eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Juvenile Systemic Sclerosis

Author: Luke M Webb, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center
Coauthor(s): David J Schwartz, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center; Cecilia P Mikita, MD, MPH, Associate Program Director, Allergy-Immunology Fellowship, Assistant Professor of Pediatrics and Medicine, Uniformed Services University of the Health Sciences; Hospital Intern Director, Staff Allergist/Immunologist, Walter Reed Army Medical Center
Contributor Information and Disclosures

Updated: Jul 20, 2009

Introduction

Background

Juvenile systemic sclerosis (JSSc) is a rare connective tissue disease of unknown etiology. Characteristic features include fibrosis of the skin, subcutaneous tissues, and internal organs as well as abnormalities of the vascular and immune systems occurring in children 16 and younger. This disease is one of the most severe rheumatologic conditions diagnosed in children.

Pathophysiology

One of the earliest processes thought to occur in juvenile systemic sclerosis is vascular injury. This results in upregulation of endothelial cell adhesion molecules, which facilitates local platelet aggregation and infiltration of inflammatory cells. This endothelial injury is manifested clinically as Raynaud phenomenon, pulmonary hypertension, and renovascular hypertension. Fibrosis is due to increased organ and dermal infiltration of lymphocytes, macrophages, eosinophils and mast cells.

These inflammatory cells release numerous cytokines, including transforming growth factor beta (TGF-β) and interleukin-1 (IL-1). Among its numerous effects, IL-1 is known to stimulate the release of platelet-derived growth factor, which stimulates fibroblasts to increase production and deposition of extracellular matrix components such as collagen, fibronectin, and glycosaminoglycans. This fibrosis may affect any organ of the body, most commonly the skin, GI tract, lungs, heart, kidneys, and musculoskeletal system.

Little is known about the role of the various autoantibodies, such as ANA, seen in almost all cases of juvenile systemic sclerosis, but their presence is suggestive of an autoimmune process underlying the aforementioned vascular injury and fibrosis. Resistance of lymphocytes to apoptosis seen in these patients is a potential mechanism for the persistence of autoreactive T cells in juvenile systemic sclerosis.

Frequency

United States

Juvenile systemic sclerosis is a rare childhood disorder. Foeldvari reported an incidence of approximately .05 per 100,000 children.¹  In addition, 5-10% of adult cases of systemic sclerosis arise before age 16 years, meeting the age criterion for juvenile systemic sclerosis. New criteria aimed at more uniformly defining juvenile systemic sclerosis will aid in better estimation of incidence and prevalence of juvenile systemic sclerosis.

Mortality/Morbidity

Mortality rates in juvenile systemic sclerosis are more optimistic than that seen in adult systemic sclerosis. Five year and 20 year survival rates in juvenile systemic sclerosis are 89% and 69-82.5%, respectively. 

The greatest morbidity and mortality is seen in those children who develop pulmonary, cardiac, and renal manifestations of the disease. A recently published report reveals that the most significant predictors of mortality at the time of diagnosis are pericarditis, elevated creatinine levels, and fibrosis on chest radiography.² The most common cause of early death in patients with juvenile systemic sclerosis is heart failure due to dilated cardiomyopathy, likely related to pulmonary hypertension and myocardial fibrosis. 

In a study of 153 patients with juvenile systemic sclerosis, those patients that succumbed to this disease had a significantly shorter time to diagnosis from onset of symptoms (8.8 mo) compared with patients that were still alive at follow-up (23 mo).³ This demonstrates that those patients who eventually die due to complications of juvenile systemic sclerosis likely have a more progressive form that is more quickly recognized by doctors due to the severity of symptoms. This is consistent with mortality rates of most studies that show most deaths from juvenile systemic sclerosis occur within the first 5 years after diagnosis.

Morbidity from the disease is seen in most patients in the form of fibrosis of the skin, which may lead to contractures and loss of mobility, and Raynaud phenomenon with associated pain and paresthesias, as well as occasional digital ulcers. Arthralgias, arthritis, and muscle weakness may occur in as many as 26% of patients, and a small number may experience dyspnea, weight loss and dysphagia as well.

Race

In the United States, adult systemic sclerosis is more common in blacks than in whites, with a ratio of 2:1. No specific demographic data are available for juvenile systemic sclerosis.

Sex

Females are more commonly affected than males in juvenile systemic sclerosis, with an overall female-to-male ratio of approximately 3.6:1. This is much lower than the 15:1 female-to-male predominance seen in adult systemic sclerosis.

Age

A child must be younger than 17 years at the time of disease onset to the meet the criteria for juvenile systemic sclerosis. The youngest patient documented with juvenile systemic sclerosis was only a few months old at disease onset. The average age of onset is 8.1-8.8 years in the two largest case series published on juvenile systemic sclerosis. Due to the rarity of this childhood disease and the subtle nature by which it can first appear, the average time from symptom onset to diagnosis is 1.9 years, taking as long as 12 years in some cases. Of note, children who died from juvenile systemic sclerosis in these 2 studies were diagnosed almost 2 years later than the average child with juvenile systemic sclerosis.

Clinical

History

Raynaud phenomenon is the most common finding at the time of diagnosis and is present in approximately 75% of patients. Cold exposure or stress may induce vasoconstriction with the attendant episodic pallor and cyanosis, followed by erythema. Other skin changes such as induration and sclerodactyly are the next most common symptoms. Skin changes are often subtle and may take months to years to evolve. Swelling and puffiness of the hands and fingers, polyarthralgia, or polyarthritis of the hands, fingers, feet, and toes are also early symptoms seen in patients that go on to develop juvenile systemic sclerosis. Most cases of Raynaud phenomenon are primary and unrelated to any connective tissue disease such as juvenile systemic sclerosis or systemic lupus erythematosus (SLE). 

In patients with primary Raynaud phenomenon, common findings include bilateral involvement, no tissue necrosis, normal nail-fold capillaries, a normal erythrocyte sedimentation rate (ESR), and no autoantibodies. At least some of these features are expected in patients with Raynaud phenomenon secondary to juvenile systemic sclerosis, especially nail-fold capillary abnormalities and a positive ANA finding in addition to other skin findings proximal to the metacarpophalangeal and metatarsophalangeal joints. 

Systemic sclerosis requires organ or tissue involvement in addition to skin changes. This involvement may be manifested as dysphagia, gastroesophageal reflux, dyspnea, palpitations, arthritis, muscle weakness, and neuropathies.

Physical

• Cutaneous
  • Skin - Diffuse puffiness of the hands and feet, which may be followed by development of tautness of the skin 
  • Hyperpigmentation or hypopigmentation - Commonly misdiagnosed as vitiligo
  • Telangiectasias
  • Face - Pursed lips, flattened and lost facial folds and features, and difficulty opening the mouth and chewing
• Peripheral vascular
  • Raynaud phenomenon - Pallor, cyanosis, suffusion, and tingling of the fingers, which occurs abruptly and episodically (When the phenomenon is associated with a known cause [eg, scleroderma], it is termed Raynaud syndrome.)
  • Abnormal nailfold capillaroscopy - Hemorrhages, abnormal or dilated loops, megacapillaries, arborization, and avascular areas 
• GI
  • Esophageal dysmotility – Detected by newer diagnostic techniques in 90% of patients (Symptomatic dysphagia is seen in only 24% of patients.) 
  • Reflux - Seen in 30% of children (Some also develop significant weight loss and diarrhea, possibly due to malabsorption.) 
• Pulmonary
  • Interstitial pulmonary fibrosis, inflammatory alveolitis, and pulmonary hypertension either alone or in combination
  • Pulmonary hypertension and fibrosing alveolitis leading to interstitial pulmonary fibrosis (major complication and cause of death in juvenile systemic sclerosis)
• Cardiac
  • Heart failure - Most common cause of death in juvenile systemic sclerosis, although often complicated by concomitant pulmonary hypertension
  • Arrhythmias- Inflammatory and fibrotic processes such as pericarditis, myocardial fibrosis, and contraction band necrosis of coronary vessels
• Musculoskeletal
  • Sclerodactyly (ie, tightening of the skin over the fingers), often with a tapered appearance of the fingertips and flexion contractures, leading to a decreased ability to use the hands (This is seen in 46% of patients at the time of diagnosis and develops in 66% of patients over the course of the disease.)
    
    

    

    Photo of hands revealing sclerodactyly. This demonstrates the progression of disease over 7 years.

    [ CLOSE WINDOW ]

    

    Photo of hands revealing sclerodactyly. This demonstrates the progression of disease over 7 years.

  • Digital tuft resorption - Observed on radiography, known as acro-osteolysis
  • Chronic myopathy - Mild weakness and minimal muscle enzyme elevations
  • Myositis - Not uncommon in systemic sclerosis, must be distinguished from other connective tissue diseases
  • Long-bone growth arrest and fibrotic bands that involve the joint capsule (in long-standing cases)
  • Contractures of the fingers and toes
  • Subcutaneous calcinosis - Seen in 19% of patients diagnosed with juvenile systemic sclerosis, usually involving extensor surfaces of both upper and lower extremities
  • Arthritis and arthralgias -More commonly seen in children with juvenile systemic sclerosis than in adult-onset disease
• Renal
  • Kidney involvement may be subtle, such as a slow rise in creatinine levels. 
  • Renal changes were reported in only 13% of cases of juvenile systemic sclerosis, but patients who develop proteinuria or hypertension are at increased risk of death.
  • The renal lesion is a slowly progressive vasculitis.
  • Intimal proliferation, medial thinning, and adventitial fibrosis, with decreased blood flow and glomerular function, characterize this disorder. 
• Neurological
  • Although seizures are rare in this population, 3% of patients with juvenile systemic sclerosis developed seizures at some time during their disease. 
  • Peripheral neuropathy, such as carpal tunnel syndrome, is also rare and is caused by fibrotic impingement of a nerve. 
  • Trigeminal neuropathy can also be seen in patients with facial skin involvement.

Causes

Juvenile systemic sclerosis is a condition with no known cause, but numerous conditions may be associated with cutaneous features that resemble scleroderma. Environmental exposures and other disease with sclerodermalike skin changes include the following:

• Toxic oil syndrome (eg, adulterated rapeseed oil)
• Eosinophilia myalgia syndrome (eg, contaminated L-tryptophan)
• Silica-associated and silicon-associated scleroderma
• Chemical-associated fibrosis (eg, bleomycin, vinyl chloride, pentazocine, other amines)
• Epoxy resin vapor
• Organic solvents (eg, benzene, xylene, toluene, methylene chloride, trichloroethylene, trichloroethane)
• Digital fibrosis in diabetes mellitus
• Scleromyxedema
• Carcinoid syndrome
• Eosinophilic fasciitis
• Porphyria cutanea tarda
• Acromegaly
• Werner syndrome (premature aging with sclerodermatous skin changes and subcutaneous calcifications)
• Hutchinson-Gilford syndrome (progeria)
• Rothmund syndrome, also termed Rothmund-Thompson syndrome or poikiloderma congenitale (atrophic, hyperpigmented, telangiectatic cutaneous plaques)
• Amyloidosis
• Lichen sclerosis et atrophicus (occasionally confused with sexual abuse in young females)

• Search for CME/CE on This Topic »

• Factors Affecting Survival in Juvenile Systemic Sclerosis