Darier's disease in Slovenia 
Darier's d-isease in SWVenia 
J. Miljkovič, N. Kecelj, V Balkovec, M. Penko andA. Kansky 
ABS TRACT 
Background. Dyskeratosis tollicularis (Darier-White, morbus Darier, MD) is an autosomal dominant skin 
disorder characterized by warty papules and plaques primarily in seborrheic areas, palmo-plantar pits 
and nail abnormalities. Our purpose was to collect the intormation on the prevalence ot patients affected 
with MD in Slovenia. 
Materials and methods. Records from Departments ot dermatology in Slovenia were studied and new 
cases were registered. Clinical symptoms and other relevant data from 27 patients who had followed our 
invitation tora re-examination were collected in special questionnaires. 
Results. Altogether 44 patients were recorded, 20 were males and 24 temales. Taking into account that 
the Slovenian population amounts to roughly 2 million, this would give a prevalence ot 2.2/100 000. 
Altogether 27 patients followed the invitation tora re-examination. Greasy papules were expressed in all 
the patients, nail involvement ranked second with 89%. Trunk and limbs were involved in 89% ot patients 
and the face in 89%. The onset of the disease was in the majority ot cases in the second decade ot lite, 
in all patients the symptoms appeared betore the age ot forty. 
Conclusion. The prevalence of this condition is similar to that in England, Denmark and Croatia. 
Introduction 
Dyskeratosis follocularis (Darier-White disease, mor-
bus Darier, MD) is an autosomal dominant skin disorder 
characterized by warty papules and plaques primarily 
in seborrheic areas, palmo-plantar pits and nail abnor-
malities. The prevalence of the disease has been esti-
mated at 1.8/100 000 inhabitants from Central England 
(1), 2.8/100 000 from Northeast England (2) , 1/ 100 000 
from Denmark (3) , 1.3/100 000 from Croatia (4). 
We know from previous studies , that certain geno-
dermatoses are quite frequent in Slovenia: e.g. palmo-
plantar keratoderma (5,6, 7), epiclermolysis bu llosa 
hereclitaria, erythropoetic protoporphyria and others. 
Our purpose was to collect the information on the 
prevalence of patients affected with MD in Slovenia. 
Clini c al study 
10 - - ----- - -------- - - - ---------- - - - Acta Dermatoven APA Vol 9, 2000, No 1 
Clinical study Darier's disease in Slovenia 
Table 1. Darier's disease in Slovenia: symptoms investigated in 27 patients. 
follicular and extrafollicular greasy, keratotic papules 27 100 
hypertrophic plaques 12 44 
erosions 8 30 
leukoderma 4 15 
scales on the scalp 11 41 
punktiform keratoses on the palms and soles 3 11 
broken papilla1y lines 3 11 
plane papules on the back of the hands and feet 12 45 
white "cobblestone" papules of the mucous membranes in the oral cavity 3 11 
white longitudinal bands on the nail plate 
red longitudinal bands on the nail plate 
v-shaped nick at the free margin of the nail 
subungual keratoses 
fragility of the nails 
Material and methods 
In order to obtain the data on MD patients in Slovenia 
records were studied in the Departments of Dermato-
venereology in Ljubljana, Maribor, Celje and Novo 
Mesto. New cases were also registered; thus a 30-years-
period was covered. The diagnosis was established by 
clinical observation and patients' histories , in 24 cases 
a skin biopsy was performed. For families w ith two or 
more affected members pedigrees were prepared. 
Symptoms and other relevant data from 27 patients who 
had followed our invitation for a re-examination were 
collected in specially prepared questionnaires and 
analyzed. 
Results 
Altogether 44 patients were recorded, 20 males and 
24 females. Taking into account that the Slovenian 
population amounts to roughly 2 million, this would 
_give a prevalence of 2.2/ 100 000. 
The 27 personally observed patients were from 15 
to 72 years old ancl belongecl to 21 families, 10 ofthem 
were isolatecl cases. There were four Slovene families 
with two cases; three families with three cases, one fa-
mily with four cases ancl two families with five cases of 
MD (Fig. 1). 
Ali examinecl patients had typical clinical symptoms: 
follicular and extrafollicular greasy, keratotic papules, 
half ofthem also hypertrophic plaques. Other symptoms 
observed were: sca les on the scalp; plane papules on 
the back of the hands and feet; white or red longitudinal 
bands of the nail p late with V shaped notches at the 
free edge, indicating a fragility of the nails. Only a mino-
17 63 
9 33 
6 22 
6 22 
14 52 
rity of patients observecl had white »cobblestone« papu-
les of the mucous membranes in the oral cavity. The 
symptoms recorcled in the 27 patients who followed 
our invitation for a re-examination are presentecl in 
Table l. Preclilection sites were the neck, trunk, nails, 
face, limbs, scalp and scalp margins and back of hancls 
(Table 2). Almost half of patients complainecl of itching 
and deterioration, if exposed to sunshine. 
The onset of MD in our patients occurrecl before 
the fourth decade . In the half of the patients skin 
symptoms appearecl in the second clecacle of life. Only 
in two patients the onset of MD was during the first 
year of life, in one in the 5th year, in two in the 9th year, 
Table 2 . Darier's disease in Slovenia: predilection sites 
investigated in 27 patients. 
face 17 63 
neck 24 89 
trunk 24 89 
limbs 14 52 
axillae 7 26 
groins 3 11 
anogenital region 3 11 
scalp and scalp margins 16 59 
palms 9 33 
soles 4 15 
back of the hands 13 48 
back of the feet 7 26 
buccal mucosa 4 15 
nails 24 89 
clavicular region 6 22 
Acta Dermatoven APA Vol 9, 2000, No 1 11 
Clinical study 
while in two of them the disease cleveloped after 40 
years. 
We also triecl to evaluate the eclucation leve! of our 
patients; 20 of them (75%) finished only the prima1y 
school or a vocational school, 2 of them (7%) gracluatecl 
from a seconclaiy school, 2 of them (7%) finishecl coli ege 
of further eclucation, while three are still attencling the 
school: one a prima1y school, the seconcl one a secon-
clary school ancl the thircl one a college of further 
eclucation (Graph 1). 
We also observed an impairment of memory and 
concentration with the majority of our patients, though 
in two of them serious symptoms were expressed: one 
of them hacl epilepsy ancl a seconcl paresthesia. 
Involvement of the skin was relatively mile! in 18 
patients (66%), severe in 8 patients (30%) ancl very 
severe in one C 4%). Approximately 37% of ali observed 
patients, mostly with a severe form of the clisease, were 
treated with synthetic retinoicls orally. 
Discussion 
Our results show a relatively high prevalence of MD 
in Slovenia. Compared with data on occurrence of MD 
in Croatia, Denmark and Englancl, the prevalence was 
higher only in Northeastern Englancl (1-4). 
MD is inherited as an autosomal dominant trait with 
variable penetrance ancl expressivity (8). We examinecl 
eleven families with more than two affectecl members. 
10 sporaclic cases, whose parents are normal, probably 
represent new mutations, but other possibilities must 
also be considerecl: penetrance might be incomplete, 
not recognizecl ve1y mile! symptoms in parents as well 
as 11011-paternity (9). 
Various groups of researchers triecl to cletect the 
genetic clefect in MD; clesmoglein, clesmocollin, clesmo-
plakin ancl other components of the desmosome were 
incriminatecl (10-13). An abnormality in the desmosome 
-keratin filament interaction appears to be responsible 
for the breakclown of celi adhesion. The histopatho-
logical characteristics of MD are suprabasal clefting 
(lacunae) in-between suprabasal epidermal cells (acan-
tholysis) and abnormal keratinization (dyskeratosis) 
with rouncl dyskeratotic cells (corps ronds). Insicle the 
lacunae there are single as well as small groups of epi-
clermal cells (acantholytic cells) (8,14,15). The inter-
cellular spaces between the prickle cells adjacent to 
lacunae are wiclened and the number of desmosomes 
is reduced. Electron microscopy also revealecl loss of 
desmosomal attachments, perinuclear aggregations of 
keratin filaments ancl cytoplasmic vacuolisation (16-18). 
This data suggest that molecules, which mediate 
adhesion between keratinocytes might be involved in 
the loss of celi-celi aclhesion in the epidermis. Desmo-
somes are the prime celi-celi adhesion junctions in the 
epidermis and are composecl of various components, 
12 
Darier's disease in Slovenia 
Darier's disease in Slovenia: educational leve! in 27 
patients 
11% ~ primary school 
lwl vocational school 
tffill secondary school 
lwl college 
42% mm attend the school 
Graph 1 . Darier's disease in Slovenia: 
educational leve! in 27 patients. 
e.g.: desmosomal transmembrane proteins (desmo-
gleins and desmocollins), desmosomal plaque proteins 
(desmoplakin, envoplakin ancl plakoglobulin) and 
plaque-associated proteins such as plakophilin I (19-
21). Desmosomes interfere with the keratin intermediate 
filaments network in cytosol. In 1993 two British group 
excluded linkage of MD to any of the desmosomal genes 
mapped on chromosome 18 and to the type II keratin 
cluster at the chromosomal region 12qll-q13 (22,23). 
The clefective gene probably regulates the expression 
of certain adhesion molecule. 
New c!ata concerning the pathogenesis were publi-
Graph 2. Darier's disease: age at onset in 
different countries. 
Darier's disease: age at onset in different countries 
70 
60-
50 
>?. o 
s, 40 -
'O 
!!l. 
a;· 
30 ::, 
ur 
20 
10 -
o 
1-1 O 11-20 21-30 
years 
>30 
• SLOVENJA (S) 
ITI CROATIA (C) 
lilil ENGLAND (E) 
• DENMARK (D) 
Acta Dermatoven APA Vol 9, 2000, No 1 
Darier's disease in Slovenia 
Family l. 
M 
l. 
II. 
Family 2. 
l. + 
II. 
III. 
Family 4. 
l. 
II. 
III. 
IV. 
+ 
Clinical study 
Family 3. 
l. + 
II. + 
III. 
Family 5. 
I. 
II. 
III. 
IV. 
Family 6. 
I. 
Figure 1. Pedigrees of six families with morbus Darier including three or more involved persons. 
14 Acta Dermatoven APA Vol 9, 2000, No 1 
Clinical study 
shed by Sakuntabhai et al. who iclentified mutations in 
the ATP2A2 gene, which encodes the sarco/endoplas-
mic reticulum Ca2•-ATPase isoform 2 (SERCA2) ancl is 
highly notable in keratinocytes (24). ATP2A2 gene is 
located on chromosome 12q23-24.1. SERCA2 is a Ca2• 
pump that bas a pivotal role in intracellular Ca2• signa-
lling ancl maintaining low cytosolic Ca2• concentration. 
ATP2A2 gene mutation coulcl be responsible for MD 
because cytosolic Ca 2• is known to have a role in the 
development of epithelial junctions and in regulating 
cel! differentiation. Mutation in ATP2A2 gene disrupts 
important domains of the molecule and is likely to result 
in complete or partial loss of function of the SERCA2 
mutated pumps. 
Clinical symptoms of MD vary, they may be minimal 
or severe with widespreacl itchy malodorous crusted 
plaques, painful erosions, blistering and mucosal lesions 
(25). The majority of patients have rather mild clinical 
symptoms. We found some similar reports in literature: 
according to Burge and Wilkinson (25) the chest, the 
back, the forehead and the supraclavicular fossae were 
involved in more than 80% of cases under observation. 
The nail involvement was observed in over 90% of 
English and in 71 % of Croatian patients (24). Lesions of 
oral mucosa and neuropsychiatric abnormalities were 
relatively rare in our patients ancl also in other stuclies : 
according to Burge ancl Wilkinson in 15% of patients 
and in Croatian patients in 18 %. Many of our patients 
complained about disturbance of concentration and of 
an impairecl memory. The majority of them finished only 
the primary school or a professional school. All these 
data suggest that in the majority of patients w ith MD a 
miki mental retardation exist. Munro (2) believes that 
the observation of a frequent mental subnormality in 
patients with MD in Denmark could indicate that 
additional genes are involved in cases observed in that 
count1y. 
Sunlight, heat, sweating and poor personal hygiene 
exacerbated the disease in the majority of our patients, 
whereas on the contra1y psychic stress, various infec-
tions, operations and pregnancy usually did not affect 
1:-, " 'I . ··1 .... . "'I . y "°'! ........ 
. n.B.;J, .b.H L N ChS 
Darier's disease in Slovenia 
their condition. Sunlight has been mentioned as an exa-
cerbating factor in 58% by British and in 89% by Croatian 
patients (25). 
At the onset of the disease the age in our patients 
was under forty, while in half of the cases clinical 
symptoms appeared in the second decade. There are 
similar reports from other countries (Graph 2). Burge 
and Wilkinson (26) mentioned that in their study the 
peak of onset of MD occurred between the ages of 11 
and 15. Sokol and Kansky ( 4) reported in their 28 cases 
two peaks of onset, namely in the age group 5 to 9 and 
in 20 to 24 years. 
We stili do not have an ideal method for treatment 
of MD (24). First of all, the patient should eliminate all 
the triggering factors and maintain a regular personal 
hygiene. For mild forms of MD simple emollients are 
usually sufficient. Cryotherapy with liquid nitrogen, 
topical application of tretinoin gel, calcipotriol or 5-
fluorouracil can be used successfully on 11011-i.rritated 
skin. Corticosteroid creams and ointments are necessary 
during periods of irritated skin. For the patients with a 
severe form of the d isease systemic retinoids are 
recommended. The patients with severe form of disease 
in our study were treated with synthetic retinoids orally, 
at least for the first couple of months. One patient with 
a very severe form of disease who is being treated with 
synthetic retinoids for over 1 O years does not exhibit 
serious side effects. 
It is interesting that in certain genodermatoses the 
symptoms become notable only at a later stage of the 
disease. This is also a reason to search for a sensitive 
and specific diagnostic method for an early diagnosis 
of MD. The replacement of mutated genes that are 
responsible for MD, may be a solution of this problem 
in the future. 
Acknowledgement 
The study was supported by the Slovenian Minist1y of 
Science and Technology, Grant No ]3-9105. 
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Jovan Miljkovič MD, Dpt. Dermatovenereology, Maribor Teaching 
Hospital, Ljubljanska 5, 2000 Maribor, Slovenia 
NadaKecelj MD, Dpt. Dermatovenereology, University Clinical Centre, 
Zaloška 2, 1525 Ljubljana, Slovenia 
ValerijaBallwvecMD, Dpt. Dermatovenereology, GeneralHospital, 
Šmihelska 1, 8000 Novo mesto 
Marta Penko MD, Director Dpt. Dermatovenereology, University Clinical 
Centre, Zaloška 2, 1525 Ljubljana, Slovenia 
Aleksey J{ansky MD, PhD, projessor oj dermatovenereology, corresponding 
author, same address 
17