Follicular disorders of the face Kabir Sardana MD PII: DOI: Reference:
S0738-081X(14)00058-3 doi: 10.1016/j.clindermatol.2014.02.024 CID 6841
To appear in:
Clinics in Dermatology
Please cite this article as: Sardana Kabir, Follicular disorders of the face, Clinics in Dermatology (2014), doi: 10.1016/j.clindermatol.2014.02.024
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Follicular Disorders of the Face
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Kabir Sardana MD, Department of Dermatology & Sexually Transmitted Diseases, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi ,India
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CORRESPONDING AUTHOR:
Dr Kabir Sardana
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466, Sector 28
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NOIDA, UP, India 201303
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[email protected]
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Abstract:
Follicular disorders are possibly a commonly seen group of disorder which are defined as being localized around follicles and appendages and clinically present as small papules .Classically
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clinicopathological follicular plugging should be demonstrated in the “true” follicular disorders which are appropriately referred to as follicular keratosis. Another subtype is folliculitis (infectious or non infectious) and the follicular mimickers which clinically resemble “true” follicular disorders without the follicular keratoses . Acne vulgaris has a amalgamation of all the above lesion types . The “true” follicular disorders can have two clinical presentations , either keratotic papules or papules with prominent spines . The common disorders seen on the face include keratosis rubra pilaris, erythromelanosis follicularis , Dariers disease , pityriasis rubra pilaris, phrynoderma, follicular dermatitis, and lichen spinulosus .Rare disorder can be sometimes crucial markers for underlying disorder and include AIDS associated follicular eruptions , trichodysplasia spinulosa,MMDK,hyeprkeratotic spicules and acquired perforating disorders . The evergreen mimickers sarcoidosis ,syphilis ,drug eruptions, and contact dermatitis true to their reputation also have follicular presentations
ACCEPTED MANUSCRIPT Though a comprehensive list of conditions based on the various etiological causes is useful it most of the commonly seen follicular disorders are seen on the trunk and the extremities, though facial localizations leads to an early diagnosis and thus needs emergent intervention.
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Follicular disorders can be defined as conditions that morphologically are localized around the follicles and appendages and usually present as small papules and rarely as plaques that characteristically exhibit follicular keratotic plugging or have a visible hair emanating from it. 1
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The term “follicular‟‟ has been used both clinically and histologically and can have different meanings which is probably a reason why this group of disorders has rarely been classified 1 with no major textbook focusing adequately on this important and common entity. We feel that a morphological classification is a useful starting point instead of the conventional etiological classification especially in dermatological disorders even though purists would prefer a clinichistological correlation which is not always seen.
Clinical Connotation
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There are numerous disparate conditions that manifest clinically with a “follicular morphology‟ and can be either “true” follicular disorders or follicular “mimickers”. The “true” follicular disorders are conditions with a demonstrable clinicopathological follicular plugging and these are also referred to as follicular keratosis 2. Some books use the term “folliculocentric” disorders to describe this entity.2 Probably the most classic primary disorders are keratosis pilaris, pityriasis rubra pilaris and keratosis follicularis. This also includes disorders which have a follicular
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predilection such as GVHD, follicular syphilis, papular eczema (seen in darkly pigmented individuals) and follicular pityriasis rosea. The second category of “true” follicular disorder are disorders which
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are characterized by inflammation histologically and are clinically referred to as “folliculitis” and can be either infectious or non infectious in origin. A polymorphic amalgamation of these three forms is seen in acne vulgaris .The follicular “mimickers‟‟ are conditions that have a follicular morphology because of their size and localization but are papules without any evidence of follicular keratosis. These include entities like follicular contact dermatitis and appendageal tumours on the face and are best called follicular “mimickers”. Clinically the true follicular lesions can either have a discernible keratotic papule or a predominant spine with a small papule and we will largely focus on this category (“true” follicular disorders) in our review (fig 1)
Histological Connotation Paradoxically, there are entities that may have a pathology localized to the follicles which may not always have a clinical follicular morphology and include histological entities like follicular spongiosis (table1)3 and transepithelial elimination (table 2)4 with an enlarged follicular infundibulum. On the face, most biopsies show a follicular involvement more so if there is associated parakeratosis 5.This is because of the large number of follicles on the face which are more likely to be involved incidentally in any condition with parakeratosis 5 Also chronic itching
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leads to enlarged follicular infundibula and this may not always have a corresponding clinical follicular morphology 5 .This is seen in cases of prurigo simplex/nodularis and lichen simplex chronicus. 5 Conversely histological entities like follicular SCC, follicular melanoma, follicular baso-squamous melanocytic tumor and follicular pigmented cyst do not clinically have a follicular morphology. To complicate matters lymphomas have been described to have a follicular histology which has different connotations as here the term relates to the “lymph node” like architecture seen in this condition.1 For example follicle center cell lymphoma describes a group of conditions with follicular dendritic cells and reactive follicles, with a histology resembling a lymphnode with a variably mature mantle or germinal centers. The clinical morphology though is characterized by solitary or grouped papules, plaques and tumours, often surrounded by erythematous patches. Lastly there are tumors with a follicular differentiation which arise from the follicular sebaceous unit. Histology this is important in the “true” follicular disorders but converse is not true as not all follicular histological entities have a corresponding clinical morphology.
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As there is never been a previous classification of follicular disorders, our classification is an all encompassing morphological approach with entities that may “look‟ follicular without a corresponding histolological correlation. (Table 3) This is as our focus is the clinician for whom the clinical morphology is probably more important. Though there is never been a previous study on these disorders , we had sub-analysed follicular eruptions (table 4) in our study on pediatric dermatoses, wherein keratosis pilaris ,lichen spinulosus and follicular eczema were the commonest conditions seen 6 apart from acne which is not the focus of this review . To make the classification simple we have divided the conditions into primary and secondary disorders which have been further subclassified into common and rare causes (Table 3). Acne vulgaris, folliculitis and genodermatosis /syndromes with follicular keratoses will not be discussed here.
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Overview of Common Conditions
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We will discuss the important conditions and for sake of simplicity have divided them into the major or common disorders and the minor or the relatively uncommon disorders.
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Major Conditions
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Keratosis Pilaris
Synonym(s): Lichen pilaris; keratosis suprafollicularis; pityriasis pilaris
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This is the prototype primarily follicular keratotic disorders and the variants that predominantly affect the face include keratosis rubra pilaris and keratosis atrophicans facei .It may be either
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physiological or associated with dry skin and is often seen in ichthyosis vulgaris (40%) and atopic eczema (70%)7. In a large pediatric dermatology study
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keratosis pilaris was the
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commonest follicular disorder seen (table 4, fig 2).
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Aetiology
It may occur in isolation or can be consequent to a mutation in filaggrin as is seen in ichthyosis 8
A severe form has been reported (translocations and deletions of chromosome 18p)
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vulgaris.
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and a X-linked dominant form has been reported in women 9. Clinical Features
The common sites of affliction are the extensor surfaces of the upper arms, thighs and buttocks and cheeks though uncommonly a generalised or unilateral distribution has been reported. The term keratosis rubra pilaris is used when erythema is marked and is seen on the cheeks and eyebrows10, though the erythema is not obvious in pigmented skin .This entity probably is a forme frust of erythromelanosis follicularis facei et colli which is associated with truncal keratosis pilaris. 1,2,11,12 Morphologically, the lesions consist of multiple acuminate follicular keratotic papules with perifollicular erythema1,2,12 (Fig 3 ). The follicular lesions may have a protruding keratin spine which is referred to as the „antenna sign‟2(fig 3). Classically, on removal of the keratotic
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.This plug is composed of keratin, sebum or
hair .Once the papule is removed a new one forms rapidly. The lesions get worse in dry climates and in the winter months but tend to improve with age. In tropical countries, the lesions improve
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during summers due to the ambient humidity.
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Clinical Variants
1. Keratosis pilaris atrophicans (KPA) These are a group of clinically related disorders
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characterised by follicular keratotic papules, variable perifollicular inflammation and end-stage atrophy1,2 which involve the face1 . The nosology is debated
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as only keratosis follicularis
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spinulosa decalvans has been comprehensively genetically mapped. The various subtypes are
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given below. 12
(a) Keratosis pilaris rubra atrophicans faciei (ulerythema ophryogenes) variant (18p11.2) 1,2,12 This autosomal dominant or sporadic condition is characterised by
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follicular papules with an erythematous halo, localised over the lateral eyebrows
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which eventually lead to scarring alopecia (fig 4) . It begins shortly after birth and diminishes with age. Alopecia is localised to the eyebrows and photophobia is
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absent. There can be associated keratosis pilaris on extensor surfaces. The associated syndromes seen include Noonan‟s syndrome and woolly hair syndrome
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alone .
(b) Atrophoderma vermiculatum:
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It is autosomal dominant or sporadic in
inheritance with an onset between the ages 5 and 12 years. There are follicular keratotic papules with surrounding erythema which heal with atrophic pits in a
reticulate honeycomb pattern. It involves the cheek, neck and the limbs. There is no alopecia and photophobia is absent. (c) Keratosis follicularis spinulosa decalvans:1,2,12,15 This sporadic or X-linked recessive dominant disorder (Xp21.13–p22.2) has been associated with the SSAT gene which is associated with hair loss in mice and is characterized by follicular hyperkeratosis of the skin and corneal dystrophy. Symptoms are never present at birth and generally develop in early childhood. Symptomatic female carriers develop dry skin, minimal follicular hyperkeratosis and mild
ACCEPTED MANUSCRIPT hyperkeratosis of the soles, but have no eye findings . The sites involved are the scalp, eyebrows, eyelashes, cheeks, nose, neck and dorsa of hand and the follicular papules are associated with loss of hair, especially of the scalp, eyebrows and eyelashes (fig 5). Scarring alopecia,(fig 6) with marked
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photophobia is seen. The keratotic follicular papules develop on the scalp in the first few years of life followed by progressive scarring alopecia resembling
are,
follicular
hyperkeratosis,
hyperkeratosis of the knees
prominent
cuticles,
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and
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findings
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folliculitis decalvans(fig 6) with variable degrees of inflammatory change .Other
and calcaneal region of the soles . Complete
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spontaneous improvement often occurs at puberty. (d) Folliculitis spinulosa decalvans:1,12 It is an autosomal dominant condition seen at
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puberty. It is characterised by formation of follicular pustules on the scalp with alopecia.
2. Erythromelanosis follicularis faciei et colli:1,2,11,12 (EFFC)This is characterised by a triad of
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erythema, hyperpigmentation and follicular plugging on the cheeks and the preauricular centrifacial erythrosis
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area (Fig.7). Interestingly there is a report of a woman who had
pigmentosa peribuccalis which involved the cheeks. Other areas affected include the neck
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anterior to the angle of the mandible. It is frequently misdiagnosed in pigmented skin as the erythema is masked substantially by the natural pigmented skin colour. All cases have
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associated keratosis pilaris. A list of differentials of this disorder is given in table 5. 3. Keratosis Rubra Pilaris 10(KRP) This condition is probably more commonly seen in fair skinned population and was first described by Voss et al 17 .The term used initially was keratosis follicularis17 and this was subclassified as keratosis follicularis alba and keratosis follicularis rubra.17 The alba form had follicular papules without erythema, was seen in children younger than 10 years, with a equal sex distribution. The rubra form had erythematous follicular-based papules, increased in frequency with age, and was seen in patients of 20 to 40 years of age. The description of the latter form is similar to the entity KRP. The conditions that closely mimic this including EFFC wherein the follicular papules with perifollicular erythema involving the cheeks, forehead, and neck. The features that differentiate EFFC
ACCEPTED MANUSCRIPT from KRP are lack of reported involvement on the torso and the presence of hyperpigmentation in EFFC. KPA is distinguished by the inevitable scarring and is localised to the face contrary to the widespread areas of skin involvement in KRP.
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4. Follicular ichthyosis: This entity might be the same as keratosis pilaris but is frequently described as follicular papules in association with ichthyosis and is described later.
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Histopathology 1,2,11,12
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Classically the follicular orifice is distended by a horny plug which may contain one or more twisted hair with mild inflammatory changes in the dermis. The histopathology though in most
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cases is non - specific, resembles lichen spinulosus and is generally not useful in diagnosis.
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In keratosis pilaris atrophicans, severe inflammation may occur in the early stages and in the late stages, atrophy of the epidermis is noted. In EFFC there is slight follicular hyperkeratosis with increased epidermal pigmentation. Diameters of the hair shafts and outer root sheaths are
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decreased, as is the thickness of the inner root sheath. The adnexae are often surrounded by a
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lymphocytic infiltrate, the thickness and the compactness of the horny layer are usually increased
Therapy 1,2,11,12
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and an increase in the percent area of superficial blood vessels has been noted.
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The therapy is never satisfactory and the results are never complete and this should be explained to the patient upfront. It is important to keep the skin hydrated by avoiding harsh soaps which aggravate xerosis. A trend towards aggravation in winter and partial subsidence in summers supports this concept. The basic principle is to target the inflammation and the hyperkeratosis concomitantly. Topical therapy:1,2,11,18 The various agents tried include emollients; tretinoin (0.050.1%),; 12 % ammonium lactate ; medium potency corticosteroids, keratolytics such as lactic acid, 10% -20% urea cream and salicylic acid 2–5% cream or gel applied twice daily. The basic principle of topical therapy is to use a mild cleanser (salicylic acid 2 %) followed by application of a cream containing a keratolytic/humectants alternating with a
ACCEPTED MANUSCRIPT mild steroid. In case of inflammation, a short course of topical steroids or tacrolimus is helpful. In case of infection, topical clindamycin can be used. Oral therapy:1,11 Amongst oral agents, isotretinoin is a useful agent specially in cases
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of EFFC. Isotretinoin in a low dose of about 20 mg alternate day for a month can be used
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for initial control of the condition.
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Peels 1
Both salicylic acid peels (20-30%) and glycolic acid peels have been employed
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empirically but the results are not consistent or permanent. Lasers:19-22 The initial lasers tried were the IPL and PDL which
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largely improved
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the erythema and probably are of value in patients with fair skin. It should be emphasised that in pigmented skin, the results are not dramatic with an added risk of
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postinflammatory hyperpigmentation. Though a plethora of lasers from Q switched lasers to milipulse lasers22 have been used targeting the erythema, pigmentation and the
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keratotic papules, with the basic principle being targeting the chromophore which is the
temporary.
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vessels, the pigment or the hair in the follicle. But the results of lasers are variable and
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Pityriasis rubra pilaris
Pityriasis rubra pilaris (PRP) is a folliculocentric disorder that involves the head and neck region1,23,24 .The Griffiths 25 classification is conventionally followed (Table 6) though other classifications have been proposed26,23 (table 7) and occasionally there may be a transition of the clinical condition between these types . Aetiopathogenesis 23,24,27,28
The exact cause remains largely unknown though the epidermis exhibits an increased epidermal thymidine labelling .Some believe that there is a relationship between PRP and vitamin A metabolism but this has not been consistently proven . Some types (Type V) may have familial clustering and autosomal dominant inheritance with variable expression and incomplete penetrance .Occasionally autosomal recessive inheritance has been documented. Clinical Features2,23-25
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In the classical type the eruption begins as an erythematous, scaly macule on the head, neck or upper trunk (fig 8). This is followed by erythematous perifollicular keratotic papules which coalesce to form plaques (fig 9) and may merge to involve the whole body with erythroderma within 12 weeks. Classically there are areas of unaffected skin, the so called “island of sparing ‟‟ seen on the trunk (fig 9). The scalp has diffuse branny scaling while the palms and soles are hyperkeratotic (PRP „sandal‟) .The nails are thickened, discoloured and show splinter haemorrhages .
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Investigations 29,30
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The histology of classical PRP is diagnostic but is dependent on the site and stage of the disease. A non - follicular erythematous plaque is preferred for biopsy as it gives consistent results than a biopsy of an active follicle. Early PRP lesions are difficult to diagnose histologically because of poorly developed pathology. There is follicular plugging with parakeratosis in the perifollicular zone and the interfollicular epidermis. There is a basket-weave hyperkeratosis with hypergranulosis alternating with parakeratosis with hypogranulosis. Parakeratosis is patchy, varying in both vertical and horizontal planes (alternating orthokeratosis and parakeratosis), suggesting an intermittent defect, and is referred to as the “checker-board ‟‟pattern. A pathognomic finding is the presence of suprabasal perinuclear vacuolation in isolated cells, resembling “poached eggs”. Liquefactive degeneration of the basal layer has been reported and is most likely to be seen overlying the dermal papillae. Mild superficial vasodilatation of the capillaries, with a slight to moderate lymphohistiocytic perivascular infiltrate can also be seen Therapy
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There is no cure for PRP, and a standard universal treatment is lacking. In cases with erythroderma an intensive topical and supportive treatment is needed which is beyond the scope of this review. As a general rule in Type 2,4,5,6 (Table 6) systemic therapy may be needed while in other types topical therapy will suffice. Most children should be treated with topical therapy alone with the goal of increasing skin comfort. An evidence based approach is given below. Systemic Therapy23,24 First-Line Therapy 1. Retinoids Oral retinoids are widely used but the results are unpredictable and the patient should be counseled about this at the outset. The use of systemic retinoids may shorten the natural history of the disease, but further studies are needed to confirm this finding 31 . Acitretin 23,31,32
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It is considered the first-line systemic therapy for PRP. Initial dosing typically starts at 1 mg/kg/d divided into two doses and can be increased to 2 mg/kg/d if needed. Significant clearing is typically seen over a 3- to 6-month course. The cure rate is estimated at 82%. Although systemic retinoids are associated with premature closure of the epiphyseal growth plate, acitretin has been used with success in type III PRP. Isotretinoin 33 has also been used in doses up to 2 mg/kg/d in children under 19 years of age with good results. 2 Methotrexate 2,23, 34
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It is a commonly used systemic immunosuppressant for the treatment of PRP but the response is not as dramatic as in psoriasis .Therapy is initiated at a dose of 2.5 mg once weekly, with incremental increases in dosing as needed for disease control. Patients typically require 10–25 mg weekly, with an expected response in 3–6 months. Doses up to 50 mg weekly have been used. Folic acid 1 mg daily is typically taken with methotrexate to prevent myelosuppression and reduce mucositis. Second-Line Therapy
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Biologicals 2,23,335-37
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Third-Line Therapy
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Biological agents such as infliximab, etanercept and efalizumab, have been used but are not effective in all cases. Biologic agents targeting tumour necrosis factor (TNF) are now considered second-line therapy, and they are typically used for patients who have not or have only partially responded to systemic retinoids and/or methotrexate. A recent meta analysis has found that 36TNF-antagonists may be of value in treating adult type 1 PRP refractory to other systemic agents but selective reporting bias, together with the lack of standard diagnostic criteria and established spontaneous resolution in PRP, prevent any firm recommendations on their place in management.
If PRP is refractory to retinoids, methotrexate and TNF immunosuppressive agents should be considered for third-line therapy. 1.Cyclosporine 23,38Several isolated cases of PRP reportedly responded well to cyclosporine therapy. response in 3–4 weeks, followed by rapid decrease minimise adverse effects. Full response often requires
antagonists,
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refractory to systemic retinoids have Dosing is initiated at 5 mg/kg/d with in dosing to 2–3 mg/kg/d in order to 12–20 weeks of therapy.
2 Azathioprine 23 Although azathioprine has been shown to be efficacious in some isolated cases of difficult to manage PRP, it is less commonly used than cyclosporine. Dosing usually begins at 2–2.5 mg/kg/d divided into one to three doses. 3 Corticosteroids 23 PRP is poorly responsive to oral steroids; however, they can be used for short-term symptomatic management of severe and acute-onset PRP. Typically, patients are
ACCEPTED MANUSCRIPT started on prednisone 1 mg/kg/d, tapering over 2–4 weeks while other systemic medications are initiated. Fourth-Line Therapy 23
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1 Intravenous Immunoglobulin There is one report where a patient with refractory PRP, ongoing for 10 years, was treated successfully with IVIg therapy. IVIg 2 g/kg was administered over 3 days and then repeated every 4 weeks with significant improvement of acral hyperkeratosis. 23,39,40
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2 Phototherapy and Extracorporeal Photochemotherapy
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Phototherapy in general is not believed to be a reliable treatment for PRP, and on occasion, is actually felt to trigger this condition. Narrow-band UVB, UVA1, PUVA, bath PUVA and extracorporeal photopheresis have all been reported to be beneficial and can be used in some cases .Phototherapy may be combined with acitretin akin to its use in psoriasis.
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3 HAART 2,41
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Antiretroviral therapy is of variable value in the Type VI PRP-like eruption of HIV disease and was not found to be useful in three non-HIV cases.
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Topical Therapy 2,23,24,42,43
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This may be used for the management of localised or mild PRP, either alone or in addition to systemic agents. Topical agents may also be the drug of choice in children with PRP.
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1 Topical Corticosteroids: Medium (class III) to high potency (class I) topical corticosteroids applied twice daily to affected areas of the body can help with symptomatic management of burning and pruritus. However, generally PRP is poorly responsive to topical steroids. 2 Topical Calcineurin: Inhibitors These may be used for localised disease in thin-skinned areas including the face, scalp and intertriginous areas. 3 Topical Retinoids: Topical retinoids such as tazarotene have been exclusively used in the management of type IV PRP however, this is better used in conjunction with other topical or systemic agents. Tretinoin 0.05% cream has been shown to improve pruritus, erythema and hyperkeratosis after 2 months, and lesion size by 50% after 6 months, in patients with type IV PRP. 4 Emollients and Keratolytics: These are useful for symptomatic management of PRP. Griffiths 42 favored a mixture of 20% propylene glycol, 10% urea in equal parts of liquid paraffin and white soft paraffin, occluded at night. Emollients such as hydrated petrolatum or
ACCEPTED MANUSCRIPT petroleum jelly applied liberally several times daily can aid in preserving skin moisture by preventing skin fissuring, maintaining skin integrity and decreasing restriction secondary to skin tightness. Keratolytics such as urea 20% cream or salicylic acid 3–10% in petroleum jelly applied twice daily to palms and soles can improve thickened acral surfaces and ease discomfort associated with palmoplantar keratoderma.
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Darier’s disease (Keratosis follicularis) 2,44
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Darier‟s disease is a genetic disease of disordered keratinisation which affects the skin, mucosa and nails .It is inherited as an autosomal dominant disease with a high penetrance (95%), but variable expressivity, and considerable interfamilial phenotypic differences have been noted 2,44. Occasional sporadic cases also occur due to de novo mutations. Aetiology
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It is reliably believed that Darier‟s disease is consequent to mutations in the ATP2A2 gene at chromosome 12q24.1, which encodes the sarco/endoplasmic reticulum calcium ATPase type 2 (SERCA2)45,46. The defect can be either a nonsense or insertion/deletion mutations which produces haploinsufficiency, leading to a defective function in the SERCA2b function44-46 . This affects the compensatory mechanisms which regulate the endoplasmic reticulum leading to reduced calcium concentrations with consequent disruption of the membrane proteins . Furthermore the keratinocytes desmosomal proteins are affected leading to a failure of 47. adhesion Clinical Features
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1. Cutaneous changes2,44,48: Skin signs generally develop between 6 and 20 years of age, with a peak around puberty. A change in sweating pattern, pattern of sebum secretion and bacterial flora may play a part in this. The lesions may vary from the subtle minute acanthomas to the more pronounced flat and freckle-like pale macules (guttate leukoderma) in pigmented skin. Skin-coloured to yellow-brown, firm, greasy papules (Fig.10) are the salient morphologic markers of Darier‟s disease. These lesions predominantly affect the „seborrhoeic sites‟ such as the scalp, forehead, behind and in front of the ears, nasolabial folds and the adjoining cheeks, front and back of the chest, axilla groin and natal cleft. The heavy scalp crusting imparts a characteristic spiny feel but hair loss is uncommon. Coalescence of the papules produces irregular warty plaques or papillomatous masses, which, in the flexures, become hypertrophic, fissured and malodorous. On the dorsa of the hands and feet, discrete papules are clinically indistinguishable from acrokeratosis verruciformis of Hopf. Small pits or punctuate keratoses may be found involving the palms and soles. Pruritus is common, occurring in 80% of patients, and may be intractable; pain is unusual. The other variants include hypertrophic, vesiculobullous, cornifying, comedonal, haemorrhagic, hypopigmented and acral forms.
ACCEPTED MANUSCRIPT 2. Mucosal changes2,44,48: These are observed in 15–50% of cases, with oral mucosal involvement being the most common. White umbilicated/cobblestone papules (Fig. 5) may be found affecting the palate, alveolar mucosa, tongue, buccal mucosa, epiglottis, pharyngeal walls, esophagus, vulva and rectum. Confluence of papules leads to the formation of leukoplakic plaques. Blockage of salivary glands has also been reported.
Clinical Variants
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3. Nails 2,44,48: These may be affected in up to 90% of the cases. Commonly observed changes are nail fragility, longitudinal ridging and splitting, subungual hyperkeratotic fragments beneath the free margin of the nail, longitudinal red or white lines and a characteristic V-shaped scalloping of the nails at the distal end. 2,49
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Some patients present with multiple comedones or nodulocystic acne with deep pitted scars with a histology of Darier‟s disease50. Haemorrhagic macules represent a rare form where lesions are seen on the hands and feet 51
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Course of the Disease
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Unilateral localised variants have been seen which are phenotypically and histologically identical to the lesions of classic Darier‟s disease with the notable absence of nail manifestations.
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Darier‟s disease runs a chronic course with exacerbations and remissions. Exacerbations occur in hot weather, with excessive exposure to sunlight or UVB radiation, friction, sweating and infections. Lithium therapy and steroids are known to precipitate and exacerbate the condition .Occasionally, women describe deterioration perimenstrually. Severe complications are rare, but there is an increased susceptibility to herpes simplex infections, Kaposi‟s varicelliform eruptions and pox virus infections. Chronic dermatophytosis and secondary bacterial overgrowth are also common. Histopathology.
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Early lesions show lacunae which appear above the basal layer and extend irregularly throughout the epidermis .The cells separate and have a darkly staining nucleus surrounded by clear cytoplasm and a glistening ring and are known as „corps ronds‟ and this is consequent to premature partial keratinization (dyskeratosis).These eventually turn into grains wherein the cells become smaller and are seen in the upper layers of the epidermis. The histology is not strictly follicular53,54 as these findings can also localized around around sweat ducts and mucous and salivary glands .Focal acantholytic dyskeratosis also occurs in other conditions, like solitary dyskeratoma, transient and persistent acantholytic dermatoses and Hailey–Hailey disease (chronic familial benign pemphigus) the last of which may overlap clinically and histologically.54 The differences are that the hyperkeratosis and follicular plugging is more
ACCEPTED MANUSCRIPT pronounced in Darier‟s disease , suprabasal clefts are smaller , dyskeratotic cells (corps ronds and grains) are more evident while acantholytic cells are less evident than in Hailey–Hailey disease.55 Therapy 2,44,56
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The patient should be told upfront that the disease will flare and will last a lifetime in most cases with a definite risk of transmission to the progeny. In mild cases emollients, simple hygiene and photoprotection will suffice. Though topical tretinoin and isotretinoin, adapalene and tazarotene are effective irritancy is a deterrent to continue use .A regimen of emollients in conjunction with retinoids is a practical therapeutic regimen. A topical steroid/antibiotic combination is a useful adjunct which can be used twice weekly to prevent infection and ameliorate the inflammation. In severe cases oral therapy is given commonly with acitretin and isotretinoin while occasionally cyclosporine has been tried.
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Topical Therapy 2.44.57
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Topical tazarotene: Tazarotene gel has been used in concentrations of 0.05, 0.03 (0.05% gel diluted with purified water) and 0.1% in various studies. Short contact therapy (15 minutes) and concomitant topical steroids can allay the irritation and dryness. Remission can be achieved in 2–6 weeks.
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Topical vitamin D3 analogues: Use of 0.002% tacalcitol has been shown to improve skin changes within 2 weeks and normalize the histopathological as well as immunohistochemical alterations (in the form of altered involucrin expression) associated with the disease.
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Topical tacrolimus: Use of topical tacrolimus 0.1% ointment twice a day led to a dramatic improvement within 2 weeks and complete remission after 6 weeks of use, in a patient in whom systemic retinoids had to be stopped due to depressive symptoms. Topical steroids: These control the overlying inflammation with little impact on the disease per se. Topical antibacterials/antifungals: These are used in the presence of a superimposed bacterial/fungal infection. Topical 5-FU: Use of 1% 5-FU daily/alternate day has shown good responses in a few case reports, with no associated systemic side effects.
Oral Therapy 2,44,
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• Oral retinoids58: Retinoids are the most effective drugs for this disease. They can reduce the hyperkeratosis and flatten the papules, and may also improve the malodour. Acitretin is the commonly used retinoid in Darier‟s disease. A dose of 10–25 mg daily is a reasonable starting dose and it can be increased gradually depending on the response. It may take 2–3 months before acitretin shows its maximal effect. In some cases, etretinate may be useful, particularly if acitretin fails. Isotretinoin, 0.5–1 mg/kg/d, is recommended for young females because pregnancy needs to be avoided for only 1 month after stopping treatment, in contrast to 2–3 years with acitretin. A low-dose maintenance therapy may be warranted to avoid a possible future relapse, though some patients require oral retinoids only in summers to prevent exacerbations during this time.
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•Oral prednisolone and cyclosporine59: Oral steroids or cyclosporine can be used to reduce inflammation in patients with „eczematised‟ disease.
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• Oral contraceptives: Its continuous use helps in clearing the disease in females who have perimenstrual exacerbations. • Diltiazem: It is shown to be of benefit in recalcitrant cases.
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Surgical Therapy 2,44,60,61
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• Dermabrasion: It has been employed to smoothen the keratotic papules and plaques, and has given cosmetically acceptable result. It is recommended that the procedure should include the entire papillary dermis in order to achieve favourable results
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• Electrosurgery: It has been employed in a few cases resistant to medical therapy, with good results.
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• Laser ablation: Er:YAG and CO2 Laser ablation has shown variable clinical efficacy in Darier‟s disease. Treatment with the flashlamp-pumped pulsed-dye laser has also been shown to improve the cutaneous condition. Recently, fractional photothermolysis using fractionated 1550-nm erbium-doped fibre laser has been shown to be efficacious in Darier‟s disease with a low complication rate. • Photodynamic therapy: Using aminolaevulinic acid/methylaminolevulinate has been evaluated as sole/adjunctive treatment with variable responses. A few patients have been shown to have an excellent response while in others, exacerbations developed after treatment. Follicular eczema 1,6,62-66 (Syn :Patchy Pityriasiform Lichenoid Eczema, Follicular Atopic Eczema, Papular eczema )
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Though this entity is mentioned in passing in specialty textbooks 1,62,64 and is largely associated with atopic dermatitis64,65 it is our belief that in pigmented skin it is commonly seen but frequently misdiagnosed and is associated with a generally dry skin 63. In fact a large pediatric analysis of skin conditions from India (table 4, fig 2) 6 found that follicular eczema was the fourth commonest follicular disorder . Clinical Features
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This dry, slightly itchy, follicular form of eczema (fig 11) that can resemble “goose-skin” is seen in childhood and was described first by Japanese authors and is believed to be a minor variant of atopic eczema 62,64,65. The partly confluent follicular skin coloured papules with a mildly branlike, scaling superimposed on a generally dry skin is the reason for its apt alternative name “patchy pityriasiform lichenoid eczema” 1,63,66.Other features seen include mildly scaly depigmented areas which resemble pityriasis alba, and isolated, frequently asymmetric, lichenified lesions on the backs of the hands or elbows .The common sites are the lateral trunk, nape of the neck, extensor aspect of the knees and uncommonly the face which is seen in the localized form of the condition (fig 11) 62,64,65 The condition characteristically worsens in winter or in dry conditions and improves in summer or in the humid seasons. 62,63,65
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Histopathology 4,
Therapy63
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Histologically , the lesions exhibit spongiosis of the follicular epithelium and an intra- and perifollicular lymphohistiocytic infiltration, which not only is indicative of the eczematous nature of this condition but is an reason for the apt alternative name “follicular eczema ‟‟ appended to this entity 1,62,63 The adjacent epidermis may show mild acanthosis and focal parakeratosis .
Apart from measures to alleviate the xerosis, midpotent steroids can be used which helps in achieving complete resolution in about three weeks.
Nutritional Follicular Keratoses 1,67 This all encompassing entity describes dermatoses which are consequent to nutritional defects due to vitamins, essential fatty acids and proteins and lead to follicular eruptions which include phrynoderma, dyssebacea and scurvy 1. The cutaneous manifestations of riboflavin, pyridoxine, niacin, and EFA deficiency probably have similar clinical presentations 67,68. This is consequent to the intersecting biochemical pathways that involve these nutrients which can explain the common cutaneous findings including the follicular eruption. Riboflavin is required for pyridoxine metabolism, which, in turn, is required for tryptophan-niacin metabolism, and niacin is necessary for fatty acid synthesis. 70 This explains cases of pellagra which have follicular manifestations on the face resembling phrynoderma (fig 12 ). 67. The entity nutritional follicular
ACCEPTED MANUSCRIPT keratoses also has therapeutic implications as a wide based nutritional supplementation is essential in cases of follicular dermatoses with nutritional deficiency.
1,12,69
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Phrynoderma
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Phrynoderma (toad skin) is a form of follicular hyperkeratosis that is associated with various nutritional deficiencies. Though historically associated with Vitamin A deficiency it is now known to occur with various nutritional states like malnutrition, intestinal malabsorption, anorexia nervosa or fad diets . It is seen in children and adolescents aged between 5 and 15 years but adults and lactating women may also be affected.
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Aetiology
There are three theories which have been proposed to explain this condition.
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Vitamin deficiency: The term „phrynoderma‟, was first used by Lucius Nicholls in 1933 to describe the hyperkeratotic folliculitis which he had observed in African labourers who were vitamin A deficient. But diet survey and serum Vit A levels in apparently healthy phrynoderma patients and normal controls revealed no statistically significant difference between the two groups71. Also the earlier belief that Vit A deficiency as a cause of phrynoderma was largely based on the therapeutic response to cod liver oil, which was considered to be a source of Vit A but is now known to contain EFA also . Phrynoderma has been reported even in individuals who were fed Vit A rich diet.72 Conversely not all those with vitamin A deficiency develop this cutaneous manifestation and other deficiencies of vitamins B complex, C and E have now been implicated. It is now certain that the response to Vit A therapy/isotretinoin is attributable to its effect on keratinisation and not primarily as a nutritional supplement. Nutritional deficiency1,12,69: It is believed that phrynoderma may be a manifestation of nutritional deficiency without any specific deficit of vitamins. This is because there are patients on calorie-restricted diet (
S0738-081X(14)00058-3 doi: 10.1016/j.clindermatol.2014.02.024 CID 6841
To appear in:
Clinics in Dermatology
Please cite this article as: Sardana Kabir, Follicular disorders of the face, Clinics in Dermatology (2014), doi: 10.1016/j.clindermatol.2014.02.024
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Follicular Disorders of the Face
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Kabir Sardana MD, Department of Dermatology & Sexually Transmitted Diseases, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi ,India
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CORRESPONDING AUTHOR:
Dr Kabir Sardana
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466, Sector 28
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NOIDA, UP, India 201303
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[email protected]
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Abstract:
Follicular disorders are possibly a commonly seen group of disorder which are defined as being localized around follicles and appendages and clinically present as small papules .Classically
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clinicopathological follicular plugging should be demonstrated in the “true” follicular disorders which are appropriately referred to as follicular keratosis. Another subtype is folliculitis (infectious or non infectious) and the follicular mimickers which clinically resemble “true” follicular disorders without the follicular keratoses . Acne vulgaris has a amalgamation of all the above lesion types . The “true” follicular disorders can have two clinical presentations , either keratotic papules or papules with prominent spines . The common disorders seen on the face include keratosis rubra pilaris, erythromelanosis follicularis , Dariers disease , pityriasis rubra pilaris, phrynoderma, follicular dermatitis, and lichen spinulosus .Rare disorder can be sometimes crucial markers for underlying disorder and include AIDS associated follicular eruptions , trichodysplasia spinulosa,MMDK,hyeprkeratotic spicules and acquired perforating disorders . The evergreen mimickers sarcoidosis ,syphilis ,drug eruptions, and contact dermatitis true to their reputation also have follicular presentations
ACCEPTED MANUSCRIPT Though a comprehensive list of conditions based on the various etiological causes is useful it most of the commonly seen follicular disorders are seen on the trunk and the extremities, though facial localizations leads to an early diagnosis and thus needs emergent intervention.
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Follicular disorders can be defined as conditions that morphologically are localized around the follicles and appendages and usually present as small papules and rarely as plaques that characteristically exhibit follicular keratotic plugging or have a visible hair emanating from it. 1
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The term “follicular‟‟ has been used both clinically and histologically and can have different meanings which is probably a reason why this group of disorders has rarely been classified 1 with no major textbook focusing adequately on this important and common entity. We feel that a morphological classification is a useful starting point instead of the conventional etiological classification especially in dermatological disorders even though purists would prefer a clinichistological correlation which is not always seen.
Clinical Connotation
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There are numerous disparate conditions that manifest clinically with a “follicular morphology‟ and can be either “true” follicular disorders or follicular “mimickers”. The “true” follicular disorders are conditions with a demonstrable clinicopathological follicular plugging and these are also referred to as follicular keratosis 2. Some books use the term “folliculocentric” disorders to describe this entity.2 Probably the most classic primary disorders are keratosis pilaris, pityriasis rubra pilaris and keratosis follicularis. This also includes disorders which have a follicular
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predilection such as GVHD, follicular syphilis, papular eczema (seen in darkly pigmented individuals) and follicular pityriasis rosea. The second category of “true” follicular disorder are disorders which
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are characterized by inflammation histologically and are clinically referred to as “folliculitis” and can be either infectious or non infectious in origin. A polymorphic amalgamation of these three forms is seen in acne vulgaris .The follicular “mimickers‟‟ are conditions that have a follicular morphology because of their size and localization but are papules without any evidence of follicular keratosis. These include entities like follicular contact dermatitis and appendageal tumours on the face and are best called follicular “mimickers”. Clinically the true follicular lesions can either have a discernible keratotic papule or a predominant spine with a small papule and we will largely focus on this category (“true” follicular disorders) in our review (fig 1)
Histological Connotation Paradoxically, there are entities that may have a pathology localized to the follicles which may not always have a clinical follicular morphology and include histological entities like follicular spongiosis (table1)3 and transepithelial elimination (table 2)4 with an enlarged follicular infundibulum. On the face, most biopsies show a follicular involvement more so if there is associated parakeratosis 5.This is because of the large number of follicles on the face which are more likely to be involved incidentally in any condition with parakeratosis 5 Also chronic itching
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leads to enlarged follicular infundibula and this may not always have a corresponding clinical follicular morphology 5 .This is seen in cases of prurigo simplex/nodularis and lichen simplex chronicus. 5 Conversely histological entities like follicular SCC, follicular melanoma, follicular baso-squamous melanocytic tumor and follicular pigmented cyst do not clinically have a follicular morphology. To complicate matters lymphomas have been described to have a follicular histology which has different connotations as here the term relates to the “lymph node” like architecture seen in this condition.1 For example follicle center cell lymphoma describes a group of conditions with follicular dendritic cells and reactive follicles, with a histology resembling a lymphnode with a variably mature mantle or germinal centers. The clinical morphology though is characterized by solitary or grouped papules, plaques and tumours, often surrounded by erythematous patches. Lastly there are tumors with a follicular differentiation which arise from the follicular sebaceous unit. Histology this is important in the “true” follicular disorders but converse is not true as not all follicular histological entities have a corresponding clinical morphology.
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As there is never been a previous classification of follicular disorders, our classification is an all encompassing morphological approach with entities that may “look‟ follicular without a corresponding histolological correlation. (Table 3) This is as our focus is the clinician for whom the clinical morphology is probably more important. Though there is never been a previous study on these disorders , we had sub-analysed follicular eruptions (table 4) in our study on pediatric dermatoses, wherein keratosis pilaris ,lichen spinulosus and follicular eczema were the commonest conditions seen 6 apart from acne which is not the focus of this review . To make the classification simple we have divided the conditions into primary and secondary disorders which have been further subclassified into common and rare causes (Table 3). Acne vulgaris, folliculitis and genodermatosis /syndromes with follicular keratoses will not be discussed here.
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Overview of Common Conditions
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We will discuss the important conditions and for sake of simplicity have divided them into the major or common disorders and the minor or the relatively uncommon disorders.
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Major Conditions
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Keratosis Pilaris
Synonym(s): Lichen pilaris; keratosis suprafollicularis; pityriasis pilaris
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This is the prototype primarily follicular keratotic disorders and the variants that predominantly affect the face include keratosis rubra pilaris and keratosis atrophicans facei .It may be either
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physiological or associated with dry skin and is often seen in ichthyosis vulgaris (40%) and atopic eczema (70%)7. In a large pediatric dermatology study
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keratosis pilaris was the
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commonest follicular disorder seen (table 4, fig 2).
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Aetiology
It may occur in isolation or can be consequent to a mutation in filaggrin as is seen in ichthyosis 8
A severe form has been reported (translocations and deletions of chromosome 18p)
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vulgaris.
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and a X-linked dominant form has been reported in women 9. Clinical Features
The common sites of affliction are the extensor surfaces of the upper arms, thighs and buttocks and cheeks though uncommonly a generalised or unilateral distribution has been reported. The term keratosis rubra pilaris is used when erythema is marked and is seen on the cheeks and eyebrows10, though the erythema is not obvious in pigmented skin .This entity probably is a forme frust of erythromelanosis follicularis facei et colli which is associated with truncal keratosis pilaris. 1,2,11,12 Morphologically, the lesions consist of multiple acuminate follicular keratotic papules with perifollicular erythema1,2,12 (Fig 3 ). The follicular lesions may have a protruding keratin spine which is referred to as the „antenna sign‟2(fig 3). Classically, on removal of the keratotic
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1,2
.This plug is composed of keratin, sebum or
hair .Once the papule is removed a new one forms rapidly. The lesions get worse in dry climates and in the winter months but tend to improve with age. In tropical countries, the lesions improve
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during summers due to the ambient humidity.
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Clinical Variants
1. Keratosis pilaris atrophicans (KPA) These are a group of clinically related disorders
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characterised by follicular keratotic papules, variable perifollicular inflammation and end-stage atrophy1,2 which involve the face1 . The nosology is debated
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as only keratosis follicularis
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spinulosa decalvans has been comprehensively genetically mapped. The various subtypes are
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given below. 12
(a) Keratosis pilaris rubra atrophicans faciei (ulerythema ophryogenes) variant (18p11.2) 1,2,12 This autosomal dominant or sporadic condition is characterised by
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follicular papules with an erythematous halo, localised over the lateral eyebrows
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which eventually lead to scarring alopecia (fig 4) . It begins shortly after birth and diminishes with age. Alopecia is localised to the eyebrows and photophobia is
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absent. There can be associated keratosis pilaris on extensor surfaces. The associated syndromes seen include Noonan‟s syndrome and woolly hair syndrome
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alone .
(b) Atrophoderma vermiculatum:
1,2,12
It is autosomal dominant or sporadic in
inheritance with an onset between the ages 5 and 12 years. There are follicular keratotic papules with surrounding erythema which heal with atrophic pits in a
reticulate honeycomb pattern. It involves the cheek, neck and the limbs. There is no alopecia and photophobia is absent. (c) Keratosis follicularis spinulosa decalvans:1,2,12,15 This sporadic or X-linked recessive dominant disorder (Xp21.13–p22.2) has been associated with the SSAT gene which is associated with hair loss in mice and is characterized by follicular hyperkeratosis of the skin and corneal dystrophy. Symptoms are never present at birth and generally develop in early childhood. Symptomatic female carriers develop dry skin, minimal follicular hyperkeratosis and mild
ACCEPTED MANUSCRIPT hyperkeratosis of the soles, but have no eye findings . The sites involved are the scalp, eyebrows, eyelashes, cheeks, nose, neck and dorsa of hand and the follicular papules are associated with loss of hair, especially of the scalp, eyebrows and eyelashes (fig 5). Scarring alopecia,(fig 6) with marked
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photophobia is seen. The keratotic follicular papules develop on the scalp in the first few years of life followed by progressive scarring alopecia resembling
are,
follicular
hyperkeratosis,
hyperkeratosis of the knees
prominent
cuticles,
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and
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findings
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folliculitis decalvans(fig 6) with variable degrees of inflammatory change .Other
and calcaneal region of the soles . Complete
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spontaneous improvement often occurs at puberty. (d) Folliculitis spinulosa decalvans:1,12 It is an autosomal dominant condition seen at
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puberty. It is characterised by formation of follicular pustules on the scalp with alopecia.
2. Erythromelanosis follicularis faciei et colli:1,2,11,12 (EFFC)This is characterised by a triad of
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erythema, hyperpigmentation and follicular plugging on the cheeks and the preauricular centrifacial erythrosis
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area (Fig.7). Interestingly there is a report of a woman who had
pigmentosa peribuccalis which involved the cheeks. Other areas affected include the neck
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anterior to the angle of the mandible. It is frequently misdiagnosed in pigmented skin as the erythema is masked substantially by the natural pigmented skin colour. All cases have
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associated keratosis pilaris. A list of differentials of this disorder is given in table 5. 3. Keratosis Rubra Pilaris 10(KRP) This condition is probably more commonly seen in fair skinned population and was first described by Voss et al 17 .The term used initially was keratosis follicularis17 and this was subclassified as keratosis follicularis alba and keratosis follicularis rubra.17 The alba form had follicular papules without erythema, was seen in children younger than 10 years, with a equal sex distribution. The rubra form had erythematous follicular-based papules, increased in frequency with age, and was seen in patients of 20 to 40 years of age. The description of the latter form is similar to the entity KRP. The conditions that closely mimic this including EFFC wherein the follicular papules with perifollicular erythema involving the cheeks, forehead, and neck. The features that differentiate EFFC
ACCEPTED MANUSCRIPT from KRP are lack of reported involvement on the torso and the presence of hyperpigmentation in EFFC. KPA is distinguished by the inevitable scarring and is localised to the face contrary to the widespread areas of skin involvement in KRP.
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4. Follicular ichthyosis: This entity might be the same as keratosis pilaris but is frequently described as follicular papules in association with ichthyosis and is described later.
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Histopathology 1,2,11,12
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Classically the follicular orifice is distended by a horny plug which may contain one or more twisted hair with mild inflammatory changes in the dermis. The histopathology though in most
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cases is non - specific, resembles lichen spinulosus and is generally not useful in diagnosis.
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In keratosis pilaris atrophicans, severe inflammation may occur in the early stages and in the late stages, atrophy of the epidermis is noted. In EFFC there is slight follicular hyperkeratosis with increased epidermal pigmentation. Diameters of the hair shafts and outer root sheaths are
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decreased, as is the thickness of the inner root sheath. The adnexae are often surrounded by a
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lymphocytic infiltrate, the thickness and the compactness of the horny layer are usually increased
Therapy 1,2,11,12
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and an increase in the percent area of superficial blood vessels has been noted.
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The therapy is never satisfactory and the results are never complete and this should be explained to the patient upfront. It is important to keep the skin hydrated by avoiding harsh soaps which aggravate xerosis. A trend towards aggravation in winter and partial subsidence in summers supports this concept. The basic principle is to target the inflammation and the hyperkeratosis concomitantly. Topical therapy:1,2,11,18 The various agents tried include emollients; tretinoin (0.050.1%),; 12 % ammonium lactate ; medium potency corticosteroids, keratolytics such as lactic acid, 10% -20% urea cream and salicylic acid 2–5% cream or gel applied twice daily. The basic principle of topical therapy is to use a mild cleanser (salicylic acid 2 %) followed by application of a cream containing a keratolytic/humectants alternating with a
ACCEPTED MANUSCRIPT mild steroid. In case of inflammation, a short course of topical steroids or tacrolimus is helpful. In case of infection, topical clindamycin can be used. Oral therapy:1,11 Amongst oral agents, isotretinoin is a useful agent specially in cases
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of EFFC. Isotretinoin in a low dose of about 20 mg alternate day for a month can be used
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for initial control of the condition.
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Peels 1
Both salicylic acid peels (20-30%) and glycolic acid peels have been employed
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empirically but the results are not consistent or permanent. Lasers:19-22 The initial lasers tried were the IPL and PDL which
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largely improved
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the erythema and probably are of value in patients with fair skin. It should be emphasised that in pigmented skin, the results are not dramatic with an added risk of
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postinflammatory hyperpigmentation. Though a plethora of lasers from Q switched lasers to milipulse lasers22 have been used targeting the erythema, pigmentation and the
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keratotic papules, with the basic principle being targeting the chromophore which is the
temporary.
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vessels, the pigment or the hair in the follicle. But the results of lasers are variable and
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Pityriasis rubra pilaris
Pityriasis rubra pilaris (PRP) is a folliculocentric disorder that involves the head and neck region1,23,24 .The Griffiths 25 classification is conventionally followed (Table 6) though other classifications have been proposed26,23 (table 7) and occasionally there may be a transition of the clinical condition between these types . Aetiopathogenesis 23,24,27,28
The exact cause remains largely unknown though the epidermis exhibits an increased epidermal thymidine labelling .Some believe that there is a relationship between PRP and vitamin A metabolism but this has not been consistently proven . Some types (Type V) may have familial clustering and autosomal dominant inheritance with variable expression and incomplete penetrance .Occasionally autosomal recessive inheritance has been documented. Clinical Features2,23-25
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In the classical type the eruption begins as an erythematous, scaly macule on the head, neck or upper trunk (fig 8). This is followed by erythematous perifollicular keratotic papules which coalesce to form plaques (fig 9) and may merge to involve the whole body with erythroderma within 12 weeks. Classically there are areas of unaffected skin, the so called “island of sparing ‟‟ seen on the trunk (fig 9). The scalp has diffuse branny scaling while the palms and soles are hyperkeratotic (PRP „sandal‟) .The nails are thickened, discoloured and show splinter haemorrhages .
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Investigations 29,30
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The histology of classical PRP is diagnostic but is dependent on the site and stage of the disease. A non - follicular erythematous plaque is preferred for biopsy as it gives consistent results than a biopsy of an active follicle. Early PRP lesions are difficult to diagnose histologically because of poorly developed pathology. There is follicular plugging with parakeratosis in the perifollicular zone and the interfollicular epidermis. There is a basket-weave hyperkeratosis with hypergranulosis alternating with parakeratosis with hypogranulosis. Parakeratosis is patchy, varying in both vertical and horizontal planes (alternating orthokeratosis and parakeratosis), suggesting an intermittent defect, and is referred to as the “checker-board ‟‟pattern. A pathognomic finding is the presence of suprabasal perinuclear vacuolation in isolated cells, resembling “poached eggs”. Liquefactive degeneration of the basal layer has been reported and is most likely to be seen overlying the dermal papillae. Mild superficial vasodilatation of the capillaries, with a slight to moderate lymphohistiocytic perivascular infiltrate can also be seen Therapy
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There is no cure for PRP, and a standard universal treatment is lacking. In cases with erythroderma an intensive topical and supportive treatment is needed which is beyond the scope of this review. As a general rule in Type 2,4,5,6 (Table 6) systemic therapy may be needed while in other types topical therapy will suffice. Most children should be treated with topical therapy alone with the goal of increasing skin comfort. An evidence based approach is given below. Systemic Therapy23,24 First-Line Therapy 1. Retinoids Oral retinoids are widely used but the results are unpredictable and the patient should be counseled about this at the outset. The use of systemic retinoids may shorten the natural history of the disease, but further studies are needed to confirm this finding 31 . Acitretin 23,31,32
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It is considered the first-line systemic therapy for PRP. Initial dosing typically starts at 1 mg/kg/d divided into two doses and can be increased to 2 mg/kg/d if needed. Significant clearing is typically seen over a 3- to 6-month course. The cure rate is estimated at 82%. Although systemic retinoids are associated with premature closure of the epiphyseal growth plate, acitretin has been used with success in type III PRP. Isotretinoin 33 has also been used in doses up to 2 mg/kg/d in children under 19 years of age with good results. 2 Methotrexate 2,23, 34
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It is a commonly used systemic immunosuppressant for the treatment of PRP but the response is not as dramatic as in psoriasis .Therapy is initiated at a dose of 2.5 mg once weekly, with incremental increases in dosing as needed for disease control. Patients typically require 10–25 mg weekly, with an expected response in 3–6 months. Doses up to 50 mg weekly have been used. Folic acid 1 mg daily is typically taken with methotrexate to prevent myelosuppression and reduce mucositis. Second-Line Therapy
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Biologicals 2,23,335-37
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Third-Line Therapy
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Biological agents such as infliximab, etanercept and efalizumab, have been used but are not effective in all cases. Biologic agents targeting tumour necrosis factor (TNF) are now considered second-line therapy, and they are typically used for patients who have not or have only partially responded to systemic retinoids and/or methotrexate. A recent meta analysis has found that 36TNF-antagonists may be of value in treating adult type 1 PRP refractory to other systemic agents but selective reporting bias, together with the lack of standard diagnostic criteria and established spontaneous resolution in PRP, prevent any firm recommendations on their place in management.
If PRP is refractory to retinoids, methotrexate and TNF immunosuppressive agents should be considered for third-line therapy. 1.Cyclosporine 23,38Several isolated cases of PRP reportedly responded well to cyclosporine therapy. response in 3–4 weeks, followed by rapid decrease minimise adverse effects. Full response often requires
antagonists,
other
refractory to systemic retinoids have Dosing is initiated at 5 mg/kg/d with in dosing to 2–3 mg/kg/d in order to 12–20 weeks of therapy.
2 Azathioprine 23 Although azathioprine has been shown to be efficacious in some isolated cases of difficult to manage PRP, it is less commonly used than cyclosporine. Dosing usually begins at 2–2.5 mg/kg/d divided into one to three doses. 3 Corticosteroids 23 PRP is poorly responsive to oral steroids; however, they can be used for short-term symptomatic management of severe and acute-onset PRP. Typically, patients are
ACCEPTED MANUSCRIPT started on prednisone 1 mg/kg/d, tapering over 2–4 weeks while other systemic medications are initiated. Fourth-Line Therapy 23
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1 Intravenous Immunoglobulin There is one report where a patient with refractory PRP, ongoing for 10 years, was treated successfully with IVIg therapy. IVIg 2 g/kg was administered over 3 days and then repeated every 4 weeks with significant improvement of acral hyperkeratosis. 23,39,40
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2 Phototherapy and Extracorporeal Photochemotherapy
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Phototherapy in general is not believed to be a reliable treatment for PRP, and on occasion, is actually felt to trigger this condition. Narrow-band UVB, UVA1, PUVA, bath PUVA and extracorporeal photopheresis have all been reported to be beneficial and can be used in some cases .Phototherapy may be combined with acitretin akin to its use in psoriasis.
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3 HAART 2,41
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Antiretroviral therapy is of variable value in the Type VI PRP-like eruption of HIV disease and was not found to be useful in three non-HIV cases.
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Topical Therapy 2,23,24,42,43
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This may be used for the management of localised or mild PRP, either alone or in addition to systemic agents. Topical agents may also be the drug of choice in children with PRP.
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1 Topical Corticosteroids: Medium (class III) to high potency (class I) topical corticosteroids applied twice daily to affected areas of the body can help with symptomatic management of burning and pruritus. However, generally PRP is poorly responsive to topical steroids. 2 Topical Calcineurin: Inhibitors These may be used for localised disease in thin-skinned areas including the face, scalp and intertriginous areas. 3 Topical Retinoids: Topical retinoids such as tazarotene have been exclusively used in the management of type IV PRP however, this is better used in conjunction with other topical or systemic agents. Tretinoin 0.05% cream has been shown to improve pruritus, erythema and hyperkeratosis after 2 months, and lesion size by 50% after 6 months, in patients with type IV PRP. 4 Emollients and Keratolytics: These are useful for symptomatic management of PRP. Griffiths 42 favored a mixture of 20% propylene glycol, 10% urea in equal parts of liquid paraffin and white soft paraffin, occluded at night. Emollients such as hydrated petrolatum or
ACCEPTED MANUSCRIPT petroleum jelly applied liberally several times daily can aid in preserving skin moisture by preventing skin fissuring, maintaining skin integrity and decreasing restriction secondary to skin tightness. Keratolytics such as urea 20% cream or salicylic acid 3–10% in petroleum jelly applied twice daily to palms and soles can improve thickened acral surfaces and ease discomfort associated with palmoplantar keratoderma.
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Darier’s disease (Keratosis follicularis) 2,44
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Darier‟s disease is a genetic disease of disordered keratinisation which affects the skin, mucosa and nails .It is inherited as an autosomal dominant disease with a high penetrance (95%), but variable expressivity, and considerable interfamilial phenotypic differences have been noted 2,44. Occasional sporadic cases also occur due to de novo mutations. Aetiology
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It is reliably believed that Darier‟s disease is consequent to mutations in the ATP2A2 gene at chromosome 12q24.1, which encodes the sarco/endoplasmic reticulum calcium ATPase type 2 (SERCA2)45,46. The defect can be either a nonsense or insertion/deletion mutations which produces haploinsufficiency, leading to a defective function in the SERCA2b function44-46 . This affects the compensatory mechanisms which regulate the endoplasmic reticulum leading to reduced calcium concentrations with consequent disruption of the membrane proteins . Furthermore the keratinocytes desmosomal proteins are affected leading to a failure of 47. adhesion Clinical Features
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1. Cutaneous changes2,44,48: Skin signs generally develop between 6 and 20 years of age, with a peak around puberty. A change in sweating pattern, pattern of sebum secretion and bacterial flora may play a part in this. The lesions may vary from the subtle minute acanthomas to the more pronounced flat and freckle-like pale macules (guttate leukoderma) in pigmented skin. Skin-coloured to yellow-brown, firm, greasy papules (Fig.10) are the salient morphologic markers of Darier‟s disease. These lesions predominantly affect the „seborrhoeic sites‟ such as the scalp, forehead, behind and in front of the ears, nasolabial folds and the adjoining cheeks, front and back of the chest, axilla groin and natal cleft. The heavy scalp crusting imparts a characteristic spiny feel but hair loss is uncommon. Coalescence of the papules produces irregular warty plaques or papillomatous masses, which, in the flexures, become hypertrophic, fissured and malodorous. On the dorsa of the hands and feet, discrete papules are clinically indistinguishable from acrokeratosis verruciformis of Hopf. Small pits or punctuate keratoses may be found involving the palms and soles. Pruritus is common, occurring in 80% of patients, and may be intractable; pain is unusual. The other variants include hypertrophic, vesiculobullous, cornifying, comedonal, haemorrhagic, hypopigmented and acral forms.
ACCEPTED MANUSCRIPT 2. Mucosal changes2,44,48: These are observed in 15–50% of cases, with oral mucosal involvement being the most common. White umbilicated/cobblestone papules (Fig. 5) may be found affecting the palate, alveolar mucosa, tongue, buccal mucosa, epiglottis, pharyngeal walls, esophagus, vulva and rectum. Confluence of papules leads to the formation of leukoplakic plaques. Blockage of salivary glands has also been reported.
Clinical Variants
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3. Nails 2,44,48: These may be affected in up to 90% of the cases. Commonly observed changes are nail fragility, longitudinal ridging and splitting, subungual hyperkeratotic fragments beneath the free margin of the nail, longitudinal red or white lines and a characteristic V-shaped scalloping of the nails at the distal end. 2,49
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Some patients present with multiple comedones or nodulocystic acne with deep pitted scars with a histology of Darier‟s disease50. Haemorrhagic macules represent a rare form where lesions are seen on the hands and feet 51
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Course of the Disease
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Unilateral localised variants have been seen which are phenotypically and histologically identical to the lesions of classic Darier‟s disease with the notable absence of nail manifestations.
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Darier‟s disease runs a chronic course with exacerbations and remissions. Exacerbations occur in hot weather, with excessive exposure to sunlight or UVB radiation, friction, sweating and infections. Lithium therapy and steroids are known to precipitate and exacerbate the condition .Occasionally, women describe deterioration perimenstrually. Severe complications are rare, but there is an increased susceptibility to herpes simplex infections, Kaposi‟s varicelliform eruptions and pox virus infections. Chronic dermatophytosis and secondary bacterial overgrowth are also common. Histopathology.
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Early lesions show lacunae which appear above the basal layer and extend irregularly throughout the epidermis .The cells separate and have a darkly staining nucleus surrounded by clear cytoplasm and a glistening ring and are known as „corps ronds‟ and this is consequent to premature partial keratinization (dyskeratosis).These eventually turn into grains wherein the cells become smaller and are seen in the upper layers of the epidermis. The histology is not strictly follicular53,54 as these findings can also localized around around sweat ducts and mucous and salivary glands .Focal acantholytic dyskeratosis also occurs in other conditions, like solitary dyskeratoma, transient and persistent acantholytic dermatoses and Hailey–Hailey disease (chronic familial benign pemphigus) the last of which may overlap clinically and histologically.54 The differences are that the hyperkeratosis and follicular plugging is more
ACCEPTED MANUSCRIPT pronounced in Darier‟s disease , suprabasal clefts are smaller , dyskeratotic cells (corps ronds and grains) are more evident while acantholytic cells are less evident than in Hailey–Hailey disease.55 Therapy 2,44,56
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The patient should be told upfront that the disease will flare and will last a lifetime in most cases with a definite risk of transmission to the progeny. In mild cases emollients, simple hygiene and photoprotection will suffice. Though topical tretinoin and isotretinoin, adapalene and tazarotene are effective irritancy is a deterrent to continue use .A regimen of emollients in conjunction with retinoids is a practical therapeutic regimen. A topical steroid/antibiotic combination is a useful adjunct which can be used twice weekly to prevent infection and ameliorate the inflammation. In severe cases oral therapy is given commonly with acitretin and isotretinoin while occasionally cyclosporine has been tried.
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Topical Therapy 2.44.57
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Topical tazarotene: Tazarotene gel has been used in concentrations of 0.05, 0.03 (0.05% gel diluted with purified water) and 0.1% in various studies. Short contact therapy (15 minutes) and concomitant topical steroids can allay the irritation and dryness. Remission can be achieved in 2–6 weeks.
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Topical vitamin D3 analogues: Use of 0.002% tacalcitol has been shown to improve skin changes within 2 weeks and normalize the histopathological as well as immunohistochemical alterations (in the form of altered involucrin expression) associated with the disease.
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Topical tacrolimus: Use of topical tacrolimus 0.1% ointment twice a day led to a dramatic improvement within 2 weeks and complete remission after 6 weeks of use, in a patient in whom systemic retinoids had to be stopped due to depressive symptoms. Topical steroids: These control the overlying inflammation with little impact on the disease per se. Topical antibacterials/antifungals: These are used in the presence of a superimposed bacterial/fungal infection. Topical 5-FU: Use of 1% 5-FU daily/alternate day has shown good responses in a few case reports, with no associated systemic side effects.
Oral Therapy 2,44,
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• Oral retinoids58: Retinoids are the most effective drugs for this disease. They can reduce the hyperkeratosis and flatten the papules, and may also improve the malodour. Acitretin is the commonly used retinoid in Darier‟s disease. A dose of 10–25 mg daily is a reasonable starting dose and it can be increased gradually depending on the response. It may take 2–3 months before acitretin shows its maximal effect. In some cases, etretinate may be useful, particularly if acitretin fails. Isotretinoin, 0.5–1 mg/kg/d, is recommended for young females because pregnancy needs to be avoided for only 1 month after stopping treatment, in contrast to 2–3 years with acitretin. A low-dose maintenance therapy may be warranted to avoid a possible future relapse, though some patients require oral retinoids only in summers to prevent exacerbations during this time.
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•Oral prednisolone and cyclosporine59: Oral steroids or cyclosporine can be used to reduce inflammation in patients with „eczematised‟ disease.
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• Oral contraceptives: Its continuous use helps in clearing the disease in females who have perimenstrual exacerbations. • Diltiazem: It is shown to be of benefit in recalcitrant cases.
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Surgical Therapy 2,44,60,61
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• Dermabrasion: It has been employed to smoothen the keratotic papules and plaques, and has given cosmetically acceptable result. It is recommended that the procedure should include the entire papillary dermis in order to achieve favourable results
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• Electrosurgery: It has been employed in a few cases resistant to medical therapy, with good results.
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• Laser ablation: Er:YAG and CO2 Laser ablation has shown variable clinical efficacy in Darier‟s disease. Treatment with the flashlamp-pumped pulsed-dye laser has also been shown to improve the cutaneous condition. Recently, fractional photothermolysis using fractionated 1550-nm erbium-doped fibre laser has been shown to be efficacious in Darier‟s disease with a low complication rate. • Photodynamic therapy: Using aminolaevulinic acid/methylaminolevulinate has been evaluated as sole/adjunctive treatment with variable responses. A few patients have been shown to have an excellent response while in others, exacerbations developed after treatment. Follicular eczema 1,6,62-66 (Syn :Patchy Pityriasiform Lichenoid Eczema, Follicular Atopic Eczema, Papular eczema )
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Though this entity is mentioned in passing in specialty textbooks 1,62,64 and is largely associated with atopic dermatitis64,65 it is our belief that in pigmented skin it is commonly seen but frequently misdiagnosed and is associated with a generally dry skin 63. In fact a large pediatric analysis of skin conditions from India (table 4, fig 2) 6 found that follicular eczema was the fourth commonest follicular disorder . Clinical Features
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This dry, slightly itchy, follicular form of eczema (fig 11) that can resemble “goose-skin” is seen in childhood and was described first by Japanese authors and is believed to be a minor variant of atopic eczema 62,64,65. The partly confluent follicular skin coloured papules with a mildly branlike, scaling superimposed on a generally dry skin is the reason for its apt alternative name “patchy pityriasiform lichenoid eczema” 1,63,66.Other features seen include mildly scaly depigmented areas which resemble pityriasis alba, and isolated, frequently asymmetric, lichenified lesions on the backs of the hands or elbows .The common sites are the lateral trunk, nape of the neck, extensor aspect of the knees and uncommonly the face which is seen in the localized form of the condition (fig 11) 62,64,65 The condition characteristically worsens in winter or in dry conditions and improves in summer or in the humid seasons. 62,63,65
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Histopathology 4,
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Histologically , the lesions exhibit spongiosis of the follicular epithelium and an intra- and perifollicular lymphohistiocytic infiltration, which not only is indicative of the eczematous nature of this condition but is an reason for the apt alternative name “follicular eczema ‟‟ appended to this entity 1,62,63 The adjacent epidermis may show mild acanthosis and focal parakeratosis .
Apart from measures to alleviate the xerosis, midpotent steroids can be used which helps in achieving complete resolution in about three weeks.
Nutritional Follicular Keratoses 1,67 This all encompassing entity describes dermatoses which are consequent to nutritional defects due to vitamins, essential fatty acids and proteins and lead to follicular eruptions which include phrynoderma, dyssebacea and scurvy 1. The cutaneous manifestations of riboflavin, pyridoxine, niacin, and EFA deficiency probably have similar clinical presentations 67,68. This is consequent to the intersecting biochemical pathways that involve these nutrients which can explain the common cutaneous findings including the follicular eruption. Riboflavin is required for pyridoxine metabolism, which, in turn, is required for tryptophan-niacin metabolism, and niacin is necessary for fatty acid synthesis. 70 This explains cases of pellagra which have follicular manifestations on the face resembling phrynoderma (fig 12 ). 67. The entity nutritional follicular
ACCEPTED MANUSCRIPT keratoses also has therapeutic implications as a wide based nutritional supplementation is essential in cases of follicular dermatoses with nutritional deficiency.
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Phrynoderma
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Phrynoderma (toad skin) is a form of follicular hyperkeratosis that is associated with various nutritional deficiencies. Though historically associated with Vitamin A deficiency it is now known to occur with various nutritional states like malnutrition, intestinal malabsorption, anorexia nervosa or fad diets . It is seen in children and adolescents aged between 5 and 15 years but adults and lactating women may also be affected.
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Aetiology
There are three theories which have been proposed to explain this condition.
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Vitamin deficiency: The term „phrynoderma‟, was first used by Lucius Nicholls in 1933 to describe the hyperkeratotic folliculitis which he had observed in African labourers who were vitamin A deficient. But diet survey and serum Vit A levels in apparently healthy phrynoderma patients and normal controls revealed no statistically significant difference between the two groups71. Also the earlier belief that Vit A deficiency as a cause of phrynoderma was largely based on the therapeutic response to cod liver oil, which was considered to be a source of Vit A but is now known to contain EFA also . Phrynoderma has been reported even in individuals who were fed Vit A rich diet.72 Conversely not all those with vitamin A deficiency develop this cutaneous manifestation and other deficiencies of vitamins B complex, C and E have now been implicated. It is now certain that the response to Vit A therapy/isotretinoin is attributable to its effect on keratinisation and not primarily as a nutritional supplement. Nutritional deficiency1,12,69: It is believed that phrynoderma may be a manifestation of nutritional deficiency without any specific deficit of vitamins. This is because there are patients on calorie-restricted diet (
