Chapter 88. Hair Growth Disorders

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

Topical Minoxidil

There is some evidence of clinically acceptable hair regrowth using topical minoxidil 5% solution.172,173 Better results can be achieved when minoxidil is used in combination with class II topical corticosteroids or anthralin.170 Minoxidil shows little efficacy in alopecia totalis and universalis.

Anthralin

Anthralin is an irritant that may have a nonspecific immunomodulating effect and is primarily used in the treatment of psoriasis (Chapter 18).174 Several studies have shown efficacy in the treatment of alopecia areata with cosmetically acceptable improvement varying from 20% to 25% for patchy alopecia areata.175,176 Anthralin is used as a 0.2%–1.0% cream or ointment. It is usually applied daily to the affected scalp areas and left on for 20–30 minutes for the first 2 week, and then 45 minutes daily for 2 week, up to a maximum of 1 hour daily. Some patient may tolerate overnight therapy.109,175 When therapy is effective, new hair growth can usually be seen after 2–3 months of treatment. Because of its good safety profile, anthralin can be used safely in affected children. Side effects of anthralin are irritation, scaling, folliculitis and regional lymphadenopathy. Anthralin is not suitable for the treatment of eyebrows and beard area. Patients should be cautious not to get anthralin in the eyes and to protect the treated skin areas from UV irradiation. Brown discoloration of the treated skin and brown staining of clothes and linen may occur. The patient should be advised to rinse off the anthralin with cool or luke-warm water, since hot water increases the likelihood of brown stains of tiles and bathtub.

Topical Immunotherapy

Although not approved by the FDA, topical immunotherapy seems to be the most effective therapeutic option with the best safety profile in the treatment of chronic severe alopecia areata. The exact mechanism of action is not fully understood. A decrease in the peribulbar CD4+/CD8+ lymphocyte ratio and a shift in the position of T-lymphocytes from the perifollicular area to the interfollicular area and dermis are believed to be responsible for the immunomodulating effect.177–179 The desired effect of the treatment is the creation of a contact dermatitis. Diphenylcyclopropenone (DPCP) and squaric acid dibutyl ester (SADBE) are the most commonly used contact sensitizers. DPCP and SADBE are compounded in an acetone base and stored in opaque bottles to protect the solution from photodegradation. Applying a small amount of a 2% solution to a small scalp or other area (often the arm) one week prior to treatment initiation sensitizes the patient. The DPCP or SADBE solution is then applied weekly to the scalp, starting at a concentration of 0.0001%. The scalp should not be washed for 48h post treatment and should be protected from UV radiation. Every week the concentration is carefully increased until the patient develops a mild erythema and mild itching. The treatment is continued with this concentration; the highest concentration used is 2%. Success rates vary from 17%–75% with the lowest success rates in patients with alopecia totalis and universalis.20 Side effects include lymphadenopathy in 100% of patients, severe contact eczema, discoloration of the skin including vitiliginous patches and hyperpigmentation on the scalp and other arts of the body. Greater caution is indicated in patients with atopic dermatitis and dark skin types.

Photo(chemo)Therapy

Ultraviolet B light has been reported to be useful in some patients with alopecia areata.180 Further therapeutic options include both oral and topical administration of psoralen followed by UVA irradiation (PUVA-therapy). PUVA may affect T cell function and antigen presentation, and possibly inhibits the local immunologic attack against the hair follicle by depleting Langerhans cells.181 Photo(chemo)therapy shows a very high relapse rate especially after tapering the treatment. The major concern about long term UV irradiation of any kind is its promotion of all types of skin cancer, including melanoma. Therefore phototherapy should only be considered in exceptional cases.20

Cyclosporine

Systemic cyclosporine at doses of 4–6 mg/kg/day has been shown to have a beneficial effect in some patients with alopecia areata.20,182 Side effect of oral cyclosporine include elevated serum transaminases and cholesterol levels, as well as headaches, dysesthesia, fatigue, diarrhea, gingival hyperplasia, flushing and myalgias. Cyclosporine can be combined with low dose oral prednisone and may be considered in patients with severe atopic dermatitis and alopecia areata. However, due to its side effect profile and the high recurrence rate observed after discontinuation, cyclosporine seems to be a relatively impractical treatment for alopecia areata.

Camouflage, Wigs, and Hairpieces

When alopecia is progressive despite treatment and sometimes during treatment for improved cosmesis, extensive alopecia areata of the scalp can be camouflaged with wigs. In women with alopecia areata of the eyebrows, permanent makeup may be considered.

The treating physician should provide psychological support. Local and national alopecia areata support groups (National Alopecia Areata Foundation, www.naaf.org) can be very helpful for patients and their relatives.

Temporal Triangular Alopecia

Temporal triangular alopecia (TTA) is a nonscarring, noninflammatory alopecia that presents with one or more roughly triangular, oval, or lancet-shaped alopecic patches in the fronto-temporal area.183–185 A few terminal hairs or vellus-like hairs can often be found in the periphery of the affected area and the scalp is normal.186–190 The lesions are usually asymptomatic and the hair elsewhere on the scalp is of normal density. The patches are mostly unilateral (80%) but can occur bitemporally as well (20%)34,185,190 (Fig. 88-14). A strip of hair of normal density can be seen between the affected patch and the forehead. Lesions can be present at birth or first appear before school age. TTA has been reported in Asian and Caucasian patients with no sexual predilection. TTA seems to be unresponsive to medical treatment. Hair transplantation or excision is reasonable therapeutic approaches.191 TTA is often misdiagnosed as alopecia areata.

Syphilis

Hair loss is a common symptom of secondary or tertiary syphilis. In its classical form, the hair loss is an irregular, patchy loss of hair scattered throughout the scalp, which has been described as “moth eaten” (Fig. 88-15). Eyebrows may be shed and patchy alopecia may occur in the beard or other hair-bearing areas of the body. Syphilitic alopecia can be very difficult to distinguish from alopecia areata. The presence of plasma cells, lack of peribulbar eosinophils, and abundant lymphocytes in the isthmus are histological features of syphilitic alopecia. Essential syphilitic alopecia occurs in the absence of any other cutaneous sign of secondary syphilis,192 and is characterized by a diffuse shedding, thereby resembling TE.

Cicatricial or scarring alopecias comprise a diverse group of scalp disorders that result in permanent hair loss. The destructive process can occur as a primary or secondary cicatricial alopecia. Primary cicatricial alopecia refers to a group of idiopathic inflammatory diseases, characterized by a folliculocentric inflammatory process that ultimately destroys the hair follicle. Secondary cicatricial alopecias can be caused by almost any cutaneous inflammatory process of the scalp skin or by physical trauma, which injures the skin and skin appendages. Regardless of whether a cicatricial alopecia is primary or secondary in nature, all scarring alopecias are characterized clinically by a loss of follicular ostia and pathologically by a replacement of hair follicles with fibrous tissue. Cicatricial alopecias are psychosocially distressing for the affected patient and medico-surgically challenging for the treating physician.

Primary Cicatricial Alopecias

Epidemiology

Inflammatory cicatricial alopecias are rare.

Etiology and Pathogenesis

The mechanisms causing the follicle stem cell destruction are not completely understood, and there is no cure to date. Primary cicatricial alopecias are characterized by an inflammatory infiltrate affecting the upper, permanent portion of the follicles referred to as the infundibulum, and below it, the isthmus of the follicle. The isthmus is the home of pluripotent hair stem cells, which are found in the bulge region where the arrector pili muscle attaches to the outer root sheath. Pluripotent hair follicle stem cells are responsible for the renewal of the upper part of the hair follicle and sebaceous glands, and for the restoration of the lower cyclical component of the follicles at the onset of a new anagen period.27,193 Damage to the bulge area and the sebaceous gland with the isthmus, affected either stem cells or sebaceous glands, may result in an incomplete hair cycle and can be associated with chronic follicular inflammation and foreign body reaction.194 Scarring hair loss is the consequence.5,195–197

A working classification on the basis of pathology of scalp biopsy was suggested by the North American Hair Research Society in 200127 (Box 88-5).

Clinical Findings

Primary cicatricial alopecia usually affects the central and parietal scalp before progressing to other sites of the scalp. Isolated alopecic patches showing atrophy and a lack of follicular ostia with inflammatory changes such as diffuse or perifollicular erythema, follicular hyperkeratosis, pigment changes, tufting, and pustules provide hints to the diagnosis.20,198 However, clinically visible inflammatory change might be absent in the affected lesions and may present histologically as inflammatory infiltrates in the deep dermis and subcutaneous tissue. Diagnostic tools such as a tenfold magnifying dermatoscope with and without polarized light can help to identify the presence or absence of follicular ostia, perifollicular erythema and follicular hyperkeratosis in the affected areas.

A thorough examination of the entire scalp, a detailed clinical history, and skin biopsies of an active lesion are crucial in the correct diagnosis of cicatricial alopecia. Patient-reported symptoms such as itching or pain might be used as approximate indicators of disease activity but can also be completely absent. The presence of other indirectly related symptoms, such as sun sensitivity, can also help support a particular diagnosis [e.g., discoid lupus erythematosus (DLE)]. A scalp biopsy is necessary to confirm the diagnosis of scarring alopecia, and should be taken as described in Section “Diagnostic Techniques for Evaluating Hair Growth Disorders” under “Biopsy.”1,27,199,200 Keratoses follicularis spinulosa decalvans is a form of cicatricial alopecia associated with follicular plugging that is more fully described in Chapter 87 as well as online.

Lymphocytic Primary Cicatricial Alopecias

Chronic Cutaneous Lupus Erythematosus (Discoid Lupus Erythematosus)

(See also Chapter 155).

Discoid lupus erythematosus (DLE), together with LPP, is the most common cause of inflammatory cicatricial alopecia.198 Women are more often affected than men and the disease is more common in adults (with first onset typically at the age of 20–40 years) than in children.201–203

Systemic lupus erythematosus (SLE) will develop in 26%–31% of children and approximately 5%–10% of adult patients with DLE.203,204 Patients with DLE are found to have a higher incidence of concurrent alopecia areata. Moreover, DLE has also been associated with verruciform xanthoma and papulonodular dermal mucinosis.205

Clinical Presentation

DLE usually presents with one or more erythematous, atrophic, and alopecic patches on the scalp (Fig. 88-16). Follicular hyperkeratosis, hyperpigmentation, hypopigmentation and telangiectasia can be present.194,206 Hyperpigmentation is frequently found in the center of the lesion. Active lesions can be sensitive or pruritic, and the patient might report a worsening after UV exposure.

Pathology

Characteristic features of early, active DLE lesions are lymphocyte-mediated interface dermatitis with vacuolar degeneration of the basal cell layer and necrotic keratinocytes, a thickening of the basement membrane and destruction of sebaceous glands. Elastic fibers are frequently destroyed throughout the reticular dermis.1,195 The lymphocytic infiltrate is predominantly found in the upper part of the follicle, but can also be found in deeper parts of the follicle, in the interfollicular epidermis and around the periadnexal vessels.18,207–209 DIF typically shows a linear granular deposition of IgG and C3 at the dermal–epidermal junction. IgM, C1q, and rarely IgA can also be found.

Management and Treatment

Hydroxychloroquine at a dose of 200–400 mg daily in adults or 4–6 mg/kg in children has been shown to be highly effective. A baseline ophthalmologic examination and complete blood count is required before the therapy is started.201,203 Bridge therapy with oral prednisone (1 mg/kg) tapered over the first 8 weeks of treatment might be helpful in adult patients with rapidly progressive disease.20,198

In limited or slowly progressive DLE, intralesional triamcinolone acetonide should be used at a concentration of 10 mg/cc every 4–6 weeks, alone or in addition to oral therapy.198 Intralesional triamcinolone acetonide can be used with or without topical class I or class II corticosteroids. Topical corticosteroids alone have also been shown to be effective in milder forms of DLE,1,18,20,203 and oral acitretin and isotretinoin have shown some efficacy.210,211 Immunosuppressive therapies such as mycophenolate mofetil, methotrexate, or azathioprine should only be considered if the above therapies fail. Multimodal aggressive therapy in rapidly progressive DLE might reverse early alopecic patches and save hair follicles from the destructive process.212

Lichen Planopilaris

LPP is a follicular variant of lichen planus. Together with DLE, this is the most common cause of primary cicatricial alopecia. LPP can be divided in classic LPP, frontal fibrosing alopecia (FFA), and Graham–Little syndrome. The typical age of onset of classic LPP is around the fifth decade, and women are more often affected than men. Extracranial lichen planus may occur in up to 28% of patients.196,213,214 FFA predominantly affects postmenopausal women. Graham–Little–Piccardi–Lassueur Syndrome is a very rare condition that predominantly affects female adults. It is characterized by LPP of the scalp, noncicatricial of the eyebrows, axilla, and groin and keratosis pilaris.

Lichenoid drug eruptions can be triggered by many drugs and might present as LPP. Some of the most common drugs, causing lichenoid drug eruption are gold, antimalarials and captopril. Actinic lichenoid drug eruption is confined to sun exposed sites. The most likely drugs to cause this are quinine, and thiazide diuretics.215–217

Clinical Presentations of LPP

Classic LPP typically starts at the crown and vertex area. In classic LPP, the affected areas usually show perifollicular erythema and follicular hyperkeratosis. The alopecic areas of LPP are often smaller, irregularly shaped and interconnected, which can lead to a reticulated clinical pattern as compared to DLE. However, overlapping clinical features with those of DLE are frequently seen. Patients complain about itching, burning sensations and sensitivity of the scalp (Fig. 88-17).

FFA is characterized by a frontal, band-like, or circumferential scarring alopecia.195 In some cases a few hairs are spared in the original frontal hairline. Follicular hyperkeratosis and perifollicular erythema may be found in a band-like pattern in the frontal hairline. Alopecia of the eyebrows is also frequently seen in FFA (Fig. 88-18). Graham–Little syndrome presents with lesions of classic LPP on the scalp, nonscarring alopecia of axillae, pubic area, and eyebrows as well as keratosis pilaris of the trunk and extremities.

Pathology

The three subgroups of LPP show similar histopathological features. A lymphocytic infiltrate and interface dermatitis are predominantly found in and around the upper permanent part of the hair follicle. Unlike DLE, the vascular plexus is not affected by inflammation and mucin deposits are absent.195 DIF typically shows globular cytoid depositions of IgM, and rarely IgA, IgG or C3, in the dermis around the infundibulum.218

Management and Treatment

First line treatment for moderately active classic LPP lesions is intralesional triamcinolone acetonide at a concentration of 10 mg/cc every 4–6 weeks or in combination with topical class I or class II corticosteroids.198,211 Literature on the efficacy of oral medication is limited. Oral cyclosporine, retinoids, antimalarials and griseofulvin194,206,219–222 have been shown to have a positive effect in patients with rapidly progressive LPP. Oral corticosteroids in the first weeks of treatment as bridge therapy might be considered in very active cases. In FFA, a lower dose of intralesional triamcinolone acetonide (2.5–5 mg/cc), or topical application of minoxidil or tacrolimus can be considered, although no effective treatment has been reported yet. The treatment of Graham–Little syndrome is typically similar to the management of classic LPP.

Classic Pseudopelade of Brocq

PPB is classified as an idiopathic lymphocytic primary cicatricial alopecia that predominantly affects the scalp. It is the second most common cause of primary cicatricial alopecia.196 Women between 30 and 50 years of age are most frequently affected.

Clinical Presentation

Pseudopelade of Brocq usually affects the vertex and occipital area of the scalp. It presents with small flesh-toned alopecic patches with irregular margins. This pattern has been described as “footprints in the snow.”223 PPB can also present as a noninflammatory centrifugally spreading patch of alopecia, which might be seen as a variant of central centrifugal cicatricial alopecia in Caucasians. Follicular hyperkeratosis and perifollicular or diffuse erythema is mostly absent.206 Clinically the features may overlap with LPP.

Pathology

Early PPB lesions typically show a sparse to moderate lymphocytic infiltrate around the follicular infundibulum with a complete destruction of the sebaceous glands.176 In later disease stages, hair follicles are completely replaced by fibrous tracts. Unlike DLE and LPP, interface dermatitis is usually absent and the elastic fibers are preserved and thickened in PPB.224

Management and Treatment

Intralesional triamcinolone acetonide at a concentration of 10 mg/cc every 4–6 weeks in combination with topical corticosteroids is the treatment of first choice. Hydroxychloroquine, oral prednisone, and isotretinoin have shown some effectiveness in treating PPB.196,206,225,226

Central Centrifugal Cicatricial Alopecia

CCCA is classified as a lymphocytic primary cicatricial alopecia, primarily affecting women of color. It remains unclear which of the following contribute most to its formation: chemical processing, heat, traction or other traumas.1,18 CCCA can rarely be seen in Caucasians (sometimes called “central elliptical pseudopelade”) and African-American men. Due to clinical and histopathological similarities, it has been debated whether CCCA is a variant of PPB.

Clinical Presentation

CCCA presents with a skin colored patch of scarring alopecia on the crown, gradually progressing centrifugally to the parietal areas. Perifollicular hyperpigmentation and polytrichia might be present.198 Patients may complain about itching, tenderness and “pins and needle” sensations227 (Fig. 88-19).

Pathology

Limited studies suggest that histopathological features of CCCA seem to be similar to those of PPB.18,194

Management and Treatment

Topical corticosteroids and tetracycline have shown to be effective in active progressive cases.18 Since a multifactorial etiology is debated for CCCA, some dermatologists recommend a switch to more natural, less traumatizing, hair care practices.1,206,228 Wigs and hairpieces can help camouflage the alopecia and are frequently used by women with CCCA.

Alopecia Mucinosa

Alopecia mucinosa (AM) can present as indurated, well-demarcated erythematosus or skin colored patches of scarring or nonscarring alopecia that can be accompanied by diffuse hair loss229 and alopecia of the eyebrows.230 Grouped follicular papules, follicular cysts and follicular hyperkeratosis may be present in some cases. Early lesions of AM show mucin deposition in the outer root sheath and replacement of the entire pilo-sebaceous unit by pools of mucin in more advanced lesions.195,230 AM strictly speaking it is not a primary cicatricial alopecia because the hair follicle is not replaced by a true scar.195 AM can occur idiopathically or in the setting of cutaneous T-cell lymphoma or mycosis fungoides.231 Cell atypia and monoclonal populations of T-lymphocytes can be present in the idiopathic form of AM as well as in the latter form.231

Management and Treatment

A complete workup is necessary to rule out an underlying malignancy such as mycosis fungoides and Sézary syndrome, its advanced endpoint. Oral corticosteroids, minocycline and isotretinoin have been shown to be effective. Topical and intralesional corticosteroids, dapsone, indomethacin and light therapy have also been used with variable outcomes.232

 Keratosis Follicularis Spinulosa Decalvans

Neutrophilic Primary Cicatricial Alopecia

Folliculitis Decalvans

Approximately, 11% of all primary cicatricial alopecia cases are diagnosed with folliculitis decalvans (FD).194,196 FD predominantly occurs in young and middle-aged adults with a slight preference of the male gender. A bacterial infection involving S. aureus, in combination with hypersensitivity reaction to “superantigens” and defect in host cell-mediated immunity have all been suspected as possible pathogenetic factors.194,234,235

Clinical Presentation

FD frequently starts at the vertex area of the scalp with erythematous alopecic patches, follicular pustules and follicular hyperkeratosis. Tufted folliculitis is typically found in FD, but can also occur in other cicatricial inflammatory alopecias. Tufted folliculitis is characterized by multiple hairs (5–15) emerging from one single, dilated follicular orifice. In older lesions pustules might be absent but progressive scarring may still continue (Fig. 88-20). An overlap with acne keloidalis is possible since some patients with acne keloidalis not only develop cicatricial lesion on the nape of the neck but also develop progressive cicatricial alopecia that resembles FD in other areas of the scalp. Patients frequently complain about pain, itching and/or burning sensations.

Pathology

Early lesions are characterized by keratin aggregation in the infundibulum with numerous intraluminal neutrophils, as well as an intrafollicular and perifollicular neutrophilic infiltrate.194,195,206 Sebaceous glands are destroyed early. In advanced lesions, the infiltrate may consist of neutrophils, lymphocytes, and plasma cells and extend into the dermis.198,206 Hair shaft granulomas with foreign-body giant cells can frequently be found.194,206 In end-stage lesions, follicular and interstitial dermal fibrosis as well as hypertrophic scarring can be observed.206

Management and Treatment

Treatment of FD in general is difficult and disease activity can be noted over many years. Bacterial cultures with the testing of antibiotic sensitivities are recommended. Eradication of Staphylococcus aureus with minocycline, erythromycin, cephalosporines, and sulfamethoxazole-trimethoprim has shown some effectiveness. Relapse can often be observed after the antibiotics are discontinued.20,234,236 If so, the patient might have to stay on low dose antibiotics for many years. Rifampin in combination with clindamycin has shown good response; however, this combination shows a higher incidence of side effects.234,237 Oral fucidic acid alone or in combination with other agents has also shown to be effective in some patients.238 Oral therapy should be combined with topical antibiotics such as mupirocin, 1.5% fusidic acid and 2% erythromycin237,238 and antibacterial cleansers. Intralesional triamcinolone acetonide at a concentration of 10 mg/cc every 4–6 weeks might help to reduce the inflammation and reduces symptoms such as itching, burning, and pain.20,196 Intranasal eradication of S. aureus with topical antibacterial agents have been described to be useful.206

Dissecting Folliculitis

Dissecting folliculitis (DF) (or dissecting cellulites or perifolliculitis capitis abscedens et suffodiens of Hoffman) is related to acne conglobata and hidradenitis suppurativa. These three diseases have been described as follicular occlusion triad. DF predominantly occurs in young men between 18 and 40 years of age.198 African-American men seem to be more commonly affected compared to Caucasian men. The pathogenesis of DF may include follicular occlusion, seborrhea, androgens and secondary bacterial overpopulation as well as an abnormal host response to bacterial antigens.239–246

Clinical Presentation

DF typically presents with fluctuating nodules, abscesses, and sinuses, which frequently show spontaneous discharge of pus, as well as with erythematous, follicular papules and pustules. Initial lesions are mostly found on the vertex and occipital scalp. Multifocal lesions can form an intercommunicating ridge and sero-purulent exudates can be discharged when pressure is applied to one region of the scalp (Fig. 88-21). The lesions can be pruritic and tender. Chronic and relapsing courses result in cicatricial alopecia, which can show hypertrophic or keloidal scars.246

Pathology

The main histological feature is an intrafollicular and perifollicular neutrophilic infiltrate with follicular occlusion in early lesions.195 In more advanced stages, interconnecting sinus tracts lined by squamous epithelium, follicular perforation, perifollicular and deep dermal abscesses are typical findings.195,206,209

Management and Treatment

Multimodal treatment has been reported with successful results, such as systemic antibiotics (minocycline, tetracycline, cloxacillin, erythromycin, cephalosporin or clindamycin), intralesional corticosteroids, and oral prednisolone.247,248 The benefits of systemic antibiotics are most likely due to their antiinflammatory effects rather than to their antibacterial action. Isotretinoin at a dose of 0.5–1 mg/kg/d has shown prolonged remission.249,250 Incision and drainage of therapy resisted, painful nodules, marsupialization with curettage of the cyst wall, complete scalp extirpation with skin grafting have been reported, but should be an exception for extreme and therapy refractory cases.250–252

Mixed Primary Cicatricial Alopecias

Acne Keloidalis Nuchae

Acne keloidalis nuchae (AKN) predominantly occurs in African-American men age 14 to 25. This idiopathic primary cicatricial alopecia might be triggered by trauma (shirt collars) or infection (Demodex or bacteria). Clinically AKN presents with skin-colored follicular papules, pustules and plaques as well as keloid-like scarred lesions in the occipital scalp (Fig. 88-22). Histologically, acne keloidalis is characterized by an acute inflammation with neutrophilic or lymphocytic infiltration and chronic granulomatous inflammation around the isthmus and the lower infundibulum. Treatment is usually difficult and protracted. Monthly intralesional triamcinolone acetonide (10–40 mg/mL) alone or combined with topical 2% clindamycin or oral (tetracyclines) antibiotics is the treatment of first choice.1,18,194,253,254 Class I or II topical steroids alone or in combination with topical antibiotics for mild cases of AKN as well as cryotherapy and laser therapy have shown some success. Surgical excision of extensive keloidal lesions may be considered but should be reserved for therapy refractory, extensive and symptomatic cases.

Acne Necrotica (Varioliformis)

Acne necrotica varioliformis is a very rare, chronic condition, which predominantly occurs in adults. Frontal and parietal scalp as well as seborrheic areas of the face are most commonly affected. Acne necrotica presents with umbilicated, pruritic or painful papules that undergo central necrosis. The condition leaves varioliform, or smallpox-like scars.255,256 Histology shows a suppurative, necrotic, infundibular folliculitis with lymphocytic or mixed inflammatory infiltrate.256 Oral antibiotics, isotretinoin, intralesional or topical corticosteroids have shown success.257 Excision of larger scarred areas can be considered.

Erosive Pustular Dermatosis

Erosive pustular dermatosis is an uncommon disorder predominantly occurring in elderly women.258,259 The characteristic lesion is a suppurative, necrotic, erosive papule or plaque.258,260 Histology of early lesions is nonspecific, but older lesions show an extensive, chronic mixed inflammatory infiltrate the dermis and later dermal fibrosis. Treatment include class I or II topical steroids with or without topical antibiotics, systemic antibiotics, and oral isotretinoin.258,260

Differential Diagnosis

(Box 88-6)

Prognosis and Clinical Course

Once the hair follicle is destroyed and replaced by fibrous tissue, there is no hope for hair regrowth. Various medical treatment options may fail and the inflammatory process may continue and leave the patient with a disfiguring permanent alopecia.

Treatment

The main goal in treating primary cicatricial alopecia is to stop the inflammation and therefore further progression of the disease. If hair loss is already extensive and/or medical treatment fails, patients should be advised about camouflage techniques, hairpieces and wigs. Women with extensive LPP lesion on the crown and vertex benefit highly from a well designed hair piece, which can look very natural, particularly if the frontal hairline is preserved and is usually more comfortable to wear compared to a full wig. Hair restoration surgery including HT and scalp reduction can be an option for burnt out cicatricial alopecia. No disease activity should occurs on the scalp for at least 1 year without therapy. The patient has to be warned about a possible limited graft survival and disease recurrence, which seems to be higher in neutrophilic primary.

Secondary Cicatricial Alopecia

Etiology and Pathogenesis

In secondary cicatricial alopecias, permanent hair loss is caused by various other scalp conditions not related to the hair follicle. In these conditions, the primary event develops outside the FU and this leads to incidental destruction of the follicle. Possible causes are congenital defects, trauma, inflammatory conditions, infections, neoplasms, and rarely drugs (eBox 88-6.1). Permanent, chronic traction alopecia and scars from surgery can be considered secondary scarring alopecias as well.261

Clinical Findings

A thorough clinical history is crucial in the diagnosis of secondary cicatricial alopecia. Diagnosis in early stages can sometimes be made based on specific clinical and histological features of the underlying disorder. Follicular orifices are lost clinically, and histology shows extensive scarring with fibrosis, loss of elastic fibers and adnexal structures.261

Differential Diagnosis

(Box 88-7)

Prognosis and Clinical Course

Prognosis and clinical course of secondary cicatricial alopecia depend on the underlying disease. Once scar tissue has formed and the adnexal structures are destroyed no hair regrowth can be expected.

Treatment

Treatment is specific in active conditions, while in localized end-stage lesions, specific medical treatment is no longer efficient and hair restoration surgery techniques become the mainstay of therapy.

An acute or chronic mechanical insult to the scalp hair may lead to reversible or irreversible alopecia of the scalp. Traumatic alopecias are usually of three types: (1) acute trauma, (2) prolonged traction, and (3) pressure.

Traumatic Injuries

Minimal or severe injuries to the scalp can result in alopecia. It usually presents with fine streaks of hair loss in the injured scalp area, but if the wound borders undergo contusion or destruction, this may result in irregular and large patches of hair loss. Traumatic hair loss can occur after scalp surgery, especially after extensive scalp reduction or large donor strip harvesting in hair restoration surgery, if too much tension is applied with wound closure. This type of hair loss is usually reversible but can also be permanent. Traumatic birth induced alopecia is infrequent; causes include mechanical extractor marks, tears or contusions or resulting infections. Aplasia cutis congenita should be considered in the differential diagnosis of cicatricial alopecia at birth.1

Traction Alopecia

Prolonged traction of the hair may lead to transient or if continued over a period of time, may lead to follicular atrophy, resulting in cicatricial alopecia. Chronic traction can be caused by tight ponytails, braids, heavy dread locks, or extensive use of rollers. Due to ethnic differences in hair fragility and cultural differences in hair styling practices, marginal traction alopecia is more commonly seen in African-American women due to hair braiding and weaving procedures1 (Fig. 88-23). Patchy traction alopecia in the frontal hairline or temples is commonly seen in Sikh boys, whose hair is usually tight up in a “topknot.”270 Cicatricial alopecia caused by prolonged traction can be treated with HT, if the patient discontinues the injuring hairstyles and sufficient donor hair supply is available.

Trichotillomania

Trichotillomania (Greek: tricho = hair, tillo = pull, mania = excessive excitement) is a form of traumatic alopecia caused by an irresistible compulsion to pull out or twist or break of one's own hair. Trichotillomania is relatively common with an estimated incidence of 1 million Americans.1 Two forms of trichotillomania can be distinguished: (1) infantile trichotillomania or (2) early onset trichotillomania, which starts in early childhood is typically of short duration and may resolve spontaneously or with simple interventions.271,272 Childhood trichotillomania may be seen analogous to other habitual infantile behaviors such as thumb sucking. Boys are more frequently affected. Trichotillomania, which starts around or after puberty, shows a more chronic course and is usually a sign of a more severe underlying psychopathology. It is classified as an impulse control disorder.273–275 Women are far more often affected than men. The clinical presentation is usually quite distinctive with a single or multiple asymmetrical, occasionally geometrically shaped areas of hair loss on the scalp or other areas of the body (Fig. 88-24). The areas are not smoothly devoid of hairs, as seen in alopecia areata but display short or bristly anagen hair. Telogen hair in the involved area is usually plugged out easily; anagen hair may be plucked out, twisted and broken at various lengths. Regrowing anagen hair needs to reach a certain length before it can be plugged out again. Alopecia areata and tinea capitis should be considered as differential diagnosis. Where doubt remains, a scalp biopsy can be diagnostic, showing a characteristic increase in catagen hair, trichomalacia and pigment casts within the follicular canal secondary to traumatic hair removal. Most important in the therapy of trichotillomania is the education of patient and/or parents and in late onset trichotillomania the treatment of the underlying psychopathology. Especially if patients deny the self-inflicting nature of their hair loss, a referral to a psychiatrist or psychologist is usually refused and treatment becomes difficult.

Pressure Alopecia

Pressure alopecia can occur after a patient was unconscious and completely immobile for a certain length of time. Hair loss is presumably due to ischemia caused by the pressure of the body weight to a certain scalp area. The ischemic injury may lead to permanent hair loss.

Hair shaft abnormalities are structural defects of the hair shaft. They can be inherited or acquired. Inherited hair shaft abnormalities can be associated with increased hair breakage or can lead to unruliness of the scalp hair.

Hair Shaft Abnormalities with Increased Hair Breakage

Trichorrhexis Nodosa

Trichorrhexis nodosa can be inherited or acquired. Affected hair shafts develop a breach in the cuticle with separation and fraying of the exposed cortical fibers, which leads to a node-like swelling.142 The fibers then fracture and the shaft breaks with the resultant appearance of a splayed paint brush or fan-like array (Fig. 88-25). Congenital trichorrhexis nodosa can be present at birth or may develop in the first months of life. In rare cases, Trichorrhexis nodosa can be associated with teeth and nail defects or hyperkeratosis1 and with metabolic disorders such as argininosuccinic aciduria (see Chapter 131), Menkes syndrome, and trichothiodystrophy.

Acquired trichorrhexis nodosa is much more common. Hair breakage may either occur in the proximal or distal hair shaft. Proximal trichorrhexis nodosa is more commonly seen in African-American women usually after repetitive chemical or hot-comb straightening. Distal trichorrhexis nodosa is mostly secondary to excessive brushing, teasing or chemical treatment such as bleaching or permanent waves. Patients with trichorrhexis nodosa should be advised to avoid any harsh chemical or physical hair styling practice. Proximal trichorrhexis nodosa may take month to year to resolve even if the initiating hair care is avoided.

Trichoschisis and Trichothiodystrophy

Trichoschisis is characterized by a clean transverse fracture of the hair shaft in an area of a focal absence of the cuticle. It is usually, but not specifically, a marker for sulfur-deficient hair in trichothiodystrophy, in which the scalp hair, eyelashes and eyebrows are short and brittle (see Chapter 139). The hair cysteine content is less than one-half normal, primarily from a major reduction and altered composition of the ultrahigh-sulfur matrix proteins.276 Microscopic examination with polarized light characteristically shows a “tiger tail” pattern with altering light and dark bands, secondary to alterations in the sulfur content1 (eFig. 88-25.1). Various structural abnormalities can be detected by confocal and scanning electron microscopy. These complex alterations make hair shafts in trichothiodystrophy excessively prone to breakage and weathering.1 Sulfur and amino acid analysis of the hair is diagnostic. Hair shaft abnormalities in trichothiodystrophy identify a group of autosomal recessive disorders that are associated with neuroectodermal abnormalities (eTable 88-1.2).

Trichoclasis

Trichoclasis is the common “greenstick” fracture of the hair shaft. It is characterized by a transverse fracture of the shaft, which is splinted partly or completely by intact cuticle. Cuticle, cortex and sulfur content are normal. Trichoclasis does not indicate any specific underlying disease. It can occur in normal hair or may be associated with pili torti.1

Pili Torti and Menkes Syndrome

In pili torti, the affected hair shafts are flattened and twisted on their axis, usually through an angle of 180°, with a range of 90°–360° (Fig. 88-26). The twisting occurs in multiple irregular intervals along an otherwise straight hair shaft. Pili torti do not signify a particular abnormality but can be seen in many different syndromes and in the presence of other hair shaft disorders.277 The way of inheritance in pili torti is mostly autosomal dominate, but can also be autosomal recessive or sporadic. Clinically, the patients may present with patchy alopecia with coarse stubble or longer broken hairs. Hair fragility usually improves after puberty.

Pili torti occurs in combination with trichorrhexis nodosa, trichoclasis, and trichoptilosis in Menkes kinky hair syndrome, also called steely hair syndrome or trichopoliodystrophy. Menkes syndrome is an X-linked recessive multisystem disease, which begins in infancy. It is associated with depigmented hairs, hypopigmentation of the skin, metal retardation, neurologic impairment secondary to degeneration of cerebral, cerebellar, as well as bone and connective tissue degeneration. The clinical features result from a defective copper transport and an accumulation of intracellular copper, which results in a functional deficiency of copper-dependent enzymes. Most patients die by the age of 3 years. In Menkes’ syndrome, copper uptake is normal, therefore copper supplementation is ineffective, but copper-histidin given immediately postpartum may prevent or ameliorate the severe neurodegeneration. Low serum concentrations and ceruloplasmin levels are diagnostic.1

Trichorrhexis Invaginata (“Baboo Hair”) and Netherton Syndrome

Trichorrhexis invaginata is a diagnostic marker for Netherton syndrome, although it also may occur sporadically and in association with other hair shaft abnormalities. Netherton syndrome is an autosomal recessive inherited disorder, characterized by a triad of atopic diathesis, ichthyosiform skin changes and trichorrhexis invaginata (see Chapter 49). The primary hair defect appears to be abnormal keratinization of the hair shaft in the keratogenous zone, allowing intussusception of the fully keratinized and hard distal shaft into the incompletely keratinized and soft proximal portion of the shaft.278 This leads to the typical “ball-and-socket” deformity (Fig. 88-27). Once the hair fractures, it shows a typical golf tee-shaped the distal end. Affected short, brittle hairs can be distributes over the scalp, which may result in sampling errors. Retinoids and phototherapy may be considered as therapy, although the condition frequently improves, as the patient gets older.

Monilethrix

Monilethrix present with extremely short, brittle, fragile, beaded hairs emerging from a hyperkeratotic follicular orifice. Monilethrix hair shafts show elliptical nodes, 0.7–1 mm apart, with intervening, tapered constrictions that are nonmedullated (Fig. 88-28). These internodes are the predetermined breaking points and often present with longitudinal ridges. Most cases of monilethrix are of autosomal dominant inheritance, with variable expression. In rare cases it is autosomal recessive. It is caused by one of the three genes encoding type II hair keratin (KHb1 or KRT81, KHb3 or KRT83, and KHb6 or KRT86). In the case of autosomal recessive inheritance, the underling gene encodes desmoglein 4 (DSG4). In mildest cases monilethrix is localized to the occiput or the nape of the neck. The hair shaft defect may occur alone or in association with keratosis pilaris, nail and teeth abnormalities, syndactyly, cataracts and physical retardation. Retinoids and topical minoxidil may improve the condition, although monilethrix frequently improves spontaneously with age.1,279,280

Localized Autosomal Recessive Hypotrichosis

This rare autosomal recessive disorder present with localized sparse broken hair involving scalp and eyebrows. The gene defect lies in a mutation in the gene for desmoglein 4 (DSG4). Unlike Monilethrix, the hair does not present with beading.281

Hair Shaft Abnormalities Associated with Unruly Hair

Uncombable Hair Syndrome

Uncombable hair syndrome, also known as spun glass hair or pili trianguli et canaliculi is an inherited autosomal dominant trait or a sporadic structural hair abnormality.282 This unique syndrome is characterized by rigid hair shafts with a triangular or kidney bean-shaped cross section, but irregular forms, such as flattened, heart-shaped and longitudinal grooves may be present. Clinically, the hair is dry, coarse, usually blond to light brown, and with a spangled appearance. The scalp hair is frizzy, unruly, kinky and unmanageable from infancy, grows in multiple directions and cannot be combed flat (Fig. 88-29). Male and female individuals are equally affected. It first occurs more often during early childhood, but it can develop as late as age 12 years. Microscopic analysis of hair samples under polarized light shows a homogeneous band on one edge caused by the shadow thrown as light passes over the pili canaliculi.283 There is no definitive therapy, but uncombable hair syndrome may improve over time without treatment.284

Wooly Hair

Wooly hair is a rare congenital structural anomaly of scalp hair. It is marked by an extreme kinkiness of the hair in Caucasians. Wooly hair can be present at birth or appear in the first months of life. The curls, which have an average diameter of only 0.5 cm, lie closely together and usually make the hair difficult to comb. In addition, the hairs may be more fragile than usual. Hair growth rate is usually normal but the anagen phase may be truncated, with the result that the hairs do not grow to be long. The hair shaft exhibits an elliptical cross section, an axial rotation and a kinked formation. A circumscribed occurrence of wooly hair in the form of a wooly hair nevus285 is distinguished from the forms that affect the entire scalp. The latter forms are: autosomal dominant wooly hair (hereditary wooly hair) and, the much rarer form, autosomal recessive hereditary wooly hair (familial wooly hair).286 Autosomal recessive hereditary wooly hair can be syndromic and accompanied by palmoplantar hyperkeratosis and heart anomalies (Fig. 88-30). No treatment is currently available. Harsh physical and chemical cosmetic treatments should be avoided. Wooly hair is most pronounced during childhood; the manifestation often becomes less severe in adulthood.

Marie–Unna Hypotrichosis

Marie–Unna hypotrichosis is of autosomal dominant inheritance and is characterized by sparse or absent hair at birth and variable coarse, wiry hair growth during childhood, affecting scalp and eyebrows. Once the child grows older, scalp hair is lost in a pattern, resembling AGA with scattered thick hair in the balding areas. Body hair is sparse or absent. Male and female individuals are equally affected. Light and electron microscopic examination shows irregular twisting, longitudinal ridging and cuticle peeling. Diffuse follicular hyperkeratosis and facial milia-like lesions may be present. Marie–Unna hypotrichosis results from mutations in the upstream untranslated open reading frame region of the hairless gene,287 which maps to chromosome 8p21.288 There is no known treatment.

Hair Shaft Abnormalities Unassociated with Breakage or Unruliness

Pili Annulati

Pili annulati or ringed hairs occur as an autosomal dominant or sporadic hair shaft abnormality without increased hair breakage. Pili annulati can be present at birth or develop during infancy. It is characterized by altering light and dark bands, which are secondary to air-filled cavities in the cortex.289 The ringed appearance is clinically only detectable in blond or light brown hair. The gene locus for pili annulati maps to chromosome 12q24.290,291 No treatment is necessary, although hair care practices should be gentle.

Hirsutism is defined as excessive growth of terminal hair in a male distribution in women.292 Hirsutism is indicated by a hirsutism score of 8 or more on the Ferriman–Gallwey scale (Fig. 88-31).61 It must be distinguished from hypertrichosis, generalized excessive hair growth that may be hereditary or result from certain medications in men and women. Hypertrichosis is distributed in a generalized, nonsexual pattern and is not caused by excess androgen (although hyperandrogenism may aggravate it).

Epidemiology

Approximately 5% of women of childbearing age are suffering from mild to severe hirsutism (Ferriman–Gallwey score 8 or higher).

Etiology and Pathogenesis

Prior to puberty, body hair is vellus (small, straight, and fair), and the sebaceous glands are small. In response to the increased levels of androgens at puberty, vellus follicles in specific areas develop into terminal hair follicles (larger, curlier, and darker). The growth of terminal body hair (sexual hair) is entirely dependent on the presence of androgens, especially testosterone.292 Higher androgen levels are required for the growth of beard hair than for pubic and axillary hair. In other areas of the body (for example, the forehead and cheeks), the increased androgen levels dramatically increase the size of the sebaceous glands while the hair remains vellus.

Hirsutism results from an interaction between the androgen level and the sensitivity of the hair follicle to androgens. Some women have hirsutism without evidence of androgen excess (“idiopathic hirsutism”). Most women with a twofold or greater elevation of androgen levels have some degree of hirsutism, but in others these levels are associated with a “hirsutism equivalent” (acne vulgaris, seborrhea, pattern alopecia, hidradenitis suppurativa, or hyperhidrosis).292

Androgen excess relates to an increase in bioactive free testosterone plasma levels. Total testosterone includes the albumin bound and SHBG (sex hormone binding globulin) bound testosterone. Hirsute women commonly have a relatively low level of SHBG and therefore more bioactive testosterone.62,293,294 Thus, the free testosterone level may be elevated when the total testosterone level is normal. SHBG levels are suppressed by the hyperinsulinemia of insulin-resistance and by androgen excess itself.62,295 The level of SHBG is also low in persons with hypothyroidism; rarely, it is congenitally absent.296

Clinical Findings and Diagnosis

Clinical diagnosis and scoring can be difficult since most women with hirsutism will practice various hair removal techniques. Therefore, it is useful to let the patient rate her degree of hair growth is different skin areas according to the Ferriman–Gallwey score (upper lip, chin and checks, chest, abdomen, pubic area and lower abdomen, arms, legs, upper back and lower back, and buttocks) with the help of images.

Laboratory Tests

If hirsutism is mild (Ferriman–Gallwey score 8–15) and menses are regular with no evidence of risk factors that would suggest a secondary cause, it is reasonable not to pursue laboratory evaluation, given the very high likelihood of idiopathic hirsutism. If hirsutism is moderate or severe (Ferriman–Gallwey score over 15), or there are features to suggest an underlying disorder (Box 88-8), androgen excess must be ruled out. An onset or progression of hirsutism or evidence of virilization (such as clitoromegaly or increasing muscularity) would raise concern for an androgen-secreting neoplasm.62,297 Since most androgenic drugs are not detected by testosterone assays, the history is particularly important. Medications that cause hirsutism include anabolic or androgenic steroids; thus, whether the patient is an athlete or has endometriosis or sexual dysfunction heightens this risk. Valproic acid is unique in raising plasma testosterone.298 The high frequency of PCOS as a cause of hirsutism warrants attention to evidence for anovulation (such as menstrual irregularity), obesity, metabolic syndrome, or insulin resistance (acanthosis nigricans or a family history of type 2 diabetes mellitus). If risk factors like menstrual irregularity are present, even normal degrees of focal hirsutism are usually associated with androgen excess.299 Other disorders to be considered include various endocrinopathies. Cushing syndrome is suggested by the development of truncal obesity, moon facies, buffalo hump, purple striae, or proximal muscle weakness; virilizing congenital adrenal hyperplasia or PCOS by a history of the premature development of pubic hair or acne; hyperprolactinemia by the presence of galactorrhea; and acromegaly by coarsening of the facial features or hand or foot enlargement.292

Special Tests

Once androgen excess is confirmed, further tests should be considered such as pregnancy test (if the patient has amenorrhea), pelvic ultrasonography (if an ovarian neoplasm or PCOS is suspected) and measurement of dehydroepiandrosterone sulfate and early morning 17-hydroxyprogesterone (if congenital adrenal hyperplasia or adrenal neoplasm is suspected), and a prolactin level. It may include measurement of thyroid function, adrenocortical function, and IGF-I. Further workup typically begins with dexamethasone suppression testing to determine the source of androgen. If androgen excess is not suppressible by dexamethasone, the presence of Cushing's syndrome, neoplasm, and PCOS must be considered. If androgen excess is dexamethasone-suppressible, an adrenocorticotropic hormone (ACTH) test for congenital adrenal hyperplasia is indicated. If an undetected neoplasm is suggested, further imaging studies may be warranted, such as abdominal computed tomography for adrenal neoplasm.300

Prognosis and Clinical Course

Hirsutism tends to get more severe as the patient gets older. Underlying disorders associated with hyperandrogenemia as mentioned earlier have to be ruled out.

Treatment

The main treatment goals are to remove the existing terminal hair and to prevent further vellus-to-terminal hair transformation. Direct hair removal should be considered for all women with hirsutism. In patients with moderate to severe hirsutism and women with androgen access additional medical therapy is necessary. Direct hair removal can be achieved with nonpermanent techniques such as shaving, depilatories (lasts 12 hours to a few days), waxing, threading and sugaring (lasts up to 4 weeks), or permanent hair removal techniques such as electrolysis (for white and blond hair) and photoepilation (intense pulsed light or laser). Several sessions of photoepilation at intervals of 4–6 weeks are necessary to achieve a satisfying result, since only anagen hair follicles with dark bulb areas can be destroyed by the light source. Topical eflornithine has been shown to slow down the hair cycle and can be used in combination with every hair removal technique.

The first line medical therapy is oral contraceptives, eventually in combination with antiandrogens. Glucocorticoids can be considered for women with hirsutism due to nonclassic congenital adrenal hyperplasia who have a suboptimal response to oral contraceptives and/or antiandrogens, cannot tolerate them, or are seeking ovulation induction. GnRH agonists in women with severe forms of hyperandrogenemia, such as ovarian hyperthecosis, who have a suboptimal response to oral contraceptives and antiandrogens.

Hypertrichosis is defined as an androgen-independent generalized, increased growth of hair on the body. The hair can be terminal or lanugo. Hypertrichosis can be acquired or inherited. Congenital hypertrichosis lanuginosa is characterized by a generalized overgrowth of silvery blonde to gray lanugo hair at birth or in early childhood. This rare condtion is thought to be of autosomal dominant inheritance with variable expressivity. Most patients display anomalous dental eruptions. Lanugo hair may persist, increase or decrease with age.301,302 Autosomal dominant Ambras syndrome or Hypertrichosis universalis congenita is characterized by much longer thicker hair distributed over the entire body with accentuation over the face ears and shoulders. Ambras syndrome can be associated with facial dysmorphism and dental anomalies.303–305 An X-linked dominant congenital generalized Hypertrichosis has been described in a five-generation family with an accentuation on the face and upper body.302,306 Patients with autosomal dominant or recessive gingival fibromatosis frequently display hypertrichosis, mostly on the face, eyebrows limbs and upper back, which may be associated with seizures and oligophrenia. Hypertrichosis may show a delayed onset until puberty although gingival fibromatosis usually appear with the emergence of the primary teeth1 (eBox 88-8.1).

Thanks to Dr. Elise Olsen, an active investigator of hair diseases, and author of this chapter in three previous editions for her contributions to hair research and to this text.