Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis

INTRODUCTION — Scleroderma is a group of diseases that vary in severity and that can occur at any stage of life, although the clinical patterns of scleroderma in children differ from those in adulthood [1]. The predominant form of scleroderma in childhood is localized scleroderma. The juvenile systemic sclerosis (JSSc) form of scleroderma is uncommon but generally has more serious, potentially life-threatening morbidity than the other sclerotic disorders.

JSSc is a chronic, multisystem, connective tissue disease typically characterized by symmetrical fibrous thickening and hardening of the skin combined with fibrous changes in internal organs, such as the esophagus, intestinal tract, heart, lungs, and kidneys. The extent of skin involvement and the accompanying pattern of internal organ involvement form the basis for the classification of SSc in children [2].

This topic reviews the classification, clinical presentation, and diagnosis of JSSc. Management of JSSc is discussed in detail separately. Localized scleroderma in children and the pathogenesis of SSc are also discussed in detail elsewhere. (See "Juvenile systemic sclerosis (scleroderma): Assessment and approaches to treatment" and "Juvenile localized scleroderma" and "Pathogenesis of systemic sclerosis (scleroderma)".)

SSc in adults is also discussed in detail separately. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" and "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults".)

CLASSIFICATION — The classification of JSSc is primarily based upon clinical manifestations, the most important being skin thickening and/or induration of the fingers (table 1) [2]. Other key clinical findings include Raynaud phenomenon (RP), telangiectasia, fingertip lesions, and abnormal nailfold capillaries [3]. A 2013 review of the classification criteria for SSc in adults confirmed skin thickening of the fingers extending proximal to the metacarpophalangeal joints as a key finding [4]. This finding, along with seven others, comprise the revised classification criteria in adults, which has improved sensitivity and specificity. These criteria may also be applicable to JSSc, although there are some essential differences between the two age groups and possible weak discrimination power with other pediatric conditions that enter in the differential diagnosis that must be addressed. (See 'Clinical manifestations' below and 'Diagnosis' below.)

The principal subsets of SSc in children (in order of frequency) include (table 2) (see "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Major disease subsets'):

●Diffuse cutaneous systemic sclerosis (dcSSc) – This subtype is characterized by skin induration affecting both proximal and distal limbs, chest, and abdomen. Digital ulceration and gangrene, if RP is not properly treated, are common. Internal organ involvement is more frequent than in the other subtypes and is often associated with antitopoisomerase (ATA) antibodies.

●Overlap syndromes – In this subset, patients demonstrate some features of SSc in combination with manifestations of other connective tissue diseases such as dermatomyositis, systemic lupus erythematosus, Sjögren's disease, and juvenile arthritis (not idiopathic).

●Limited cutaneous systemic sclerosis (lcSSc) – The lcSSc subset presents as skin induration classically involving the fingers, sometimes extending to the hand and lower part of the arm [2]. It also may involve the perioral area of the face and less often the feet. Involvement of the hands can be disabling, and it is exacerbated by vascular insufficiency, digital pitting scars (picture 1), terminal bone tuft resorption (picture 2), and digital ulcers.

RP may be complicated with digital ulceration and, rarely, with critical ischemia leading to gangrene. Calcinosis (picture 3) is often more severe in lcSSc than in dcSSc, and telangiectasia (picture 4) is more widespread. Gastrointestinal involvement with esophageal dysfunction is seen at presentation. The small and large intestine may become involved later. Progressive pulmonary hypertension occurs infrequently in children but is the most common cause of death for those with lcSSc.

●Systemic sclerosis-sine scleroderma – In this subset, patients have only internal organ involvement and no skin involvement. Juvenile systemic sclerosis-sine scleroderma (ssJSSc) is rare in childhood, with only a few cases reported [5-8]. One study reported the clinical features of 7 patients with ssJSSc who were compared with 32 patients with classical JSSc [9]. Six patients had cardiac involvement as the presenting feature, three due to primary cardiomyopathy and three secondary to pulmonary arterial hypertension (PAH). Two patients died after a brief disease course, and one rapidly underwent heart transplantation.

Cardiac involvement represents the most important clinical feature of ssJSSc at presentation and carries a high morbidity and mortality rate [9]. The longer delay in diagnosis in comparison with classical JSSc underlines the need for a comprehensive rheumatologic work-up, including the search for autoantibodies and nailfold capillaroscopy, in patients presenting with isolated cardiomyopathy and/or interstitial lung disease (ILD) or PAH, especially when associated with RP.

EPIDEMIOLOGY — The estimated incidence of JSSc ranges from 0.27 to 2.9 cases per million children per year [10-12]. In general population studies, children constitute only 3 percent of all cases of SSc [13]. The mean age of onset of JSSc is 8 to 11 years [14]. It is estimated that less than 10 percent of all patients develop SSc before the age of 20 years [15].

Girls are three times more affected than boys among those older than eight years of age [14]. However, the risk in girls and boys is similar in younger children. There is no definite racial predominance.

Most children with SSc have the diffuse cutaneous SSc (dcSSc) type (50 to 70 percent), followed by the limited cutaneous SSc (lcSSc) type (19 to 25 percent) and overlap type (12 to 20 percent) [6,14,16-19]. Only a few cases of JSSc sine scleroderma (ssJSSc) have been reported [5-9].

The overlap form of SSc is more common in children than adults [6]. In contrast, the limited cutaneous form is rare in children but occurs more frequently in adults.

PATHOGENESIS AND GENETICS — The cause of SSc is unknown, and the pathogenesis appears to be complex. The process involves three components:

●Immune activation

●Endothelial (vascular) damage

●Excessive synthesis of extracellular matrix with increased deposition of structurally normal collagen

Genetic factors appear to increase the susceptibility to development of SSc [20].

Human leukocyte antigen (HLA) alleles found associated with adult SSc have also been associated with JSSc. Patients with JSSc dermatomyositis overlap subtype demonstrated increased DQA1*05 and DRB1*03 and a trend toward decreased DRB1*15 [21]. A subsequent study of a small cohort of JSSc patients confirmed these data and reported a novel HLA association, DRB1*10, which was found in 10.5 percent of patients with JSSc compared with 1.5 percent of controls [22].

A full discussion of the pathogenesis and genetic and environmental risk factors for SSc is found elsewhere. (See "Pathogenesis of systemic sclerosis (scleroderma)" and "Risk factors for and possible causes of systemic sclerosis (scleroderma)".)

CLINICAL MANIFESTATIONS — The onset of JSSc is usually insidious, and the interval between onset and diagnosis in childhood is often prolonged. The majority of children with JSSc present with skin changes (tightening, thinning, and atrophy) of the hands and face and/or Raynaud phenomenon (RP) (table 3). Other presenting complaints include arthritis, arthralgia, muscle weakness and pain, subcutaneous calcification (calcinosis), dysphagia, and dyspnea [6,14,23,24].

This was illustrated in a multicenter, retrospective study of 153 children with JSSc [14]. The median age of onset was 8.1 years, and the mean duration of symptoms prior to diagnosis was 1.9 years. Almost 80 percent of the patients were girls. Eleven percent had a family history of autoimmune disease. Symptoms or findings at diagnosis were as follows:

●RP – 70 percent

●Proximal skin induration – 63 percent

●Musculoskeletal symptoms (eg, arthralgia, muscle weakness, and arthritis) – 33 percent

●Weight loss – 18 percent

●Dyspnea – 10 percent

●Dysphagia – 10 percent

Early signs of scleroderma in children are RP, abnormal nailfold capillaroscopic findings (particularly those with "scleroderma pattern"), and positive antinuclear antibodies (ANA) with specific autoantibodies (eg, antitopoisomerase [Scl-70] or anticentromere) (table 2 and figure 1). These manifestations may precede by years the full spectrum of JSSc manifestations [25,26]. Children with these findings should be followed up more closely since they are at increased risk of developing JSSc, although the majority do not.

Raynaud phenomenon — The primary vascular complication of SSc is RP. The classical Raynaud attack consists of three phases. The first represents vasoconstriction, where the fingers turn white. This is followed by a bluish discoloration. Then, with reperfusion, a reddish discoloration occurs. These findings primarily occur distal to the proximal interphalangeal joint on the fingers, and the thumbs are usually spared. RP is more common in the fingers but can be observed in the toes, ears, lips, tongue, and the tip of the nose. RP can result in digital ulceration and critical ischemia leading to gangrene. RP is reviewed in greater detail separately. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

Capillary abnormalities — The periungual nailfold is the most accessible site for detection of nailfold capillary abnormalities. Examination with an ophthalmoscope, but even better with a video microscope, may demonstrate capillary dropout, tortuous dilated loops, and occasionally distorted capillary architecture (figure 1 and picture 5) [27,28]. Telangiectasia is less commonly present in children than adults with JSSc (picture 4).

A multicenter study described the nailfold videocapillaroscopy (NVC) characteristics of patients with varying juvenile rheumatologic conditions in a standardized way and compared them with a large group of healthy controls [29]. The NVC images were assessed quantitatively and qualitatively, according to the standardized international consensus definitions from the European Alliance of Associations for Rheumatology (EULAR; formerly known as the European League Against Rheumatism) Study Group on Microcirculation in Rheumatic Diseases [30]. The quantitative NVC assessment consists of four parameters: capillary density, capillary dimension, capillary morphology, and presence of microhemorrhages. The qualitative NVC assessment consists of categorizing the capillary pattern in a "scleroderma pattern" (presence of giant capillaries or the combination of abnormal shapes with an extremely reduced number of capillaries of <3 capillaries/linear mm) or a "nonscleroderma pattern" including the "normal pattern" (the capillaries of the distal row are normally shaped, homogeneous in dimension, and their density is >7/linear mm) and a "nonspecific pattern" (normal density, few dilations [20 to 50 micrometers] but no giant morphology [>50 micrometers], rare capillaries with abnormal shapes and rare microhemorrhages). A standardized NVC assessment of patients with JSSc will clarify potential clinical associations with specific NVC abnormalities and also be used in disease monitoring.

Skin changes — Skin changes characteristically evolve in the following sequence:

●Edema

●Induration and edema, resulting in skin tightening and contractures

●Atrophy

Patients with JSSc often present with swollen hands or feet (picture 6), which can mimic polyarticular juvenile idiopathic arthritis. Edema may persist for weeks to months before skin changes, as a result of sclerosis and/or RP, emerge. The induration usually progresses bilaterally with variable speed and without clear demarcation and may last from three to five years. The residual atrophic phase persists as an integral part of the disease process.

During the atrophic phase, the skin becomes sclerotic (waxy in texture, tight, and hard) and bonds to subcutaneous structures. This is particularly noticeable over the distal digits and face. The loss of adnexal structures leads to a shinier, smoother appearance, with the face often developing an unwrinkled, immobile, and expressionless appearance with limited oral aperture. The characteristic facial appearance may be the first clue to the diagnosis.

Musculoskeletal features — Musculoskeletal involvement is common and characteristically occurs at or shortly after disease onset [13,28].

●Arthralgia is usually mild and transient. It is the presenting symptom in approximately 15 percent of children [14].

●Joint contractures are most common at the proximal interphalangeal joints and elbows.

●Arthritis and myositis may occur in up to 30 percent of children and are characteristic of the overlap subset of SSc rather than representing a general precursor to JSSc. Myositis leads to muscle weakness and myalgia and is associated with elevated levels of creatine kinase (CK). Since myocarditis may also occur, children with significantly elevated CK should be appropriately evaluated.

●Periarticular and subcutaneous calcinosis may occur in one-fifth of patients [14], whereas bone resorption is uncommon in children and adolescents [31].

Organ involvement — Children rarely present at disease onset with complaints of visceral organ involvement. Rather, the main complaints are related to RP and skin tightness and sometimes weight loss or poor growth (see 'Raynaud phenomenon' above and 'Skin changes' above). Direct questioning is often required to elicit a history of dysphagia, diarrhea, myalgia, or dyspnea. Internal organ involvement can be associated with significant morbidity. Monitoring for and treatment of organ system involvement are reviewed separately. (See "Juvenile systemic sclerosis (scleroderma): Assessment and approaches to treatment", section on 'Organ system monitoring' and "Juvenile systemic sclerosis (scleroderma): Assessment and approaches to treatment", section on 'Organ-targeted therapy'.)

●Gastrointestinal disease – During the disease course, gastrointestinal involvement is reported to occur in 30 to 74 percent of children with JSSc [6,14,32]. Most affected patients have esophageal dysfunction, resulting in gastroesophageal reflux and dysphagia. Large bowel involvement may present as alternating complaints of constipation and diarrhea, bloating, abdominal discomfort, or malabsorptive stools. (See "Gastrointestinal manifestations of systemic sclerosis (scleroderma)".)

Growth represents a major concern as poor weight gain or weight loss are reported in 14 to 18 percent of patients [14,32].

Radiologic and functional studies of the gastrointestinal tract often demonstrate abnormalities even in the absence of symptoms. Manometry and intraesophageal 24-hour pH monitoring are sensitive indicators of diminished lower esophageal sphincter tone and gastroesophageal reflux disease (GERD) [33]. However, esophageal scintigraphy scan is the preferred tool to evaluate and monitor GERD and esophageal dysmotility because it is faster and less invasive.

●Pulmonary disease – Patients with pulmonary involvement are frequently asymptomatic initially but eventually present with dyspnea, although some may present with a dry, hacking cough [34]. Interstitial lung disease (ILD) has been reported in 30 to 50 percent of children with JSSc, whereas pulmonary fibrosis, which represents the final irreversible stage of ILD, is common in adults with SSc but rarely reported in children [6,14,32]. Pulmonary vascular disease occurs either independently or as a result of pulmonary fibrosis in less than 4 percent of patients [6]. Patients with pulmonary arterial hypertension (PAH) frequently present with nonspecific symptoms; therefore, it is reasonable to have a high index of suspicion for PAH in this at-risk population. Red-flag findings for the presence of JSSc-PAH are decreased diffusing capacity of the lung for carbon monoxide (DLCO) and increased ratio of forced vital capacity (FVC) to DLCO. In contrast to adult SSc-PAH, presence of anticentromere antibodies are not appropriate for PAH screening in children with SSc, as they are found only rarely in childhood [35]. Although rare, early diagnosis and therapy are important as severe lung disease is one of the major causes of death in children with JSSc [36-38]. (See "Overview of pulmonary complications of systemic sclerosis (scleroderma)" and "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening".)

Screening tests for pulmonary disease in children with JSSc include, in order, pulmonary function studies, chest radiograph, high-resolution computed tomography (HRCT), and echocardiography. Some also use a six-minute walk test to assess pulmonary function [39].

•Pulmonary function tests – Pulmonary diffusion (DLCO) and spirometry are sensitive measures of involvement of the respiratory tract and are used as a screening test for pulmonary disease in children with JSSc. However, the performance of pulmonary function tests (PFTs), namely FVC, to detect underlying ILD in patients with JSSc is not universal, and ILD changes are sometimes underdetected on the accompanying HRCT. DLCO is more sensitive but less specific than FVC [40]. Ideally, PFTs should be performed in a setting with pediatric expertise, as is recommended by European Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines [41]. (See "Overview of pulmonary function testing in children".)

•Chest radiograph – The chest radiograph should not be used as a screening test for intrinsic pulmonary disease in children with JSSc, due to its low sensitivity in revealing early signs of lung involvement. However, a chest radiograph is a useful tool to assess for comorbidities such as infection and pleural effusion.

•High-resolution computed tomography – HRCT may reveal pulmonary disease even in the presence of a normal chest radiograph. In children with JSSc, HRCT findings may include ground-glass opacification, subpleural micronodules, and linear opacities consistent with ILD and honeycombing appearance consistent with pulmonary fibrosis [42-44]. An HRCT of the chest is usually obtained at disease onset and repeated if PFT becomes abnormal. Pulmonary micronodules have been reported in one-third of patients with JSSc and may reflect lymphoid aggregates or hyperplasia [45]. Most are subpleural or parenchymal and >5 mm in width. They may be associated with structural esophageal abnormalities and abnormal PFTs, especially in those with JSSc-overlap and in combination with ILD. Potential sources of inflammation in JSSc include retrograde aspiration from esophageal dysfunction, underlying inflammation due to JSSc itself, or infection due to immunosuppression.

•Echocardiography – Echocardiography is important for detecting PAH, which is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest or greater than 30 mmHg during exercise [46]. Echocardiography is typically performed at disease onset and then repeated at least twice a year or more frequently in the presence of sign/symptoms of cardiac dysfunction, arrhythmia, or abnormal pulmonary function testing.

●Cardiac involvement – Clinically evident cardiac involvement in JSSc is rarely reported, with a frequency ranging between 5 and 24 percent [47]. Although uncommon, cardiac involvement is a significant cause of morbidity among children with JSSc, and cardiorespiratory complications are the leading cause of death [6,14,36-38]. Cardiac complications of JSSc are either primary (myocardial damage, fibrosis of the conduction system, and pericardial effusion) or secondary to PAH [48]. Cardiac fibrosis may lead to conduction defects, arrhythmias, cardiomyopathy, and impaired ventricular function. Pericardial effusions are common but are not usually of hemodynamic significance. Isolated cardiac disease is rare. More frequently, cardiac and pulmonary involvement appear as one complex of organ involvement where changes in one cause changes in the other. As an example, PAH caused by pulmonary vascular disease or fibrosis can lead to myocardial damage and right heart failure. (See "Cardiac manifestations of systemic sclerosis (scleroderma)".)

●Kidney involvement – The reported prevalence of renal crisis in children with JSSc ranges from 0.7 to 4 percent [6,14,32]. In a case series of 153 children with JSSc, approximately 10 percent had kidney involvement (such as proteinuria, hematuria, or progressive kidney failure), but there was only one child with acute renal crisis, accelerated hypertension, and kidney failure [14]. Although kidney involvement in children is generally not as severe as what is seen in adult patients, the abrupt onset of accelerated hypertension with acute kidney injury (scleroderma renal crisis) is a severe and life-threatening complication. (See "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis".)

●Calcinosis – Calcinosis in JSSc is associated with longer disease duration and occurs most frequently in the hands, particularly the fingers [49]. Unlike dermatomyositis, the primary mineral component of calcinosis is hydroxyapatite, and vascular hypoxia seems to play an important pathogenetic role.

LABORATORY FINDINGS — Unlike many other connective tissue diseases of childhood, JSSc usually does not cause elevation of the acute-phase reactants, namely erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), unless an infectious complication occurs [31]. Approximately one-fourth of patients have anemia of chronic disease/inflammation or, less commonly, macrocytic anemia due to malabsorption of vitamin B12 or folate secondary to gastrointestinal involvement [14]. Leukocytosis is not prominent. Patients with myositis will have elevated creatine kinase (CK). Eosinophilia is present in 15 percent of patients, although the etiology of this finding is unclear.

Although no laboratory test confirms the diagnosis of JSSc, the presence of autoantibodies is supportive. High titers of antinuclear antibody (ANA) are reported in 80 to 97 percent of children with JSSc [6,14]. Antitopoisomerase I (ScI-70) antibodies are less frequent in children (20 to 30 percent) compared with adults (30 to 40 percent), as are anticentromere antibodies, which are found in 7 to 8 percent of children [6,14].

By comparison, routine blood tests (eg, complete blood cell count, serum chemistries, and urinalysis) are not helpful diagnostically. Brain natriuretic peptide is a biomarker that seems to correlate with the degree of pulmonary hypertension in adults and may also be a promising biomarker in children [50].

A skin biopsy may sometimes be helpful to differentiate JSSc from other syndromes. (See 'Differential diagnosis' below.)

REFERRAL — Children with clinical features suspicious for JSSc should be promptly referred to a specialized pediatric rheumatology center for the appropriate assessment and treatment [51]. Suspicious clinical findings include moderate-to-severe Raynaud phenomenon (RP), especially in association with digital ulcers and/or abnormal nailfold capillaroscopy, and limited range of finger motion due to edema or skin thickening.

DIAGNOSIS — The diagnosis of JSSc in childhood is often delayed because of its rarity and the subtle initial manifestations. The diagnosis is established clinically by the presence of typical skin thickening and hardening (sclerosis) that is not confined to one area (ie, not localized scleroderma) and visceral involvement. The diagnosis is further supported by the presence of associated autoantibodies.

In 2007, a multicenter, multinational group representing the Paediatric Rheumatology European Society (PRES), the American College of Rheumatology (ACR), and the European Alliance of Associations for Rheumatology (EULAR) defined nomenclature and criteria to diagnosis and classify JSSc based upon clinical features and laboratory parameters [2]. In a patient less than 16 years of age, JSSc is diagnosed if the major criterion and at least 2 of 20 minor criteria listed in the table (table 1) are present [2].

The classification criteria for SSc in adults were revised in 2013 in order to identify patients at an earlier stage of the disease, thereby enabling earlier treatment [52]. According to these newer criteria (table 4), the presence of skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient to classify the patient as having SSc. However, in the absence of this sign, patients are evaluated for seven alternative weighted criteria (each ranging from two to four points; patients with a score ≥9 are classified as SSc). The adult criteria have not been validated in children. However, these criteria may be helpful in children who do not have a clear diagnosis using the JSSc criteria. (See 'Classification' above.)

An evaluation of a cohort of patients with JSSc followed at the Pediatric Rheumatology Division of the University of Padua showed that 84 percent were classified as having JSSc using the 2013 ACR/EULAR adult SSc criteria compared with 68 percent using the 2007 PRES/ACR/EULAR provisional JSSc criteria [53]. This finding suggests that the provisional pediatric criteria are too specific, at the cost of sensitivity for early disease manifestations.

In accordance with the definition in adults, patients are diagnosed with systemic sclerosis-sine scleroderma (ssJSSc) if they satisfied all the following criteria [54]:

●Raynaud phenomenon (RP) or a peripheral vascular equivalent such as digital pitting scars, digital-tip ulcers, abnormal nailfold capillaries

●Positive antinuclear antibody (ANA)

●Any one of the following: distal esophageal hypomotility, pulmonary interstitial fibrosis, pulmonary arterial hypertension (PAH), cardiac involvement typical of scleroderma, or kidney failure consistent with scleroderma renal crisis

●No other defined connective tissue diseases

DIFFERENTIAL DIAGNOSIS — Because JSSc involves the skin, muscle, and internal organs, the differential diagnosis involves other multisystem organ diseases with skin involvement including the following:

●Juvenile dermatomyositis (can be part of the overlap subtype) (see 'Classification' above and "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Epidemiology, pathogenesis, and clinical manifestations")

●Systemic lupus erythematosus (can be part of the overlap subtype) (see "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis")

●Juvenile idiopathic arthritis (arthritis seen in the overlap subtype is not idiopathic and is associated with skin induration) (see "Classification of juvenile idiopathic arthritis")

●Scleredema (see "Scleredema")

●Pansclerotic morphea (see "Juvenile localized scleroderma", section on 'Pansclerotic morphea')

●Eosinophilic fasciitis (see "Eosinophilic fasciitis")

●Chronic graft-versus-host disease (see "Clinical manifestations and diagnosis of chronic graft-versus-host disease")

●Nephrogenic systemic fibrosis (NSF) (see "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease")

●Phenylketonuria with sclerodermatous skin lesions (see "Overview of phenylketonuria")

●Syndromes of premature aging (eg, progeria and Werner syndrome) (see "Hutchinson-Gilford progeria syndrome")

Other rheumatologic disorders with both skin and internal organ involvement, such as mixed connective tissue disease, are the most difficult conditions to differentiate from JSSc. Juvenile idiopathic arthritis with "dry arthritis" (joint stiffness associated with minimal joint effusion, morning stiffness, and loss of range of motion with or without contractures of involved joints) and mild inflammatory laboratory changes may be especially difficult to distinguish from JSSc. (See "Mixed connective tissue disease".)

Scleredema, a nonsuppurative disorder that can arise following beta-hemolytic streptococcal infection, is characterized by edematous induration of the face, neck, shoulders, thorax, and proximal extremities but not the hands [55]. Onset is characteristically insidious, and resolution spontaneously occurs after 6 to 12 months. Diagnosis is based upon documentation of nonpitting, indurated edema or stiffness of the skin in the typical locations. Dysphagia may be present, but Raynaud phenomenon (RP) and telangiectasias are not. Histologically, the dermis is thickened; there are multiple fenestrations between swollen collagen bundles, a scant perivascular lymphocytic infiltrate, and minimal deposits of acid mucopolysaccharides within the fenestrations. (See "Scleredema".)

NSF is a fibrosing disorder seen only in patients with kidney failure, and gadolinium-containing contrast agents may play a pathogenic role [56]. NSF is characterized by thickening and hardening of the skin overlying the extremities and trunk. The skin becomes tethered to the underlying tissue, resulting in reduced range of motion and contractures. Internal organs, including the lungs, heart, dura mater, and muscles, can be involved in the fibrosing process. Histology is required to differentiate NSF from JSSc. On histology, there is marked expansion and fibrosis of the dermis in association with CD34-positive fibrocytes in NSF [56]. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

In phenylketonuria, skin lesions usually appear during the first year of life, are symmetric and poorly demarcated, and occur most frequently on the lower extremities and trunk [57,58]. (See "Overview of phenylketonuria".)

In progeria (Hutchinson-Gilford syndrome), the skin changes typically develop during the first year of life. Lesions are characterized by thickened, bound-down skin on the abdomen, flanks, proximal thighs, and upper buttocks [59]. The lesions usually soften over time with thinning of the skin and loss of subcutaneous fat. Severe arthropathy is also associated with these lesions. The other syndrome of premature aging (Werner syndrome) most often presents in adolescents. It is characterized by generalized atrophy of the muscle and subcutaneous tissue, graying of the hair, baldness, and scleroderma-like skin changes and ulcers on the extremities [60]. (See "Hutchinson-Gilford progeria syndrome".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Mixed connective tissue disease" and "Society guideline links: Systemic sclerosis (scleroderma)".)

SUMMARY AND RECOMMENDATIONS

●Typical presenting features – Juvenile systemic sclerosis (JSSc) is characterized by symmetrical fibrous thickening and hardening of the skin combined with fibrous changes in internal organs, such as the gastrointestinal tract, heart, lungs, and kidneys. (See 'Introduction' above.)

●Systemic sclerosis subtypes – The extent of skin involvement and the accompanying pattern of internal organ involvement form the basis for the classification of SSc in children (table 1). The three most common subsets of JSSc are diffuse cutaneous SSc (dcSSc), overlap syndromes (features of JSSc and another connective tissue disease), and limited cutaneous SSc (lcSSc) (table 2). A rare form, systemic sclerosis sine scleroderma, has no skin involvement. (See 'Classification' above.)

●Clinical manifestations – The onset of JSSc is usually insidious. The majority of children with JSSc present with skin changes (tightening, thinning, and atrophy) of the hands and face and/or Raynaud phenomenon (RP) (table 3). Other presenting complaints include arthritis, arthralgia, muscle weakness and pain, subcutaneous calcification (calcinosis), dysphagia, and dyspnea. (See 'Clinical manifestations' above.)

●Laboratory findings – Unlike many other connective tissue diseases of childhood, JSSc usually does not cause elevation of the acute-phase reactants, namely erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), but most patients do have elevated antinuclear antibody (ANA) titers. (See 'Laboratory findings' above.)

●Diagnosis – The diagnosis of JSSc in childhood is often delayed because of its rarity and the subtle initial manifestations. The diagnosis is established clinically by the presence of typical skin thickening and hardening (sclerosis) that is not confined to one area (ie, not localized scleroderma) and visceral involvement. The diagnosis is further supported by the presence of associated autoantibodies (table 1). (See 'Diagnosis' above.)

●Differential diagnosis – Other rheumatologic disorders with both skin and internal organ involvement, such as mixed connective tissue diseases, are the most difficult conditions to differentiate from JSSc. (See 'Differential diagnosis' above.)