Systemic sclerosis sine scleroderma (ssSSc) is a rare variant of systemic sclerosis, with only one pediatric case reported in the medical literature to date. Pulmonary arterial hypertension as the presenting feature of ssSSc is extremely rare, even in adults, and so far has never been reported in children. We report, for the first time, a case of pediatric ssSSc in a 3-year-old girl, who presented with interstitial lung disease and pulmonary hypertension. The patient was prescribed early aggressive pulmonary vasodilators combined with anti-inflammatory medications. The clinical response was good, and her current condition at 12 years of age is remarkable, considering the high mortality rates reported in adults. We underscore the importance of early aggressive treatment in future cases of similar presentation.

Systemic sclerosis (SSc) is a multisystem disease characterized by functional and structural abnormalities of small blood vessels, immune system activation, inflammation, and fibrosis of the skin and internal organs. Over the last decade, differences with regard to clinical manifestations, organ involvement, and prognosis between the adult and juvenile diseases have come to light.1,2 

Systemic sclerosis sine scleroderma (ssSSc) is an extremely rare variant of this syndrome, first described in 1954.3  This subset is characterized by internal organ involvement and serological abnormalities, without skin changes. In children, only one case of ssSSc has been reported so far, which manifested with nocturnal seizures and Raynaud phenomenon (RP).4 

Pulmonary arterial hypertension (PAH) as the presenting feature of ssSSc is extremely rare, even in adults,5  and to date has never been reported in children. We describe, for the first time, a child with juvenile ssSSc, who presented with RP in addition to PAH secondary to interstitial lung disease.

A previously healthy 3.5-year-old Israeli girl of Yemenite origin was referred for the evaluation of a new 2-month onset of RP, in the absence of skin changes, dysphagia, or arthralgia. Her parents and 4 siblings were healthy, and family history for connective tissue diseases was negative.

Physical examination revealed RP of fingers with digital ulcers, without sclerodactyly or skin change, and exertional dyspnea (Fig 1). Capillaroscopy demonstrated capillary dropout and tortuous dilated loops. Physical examination was otherwise normal. Weight and height were in the sixth and 20th percentiles, respectively.

FIGURE 1

A recent photo of the patient’s fingers showing RP.

FIGURE 1

A recent photo of the patient’s fingers showing RP.

Close modal

Complete blood cell count, muscle and liver enzymes, erythrocyte sedimentation rate, and C-reactive protein were within normal limits. The immunologic laboratory results were positive for antinuclear antibody at titer levels >> 1:160, mixed pattern, and antitopoisomerase I (anti–Scl-70) antibody was 163 U/mL (0–15). Von Willebrand antigen was 181% (50–150). Anti-dsDNA, anti-Ro/SSA, anti-La/SSB, anti-RNP, anti- Sm, antihistone, anticentromere, anti-RNA polymerase, Rheumatoid factor, and antiphospholipid antibodies were all negative results. Complement levels (C3, C4) were normal.

Chest radiograph images revealed bilateral central infiltrates and an enlarged heart (Fig 2). Electrocardiography (ECG) was compatible with right ventricular hypertrophy (Table 1, Fig 3). There was clear evidence of severely elevated (near systemic) pulmonary hypertension and tricuspid regurgitation. No cardiac defects were noted, and the cardiac output was normal. A diagnostic right heart catheterization demonstrated moderate PAH (mean 30 mm Hg) and a normal pulmonary capillary wedge pressure of 10 mm Hg (Table 1). High-resolution computerized tomography revealed ground glass and mosaic perfusion and cardiomegaly. The inferior vena cava and hepatic veins were congested. Pulmonary arteries were enlarged (Fig 4). Pulmonary function tests were of limited value because of the patient’s young age.

FIGURE 2

Chest radiograph revealing bilateral central infiltrates and an enlarged heart shadow.

FIGURE 2

Chest radiograph revealing bilateral central infiltrates and an enlarged heart shadow.

Close modal
TABLE 1

Cardiac Catheterization at Presentation and at Evaluation for Syncope Events

CriterionCardiac Catheterization
At PresentationEvaluation for Syncope
BaselineAfter 80 ppm of Inhaled NO and 100% O2BaselineAfter 80 ppm of Inhaled NO and 100% O2
Mean pulmonary systolic pressure, mm Hg 30 — 26 — 
Pulmonary capillary wedge pressure, mm Hg 10 — 11 — 
Mean aortic systolic pressure, mm Hg 50 — 52 — 
Calculated pulmonary vascular resistance, Woods units 5.5 3.2 4.5 2.5 
Pulmonary resistance and systemic resistance 0.48 0.28 0.41 0.18 
CriterionCardiac Catheterization
At PresentationEvaluation for Syncope
BaselineAfter 80 ppm of Inhaled NO and 100% O2BaselineAfter 80 ppm of Inhaled NO and 100% O2
Mean pulmonary systolic pressure, mm Hg 30 — 26 — 
Pulmonary capillary wedge pressure, mm Hg 10 — 11 — 
Mean aortic systolic pressure, mm Hg 50 — 52 — 
Calculated pulmonary vascular resistance, Woods units 5.5 3.2 4.5 2.5 
Pulmonary resistance and systemic resistance 0.48 0.28 0.41 0.18 

NO, nitric oxide. —, not applicable.

FIGURE 3

Echocardiographic image of a moderately dilated and hypertrophied right ventricle. bpm, beats per minute; HR, heart rate; Ped, pediatric echocardiography; SCMCI, Schnider Children Medical Center of Israel.

FIGURE 3

Echocardiographic image of a moderately dilated and hypertrophied right ventricle. bpm, beats per minute; HR, heart rate; Ped, pediatric echocardiography; SCMCI, Schnider Children Medical Center of Israel.

Close modal
FIGURE 4

High-resolution computed tomography showing lung tissue with matte glass and mosaic diffusion shape in both lungs, without pleural effusion.

FIGURE 4

High-resolution computed tomography showing lung tissue with matte glass and mosaic diffusion shape in both lungs, without pleural effusion.

Close modal

A diagnosis of SSc with interstitial lung involvement and pulmonary hypertension without skin changes was established.2  Immunomodulatory treatment was initiated with monthly pulses of intravenous cyclophosphamide (750 mg/m2 per month for 6 months). Glucocorticoids were avoided owing to the risk of scleroderma renal crisis. An endothelin receptor antagonist (31.25 mg of bosentan 2 times per day) and a phosphodiesterase type 5 inhibitor (25 mg of sildenafil 4 times per day) were added.

Over the next 6 months, the patient’s RP greatly improved, and the digital ulcers healed. However, the dyspnea worsened, even during mild exercise (functional class II), and the patient failed to gain weight. Additionally, the patient complained of new episodes of presyncope and abdominal pain, occurring on a daily basis for almost 2 weeks. She was readmitted for evaluation. The physical examination was unchanged. Blood tests, including D-dimer and troponin levels, were within normal limits, and no changes in the ECG were observed. A continuous 24-hour ECG recording revealed 2 episodes of sinus tachycardia with ST depression and T wave inversion, followed by a sudden decrease in heart rate, which correlated with the episodes of weakness and presyncope, suggesting a cardiac etiology. Heart catheterization revealed normal coronary arteries and improvement of the pulmonary vascular resistance under nitric oxide and 100% oxygen. Because of these dramatic and life-threatening clinical events, treatment with intravenous epoprostenol (20 ng/kg per minute) was added. High-resolution computerized tomography demonstrated worsening of the interstitial lung disease and signs of pulmonary hypertension. Cyclophosphamide was switched to mycophenolate mofetil (400 mg 2 times per day). With triple drug therapy for PAH (sildenafil, bosentan, and epoprostenol) and the mycophenolate mofetil, the presyncope episodes ceased, and the patient’s functional class improved from class III to class I–II (Table 2).

TABLE 2

Hemodynamics and Echocardiography Findings at Presentation, Evaluation for Syncope Events, and Most Recent Follow-up

At PresentationEvaluation for SyncopeRecent
Systemic blood pressure, mm Hg 100/60 100/60 100/60 
Estimated right ventricular systolic pressure, mm Hg 80 80 <40 
Right ventricle Moderately dilated, hypertrophied Mildly dilated Mild residual dilation 
Interventricular septum Flattened in systole Partial systolic flattening Round in systole 
Left ventricle systolic index, eccentricity index 2.0 1.4 1.1 
Doppler flow in pulmonary arteries Increased resistance — Normal 
At PresentationEvaluation for SyncopeRecent
Systemic blood pressure, mm Hg 100/60 100/60 100/60 
Estimated right ventricular systolic pressure, mm Hg 80 80 <40 
Right ventricle Moderately dilated, hypertrophied Mildly dilated Mild residual dilation 
Interventricular septum Flattened in systole Partial systolic flattening Round in systole 
Left ventricle systolic index, eccentricity index 2.0 1.4 1.1 
Doppler flow in pulmonary arteries Increased resistance — Normal 

—, not applicable.

Over the last 8 years, the patient has been monitored closely by a pediatric multidisciplinary team (rheumatologists, cardiologists, and pulmonologists) at Schneider Children’s Medical Center of Israel. Except for dosage adjustments to match her growth, the pharmacologic treatment remains unchanged.

Presyncope, arthralgia, and gastrointestinal complaints have not recurred, and no skin abnormalities have been noted to date. Weight and height correlated with the sixth and 20th percentiles, antitopoisomerase I (anti–Scl-70) antibody was 60 U/mL (0–15), and Von Willebrand antigen values were normalized at the last follow-up visit in 2019.

The pulmonary function was first assessed at the age of 8 years and revealed a restrictive pattern with a forced vital capacity of 63% predicted for age and body size. Repeated assessments at the age of 11 revealed a stable pattern with a forced vital capacity of 49%. The most recent high-resolution computerized tomography revealed a slight worsening in parenchymal findings compared with previous scans. However, signs of elevated pulmonary blood pressure significantly decreased. In recent echocardiography assessments, pulmonary arterial pressure was only mildly elevated. The ventricular function was normal, with a mild residual right ventricular dilation (Table 1).

SSc rarely occurs in children younger than 16 years, with a reported annual incidence of 0.45 to 1.9 cases per 100 000 persons.6  In the largest series of patients with juvenile SSc (n = 153), no case of ssSSc was reported. Characteristic skin changes were the most common feature reported, followed by RP (∼75%) and musculoskeletal symptoms (33%). Dyspnea and pulmonary hypertension occurred in 18% and 7% of patients, respectively.7 

To the best of our knowledge, there is only one other case of childhood ssSSc reported,4  in a 6-year-old girl who was diagnosed during evaluation for refractory night convulsions for 3 years and found to have RP, minor skin changes, esophageal dysmotility, and PAH. The patient died within 4 months after being diagnosed with PAH. Our patient presented with RP, interstitial lung disease, and pulmonary hypertension, without gastrointestinal or skin involvement. Nailfold capillaroscopy and elevated antinuclear antibody and antitopoisomerase I titers strongly suggested the diagnosis of ssSSc. Antitopoisomerase I is considered to have a specificity of 95% and greater for SSc.8 

Even in adults, ssSSc is a challenging diagnosis because of its rarity and the absence of the typical scleroderma skin changes.9  Considering the patient’s young age, a genetic etiology was considered. Because of the lack of consanguinity or a family history of a connective tissue disorder, the possibility of a genetic disorder (eg, COPA) was considered to be low. Major features of the syndrome, such as arthritis or renal involvement, were absent. Moreover, RP and high antitopoisomerase were never described as being associated with COPA.10,11 

Because no guidelines for therapy of ssSSc in children are available, we followed the treatment guidelines for adults.12,13  The pulmonary hypertension in our patient warrants further discussion. We could find only one case of ssSSc diagnosed with pulmonary hypertension at first presentation in the medical literature.5  Associated PAH with connective tissue disease is rare in children, especially in the first decade of life. Early pulmonary hypertension in scleroderma lung is an unusual event. In patients with SSc, pulmonary hypertension may occur secondary to the interstitial lung disease or as primary arterial hypertension. The latter is more common in long-standing limited scleroderma with positive anticentromere antibodies. PAH secondary to interstitial lung disease is usually less responsive to vasodilators and carries an ominous prognosis. Considering the generally poor prognosis,14  we opted for a more-aggressive initial treatment with a combination of 2 vasodilators to address the pulmonary hypertension and an immunomodulator to control the inflammatory process and slow the progression toward fibrosis. Because clear treatment guidelines supported by randomized controlled trials were unavailable, we chose cyclophosphamide as an initial immunomodulatory therapy because of the large body of data from controlled trials in SSc-related lung disease.15,16  The initial treatment resulted in some clinical and hemodynamic improvement as assessed by echocardiography and cardiac catheterization. However, because of the onset of cardiac syncope episodes, the pulmonary vasodilator therapy was supplemented with intravenous epoprostenol. Acknowledging the prognostic implications of SSc-related lung disease,17,18  we also addressed the lack of improvement in interstitial lung disease, and cyclophosphamide was switched to mycophenolate mofetil.1921 

At the time of writing, the patient continues to improve. Right ventricular function and size has normalized, and PAH is mild. This patient’s good clinical response to therapy during several years of follow-up is encouraging, especially in light of the expected high mortality rate.

It is possible that the aggressive early pulmonary vasodilator treatment combined with anti-inflammatory treatment may have led to clinical and imaging improvement, which has been significantly better than the expected course, according to the adult literature.

We recommend that the pediatric community be aware of the possibility of SSc in children. Pulmonary hypertension in the presence of active inflammation should be diagnosed quickly and treated aggressively. Awareness and reporting of such cases will lead to a better characterization of the disease, enhance early diagnosis, and improve prognosis.

Dr Harel was the case manager; Dr Zloof and Ms Braun drafted the initial manuscript; and all authors reviewed and revised the manuscript, agree to be accountable for all aspects of the work, and approved the final manuscript as submitted.

FUNDING: No external funding.

     
  • ECG

    electrocardiography

  •  
  • PAH

    pulmonary arterial hypertension

  •  
  • RP

    Raynaud phenomenon

  •  
  • SSc

    systemic sclerosis

  •  
  • ssSSc

    systemic sclerosis sine scleroderma

1
Denton
CP
,
Derrett-Smith
EC
.
Juvenile-onset systemic sclerosis: children are not small adults
.
Rheumatology (Oxford)
.
2009
;
48
(
2
):
96
97
2
Zulian
F
,
Woo
P
,
Athreya
BH
, et al
.
The Pediatric Rheumatology European Society/American College of Rheumatology/European League against Rheumatism provisional classification criteria for juvenile systemic sclerosis
.
Arthritis Rheum
.
2007
;
57
(
2
):
203
212
3
Abrams
HL
,
Carnes
WH
,
Eaton
J
.
Alimentary tract in disseminated scleroderma with emphasis on small bowel
.
AMA Arch Intern Med
.
1954
;
94
(
1
):
61
81
4
Navon
P
,
Halevi
A
,
Brand
A
,
Branski
D
,
Rubinow
A
.
Progressive systemic sclerosis sine scleroderma in a child presenting as nocturnal seizures and Raynaud’s phenomenon
.
Acta Paediatr
.
1993
;
82
(
1
):
122
123
5
Pauling
JD
,
Gunawardena
H
,
Coghlan
JG
,
Easaw
J
,
Suntharalingam
J
,
McHugh
NJ
.
Pulmonary artery hypertension as the presenting feature of systemic sclerosis sine scleroderma
.
Rheumatology (Oxford)
.
2008
;
47
(
9
):
1431
1432
6
Herrick
AL
,
Ennis
H
,
Bhushan
M
,
Silman
AJ
,
Baildam
EM
.
Incidence of childhood linear scleroderma and systemic sclerosis in the UK and Ireland
.
Arthritis Care Res (Hoboken)
.
2010
;
62
(
2
):
213
218
7
Martini
G
,
Foeldvari
I
,
Russo
R
, et al;
Juvenile Scleroderma Working Group of the Pediatric Rheumatology European Society
.
Systemic sclerosis in childhood: clinical and immunologic features of 153 patients in an international database
.
Arthritis Rheum
.
2006
;
54
(
12
):
3971
3978
8
Tamby
MC
,
Bussone
G
,
Mouthon
L
.
Antitopoisomerase 1 antibodies in systemic sclerosis: how to improve the detection?
Ann N Y Acad Sci
.
2007
;
1109
:
221
228
9
Diab
S
,
Dostrovsky
N
,
Hudson
M
, et al;
Canadian Scleroderma Research Group
.
Systemic sclerosis sine scleroderma: a multicenter study of 1417 subjects
.
J Rheumatol
.
2014
;
41
(
11
):
2179
2185
10
Watkin
LB
,
Jessen
B
,
Wiszniewski
W
, et al;
Baylor-Hopkins Center for Mendelian Genomics
.
COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis
.
Nat Genet
.
2015
;
47
(
6
):
654
660
11
Vece
TJ
,
Watkin
LB
,
Nicholas
S
, et al
.
Copa syndrome: a novel autosomal dominant immune dysregulatory disease
.
J Clin Immunol
.
2016
;
36
(
4
):
377
387
12
Balbir-Gurman
A
,
Yigla
M
,
Guralnik
L
, et al
.
Long-term follow-up of patients with scleroderma interstitial lung disease treated with intravenous cyclophosphamide pulse therapy: a single-center experience
.
Isr Med Assoc J
.
2015
;
17
(
3
):
150
156
13
Kowal-Bielecka
O
,
Fransen
J
,
Avouac
J
, et al;
EUSTAR Coauthors
.
Update of EULAR recommendations for the treatment of systemic sclerosis
.
Ann Rheum Dis
.
2017
;
76
(
8
):
1327
1339
14
Toya
SP
,
Tzelepis
GE
.
The many faces of scleroderma sine scleroderma: a literature review focusing on cardiopulmonary complications
.
Rheumatol Int
.
2009
;
29
(
8
):
861
868
15
Denton
CP
.
Scleroderma Lung Study II-clarity or obfuscation?
Lancet Respir Med
.
2016
;
4
(
9
):
678
679
16
Tashkin
DP
,
Elashoff
R
,
Clements
PJ
, et al;
Scleroderma Lung Study Research Group
.
Cyclophosphamide versus placebo in scleroderma lung disease
.
N Engl J Med
.
2006
;
354
(
25
):
2655
2666
17
Lefèvre
G
,
Dauchet
L
,
Hachulla
E
, et al
.
Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis
.
Arthritis Rheum
.
2013
;
65
(
9
):
2412
2423
18
Mathai
SC
,
Hummers
LK
,
Champion
HC
, et al
.
Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease
.
Arthritis Rheum
.
2009
;
60
(
2
):
569
577
19
Derk
CT
,
Grace
E
,
Shenin
M
,
Naik
M
,
Schulz
S
,
Xiong
W
.
A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis
.
Rheumatology (Oxford)
.
2009
;
48
(
12
):
1595
1599
20
Herrick
AL
,
Pan
X
,
Peytrignet
S
, et al
.
Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS)
.
Ann Rheum Dis
.
2017
;
76
(
7
):
1207
1218
21
Tashkin
DP
,
Roth
MD
,
Clements
PJ
, et al;
Sclerodema Lung Study II Investigators
.
Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial
.
Lancet Respir Med
.
2016
;
4
(
9
):
708
719

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.