diets have been pinpointed as potential triggers for acute TE, chronic malnutrition can analogously lead to CTE. Protein deficiency is the likely mechanism in this type of balding. It is less clear whether zinc148 or biotin deficiencies are also correlated with chronic diffuse hair loss. Although controversial, iron deficiency, as evidenced by decreased serum ferritin and anemia, may be a trigger for CTE.27,149,150,151 Hypothyroidism has also been associated with CTE (Box 88-2).

Clinical Findings

CTE can most commonly be seen in women. Patients report ongoing massive shedding or recurrent episodes of shedding. As a rule of thumb, any diffuse hair shedding lasting longer than 6 months after any triggering event, or after withdrawal from suspected causal drugs, should be considered CTE. The clinical examination can show a normal or reduced hair density. Regrowth of tapered new anagen hair can usually be found. The pull test may be moderately positive. A trichogram or phototrichogram can be used to confirm and quantify the diagnosis. A scalp biopsy is very helpful for the confirmation of the diagnosis and to distinguish the condition other forms of alopecia. Since other types of hair loss disorders, chiefly FPHL/MPHL and alopecia areata, may copresent with TE and CTE, clinicians may be advised to assay serum iron and thyroid hormone concentrations in order to eliminate iron deficiency and hypothyroidism as treatable causes for the patient's baldness.152

Differential Diagnosis

(Box 88-3)

Prognosis and Clinical Course

Both acute and CTE usually resolve once trigger factors are eliminated. However, in CTE triggers may be difficult to identify. Women with TE are often most concerned about complete baldness. The patient has to be reassured that the condition does not lead to complete baldness and that the hair likely grows back around 6 months after removal of the initiating trigger. The patient should understand that the condition is reversible, but that the shedding may persist for a few weeks or months once the initiation factor is eliminated.

Treatment

The removal of the cause is the major goal in the treatment of TE. Iron supplementation is recommended if the ferritin level is less than 70 ng/mL.150,153 Borderline hypothyroidism can be difficult to identify. Women, who complain about hair loss, depression, lack of energy, mental fatigue, cold intolerance, weight gain or/and constipation are suspicious for the diagnosis of hypothyroidism. TSH levels may fluctuate but are usually elevated, with normal or reduced thyroid hormone levels. If a thyroid dysfunction is suspected, the patient should be closely followed by an endocrinologist. Topical 2% or 5% minoxidil solution 1 mL twice daily can be helpful, especially in women with prolonged hair loss with unknown triggers or in patients with drug related hair loss who are unable to discontinue the initiating medication.

AE is a result of a disturbance of hair follicle matrix cells. The anagen phase is interrupted and the hair falls out 7–14 days after the initiating event without entering catagen or telogen. Two different types of AE can be distinguished: Dystrophic AE and Immediate anagen release. Dystrophic AE can be caused by chemotherapy, radiation, toxins or alopecia areata. Microscopic investigation of the hair bulbs, obtained from a hair pull test or trichogram, usually shows a tapered tip with the weakened hair shaft broken shortly above the bulb (“dystrophic hair”).1

Drugs used in chemotherapy quickly produce severe hair loss and even total baldness. A rapid onset undoubtedly indicates an immediate release from anagen hair. Immediate anagen hair release is characterized by an easy release of anagen hairs after gentle pulling. The anagen hair has a broom-shaped, pigmented bulb. Therapeutic agents that can cause immediate anagen hair shedding include vincristine, vinblastine, methotrexate, doxorubicin, and fluorouracil.

Normal appearing anagen hair with inner and outer root sheath can be found to some extent in every AE, but especially in bullous dermatosis of the scalp with sub- or intraepidermal blisters.

Once the initiating trigger is removed, the hair usually regrows after around 120 days. Cases of incomplete recovery following multiagent chemotherapy have been reported.1 Patients should be advised about scalp prostheses and other forms of head covering.

Alopecia Areata

Epidemiology

At any given time, approximately 0.2% of the world population is suffering from alopecia areata with an estimated lifetime risk of 1.7%.154,155 It is a common cause of abrupt-onset hair loss, but occurs less frequent than androgenic alopecia or TE. Both sexes are affected equally. Although it may occur at any age, incidence at younger age is higher. Alopecia areata is the most common form of alopecia seen in children. The familial occurrence is around 15% but expression of the disorder is variable among different family members. 5% of patients suffering from alopecia areata develop hair loss of their entire scalp hair (alopecia totalis), and 1% of patients develop loss of total body hair (alopecia universalis) at some point.

Etiology and Pathogenesis

Alopecia areata is a chronic, organ-specific autoimmune disease, mediated by autoreactive CD8+ T-cells, which affects hair follicles and sometimes nails.156–159 Alopecia areata is thought to be an autoimmune disease with inappropriate immune- response to hair follicle associated antigens. A collapse of the normal immune privilege of the anagen hairbulb, probably induced by interferon-γ, may play a key role in the pathogenesis of this disease.156,159 Melanogenesis-associated autoantigens, which are normally sequestered from immune recognition by a functional hair follicle immune privilege, may be one key target of autoaggressive inflammation in alopecia areata.160 There is a high frequency of a positive family history of alopecia areata in affected individuals, ranging from 10% up to 42% of cases,161 and a much higher incidence of a positive family history in early onset alopecia areata.162 Many patients report the experience of major emotional stress prior to the onset of alopecia. A genome-wide association studies recently showed several loci linked to alopecia areata containing genes controlling both innate and acquired immunity, as well as genes expressed in the hair follicle itself.163

Histologically, alopecia areata is characterized by an inflammatory infiltrate, comprised mainly of T-cells, in and around the bulbs of anagen hair follicles (“swam of bees”). However, the classic inflammatory infiltrate may be missing in subacute or chronic forms. Alopecia areata should be in the differential diagnosis whenever high percentages of telogen hairs or miniaturized hairs are present, even in the absence of peribulbar inflammation.

Clinical Findings

Alopecia areata is characterized by an acute onset. It typically presents with oval or round, well-circumscribed, bald patches with a smooth surface in a diffuse distribution (Fig. 88-11). Alopecia totalis results in the loss of the entire scalp hair and may occur suddenly or follow partial alopecia (Fig. 88-12). Partial alopecia may be observed in other areas of the body as well. Loss of total body hair is called alopecia universalis and may also occur suddenly or follow of long-standing partial alopecia.

Characteristic hallmarks of alopecia areata are “black dots” (cadaver hairs, point noir), resulting from hair that breaks before it reaches the skin surface. Exclamation point hairs, with a blunt distal end and taper proximally, appear when the broken hairs (black dots) are pushed out of the follicle. Localization of the initial patch is most frequently on the scalp, but may occur on any hair-bearing part of the body. Patches are usually without further symptoms, but may show mild itching and erythema in some cases. Alopecia areata can less commonly present in a diffuse generalized pattern that resembles androgenic alopecia or TE. In the acute stages, gentle pulling from the periphery of bald areas will yield more than 10 hairs. Involvement of nails is common with nail pitting and a sandpaper-like appearance. The disease has been described in association with a variety of other disorders, such as cataracts, thyroid disease, vitiligo, atopic dermatitis, psoriasis, and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), Cronkhite–Canada, and Down syndromes.164,165

Clinical features, such as shape and look of the patches, presents of exclamation point hair, nail changes (pitting or sandpaper nails) lead to the diagnosis of alopecia areata. In most patients the physical findings are so characteristic that the diagnosis is obvious. Moreover, positive family history and/or the presence of associated diseases may give further evidence in cases of doubt. Scalp biopsy reveals a generalized miniaturization and a marked increase in catagen and telogen hair follicles. In the acute phase, a peribulbar lymphocytic infiltrate, which has been described as a “swarm of bees” may be found. Sometimes mast cell, plasma cells and eosinophils can also be seen. Laboratory tests to rule out thyroid dysfunction should be performed.

Differential Diagnosis

(Box 88-4)

Complications

A relapsing course and progression of hair loss to severe forms of alopecia totalis or universalis are dreaded complications. Missing hair on the scalp and face, including nasal hair and eye lashes/brows can increase the incidence of sunburn and skin cancer, as well as nasopharyngeal and ophthalmologic inflammation. Although the condition is not life threatening, changes in appearance frequently cause a diminished sense of personal well-being and self-esteem, leading to severe depression and withdrawal from social situations.

Prognosis and Clinical Course

The course of the disease is very variable and characterized by an irregular relapsing course, with about 25% of affected individuals having a solitary episode. Spontaneous regrowth of hair is common. Different body areas appear to regrowth independently. About 60% of patients have at least a partial regrowth by 1 year, but this is often followed by repeated episodes of hair loss. About 40% of the relapses occur within the first year, but a large percentage of patients may relapse after 5 years. Hair can regrow white but may change to the patient's natural color over time. Poor prognosis is linked to involvement of the occiput and/or hairline (called the ophiasis pattern if sweeping around the periphery of the scalp), a chronic relapsing course, the presence of nail changes, and onset during childhood.166–168 The number of patients progressing to alopecia totalis also higher in patients with hair loss from the trunk and extremities.

Treatment

Very little evidence-based data is available for the treatment of alopecia areata; recommendations are mainly based on case series and clinical experience. At this time all available treatments for alopecia areata are palliative, only controlling the ongoing episode of hair loss and not curing the condition itself. However, helpful treatment guidelines have been published.166–168 Fig. 88-13 shows an algorithm for treating alopecia areata based on age and scalp involvement.

Conservative Management

Alopecia areata shows a high rate of spontaneous remission, especially in those patients with a short history and limited scalp involvement. On the other hand, in alopecia totalis and universalis, treatments have a high failure rate. After the discussion of possible risks and benefits of all options, “no treatment” may be a legitimate option for some patients.

Topical Corticosteroids

Superpotent (class I) and potent (class II) topical corticosteroids are widely used to treat alopecia areata. Evidence of efficacy has been proven for class I corticosteroids when applied under occlusion169 and for class II corticosteroids when used in combination with minoxidil.170

Intralesional Corticosteroids

Intralesional corticosteroid (triamcinolone acetonide or triamcinolone hexacetonide) injection is first line therapy for adult patients with less than 50% scalp involvement. Triamcinolone acetonide is used at concentrations from 2.5–10 mg/mL. Treatment are repeated every 4 to 6 weeks, and the total amount injected per session varies from 15–40 mg.109,166–168,171 An initial response is often seen after 4–8 weeks. Some patients experience indentation of the scalp skin in the injection sites due to a nonpermanent atrophy of the subcutaneous fat. Permanent skin atrophy can occur if the same skin area is injected repeatedly over months and years. If no regrowth can be seen after 4 months of treatment, other treatment options should be considered. Intralesional corticosteroids injections are usually used on the scalp, eyebrows and beard area and can be combined with topical treatment.

Systemic Corticosteroids

Systemic corticosteroids are effective in the treatment of alopecia areata. However, the regrown hair frequently falls out again when the treatment is discontinued. The use of systemic corticosteroids is controversial and largely used on a short-term basis with rapidly advancing hair loss. They should not be used as routine treatments because they do not alter the long-term prognosis and can cause side effects such as striae, acne, obesity, cataracts and hypertension. Dosages vary from initial 20–40 mg prednisone daily tapered down to 5 mg daily in a few weeks or different pulse therapies regiments with short-term high doses of oral prednisolone (100–300 mg) or i.v. methylprednisolone (250 mg).109,166–168