fchthyoses in Slovenian population preliminary reporl Clinical study ICHTHYOSES IN SLOVENIAN POPULATION PRELIMINARY REPORT B. Podrumac, A. Kansky, I. Prelog and A. Pejovnik-Pustinek ABSTRACT Introduction. Ichthyoses are a heterogeneous group of disorders, up to now no generally accepted classification exists. Additionally to the recessive x-linked ichthyosis (RXLI) in certain families of patients with lamellar ichthyosis (LI) the metabolic defect was elucidated. As known from previous studies the palmoplantar keratodermas and other genodermatoses are quite frequent in Slovenia. As there are no data on prevalence of ichthyosis in our country we decided to carry out a pilot study. Methods. Out- and in-patients' records were studied in the University Department of Dermatology in Ljubljana as well as in the dermatology departments of General Hospitals in Maribor and Celje. In Ljubljana data for a 20-year-period, in Maribor for a 10-year period and in Celje for an even shorter period were collected. Results. In Ljubljana 190 cases were recorded: 167 cases of ichthyosis vulgaris (the documentation did not allow a differentiation between the autosomal dominant ichthyosis and RXLI), 19 of non-bullous ichthyosiform erythroderma (NBIE) and 4 cases of LI. In Maribor there were 95 cases of ichthyosis vulgaris and 5 of NBIE. In Celje were registered 36 cases of autosomal dominant ichthyosis (ADI), 8 of RXLI, 4 of NBIE and 1 with neurological implication. Altogether 339 patients were recorded. Discussion. Although the material obtained is not suitable for an exact statistical analysis, the total of 339 cases of ichthyoses represents a rather high figure for a population of barely 2 million. The result includes only a minor number of affected family members. Conclusion. As the study is still in course, a substantially higher number of ichthyosis cases is to be expected. KEY WORDS ichthyosis, epidemiology, Slovenia INTRODUCTION In the literature there are some data on the prevalence of various types of ichthyoses based mainly on observations by clinicians and mostly not acta dermatovenerologica A.P.A. Vol 6, 97, No 4 collected according to strict statistical rules. A further disadvantage is that there is no generally accepted classification of ichthyoses in order to make the data 145 Ichthyoses in slovenian population prelimina,y report Table l. Ichthyosis patients diagnosed at the Depmt- ment of dermatology, University Medica! Centre, Ljubljana. ADI 167 RXLI NBIE 19 LI 4 with neurological symptoms TOTAL 190 LEGEND: ADI autosomal dominant ichthyosis vulgaris RXLI recesive x-linked ichthyosis NBIE non-bullous ichthyosiforrn e,ythroderma LI lamellar ichthyosis by various authors comparable. During the last five years facts have been accumulating revealing that · ichthyoses are a rather heterogeneous group of disorders characterized by generalized persistent scaling, but caused by different pathogenetic mechanisms. The problem is additionally complicated due to manifold non-cutaneous manifestations relatively often accom- panying skin symptoms. PREVALENCE Autosomal dominant ichthyosis vulgaris (ADI) is characterized by high penetrance and is the most common condition in this group of disorders with an estimated prevalence of 1:250 to 1:320 (1). It seems to be more frequent in certain areas in India (2). Recessive X-linked ichthyosis (RXLI) is in principles restricted to males, however female carriers may demonstrate some of the features. Its prevalence has been recorded in the literature at 1:6000 (3), in Israel 1:9500 (4) and in Spain 1:4125 (5). By screening materna! sera for Down syndrome in 15375 pregnancies in Germany, 5 in 7500 male .births were affected by steroid sulfatase (STS) defici- 'ency which is a reliable marker for RXLI ( 6), giving the prevalence rate of 1:1500 in this selected group. Prevalence of severe autosomal recessive lamellar ichthyosis (LI) is estimated at 1:200 000 (7). PATHOGENESIS The clinical diagnosis of ichthyosis includes a 146 Table 2. Ichthyosis patients diagnosed at the Depart- ment of dennatology, General Hospital Maribor. ADI RXLI NBIE LI with neurological symptoms TOTAL LEGEND: ADI autosomal dominant ichthyosis vulgaris RXLI recesive x-linked ichthyosis NBIE non-bullous ichthyosiform e,ythroderma LI lamellar ichthyosis 95 5 100 number of pathogenetically different conditions clinically displaying often \ a more or less similar appearance. The underlying metabolic or molecular- biologic mechanisms have !;ieen elucidated up to now (at least partially) only , in a few of these conditions: In 1978 Shapiro et al demonstrated the deficiency of the enzyme steroid sulfatase (STS) in cultured fibroblasts of patients with RXLI (8). The action of this enzyme which splits cholesterol sulfate into cholesterol and sulfate in the upper stratum corneum (SC), is essential for normal shedding. An increased content of cholesterol sulfate seems to be responsible for formation of scales in RXLI. In certain patients with severe LI it was possible to prave complete linkage to severa! markers within a 9.3 cM region on chromosome 14q (7). Transglu- taminase 1 (TGM-1) which is responsible for cross- linking of proteins during formation of cornified cell envelope CE), maps to this interval. In a study of 23 families with severe LI Parmentier et al detected a linkage of the disease to TGM-1 in 10 families, while in further 13 families TGM-1 was not linked to the disease (9). They concluded that LI is genetically a heterogeneous disorder, it not in all instances linked to a TGM 1 deficiency. Biochemical analysis of ichthyotic scales revealed an increase of cholesterol sulfate in scales from RXLI patients (10), and an increase of n-alkanes in scales of patients with NBIE (11). A more detailed explanation of pathogenesis was given earlier (12). acta derrnatovenerologica A .P.A. Vol 6, 97, No 4 Ichthyoses in Slovenian population prelimina,y report Table 3. lchthyosis patients diagnosed at the Depart- ment of dermatology, General Hospital Celje. ADI 36 RXLI 8 NBIE 4 LI with neurological symptoms 1 TOTAL 49 LEGEND: ADI autosomal dominant ichthyosis vulgaris RXLI recesive x-linked ichthyosis NBIE non-bullous ichthyosiform e,ythroderma LI lamel/ar ichthyosis MATERIALS AND METHODS Out- and in-patients' records were studied in the University Department of Dermatology in Ljubljana as well as in the dermatology departments of the General Hospitals in Maribor and Celje. All three mentioned departments are staffed with competent dermatologists. In Ljubljana a 20-year period was covered, whereas due to technical difficulties in Maribor a 10-year and in Celje a 2-year period. The dermatology department in Ljubljana is covering an area of approximately 800 000, the one in Maribor 450 000 and in Celje 250 000 inhabitants. Total population of Slovenia is close to 2 million. The existing clinical classifications of ichthyosis are unsatisfactory, which is due to the fact that the etiopathogenesis of various forms is still not elucidated. We have used the one which is compatible with the one by Griffiths et al (12) and by Williams (13), it was elaborated in details as already mentioned in a previous publication (12) Unfortunately in the existing records there were often not sufficient data for separation of the ADI from RXLI. LI was not an accepted as a diagnostic entity years ago, while erythrodermia ichthyosiformis non-bullosa (NBIE) was diagnosed relatively frequently. RESULTS The data from Ljubljana are presented in table 1, data from Maribor in table 2 and from Celje in acta dermatovenerologica A.P.A. Vol 6, 97, No 4 Table 4. lchthyosis patients diagnosed in Slovenia. ADI 298 RXLI 8 NBIE 28 LI 4 with neurological symptoms 1 TOTAL 339 LEGEND: ADI autosomal dominant ichthyosis vulgaris RXLI recesive x-linked ichthyosis i\/BIE non-bullous ichthyosiform e,ythroderma LI lamel/ar ichthyosis table 3. Altogether, ichthyosis was diagnosed in Slovenia in 339 instances. There were 306 ADI and RXLI patients which corresponds to a combined prevalence of 15.3 in 100 000. The diagnosis NBIE was made in 28 cases giving a prevalence of 1.4 in 100 000. and LI in 4 cases. Table 4. DISCUSSION Desquamation is a process in which corneocytes are detached from the skin surface in the terminal differentiation stage of the epidermis. It is still poorly understood and the nature of pathological desquamation of SC in ichthyosis remains unsolved. In RXLI there is evidence that the presence of cholesterol sulfate in the outer SC due to deficient activity of the STS might be responsible for the formation of scales (10). Recent studies have shown that desmosomes also play a vital role in SC adhesion and that their degradation may be a prerequisite for normal SC desquamation. It was reported that desmoglein 1 (DSG-1) which is a desmosome protein is associated with corneocyte adhesion in plantar SC (15). Suzuki et al incriminate the decreased activity of both the trypsin-like and chymotrypsin-like serine proteases in the ichthyotic SC and the following decreased degradation of DSG-1 for the abnormal desquamation (16). Many efforts were dedicated to the study of LI. The terminal differentiation in the granular layer 147 lchthyoses in Slovenian population preliminary report and the transition to corneocytes results in formation of a cornified envelope filled with a keratin matrix. Transglutaminase (TGM) catalyzes the calcium- dependent cross-linking of proteins through the formation of Ne(gama glutamyl) lysine isopeptide bonds. In the epidermis involucrin and loricrin are known to be cross-linked by TGMs in the process of formation of the CE. The newly synthesized protein undergoes post synthetic fatty acid acylation resulting in attachment of the fatty acids and ceramides derived from lamellar bodies to the surface of the envelope (16). TGM-1 plays a key role in the process of terminal differentiation and formation of the CE. Further studies stressed the importance of TGM-1 in the pathogenesis of LI specially in linking LI to a chromosom 14q region maping for TGM-1 (18), but further studies may reveal additional patho- genetic mechanisms This short review reveals how difficult it is to establish a classification of ichthyoses suitable for every day clinical use and at the same tirne reflecting ali the new achievements. CONCLUSIONS l. The preliminary aim of the study in course is to gather data for future genetic counseling. Previous investigations concerning various palmoplantar kerato- dermas and cutaneous porphyrias which have been carried out years ago, have shown that genetic defects are relatively frequent in the population of Slovenia. 2. The modem genetic counseling is based on sophisticated biochemical and molecular-biologic techniques, which have to a great deal supplemented the methods used before. 3. New techniques are complicated, tirne consuming and expensive, the biologic material (usually blood) has to be taken from patients as well as from their affected and unaffected family members. For this reason a careful case selection is necessary. 4. Clinical classification of various types of ichthyoses has to take into consideration the latest developments in the pathogenesis but stili to be relatively simple and suitable for routine clinical work. ACKNOWLEDGEMENT The clinical study was supported by the Slovenian Ministry of Science and Technology, Grant No 13- 9105. REFERENCES l. Okano M, Kitano Y, Yoshikava K et al. X-linked ichthyosis and ichthyosis vulgaris. Comparison of their clinical features based on biochemical analysis. Br J Dermatol 1988; 119: 777-83 2. Baruah MC, Deducoumar P, Garg BR et al. Clinico-epidemiologic profile of ichthyosis in South lndian patients. J Dermatol 1995; 22: 486-91 3. Wills RS, KeTT CB. Genetic classification of ichthyosis. Arch Dermatol 1965; 92: 1-6 4. Ziprkowski L, Feinstein A. A survey of ichthyosis vulgaris in Jsrael. Br J Dermatol 1972; 86: 1-8 5. Unanimo P, Martin-Pasqual A, Garcia-Perez A. A x-linked ichthyosis. ibid. 1977; 97: 53-8 6. Bartels I, Caesar J, Saucken U. Prenatal detection of x-linked ichthyosis by materna! serum screening for Down syndrome. Prenatal Diag 1944; 14: 227-9 7. Russel LI, DiGiovanna JI, Hashem N et al. Linkage of autosomal recessive lamellar ichthyosis to 148 chromosome 14q. Am J Hum Genet 1994; 55: 1146-52 8. Shapiro LI, Weiss R, Buxmann MM et al. Enzymatic basis of typical recessive x-linked ichthyosis. Lancet 1978; II: 756-7 9. Parmentier L, Blanchet-Bardon C, Nguyen C et al. Autosomal recessive lamellar ichthyosis: identification of a new mutation in transglutaminase 1 and evidence for genetic heterogeneity. Hum Mol Genet 1995; 4: 1146-52 10. Williams ML, Elias PM. Jncreased cholesterol sulfate content in stratum comeum in recessive x- linked ichthyosis. J Clin lnvest 1981; 68: 1404-10 11. Williams ML, Elias PM. Elevated n-alkanes in congenital ichthyosif orm erythroderma. Phenotypical dif.ferentiation of two types of autosomal r~cessive ichthyosis. J Ciin lnvest 1984; 74: 296-300 12. Kansky A, Podrumac B, Prelog l. Hereditary ichthyosis. Pathogenesis and possibilities of treatment. acta dermatovenerologica A .P.A. Vol 6, 97, No 4 Ichthyoses in Slovenian population preliminary report ACTA Dermatovener APA 1997; 6: 47-54. 13. Griffiths WAD, Leigh IM. Marks R. Disorders of Keratinization. In Rook et al: Textbook of dermatology. Champion RH et al edits. 5th Edition Blackwell, London, 1994 14. Williams ML. Ichthyosis and Disorders of Comification. Pediatric Dermatology. Schacher LA, Hansen RC Eds. Churchill Livingston, New York 1988 15. Lundstrom A, Egelrud T. Evidence that cel! shedding from plantar stratum corneum in vitro involves endogenous proteolysis of the desmosomal protein desmoglein I. J Invest Dermatol 1990; 94: 216-20 16. Suzuki Y, Koyama J, Moro O et al. The role of two endogenous proteases of the stratum comeum in degradation of desmoglein-1 and their reduced activity in the skin of ichthyotic patients. Br J Dermatol 1996; 134: 460-4 17. Hohl D, Huber M, Frenk E. Analysis of comified cel! envelope in lamellar ichthyosis. Arch Dermatol 1993; 129: 618-24 18. Russel LI, DiGiovanna JI, Hashem N et al. Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q. Am J Hum Genet 1994; 55: 1146-52 AUTHORS' ADDRESSES Božana Podrumac MD, Head Pediatric dermatology, Department of Dermatology, University Clinical Center, Zaloška 2, 1525 Ljubljana, Slovenia Aleksej Kansky MD, PhD, professor of dermatology, same address Ida Prelog MD, Head Department of Dermatology, Teaching Hospital Maribor, Ljubljanska 5, 2000 Maribor, Slovenia Alenka Pejovnik-Pustinek MD, Department of Dermatology, General Hospital Celje, Oblakova 5, 3000 Celje, Slovenia acta dermatovenerologica A.P.A. Vol 6, 97, No 4 149