ARTHRITIS & RHEUMATISM

Vol. 52, No. 9, September 2005, pp 28732881

DOI 10.1002/art.21264
2005, American College of Rheumatology

Localized Scleroderma in Childhood Is Not Just a Skin Disease

Francesco Zulian,1 Cristina Vallongo,1 Patricia Woo,2 Ricardo Russo,3 Nicolino Ruperto4
John Harper,2 Graciela Espada,5 Fabrizia Corona,6 Masha Mukamel,7 Richard Vesely,8
Elzbieta Musiej-Nowakowska,9 Jeff Chaitow,10 Joan Ros,11 Maria T. Apaz,12 Valeria Gerloni,13
Henryka Mazur-Zielinska,14 Susan Nielsen,15 Susanne Ullman,16 Gerd Horneff,17
Carine Wouters,18 Giorgia Martini,1 Rolando Cimaz,6 Ronald Laxer,19 and Balu H. Athreya,20
for the Juvenile Scleroderma Working Group of the
Pediatric Rheumatology European Society (PRES)
Objective. 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.
Methods. Data from a multinational study on
juvenile scleroderma was used for this in-depth study.
Clinical features of patients with extracutaneous mani-

festations were compared with those of patients who had

exclusively skin involvement.
Results. 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. Raynauds 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.
Conclusion. Extracutaneous manifestations of juvenile localized scleroderma developed in almost onefourth 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

Francesco Zulian, MD, Cristina Vallongo, MD, Giorgia

Martini, MD: Universita` di Padova, Padua, Italy; 2Patricia Woo,
FRCP, PhD, John Harper, MD, FRCP, FRCPCH: Great Ormond
Street Hospital, London, UK; 3Ricardo Russo, MD: Hospital de
Pediatria Juan P. Garrahan, Buenos Aires, Argentina; 4Nicolino
Ruperto, MD, MPH: IRCCS G. Gaslini, Genoa, Italy; 5Graciela
Espada, MD: Hospital de Ninos Ricardo Gutierrez, Buenos Aires,
Argentina; 6Fabrizia Corona, MD, Rolando Cimaz, MD: Clinica
Pediatrica II du Marchi, Milan, Italy; 7Masha Mukamel, MD: Schneider Childrens Hospital, Petah-Tikva, Israel; 8Richard Vesely, MD:
Universital Hospital, Kosice, Slovakia; 9Elzbieta Musiej-Nowakowska,
MD: Institute of Rheumatology, Warsaw, Poland; 10Jeff Chaitow, MD:
The Childrens Hospital Westmead, Sydney, Australia; 11Joan Ros,
MD: Hospital San Joan de Deu, Barcelona, Spain; 12Maria T. Apaz,
MD: Universidad Catolica, Cordoba, Argentina; 13Valeria Gerloni,
MD: Istituto G. Pini, Milan, Italy; 14Henryka Mazur-Zielinska, MD:
Medical University of Silesia, Zabrze, Poland; 15Susan Nielsen, MD:
Rigshospitalet, Copenhagen, Denmark; 16Susanne Ullman, MD:
Bispebjerg Hospital, Copenhagen, Denmark; 17Gerd Horneff, MD:
Universitatsklinik und Poliklinik fur Kinder und Jugendmedizin,
Halle, Germany; 18Carine Wouters, MD: University Hospital Gasthuisberg, Leuven, Belgium; 19Ronald Laxer, MD, FRCP: Hospital for
Sick Children, Toronto, Ontario, Canada; 20Balu H. Athreya, MD:
A. I. duPont Hospital for Children, Wilmington, Delaware.
Dr. Horneff serves on the advisory board for Wyeth, Munster,
Germany.
Address correspondence and reprint requests to Francesco
Zulian, MD, Dipartimento di Pediatria, Universita` di Padova, Via
Giustiniani 3, 35128 Padua, Italy. E-mail: zulian@pediatria.unipd.it.
Submitted for publication February 28, 2005; accepted in
revised form June 3, 2005.
2873

2874

ZULIAN ET AL

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 (35). 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 headface 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

Figure 1. Prevalence and distribution of extracutaneous involvement

in patients with juvenile localized scleroderma.

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], antidouble-stranded DNA, antiScl-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, Students t-test, or Fishers exact test was
used, as appropriate.

RESULTS
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.

EXTRACUTANEOUS MANIFESTATIONS OF JUVENILE LOCALIZED SCLERODERMA

Table 1.

2875

Characteristics of patients with juvenile localized scleroderma*

Characteristic
Female-to-male ratio
Age at disease onset, mean
Disease duration at diagnosis, mean
Environmental factors
Positive family history
Scleroderma subtype
Linear scleroderma
ECDS/PRS
Plaque morphea
Generalized morphea
Deep morphea
Followup, mean

Skin
involvement only
(n 582)

Extracutaneous
involvement
(n 168)

2.3:1
7 years 2 months
1 year 6 months
74 (12.7)
65 (11.2)

2.5:1
7 years 6 months
1 year 3 months
26 (15.4)
26 (15.4)

372 (63.9)
82 (14.1)
158 (27.1)
39 (6.7)
12 (2.1)
3 years 6 months

117 (69.6)
25 (14.8)
34 (20.2)
12 (7.1)
4 (2.4)
4 years 6 months

P
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
0.005

* Except where indicated otherwise, values are the number (%). NS not significant; ECDS/PRS
scleroderma en coup de sabre/Parry-Romberg syndrome.

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 seconddegree 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.
Extracutaneous manifestations. 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). Interest-

2876

ZULIAN ET AL

Figure 2. Relative prevalence of 193 extracutaneous manifestations in 168 patients

with juvenile localized scleroderma.

ingly, 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 Raynauds 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

EXTRACUTANEOUS MANIFESTATIONS OF JUVENILE LOCALIZED SCLERODERMA

2877

Table 2. Prevalence of laboratory abnormalities at the time of diagnosis in patients with juvenile
localized scleroderma*
Parameter

Skin involvement only

Extracutaneous involvement

White blood cells

Eosinophils
Hemoglobin
Platelets
Erythrocyte sedimentation rate
C-reactive protein
Creatine kinase
Serum IgG
Serum IgA
Serum IgM
Autoantibodies
Antinuclear antibodies
Antidouble-stranded DNA
AntiScl-70
Anticentromere
Anticardiolipin
Rheumatoid factor

27/532 (5.1)
82/532 (15.4)
20/535 (3.8)
15/532 (2.8)
78/504 (15.5)
16/265 (6.0)
6/261 (2.3)
48/280 (17.1)
32/280 (11.4)
31/280 (11.1)

10/161 (6.2)
20/161 (12.4)
16/161 (9.9)
12/161 (7.5)
45/159 (28.3)
17/101 (16.8)
9/94 (9.6)
29/101 (28.7)
17/101 (16.8)
18/101 (17.8)

NS
NS
0.05
0.01
0.001
0.005
0.005
0.05
NS
NS

203/514 (39.5)
13/320 (4.0)
9/303 (3.0)
2/169 (1.2)
12/100 (12.0)
46/349 (13.2)

81/157 (51.6)
3/62 (4.8)
3/75 (4.0)
2/71 (2.8)
2/11 (18.2)
28/115 (24.3)

0.01
NS
NS
NS
NS
0.01

* Values are the no. positive/no tested (%). NS not significant.

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 fre-

quent 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 evaluation. 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).
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%)

2878

ZULIAN ET AL

Table 3. Drug treatment in patients with juvenile localized

scleroderma*
Skin
involvement Extracutaneous
only
involvement

Treatment
Psoralen ultraviolet A
Vitamin D
Topical steroids
Oral steroids
Parenteral steroids
D-penicillamine
Methotrexate
Cyclosporin A
Other immunosuppressive
agents

4.3
11
14.8
23.5
7.9
22.6
36
1.5
0.9

1.8
4.8
10.8
41.3
13.2
35.9
44.9
3.6
4.2

P
NS
0.05
NS
0.0001
0.05
0.001
0.05
NS
0.01

* Values are the percentage of patients treated. NS not significant.

Azathioprine, mycophenolate mofetil, or cyclophosphamide.

(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.
Drug treatment. 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.
DISCUSSION
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 extracuta-

neous 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% (1012). 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 (1522). 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 (23,2528), 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
23,2831), their prevalence has not been reported in a

EXTRACUTANEOUS MANIFESTATIONS OF JUVENILE LOCALIZED SCLERODERMA

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 onethird 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 func-

2879

tion 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 (5,3741). 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.

2880

ZULIAN ET AL

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.
ACKNOWLEDGMENTS
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 SuijlekomSmit, 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).

REFERENCES
1. Cassidy JT, Petty RE. The systemic sclerodermas and related
disorders. In: Cassidy JT, Petty RE, editors. Textbook of pediatric
rheumatology. Philadelphia: W. B. Saunders; 2001. p. 50534.
2. Nelson A. Localized sclerodermas. In: Cassidy JT, Petty, RE,
editors. Textbook of pediatric rheumatology. Philadelphia: W. B.
Saunders; 2001. p. 53544.
3. Luderschmidt C, Konig G, Leisner B, Scholz S, Albert EE.
Circumscribed scleroderma: internal manifestations and significant correlation to HLA-DR1 and DR5. Hautarzt 1985;36:51621.
4. Dehen L, Roujeau JC, Cosnes A, Revuz J. Internal involvement in
localized scleroderma. Medicine (Baltimore) 1994;73:2415.
5. Harrington I, Dunsmore IR. An investigation into the incidence of
autoimmune disorders in patients with localized morphea. Br J
Dermatol 1989;120:6458.
6. Birdi N, Laxer RM, Thorner P, Fritzler MJ, Silverman ED.
Localized scleroderma progressing to systemic disease: case report
and review of the literature. Arthritis Rheum 1993;36:4105.
7. Mayorquin FJ, McCurley TL, Levernier JE, Myers LK, Becker JA,
Graham TP, et al. Progression of childhood linear scleroderma to
fatal systemic sclerosis. J Rheumatol 1994;21:19557.
8. Peterson LS, Nelson AM, Su WP. Classification of morphea
(localized scleroderma). Mayo Clin Proc 1995;70:106876.
9. Jablonska S, Blaszczyk M. Is superficial morphea synonymous with
atrophoderma Pasini-Pierini? J Am Acad Dermatol 2004;50:
97980.
10. Uziel Y, Krafchik BR, Silverman ED, Thorner PS, Laxer RM.
Localized scleroderma in childhood: a report of 30 cases. Semin
Arthritis Rheum 1994;23:32840.
11. Vancheeswaran R, Black CM, David J, Hasson N, Harper J,
Atherton D, et al. Childhood onset scleroderma: is it different
from adult onset disease. Arthritis Rheum 1996;39:10419.
12. Marzano AV, Menni S, Parodi A, Borghi A, Fuligni A, Fabbri P,
et al. Localized scleroderma in adults and children: clinical and
laboratory investigations on 239 cases. Eur J Dermatol 2003;13:
1716.
13. Falanga V, Medsger TA, Reichlin M, Rodnan GP. Linear scleroderma: clinical spectrum, prognosis and laboratory abnormalities.
Ann Intern Med 1986;104:84957.
14. Hanson V, Drexler E, Konreich H. Rheumatoid factor in children
with focal scleroderma. Pediatrics 1974;53:9457.
15. Heron E, Hernigou A, Fornes P, Chatellier G, Emmerich J,
Fiessinger JN. Central nervous system involvement in scleroderma. Ann Med Interne (Paris) 2002;153:17982.
16. Blaszczyk M, Krolicki L, Krasu M, Glinska O, Jablonska S.
Progressive facial hemiatrophy: central nervous system involvement and relationship with scleroderma en coup de sabre. J Rheumatol 2003;30:19972004.
17. Liu P, Uziel Y, Chuang S, Silverman E, Krafchik B, Laxer R.
Localized scleroderma: imaging features. Pediatr Radiol 1994;24:
2079.
18. Chung MH, Sum J, Morrell MJ, Horoupian DS. Intracerebral
involvement in scleroderma en coup de sabre: report of a case with
neuropathologic findings. Ann Neurol 1995;37:67981.
19. Grosso S, Fioravanti A, Biasi G, Conversano E, Marcolongo R,
Morgese G, et al. Linear scleroderma associated with progressive
brain atrophy. Brain Dev 2003;25:5761.
20. Woolfenden AR, Tong DC, Norbash AM, Albers GW. Progressive
facial hemiatrophy: abnormality of intracranial vasculature. Neurology 1998;50:19157.
21. DeFelipe J, Segura T, Arellano JI, Merchan A, DeFelipe-Oroquieta J, Martin P, et al. Neuropathological findings in a patient with

EXTRACUTANEOUS MANIFESTATIONS OF JUVENILE LOCALIZED SCLERODERMA

22.

23.
24.
25.
26.
27.
28.

29.
30.
31.
32.

epilepsy and the Parry-Romberg syndrome. Epilepsia 2001;42:

1198203.
Gambichler T, Kreuter A, Hoffmann K, Bechara FG, Altmeyer P,
Jansen T. Bilateral linear scleroderma en coup de sabre associated with facial atrophy and neurological complications. BMC
Dermatol 2001;1:9.
David J, Wilson J, Woo P. Scleroderma en coup de sabre. Ann
Rheum Dis 1991;50:2602.
Goldberg-Stern H, deGrauw T, Passo M, Ball WS Jr. ParryRomberg syndrome: follow-up imaging during suppressive therapy. Neuroradiology 1997;39:8736.
Kanzato N, Matsuzaki T, Komine Y, Saito M, Saito A, Yoshio T,
et al. Localized scleroderma associated with progressing ischemic
stroke. J Neurol Sci 1999;163:869.
Dupont S, Catala M, Hasboun D, Semah F, Baulac M. Progressive
facial hemiatrophy and epilepsy: a common underlying dysgenetic
mechanism. Neurology 1997;48:10138.
Littman BH. Linear scleroderma: a response to neurologic injury?
Report and literature review. J Rheumatol 1989;16:113540.
Flores-Alvarado DE, Esquivel-Valerio JA, Garza-Elizondo M,
Espinoza LR. Linear scleroderma en coup de sabre and brain
calcifications: is there a pathogenic relationship? J Rheumatol
2003;30:1935.
Higashi Y, Kanekura T, Fukumaru K, Kanzaki T. Scleroderma en
coup de sabre with central nervous system involvement. J Dermatol 2000;27:4868.
Luer W, Jockel D, Henze T, Schipper HI. Progressive inflammatory lesions of the brain parenchyma in localized scleroderma of
the head. J Neurol 1990;237:37981.
Miedziak AI, Stefanyszyn M, Flamagan J, Eagle RC Jr. ParryRomberg syndrome associated with intracranial vascular malformations. Arch Ophthalmol 1998;116:12357.
Weber P, Ganser G, Frosch M, Roth J, Hulskamp G, Zimmer KP.
Twenty-four hour intraesophageal pH monitoring in children and
adolescents with scleroderma and mixed connective tissue disease.
J Rheumatol 2000;27:26925.

2881

33. Bourgeois-Droin C, Touraine R. Scleroderma plaques: immunological and visceral disturbances. Ann Med Interne (Paris) 1978;
129:10712.
34. Allen HD, Gutgesel HP, editors. Moss and Adams heart disease
in infants, children and adolescents: including the fetus and young
adults. 6th ed. Philadelphia: Lippincott William & Wilkins; 2001.
35. Rokicki W, Dukalska M, Rubisz-Brzezinska J, Gasior Z. Circulatory system in children with localized scleroderma. Pediatr Cardiol
1997;18:2137.
36. Targa L, Cardin G, Cozzi F. ECG abnormalities in the various
clinical subtypes of scleroderma. G Clin Med 1990;71:1724.
37. Lee HJ, Kim MY, Ha SJ, Kim JW. Two cases of morphea
associated with Hashimotos thyroiditis. Acta Derm Venereol
2002;82:589.
38. Dervis E, Acbay O, Barut G, Karaoglu A, Ersoy L. Association of
vitiligo, morphea and Hashimotos thyroiditis. Int J Dermatol
2004;43:2367.
39. Finkelstein E, Amichai B, Metzker A. Coexistence of vitiligo and
morphea: a case report and review of the literature. J Dermatol
1995;22:3513.
40. Lerner AB, Sansung J. Vitiligo and linear scleroderma. Arch
Dermatol 1973;108:2867.
41. Thompson DM, Robinson TW, Lennard-Jones J. Alopecia areata,
vitiligo, scleroderma and ulcerative colitis. Proc R Soc Med
1974;67:10102.
42. Reed JR, de Luca N, McIntyre AS, Wilkinson JD. Localized
morphea, xantomatosis and primary biliary cirrhosis. Br J Dermatol 2000;143:6523.
43. Kim HS, Chun YS, Hann SK, Park WH. A case of linear
scleroderma and myasthenia gravis. J Dermatol 2000;27:314.
44. De P, Lloyd HJ, Rashid AM, Anstey AV. Morphea presenting
shortly after the onset of Schmidts syndrome. Clin Exp Dermatol
2000;25:1689.
45. Christianson HB, Dorsey CS, OLeary PA, Kierland RR. Localized scleroderma: a clinical study of two hundred thirty-five cases.
Arch Dermatol 1956;74:62939.