/chthyosis Review paper HEREDITARY ICHTHYOSIS. PATHOGENESIS AND POSSIBILITIES OF TREATMENT A. Kansky, B. Podrumac and I. Prelog ABSTRACT Introduction. The term ichthyosis includes a number of pathogenetically different conditions, clinically displaying a more or less similar appearance. The underlying metabolic or molecular-biologic mechanisms have been elucidated up to now only in some of these conditions. Known pathogenetic mechanisms. In recessive x-linked ichthyosis (RXLI) the deficiency of the steroid sulfatase has been demonstrated in cultured fibroblasts, leukocytes and keratinocytes. In certain patients with lamellar ichthyosis (LI) a deficient transglutaminase 1 was detected, the defect was located to a 9.3 cM region of chromosome 14q. In ichthyotic scales of non-bullous ichthyosiform erythroderma (NBIE) an increase of n- alkanes was reported. In bullous ichthyosiform erythroderma (BIE) genetic defects in keratins 1 and 10, and in ichthyosis bullosa Siemens (IBS) in keratin 2e were detected. Svstemic treatment. Unfortunately, there is no specific treatment for various entities of ichthyosis. In severe forms of LI, NBIE and BIE retinoids as etretinatate, etretin and isotretinoin have been applied with varied success, in all instances, however, symptoms recurred after the treatment was stopped. The same is trne for corticoids. Certain antimetabolites were also used for suppressing the symptoms. Topical treatment. This is at present stili the most important modality. Various ointment bases including salicylates, urea, corticosteroids as well as other ingredients are commonly applied. During the last years an impaired barrier function in ichthyosis, and in the frequently associated atopic dermatitis, is being stressed. For this reason unsaturated fatty acids and cholesterol are incorporated into ointments. General Management. As it is known that small children with the severe forms of ichthyosis are sensitive to exposure to lower temperatures, to infections and to inappropriate diet, an adequate general regimen has to be observed. Conclusion. As intense research is going on and new therapeutic modalities can be expected during the coming years. KEY WORDS heredita,y ichthyosis, classification, pathogenesis, systemic, topical treatment acta dennatovenerologica A.P.A. Vol 6, 97, No 2 47 Ichthyosis INTRODUCTION The clinical diagnosis hereditary ichthyosis includes a number of pathogenetically different conditions displaying a more or less similar appearance. There exists at present no generally accepted clinical classification of ichthyoses. In Europe the scheme presented in Fig. 1 is widely accepted. The underlying pathogenetic mechanisms have been elucidated only in certain variants of ichthyoses and even in these probably stili not completely. The problem is complicated by the obser\ration that quite a number of substances and pathogenetic events may provoke ichthyosis-like manifestations in humans as well as in animals. Table 2. PATHOGENESIS During the last 20 years many new data concerning ichthyosis have been reported. The most important information of interest to the clinicians is summarized as follows. In the recessive x-linked ichthyosis (RXLI) the deficiency of the enzyme steroid sulfatase has been demonstrated in cultured fibroblasts, leukocytes and keratinocytes (1). An increased content of cholesterol sulfate in the ichthyotic scales seems to be responsible for the poor shedding. A deficient transglutaminase 1 (TGM 1) was detected in certain patients with lamellar ichthyosis (LI), the genetic defect being located to a 9.3 cM region of chromosome 14q (2). TGM 1 is responsible for cross- linking of proteins in forming the cornified envelope of keratinocytes. This anomaly could be, however, demonstrated only in certain patients and LI turns out to be a genetically heterogeneous condition (3 ,4). In ichthyotic scales of non-bullous ichthyosiform erythroderma (NBIE, erythrodermia ichthyosiformis congenita) an increased content of n-alkanes was reported (5). In bullous ichthyosiform erythroderma (BIE, epidermolytic hyperkeratosis) vacuolar degeneration and bullae develop after birth in the stratum spinosum. Genetically deficient keratins Kl and KlO are responsible for the clumping of tonofilaments and the following formation of bullae (6,7,8,9). It was shown that point mutations of either Kl or KlO in suprabasal keratinocytes can disrupt the keratin intermediate filaments resulting in blister formation and hyper- keratosis . In patients with ichthyosis bullosa Siemens (IBS) a genetic defect of K2e was reported (10,11). Table l. 48 Further pathogenetic mechanisms were mentioned in ichthyoses. Suzuki et al (12) reported that the degradation of desmoglein 1, which is a desmosome component and plays a role in stratum corneum (SC) cell-adhesion, is decreased in ichthyoses. Normally endogeneous trypsin-like and chemotrypsin-Iike proteases are active in the process of degradation of desmoglein 1 in SC. BARRIER FUNCTION Dry skin and scaling are impor tant clinical manifestations in ichthyosis. Dry skin is caused by an increased evaporation through the skin and this can be assayed by measuring the transepidermal water loss (TEWL). The intact SC offers the main protection against an increased TEWL as well as against penetration of foreign substances through the skin and against UV radiation. The mentioned protective activity is known as barrier function and Table l. Proposed classification of ichthyoses far clinical use Adapted to viewpoints of Griffith A, Leigh IM, Marks R in Disorders of Keratinization, Rook et al, Textbook of Dennatology, 5th Edition, 1330-41 l. autosomal dominant ichthyosis (ADI) ichthyosis vulgaris autosomalis dominans 2. recessive x-linked ichthyosis (RXLI) ichthyosis vulgaris recessiva 3. bullous ichthyosiform erythroderma (BIE) epidermolytic hyperkeratosis erythrodermia ichthyosiformis bullosa 4. ichthyosis bullosa Siemens (IBS) 5. non-bullous ichthyosiform erythroderma (NBIE) erythrodermia ichthyosiformis (including erythematous collodion baby) 6. lamellar ichthyosis (LI) ichthyosis lamellaris, (ichthyosis congenita including harlequin fe tus,non-erythematous collodion baby) 7. ichthyosis with neurological symptoms 8. ichthyosis with other noncutaneous symptoms acta dennatovenerologica A .P.A. Vol 6, 97, No 2 Jchthyosis Table 2. Substances and pathogenetic mechanisms inducing ichthyosis-like manifestations in humans and certain e.xperimental animals linoleic acid defic diet diazocholesterol genetic mechanism defic steroid sulfatase defic transglutaminase defic keratin 1 or 10 vitamin A and B defic cu tis senilis vitamin A hypervitamin chronic !iver, kidney dis Infectious diseases: lepra, Tbc, AIDS malignancies: mb Hodgkin Iymphoma, carcinoma drug eruption: increase TEWL hyperkeratosis XLRI-like ichthyosis XLRI Iamellar ichthyosis bul ichthyo erythro dry skin ichthyosis-Iike symp ichthyosis-Iike symp dry skin, ichthyosis dry skin, ichthyosis dry skin, ichthyosis experimental model mice hairless mice humans humans humans humans humans humans humans humans Elias, J Invest Derm 1983 Elias, J clin Lab Inv 1983 Shapiro, Lancet 1978 Permantier, Hum Mol Gen 1995 Rothnagel, Science 1992 Sclmyder, Jad-Erganzunswerk VII, 1966 Braun-Falco, 4th ed 1996, p 683 Rook, Textbook, 4th ed, p 2322 Braun-Falco, 4th ed, 1996, p 683 Rook,Textbook,4th ed, 1986, p 2322 nicotin ac, alopurinol, cimetidin dry skin, ichthyosis-like humans Braun-Falco, 4th ed, 1996, p 863 depends on both, intact corneocytes and the extra- cellular component of SC, which is characterized by abundat intercellular lamellae (called also bilayers) . A proper functionning of the granular layer including the lamellar bodies (LB, kaeratinosomes) is a prere- quisite for proper function of the extracellular com- ponent which is composed mainly of lipids. The normal extracellular component appears by electron microscopy as repleted by membrane structures called also intercellular lamellae (13). As it was shown by Elias in experiments on mice the TEWL was essentially increased and a hyper- keratosis of the proliferative type developed, if the animals were fed a diet deficient in essential fatty acids (14). The increased TEWL could be abolished by topical or systemic application of linoleic acid whereas the hyperproliferation was ameliorated by arachidonic acicl. acta dermatovenerologica A.P.A. Vol 6, 97, No 2 That cholesterol plays an essential role in regulation of proper keratinization as is further substantiated by experiments with diazocholesterol which inhibits cholesterol synthesis ancl incluces in hairless mice a retention-type hyperkeratosis similar to XLRI in humans (15). Further experiments have shown that in aged human skin there is a decreased number of extra- cellular lamellar bylayers (16). In agecl humans as well as in aged mice under normal conditions the barrier functions more or less normally, however if it was perturbecl after either aceton extraction or tape stripping, it recoverecl more slowly in aged than in young subjects (16). The process of restoring the barrier function coulcl be speeded up by topical application of an equimolar mixture of cholesterol, ceramide, linoleic and palmitinic acicl or choles.terol alone. In untreated LI the extracellular lamellar bilayers were decreased and lipid vacuoles were observecl in keratinocytes (17). 49 Jchthyosis Table 3. Laboratory investigations in various types of ichthyosis ADI RXLI NBIE LI BIE IBS autos dom filagrin decreased x-linked rec steroid sulf decreased autos rec autos rec beterogeneous transglut 1 cbrom 14q autos dom Kl or KlO autos dom K2e normal normal cbolesterol sulfate increased increased n-alkanes increased no essential increased sterols, increase free fatty acids increased byperkeratosis str gran reduced byperkeratosis byperkeratosis parakeratosis acantbosis compact byperkeratosis bypergranulosis vacuolar deg str spinosum suprabasal epidermolysis Legend: ADI - autosomal dominant ichthyosis vulgaris, RXLI - recessive x-linked ichthyosis vulgaris, NEJE - non-bullous ichthyosif orm erythroderma, LI - lamellar ichthyosis, BIE - bullous ichthyosiform erythroderma, IBS - ichthyosis bullosa Siemens SYSTEMIC TREATMENT As etiologic treatment at present is not possible, various ratber different drugs are being used, especially in moderately severe and severe cases. Due to tbeir side-effects tbese are applied eitber on a temporary basis or, in severe cases, patients may remain on a maintaining dose for years. One bas to be extremely careful in treating cbildren. Corticosteroids seem to be indicated in severe forms of NBIE, less frequently in otber severe forms of ichtbyoses. Tbe dosis is usually being prescribed at an individual basis (18). Retinoids. Etretinate in a dose of 0.5 to 1.0 mg per kg body weigbt (b.w.) is efficiently reducing tbe byperkeratosis but usually bas less effect on erythroderma. Tbe first reports, dealing mostly with single cases, were ratber encouraging (19,20). Atberton and Wells treated with etretinate 9 patients witb NBIE and 11 patients with BIE, tbe latter responding better to tbe treatment. Tbe average dose used was 1.5 mg/kg b.w. in NBIE and 1.2 b.w. in BIE (21). 50 In a furtber clinical study 7 patients witb LI were treated first witb etretinate and later on witb acitretin, producing a marked improvement. Tbe dynamics of dosage adjustment provided two response patterns: some patients required 35 mg daily or more, wbile otbers responded well to 10-25 mg daily (22). From tbese as well as from furtber reports it may be deducted that LI answers to treatment witb retinods and specially to acitretin. Lacour et al. (23) confirm tbat acitretin was a safe drug in 46 cbildren, they observed only minor abnormalities in !iver function tests and triglicerides, whicb did not necessitate a change in therapy. They suggest a starting dose of 0.5 mg/kg body weight. Essential fatty acids (EFA ) given orally were efficient in removing icbthyosis-like hyperkeratosis in an experimental model in mice. According to several reports treatment with EFA was successful in patients with atopic dermatitis wbere an increase of linoleic acid and a decrease of its metabolite the gama- linoleic acid was observed in plasma (24). Therapeutic attempts in patients with hereditary ichthyosis seem to be not that much encouraging. acta dennatovenerologica A.P.A. Vol 6, 97, No 2 Jchthyosis Cyclosporine A . Some observations were made in ichthyosis patients who were treated with cyclosporin A after kidney transplantation. Ho et al included ichthyoses into the group with minimal response to cyclosporine (25). LOCAL TREATMENT In view of many side effects of different systemic treatment modalities, the topical treatment is still of primary importance, even in the most severe cases. The main objectives of topical treatment are to reduce the dryness, TEWL, soreness, eventually also redness, as well as to remove the scales and in such a way to restore the normal hydratation of the skin. Unfortunately the success is usually only a partial one. The commonly used vehicles (basis ointments or creams), the most important therapeutical compo- nents and further ingredients such as emulsifiers, stabilizers, preservatives and accelerants are shortly discussed. Vehicles. Up to two decades ago or so, the vehicles were relatively simple materials, such as various animal greases, soft paraffin (vaseline, petrolatum), lanolin and others. Dermatological preparations for topical use were developped empirically, active ingre- dients were mixed with the vehicle according to physicians ' prescription, the mutual influence of the vehicle and the active ingredient were not studied in details. At present a topical preparation has to fulfill a number of criteria: the vehicle should be easy to apply and remove, non-toxic, non-irritant, non-aller- gogenic, chemically stable, homogeneous. bacteriostatic, resistent to moulds, cosmetically acceptable and pharmacologically inert. For these reason, in treating ichthyoses mostly emulsions oil in water (O/W) and water in oil (W/O) or semisolid water-free and water-containing ointments produced by pharmaceutical companies are being used. The importance of vehicle is now well recognized not only for its physical properties but also as a delivery system for the many new active topical drugs. The vehicle is chosen as carefully as the incorporated drug (18,26). The so-called magisterial preparations ( extemporaneous dermatological formulations) are being restricted to selected situations, ichthyoses will probabely remain such a field of activities . Active ingredients. Following are a few substances which have been reccommended for topical treatment acta dennatovenerologica A.P.A. Vol 6, 97, No 2 of ichthyoses: - salicylic acid 2-6% and urea 10% in O/W creams or ointments for removing the scales; - cholesterol 10% is both active in restoring the barrier function (16) and is also an emulsifier (26). Various alpha hydroxy acids (AHAs) e.g. glycolic, lactic, pyruvic and tartaric acid or ethylpyruvate dissolved in water or ethanol, incorporated in W/O or O/W ointments or creams in 2-5% concentration, were advocated (27) in treatment of lamellar ichthyosis. Individuals with sensitive skin may not tolerate products formulated with AHAs. For this reason a neutral amid derivative, methoxypropylgluconamide was developped (28) . Tretinoin 0.25% in a gel or 0.5 % in a cream was also mentioned as being efficient (18) . Topically applied calcipotriol was reported to be beneficial in congenital ichthyoses, especially in LI (29). In a further study 27 patients with ichthyosis vulgaris, RXLI and congenital ichthyoses were treated with calcipotriol ointment (50 ug/g) in amounts up to 100 g weekly, twice daily. The authors concluded such short-term treatment (a few weeks) was mode- rately efficacious and safe in adult patients (30). Preservatives are needed to prevent secondary infections with bacteria, fungi, molds and viruses. Various esters of the parahydroxybenzoic acid (parabens) are widely used, occasionally they may provoke sensitization. Further such substances are chlorocresol, phenoxyethanol, sorbic acid as well as others. Emulsifiers are large molecules with both strongly polar (water soluble, hydrophilic) and non-polar ( oil soluble, lipophilic) groups; they dissolve partly in water and partly in oil. Two types are differentiated: l. producing W/O systems e.g. polyvalent metallic soaps, propylene glycol fatty acid esters and others. 2. producing O/W systems like alkylsulphates, synthetic phosphoric acid esters and others. Stabilizers prevent reactions between the vehicle and the active ingredient as well as other chemical reactions so that do not change in a given period of tirne. Accelerators increase the permeability of the skin. Propylene glycol or dimethyl sulphoxide (DJ\1SO) can be mentioned as examples. 51 VEHICLES RECCOMMENDED The vehicles which are mostly used in Slovenia are Lekobaza*and Linola** but also Diprobase*** and Belobaza****. In the Table 2 the active ingredients and their concentrations are given as suggested by the producers. Ichthyosis CONCLUSIONS As it was mentioned ichthyoses are a rather heterogeneous group. A number of pathogenetic mechanisms have been elucidated, an etiologic treatment is however stili not possible. Systemic medicaments e.g. corticosteroids and retinoids are quite efficient, but usually produce considerable side effects, for this reason a continuous, long lasting application can not be recommended. Adequate local treatment chosen according to patient's condition is stili of great benefit. REFERENCES l. Shapiro LJ, Weiss R, Buxmann MM et al. Enzymatic basis of typical recessive x-linked ichthyosis. Lancet 1878, ii. 756-7. 2. Russell LI, DiGiovanna JI, Hashem N et al. Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q. Am J Hum Genet 1994; 55: 1146- 52. 3. Parmentier L, Blanchet-Bardon C, Nguyen C et al. Autosomal recessive lamellar ichthyosis: identification of a new mutation in TGM 1 and evidence for genetic heterogeneity. Hum Mol Genet 1995; 4: 1391-5. 4. Huber M, Reuter I, Bernasconi K et al. Lamellar ichthyosis is genetically heterogeneous. Cases with normal keratinocyte transglutaminase. J Jnvst dermatol 1995; 105: 633-4. 5. Williams ML, Elias PM. n-alkanes in normal and pathological human scale. Biochem Biophys Res Commun 1982; 107: 322-8. 6. Yamamoto AI, McGrath JA, Judge MR et al. Selective involvement of KI and KI O in the cytoskeletal abnormality of epidermolytic hyperkeratosis. J Invest Dermatol 1992; 99: 19-26. 7. Rothnagel JA, Dominey AM, Demsey LD et al. Mutations in the domains of KI and KJO in epidermolytic hyperkeratosis. Science 1992; 257: 1128-30. 8. Chipev CC, Korge EP, Markova N et al. A leucine to proline mutation in the H 1 subdomain of KI causes epidermolytic hyperkeratosis. Cel! 1992; 70: 821-8. 9. Cheng J, Syder AJ, YU QC et al. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation of specific epidermal keratin genes. cel! 1992; 70: 811- 19. 10. McLean WH, Morley SM, Lane EB et al. Jchthyosis bullosa Siemens - a disease involving K2e. J Invest Dermatol 1994; 103: 277-81. 11. Kremer H, Zeeuwen P, Mclean WH et al. Jchthyosis bullosa Siemens is caused by mutation in keratin 2e gene. J Invest Dermatol 1994; 103: 286-9. 12. Suzuki Y, Koyama J, Moro O et al. The role of endogenous proteases of str. corneum in degradation of desmoglein 1 and their reduced activity in the skin of ichthyotic patients. Er J Dermatol 1996; 134: 460- 4. 13. Ghadially R, Brown BE, Seguiera-Martin SM et al. The aged epidermal permeability barrier. Structural, functional and lipid biochemical abnormalities in humans and a senescent murine model. J Clin Investig 1995; 95: 2281-90 . 14. Elias PM, Brown BE, Ziboh VA. Permeability barrier in essential fatty acids deficiency: Evidence for a direct role of linoleic acid in barrier function. J Jnvest Dermatol 1983; 74: 230-3. 15. Elias PM, Lampe MA, Chang JC et al. Diazocholesterol-induced ichthyosis in the hairless mouse. I. Morphologic, hisochemical and lipid biochemical characterization of a new animal model Lab Invest 1983; 48: 565-77. 16. Ghadially R, Brown BE, Hanley K et al. Decreased Lekobaza*- LEK, Ljubljana; Linola**- A. Wo/ff, Bielefeld; Diprobase***- Schering-Plough, Keni/worth; Belobaza****- BELUPO, Koprivnica acta dennatovenerologica A.P.A. Vol 6, 97, No 2 53 lchthyosis epidermal lipid synthesis accounts for altered barrier function in aged mice. J in vest dermatol 1996; 106: 1064-9. 17. Kanerva L, KM Niemi, Lauharanta J et al. New observations on fine structure of lamellar ichthyosis and the effect of treatment with etretinate. Amer J Dermatopathol 1983; 5: 555-68. 18. Griffiths WAD, Leigh IM, Marks R. Disorders of keratinization. In Rook A et al. Textbook of De,matology, Champion RH et al edts. 5th ed, Blackwell, London 1994; 1325-90. 19. Pehamberger H, Neumann H, Holubar K. Oral treatment of ichthyosis with an aromatic retinoid. Br J dermatol 1978; 99: 319. 20. Schnyder UW, Vogel A. Zur Behandlung der E,ythro- delmia congenitalis ichthyosif01mis bullosa mit aromatischen Retinoiden. Aktuel De,matol 1980; 6: 133-8. 21. Atherton DI, Wells RS. Etretinate in ichthyosiform er,ythroderma. In Retinoid Therapy, Cunliffe WJ and Miller AJ edts. MTP Press, Lancaster, 1984. 22. Steijlen PM, van Dooren-Grebe RJ, van de Kerkhof Acitretin in the treatment of lamellar ichthyosis. Br J Dermatol 1994; 130: 211-4. 23. Lacour M, Mehta-Nikhar, Atherton DI et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J dermatol 1996; 134: 1023-9. 24. Morse PF, Horrobin DF, Manku MS et al. Meta- analysis of placebo controlled studies of efficacy of epogam in the treatment of atopic eczema. Relationship between plasma essential fatty acids and clinical response. Br J dermatol 1989; 121: 75-90. 25. Ho VC, Lui H, McLean DI. Cyclosporine in nonpsoriatic dermatoses. J Amer Acad Dermatol 1990; 23: 1248-59. 26. Griffiths WAD, Ive FA, Wilkinson ID. Topical therapy. Rook et al. Textbook of Dermatology, 4th ed, Blackwell, Oxford, 1986; 2529-73. 27. Van Scot EJ, Yu RJ. Control of keratinization with alpha hydroxy acids and related compounds. I. Topical treatment of ichthyotic disorders. Arch Dermatol 1974; 110: 586-90. 28. Wolf A, Parler A, Levy SB. An alpha hydroxy acid derivative suitable far sensitive skin. Dermatol Surgery 1996; 22: 469-73. 29. Lucker GP, van de Kerkhof PC, van Dijk et al. Effect of topical calcipotriol on congenital ichthyoses. Br J Dermatol 1994; 131: 546-50. 30. Kragballe K, Steijlen PM, Ibsen HH et al. Efficacy, tolerability and safety of calcipotriol ointment in disorders of keratinization. Arch Dermatol 1995; 131: 556-60. AUTHORS' ADDRESSES Aleksej Kansky MD, PhD, professor of dermatology, Department of Dermatology, University Clinical Center, 1525 Ljubljana, Slovenija Božana Podrumac MD, Mr Se, same address Ida Prelog MD, Head Department of Dermatology Maribor Teaching Hospital, Ljubljanska 5, 2000 Maribor, Slovenija 54 acta dennatovenerologica A.P.A. Vol 6, 97, No 2