For reprint orders, please contact reprints@expert-reviews.com

211

Review

www.expert-reviews.com ISSN 1746-9872© 2011 Expert Reviews Ltd 10.1586/EDM.11.13

Disorders of keratinzation (DOK) are a hetero-genous group of monogenic skin diseases (genodermatoses) affecting the epidermis, its appendages and sometimes also the mucous membranes [1]. With the exception of ichthy osis due to filaggrin or steroid sulfatase deficiency (i.e., ichthyosis vulgaris [IV] and X-linked recessive ichthyosis [XRI]), DOK are rare dis-eases, usually with a prevalence of less than 1/50,000 [1]. Although there are more than 50 different types of DOK, this article will only focus on the following three groups of rare dis-eases: autosomal-recessive congenital ichthyo-sis (ARCI), including lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE); dominant-negative keratinopathies, including epidermolytic ichthyosis (EI), epi-dermolysis bullosa simplex (EBS) and pachyo-nychia congenita (PC); and familial acantho-lytic disorders, including Darier–White (DW) and Hailey–Hailey (HH) diseases. Although genetically distinct, all of these diseases have in common a disturbance of epidermal differen-tiation leading to hyper keratosis and/or tissue fragility with a deficient skin barrier function.

The patients’ skin problems usually start at birth or in early childhood, but in the case of DW and HH, the debut is often delayed until puberty. Hence, most patients have persistent skin symptoms throughout life and the impact on the quality of life ranges from moderate to severe depending on:

• The extent of skin involvement;

• The severity of the underlying gene defect;

• The amount of harmful exposure to physical activities and environmental factors;

• The patient’s professional, socioeconomic and psychological status.

In most cases, there is an imperative need for daily treatment, but the composition of therapy may vary over time depending on, for example, climate and seasonal factors (some get better in the summer, while others get worse due to prob-lems with sweating and bacterial infections). Various topical and systemic agents have long been available to treat DOK, but they represent purely symptomatic therapies that are often tedious to use and sometimes potentially toxic

Anders VahlquistDepartment of Medical Sciences, Uppsala University, Uppsala, Sweden anders.vahlquist@medsci.uu.se

Disorders of keratinization encompass a wide variety of monogenic skin diseases characterized by inheritable disturbances in the differentiation of epidermal keratinocytes leading to hyperkeratosis and/or epidermal fragility. Over the last decade, many new etiologies have been found for these diseases, but until recently this has not been paralleled by a similar good progress in therapy. The purpose of this article is to review the treatment of three groups of disorders of keratinization: congenital ichthyoses due to autosomal-recessive inheritance (e.g., lamellar ichthyosis and ichthyosiform erythroderma); keratinopathies due to dominant-negative keratin mutations (epidermolytic ichthyosis, epidermolysis bullosa simplex and pachyonychia congenita); and acantholytic diseases due to autosomal-dominant disorders of cell adhesion (Darier–White and Hailey–Hailey diseases). Recent advances in the use of keratolytic agents, retinoids, botulinum toxin and molecular biology techniques are discussed. In conclusion, there is reason for optimism among patients with keratinization disorders as there are now an increasing number of improved therapeutic strategies.

Keywords: autosomal recessive congenital ichthyosis • botulinum toxin • Darier–White disease • epidermolysis bullosa simplex • epidermolytic ichthyosis • Hailey–Hailey disease • pachyonychia congenita • retinoids • siRNA

Treatment of rare keratinization disorders: what’s new?Expert Rev. Dermatol. 6(2), 211–216 (2011)

GeNerAL CoNTeNT

Exp

ert R

evie

w o

f D

erm

atol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/1

1/14

For

pers

onal

use

onl

y.

Expert Rev. Dermatol. 6(2), (2011)212

Review

for the patients (for a review, see [2]). This article will concentrate on new developments in this field that may ultimately improve and simplify the treatment of DOK. In order to facilitate a discus-sion regarding the mechanisms of action of such therapies, each section will begin with a summary of the classification and etio-pathogenesis of the three groups of DOK, beginning with ARCI.

Autosomal-recessive congenital ichthyosis Autosomal-recessive congenital ichthyosis is the collective name for a large group of inherited nonsyndromic DOK that are by definition always apparent at birth [1]. The rarest, albeit most severe and sometimes lethal, form is Harlequin ichthyosis. The two largest subtypes of ARCI are LI and CIE, the latter also known as erythrodermic ichthyosis. LI is characterized by large, plate-like scales covering the entire body, whereas CIE shows thinner scales, more skin inflammation and a higher turnover of epidermis (Figure 1A & B). A subset of ARCI patients will have much milder symptoms, clearly incompatible with LI/CIE and sometimes misdiagnosed as IV or XRI in adults, which may lead to incorrect advice (Figure 1C). This phenotype, which in some countries accounts for nearly a third of all ARCI patients [3], has been tentatively called pleomorphic ichthyosis [4]. The word pleo-morphism (a condition in which an individual assumes a number of different forms during its life cycle) refers in this context to the very pregnant phenotypic shift commonly observed in the first months of life, as well as to the numerous (g. pleo-) distinct disorders found in this group of ARCI, including, for exam-ple, self-improving collodion baby and ichthyosis prematurity syndrome [4].

TABle 1 summarizes the etiologies of inherited ichthyosis, clearly incriminating a wide range of genes that in one way or other affect epidermal differentiation and barrier function [5–8]. From a teleo-logic perspective, homeostatic mechanisms aimed at improving the epidermal barrier probably initiate skin inflammation, hyper-keratosis and a massive scaling – that is, the very symptoms and

signs that constitute the patients’ health problem [8]. A vigorous removal of scales may thus paradoxically exaggerate the under-lying disease process [9]. This needs to be taken into consideration when deciding different treatment regimens for ARCI.

Topical treatmentAlthough a daily application of emollients or lubricants are a sine qua non for most patients with ichthyosis, the efficiency of such therapy is often insufficient for ARCI [2]. By mixing several keratolytic and hydrating agents into a suitable cream formula-tion, additive or even synergistic effects may be achieved. In this context, mixtures of propylene glycol, urea and a-hydroxy acids, such as lactic acid and glycolic acid, are particularly effective [9]. By testing different combinations and concentrations of these agents in different cream bases it is often possible to tailor the individually most effective and best tolerated topical treatment for each patient. For instance, some patients may want a ‘dry’ cream that rapidly disappears into the skin, whereas others pre-fer a more grease-like preparation that stays on the surface and lubricates the skin.

One way of potentiating topical treatment is to add certain pharmaceutical agents, which when given per os may pose toxicity problems. Retinoids have been tried for this purpose, but no ideal topical formulation for ichthyosis has been available. By selecting retinoids that target nuclear receptors predominantly expressed in epidermis, a strong ‘anti-keratinizing’ effect with little skin irritation can probably be obtained, provided a suitable vehicle is used. One such formulation containing tazarotene is currently on trial in patients with LI of moderate severity, including children [Dupuy P, Orfagen. Pers. comm.]. If successful in the trials, this product will hopefully fill the present therapeutic gap between potent topical keratolytics and systemic retinoids.

Another way of obtaining retinoid-like effects in the skin with-out major toxicity is to pharmaceutically block the metabolic deg-radation of endogenous retinoic acid (RA), hence increasing the

steady state levels of RA in keratinocytes [10]. RA is normally produced in epidermis by enzymatic oxidation of retinol, and its level is strictly controlled by further oxi-dation to inactivate 4-oxo-RA. The latter reaction is catalyzed by cytochrome P450 26, which can be inhibited by certain imid-azole compunds, collectively known as RA metabolism blocking agents (RAMBAs). Two such drugs, liarozole and rambazole (talarozole), have been tested topically in LI [10]. The effects have been promising, but no product containing RAMBA is cur-rently on the market.

Topical vitamin D derivatives have also been used off-label to treat ARCI, but there is little support in the literature for this therapy and the risk of systemic absorp-tion causing hypercalcemia is a concern, especially in children.

Figure 1. The clinical spectrum of congenital ichthyosis.Figures available in color online at www.expert-reviews.com/loi/edm.Reproduced with permission from [2,4].

Vahlquist

Exp

ert R

evie

w o

f D

erm

atol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/1

1/14

For

pers

onal

use

onl

y.

www.expert-reviews.com 213

Review

Systemic therapyA new oral retinoid, alitretinoin (9-cis RA), was recently approved in Canada and most European countries for use in chronic hand eczema, including hyperkeratotic variants reminiscent of ichthyotic keratoderma [11]. Although not approved for ichthyosis, we recently tried it off-label in a few patients with ARCI and kerato derma and found an antikeratinizing effect similar to that of acitretin, but only at relatively high doses (30–50 mg per day) [12]. Alitretinoin has the advantage in female patients of being more rapidly excreted than acitretin/etreti-nate, but in common with other retinoid X receptor (RXR) ligands, it may induce hypothyreosis [13].

Systemic RAMBA is another way of achieving retinoid-like effects without major toxicity problems [14,15]. A randomized trial, comparing two dose levels of liarozole (75 vs 150 mg) and placebo in 67 adult patients with LI showed promising results with signifi-cantly reduced scaling scores after 2 months of therapy, especially with the higher dose of liarozole [16]. The retinoid-like side effects were mild and reversible. Hopefully, RAMBAs will be further developed as orphan drugs for treatment of moderate-to-severe LI.

An additional possibility is that anti-inflammatory agents might prove effective in the treatment of ARCI. In an in vitro model of LI, which exploits siRNA knock-down of TGM1 in human epidermis, O´Shaughnesssy et al. recently found an upregulation of IL-1a that correlated with the induction of hyperkeratosis and could be reversed by IL-1a antagonists without any loss of barrier lipids [17]. However, whether or not IL-1a antagonists are feasible as topical or systemic treatments for ARCI patients remains to be shown.

Dominant-negative keratinopathiesInherited keratinopathies are a family of rare skin fragility disorders that are due to keratin gene (KRT ) mutations negatively affecting the cytoskeletal stability in the epi-dermis [18]. The three most common types of keratinopathy, EBS, EI and PC, are all characterized by epidermal blistering and painful hyper keratinization (e.g., callosities on hands and feet), which is precipitated by mechanical friction, high ambient tem-perature and sweating (Figure 2 shows typical examples of EI and PC). EBS (prevalence 1/40,000) is due to mutations in KRTs 5/14 expressed in the basal layer of epidermis, whereas EI and PC (prevalence 1/200,000) are due to suprabasally expressed KRTs 1/10 and 6/16/17 mutations, respectively.

Despite vast knowledge about the eti-ology of keratinopathies, no eff icient

remedies exist for this group of diseases. Retinoids, antiseptic agents and various dressings have all been tried, but often with limited success [2,19]. Recently, promising attempts have been made to stabilize the malfunctioning cytoskeleton by:

• Silencing the mutated keratin gene using siRNA;

• Adding chemical chaperones to protect the misfolded keratin polymers;

• Preventing sweat-induced cytolysis and painful foot blisters by injections of botulinum toxin (btx).

With regards to the first treatment option, members of the PC project recently pioneered the use of siRNA technology in der-matology by applying mutation-specific RNA probes to lesional foot skin in a patient with PC keratoderma due to a KRT6a

Table 1. Debut and genetic etiology of common versus rare forms of nonbullous, nonsyndromic ichthyosis.

Form of ichthyosis

Debut Genetic etiology (in order of frequency)

Common ichthyosis

Ichthyosis vulgaris Childhood FLG

X-linked Infancy STS

Rare ichthyosis

Harlequin Congenital ABCA12

Lamellar Congenital TGM1, NIPAL4, ALOX12B, ABCA12

Erythrodermic Congenital ALOXE3, ALOX12B, ABCA12, TGM1, NIPAL4, CYP4F22

Pleomorphic Congenital ALOX12B, TGM1, ALOXE3, POMP, FATP4

Adapted with permission from [4].

Figure 2. Keratinopathies: epidermolytic ichthyosis (A) and pachyonychia congenita patient receiving injections with botulinum toxin (B).Figures available in color online at www.expert-reviews.com/loi/edm.

Treatment of rare keratinization disorders: what’s new?

Exp

ert R

evie

w o

f D

erm

atol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/1

1/14

For

pers

onal

use

onl

y.

Expert Rev. Dermatol. 6(2), (2011)214

Review

mutation [20]. After several weeks of daily injections of siRNA, a reduction in hyperkeratosis and pain was noted compared with placebo injections. This raises future hope for effective siRNA therapy of keratinopathies.

The second, low-tech approach is still experimental. By study-ing cultured keratinocytes from EBS and EI patients [21,22], we recently showed that chemical chaperones may protect the cyto-skeleton against heat stress-induced disruption. In future tri-als, topically applied chaperones will be tested in vivo against EBS, and the search for novel drugs with the ability to stabilize keratin filaments will continue using high-content screening methodology [Törmä H et al. Unpublished data].

As to the third option, we and others have reported the use of btx as an antisweating agent in patients with EBS and PC [23,24]. Plantar injections of btx produce astonishingly good results on foot blistering and pain, with effects persisting for many months [25]. However, since btx is costly and the injections painful (Figure 2B), an alternative delivery system for btx would greatly benefit its use in keratinopathies.

Familial acantholytic disordersDarier–White and HH are etiologically closely related diseases due to defective Ca2+ pumps in the endoplasmic reticula (ATP2A2) or Golgi apparatus (ATP2C1), which negatively interferes with cell-to-cell adhesion in keratinocytes [1,26]. Both these autosomal-dominant diseases share a common feature of fragile skin with erosions that easily become infected (Figure 3). Whereas DW ini-tially manifests as keratotic papules in the seborrhoic areas but may later occur on any part of the skin, HH is usually confined to the intertriginous areas, particularly the axillae and groins.

Treatment of DW and HH is notoriously difficult. Topical agents, including antiseptics, are a mainstay in therapy [27]. The introduction of oral retinoids in the late 1970s was a major break-through for many patients with DW. In the ‘dry’ forms of DW, retinoid therapy is often extremely effective in suppressing the skin symptoms. However, prolonged courses and a careful tailor-ing of the dose of acitretin or isotretinoin are required to avoid the isomorphic reactions that can easily appear at higher doses. The acantholytic process per se is particularly unresponsive to the action of retinoids, explaining why retinoid therapy is rarely helpful in HH where skin erosions predominate. In situations with widespread erosions, addition of systemic antibiotics is often recommendable. Even with optimized therapy, both DW and HH may be very disabling diseases, particularly when affecting the intertriginous areas. In this situation, anecdotal reports support the use of skin transplantation, Bucky therapy and, more lately, electron beam irradiation [28].

Since sweating is a well-known aggravating factor in intertrigi-nous DW and HH, btx is an obvious pharmacologic candidate. The first report of using btx injections in HH came a decade ago [29], but since then only a few reports about its use in DW and HH have appeared (see [30]). We have used btx in a total of 15 patients with intertriginous DW and HH, all respond-ing quite favourably to the injections, provided lidocaine/pri-locaine (EMLA®) cream is applied as pretreatment to reduce pain [Swartling C, Vahlquist A. Unpublished observation]. Again, a formulation allowing better penetration of btx into the skin would be a major advantage.

The recent observation that btx not only blocks neurotransmis-sion to the sweat glands but also has direct effects on epithelial

cells [31] should further propel the develop-ment of this therapy in DOK precipitated by sweating.

Expert commentary & five-year viewTreatment of DOK is often problematic both because a life-long perspective has to be considered and because the patients’ individual tolerances and preferences often differ tremendously. A combina-tion of several topical agents and systemic retinoids is currently the most powerful treatment for many types of DOK, albeit frequently hampered by side effects. Clearly there is room for new innovations in this field of dermatology. Indeed several avenues are presently being pursued, with siRNA treatment of dominant-negative DOK and anti-inflammatory therapy of ARCI being perhaps the most exciting ones. Chemical chaperones may become a new therapy for keratinopathies, and the use of btx in hidrosis-exacerbated DOK is already a viable treatment option that

Figure 3. Acantholytic disorders: Morbus Darier–White on the shin (A) and Hailey–Hailey disease in groins after botulinum toxin treatment (B).Figures available in color online at www.expert-reviews.com/loi/edm.

Vahlquist

Exp

ert R

evie

w o

f D

erm

atol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/1

1/14

For

pers

onal

use

onl

y.

www.expert-reviews.com 215

Review

References1 Oji V, Tadini G, Akiyama M et al. Revised

nomenclature and classification of inherited ichthyoses: results of the first ichthyosis consensus conference in Soreze 2009. J. Am. Acad. Dermatol. 63, 607–641 (2010).

2 Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: an overview of current and emerging therapies. Acta Derm. Venereol. 88, 4–14 (2008).

3 Traupe H. Rapid categorization of mild types of autosomal recessive congenital ichthyosis undergoing a phenotypic shift: should it be called “pleomorphic ichthyosis” or “congenital ichthyosis with mild scaling (CIMS)”? Acta Derm. Venereol. 90, 450–453 (2010).

4 Vahlquist A. Pleomorphic ichthyosis: proposed name for a heterogenous group of congenital ichthyoses with phenotypic shifting and mild residual scaling. Acta Derm. Venereol. 90, 454–460 (2010).

5 Eckl KM, de Juanes S, Kurtenbach J et al. Molecular analysis of 250 patients with autosomal recessive congenital ichthyosis: evidence for mutation hotspots in ALOXE3 and allelic heterogeneity in ALOX12B. J. Invest. Dermatol. 129, 1421–1428 (2009).

6 Akiyama M, Shimizu H. An update on molecular aspects of the nonsyndromic ichthyoses. Exp. Dermatol. 17, 373–382 (2008).

7 Fischer J. Autosomal recessive congenital ichthyosis. J. Invest. Dermatol. 129, 1319–1321 (2009).

8 Schmuth M, Gruber R, Elias PM, Williams ML. Ichthyosis update: towards a function-driven model of pathogenesis of the disorders of cornification and the role of corneocyte proteins in these disorders. Adv. Dermatol. 23, 231–256 (2007).

9 Gånemo A, Virtanen M, Vahlquist A, Improved topical treatment of lamellar

ichthyosis: a double-blind study of four different cream formulations. Br. J. Dermatol. 141, 1027–1032 (1999).

10 Verfaille CJ, Borgen M, van Steensel MA. Retinoic acid metabolism blocking agents (RAMBAs): a new paradigm in the treatment of hyperkeratotic diseases. J. Dtsch. Dermatol. Ges. 6, 355–364 (2008).

11 Ruzicka T, Larsen FG, Galewicz D et al. Oral alitretinoin (9-cis-retinoic acid) therapy for chronic hand dermatitis in patients refractory to standard therapy: results of a randomized, double-blind, placebo-controlled, multicenter trial. Arch. Dermatol. 140(12), 1453–1459 (2004)

12 Gånemo A, Sommerlund M, Vahlquist A. Alitretinoin in lamellar ichthyosis: a pilot study of the effect. Presented at: Congress of the European Academy of Dermatology and Venereology, Gothenburg, Sweden, 6–10 October, 2010 (Abstract).

13 Vahlquist A. Retinoids and the skin: from vitamin A to pharmacology of oral retinoids in dermatology. In: Retinoids and Carotenoids in Dermatology. Vahlquist A, Duvic M (Eds). Informa Healthcare USA Inc., NY, USA, 55–68 (2007).

14 Lucker GP, Heremans AM, Borgenheim PJ, van de Kerkhof PC, van Steijlen PM. Oral treatment of ichthyosis by cytochrome P-450 inhibitor liarozole. Br. J. Dermatol 136, 71–75 (1997).

15 Pavez-Loriè E, Gånemo A, Borgers M et al. Expression of retinoid-regulated genes in lamellar ichthyosis vs. healthy control epidermis: changes after oral treatment with liarozole. Acta Derm. Venereol. 89, 12–20 (2009).

16 Vahlquist A, Traupe H, Blockhuys S, Shroot B. Liarozole effective in the treatment of lamellar ichthyosis. Presented at: The International Investigative Dermatology Meeting, Kyoto, Japan, 14–17 May, 2008 (Abstract).

17 O´Shaughnessy RF, Choudhary I, Harper JI. Interleukin-1 a blockade prevents hyperkeratosis in an in vitro model of lamellar ichthyosis. Hum. Mol. Genet. 19, 2594–2605 (2010).

18 Lane EB, McLean WH. Keratins and skin disorders. J. Pathol. 204, 355–366 (2004).

19 Virtanen M, Gedde-Dahl T Jr, Mork NJ et al. Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression. Acta Derm. Venereol. 81, 163–170 (2001).

20 Leachman SA, Hickerson RP, Schwartz ME et al. First-in-human mutation-targeted siRNA Phase Ib trial of an inherited skin disorder. Mol. Ther. 18, 442–446 (2010).

21 Chamcheu JC, Virtanen M, Navsaria H, Bowden P, Vahlquist A, Törmä H. Epidermolysis bullosa simplex due to KRT5 mutations: mutations-related differences in cellular fragility and the protective effets of trimethylamine N-oxide in cultured primary keratinocytes. Br. J. Dermatol. 162, 980–989 (2010).

22 Chamcheu JC, Pihl-Lundin I, Mouyobo CE et al. Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease phenotype: a useful in vitro model for testing new treatments. Br. J. Dermatol. 164, 263–272 (2010).

23 Swartling C, Vahlquist A. Treatment of pachyonychia congenita with plantar injections of botulinum toxin. Br. J. Dermatol. 154, 763–765 (2006).

24 Abitbol RJ, Zhou LH. Treatment of epidermolysis bullosa simplex, Weber–Cockayne type, with botulinum toxin type A. Arch. Dermatol. 145, 13–15 (2009).

25 Swartling C, Karlqvist M, Hymnelius K et al. Botulinum toxin in the treatment of sweat-worsened foot problems in patients with epidermolysis bullosa and pachyonychia congenita. Br. J. Dermatol. 63, 466–474 (2010).

should be further elaborated. In the case of ARCI, curatives and more convenient treatments are imminently needed in addition to tailored retinoid therapy. Hopefully, the result of ongoing research trying to pin-point the pathoetiology of DOK will help to generate new ideas about how to safely perform gene repair or gene transfer either directly or via retransplantation of trans-fected and expanded keratinocytes. Meanwhile, by elucidating which metabolic products are missing in the skin of patients with certain types of DOK, a regular substitution approach should perhaps also be tried in such cases.

AcknowledgementsThe valuable discussions with Drs Agneta Gånemo, Carl Swartling, Hans Törmä and Patrick Dupuy are gratefully acknowledged.

Financial & competing interests disclosureThe author has research royalties from Astellas A/S for the sales of LPL cream and is one of the coordinators of a clinical trial sponsored by Orfagen. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Treatment of rare keratinization disorders: what’s new?

Exp

ert R

evie

w o

f D

erm

atol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/1

1/14

For

pers

onal

use

onl

y.

Expert Rev. Dermatol. 6(2), (2011)216

Review

26 Fairclough RJ, Lonie L, Van Baelen K et al. Hailey–Hailey disease: identification of novel mutations in ATP2C1 and effect of missense mutation A528P on protein expression levels. J. Invest. Dermatol. 12, 67–71 (2004).

27 Hulatt L, Burge S. Darier’s disease: hopes and challenges. J. R. Soc. Med. 96, 439–441 (2003).

28 Narbutt J, Chrusciel A, Rychter A, Fijuth J, Lesiak A, Sysa-Jedrzejowska A. Persistent improvement of previously recalcitrant Hailey–Hailey disease with electron beam radiotherapy. Acta Derm. Venereol. 90, 179–182 (2010).

29 Lapiere JC, Hirsh A, Gordon KB, Cook B, Montalvo A. Botulinum toxin type A for the treatment of axillary Hailey–Hailey disease. Dermatol. Surg. 26, 371–374 (2000).

30 Messikh R, Atallah L, Aubin F, Humbert P. [Botulinum toxin in disabling dermatologic diseases]. Ann. Dermatol. Venereol. 136(Suppl. 4), S129–S136 (2009).

31 Shibasaki M, Davis SL, Cui J, Low DA, Keller DM, Crandall CG. Botulinum toxin abolishes sweating via impaired sweat gland responsiveness to exogenous acetylcholine. Br. J. Derm. 161, 757–761 (2009).

Vahlquist

Exp

ert R

evie

w o

f D

erm

atol

ogy

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Mic

higa

n U

nive

rsity

on

11/1

1/14

For

pers

onal

use

onl

y.