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Juvenile progressive systemic sclerosisClinical and serologic findings.

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BRIEtF REPORT
JUVENILE PROGRESSIVE SYSTEMIC SCLEROSIS: CLINICAL AND
SEROLOGIC FINDINGS
MARIA E. SUAREZ-ALMAZOR. LUIS J . CATOGGIO. JOSE A. MALDONADO-COCCO, RUBEN CUTTICA, and
OSVALDO GARCIA-MORTEO
Progressive systemic sclerosis (PSS) is a rare
disease among children. The largest series of patients
whose disease onset occurred before the age of 16
years ‘were reported by Hanson in 1976 (1) and Cassidy
et al in 1977 (2). In both reports, clinical features of
juvenile PSS appeared to be similar to those described
in adult-onset disease. Although cardiac and pulmonary involvement have been extensively studied in
adult patients with PSS, they have been rarely described in children with this disease. Using conventional methods of immunofluorescence, antinuclear
antibodies (ANA) are detected with similar frequency
in adults and in children with PSS (1,2). However, the
frequency and clinical significance of the more recently described antibodies considered to be highly specific for PSS, e.g., antinucleolar, anticentromere (ACA)
( 3 ) , and anti-Scl-70 (4), have not been determined in
the juvenile form of the disease. In this report we
describe the clinical features in 5 children with PSS,
with emphasis on the cardiovascular involvement and
serologic findings.
From the Section of Rheumatology, Department of Medicine, lnstituto Nacional de Rehabilitacion, and the Laboratory,
Centro Medico San Luis, Buenos Aires, Argentina.
Maria E. Suarez-Almazor, MD: Fellow in Rheumatology,
Instituto Nacional de Rehabilitacion; Luis J. Catoggio, MD: Physician in Charge, Rheumatology Section, Hospital Italian0 de Buenos
Aires aind Laboratory, Centro Medico San Luis; Jose A. Maldonado-Cocco, MD: Chief. Section of Rheumatology, Department of
Medicine, lnstituto Nacional de Rehabilitacih; Ruben Cuttica,
MIX St,aff Physician, Hospital de Ninos “Dr. Pedro de Elizalde,”
Buenos Aires; Osvaldo Garcia-Morteo, MD: Associate Professor of
Medicine, Universidad de Buenos Aires and Head, Department of
Medicine, Instituto Nacional de Rehabilitacion.
Address reprint requests to Jose A. Maldonado-Cocco,
MI), Seccion Reumatologia, Instituto Nacional de Rehabilitacion,
Echevei-ria 955, 1428 Buenos Aires, Argentina.
Submitted for publication June 11, 1984; accepted in revised form January 3, 1985.
Arthritis and Rheumatism, Val. 28, No. 6 (June 1985)
PATIENTS AND METHODS
Five children with juvenile PSS (4 girls and 1
boy) were studied over a 2-year period. In all patients,
disease began before age 16 years; all patients fulfilled
American Rheumatism Association criteria for the
diagnosis of PSS (5). In addition to the usual clinical
and laboratory evaluations, the following studies were
performed: barium swallow radiographs of the esophagus, resting electrocardiogram (EKG), exercise EKG
(treadmill), 24-hour ambulatory EKG (Holter), echocardiogram (M mode), spirometry , and arterial blood
gas analysis with the patient at rest, breathing room
air.
Antinuclear antibodies were detected by indirect immunofluorescence using mouse liver and
HEp-2 cells as substrates (6). Antibodies to Scl-70,
Sm, Ro (SS-A), La (SS-B), and nuclear RNP (nRNP)
were investigated by the Ouchterlony double immunodiffusion technique with 0.6% agarose (6). Human
spleen extract was used as a source of Ro (7), calf
thymus extract for La, nRNP, and Sm (8), and rabbit
thymus extract for Scl-70 (6). Rheumatoid factors
were investigated by the latex fixation test.
RESULTS
Clinical manifestations. Four of the 5 patients
studied had diffuse scleroderma, and 1 had incomplete
CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysmotility , sclerodactyly , telangiectasias), with Raynaud’s phenomenon, sclerodactyly,
and telangiectasias (Table 1). In all cases, initial signs
and symptoms were Raynaud’s phenomenon and skin
tightening on the hands; these occurred either simulta-
BRIEF REPORTS
Table 1. Clinical manifestations in 5 children with progressive systemic sclerosis (PSS)
Type
Age at Disease
of
onset duration
Patient PSS Sex (years) (years)
I
Diffuse
2
3
10
2
Diffuse F
10
3
Diffuse
F
9
2.5
4
Diffuse
F
8
1.5
5
RST*
F
10
M
8
Presenting
signs/
symptoms
HYPO/
Abnormal
Digital
Pitting
hyperTelangi- Muscle
esophageal
tuft
scars pigmentation ectasias weakness Arthritis motility resorption Calcinosis
Raynaud’s, skin
tightening,
knee arthritis
Raynaud’s, skin
tightening
Raynaud’s, skin
tightening
Raynaud’s, skin
tightening, arthralgia
Raynaud’s, skin
tightening, telangiectasias
Yes
Yes
Face,
hands
Yes
Yes
Yes
No
Yes
Yes
Yes
No
Yes
No
Yes
Yes
No
Yes
No
No
No
No
No
No
No
Yes
Yes
No
No
No
No
No
No
Yes
No
Face,
hands,
trunk
Yes
No
No
Yes
No
* Raynaud’s phenomenon, sclerodactyly, telangietasias.
neously or less than 1 year apart. Other clinical
features are shown in Table 1. Three children developed proximal muscular weakness; the electromyographic pattern was compatible with myositis in 2 of
them. Only 1 patient had mild elevation of creatine
kinase and aldolase. All patients showed joint contractures in various degrees, mainly in the hands and
elbows. Although 2 patients had radiologic evidence of
esophageal hypomotility, only 1 of them had transient
dysphagia. Digital tuft resorption was observed in the
2 children who had the longest disease duration. Nasal
septa1 perforation was observed in 1 patient. None had
intestinal symptoms or evidence of renal disease.
Cardiopulmonary findings. Patient 1 had pulmonary hypertension, heart enlargement, congestive
heart failure, and peaked P waves on the EKG (Table
2). Cardiac catheterization showed a pulmonary artery
pressure of 80/40 mm Hg (mean 56 mm Hg). During
catheterization, immersion of the patient’s hands in
cold water produced Raynaud’s phenomenon, with a
simultaneous increase of 5 mm Hg in diastolic pulmonary pressure. The child died of refractory heart
failure 2 years after disease onset; autopsy was not
performed.
None of the other patients showed clinically
significant cardiovascular disease (Table 2 ) . Although
Table 2.
Cardiopulmonary findings in 5 children with progressive systemic sclerosis*
Patient
Clinical
features
1
Pulmonary hypertension,
congestive
heart failure,
died
2
Crackling rales
3
None
NT
Normal
4
None
NT
IRBB
5
None
NT
Normal
Cardiac
catheterization
Resting EKG
Exercise
EKG
Holler EKG
LV 105/0-8 mm Right ventricle
NT
Normal
Hg, LA 1 1
hypertrophy
mm Hg, RA
10 mm Hg,
RV 80/0 mm
Hg, PA 80140
(56) mm Hg
NT
Normal
Normal
Normal
response
FVC
(spirometry)
Arterial
blood
gases
Pericardial effuCardiomegaly
sion, pericardial
and endocardial
thickening, RV
enlargement
52%
POz 59
mm Hg
Pericardial
effusion
Echocardiogram
Isolated supra- Normal
Normal
response
ventricular
arrhythmia
(2/hour)
Normal
Normal
Normal
response
Normal
Normal
Normal
response
Chest
radiograph
Bibasilar
linear
densities
Normal
37%
NT
60%
PO2 82
mm Hg
Normal
68%
Normal
Normal
73%
* EKG = electrocardiogram; FVC = forced vital capacity; LV = left ventricle; LA = left atrium; RA = right atrium; RV
PA = pulmonary artery; NT = not tested; IRBB = incomplete right bmdle branch block.
=
NT
right ventricle;
BRIEF REPORTS
only 1 (patient 2) had clinical and radiologic features of
pulmonary fibrosis, spirometric evaluation showed
varying degrees of restrictive ventilatory incapacity in
all pa.tients. Hypoxemia was observed in 2 of 3 patients (patient l , 59 mm Hg; patient 3, 82 mm Hg).
Serologic findings. By immunofluorescence
with mouse liver as substrate, 2 patients showed
ANA. However, when HEp-2 cells were used, all 5
sera had positive ANA with a nucleolar pattern (Table
3). In 2 sera, no other nuclear or cytoplasmic staining
was observed, but 1 of them had anti-Ro antibodies
shown by immunodiffusion. In the remaining 3 patients, the nucleolar pattern was accompanied by a
diffuse grainy staining of the nucleus with chromosomal staining. Anti-Scl-70 antibodies were present in
2 of them. All patients were seronegative for rheumatoid f'actor.
DISCUSSION
Reports of PSS in children have not been frequent. There have been occasional reports on small
numblers of children, and some of these series included
patients with localized scleroderma (9,lO). Hanson (1)
and Cassidy et a1 (2), respectively, described 13 and 15
juvenile patients with PSS; clinical features of disease
appeared to be the same as in adults. In most cases,
initial1 manifestations were Raynaud's phenomenon
and cutaneous induration of the hands. These features
were also observed in our juvenile patients.
Although cardiovascular abnormalities, including pulmonary hypertension, have been adequately
studied in adults (1 1-13), their prevalence and characteristics in children are unknown. To our knowledge,
only 1 juvenile patient with scleroderma and pulmonary hypertension has been described (14). As in that
case, our patient died a few months after the onset of
pulmlonary hypertension, showing the severe, rapid
course of this complication. It has been previously
suggested that pulmonary vessels are susceptible to
cold-induced vasospasm (15), and in our patient with
pulmlonary hypertension, immersion of his hands in
cold water produced Raynaud's phenomenon and a
simultaneous increase in diastolic pulmonary pressure.
Although without clinical significance, 3 other
patieints showed some cardiologic abnormalities. It is
of interest that despite the short disease duration and
absence of prominent clinical or radiologic findings of
pulmonary fibrosis in 4 of the patients, they all showed
varying degrees of restrictive ventilatory incapacity.
70 1
Table 3. Serologic findings in 5 children with progressive systemic
sclerosis
Patient
Antinuclear
antibodies
(mouse liver)
Antinuclear
antibodies
(HEp-2)
4+ nucleolar
2 1 :500, homoge- 3 + nucleolar,
neous
2 + DGt
3 Negative
2+ nucleolar,
1+ DG
4 Negative
3+ nucleolar,
2 i DG
5 1 :500, nucleo- 4+ nucleolar
lar speckled
1
Negative
* Anti-Ro, anti-La, anti-nuclear
t DG = diffuse grainy.
Anticentromere
antibodies
AntiScl-70
Other
antibodies*
Negative Negative Negative
Negative Positive Negative
Negative Negative Negative
Negative Positive Negative
Negative Negative Anti-Ro
RNP, anti-Sm.
As in adults, the children with more severe visceral
disease were those with more extensive cutaneous
involvement.
To our knowledge, there are no reports regarding the recently described antibodies characteristic of
scleroderma in the juvenile form of systemic disease.
Although only 2 of our 5 patients had ANA on mouse
liver substrate, all of them showed nuclear staining
when monolayer cell cultures (HEp-2) were used. As
has been previously shown, this is due to the higher
sensitivity of the latter substrate (16). All patients had
antinucleolar antibodies using HEp-2 cells, including
the 3 patients with negative ANA on mouse liver
substrate. This pattern is considered to be highly
characteristic of PSS, and a recent report stated that
patients with these antibodies had more severe disease
(17). However, with the increasing use of highly
sensitive substrates, their true clinical significance
remains to be determined.
No ACA were found in our patients; this is
consistent with previous data, since 4 of the 5 patients
had diffuse disease and ACA is highly characteristic of
the CREST variant (6,16,17). Two patients had antiScl-70 antibodies; both had diffuse disease and 1 of
them had severe pulmonary fibrosis. It is of interest to
note that this antibody has been associated with disease that is more systemic (6,16), in particular, with
lung involvement (6).
In summary, cardiopulmonary findings were
frequent in these children with PSS and were similar to
those observed in adult-onset systemic sclerosis. Serologic findings known to be characteristic of PSS in
adults were also found in children with this disease and
appear to have similar clinical implications.
BRIEF REPORTS
702
Acknowledgments. We wish to thank Drs. Jorge
Yabkowski and Maria Romanelli for referring 2 patients and
for their criticism of an earlier draft of this manuscript. We
would also like to thank Drs. Ricardo GenC and Horacio
CasabC for performing some of the cardiovascular studies.
REFERENCES
1 . Hanson V: Dermatomyositis, scleroderma and polyarteritis nodosa. Clin Rheum Dis 2:455-464, 1976
2 . Cassidy JT, Sullivan DB, Dabich L, Petty RE: Scleroderma in children. Arthritis Rheum (suppl) 20:35 1-354,
1977
3. Moroi Y, Peebles C, Fritzler M, Steigerwald J, Tan EM:
Autoantibody to centromere (kinetochore) in scleroderma sera. Proc Natl Acad Sci USA 77:1627-1631, 1980
4. Douvas AS, Achten M, Tan EM: Identification of a
nuclear protein (Scl-70) as a unique target of human
antinuclear antibodies in scleroderma. J Biol Chem
254:10514-10522, 1979
5. Subcommittee for Scleroderma Criteria of the American
Rheumatism Association Diagnostic and Therapeutic
Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis
Rheum 23581-590, 1980
6. Catoggio LJ, Bernstein RM, Black CM, Hughes GRV,
Maddison PJ: Serological markers in progressive systemic sclerosis: clinical correlations. Ann Rheum Dis
42:23-27, 1983
7. Clark G, Reichlin M, Tomasi TB: Characterization of a
soluble cytoplasmic antigen reactive with sera from
patients with systemic lupus erythematosus. J Immunol
102:117-122, 1969
8. Mattioli M, Reichlin M: Heterogeneity of RNA protein
antigens reactive with sera of patients with systemic
lupus erythematosus: description of a cytoplasmic nonribosomal antigen. Arthritis Rheum 17:421-429, 1974
9. Ansell BM, Nasseh GA, Bywaters EGL: Scleroderma in
childhood. Ann Rheum Dis 35: 189-197, 1976
10. Stogmann W, Sandhofer M, Fritz J: Immunological
studies in childhood scleroderma. Eur J Pediatr 124:223230, 1977
11. Clements PJ, Furst DE, Cabeen W, Tashkin D, Paulus
HE, Roberts N: The relationship of arrhythmias and
conduction disturbances to other manifestations of cardiopulmonary disease in progressive systemic sclerosis.
Am J Med 71:38-46, 1981
12. Roberts NK, Cabeen WR, Moss J, Clements PJ, Furst
DE: The prevalence of conduction defects and cardiac
arrhythmias in progressive systemic sclerosis. Ann Intern Med 94:38-40, 1981
13. Ungerer RG, Tashkin DP, Furst D, Clements PJ, Gong
H , Bein M, Smith JW, Roberts N , Cabeen W: Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med
75:65-74, 1983
14. Kass H, Hanson V, Patrick M: Scleroderma in childhood. J Pediatr 68:243-256, 1966
15. Naslund MJ, Pearson TA, Ritter JM: A documented
episode of pulmonary vasoconstriction in systemic sclerosis. Johns Hopkins Med J 148:78-80, 1981
16. Tan EM, Rodnan GP, Garcia I , Moroi Y , Fritzler MJ,
Peebles C: Diversity of antinuclear antibodies in progressive systemic sclerosis: anti-centromere antibody
and its relationship to CREST syndrome. Arthritis
Rheum 23:617-625, 1980
17. McCarty GA, Rice JR, Bembe ML, Barada FA Jr:
Anticentromere antibody: clinical correlations and association with favorable prognosis in patients with scleroderma variants. Arthritis Rheum 26: 1-7, 1983
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