Juvenile localized scleroderma is usually considered a disease that is confined to the skin and subcutaneous tissue. We studied the prevalence and clinical features of extracutaneous manifestations in a large cohort of children with juvenile localized scleroderma.
Data from a multinational study on juvenile scleroderma was used for this in-depth study. Clinical features of patients with extracutaneous manifestations were compared with those of patients who had exclusively skin involvement.
Seven hundred fifty patients entered the study. One hundred sixty-eight patients (22.4%) presented with a total of 193 extracutaneous manifestations, as follows: articular (47.2%), neurologic (17.1%), vascular (9.3%), ocular (8.3%), gastrointestinal (6.2%), respiratory (2.6%), cardiac (1%), and renal (1%). Other autoimmune conditions were present in 7.3% of patients. Neurologic involvement consisted of epilepsy, central nervous system vasculitis, peripheral neuropathy, vascular malformations, headache, and neuroimaging abnormalities. Ocular manifestations were episcleritis, uveitis, xerophthalmia, glaucoma, and papilledema. In more than one-fourth of these children, articular, neurologic, and ocular involvements were unrelated to the site of skin lesions. Raynaud's phenomenon was reported in 16 patients. Respiratory involvement consisted essentially of restrictive lung disease. Gastrointestinal involvement was reported in 12 patients and consisted exclusively of gastroesophageal reflux. Thirty patients (4%) had multiple extracutaneous features, but systemic sclerosis (SSc) developed in only 1 patient. In patients with extracutaneous involvement, the prevalence of antinuclear antibodies and rheumatoid factor was significantly higher than that among patients with only skin involvement. However, Scl-70 and anticentromere, markers of SSc, were not significantly increased.
Extracutaneous manifestations of juvenile localized scleroderma developed in almost one-fourth of the children in this study. These extracutaneous manifestations often were unrelated to the site of the skin lesions and sometimes were associated with multiple organ involvement. The risk of developing SSc was very low. This subgroup of patients with juvenile localized scleroderma should be evaluated extensively, treated more aggressively, and monitored carefully.
Scleroderma is a rare condition in children. As in adults, 2 main distinctive categories are known: juvenile systemic sclerosis (SSc), which is characterized by sclerodermatous skin changes and widespread abnormalities of the viscera, and juvenile localized scleroderma, which for the most part, is a benign, self-limited condition with manifestations confined to the skin and/or subcutaneous tissues (1, 2). Some limited case reports have suggested that localized scleroderma is not always a purely cutaneous disease (3–5). In fact, in some patients with the localized form of the disease, especially adults, there is evidence of internal organ involvement, association with other connective tissue diseases, and, sometimes, even transition to SSc (6, 7). We therefore studied the prevalence and clinical features of extracutaneous manifestations in a large cohort of children with juvenile localized scleroderma.
PATIENTS AND METHODS
We retrospectively collected data for a large population of children with localized scleroderma from pediatric rheumatology and dermatology centers in Europe, North America, South America, Asia, and Australia, as part of an international project sponsored by the Pediatric Rheumatology European Society (PRES).
Information on demographics, epidemiologic, clinical, and laboratory features, and treatment of children with juvenile localized scleroderma was anonymously collected, using a questionnaire focusing on the following items: 1) Demographics (sex, age at diagnosis, disease duration at the time of diagnosis). 2) Clinical subtype. We asked clinicians to describe the lesions according to location, size, depth, and texture but did not standardize these observations; we also asked clinicians to classify their patients into 1 of 5 groups according to the Mayo Clinic classification criteria (8), as follows: plaque morphea, generalized morphea, bullous morphea, linear scleroderma (including the head–face subtypes en coup de sabre [ECDS] and Parry-Romberg syndrome), and deep morphea. 3) Extracutaneous manifestations of the disease, with a detailed description of the clinical and laboratory features. 4) Epidemiology (environmental factors considered by physicians and by the patients or their families to be significantly related to disease onset, and family history of connective tissue or autoimmune diseases in first- and second-degree relatives). 5) Abnormal laboratory findings at diagnosis, including hemoglobin concentration, white blood cell (WBC) and eosinophil counts, platelet count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, creatine kinase level, and serum immunoglobulin levels (IgG, IgA, IgM). An ESR >35 mm/hour and a CRP level >0.5 mg/dl were considered abnormal. A WBC count, hemoglobin concentration, or serum immunoglobulin level greater than or less than 2 SD for age was considered to be abnormal. A platelet count >400 × 103/mm3 or <150 × 103/mm3 was considered abnormal. 6) Results of tests for serum autoantibodies (antinuclear antibodies [ANAs], anti–double-stranded DNA, anti–Scl-70, anticentromere antibodies [ACAs], anticardiolipin antibodies (aCL), and rheumatoid factor [RF]). Abnormal values were determined by referring to the normal range of laboratory standards at each participating center. 7) Type and duration of treatment.
Descriptive statistics were used for reporting demographic, clinical, and laboratory characteristics of the patients. The chi-square test, Student's t-test, or Fisher's exact test was used, as appropriate.
Demographics and clinical features.
From January 2002 to December 2003, cases of juvenile localized scleroderma were reported in 750 patients from 70 centers (38 European, 12 North American, 11 South American, 8 Asian, and 1 Australian). In this large group, 582 patients (77.6%) had involvement of the skin only (group 1), and 168 patients (22.4%) had 1 or more extracutaneous manifestations (group 2). Specifically, 138 patients (18.4%) had only 1 extracutaneous manifestation, and 30 patients (4%) had multiple extracutaneous manifestations (Figure 1). The clinical characteristics of the 2 groups of patients are summarized in Table 1. As shown, the female-to-male ratio, the age at disease onset, and the disease duration at diagnosis were similar in both groups.
Table 1. Characteristics of patients with juvenile localized scleroderma*
Skin involvement only (n = 582)
Extracutaneous involvement (n = 168)
Except where indicated otherwise, values are the number (%). NS = not significant; ECDS/PRS = scleroderma en coup de sabre/Parry-Romberg syndrome.
Age at disease onset, mean
7 years 2 months
7 years 6 months
Disease duration at diagnosis, mean
1 year 6 months
1 year 3 months
Positive family history
3 years 6 months
4 years 6 months
In the majority of patients (92%), the extracutaneous manifestation followed the appearance of the skin lesion. Various rheumatic diseases, such as rheumatoid arthritis, SSc, or systemic lupus erythematosus, and other autoimmune diseases involving either the skin or internal organs had been reported in first- and second-degree relatives of the patients; however, the prevalence of these disorders was similar in the 2 groups. A total of 101 patients (13.5%) reported specific events, such as trauma, infection, or exposure to drug, occurring very close to the time of disease onset, and thus these events were considered significant triggers by both parents and/or the reporting physicians. These events were equally distributed between the 2 groups.
The distribution of the various subtypes of juvenile SSc in the 2 groups was also similar (Table 1). As shown, linear scleroderma represents the most frequent subtype, followed by plaque morphea, generalized morphea, and deep morphea. Among the patients with the linear subtype, the prevalence of those with face/scalp involvement was not different in the 2 groups. The duration of followup was significantly longer for patients with extracutaneous involvement than for patients with skin involvement only.
A total of 193 extracutaneous manifestations were reported in 168 patients; that is, in some patients, more than 1 system was involved. These extracutaneous manifestations were mainly articular (47.2%), followed by neurologic, vascular, ocular, autoimmune, gastrointestinal, respiratory, renal, and cardiac manifestations (Figure 2). Arthritis, sometimes causing leg length discrepancy and limited range of motion, was reported in 91 children (12.1%). Most of these children (69.2%) had linear scleroderma, 22% had plaque morphea, 5.5% had generalized morphea, and 3.3% had deep morphea. Oligoarthritis, defined as involvement of ≤4 joints, was present in 44 patients (5.9%) while polyarthritis, defined as involvement of ≥5 joints, was present in 37 patients (4.9%); in the remaining 10 patients, the extent of joint disease was unknown. In 83 patients the relationship between the site of arthritis and the distribution of sclerodermatous lesions was reported, and in 8 patients the relationship was unknown. In one-fourth of this group of patients, arthritis was completely unrelated to the site of the skin lesion. In addition, 30% of the patients with arthritis were RF positive, compared with 13.8% of those without arthritis; this difference was statistically significant (P < 0.005).
Neurologic involvement was reported in 33 (4.4%) of the 750 patients, 29 of whom had the linear subtype of SSc, 3 of whom had plaque morphea, and 1 of whom had deep morphea. Neurologic involvement was significantly more frequent in patients with linear scleroderma of the face (ECDS/Parry-Romberg syndrome) and was rarely observed in patients with the other subtypes. Neurologic abnormalities included mainly seizures (n = 10), recent-onset headache (n = 7), peripheral neuropathy (n = 3), vascular malformations (n = 2), CNS vasculitis (n = 2; diagnosed by cerebrospinal fluid analysis and magnetic resonance imaging [MRI] of the brain in 1 patient and by MRI in the other), behavioral changes (n = 2), and neuroimaging abnormalities (e.g., white matter abnormalities, calcifications) and electroencephalogram (EEG) alterations (found in 5 and 2 asymptomatic patients, respectively). Interestingly, 10 patients had neurologic abnormalities that were unrelated to the site of skin involvement; 6 of these patients had linear scleroderma, 3 had plaque morphea, and 1 had deep morphea.
Ocular involvement, which was reported in 16 patients (2.1%), was present almost exclusively in those with ECDS/Parry-Romberg syndrome (n = 10 patients). Ocular complications consisted of anterior uveitis (n = 4), episcleritis (n = 3), acquired glaucoma unrelated to previous uveitis or drug treatment (n = 2), xerophthalmia (n = 2), keratitis (n = 2), and strabismus (n = 1). Mydriasis (n = 1) and papilledema (n = 1) were considered secondary to the concomitant CNS involvement. Ocular lesions, such as episcleritis, anterior uveitis, glaucoma, and xerophthalmia, were unrelated to the site of skin lesions in 4 patients. In the remaining 12 patients, ocular involvement was ipsilateral to the inflammatory fibrotic process.
Vascular involvement was present in 18 patients (2.4%). One of these patients had a persistent vasculitic rash involving the lower limbs that responded to a short course of corticosteroid treatment. Unfortunately, because a biopsy was not performed, information regarding pathologic features was not available. One patient had an episode of deep venous thrombosis that was unrelated to clotting abnormalities or to the presence of aCL. Sixteen patients had Raynaud's phenomenon (RP); in 5 of these patients, RP preceded the onset of skin disease. Serum ANA was positive in 10 patients, but no patient had positive Scl-70 or ACA. Interestingly, 9 of the 16 patients with RP had other, concomitant extracutaneous manifestations: 5 had arthritis, 2 had gastroesophageal reflux (GER), 1 had uveitis, and 1 patient had arrhythmias, GER, and arthritis.
Gastrointestinal involvement, consisting exclusively of GER, was reported in 12 patients (1.6%). All of these patients were symptomatic, with the presence of retrosternal discomfort, dysphagia, and/or acid regurgitation. The diagnosis of GER was made by 24-hour intraesophageal pH monitoring in 7 patients, by radiographic barium swallow in 3 patients, and by esophageal scintiscan in 2 patients. Esophageal manometry showed nonspecific abnormalities of motor function in 5 patients (reduced lower esophageal sphincter [LES] basal pressure in 1, increased LES basal pressure in 3, inadequate LES relaxation in 1). Four patients underwent esophagogastroduodenoscopy, which showed first-degree esophagitis in 3 patients and second-degree esophagitis in 1 patient. Seven (58%) of 12 patients with GER had other, concomitant extracutaneous manifestations: 3 had arthritis, 2 had RP, 1 had CNS involvement, and 1 had arrhythmias, RP, and arthritis.
Respiratory involvement was reported in 5 patients (0.7%). All of them had moderate dyspnea and/or persistent cough, and 1 had pulmonary insufficiency. Results of pulmonary function tests showed a restrictive pattern in 3 patients and abnormalities in diffusing capacity for carbon monoxide (DLCO) in 2 patients. Persistent basal infiltrates on chest radiography and high-resolution computed tomography were observed in 2 patients. None of these patients had other clinical features of juvenile SSc or the presence of SSc-specific autoantibodies at the time of disease onset.
Cardiac complications were reported in 2 children (0.3%). One had acute pericarditis soon after the onset of linear scleroderma, and the other had arrhythmias (incomplete right bundle branch block). The latter patient also had RP, GER, and arthritis.
A nephritis syndrome with proteinuria and hematuria developed in 2 patients. Both of these patients also had arthritis, but the renal changes had been documented before antiinflammatory treatment was initiated. No renal biopsy had been performed. Neither of these patients experienced renal failure during 4.8 and 5.3 years of followup, respectively.
In association with juvenile localized scleroderma, 13 children (1.7%) had 14 different kinds of autoimmune conditions, as follows: vitiligo (n = 4), insulin-dependent diabetes mellitus (IDDM) (n = 4), Hashimoto thyroiditis (n = 3), Graves' disease (n = 1), and ulcerative colitis (n = 2).
Multiple organ involvement.
Thirty patients (4%) had more than 1 extracutaneous manifestation. Twenty-four of these patients had the linear subtype of juvenile localized scleroderma, and 6 had plaque morphea. All but 1 of these patients had involvement of only 2 extracutaneous organ systems. The most frequent associations were articular/neurologic, ocular/neurologic, and RP/articular involvement. The association of GER or autoimmune conditions with arthritis was observed in 3 patients each. One patient was reported as having RP, GER, arrhythmias (incomplete right bundle branch block), and arthritis, but no systemic or cutaneous changes compatible with transition to juvenile SSc occurred during the followup period. In 1 patient with positive Scl-70 autoantibodies, SSc did not develop during 4.5 years of followup. In another patient, the full clinical spectrum of juvenile SSc developed 6 months after the onset of linear scleroderma.
Laboratory characteristics of the patients at the time of diagnosis are summarized in Table 2. As can be seen, the number of patients with an increase in parameters of inflammation was greater in the group with extracutaneous manifestations (group 2) than in the group with skin involvement only (group 1).
Table 2. Prevalence of laboratory abnormalities at the time of diagnosis in patients with juvenile localized scleroderma*
Skin involvement only
Values are the no. positive/no tested (%). NS = not significant.
White blood cells
Erythrocyte sedimentation rate
The proportion of patients in whom ANA was positive was significantly higher in group 2 compared with group 1 (P < 0.01). None of the other autoantibodies, except RF, showed a higher prevalence in either of the 2 groups. A total of 464 patients were tested for RF (349 patients in group 1 and 115 patients in group 2), and the prevalence of RF positivity was significantly higher in patients with extracutaneous involvement (24.3%) than in those with skin involvement only (13.2%) (P < 0.01). In addition, RF was positive in a significantly higher percentage of patients with arthritis (30%) compared with those without arthritis (13.8%) (P < 0.005). No difference in the prevalence of laboratory abnormalities was observed between patients with 1 extracutaneous manifestation and those with multiple extracutaneous manifestations.
Table 3 shows the various drugs that were used for treatment during the course of the disease. In general, a significantly higher percentage of patients with extracutaneous involvement were treated with steroids and second-line drugs such as methotrexate and D-penicillamine or other immunosuppressive agents. The choice of a more aggressive approach to treatment appears to be primarily related to the activity of the skin disease and partly related to the concomitant presence of extracutaneous manifestations. Conversely, vitamin D (topical or systemic) was used in a significantly higher percentage of patients in group 1 and was used very rarely in patients with extracutaneous complications. The number of patients treated with topical steroids and cyclosporin A was equal in both groups.
Table 3. Drug treatment in patients with juvenile localized scleroderma*
Skin involvement only
Values are the percentage of patients treated. NS = not significant.
Azathioprine, mycophenolate mofetil, or cyclophosphamide.
Historically, the main difference between SSc and localized scleroderma is that the former usually involves, to a varying extent, the internal organs, and such involvement affects the long-term prognosis. The latter condition is confined to the skin and has a relatively benign course. During the last decade, the publication of case reports on the possible transition from localized scleroderma to SSc (6, 7) and of series of patients with linear scleroderma and internal organ involvement (3, 4) has raised suspicions that these 2 conditions are not always clearly distinct. Based on this observation, we evaluated the prevalence of extracutaneous manifestations in a large cohort of 750 children with juvenile localized scleroderma. To our knowledge, this cohort represents the largest series to date.
Almost one-fourth of patients with juvenile localized scleroderma (22.4%) demonstrated ≥1 extracutaneous manifestation during the course of the disease. This prevalence is close to that previously reported in smaller series of both adults and children (ranging from 21% to 27%) (3, 4). The difference between those studies and ours is that we included only symptomatic children (3, 4).
No clear-cut difference in demographics, medical history, and family history was noted between patients with and those without extracutaneous manifestations. The longer duration of followup in the group with extracutaneous involvement might explain the higher probability of detecting extracutaneous involvement during the course of the disease.
Articular involvement was the most frequent complication of juvenile localized scleroderma, accounting for almost one-half of all extracutaneous manifestations. It was more frequent in patients with the linear subtype of juvenile localized scleroderma, in whom the prevalence of this complication was already reported to range from 30% to 52% (10–12). Although it is conceivable that linear bands of sclerosis, spreading across articular structures, can cause inflammation and joint contractures by a direct local mechanism, it was quite surprising that in one-fourth of these patients, arthritis was completely unrelated to the site of the skin lesion, raising the suspicion of a systemic, rather than a local, inflammatory process. This hypothesis is, in part, supported by our finding of RF positivity in a significantly higher number of patients with arthritis and, in general, in those with the linear subtype of SSc. This finding has already been reported in previous studies (10, 11, 13, 14).
Neurologic involvement was the second most frequent extracutaneous manifestation and was particularly found in patients with linear scleroderma of the face (ECDS/Parry-Romberg syndrome). Seizures and headache were the most frequent conditions, and this finding is consistent with the data already reported in the literature (15–22). Behavioral changes and learning disabilities have also been reported (23, 24), while conditions such as stroke, transverse myelitis, and hemiparesis, which have been reported in adults (23, 25–28), were not present. In our series, intraparenchymal abnormalities on MRI, vascular malformations, or CNS vasculitis represented one-third of these neurologic manifestations. Although neurologic manifestations have been previously described in case reports or case series (16–23, 28–31), their prevalence has not been reported in a large cohort of patients and particularly in children. Indeed, because neuroradiologic examinations were performed only in symptomatic patients, it is conceivable that these changes would be observed even more frequently if all patients were screened systematically.
Another interesting finding is that in the past, neurologic changes were noted on the same side as the skin lesion. In our series, however, neurologic changes were unrelated to the site of skin involvement in one-third of the patients. This may support the hypothesis that a systemic autoimmune process rather than a dysgenetic process of both cerebral and facial structures could be responsible for such an association, as suggested by some investigators (26).
Ocular involvement, which was reported in 2.1% of our patients, was observed almost exclusively in those with linear scleroderma involving the face. Inflammatory changes such as uveitis, episcleritis, and keratitis were the most frequent findings reported. Other conditions, such as glaucoma and xerophthalmia, may be explained in the context of a fibrotic process involving the anterior segment of the eye or the lachrymal glands. Once again, ocular lesions were unrelated to the site of skin lesions in one-fourth of these patients, reinforcing the suspicion of a systemic inflammatory process.
Gastroesophageal reflux was reported in 1.6% of the patients in this series. This prevalence is lower than the prevalence previously reported in 2 smaller series, which ranged from 17% to 23% (3, 4). It must be pointed out that all of the patients in our series were children and were extensively evaluated because they were symptomatic. Conversely, in the 2 smaller series, most of the patients were adults and were studied during a defined period of time, regardless of whether they did or did not have symptoms.
In the present series, none of the children in whom esophageal manometry was performed showed abnormalities typical of SSc, but rather, demonstrated only nonspecific alterations, and juvenile SSc developed in none of these patients during followup. In addition, GER is relatively common in younger children. These facts and the lack of information on the natural history of this abnormality in asymptomatic children hardly support the recent recommendation for extensive gastrointestinal evaluation of all patients with juvenile localized scleroderma (32).
Respiratory involvement, consisting of restrictive changes with a mild decrease in respiratory volume and impaired DLCO, was observed in only 5 patients. Similar findings were previously reported in patients with linear scleroderma who underwent routine respiratory function tests and chest radiography (4, 33). As in our series, SSc developed in only 1 (adult) patient, a few months after the onset of scleroderma skin lesions. The remaining patient had only mild gas-transfer defects associated with restrictive lung disease.
Regarding cardiac involvement, which was present in 2 patients as acute pericarditis and incomplete right bundle branch block, respectively, we cannot establish whether it is more frequent than one would expect to see as a chance association, because the prevalence of these 2 conditions in the general pediatric population is not known (34). However, although pericarditis has never been described in children with juvenile localized scleroderma, electrocardiographic abnormalities, mainly represented by incomplete right bundle branch block, have been reported in both children and in adults (35, 36).
Various autoimmune conditions were observed in the patients in our series, but the prevalence of these conditions (1.7%) was lower than that previously reported (5). In general, the most frequently reported conditions are Hashimoto thyroiditis, vitiligo, and IDDM (5, 37–41). Cases of linear scleroderma with primary biliary cirrhosis (42), myasthenia gravis (43), and polyglandular autoimmune disease type 2 (44) have also been described. Indeed, the incidence of autoimmune disorders and the prevalence of organ-specific autoantibodies are increased in relatives of patients with linear scleroderma compared with healthy controls (5).
Interestingly, 30 patients in our series (4%) had more than 1 extracutaneous complication. This finding does not seem to represent a risk factor for the development of juvenile SSc because the full clinical spectrum of juvenile SSc developed in only 1 patient (0.13%) 6 months after the onset of linear scleroderma. The transition from localized scleroderma to SSc has already been reported in children as single case reports (6, 7). The prevalence of such an evolution seems to be higher in adults than in children and ranges from 0.9% to 1.3% (4, 45).
In spite of the fact that patients with juvenile localized scleroderma who have extracutaneous involvement are at low risk of developing SSc, their disease appears to be more severe than that in patients with skin involvement only, as shown by evidence of systemic inflammation and the more frequent need for immunosuppressive treatment. In addition, the significant relationship between RF and articular involvement in patients with juvenile localized scleroderma suggests that RF is a major clinical marker, and that patients with RF positivity should be monitored more closely.
Based on the data collected in this study, we suggest that all patients with juvenile localized scleroderma should be examined carefully for evidence of involvement of other organ systems, particularly the joints, eyes, and CNS. We also recommend quantitative measurement of immunoglobulins, ANA, RF, Scl-70, ACA, and aCL. In patients with linear scleroderma of the face, a periodic eye examination and EEG should be performed. If the EEG results are abnormal, an MRI should be performed. Considering the low frequency of involvement of other internal organs, specific function tests should be performed only in symptomatic patients.
In conclusion, patients with juvenile localized scleroderma who have extracutaneous manifestations represent a newly described subset of patients with peculiar clinical and laboratory features. In these patients, organ impairment is milder than that seen in patients with SSc and is not life-threatening; this indicates that juvenile localized scleroderma and juvenile SSc likely represent 2 ends of a continuous disease spectrum. For this reason, patients with juvenile localized scleroderma should be identified early, evaluated extensively, treated aggressively, and monitored carefully.
We thank Francesca Loro, statistician (University of Padova, Italy), for statistical and technical assistance in preparing the manuscript and all of the following investigators for contributing patients to the study: Ruben Cuttica, MD, Stella Garay, MD (Argentina); Ana Paola Lotito, MD, Claudia Machado, MD, Claudio Len, MD, Clovis Artur Silva, MD, Flavio Sztajnbok, MD, Sheila Knupp F. De Oliveira (Brazil); Traudel Saurenmann, MD (Switzerland); Arnoldo Quezada, MD, Ximena Norambuena, MD (Chile); Dana Nemcova, MD (Czech Republic); Troels Herlin, MD (Denmark); Ivan Foeldvari, MD, Jasmin Kuemmerle, MD (Germany); Ilonka Orban, MD (Hungary); Alex Zvulunov, MD, P. J. Hashkes, MD, Riva Brik, MD, Tsivia Tauber, MD, Yoseph Uziel, MD (Israel); Alessia Provini, MD, Antonella Buoncompagni, MD, Elisabetta Cortis, MD, Fernanda Falcini, MD, Loredana Lepore, MD, Maria Giannina Alpigiani, MD, Silvia Magni Manzoni, MD, Angelo Ravelli, MD (Italy); Andrey Scegolev, MD, Dace Berzina, MD, Ruta Santere, MD, Valda Stanevicha, MD, Vita Knaliere, MD (Latvia); Carolina Duarte, MD (Mexico); Rebecca Ten Cate, MD, Lisette W. A. Van Suijlekom-Smit, MD (The Netherlands); Galina Lyskina, MD (Russia); Sulaiman Al-Mayouf, MD (Saudi Arabia); Janet Gardner Medwin, MD, Paul Galea, MD (Scotland); Tadej Avcin, MD (Slovenia); Julia Garcia Consuegra, MD, Maria Luz Gamir, MD (Spain); Stefan Berg, MD (Sweden); John Harper, MD (UK); Anne Eberhard, MD, Carol Lindsley, MD, Gloria Higgins, MD, Ilona Szer, MD, Marilynn Punaro, MD, Audrey Nelson, MD, Robert Sundel, MD, Terry L. Moore, MD (US); Dragica Galic, MD, Gordana Susic, MD (Serbia).