Demographic and clinical properties of juvenile-onsetBehcet’s disease: A controlled multicenter study

Yelda Karincaoglu, MD,a Murat Borlu, MD,b Semra Cikman Toker, MD,c Ayse Akman, MD,d

Meltem Onder, MD,e Suhan Gunasti, MD,f Aysegul Usta, MD,g Basak Kandi, MD,h Cicek Durusoy, MD,j

Muammer Seyhan, MD,a Serap Utas, MD,b Hayriye Saricaoglu, MD,c Muge Guler Ozden, MD,e

Soner Uzun, MD,f Umit Tursen, MD,g Demet Cicek, MD,h Levent Donmez, MD,i and Erkan Alpsoy, MDd

Malatya, Kayseri, Bursa, Antalya, Ankara, Adana, Mersin, Elazig, and Alanya, Turkey

Background: Behcet’s disease (BD) is a multisystemic inflammatory disorder of unknown origin. Thedisease usually occurs between the second and the fourth decades, whereas it is uncommon in children.

Objective: In this multicenter study, we aimed to describe the demographic and clinical features along withseverity in juvenile- versus adult-onset BD.

Methods: Patients with initial symptoms at age 16 years or younger were considered as having juvenile-onset BD. In all, 83 patients with juvenile-onset BD (38 male and 45 female; mean age 19.6 6 7.6 years)and 536 with adult-onset ([16 years) BD (293 male and 243 female; mean age 39.2 6 10.1 years) whofulfilled the classification criteria of the International Study Group for BD were involved in the study.

Results: Familial cases were more frequent in juvenile-onset compared with adult-onset BD (19% vs 10.3%;P = .017). The mean age of disease onset was 12.29 6 3.54 years in juvenile-onset BD and 31.66 6 8.71 years inadult-onset BD. Mucocutaneous lesions and articular symptoms were the most commonly observedmanifestations in both groups. The frequency of disease manifestations was not different between juvenile-and adult-onset BD, except neurologic and gastrointestinal involvement, which were higher in juvenile-onset BD than adult-onset BD (P = .027 and P = .024, respectively). Oral ulcer was the most common onsetmanifestation of both juvenile-onset (86.74%) and adult-onset (89.55%) BD. The frequencies of onsetmanifestations of BD were similar, except genital ulcer, which was higher in adult-onset BD (P = .025).

Limitations: Our study consisted of patients with BD mainly applying to dermatology and venerologydepartments. Therefore, it can be speculated that this study includes rather a milder spectrum of thedisease.

Conclusions: Although the clinical spectrum of juvenile-onset BD seems to be similar to adult-onset BD,the frequency of severe organ involvement was higher. Because of the higher prevalence of familial casesin juvenile-onset BD, it can be speculated that genetic factors may favor early expression of the diseasewith severe organ involvement. ( J Am Acad Dermatol 2008;58:579-84.)

Behcet’s disease (BD) is a chronic multisyste-mic inflammatory disease with unknownorigin. BD was first demonstrated by a

Turkish dermatologist, Dr Hulusi Behcet,1 in 1937.

He described a clinical triad including recurrent oralulcers, genital ulcers, and uveitis with hypopyon andproposed a viral cause. Although not defined clearly,the etiopathogenesis is currently thought to be

From the Departments of Dermatology and Venereology at Inonu

University School of Medicine, Malatyaa; Erciyes University,

School of Medicine, Kayserib; Uludag University, School of

Medicine, Bursac; Akdeniz University, School of Medicine,

Antalyad; Gazi University, School of Medicine, Ankarae; Cukur-

ova University, School of Medicine, Adanaf; Mersin University,

School of Medicineg; Firat University, School of Medicine,

Elazigh; and Baskent University Faculty of Medicine, Alanya

Hospitalj; and Department of Public Health, Akdeniz University

School of Medicine, Antalya.i

Funding sources: None.

Conflicts of interest: None declared.

Presented as free communication at the XII International Confer-

ence on Behcet’s Disease, in Lisbon, Portugal, on September

20-23, 2006.

Accepted for publication October 16, 2007.

Reprint requests: Yelda Karincaoglu, MD, _Inonu Universitesi, TıpFakultesi, Dermatoloji AD, 44315 Malatya, Turkey. E-mail:

yeldakarincaoglu@hotmail.com.

Published online November 29, 2007.

0190-9622/$34.00

ª 2008 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2007.10.452

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multifactorial consisting of genetics, viral and bacte-rial infections, and defects of humoral and/or cellularimmunity.2,3 In addition to the classic triad of symp-toms, joint, pulmonary, vascular, urogenital, gastro-intestinal, and neurologic involvement is alsoshown.3,4

BD is common in the second to fourth decades oflife, but can be seen at any age. Prepubertal onset israre, as is elderly onset ([50 years). Prepubertaldiagnosis is increasing as a result of awareness ofhealth care professionals.5-7 In addition to being rareamong children, BD may present with different signsand symptoms in the pediatric population. However,the clinical course of the disease in children will bedifferent (usually worse) from that of adults, and thediagnosis is delayed. International publications onpediatric BD are increasing consistently.7-9 In theliterature, there are many publications with limitednumbers of patients. Because of the differentmethods of investigation and interpretation, no clearidentification of organ involvement frequency anddisease severity is possible. Pediatric cases are alsoreported from Turkey but, to our knowledge, thereexists no multicenter study comparing pediatric BDwith its adult counterpart.8,10-12 The purpose of thismulticenter study was to compare demographic,clinical, and severity properties of BD betweenjuvenile- and adult-onset cases.

METHODSRecords of patients with BD from 9 medical

centers in Turkey (Akdeniz, Baskent, Cukurova,Erciyes, Firat, Gazi, Inonu, Mersin, and UludagUniversities) were involved in this study.

A registration form and a detailed study question-naire was prepared in the core center (InonuUniversity Medical Faculty Hospital, Malatya,Turkey) and sent to the satellite study centers.Medical records of all patients with juvenile- andadult-onset BD who were suitable to be includedwere cited into these forms and were processed inthe core center. Because of the retrospective natureof the trial, approval by an ethics committee was notrequired at these institutions.

The diagnosis of BD was made according to theclassification criteria of the International Study

Abbreviations used:

BD: Behcet’s diseasePPL: papulopustular lesionsT1: Time interval between initial symptom and

fulfillment of diagnostic criteriaT2: Time interval between fulfillment of criteria and

diagnosis

Group for BD, which requires recurrent oral ulcer-ation observed by a physician or patient at least 3times during a period of 12 months together with atleast two of the following symptoms: recurrentgenital ulceration, ocular lesions, skin lesions (ery-thema nodosum, pseudofolliculitis, papulopustularlesions (PPL), and acneiform nodules), and positivepathergy test in patients who did not receivecorticosteroids.13

Patients who had initial symptoms at age 16 yearsor younger were considered as juvenile-onset BD.Adult-onset BD was defined if the first manifestationappeared after age 16 years.

Data evaluated in all patients were as follows.Demographic properties: age of onset, initial

symptoms, sex, and family history.Clinical properties; oral ulcers; genital ulceration;

skin lesions (erythema nodosum, pseudofolliculitis,PPL); positive pathergy test; eye, neurologic, gastro-intestinal, cardiac and vascular (aneurysm, thrombo-sis), pulmonary, genitourinary and joint lesioninvolvement; and thrombophlebitis. Organ involve-ment was considered only if verified by clinicaland/or laboratory assessment (eg, computed tomog-raphy, magnetic resonance imaging, endoscopy,biopsy).

Course of disease: time interval between initialsymptom and fulfillment of diagnostic criteria (T1)and time interval between fulfillment of criteria anddiagnosis (T2).

Severity of disease: posterior uveitis, retinal vas-culitis, arterial thrombosis or aneurysm, thrombosisof vena cava or hepatic vein, neuro-Behcet, andintestinal perforations caused by BD were consid-ered as severe cases.7

Statistical analysis was made by independentsamples t test and chi-square test.

RESULTSA total of 83 patients with juvenile-onset BD (38

male and 45 female) with a mean age of 19.6 6 7.6years (between 5 and 46 years) and 536 patients withadult-onset BD (293 male and 243 female) with amean age of 39.2 6 10.1 years (between 19 and 75years) were enrolled. Mean age at the time of onsetwas 12.3 6 3.5 years (between 1.1 and 16.0 years) injuvenile-onset BD and 31.7 6 8.7 years (between17.1 and 71.1 years) in patients with adult-onset BD.Family history was positive in 19% of patients withjuvenile-onset BD and 10.3% of patients with adult-onset BD (P = .017, chi-square tests). Male:femaleratio was 1:1.2 in juvenile-onset BD and 1.2:1 inadult-onset BD, without any statistically significantdifference (Table I).

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Mean T1 was 3.1 6 3.5 years in juvenile-onset BD,and 3.5 6 4.6 years in adult-onset BD, without anystatistically significant difference (P = .74, indepen-dent samples test). Mean T2 was 1.0 6 3.3 years injuvenile-onset BD and 0.97 6 1.96 years in patientswith adult-onset BD, without any statistically signif-icant difference (P = .84, independent samples test)(Table II).

Initial symptomOral ulceration was the most common initial

symptom in both groups, observed in 86.7% ofpatients with juvenile-onset BD and 89.6% of pa-tients with adult-onset BD. Among patients withjuvenile-onset BD, oral ulceration was followed byeye involvement (8.4%), genital ulceration (6%),erythema nodosum (3.6%), and gastrointestinal in-volvement (1.2%). Among those with adult-onsetBD, genital ulceration (15.1%), erythema nodosum(5.9%), eye involvement (4.1%), joint disease (3.5%),thrombophlebitis (1.4%), and neurologic involve-ment (0.1%) were subsequent symptoms.

Between patients with juvenile- and adult-onsetBD, frequencies of initial symptoms were similarexcept for genital ulceration, which was more com-mon in adults (P = .025), (Table III).

Clinical findingsThe frequencies of clinical findings of patients

with juvenile- and adult-onset BD are given in Fig 1.The most common symptom was oral ulceration(83), followed by genital ulceration (68, 81.9%),erythema nodosum (43, 51.8%), PPL (42, 50.6%),articular symptoms (33, 39.8%), positive pathergytest (31, 37.3%), ocular involvement (29, 34.9%),thrombophlebitis (8, 9.6%), neurologic involvement(6, 7.2%), vascular involvement (6, 7.2%), and gas-trointestinal involvement (4, 4.8%) in juvenile-onsetBD. The most common symptom was oral ulceration(536), genital ulceration (460, 85.8%), PPL (298,

Table I. Demographic properties of juvenile- andadult-onset Behcet’s disease

Juvenile-onset

BD n = 83

Adult-onset BD

n = 536

Mean age, y 19.6 6 7.6 39.2 6 10.1Age of fulfillment of

criteria for diagnosis, y12.29 6 3.54 31.66 6 8.71

Male/female and ratio 38/45 293/2431:1.2 1.2:1

Family history 16 5519%* 10.3%

BD, Behcet’s disease.

*P = .017, chi-square tests.

55.6%), erythema nodosum (230, 42.9%), positivepathergy test (205, 38.2%), articular symptoms (181,33.8%), ocular involvement (158, 29.5%), thrombo-phlebitis (57, 10.6%), vascular involvement (23,4.3%), neurologic involvement (14, 2.6%), and gas-trointestinal involvement (7, 1.3%) in adult-onsetBD. The frequencies of disease manifestations werenot significantly different between juvenile- andadulteonset BD, except for neurologic and gastro-intestinal involvement.

Neurologic involvement was more common injuvenile-onset BD than in adult-onset BD (P = .027,chi-square test). Gastrointestinal involvement wasdiagnosed either by ulcers or perforation, and wasthe least common symptom in both groups. It wasmore common in juvenile-onset BD than in adult-onset BD (P = .024, chi-square test) (Fig 1).

Symptom severityBetween juvenile and adult forms of the disease,

only neurologic involvement and gastrointestinalinvolvement frequency revealed a significant differ-ence. Other indicators of severity such as posterioruveitis, retinal vasculitis, arterial thrombosis or an-eurysm, and thrombosis of vena cava or hepatic veinwere not statistically significant among the groups.

DISCUSSIONSince the first article on pediatric BD by Mundy

and Miller,14 several case reports and case studieshave been published on this issue. Some of thesepublications stress that family history is more prom-inent, diagnosis is delayed, and disease course ismore severe in pediatric patients with BD than adultcounterparts, whereas other publications claim thatno difference in these parameters exists.7-19 There islittle literature comparing adult- with juvenile-onsetBD regarding demographics, symptoms, andsigns.9,10,20

In our study, mean age at the time of fulfillment ofdiagnostic criteria was 12.3 6 3.5 years (1.1-16.0years) in juvenile-onset BD, concurrent with thepublication by Sarıca et al,10 who revealed the age as

Table II. No difference between two groupsconsidering time intervals

Juvenile-onset BD Adult-onset BD P *

T1 3.14 6 3.5 3.53 6 4.6 .74T2 1.02 6 3.25 0.97 6 1.96 .84

BD, Behcet’s disease; T1, time interval between initial symptom

and fulfillment of diagnostic criteria; T2, time interval between

fulfillment of criteria and diagnosis.

*Independent samples t test.

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12.8 6 3.0 years in girls and 13.1 6 2.1 years in boys.In another study by Bahabri et al,19 mean age was11.5 years at the time of diagnosis, also similar to ourresults.

Sex distribution of our patients with juvenile-onset BD was similar to that in the literature. Instudies dealing solely with juvenile-onset BD, Sarıcaet al10 noted the male:female ratio as 1.2:1, Bahabriet al19 as 1.4:1, and Treudler et al9 as 1.2:1. In studiescomparing juvenile-onset BD with adult-onset BD,Krause et al7 published the male:female ratio as 1.4:1in juvenile-onset BD and 1:1.8 in adult-onset BD;Pivetti-Pezzi et al21 gave the same ratio as 1.29:1 foradult-onset BD, which was near juvenile-onset BDvalue.10,19 No authors (including us) revealed pre-dominance of any sex in BD.

In the literature, there exists only one study thatcompares both T1 and T2 in adult- and juvenile-onsetBD. This is a publication by Treudler et al,9 whichrevealed that both T1 and T2 of juvenile-onset BD(median 35 and 101 months, respectively) are longerthan those of adult-onset BD (median 12 and 30months, respectively). Krause et al7 reported T1 ofjuvenile-onset BD as 3.9 6 3.5 years, which is similarto our study, but they did not report any comparisonwith their results in adults. In our study, however, nosignificant difference was found regarding T1 or T2

between groups. This may be caused by the elevatedT1 and T2 of adult-onset BD in our study, althoughthose of juvenile-onset BD were similar by Treudleret al.9 This may be interpreted as in nationwidehealth care conditions, there was no delay in diag-nosis of juvenile-onset BD when compared withadult-onset BD.

In our study, in agreement with the literature,family history was more prominent among patientswith juvenile-onset BD.9,11,16,22 In a publication fromTurkey, Borlu et al11 revealed that family history is

Table III. Frequencies of initial symptoms ofjuvenile- and adult-onset Behcet’s disease

Symptom

Juvenile-onset

BD n = 83 (%)

Adult-onset

BD n = 536 (%) P *

Oral ulcer 72 (86) 480 (89.5) .44Genital ulcer 5 (6.0) 81 (15.1) .025Erythema nodosum 3 (3.6) 32 (5.9) .39Eye involvement 7 (8.4) 22 (4.1) .08Articular involvement - 19 .09Thrombophlebitis - 8 .6Gastrointestinal

involvement1 - .13

Neurologic involvement - 1 .9

BD, Behcet’s disease.

*Chi-square test.

highly frequent among children with BD (8 of 17patients, 47%). Sarıca et al10 reported the same dataas 9% of 95 patients with juvenile-onset BD.

In our study, frequencies of initial symptoms weresimilar in juvenile- and adult-onset BD except forgenital ulceration, which was significantly higher inadult-onset BD group. From Turkey, Alpsoy et al23

reported similar initial and most common symptomsin 661 patients with BD, but they also mentioned thatserious organ involvement such as neurologic, large-vessel, and gastrointestinal involvement had lateronset during the course of the disease. One point tostress in this publication may be that the authorsreported juvenile- and adult-onset BD results to-gether and did not give separate result for juvenileand adult patients. Krause et al7 revealed that pa-tients with juvenile-onset BD and genital ulcerationhad later onset of disease than those without.Although the exact cause is not known, increasedrisk of microtrauma, local infections, hormonal fac-tors, or a combination of these may be causativefactors for frequent manifestation of genital ulcera-tion in patients with adult-onset BD.

When compared according to clinical and demo-graphic characteristics, frequencies of signs weresimilar between both groups with some differencessuch as determinants of severity, which were moreprominent among patients with juvenile-onset BD.Gastrointestinal involvement is reported to be fre-quent among patients with adult-onset BD fromFar East countries such as Japan, but it is rareamong Mediterranean countries such as Turkey.24

Interestingly, this rare involvement is found to bemore prominent among patients with juvenile-onset

Fig 1. Clinical manifestation in juvenile- and adult-onsetBehcet’s disease. ART, Articular involvement; EN, ery-thema nodosum; EYE, eye involvement; GIS, gastrointes-tinal involvement; GU, genital ulceration; NI, neurologicinvolvement; OU, oral ulcer; PPL, papulopustular lesions;PPT, positive pathergy test; THR, thrombophlebitis; VAS,vascular involvement. *P = .027 and **P = .024, chi-squaretests.

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BD in Turkey (4.8%). In the literature, differentresults exist on gastrointestinal involvement.Treudler et al9 did not find any difference amongfrequency of involvement of systems between adultand juvenile patients, including gastrointestinal.Krause et al7 revealed a 36.8% incidence of gastro-intestinal involvement among patients with juvenile-onset BD, which was higher than that of patientswith adult-onset BD. Their results are also higherthan ours, but they accepted signs such as chronicabdominal pain and diarrhea as indicators of gastro-intestinal involvement, whereas we did not encoun-ter symptoms unless verified by radiologic study,endoscopy, or pathologic investigation after surgery.

One of the most serious manifestations of BD thatmay lead to death is neurologic involvement. In BD,5% to 10% of patients have some degree of neuro-logic involvement. Lesions may lead to focal ormultifocal parenchymal involvement; peripheral orcentral neurologic involvement that causes tingling,pain, and numbness in hands and feet with bothmotor and sensory manifestations; migrainelikeheadache; hemiparesis; and pyramidal and extrapy-ramidal sings. Neurologic involvement may causecerebellar ataxia; cerebral vein thrombosis; cranialnerve palsy; or aneurysms.4 Neurologic involvementis reported to be high in various studies: Bahabriet al19 as 50% in 12 patients, Krause et al7 as 25%, andTreudler et al9 as 21% in a limited number of patients.Neurologic involvement of our study (7.2%) is lowerthan in all these studies, although more commonamong patients with juvenile-onset BD. FromTurkey, Borlu et al11 reported 12% and Sarıcaet al10 reported 3.1% of neurologic involvementamong patients with juvenile-onset BD. In our study,we required radiologic and/or laboratory proof ofneurologic lesion for inclusion in this symptom group,which we think is a major factor that impacts results.

In our study, the most common sign was oralulceration followed by genital ulceration in bothgroups, as in the literature. In previous publica-tions,7,9,11,15,19 frequency of genital ulceration isgiven as 30% to 95%. Juvenile and adult patientsmay have different frequencies of genital ulceration.Although Treudler et al9 did not reveal any differencebetween genital ulceration of juvenile and adultforms of BD, others reported that genital ulcerationis more common in adults. Krause et al7 showed thatalthough rare among children, genital ulceration wasmore common at later ages of juveniles.

Literature on frequency and severity of symptomsof BD is conflicting, which may be the result ofdifferences in geographic and ethnic origin of thepatients, use of different diagnostic and age criteria,and variations in the study design. Because data were

collected from different centers we think that ourresults are homogenized. The main points thatshould be stressed are: the similarity of T1 and T2 injuveniles and adults that reveals no additional delayin juvenile-onset BD diagnosis in Turkey; morefrequent severe organ involvement among juvenilesthat proposes more life-threatening conditions; and amore complicated clinical course for this patientgroup. Because of the higher prevalence of familialcases in juvenile-onset BD, it can be speculated thatgenetic factors may favor early expression of thedisease with severe organ involvement. Publicawareness of juvenile-onset BD and more informedphysicians on differences between juvenile and adultforms of BD can be achieved by studies enrollinglarge numbers of patients, which will be achieved bymulticenter studies.

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