PROCENA FREKVENClJE GENSKIH ALELA GENODERMATOZA U … · 2009-10-27 · Kljucne reci: kozne bolesti...
Transcript of PROCENA FREKVENClJE GENSKIH ALELA GENODERMATOZA U … · 2009-10-27 · Kljucne reci: kozne bolesti...
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)
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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
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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
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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
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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-
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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].
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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.
Literatura
1. Braun W, Gunther E, Schubert H. Genodermatosen. ill:Dermatologie. 3'd ed. Berlin: VEB Verlag Volk und Gesundheit, 1983;1:193-202.
2. Krstic A, Popic-Paljic F, Jovanovic-Pridvorski J, VlaskiJ, Mihic D, et al. Genetika u pedijatriji. ill: Pedijatrija, udzbenik. Beograd: Savremena administracija, 1993; 1:141-210.
3. Stojanovic S. Populaciono-genetska studija genetski uslovljenih dermatoza u Vojvodini. Doktorska disertacija. NoviSad: Medicinski fakultet 1997: 63-6.
4. Kosanovic M, Diklic V. Odabrana poglavlja iz humanegenetike. Gornji Milanovac, Beograd: Decje novine, 1986;1:37-52.
5. Spasojevic SV. Citogenetika. Beograd: Naucna knjiga,1978;1:116-20.
6. Barch JM. The Act Cytogenetics Laboratory Manual. 2th
ed. New York: Raven Press, 1991;1 :24-105.7. Krstic A. Medicinski i kvantitativno-geneticki znacaj
dermatoglifa sa posebnim osvrtom na dermatoglifiku Downovog sindroma. Doktorska disertacija. Novi Sad: Medicinskifakultet,1979:5-21.
8. Velisavljev M, Jovanovic J. Screening testovi u medicinskoj genetici. Med Pregl 1986;47 (9-10):477-82.
9. Holbrook KA, Smith LT, Elias Sh. Prenatal Diagnosisog genetic Skin Diseases Using Fetal Skin Biopsy Samples.Arch Dermatol 1993; 129:1437-54.
10.Magnus P. Genetic epidemiology-possibilities and problems. Scand J Soc Med 1992;20(4):193-5.
11. Hagenaars JA. Categorical Longitudinal Data: Log-Linear Panel, Trend, and Cohort Analysis. Newbury Park London-New Delhi: SAGE Publications,1990;1:23-57.
12. Zergollern Lj, Mardesic D, Beck M, Geber J, HranuelliD, et al. Humana genetika. Zagreb: Jumena, 1986:345-443.
13. Harper J. Genetics and Genodermatoses. ill: Textbookof Dermatology. 5th ed. London-Edinburgh-Boston-MelboumeParis-Berlin-Vienna: Blackwell Scientific Publications, 1992;1:317.
14. Traupe H. The Ichthyoses: a guide to diagnosis, geneticcounseling, and therapy. Berlin-Heidelberg-New York-LondonParis-Tokyo-Hong Kong: Springer-Verlag, 1989:3-35.
15. Griffiths WAD, Leigh 1M, Marks R. Disorders ofKeratinization. ill: Textbook of Dermatology. 5th ed. LondonEdinburgh-Boston-Melbourne-Paris-Berlin-Vienna: BlackwellScientific Publications, 1992:1330.
16. Traupe H. The Ichthyoses: a guide to diagnosis, geneticcounseling, and therapy. Berlin-Heidelberg-New York-LondonParis-Tokyo-Hong Kong: Springer - Verlag, 1989:45.
17. Traupe H. The Ichthyoses: a guide to diagnosis, geneticcounseling, and therapy. Berlin-Heidelberg-New York-LondonParis-Tokyo-Hong Kong: Springer - Verlag, 1989:55.
18. Traupe H. The Ichthyoses: a guide to diagnosis, geneticcounseling, and therapy. Berlin-Heidelberg-New York-LondonParis-Tokyo-Hong Kong: Springer -Verlag, 1989:124.
19. Ebling FJG, Marks R, Rook A. Disorders of Keratinization. ill: Textbook of Dermatology. 4th ed. Oxford-LondonEdinburgh-Boston-Palo Alto-Melbourne: Blackwell ScientificPublications, 1986:1439.
20. Harper J. Genetics and Genodermatoses. ill: Textbookof Dermatology. 5th ed. London-Edinburgh-Boston-MelbourneParis-Berlin-Vienna: Blackwell Scientific Publications, 1992:322.
21. Harper J. Genetics and Genodermatoses. In: Textbookof Dermatology. 5th ed. London-Edinburgh-Boston-MelbourneParis-Berlin-Vienna: Blackwell Scientific Publications, 1992:327-30.
22. Nora JJ, Fraser FC. Medical Genetics: Principles andPractice. 3'ded. Philadelphia, London: Lea&Febiger, 1989:14552
23. Sheldon RP, McKusick VA. Heritable disorders of connective tissue with skin changes. ill: Fitzpatrick TB, ed. Dermatology in general medicine. New York - St.Louis: McGrawHill Book Company, 1987:l775~6.
24. Ebling FIG, Marks R, Rook A. Disorders of Keratinization. ill: Textbook of Dermatology. 4th ed. Oxford-LondonEdinburgh-Boston-Palo Alto-Melbourne: Blackwell ScientificPublications, 1986:1452.
25. Ebling FIG, Marks R, Rook A. Disorders of Keratinization. ill: Textbook of Dermatology, 4th ed. Oxford-LondonEdinburgh-Boston-Palo Alto-Melbourne: Blackwell ScientificPublications, 1986:1458.
Med Preg12000; LUI (1-2): 15-27. Novi Sad: januar-februar. 27
26. Harper J. Genetics and Genodermatoses. In: Textbookof Dermatology. Sth ed. London-Edinburgh-Boston-MelbourneParis-Berlin-Vienna: Blackwell Scientific Publications, 1992:318.
27. Harper J. Genetics and Genodermatoses. In: Textbookof Dermatology. Sth ed. London-Edinburgh-Boston-MelbourneParis-Berlin-Vienna: Blackwell Scientific Publications, 1992:320.
Radje primljen 9. ill 1999.Prihvacen za stampu 17. ill 1999.BIBLID.002S-81OS:(2000):Lill:1-2:IS-27.
28. Harper 1. Genetics and Genodermatoses. In: Textbookof Dermatology. Sth ed. London-Edinburgh-Boston-Melbourne-Paris-Berlin-Vienna: Blackwell Scientific Publications,1992: 319.
29. Harper J. Genetics and Genodermatoses. In: Textbookof Dermatology. Sth ed. London-Edinburgh-Boston-MelboumeParis-Berlin-Vienna: Blackwell Scientific Publications, 1992:321.
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