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Cicatricial Alopecia

Dr. Sandeep Gera


MBBS (AIIMS), MD (Gold Medallist),
Ex-Resident, Safdarjung Hospital, Delhi
Director and Consultant,
Skin Masters Clinic
 Cicatricial (scarring) alopecias form a group of disorders in
which permanent hair loss results from replacement of
follicles by fibrosis or hyalinized collagen.

 primary event due to inflammation targeted directly at the


hair follicle or

 secondarily as a result of incidental extension of an unrelated


inflammatory process such as syphilis or sarcoidosis to the
hair follicle
 The inflammatory infiltrate typically
involves the permanent portion of the
hair follicle which houses the bulge
region.

 Permanent hair loss may also occur in


the late stages of select nonscarring
alopecias. These “biphasic pattern”
alopecias, - alopecia areata, patterned
hair loss and traction alopecia
 In both PCA and secondary cicatricial alopecia, the
permanency of hair loss results from the acquired
inability of damaged hair follicles to regenerate after
injury,

 most likely as a result of irreversible damage to


epithelial hair follicle stem cells residing in the bulge
area of the outer root sheath
Diagnostic Approach

 Clinical history, thorough examination of the entire


scalp, and skin biopsies - crucial in the correct
diagnosis

 Clinical findings such as diffuse or perifollicular


erythema, follicular hyperkeratosis ,pigment
changes, tufting, pustules and general alopecic
pattern( frontal or central location, patchy or
reticulated appearance) provide further hints to the
diagnosis
 Diagnostic tools such as 3-fold magnifying
lens or a 10-fold magnifying dermatoscope
with and without polarised light can help to
identify the presence or absence of follicular
ostia in the affected areas.

 Presence of other symptoms, such as photo


sensitivity, may also help to support a
particular diagnosis( eg.DLE)
Diagnostic principles
 Scalp biopsy is mandatory in all clinically suspected
cases of PCA, particularly when the clinical picture
does not allow a firm diagnosis

 Ideally two 4-mm punch biopsies, oriented parallel to


the hair shaft should be taken from clinically active
hair bearing skin.

 These should be submitted for both vertical and


horizontal sectioning and staining with haematoxylin
and eosin
 The Verhoeffevan Gieson (VVG) elastin
stain may be of value in differentiating
advanced cases of DLE, lichen
planopilaris, and pseudopelade of Brocq,
which often have overlap features
Therapeutic principles

 The principle aim of treatment is to reduce


symptoms and, most importantly, to slow or
stop progression of the scarring process

 lymphocyte-predominant subgroup with


immuno- suppression and neutrophil-
predominant subgroup with antimicrobials
or dapsone
 Patients with completely stable, or
‘burned-out’ scarring( i.e. without
residual inflammatory activity), may
profit from scalp reduction surgery so as
to remove or reduce the cosmetically
and psychologically disturbing scar area,
possibly complemented by hair
transplantation
 LYMPHOCYTIC CICATRICIAL ALOPECIAS

Discoid lupus erythematosus-

Introduction and clinical features-

 well demarcated, erythematous and scaly plaques on sun-exposed


sites.

 Onset typically at the age of 20–40 years

 The plaques slowly enlarge, revealing atrophic scarring with variable


degrees of telangiectasia and dyspigmentation

 Scalp involvement is common in adults with DLE. Symptoms may


include pruritus, burning or scalp tenderness. Inflammatory activity is
most pronounced centrally within the area of alopecia.
 Follicular plugging and adherent scale may
be observed.

 A thorough examination along with


measurement of full blood count, urinalysis,
antinuclear antibodies and extractable
nuclear antigens is mandatory in all
affected individuals
 DLE Cont..features
Histopathological

 It include hyperkeratosis, follicular plugging and interface changes


(vacuolar > lichenoid) with resulting basal layer damage.

 Periadnexal and perivascular lymphocytic infiltrates may be seen in


both the superficial and deep dermis.

 A moderate amount of dermal mucin is usually present.

 The characteristic thickening of the basement membrane can be


identified with periodic acid-Schiff staining; an elastic stain such as
Verhoeff-van Gieson stain may help to identify a loss of elastic
fibers throughout the reticular dermis
 Treatment-

 photoprotection with a hat or a broad-spectrum sunscreen


should be used

 First-line treatment

 Potent topical corticosteroid-

 Weekly injections of intralesional triamcinolone acetonide (10


mg mL) demonstrated ‘improvement’ or clearance in 39 of 41
patients from two separate trials.

 Oral corticosteroids are not commonly used as standard


treatment in DLE as long-term maintenance therapy with these
DLE Cont..
 Second-line treatment

 Antimalarials: Hydroxychloroquine is used in a dose of 200-400 mg/day

 Oral retinoids

 An RCT of acitretin vs. hydroxychloroquine demonstrated overall clinical


improvement in two groups

 No statistically significant difference in efficacy between the two


treatments was demonstrated.

 However, side-effects were greater in the acitretin group. In particular,


acitretin can produce a dose-dependent telogen effluvium that is poorly
tolerated by patients with existing hair loss.
DLE Cont..

 Several other systemic therapies have been advocated for


treatment of DLE, with largely mixed outcomes.

 Thalidomide, including low-dose regimens, is effective in


recalcitrant disease,

 Other agents used include dapsone, mycophenolate


mofetil, methotrexate, azathioprine, vitamin E and
derivatives, clofazamine, gold, salicylate bismuth, systemic
(and intralesional) interferon-alfa-2, and monoclonal anti-
CD4 antibodies.
Lichen planopilaris (synonym:
follicular lichen planus)

 LPP is regarded as a follicular variant of


lichen planus (LP) based on
histopathological and
immunofluorescence findings.

 Three forms of LPP are recognized:


 Classic LPP,
 Frontal fibrosing alopecia and
 Graham little syndrome.
LPP Cont..

 Clinical features-

 Presenting symptoms in LPP include alopecia,


increased hair shedding, pruritus, burning and
tenderness.

 Perifollicular erythema and follicular


hyperkeratosis are seen in affected, hair bearing
skin, and are most prominent at the edge of the
alopecia.
 An expanding rim of activity develops, leaving a central
zone of scarring. Multifocal patches, often with a central
distribution, are common.

 Characterised by a reticulated pattern of scarring.

 Anagen hairs may be extracted from areas of active


disease. LPP tends to occur in adults and is more
common in women.
 Histopathological features -

 A lichenoid interface dermatitis involving the upper follicle


may be seen along with infundibular hyperkeratosis,
hypergranulosis, basal layer destruction and cytoid bodies.

 Sebaceous glands are often atrophic or absent.



Treatment-
First-line treatment-
 Intralesional triamcinolone acetonide (10 mg/cc every 4 to 6 weeks): can be maintained until
activity has been stabilized.

 Potent topical corticosteroid

 Second-line treatment-

 Oral corticosteroids : reserved for rapidly progressing, aggressive disease, and severe
subjective symptoms. Prednisone is added at 1 mg/kg daily and it can be tapered over 2–4
months
 Oral ciclosporin (300 mg daily over 3 to5 months)
 Topical ciclosporin
 Oral tetracycline
 Third-line treatment-:
 Oral retinoids (10 mg daily- isotretinoin & Acitretin 30mg/day)
 Antimalarials : Hydroxychloroquine has been utilized in the treatment for LPP.
First noticeable effects of treatment may be found within 2–3 months and
maximal clinical efficacy may take up to 6–12 months.
 Thalidomide
 Griseofulvin
 Mycophenolate mofetil
 Excimer laser

 Surgical treatment
 If active inflammation has not been present and the hair pull test is negative
for more than 2 years, hair transplantation and/or scalp reduction can be
attempted cautiously.
Frontal fibrosing alopecia

 first described by Kossard in 1994.

 Clinical features :-

 It is characterized by progressive symmetrical recession of the frontal


hairline revealing a pale band of skin (1–8 cm), lacking follicular ostia.

 This pale skin contrasts with darker, sun-damaged skin on the forehead,
with the zone of transition suggesting the location of the original hairline.

 Perifollicular inflammation and hyperkeratosis are often present but are


confined to the immediate hairline.
Frontal fibrosing alopecia Cont..

 Eyebrow involvement, with decreased hair or


complete loss, is very common and is regarded
as a helpful diagnostic sign.

 FFA tends to run a progressive course; however,


stabilization seems to occur with time and
patients with FFA that advances beyond the mid-
frontal scalp are rare.

 Most cases are seen in postmenopausal women.


Frontal fibrosing alopecia Cont..

 Histopathological features-
 FFA is felt to be a variant of LPP and the histology findings are usually
indistinguishable.

 Treatment
 The protocol for classic LPP may be followed. The following options
have been specifically described in FFA.
 Intralesional triamcinolone acetonide
 Finasteride
 Oral corticosteroids
 Antimalarials
 Topical corticosteroids
Graham Little syndrome (synonym: Graham
Little–Piccardi–Lassueur syndrome)

 Clinical features

 GLS is a rare condition characterized by the triad of progressive


scarring scalp alopecia, nonscarring loss of pubic and axillary hair and
widespread keratosis pilaris (KP)-like horny follicular papules, that may
resemble a severe case of seborrhoeic dermatitis. These three clinical
manifestations, however, need not be present simultaneously.

 Treatment
 The protocol for classic LPP may be followed.
Pseudopelade of Brocq

 Clinical features
 Classic PB most commonly affects women between the ages of 30
and 50 years.

 PB is characterized by multifocal, asymptomatic, flesh-coloured


patches of cicatricial alopecia. - ‘footprints in the snow’.

 The patches are often atrophic with no inflammation clinically


apparent; however, early lesions may display slight scale and follicular
erythema.

 Progressive hair loss and the ability to extract anagen hairs easily with
gentle traction are often the only evidence that the disease is active.

 Spontaneous resolution has been reported after 2–18 years of disease


activity.
 Histopathology
 Early PPB lesions show a sparse or moderate
lymphocytic infiltrate around the infundibulum

 Sebaceous glands are usually completely destroyed.

 In later lesions, the follicular epithelium becomes


progressively more atrophic and affected hair follicles
are often surrounded by concentric lamellar fibroplasias
until the follicle is finally replaced by fibrous tracts.
Pseudopelade of Brocq Cont..

 Treatment-:
 A patient’s history, a hair pull test, and measurements of
the size of the lesions can help to identify active areas of
disease.

 No clear treatment consensus is established for PB. The


following options have been specifically described in PB-

 Potent topical corticosteroids


 Hydroxychloroquine
 Thalidomide
Central centrifugal cicatricial alopecia
(synonyms: hot-comb alopecia; follicular
degeneration syndrome)
 Most patients with CCCA are African-American women,
although it can occur in men and in different ethnic groups.

 CCCA is characterized by slowly progressive scarring of the


crown and vertex that spreads in a symmetrical and centrifugal
pattern, resulting in permanent alopecia.

 Although usually asymptomatic, unusual sensations, such as


pins and needles, itch or tenderness may occur.

 The alopecia is incomplete, with a number of hairs remaining


within the area of scarring.
 This condition is often associated with traumatic hair-care
CCCA Cont..

Overview of follicular degeneration syndrome in

both an African American woman (A)


 Treatment-:

 Stop damaging hair-care practices


 Potent topical steroid PLUS oral tetracycline
 Intralesional triamcinolone acetonide
 Oral steroids if inflammation is not controlled
 Minoxidil in recovery phase
 Hair restoration procedures if stopped spreading for 1
year
Alopecia mucinosa (synonym: follicular
mucinosis)

 first described by Pinkus in 1957.

 AM is characterized by distinctive skin lesions associated with


histological evidence of mucin deposition within the hair follicle.

 Clinical Features-

 AM presents with follicular papules that may coalesce into one or


more erythematous, well-defined and indurated plaques.

 Close examination reveals prominent follicular openings with loss


of hair.
 Alopecia mucinosa Cont..
Alopecia may be scarring or nonscarring. It may involve any part of the
integument, with the face and neck being the commonest involved
sites.

 Symptoms may include dysaesthesia and pruritus.

 Three clinical forms of AM are recognized.


 Group 1 = lesions limited to the head and neck that resolve
spontaneously within a few months.
 Group 2 = widespread lesions that run a chronic and relapsing
course. Both group 1 and 2 occur in younger patients without a
demonstrable underlying disease (‘primary’ AM).
 Group 3 = widespread lesions occurring in older patients that are
often associated with an underlying lymphoproliferative disorder
(‘secondary’ AM).
Alopecia mucinosa Cont..
Alopecia mucinosa Cont..

 Histopathological features

 The key histological feature is


mucinous degeneration of the ORS
and sebaceous glands.

 Mucin staining is mandatory to


confirm the diagnosis.

 A perifollicular lymphocytic infiltrate


is usually found. Serial biopsies may
be required if lymphomatous
change is suspected, especially if
there is clinical disease progression.
Alopecia
 Treatment-:
mucinosa Cont..
 The possibility of spontaneous remission makes observation,
without treatment, an option in some patients; however, long-
term follow-up is recommended so as not to miss those
progressing to lymphoma. In secondary AM the underlying
condition must be treated.

 First-line treatment
 Potent topical corticosteroids

 Second-line treatment
 Intralesional triamcinolone acetonide
 Tetracycline antibiotics
 Topical ± oral indometacin
Keratosis follicularis spinulosa decalvans (synonyms:
keratosis pilaris decalvans; folliculitis spinulosa
decalvans; follicular ichthyosis)
 Keratosis follicularis spinulosa decalvans (KFSD) is a rare condition
characterized by widespread KP and scarring alopecia.

 Clinical features
 KFSD has three main stages of development:

 Onset occurs in infancy with KP developing on the face

 A second active stage then ensues during childhood and early adolescence
where progressive scarring alopecia develops

 The final stage, characterized by clinical improvement, generally occurs


after puberty. Variable degrees of hyperkeratosis, inflammation and
atrophy are seen and the scarring may be patchy or diffuse.
 KFSD Cont..
Secondary infections, manifesting as scalp pustules, are
common, difficult to control and may exacerbate the
scarring process.

 Less common features include photophobia, ocular


abnormalities (particularly corneal dystrophy), focal
palmoplantar keratoderma and atopy.

 KFSD is part of the heterogeneous group of disorders


termed keratosis pilaris atrophicans. The three main
entities are KFSD, keratosis pilaris atrophicans faciei (=
ulerythema ophyryogenes) and atrophoderma
vermiculatum.
KFSD Cont..

 Histological features -:

 KFSD is characterized by follicular plugging and hypergranulosis.

 An inflammatory infiltrate consisting of lymphocytes and neutrophils can be


seen in the infundibular epithelium at an early stage of disease
development.

 Later, the infiltrate is predominantly lymphocytic, and the follicle is


eventually replaced by fibrous tissue.

 Aetiology is unknown but it may represent a disorder of keratinisation.


KFSD Cont..

 Treatment-:

 Evidence for treatment is poor. The following


options have been described in KFSD-
 Potent topical corticosteroids ± keratolytics
 Oral antibiotics for pustular flares
 Dapsone
 Laser epilation
 Oral retinoids
Neutrophilic group
Folliculitis decalvans ⁄ tufted folliculitis

 Clinical features-:
 It is characterized initially by painful follicular pustules that become
crusted.
 Patches of alopecia develop from an expanding zone of folliculitis,
eventually resulting in a central area of scarring.

 the scar is indurated and boggy rather than atrophic

 Multiple hair tufts may be found emerging from a common dilated


follicular opening, giving the appearance of a doll’s hair.
 Staphylococcus aureus is frequently cultured and has been.
implicated in the pathogenesis of this disorder
Folliculitis decalvans
Cont..
Characteristic histologic findings
• Follicular plugging and intra/perifollicular neutrophilic infiltrate of
the upper and middle portions of the hair follicle
• Follicular rupture with recruitment of lymphocytes, histiocytes, and
plasma cells around the follicle
• Neutrophilic abscesses common
• Hair shaft granulomas prominent
• Late-stage replacement of hair follicles with scarred fibrous tracts
and dermal scar
Folliculitis decalvans Cont..
 Treatment
 First-line treatment
 Oral antibiotic ± topical antibiotic
 Minocycline, erythromycin, cephalosporins, or sulfamethoxazole
trimethoprim is variably effective and relapse after stoping drug is
frequent.

 Second-line treatment
 Oral rifampicin and oral clindamycin
 triple therapy with oral fusidic acid 1500 mg daily for 3 weeks, zinc sulfate
400 mg daily for 6 months, and topical 1.5% fusidic acid cream for 2 weeks.
 Relapse is commonly seen after discontinuation of the antibiotic and the
patient might have to stay on low dose antibiotics for many years
Dissecting cellulitis of the scalp (synonyms: perifolliculitis
capitis abscedens et suffodiens; dissecting folliculitis of the
scalp; Hoffman’s disease)

 Clinical features-:

 It is characterized by painful fluctuant nodules, abscesses and


interconnecting sinus tracts, which evolve into scarring alopecia.

 It predominantly affects black men in their second to fourth decades and


runs a chronic, relapsing course.

 DCS is associated with acne conglobata and hidradenitis suppurativa.

 These conditions all have the common pathogenic mechanism of follicular


hyperkeratosis causing follicular occlusion.
Dissecting cellulitis of the
scalp Cont..
 Characteristic histologic findings

 • Follicular plugging and collections


of neutrophils at the follicular ostia
 • Follicular rupture into the dermis
 • Extensive subcutaneous and
dermal abscess formation
 • Extensive dermal fibrosis and
replacement of follicular units by
scarred fibrous tracts

 Distinguishing features-:
 • Hallmark finding: sinus tracts lined
by stratified squamous epithelium
Dissecting cellulitis of the scalp
Cont..

 Treatment-:
 First-line treatment
 Oral isotretinoin
 Prolonged remission of the disease has been
achieved with isotretinoin 1 mg/kg/d for a minimum
of 4 months, maintained by 0.75 to 1 mg/kg/d for
an additional 5 to 7 months, or 0.75 mg/kg/d for 6
months, followed by 0.5 mg/kg/d for 3 more months

 Second-line treatment
 Oral antibiotics
 Tetracyclines, minocycline, cloxacillin,
erythromycin, cephalosporin, and clindamycin
Dissecting cellulitis of the scalp
Cont..
Mixed group-:
Acne keloidalis nuchae (synonyms: acne keloidalis;
folliculitis keloidalis; sycosis nuchae)
 chronic scarring folliculitis that typically affects young
black males.

 Clinical features-:
 It is characterized by the development of smooth, firm
follicular papules and pustules that may coalesce into
larger plaques; follicular destruction and permanent hair
loss ensue.
 Affected areas may become secondarily infected, resulting
in discharge and pain.
 The occipital scalp is most commonly affected; however,
lesions on the vertex and crown are not uncommon.
Acne keloidalis nuchae
Cont..
 Clinical features cont..

 AKN is a misnomer: there is no


follicular occlusion, as seen in
acne, nor is the scarring keloid
like.

 The pathogenesis of AKN is


unknown. Short-necked
individuals appear predisposed
and mechanical irritation has
been suggested as a possible
trigger.
Histopathological features
It shows perifollicular mixed infiltrate around the isthmus and sebaceous
glands.
Follicular epithelial thinning and lamellar fibroplasias develop with
extrusion of hair shafts that elicit a granulomatous reaction.
In late disease sebaceous glands are absent and marked fibrosis occurs.
Acne keloidalis nuchae
Cont..
 Treatment-:
 First-line treatment
 Potent topical steroid
 Oral antibiotics PLUS topical steroids ⁄intralesional
triamcinolone acetonide

 Second-line treatment
 Surgical excision
 Carbon dioxide laser excision
 Diode laser hair epilation

Acne necrotica varioliformis
(synonym: necrotizing
lymphocytic folliculitis)
 Clinical features
 Recurrent crops of lesions typically involve the anterior scalp but may
also involve the eyebrows, nose, neck and chest.

 The initial oedematous lesions become umbilicated and then develop


a central adherent crust, which is shed within a few weeks revealing a
varioliform scar.

 The condition tends to occur from the third decade onwards and runs a
chronic course.
Acne necrotica varioliformis
Cont..
 Histopathological features-:

 It reveals a dense perivascular and perifollicular


lymphocytic infiltrate with prominent subepidermal
oedema.

 Necrosis of individual keratinocytes is initially seen and is


soon followed by confluent necrosis of the central follicle
and interfollicular epidermis.

 The pathogenesis of ANV is unknown but suggested causes


include an abnormal immune response to S. aureus, a
variant of rosacea or as a result of autoinduced
Acne necrotica varioliformis
Cont..
 Treatment-:

 First-line treatment
 Antibiotics based on microbiological culture
 Empirical tetracycline antibiotics

 Second-line treatment
 Oral isotretinoin
 Intralesional triamcinolone acetonide
 Staphylococcal toxoid injections
Erosive pustular dermatosis
(synonym: erosive pustular
dermatosis of the scalp)
 Clinical features-:

 EPD is characterized by crusted, eroded and pustular lesions, confined to the


scalp, which result in scarring alopecia.

 It has a slowly progressive course and is usually asymptomatic.

 It predominantly affects elderly female patients.

 Microbiology of early lesions is usually sterile


Erosive pustular dermatosis
Cont..
 Histopathological features-:

 It is nonspecific, with variable degrees of epidermal


atrophy, erosions and pustule formation being present.

 The dermis contains a mixed chronic inflammatory


infiltrate with reduced or absent hair follicles but
preservation of the arrector pili muscle.

 The pathogenesis is unknown; however, most reports


describe some form of preceding trauma to the scalp
Erosive pustular dermatosis Cont..
 Treatment-:

 First-line treatment
 Topical corticosteroids

 Second-line treatment
 Topical immunomodulators
 Calcipotriol cream
 Oral zinc sulphate
 Oral nimesulide
 Oral corticosteroids
 Isotretinoin

 Other
Adjunctive treatments-
 If patients have associated androgenetic alopecia, a trial of
minoxidil solution (1 mL twice daily) may improve the
cosmetic appearance by thickening and lengthening
miniaturized hairs.

 Hair cosmetics, such as wigs or camouflage make-up, may


benefit some patients, especially those with extensive
disease.
Basic Surgical Technique:

 Surgical correction of cicatricial alopecia can yield exceptional results when performed in
the appropriate clinical scenario.

 To facilitate determination of the most suitable corrective therapy, two new categories of
cicatricial alopecia are proposed: “unstable” and “stable.”

 Unstable cicatricial alopecia is intermittent and results in possible subsequent scarring


hair loss in either new or old areas.

 Stable cicatricial alopecia, on the other hand, refers to fixed permanent scarring.

 While surgical excision is preferred to hair transplantation for both categories of


cicatricial alopecia, this preference is even stronger in cases of unstable cicatricial
alopecia due to its intermittent and progressive nature.
Basic Surgical Technique:

 Prior to considering any surgical treatment, it is


vital to have identified the type of alopecia and
also to have confirmed quiescence preferably for
at least 1 year.

 It is also important to explain to the patient that


if their disease becomes reactivated at any time,
the success achieved with surgery would likely
be affected unless the disorder is promptly
controlled.
CONCLUSION:

 The initial phase of many of the primary cicatricial


alopecias is nonscarring and should be managed as
a ‘‘trichologic emergency’’

 Prompt diagnosis and therapeutic intervention are


key to thwarting permanent hair loss and a potential
lifelong struggle with the psychosocial sequelae.

 Choice of treatment is dependent on diagnosis, age,


severity of disease, and extent.
 In general, local treatment should be used in limited
disease.

 Systemic modalities should be reserved for rapidly


advancing, extensive, local treatment-refractory, and
intractably symptomatic disease

 However, given the lack of controlled studies


regarding efficacy, an initial short-term course of an
empirically effective, relatively safe topical agent
may be warranted.

References:
Textbook of dermatology-Rook’s 8th edition
 Fitzpatricks’s Dermatology- 7th edition
 Cicatricial alopecia: classification and histopathology. Dermatologic Therapy, Vol. 21, 2008,
221–237
 Management of primary cicatricial alopecias: options for treatment. British Journal of
Dermatology 2008 159, pp1–22
 The surgical treatment of cicatricial alopecia. Dermatologic Therapy, Vol. 21, 2008, 295–311
 Folliculitis decalvans including tufted folliculitis: clinical, histological and therapeutic findings.
Br J Dermatol 1999: 328–333.
 Folliculitis decalvans. Clin Exp Dermatol 2001:26: 120–122.
 Pseudopalade of Broque. Dermatologic Therapy, Vol. 21, 2008, 257–263
 Cicatricial alopecia: discoid lupus erythematosus. Dermatologic Therapy, Vol. 21, 2008, 245–
248.
 Lichen planopilaris. Dermatologic Therapy, Vol. 21, 2008, 249-256.
 Diagnosis and Management of PrimaryCicatricial Alopecia: Part I & 2. Skinmed. 2008;7:19–
26 & 78-83.
 Secondary cicatricial and other permanent alopecias. Dermatologic Therapy, Vol. 21, 2008,
279–294
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