Med Preg12000; LUI (1-2): 15-27. Novi Sad: januar-februar.

Medicinski fakultet, Novi SadKlinicki centar, Novi SadKlinika za kozno-venericne bolesti I

Institut za zdravstvenu zastitu dece i omladine, Novi Sad"UKC BeogradKlinika za dermatoveneroloske bolesti'

Originalni naucni radOriginal studyUDK 616.5:616-056.7(497.113)

15

PROCENA FREKVENClJE GENSKIH ALELA GENODERMATOZA UVOJVODANSKOJ POPULACIJI

FREQUENCY ESTIMATION OF THE GENE ALLELES }?OR GENODERMATOSES IN THEPOPULATION OF VOJVODINA

Siobodan STOJANOVICt, Aleksandar KRSTIC\ Mirjana POLJACKI1 i Olivera CVIJETIC3

Sazetak - Auton su istrazivali frekvenciju gena, vrste i klinicke oblike nas1ednih dennatoza na terenu Vojvodine, sa odredivanjempolne distribucije i uzrasta ispitivanih bo1esnika. Eksperimenta1na grupa dobijena je metodom slucajnog uzorka - odabira obolelihod genodennatoza i/ili genetskih bolesti, koji su dolazili na pregled na Kliniku za kozno-venericne bo1esti i Institut za decu i om­1adinuu Novom Sadu, pri cemu je grupa brojala ukupno 152 slucaja, To je ispitivana i ujedno pozitivna kontrolna grupa u odnosuna populaciju obolelih od genodermatoza i/ili genetskih bolesti u vojvodanskom stanovnistvu. U istrazivanju su primenjene me­tode: porodicne ananmeze sa uzimanjem rodoslovlja, dermatoglifike, genetski skrining testovi, citogenetske analize, patolosko­histoloska analiza materijala dobijenog biopsijom koze, te metod klinicko-genetickog disrnorfoloskog pregleda, primenom racunar­skog programa koji sadrzi klinicke znake nasledno i steceno nastalih oboljenja koze i sindroma. Primenom neparametrijske statis­tike, log-linearne analize, dokazano je da nema statisticki signifikantne razlike izmedu eksperimentalne grupe i populacije genet­ski obolelog stanovnistva Vojvodine. Ovim istrazivanjem dobijena je incidencija pojedinih genodennatoza i/ili genetskih bolesti isindroma u eksperimentalnoj grupi, koja statisticki validno prezentuje incidenciju istih genodennatoza i/ili genetskih bolesti i uvojvodanskoj populaciji. Iz ovako dobijene incidencije, putem primene Hardy-Weinbergovog zakona, izracunate su frekvencijegenskih aida u vojvodanskoj populaciji za pojedine genodennatoze koje su prikazane tabelarno. Na osnovu primene navedenihmetoda populaciono-genetskog istrazivanja moguce je izvrsiti validnu procenu incidencije bolesti i frekvencije gena za genoder­matoze i/ili genetske bolesti i sindrome u odredenoj populaciji stanovnistva. Nasi rezultati istrazivanja ukazuju na znacajno vecuincidenciju pojedinih gcnodennatoza u ispitivanoj populaciji, u odnosu na podatke iz literature za iste bolesti u drugimpopulacijama.Kljucne reci: kozne bolesti + kongenitalne + epidemiologija + genetika; polna distribucija; starosna distribucija; populacionagenctika

Summary - Genodermatoses are hereditary skin disorders or anomalies. The authors had investigated the frequency ofgenes, spe­cies and clinical forms ofhereditary dermatoses in Vojvodina including age and sex distribution. The experimental group was se­lected by random sampling of the diseased of genodermatosis and/or genetic diseases at the Clinic of Dermatology andVenereology and Institute for Children and Adolescents in Novi Sad. The experimental group included 152 cases, and that madesimultaneously the experimental and positive control group in relation to the diseased population with genodermatoses and/or ge­netic diseases in Vojvodina. In the investigation we applied the following methods: family history taking including genealogy; der­matoglyphic examination; screening tests in medical genetics; cytogenetic analysis of patient's karyotype; histopathologicalanalysis of the material obtained by skin biopsy; dermatovenereological, genetic and dysmorphologic examination of skin dis­eases by analysis 0/ dysmorphologic signs on the skin using a special computer program - POSSUM (pictures 0/Standard Syn­dromes and Undiagnosed Malformations). Application ofnon-parametric statistics and Log-linear analysis, revealed that there isno statistically significant difference between the experimental group and the group with genetic diseases in population of Voj­vodina. 71w obtained incidence ofgenodermatoses and/or genetic diseases was computed by "llardy-Weinberg's principle". Thesemethods ofgenetic population investigations give possibilities for valid incidence estimation of the diseases andfrequency ofthegen allele's for genodermatoses and/or genetic disorders and syndromes in defined population. Our results of investigation of theincidence genodermatoses in our's population showed significantly increased values in relation to literature datafor the same he­reditary disorders.Key words: Skin Diseases f congenital + epidemiology + genetics; Sex Distribution; Age Distribution; Genetics, Population

Uvod

lzrazom genodermatoze oznacavaju se naslednebolesti koze iIi anomalije u gradi koze koje su genet­ski determinisane i kod kojih faktori okoline nemajuodlucujucu ulogu u njihovom klinickom ispoljavanju.Usled istovremenog poremecaja u embrionalnom

Introduction

Genodermatoses are hereditary skin disorders oranomalies of the skin structure, genetically determi­ned and environmental factors have no crucial role intheir clinical manifestation. Genodermatoses are of­ten associating with disorders of other organs and or­gan systems (e.g., central nervous system, eyes and

Adresa autora: Asist. dr sc. med. dr Slobodan Stojanovic, Klinika za kozno-venericne bolcsti,21000 Novi Sad, Hajduk Veljkova 1-7

16

Skracenice

AD - autozomnodominantno nasledivanjeAR - autozomnorecesivno nasledivanjeXR - X-recesivno vezano naslede za polXD - X-dominantno vezano naslede za polPOSSUM - slike standardnih sindroma i

nedijagnostikovanih malformaciia

razvoju, genodermatoze su cesto udruzene sa istovre­menim poremecajima na drugim organima i organ­skim sistemima (npr. centralnom nervnom sistemu,ocima i usima) i mogu biti sastavni deo mnogobro­jnih genetskih sindroma [1].

Cilj rada je da se istrazi incidencija bolesti ifrekvencija gena, vrste i klinicki oblici naslednih der­matoza: autozomnodominantnih (AD), autozomnore­cesivnih (AR), i recesivnih (XR) i dominantnih (XD)vezanih za X-hromozom; uzrast i polna distribucijaobolelih sa teritorije Vojvodine.

Materijal i metode

U prikupljanju bolesnickog materijala, njegovojanalizi i obradi rezultata istrazivanja, koriscene susledece metode: metode klinicko-genetickog dismor­foloskog pregleda [2]; metode dermatovenerolosko ­genetickog dismorfoloskog pregleda koze upotrebommetode POSSUM-a (Pictures of Standard Syn­dromes and Undiagnosed Malformations) - racunar­skog programa koji sadrzi klinicke znake u pro­pedevtici nasledno i steceno nastalih koznih bolesti isindroma [3]; porodicna anamneza sa uzimanjem ro­doslovlja od sto vise clanova porodice, a najmanje udye generacije [2,4]; citogenetske analize obolelih izbolesnickog materijala [2,5,6]; dermatoglifika [2,7];skrining testovi [8]; patolosko-histoloska analiza ma­terijala dobijenog biopsijom koze [2,9]; statistickametoda neparametrijske multiple regresione analize(log-lineama analiza) [10,11]; Hardy-Weinbergovzakon binomne raspodele frekvencije gena u popu­laciji [4].

Studija je izvedena prospektivno, u periodu oddye godine, od 1. oktobra 1993. do 1. oktobra 1995,a materijal je dobijen prikupljanjem podataka putemnavedenih metoda istrazivanja, od obolelih od geno­dermatoza i/ili genetskih bolesti na teritoriji Voj­vodine, koji gravitiraju Klinici za kozno-venericnebolesti u Novom Sadu i Institutu za decu i omladinuu Novom Sadu, kao i aktivnim uvidom u bolnicku ivanbolnicku morbiditetnu statistiku Instituta zazdravstvenu zastitu u Novom Sadu. avo prospek­tivno ispitivanje izvedeno je po metodi uzorka rizic­nih grupa stanovnistva za obolevanje od genetskiuslovljenih dermatoza.

Stojanovic S, i sar. Procena frekencija genskih alela

AbbreviationsAD - autosomal dominant inheritanceAR - autosomal recessive inheritanceXR - X-recessive sex linkageXD - X-dominant sex linkagePOSSUM - Pictures of Standard Syndromes and

Undiagnosed Malformations

ears) due to embryonic development, and can be theprinciple part of many genetic syndromes [1].

The aim of investigation was to investigate the in­cidence of disorders and the frequency of genes, sortsand clinical forms of hereditary dermatoses: autoso­mal dominant (AD), autosomal recessive (AR), andX chromosome-recessive sex linkage; sex and agedistribution of patients from the territory ofVojvodina.

Material and methods

In data gathering, in analysis and processing theresults of investigation the following methods wereused: clinical, genetic and dysmorphologic examina­tions [2]; dermatovenereologic, genetic and dysmor­phologic examinations using the method of POSSUM(Pictures of Standard Syndromes and UndiagnosedMalformations) - special computer program whichcomprises the clinical signs in the prope- deutic of thehereditary dermatoses and acquired dermatoses andsyndromes [3]; history taking of the family members,in two generations the minimum [2,4]; cytogeneticanalysis of patients' karyotypes [2,5,6]; dermato­glyphic methods [2,7]; screening test methodology inmedical genetics [8]; histopathologic method ofanalysis of the materiel obtained by skin biopsy [2,91:statistical method of nonparametric multiple regres­sion analysis (log-linear analysis) [10,11]; Hardy­Weinberg equilibrium in the population [4].

The investigation was carried out as a prospec­tive, genetic-population study during a two-year pe­riod (1.10.1993 - 1.10. 1995) and the research mate­rial was gained with abovementioned methods of in­vestigation of patients with genodermatoses and/orgenetic diseases from the territory of Vojvodina,treated at Clinic of Dematovenereology in Novi Sadand the Institute for Children and Adolescents inNovi Sad, as well as by active survey of hospital andambulance statistics of morbidity at the Institute ofHealth Care in Novi Sad. This prospective investiga­tion included risk groups from the population withgenetic predisposition to genetic dermatoses.

The investigation included an experimental groupof 152 cases with genodermatoses and/or genetic dis­eases and syndromes. Out of the total number of 152patients suffering from genetic diseases and genoder­matoses, 85 (55.92%) were males and 67 (44.08%)were females. The female-male ratio was 1:1.27. In

Med Preg12000; LUI (1-2): 15-27. Novi Sad: januar-februar. 17

Iz ovog materijala istrazivanja obrazovana je ek­sperimentalna grupa sa ukupno 152 slucaja obolelihod genodermatoza i/ili genetskih bolesti i sindroma.Od toga broja su 85 slucajeva (55,92%) cinili mus­karci, a 67 slucajeva (44,08%) zene. Odnos zcnskogprema muskom polu u ispitivanoj grupi bio je 1:1,27. U grupi AD genodermatoza i genetskih bolesti,od ukupno 130 slucajeva obolelih, bio je 71 ispitanik(54,62%) muskeg pola i 59 ispitanika (45,38%) zen­skog pola, dok je u grupi AR bolesti (ukupno 15slucajeva) bilo 10 muskaraca (66,67%) i 5 zena(33,33%). U grupi XR genetskih bolesti (ukupno 7slucajeva), bili su prisutni ispitanici muskeg pola u 4slucaja - 57,14%, a zenskog pola u 3 slucaja ­42,86%.

Prosecna zivotna dob obolelih od genetskih bo­lesti i sindroma i genodermatoza u ispitivanoj grupiiznosila je 11,78 godina. Pri tome su ispitanici zen­skog pola imali vecu prosecnu zivotnu dob (13,56godina) od ispitanika muskeg pola (10,38 godina).

Prosecna zivotna dob obolelih od AD bolestiiznosila je 11,75 godina, od AR bolesti 12,93 godine,a od XR oboljenja 10,14 godina.

Najmladi bolesnici u ispitivanoj grupi imali sugenetsku bolest odnosno gcnodermatozu odmah porodenju, a najstariji bolesnik u ispitivanoj grupi imaoje 69 godina (zenskog pola). Najveca ucestalost obo­lelih od genetskih bolesti i genodermatoza bila je ugrupi od 0-9 godina zivota (100 ispitanika ­65,79%), potom u grupi od 10-19 godina (21 ispi­tanik - 13,81%), a zatim ucestalost obolelih nagloopada i odrzava se na priblizno istom nivou ucesta­losti do u starije zivotno doba. Postoji veca zas­tupljenost ispitanika zenskog pola u dobnim grupamaod 20-29 godina i 40-49 godina, sto ukazuje na gene­ralno stariju zivotnu dob zenskog pola u ispitivanojgrupi obolelih od genodermatoza, genetskih bolesti isindroma.

Primenom navcdenih metoda istrazivanja dobijenaje incidencija pojedinih genodermatoza i/ili genetskihbolcsti i sindroma u eksperimentalnoj grupi, koja sta­tisticki validno prezentuje incidenciju istih genoder­matoza i/ili genetskih bolesti i u vojvodanskoj popu­laciji. Iz ovako dobijene incidencije, putem primeneHardy-Weinbergovog zakona (p2+2pq+q2=1, odnos­no frekvencija gena u populaciji sledi binornnu dis­tribuciju) [4], dobijene su frekvencije genskih alela uvojvodanskoj populaciji za pojedine genodermatoze.

Rezultati

Prema prisutnim genodermatozama i/ili genetskimbolestima i sindromima u eksperimentalnoj grupi, na­si rezultati ukazuju na najvecu ucestalost Langdon-

the AD group of genodermatoses and genetic dise­ases out of the total number of 130 patients, 71 sub­jects (54.62%) were males and 59 (45.38%) were fe­males, while in the AR group (total number of 15cases) 10 patients (66.67%) were males and 5(33.33%) were females. In the XR group of geneticdiseases (total number of 7 cases) 4 patients(51.14%) were males and 3 cases (42.86%) werefemales.

The average age of patients suffering from ge­netic diseases, syndromes and genodermatoses withinthe examined group was 11.87 years. Accordingly,the female subjects were of higher average age(13.56 years) than male subjects (10.38 years). Theaverage age of patients with AD diseases was 11.75years, those with AR diseases 12.93 years and thoseaffected with XR disease 10.14 years.

The youngest subjects from the examined groupwere affected with genetic diseases or genodermato­sis immediately after they had been born; the oldestsubject in this group was a women, aged 69 years.The highest frequency of genetic diseases and geno­dermatoses was registered in the group aged from0-9 years (100 subjects - 65.79%), followed by thegroup aged from 10-19 years (21 subject - 13.81%),afterwards the frequency declined abruptly and re­mained on the same level during later period of life.Women were more affected in the age groups be­tween 20-29 and 40-49 years, which pointed to thefact that female subjects were generally in older agesin the examined group of patients with genodermato­ses, genetic diseases and syndromes.

Using the abovementioned methods of investiga­tion we gained the incidence of some genodermatosesand/or genetic diseases and syndromes in the experi­mental group, with statistical validity of incidence ofsome genodermatoses and/or genetics diseases and inthe population of Vojvodina. This incidence, and ap­plication of the Hardy-Weinberg law (p2+2pq+q2= I,genes frequency in the population follows the bino­mial distribution) [4], we gained the frequencies ofthe genetic alleles in the population of Vojvodina forthe same genodermatoses.

Results

According to recorded genodermatoses and/or ge­netic diseases and syndromes in the experimentalgroup, our results showed that the most frequent wasLangdon-Down syndrome with the total of 66 dis­eased individuals (43.42%), predominantly males(ratio 1:1.7) and AD inheritance (Table 1). The nextwere various clinical forms of ichthyosis (ichthyosisvulgaris, X recessive or congenital) with all threeforms of inheritance and predominance of male pa­tients, due to presence of X-recessive forms of ich­thyosis (Table 1). There were 13 subjects affectedwith ichthyosis vulgaris with AD inheritance

18

Downovog sindroma s ukupno 66 obolelih (43,42%),pretezno muskeg pola (odnos 1:1,75) (tabela 1).Slede razliciti klinicki oblici ihtioza sa sva tri oblikanasleda i vecim delom obolelih muskeg pola, sto semoze objasniti prisustvom X-recesivnih oblika ihtio­ze (tabela 1). Ukupno je bilo 13 obolelih od vulgarneihtioze s AD nasledem (8,55%) s frekvencijom domi­nantnoheterozigotnog aida od 0,18, dok je frekven­cija dominantnohomozigotnog alela iznosila 0,6(tabela 2). Nadeno je 9 obolelih (5,92%) od kongeni­talne ihtioze sa AR nasledem s frekvencijom gena od0,004, sto je zanemarljivo mali broj u populaciji re­cesivnih homozigota sa ispoljenim klinickim feno­tipom, ali sa 0,12 recesivnih heterozigotnih, zdravihnosilaca ove bolesti u populaciji, koji nemaju feno­tipski ispoljeno oboljenje. Na kraju, bilo je sarno dvaobolela od X-recesivne vulgarne ihtioze (1,32%) safrekvencijom gena od sarno 0,02 u populaciji. Rece­sivni gen se ispoljava fenotipski sarno kod muskihosoba u populaciji u hemozigotnom stanju s obziromna to da postoji sarno jedan X-hromozom, a pri tomeje zanemarljivo mala vrednost frekvence zdravihmuskih osoba prenosilaca od svega 0,00005 u

Stojanovic S, i sar. Procena frekencija genskih alela

(8.55%) and with frequency of dominantly heterozy­gotic allele of 0.18, while the frequency of domi­nantly homozygotic allele was 0.6 (Table 2). Therewere nine (5.92%) subjects affected with congenitalichthyosis with AD inheritance and gene frequencyof 0.004. This could be considered as irrelevantlysmall number for the population which might be cha­racterized with the amount of 0.004 that is 4/1000 (4per thousand) of recessive homozygotes with evidentclinical phenotype, but with 0.12 of recessive hetero­erozygotic, healthy carriers of this disease in thepopulation, without phenotipically evident disease.At the end, there were only two subjects who had X­recessive ishthyosis vulgaris (1.32%) with gene fre­quency of only 0.02 in the population. Recessivegenes demonstrated phenotypically only with maleindividulas of the population in heterozygotic (hemi­zygotic) condition, considering that there was irrele­vantly small value of frequency of homozygotic car­riers - healthy male carriers of only 0.00005 in thepopulation. For the same reasons the females do notget ill from this disease, and according to the abovestated value of 0.98, that is 98/100 in the population,present the carriers of the recessive gene, i.e. the car­riers (Table 2).

Tabela 1. Distribucija obolelih u ispitivanoj grupi prema genetskim bolestima, sindromima i genodermatozamaTable 1. Distribution ofillnesses in the experimental group - genodermatoses and/or genetic diseases and syndromesGenetska bolest, sindrom odnosno genodermatoza Muskarci Zene Nacin nasleda UkupnoGenodermatosis and/or genetic disease and syndrome Male Female (AD,AR,XR,XD) Total

Type ofinheritanceEpidermolysis bullosa hereditaria I 0 0 2Ichthyosis vulgaris 5 8Lvulgaris X-recessiva 2 0Ichthyosis congenita 7 2Erythrodermia ichthyosiformis congenita 1 0Keratodermia palmo-plantaris hereditaria 3 1M.Darier 7 6Ulerythema ophryogenes 0 1Incontinentio pigmenti 0 1

Pilli annulati - alopecia areata totalis cum tendentio universalis 0 I

Neurofibromatosis 4 8Syndroma Netherton 0 ISyndroma Ehlers Danlos 2 0Syndroma Langdon-Down 42 24

Syndroma Turner 0 2Syndroma Noonan 2 ISyndroma Edwards 0 3Syndroma Patau ] 0M.Bournevill-Pringle I 3Syndroma Klinefelter 2 0Syndroma Marfan 2 2Syndroma Klippel-Trenaunay-Weber 0 ISyndroma Sturge-Weber-Krabe 2 0Naevus tlammeus 1 0

Ukupno (Total) 85 67

Legenda: AD - autozomnodominantno, AR - autozomnorecesivno, XR - recesivno za polLegend: AD - autosomal dominant, AR - autosomal recessive, XR - recessive sex linkage

ARADADXRARARADADADARARADARAR

ADADAD

324

I4

13III121266233

I4

24I21

152

ProccnatPercent

('Yo)1,9715,78

0,662,638,550,660,660,66

7,890,661,32

43,421,321,971,97

0,662,631,32

2,630,661,320,66

100,00

Med Preg12000; LUI (1-2): 15-27. Novi Sad: januar-februar. 19

populaciji. Iz istih razloga zenske osobe ne obolevajuod ove bolesti, a prema iznesenom u iznosu od 0,98odnosno u populaciji 98/100 nosilac je recesivnoggena, odnosno konduktor (tabela 2). Odmah potompo ucestalosti sledi Darierova bolest (dyskeratosisfollicularisi sa ukupno 13 obolelih (8,55%),priblizno jednakim odnosom po polu i AD nasledem(tabela 1). Ukupna frekvencija gena za Darierovubolest u voj- vodanskoj populaciji iznosi 0,15. Pritome frekvencija homozigotnog dominantnog alelaiznosi priblizno 0,0 1, a frekvencija heterozigotnogdominantnog alela 0,014 odnosno 1411000 (tabela2). Treca po ucestalosti bila je neurofibromatoza sukupno 12 obolelih (7,89%), preteznim obolevanjemzenskog pola (u odnosu 2:1) i AD nasledem (tabelaI). Ukupna frekvencija gena za von Reckling­hausenovu bolest iznosi, gotovo isto kao i za Dari­erovu bolest, 0,15, sa istim ucescem frekvencijahomozigotnih i heterozigotnih dominantnih alela kaoi kod Darierove bolesti (tabela 2).

Jednaku ucestalost imaju Bourneville-Pringleovabolest (tuberozna skleroza), Marfanov sindrom i pal­moplantarna hereditarna keratodermija sa po 4 obo-

Darier's disease (dyskeratosis follicularis) was thenext with a total number of 13 diseased subjects(8.55%) and approximately equal proportion by sexand AD inheritance. The total gene frequency forDarier's disease in the population of Vojvodina was0.15. The frequency of homozygotic dominant allelewas approximately 0.01, that is ]/100, and the fre­quency of heterozygotic dominant allele was 0.°14,that is 14/1000 (Table 2).

The third by frequency was neurofibromatosiswith the total of 12 diseased subjects (7.89%), ma­inly females (with the ratio 2:1) and AD inheritance(Table 1). The total gene frequency for Von Reck­linghausen disease was almost the same as in case ofDarier's disease - 0.15, with the same share of fre­quency of homozygotic and heterozygotic dominantalleles, the same as with Darier's disease (Table 2).

The same frequency was registered for Bourne­ville-Pringle disease (tuberous sclerosis), Marfan'ssyndrome and palmoplantar hereditary keratodermawith 4 diseased persons respectively (2.63%), AD in­heritance and sex ratio: in favor of females (3:1) incase of Pringle disease, same sex ratio in Marfan'ssyndrome (1:1) and ratio of 3: I in favor of males in

Tabcla 2. Distribucija frckvcncije alela u ispitivanoj grupi prcma genetskim bolestima, sindromima i genodermatozama proce­njcna za vojvodansku populacijuTable 2. Distribution of alleles frequency in the experimental group - genodermatoses and/or genetic diseases and syndromesestablished the population of VojvodinaGcnctska bolest, sindrom odnosno Tip nasleda

gcnodermatoza Type of

Genodermatosis and/or genetic dis- inheritance

ease and syndrome

Frekvencija alcla u

populac.

Frequen. ofalleles in

the population

Frekvencija

homo-zigota

Frequen. of

homozygotes

Frekvcncija

hcterozigota

Frequen.of

heterozygotes

Zdravi nosioci rccesivnih alela

u populaciji

Healthy carriers ofthe rece­

ssive alleles in the population

Epidermolysis bullosa hereditaria AD

Epidermolysis bullosa hereditaria AR

Ichthyosis vulgaris AD

Ichthyosis congenita AR

I.vulgaris X-recessiva XR

Erythrodennia ichthyosiformis

congenita AR

Kcratodcrmia palmo-plantaris

hereditaria AD

M.Darier AD

Ulerythema ophryogcncs AD

Incontinentio pigmenti AR

Pilli annulati - alopecia arcata totalis

cum tendcntio universalis AR

Neurofibromatosis AD

Syndroma Ncthcrton AR

Syndroma Ehlers Danlos AR

M.Boumevill-Pringle AD

Syndroma Marfan AD

Svndroma Klippcl-Trcnaunay-Wcbcr AD

Syndroma Sturge-Wcbcr-Krahc AD

Naevus flammeus AD

0.02 0,0001 0.02 0

0,00005 0,00005 0,014 0,014

OJ s 0,6 0,1& 0

0,004 0,004 0,12 0,12

0.02 - M 0 O,02-M i 0,9& - 1 O,00005-M i 0,98 -1

0.00005 0,00005 0,014 0,014

O.G O,G 0

0,15 0,1 0,14 0

0,014 0,00005 0,014 0

O,OOOOS 0,00005 0,014 0,014

0,00005 0,00005 0,014 0,014

0,15 0,1 0,14 0

0,00005 0,00005 0,014 0,014

0,00005 0,00005 0,02 0.02

0,6 0,6 0

0,6 0,6 0

0.014 0,00005 0,014 0

0.02 0,00005 0,02 0

0,014 0,00005 0,014 0

Legenda: Afr-autozomnodominantno. Alc-aurozomnorcccsivno, XR-recesivno za pol

Legend: AD - autosomal dominant, AR - autosomal recessive, XR - recessive sex linkage

20

lela (po 2,63%), AD nasledem i sa odnosom po po­lovima : 3: I u korist zenskog pola kod Pringleovebolesti, jednakim odnosom po polovima kod Marfa­novog sindroma (I: I), i odnosom 3: I u korist mus­kog pola kod palmo-plantarne hereditarne keratoder­mije (tabela I). Ukupna frekvencija gena za pome­nute genodermatoze i/ili genetske bolesti iznosi 0,06.Pri tome je frekvencija homozigotnog dominantnogalela gotovo zanemarljiva, tako da su svi slucajeviuglavnom posledica heterozigotnog dominantnog ale­la (0,06) (tabela 2).

Nadalje, jednaku ucestalost, po 3 obolela (po1,97%), imaju bulozna hereditarna epidermoliza saAD i AR tipom nasleda, Noonanin sindrom i Ed­wardsov sindrom. Kod bulozne hereditarne epider­molize odnos po polovima iznosi 1:2 u korist zen­skog pola, kod Noonaninog sindroma 2: I u koristmuskog pola, dok su kod Edwardsovog sindroma svioboleli zenskog pola (tabela I). Medutim, frekvencijahomozigotnog recesivnog alela za buloznu heredi­tarnu epidermolizu sa AR nasledem (I oboleli ­0,66%) vrlo je mala i iznosi 0,00005, dok frekvencijaheterozigotnog recesivnog alela za ovu bolest kojaoznacava broj heterozigotnih nosilaca iznosi 0,014odnosno 14 promila. Ukupna frekvencija alela za bu­loznu hereditarnu epidermolizu sa AD nasledem (2obolela - 1,31%) iznosi 0,02, s tim da su svi oboleliuglavnom nosioci dominantnog heterozigotnog alelaza ovu bolest, a dominantni homozigotni aIel je pri­sutan kod 0,0001 odnosno 1/10000 obolelih od ovebolesti (tabela 2).

Ucestalost od po 1,32% (2 obolela) imaju EhlersDanlosov sindrom sa AR nasledem (svi oboleli sumuskeg pola) i Sturge-Weber-Krabbeov sindrom (svioboleli su muskeg pola) (tabela I). Frekvencija rece­sivnog homozigotnog alela obolelih od Ehlers Dan­losovog sindroma sa AR nasledem vrlo je mala iiznosi svega 0,00005 u populaciji, dok je frekvencijaheterozigotnih recesivnih nosilaca bolesti 0,02 u istojpopulaciji. Sturge-Weber-Krabbeov sindrom imao jeukupnu frekvenciju alela od 0,02 u populaciji, s timsto su gotovo svi oboleli imali dominantni heterozig­otni alel, a dominantni homozigotni aIel je zane­marljivo male frekvencije od 0,00005 (tabela 2).

Ucestalost od po 0,66% (po I oboleli) imaju kon­genitalna ihtioziforrnna eritrodermija s AR nasledem(muskarac), incontinentio pigmenti s AR nasledem(zena), totalna alopecija s tendencijom ka univerzal­noj alopeciji kombinovana s pilli annulati i AR nas­ledivanjem (zena), Nethertonov sindrom s AR nas­ledem (zena), Patauov sindrom (muskarac), Klippel­Trenaunay-Weberov sindrom (zena) i naevus flam­meus (muskarac) (tabela 1). Ukupna frekvencija ale­la u vojvodanskoj populaciji za kongenitalnu

Stojanovic S, i sar. Procena frekencija genskih alela

case of palmoplantar hereditary keratoderma (TableI). The total gene frequency for mentioned genoder­matoses and/or genetic diseases was 0.06. The fre­quency of homozygotic dominant allele was almostirrelevant, and therefore all the cases were mainly theresult of heterozygotic dominant allele (0.06) (Table2).

The same frequency of 3 diseased subjects(1.97%) was registered in bullous hereditary epider­molysis with AD and AR inheritance type, Noonansyndrome and Edwards' syndrome with AD type ofinheritance and sex ratio 1:2 in favor of females incase of bullous hereditary epidermolysis, 2:1 in favorof males in case of Noonan syndrome, and all fe­males in case of Edwards' syndrome (Table 1). How­ever, the frequency of homozygotic recessive allele inbullous hereditary epidermolysis with AR heredity (1ill person - 0.66%) was very small - 0.00005, whilethe frequency of heterozygotic recessive allele for thisdisease, which marked the number of heterozygoticcarriers, was 0.014, i.e. 1411000. The overall fre­quency of alleles for bullous hereditary epidermolysiswith AD inheritance (2 diseased persons - 1.31'%)was 0.02, the deseased persons were mostly the carri­ers of dominant heterozygotic allele for this disease,while dominant homozygotic allele was present incase of 0.000 I, i.e. 1110 000 of those affected by thisdisease (Table 2).

The frequency of 1.32% (2 diseased) was found inEhlers-Danlos syndrome with AR inheritance (all we­re males), and Sturge-Weber-Krabbe syndrome withAD inheritance (all diseased were males) (Table 1).The frequency of recessive homozygotic allele inthose with Ehlers-Danlos syndrome with AR inheri­tance was very small - 0.00005 of diseased in popu­lation; however, the frequency of heterozygotic rece­ssive carriers was 0.02, i.e. 2/1 00 in the same popu­lation. Sturger-Weber-Krabbe syndrome with AD in­heritance had a total frequency of allele of 0.02 in thepopulation, in which almost all diseased had a domi­nant heterozygote allele, while dominant homozygoticallele was of irrelevant frequency of 0.00005 (Table2).

The frequency of 0.66% (only I diseased respec­tively) was found in congenital ichthyosiform ery­throderma with AR inheritance (male), incontinentiapigmenti with AR inheritance (female), total alopeciawith tedency towards universal alopecia combinedwith pili annulati and AR inheritance (female), Net­herton's syndrome with AR inheritance (female),Patau's syndrome with AD inheritance (male),Klippel-Trenaunay-Weber syndrome with AD inheri­tance (female) and naevus flammeus with AD inheri­tance (male) (Table 1). The total frequency of allelesin the population of Vojvodina for congenital ich­thyosiform erythoderma, incontinentia pigmenti, totalalopecia with tendency towards universal alopecia

Med Preg12000; LUI (1-2): 15-27. Novi Sad: januar-februar. 21

ihtioziformnu eritrodermiju, totalnu alopeciju s ten­dencijom ka univerzalnoj alopeciji i pilli annulati, ikod Nethertonovog sindroma, svi sa AR nasledem,bila je ponaosob vrlo mala za svaku od ovih genoder­matoza i/ili genetskih bolesti i sindroma i iznosila je0,00005 za homozigotni recesivni aIel. Medutim,nosioci recesivnog heterozigotnog alela u populaciji,fenotipski zdravi, procenjeni su na 0,014 odnosno 14promila (tabela 2).

Ucestalost od 0,66% (1 oboleli) ima ofriogeni ul­eritem (keratosis pilaris atrophicans - zena) sa ADnasledem (tabela 1). Ukupna frekvencija alela zaofriogeni uleritem bila je vrlo mala sa iznosom od0,014 odnosno 14 promila, s pretezno dominantnoheterozigotnim alelom i vrlo malim ucescem domi­nantnog homozigotnog alela od svega 0,00005 (ta­bela 2).

Primenom statistickog modela Log-lineame anali­ze (multiple regresione analize) testirane su razlikeizmedu dobijenih frekvencija u eksperimentalnoj­kontrolnoj grupi obolelih od genodermatoza ilili gen­etskih bolesti i ocekivanih frekvencija u odnosu napopulaciju stanovnistva /pri cemu je model fitovanza p(1» 0,10000, a efekti su eliminisani na nivousignifikantnosti p(2»0,05000):

I) U okviru tipa nasledivanja odredenih genoder­matoza i/ili genetskih bolesti u eksperimentalnojgrupi, ispitivanjem interakcije pola i zivotnog dobaispitanika, najveci doprinos tome da nema signifi­kantne razlike izmedu dobijenih i ocekivanih vred­nosti u populaciji stanovnistva obolelog od genetskihbolesti i genodermatoza, daje korelacija s zivotnimdobima (1-7. dekade) ispitanika, pored prisutne in­terakcije pola i zivotnog doba bolesnika u eksperi­mentalnoj grupi. Pri tome je vrednost PearsonovogX2 testa iznosila 6,476528, za nivo verovatnoce p=0,9999997 i pri 35 stepeni slobode.

2) U okviru prisustva odredenih genodermatozailili genetskih bolesti u eksperimentalnoj grupi, ispiti­vanjem interakcije pola i zivotnog doba ispitanika,najveci doprinos tome da nema signifikantne razlikedobijenih i ocekivanih vrednosti u populaciji stanov­nistva obolelog od genetskih bolesti i genodermatoza,daje korelacija interakcije pola i zivotnih doba (1-7.dekade) ispitanika obolelih od odredene genoderma­toze ilili genetske bolesti. Pri tome je statisticka zna­cajnost bila na nivou verovatnoce p=l,OOOOOO zavrednost Pearsonovog X2 testa od 0,00000 pri nultomstepenu slobode.

3) U okviru prisustva odredenih genodermatozailili genetskih bolesti u eksperimentalnoj grupi, ispiti­vanjem interakcije pola i tipa nasledivanja ovih bo­lesti, najveci doprinos tome da nema signifikantnerazlike dobijenih i ocekivanih vrednosti u populaciji

and pili annulati and Netherton's syndrome, all withAR inheritance, was very small for each of these ge­nodermatoses and/or genetic diseases and syndromesand it was 0.00005 for homozygotic recessive alleles.However, the carriers of the recessive heterozygoticallele in the population, phenotipically healthy, wereestimated to be 0.014, that is 14/1000 (Table 2).

The frequency of 0.66% (only 1 diseased respec­tively) ulerythema ophryogenes (keratosis pilaris at­rophicans - female) with AD inheritance (Table 1).The total frequency of allele for ulerythema ophryo­genes was also very small - 0.014, i.e. 14/1000, do­minantly with dominant heterozygotic allele and verysmall share of dominant homozygotic allele of only0.00005 (Table 2).

Application of a statistical model - log-linear ana­lysis (multiple regression analysis) - enabled testingthe differences between the obtained frequencies inthe experimental group of subjects with genodermato­ses and/or genetic diseases and expected frequenciesin relation to the overall population, nevertheless themodel was fitted for pt l) 0,10000, and effects wereeliminated on the level of significance of p(2»0,50000 :

1) Within the type of inheritance of particulargenodermatoses and/or genetic diseases among thesubjects of the experimental group, by examiningtheir sex and age distribution, the greatest contribu­tion to the fact that there was no significant differ­ence between the obtained and expected values in thepopulation affected with genetic diseases and geno­dermatoses, except correlation with the age (1-7 dec­ade) of the examined subjects, aoart from the existinginteraction between sex and age of patients from theexperimental group. Nevertheless, the value of Pear­son's Chi-square tests was 6,476528, for the level ofsignificance p= 0,9999997 and at 35 degrees offreedom.

2) In regard to occurrence of certain genodermato­ses and/or genetic diseases in the experimental gro­up, by examination of patients' sex and age, the gre­atest contribution to the fact that there was no signifi­cant difference between the obtained and expectedvalues in the population affected with genetic dis­eases and genodermatoses was found in the correla­tion between sex and age (1-7 decade) of the exami­ned subjects affected with particular genodermatosesand/or genetic diseases. Nevertheless, the statisticalsignificance was on the level of probabilityp=l,OOOOOO for the value of Pearson's Chi-squaretest of 0,00000 at degree of freedom null.

3) In regard to occurrence of certain genodermato­ses and/or genetic disease in the examined group, byexamination of interaction of sex and type of inheri­tance of these diseases, the greatest contribution tothe fact that there was no significant difference be­tween the obtained and expected values in the popula-

22

stanovnistva obolelog od genetskih bolesti i genoder­matoza, daje korelacija interakcije pola i tipa nasle­divanja, kao i korelacija interakcije tipa nasledivanjai odredene genodermatoze i/ili genetske bolesti. Sta­tisticka znacajnost ove razlike je dobijena pri nivouverovatnoce p= 0,9948582, za vrednost PearsonovogX2 testa od 40,22279 i pri 66 stepeni slobode.

4) U odnosu na sve prisutne dismorfoloske znako­ve (1-60) u eksperimentalnoj grupi, ispitivanjem in­terakcije pola i zivotnog doba ispitanika, najveci do­prinos tome da nema signifikantne razlike dobijenih iocekivanih vrednosti u populaciji stanovnistva obo­lelog od genetskih bolesti i genodermatoza, daje ko­relacija interakcije pola i zivotnog doba ispitanika saodredenim dismorfoloskim znacima u eksperi- men­talnoj grupi. Pri tome je vrednost Pearsonovog X2

testa iznosila 0,000 000, pri nivou verovatnoce od p= 1,000 000 i nultom stepenu slobode.

5) U odnosu na vrstu genodermatoze i/ili genetskebolesti u eksperimentalnoj grupi, pri ispitivanju ro­doslovlja ispitanika, zapaza se najveci korelativni do­prinos interakcije kolena (mutacija, 1. i 2. kolcno) ilinijc nasleda (horizontalna, vertikalna, kosa linija)kod oba pola ispitanika na to da nema signifikantnerazlike izmedu dobijenih i ocekivanih vrednosti ovihvarijabli u populaciji stanovnistva obolelog od genet­skih bolesti i genodermatoza. Pri tome statisticka sig­nifikantnost u Pearsonovom X2 testu iznosi40,84557, pri nivou verovatnoce od p = 1,000 000 ipri 429 stepeni slobode.

6) U odnosu na vrstu genodermatoze i/ili genctskebolesti u eksperimentalnoj grupi, pri ispitivanju ro­doslovlja ispitanika, zapaza se i najveci korelativnidoprinos intcrakcijc pola obolelih i linijc nasleda(horizontalna, vertikalna, kosa linija) u svim koleni­rna (mutacija, I. i 2. koleno) na to da nema signifi­kantnc razlike izmedu dobijenih i ocekivanih vrcd­nosti ovih varijabli u populaciji stanovnistva obo­lelog od genetskih bolesti i genodermatoza. Pri tomestatisticka signifikantnost u Pearsonovom X2 testuiznosi 116,8730 pri nivou verovatnoce od p = 1,000000 i pri 410 stepeni slobode.

7) U odnosu na vrstu genodermatoze ilili genetskebolesti u eksperimcntalnoj grupi, pri ispitivanju ro­doslovlja ispitanika, zapaza se i najveci doprinos ko­relacije s linijom nasledivanja (horizontalna, verti­kalna, kosa) i interakcije izmedu kolena (mutacija, I.i 2. koleno) i pola obolelih na to da nema signifi­kantne razlikc izmcdu dobijenih i ocekivanih vred­nosti ovih varijabli u populaciji stanovnistva obo­lelog od genetskih bolesti i gcnodermatoza. Pri tomestatisticka signifikantnost u Pearsonovom X2 testuiznosi 0,000 000 pri nivou verovarnocc od p = 1,000000 i pri nultom stepenu slobode.

Stojanovic S, i sar. Procena frekencija genskih alela

affected with genetic diseases and genoder- matoses,was found in the correlation of the interaction be­tween the sex and type of inheritance, and the corre­lation of interaction between the type of inheritanceand particular genodermatoses and/or genetic dis­eases. The statistical significance of these differencesobtained at the level of probability p= 0,9948582, forthe value of Pearson's Chi-square test of 40,22279and at 66 degrees of freedom.

4) In relation to all dysmorphologic sings on theskin (1-60) of patients from the examined group, byexamination of the interaction between their age andsex, the greatest contribution to the fact that therewas no significant difference between the obtainedand expected values in the population affected withgenetic diseases and genodermatoses, was found inthe correlation of the interaction between the sex andage of patients with certain dysmorphologic signsfrom the examined group. Nevertheless, the value ofPearson's Chi-square test was 0,000 000, at the levelof probability of p = 1,000 000 and at degree offreedom null.

5) In relation to the type of genodermatosis and/orgenetic disease in the experimental group, during theexamination of the genealogy of patients, it was ob­served that the greatest correlative contribution oftheinteraction in all degrees of kinship (mutation of thefirst and second descendants) and inheritance pattern(horizontal, vertical and bias) in patients of bothsexes) was found in the absence of any significantdifference between the obtained and expected valuesof these variables in the population affected with ge­netic diseases and genodermatoses. Nevertheless, thestatistical significance was 40,84557 in the Pearson'sChi-square test, at the level of probability of p =1,000000 and at 429 degrees of freedom.

6) In relation to the type of genodermatosis and/orgenetic disease in the experimental group, during theexamination of the genealogy of patients, it was ob­served that the greatest correlative contribution of theinteraction between the sex and inheritance pattern(horizontal, vertical and bias) in all degrees of kin­ship (mutation of the first and second descendant)was found in the absence of any significant differ­ence between the obtained and expected values ofthese variables in the population affected with ge­netic diseases and genodermatoses. Nevertheless, thestatistical significance was 116,8730 in the Pearson'sChi-square test, at the level of probability of p =1,000 000 and at 410 degrees of freedom.

7) In relation to the type of genodermatosis and/orgenetic disease in the experimental group, during theexamination of the genealogy of patients, it was ob­served that the greatest contribution of the correla­tion with the inheritance pattern (horizontal. vertical.bias) and the interaction between the degrees of kin­ship (mutation, first and second descendant) and pa­tients' sex was found in the fact that there was nosignificant difference between the obtained and expe-

Med Preg12000; LUI (1-2): 15-27. Novi Sad: januar-februar. 23

8) U odnosu na koleno u kojem se genodermatozailili genetska bolest javila u uzoj porodici obolelog izeksperimentalne grupe (mutacija, 1. i 2. koleno) za­paza se najveci korelativni doprinos interakcije linijenasledivanja (horizontalna, vertikalna, kosa), polaobolelih i vrste genodermatoze ilili genetske bolesti ueksperimentalnoj grupi na to da nema signifikantnerazlike izmedu dobijenih i ocekivanih vrednosti ovihvarijabli u populaciji stanovnistva obolelog od genet­skih bolesti i genodermatoza. Pri tome statisticka sig­nifikantnost u Pearsonovom X2 testu iznosi 0,000000 pri nivou verovatnoce od p = 1,000 000 i prinultom stepenu slobode.

9) U odnosu na pol obolelih u ispitivanoj grupi,pri ispitivanju rodoslovlja ispitanika, zapaza se naj­veci korelativni doprinos interakcije linije nasle­divanja (horizontalna, vertikalna, kosa) i kolena (mu­tacija, 1. i 2. koleno) i vrste genodermatoze i/ili gen­etske bolesti u eksperimentalnoj grupi na to da nemasignifikantne razlike izmedu dobijenih i oceki- vanihvrednosti ovih varijabli u populaciji stanovnistvaobolelog od genetskih bolesti i genodermatoza. Pritome statisticka signifikantnost u Pearsonovom X2

testu iznosi 0,000 000 pri nivou verovatnoce od p =

1,000 000 i pri nultom stepenu slobode.U ovom ispitivanju je dokazano da nema statis­

ticki signifikantne razlike izmedu eksperimentalnegrupe i zvanicnih statistickih podataka za stanov­nistvo Vojvodine, cime je metoda, sa tacnoscu vecomod 95%, kakvu inace zahtevaju bioloska istrazivanja,zadovoljila kriterijume konzistentnosti i efikasnostitipa "maximum likelihood estimation" [10,11], iukazala na reprezentativnost eksperimentalne grupe.

Diskusija

Teorija genetskih procesa u populacijama razvijase upotrebom matematicko-statistickih modela. Podpojmom populacije podrazumeva se odredeno sta­novnistvo ili populaciona grupa definisani razlicitimbioloskim, geografskim, etnicko-istorijskim, socijal­nim i drustveno-politickim kriterijumima. Medutim,pojam populacije moze se upotrebiti i kao statistickipojam kada je istovetan statistickoj masi pod kojomse podrazumeva grupa na koju se odnose statistickaistrazivanja [12].

U odnosu na nase rezultate istrazivanja inciden­cije pojedinih genodermatoza iiiIi genetskih bolesti isindroma i frekvencije gena u populaciji Vojvodineza iste bolesti, u literaturi smo nasli podatak 0

ucestalosti Langdon-Downovog sindroma u popu­laciji od 1/739 zivorodenih [2], odnosno 1/700 zivo­rodenih [13]. Nasa procena, zasnovana na incidenciji

cted values of these variables in the population af­fected with particular genetic diseases and genoder­matoses. Nevertheless, the statistical significance is0,000 000 in the Pearson's Chi-square test, at thelevel of probability ofp = 1,000000 and at degree offreedom null.

8) In relation to the degree of kinship in which thegenodermatosis and/or genetic disease occurred inthe nearer family of patients from the experimentalgroup (mutation, first and second descendant), it wasobserved that the greatest contribution of the corre­lation with the inheritance pattern (horizontal, verti­cal, bias), the patients' sex and the type of genoder­matosis and/or genetic disease in the experimentalgroup was found in the fact that there was no signifi­cant difference between the obtained and expectedvalues of these variables in the population affectedwith particular genetic diseases and genoder- mato­ses. Nevertheless, the statistical significance is 0,000000 in the Pearson's Chi-square test, at the level ofprobability of p = 1,000 000 and at degree of free­dom null.

9) In relation to patient's sex in the experimentalgroup, during the examination of the genealogy ofpatients, the greatest contribution to the correlationwith the inheritance pattern (horizontal, vertical,bias) and all degrees of kinship (mutation of the firstand second descendant) and the type ofgenodermato­sis and/or genetic disease in the experimental groupwas found in the fact that there was no significantdifference between the obtained and expected valuesof these variables in the population affected with par­ticular genetic diseases and genodermatoses. Never­theless, the statistical significance is 0,000 000 in thePearson's Chi-square test, at the level of probabilityofp = 1,000000 and at degree of freedom null.

This investigation proved that there was no sig­nificant difference between the experimental groupand the formal statistical data for the population ofVojvodina, whereas the method satisfied the criteriaof consistency and efficacy of "maximum likelihoodestimation" [10, II], with accuracy greater than 95%pointing to the representativeness of the experimentalgroup.

Discussion

The theory of genetic processes in populations isdeveloped by application of mathematical statisti­calmodels. Population is the total number of personsinhabiting a particular region or area with certain bi­ological, geographical, ethnic-historical, social andsocio-political criteria. However, the concept of po­pulation can be used also as a statistical concept ofthe group included in the statistical investigations[12].

24

od 43,42% za Langdon-Downov sindrom, govori 0vecoj ucestalosti ovog sindroma u nasoj populaciji.

Podatke za vulgarnu ihtiozu sa AD nasledem od1/250 u opstoj populaciji dobili su Wells i Kerr ustudiji koja je obuhvatila 6061 dete [14). Drugi au­tori pominju incidenciju koja se krece od 1/250 do1/320 [15). Kao uzgredni nalaz pominje se pojavakonkornitantnog atopskog dermatita. Ova bolest jepet puta ucestalija kod X-recesivne vulgarne ihtioze[16). U suprotnosti od kongenitalne ihtioze i X­recesivne vulgarne ihtioze, ova bolest nije prisutna narodenju deteta. X-recesivna vulgarna ihtioza imaprevalenciju u muskoj populaciji, prema literaturnimpodacima iz genetskih populacionih studija, od1/6390 u Juznoj Engleskoj, 1/9500 u Izraelu, do1/4152 u spanskoj provinciji Salamanka [17]. Ak­tuelna incidencija ove bolesti u muskoj populaciji jemnogo veca. Rutinski skrining trudnica na deficijen­ciju placentalne sulfataze kod dye grupe iz Engleske iDanske indikovao je incidenciju vecu od 1/2000 kodmuskeg pola [17]. Kongenitalna ihtioza s ARnasledem predstavlja genetski heterogenu grupuihtioza, sto je i potvrdeno putem enzimskih studija odstrane

Happleove grupe [18]. U literaturi nije nadentacan podatak 0 incidenciji ove bolesti.

Nasi rezultati ukazuju na znacajno vecu inciden­ciju vulgarne i X-recesivne ihtioze u odnosu na po­menute rezultate drugih autora, a za kongenitalnuihtiozu s AR nasledem nadena je incidencija od0,0040dnosno 1/250 u nasoj populaciji.

U literaturi se pominje varijabilna penetrantnostgena za Darierovu bolest s prilicno visokim udelomslucajeva koji predstavljaju novu mutaciju, sto seslaze i s nasim rezultatima. Prevalencija ove bolesti ucentralnoj Engleskoj procenjuje se na 1/55.000 upopulaciji, a u Danskoj na 1/100.000 [19). Premapodacima iz literature, prevalencija neurofibromato­ze u populaciji procenjuje se na 1/5000 zivorodenih,pri cemu je za AD naslede bolesti penetrantnost100% u dobi od 5 godina. Sporadicni slucajevi surezultat veoma visoke mutacije gena [20). Ranijepopulacione studije su znatno potcenjivale prevalen­ciju tuberozne skleroze. Recentne studije pokazujuincidenciju tuberozne skleroze od 1/10.000 zivorode­nih (Oksfordska regija) do 1/27.000 (zapadna Skot­ska) [21]. Medutim, ostaje otvoreno pitanje hetero­genosti ove bolesti. Nairne, oko 50% slucajeva ovebolesti su rezultat novih mutacija. Prema literaturnimpodacima, Marfanov sindrom ima prevalenciju od1/20.000 zivorodenih [2], ali se navodi i podatak 0prevalenciji od 1/60.000 zivorodenih [22]. Penetrant­nost bolesti je visoka, a ekspresivnost varira. U 15%slucajeva obolelih, roditelji su zdravi, sto znaci da se

Stojanovic S, i sar. Procena frekencija genskih alela

In relation to our results of investigation the inci­dence of genodermatoses and/or genetic diseases andsyndromes and the gene frequency in the populationof Vojvodina for the same diseases, we detected inthe literature data the frequency of Langdon-Downsyndrome in the population of 1/739 liveborns [2],that is 1/700 liveborns [13]. Our estimation revealedgreater frequency of this syndromes in our popula­tion, with incidence of 43.42% for Langdon-Downsyndrome.

The data for ichthyosis vulgaris with AD inheri­tance of 11250 in the common population were ob­tained by Wells and Kerr in the study that comprised6061 children [14]. Other authors name the incidenceof 1/250 to 1/320 [15). Concomitant atopic dermati­tis was an incidental finding. This disease occurs fivetimes more often than X-recessive ichthyosis vulgaris[16]. In contrast to congenital ichthyosis and X­recessive ichthyosis vulgaris, this disease is not pre­sent at birth. X-recessive ichthyosis vulgaris has theprevalence in the population of males, according tothe literary data from the genetic - population studies,of 116390 in South England, 1/9500 in Israel, to1/4152 in the Spanish province Salamanca [17]. Theactual incidence of this disease in male population ismuch greater. The routine screening of pregnantwomen for placental sulphatase deficiency in twogroups from England and Denmark indicated inci­dence greater than 1/2000 in males [17].

Congenital ichthyosis with AR inheritance repre­sents a genetically heterogene group, and it was con­firmed by enzyme studiesba Happle's group [18).Precise data about incidence of this disease have notbeen found in literature. Our results revealed a sig­nificantly greater incidence of ichthyosis vulgaris andX-recessive ichthyosis in relation to results of otherauthors, with incidence of congenital icthyosis withAR inheritance of 0,004 that is 11250 in ourpopulation.

Variability of genetic penetrance for Darier's dis­ease is present in literature with high incidence ofcases which represent a new mutation and this is inaccordance with our results. The prevalence of thisdisease in Central England is being estimated as 1155000 in the population, and in Denmark at 1/100 000[19). According to the literature data, the prevalenceof neurofibromatosis in the population is being esti­mated at 115000 liveborn, nevertheless, for AD in­heritance of the disease the penetration is 100% atthe age of 5 years. Sporadic cases are the result of avery high rate of gene mutation [20]. The earlierpopulation studies understated the prevalence of tu­berous sclerosis. The recent studies show the inci­dence of tuberous sclerosis of 1/10 000 liveborn (TheOxford region) to 1127 000 (West Scotland) [21].However, heterogeneity of these diseases remains anopen question. Namely, about 50% of cases of thesediseases are the result of new mutations. Accordingto the literary data, Marfan syndrome has the preva-

Med Pregl2000j LUI (1-2): 15-27. Novi Sad: januar-februar. 25

radi 0 novoj mutaciji. Kod ovog sindroma pominje seprisustvo starije zivotne dobi kod oca (paternal ageeffect), koje je inace odlika prisustva kod svih auto­zomnodominantnih genetskih bolesti i malog je uti­caja na familijarnu pojavu point mutacija. Starijezivotno doba majke (maternal age effict) dobro jepoznato kod nekih hromozomopatija, posebno kodLangdon-Downovog sindroma [2,23]. U odnosu nanase rezultate istrazivanja dobijenih incidencija zaDarierovu bolest, neurofibromatozu, tuberoznu skle­rozu i Marfanov sindrom, postoji znacajno veca inci­dencija ovih bolesti u populaciji nego sto je to pri­sutno u rezultatima pomenutih autora.

U literaturi se pominje incidencija difuzne heredi­tame palmoplantarne keratodermije tipa sindromaUnna-Thost s aAD nasledem od 1/40.000, procenje­na u populaciji severne Irske [24]. Mnogo reda for­ma hereditarne keratodermije asocirana s periodonto­patijom tipa PapilIon-Lefevre sa AR nasledem imaprocenjenu frekvenciju aficiranih homozigota od1-4/1.000.000 [25]. Nasi rezultati, ukazuju naznacajno vecu incidenciju palmoplantarne keratoder­mije sa AD nasledem.

U podacima iz literature pominje sc ucestalostEdwardsovog sindroma od 1/3000 zivorodenih, pricemu 95% aficiranih fetusa dovode do spontanog po­bacaja [26]. Nasi rezultati ukazuju na znacajno vecuincidenciju, koja je iznosila 1,97%. Noonanin sin­drom, vida se u oba pola s fenotipskim izgledomTurnerovog sindroma ali s normalnim kariotipom (46XY ili 46 XX) i s frekvencijom u populaciji od1:1000 do 1:2500 [22,27J. Nasi rezultati daju zna­cajno vecu incidenciju od 1,97% za Noonanin sin­drom. Literaturni podaci upucuju na ucestalost Tur­nerovog sindroma od 1/2500 zivorodenih zenskogpola, jer obolevaju osobe iskljucivo zenskog pola[281, dok je nasa incidencija koju smo dobili za ovajsindrom iznosila 1,32%, tj. bilajc znacajno veca. ZaKlinefelterov sindrom nalazi se ucestalost u literaturiod 1/600 zivorodenih muskeg pola, jer obolcvaju sa­rno rnuske osobe [29]. U nasim rezultatima inciden­cija za ovaj sindrom je znacajno veca i iznosi 1,32%.Podaci iz literature navode ucestalost Patauovog sin­droma od 1/5000 zivorodenih u populaciji [26], dokprcma nasim rezultatima, ucestalost ovih sindroma unasoj populaciji znacajno je veca i iznosi 0,66%.

U literaturi sc nije mogla pronaci validno procen­jena incidencija za kongenitalnu ihtioziformnu eri­trodermiju sa AR nasledem, Nethertonov sindrom saAR nasledem, totalnu alopeciju s tendencijom ka uni­verzalnoj alopeciji kombinovanoj sa pilli annulati iAR nasledem, i pigmentnu inkontinenciju sa AR na­sledem.

lence 1/20 000 liveborn [2], but also the prevalenceof 1/60 000 liveborn [22]. The penetration of the dis­ease is high, but the expression varies. In 15% of dis­eased, parents are healthy, implying a new mutation.This syndrome is associated with older age of father("paternal age effect"), being the characteristic of alldominant genetic diseases, with little influence on oc­currence of familial point mutations. Older age ofmother ("maternal age effect") is well-known in thesame chromosomopathies, especially in Langdon­Down syndrome [2,23]. In relation to our results ofinvestigation the obtained incidences for Darier's dis­ease, neurofibromatosis, tuberous sclerosis and Mar­fan syndrome, there is a significantly greater inci­dence of these diseases in the population than in theresults of other authors.

According to literature data the incidence of con­genital palmoplantar keratoderma (Unna-Thost syn­drome with AD inheritance) in Northern Ireland is1/40.000 [24]. A much rarer form of inheritancekeratoderma associated with periodontopathy typePapillon-Lefevre with AR inheritance has the esti­mated frequency of affected homozygotes of 1-4/1000 000 [25]. Our results revealed significantlygreater incidence of palmoplantar keratoderma withAD inheritance.

According to literature data the frequency of Ed­wards' syndrome is 1/3000 liveborn, nevertheless,95% of pregnancies with affected fetuses end inspontaneous abortion [26]. Our results revealed sig­nificantly greater incidence, 1.97%. Noonan syndro­me, occurs in both sexes with the phenotypic aspectsof Turner's syndrome but with normal cariotypes (46XY or 46 XX) and with the frequencies in the popu­lation of l:l000 to 1:2500 [22,27]. Our results reve­aled significantly greater incidence of 1.97% for No­onan syndrome. The frequency of Turner's syndro­mes is 1/2500 liveborn, whereas only females are af­fected [28]; our incidence was 1.32%, significantlygreater. The frequency of Klinefelter's syndrome is1/600 liveborn males, whereas only males arc affec­ted [29]. In our results the incidence of this syndromeis significantly greater and it amounts to 1.32%. Thefrequency of Patau syndrome is 1/5000 liveborn inthe population [26], while according to our results,the frequency of this syndrome in our population issignificantly greater and amounts to 0.66%.

In the literature no valid incidence can be foundfor congenital ichthyosiform erythroderma with ARinheritance, Netherton's syndrome with AR inheri­tance, total alopecia with tedency towards universalalopecia combined with pili annulati and AR inheri­tance, and incontinention pigmenti with AR inheri­tance.

26

Zakljucak

Na osnovu primene navedenih metoda popula­ciono genetskog istrazivanja moguce je, uz upotrebuneparametrijske multiple regresione analize (log-line­arne analize) i Hardy-Weinbergovog zakona, izvrsitivalidnu procenu incidencije bolesti i frekvencije genaza genodermatoze ilili genetske bolesti stanovnistva,u ovom slucaju vojvodanske populacije, sa tacnoscuvecom od 95%, kakvu inace zahtevaju bioloska is­trazivanja. Nasi rezultati istrazivanja ukazuju naznacajno vecu incidenciju pojedinih genodermatoza uispitivanoj populaciji, u odnosu na podatke iz litera­ture za iste bolesti u drugim populacijama.

Stojanovic S, i sar. Procena frekencija genskih aiela

Conclusion

On the basis of aforementioned methods of thepopulation genetic investigations, it is possible, byusing nonparametrics multiple regression analysis(log-linear analysis) and Hardy-Weinberg's law, tomake valid estimations of the incidence of diseasesand gene frequencies for genodermatoses and/or ge­netic diseases of populations, in this case populationof Vojvodina, with accuracy greater than 95%. Ourresults of investigations revealed a significantlygreater incidence of genodermatoses in our popula­tion, in relation to literature data for the same dis­eases in other populations.

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