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Juvenile localized scleroderma

Juvenile localized scleroderma
Author:
Francesco Zulian, MD
Section Editors:
Suzanne C Li, MD, PhD
John S Axford, DSc, MD, FRCP, FRCPCH
Jeffrey Callen, MD, FACP, FAAD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Sep 2022. | This topic last updated: May 11, 2021.

INTRODUCTION — Although scleroderma is a spectrum of disorders that can occur at any stage of life, the clinical patterns of childhood scleroderma differ from that of adulthood.

The predominant form of scleroderma in children is juvenile localized scleroderma (JLS), also sometimes called morphea, which principally involves the skin, fascia, muscle, and bone [1-3]. Juvenile systemic sclerosis (jSSc) is a chronic multisystem connective tissue disorder characterized by hardening of the skin accompanied by abnormalities of the visceral organs. JLS is only very rarely associated with systemic disease [4-6]. However, it can sometimes mimic eosinophilic fasciitis. (See "Eosinophilic fasciitis".)

This topic reviews the incidence, etiology, diagnosis, and management of JLS in children. JSSc and the pathogenesis of systemic sclerosis (SSc) are discussed in detail elsewhere, as are the scleroderma-like disorders in adults. (See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis" and "Pathogenesis of systemic sclerosis (scleroderma)".)

CLASSIFICATION — JLS is differentiated from systemic sclerosis (SSc) based upon the pattern of cutaneous and extracutaneous involvement. In JLS, there is cutaneous involvement, typically with some involvement of the underlying musculature and/or bony structures, but rarely the nervous system, and absence of the internal organ involvement that typifies SSc (ie, the lungs and gastrointestinal tract). (See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis" and 'Extracutaneous manifestations' below and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Background'.)

The forms of JLS are distinguished by the distribution of skin lesions and other associated findings. One of the commonly used classifications divides JLS into five types (table 1) [1]:

Linear scleroderma (65 percent) – This is the most common type of JLS in children. The fibrotic lesion presents in a linear distribution, and the orientation is usually transverse when on the trunk and longitudinal on the limbs (picture 1). During the active phase, the border of the lesion is reddish (hyperemic) while the center is ivory color and waxy. During the inactive phase, it can be either hypo- or hyperpigmented. Patients may develop contractures and defects of the limb with associated poor growth and disabilities.

When the lesion involves the face or scalp, it is also referred to as "en coup de sabre" (picture 2). (See 'Linear scleroderma' below.)

Circumscribed (plaque) morphea (26 percent) – This is the most benign form of JLS. Circumscribed morphea is characterized by oval or round circumscribed areas of induration with a central waxy, ivory color surrounded by a violaceous halo. In the superficial variety, the lesion is confined to the dermis with only occasional involvement of the superficial panniculus (picture 3 and picture 4). In the deep variety, the primary site of involvement is the panniculus or subcutaneous tissue. In this case, the entire skin feels thickened, taut, and bound down (picture 5). Plaques are discrete, few in number, and confined to two or fewer anatomic areas. (See 'Circumscribed (plaque) morphea' below.)

Generalized morphea (7 percent) – This form of JLS occurs when there are four or more plaques that affect two or more anatomic sites and become confluent (picture 6). Generalized morphea can be superficial or deep. (See 'Generalized morphea' below.)

Pansclerotic (deep) morphea (2 percent) – This is the least common but the most disabling form of JLS. The primary site of involvement is the panniculus or subcutaneous tissue. (See 'Pansclerotic morphea' below.)

Mixed morphea – A combination of two or more of the above subtypes occurs in approximately 15 percent of patients [7]. This overlap occurs most frequently with circumscribed morphea and linear scleroderma. (See 'Mixed morphea' below.)

EPIDEMIOLOGY — Although JLS is uncommon, it is 6 to 10 times more common in children than systemic sclerosis (SSc) [2,8]. Few studies have addressed the incidence or prevalence of this disorder in children [8,9]. Approximately one-third of all patients with localized scleroderma have disease onset in childhood [10], with an estimated incidence rate of 0.34 to 0.9 cases per 100,000 children per year age ≤16 years [8,9]. However, JLS may be underreported because of referral bias patterns and misdiagnosis as other cutaneous diseases [10].

Linear scleroderma is the predominant form of JLS in childhood, whereas circumscribed morphea is the predominant form in adults [11]. JLS was reported at birth in 25 neonates. Linear morphea, including en coup de sabre and Parry-Romberg syndrome (PRS), was the most common subtype observed (76 percent), followed by circumscribed (20 percent). The face/scalp (56 percent) and trunk (24 percent) were the most common locations affected. Extracutaneous involvement was seen in 12 (48 percent) patients, all with linear subtype. Neurologic involvement was seen in those with linear scleroderma of the head (8 of 13, 62 percent) [12,13]. At this age, linear scleroderma can be misdiagnosed as skin infection, nevus, or salmon patch, and, in older children, it may be misdiagnosed as alopecia. These diagnostic errors can lead to a delay in diagnosis, which can result in use of inappropriate treatments and may lead to more severe extracutaneous manifestations and disfigurement [10]. (See 'Differential diagnosis' below.)

ETIOLOGY AND PATHOGENESIS — The etiology and pathogenesis of JLS remain uncertain. Numerous etiologic agents have been suggested as possible causes of JLS, including drugs and environmental toxins, local trauma, and infection. However, no definitive link has been established in any of these. Two possible contributing pathogenic processes include abnormal fibroblast function and immune dysfunction resulting in autoimmunity.

The skin lesions of JLS demonstrate an initial marked inflammatory reaction, followed by matrix deposition (including collagen), fibrosis, and ultimately atrophy (picture 7). Because of these histologic changes, investigations have focused on abnormal regulation of collagen production by fibroblasts. Although developmental origins have been hypothesized, evidence suggests that JLS is a systemic autoimmune disorder as there is a strong correlation with family history of autoimmune disease, the presence of shared human leukocyte antigen (HLA) types with rheumatoid arthritis, high frequency of autoantibodies, and elevated circulating chemokines and cytokines associated with T helper cell, interferon (IFN) gamma, and other inflammatory pathways. This inflammatory phenotype of the peripheral blood is reflected in the skin via microarray, RNA sequencing, and tissue staining [14].

Raised levels of cytokines that increase collagen synthesis by fibroblasts have been reported in JLS lesions [15]. A T helper cell type 1 (Th1; IFN-gamma) and T helper cell type 17 (Th17; interleukin [IL] 17 alpha) predominance was demonstrated in peripheral blood of children with JLS compared with healthy controls. An IFN-gamma signature, consisting of elevated IFN-gamma-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and IFN-gamma, has also been demonstrated in systemic sclerosis (SSc), suggesting a shared pathophysiology [16].

Autoimmunity as a contributing cause of JLS is supported by the following observations:

There is an increased incidence of autoimmune disorders (particularly Hashimoto's thyroiditis, vitiligo, and type 1 diabetes mellitus) in patients with JLS [17-21] and their relatives [7,8,17,22].

Biopsies of linear scleroderma lesions have similar histologic findings to those seen in skin lesions of patients with graft-versus-host disease (GVHD), and morphea-like lesions are seen in patients with chronic GVHD [23].

In one study, tissue biopsies of JLS were found to contain chimeric-infiltrating cells, which were primarily epithelial cells surrounded by CD4+CD8+ T cells and B cells [24]. These findings resembled lymphoid aggregates, which have been reported in other autoimmune processes such as juvenile dermatomyositis, neonatal lupus erythematosus, Sjögren's syndrome, and SSc.

Organ-specific autoantibodies are a frequent finding in patients with JLS [7,8,17] and their relatives [18]. Unlike many autoimmune diseases, there appears to be no significant increased risk for JLS in family members.

Specific HLA class I and class II alleles are associated with JLS [25]. These alleles are different than those associated with SSc, suggesting that they are immunogenetically distinct entities.

In a multicenter retrospective review of 750 patients, 13.3 percent reported specific environmental events as a potential trigger for their disease [7]. These included infections, drugs, mechanical events (eg, accidental trauma, insect bite, and vaccination), and psychologic stress:

Drugs and environmental toxins that have been associated with scleroderma-like skin reactions include bleomycin, ergot, bromocriptine, pentazocine, carbidopa, and vitamin K [26].

Trauma has been implicated in the initiation of JLS lesions and also with the onset of eosinophilic fasciitis. A history of trauma has been reported in 3 to 13 percent of patients with JLS [7,8,27,28]. The underlying pathogenesis of how trauma would contribute to the development of JLS is unclear. Although cytokines and neuropeptides (eg, endothelin-1), which are normally involved in wound healing, have been suggested to play a causative role [8], there is no confirmatory evidence.

CLINICAL MANIFESTATIONS — The mean age of presentation is 7 to 8.2 years (range: birth to 17 years; median age: 6 years) [3,7]. Clinical manifestations vary depending upon the type of JLS (see 'Classification' above). Extracutaneous manifestations occur in over 20 percent of patients with JLS.

Linear scleroderma — Linear scleroderma is the most frequent form of JLS in children [3,7]. The fibrotic lesion appears as linear bands. Limbs are more commonly affected than the face. The orientation of the fibrotic band is usually transverse on the trunk and longitudinal in the extremities. Recurrence in JLS occurs in almost one-quarter of patients and is more frequent in the linear subtype involving the limbs, independently of the age of the disease onset [29,30]. Extracutaneous manifestations are most common in patients with linear scleroderma. (See 'Extracutaneous manifestations' below.)

There is considerable debate on whether these lesions follow specific dermatomes [31]. One theory speculates that the involved distribution reflects an abnormal migration of neuroectodermal cells during embryogenesis [32]. This theory is supported by the frequent development of seizures, headaches, and muscle weakness on the affected side during the evolution of facial lesions [33]. Imaging studies of the brain also have shown vascular and cerebral changes even in patients without neurologic symptoms. Other data suggest that linear lesions follow the lines of Blaschko [34]. (See 'Linear scleroderma of the head/face' below.)

Linear scleroderma of the limbs and trunk — Linear scleroderma of the limbs (picture 1) and trunk may result in the following findings and complications:

Atrophy of soft tissue, muscle, periosteum, bone, and occasionally synovium.

Extensive and disfiguring growth defects in either all or part of an affected limb. These defects may require major surgery and may continue even after the cutaneous inflammation abates.

Truncal hemiatrophy.

Fixed valgus or varus deformities, which occur because of leg-length inequalities.

Lesions that cross joint lines, causing disabling flexion contractures.

Hammer toes or claw hands, which may develop if the toes or fingers are involved.

Linear scleroderma of the head/face — On the head/face, linear scleroderma can manifest as typical linear lesions, also known as "en coup de sabre," a term that denotes the resemblance of the lesion to the consequence of a sabre blow and Parry-Romberg syndrome (PRS) or as both forms together [35]. In PRS, there is inflammation and atrophy of underlying tissues without obvious overlying skin fibrosis [2]. Linear lesions occur on the face or scalp and, after an acute inflammatory phase (picture 8), assume a depressed, ivory appearance (picture 9). They usually are restricted to one-half of the face, often with a loss of scalp and eyebrow hair (picture 2), as well as asymmetric facial development.

Perioral skin involvement may extend into the oral cavity and cause major dental problems, such as early loss of the primary teeth, delayed or abnormal eruption of the permanent teeth, and lack of bone growth [36]. The most frequently orofacial abnormalities are malocclusion, overgrowth of the anterior lower third of the face, problems with chewing, dental anomalies, skeletal asymmetry, and bony or temporomandibular joint involvement [35,36].

Vascular abnormalities of the brain also may occur, and several eye lesions have been described, reflecting extension of the same pathologic processes into the brain and orbit [37]. In addition, patients with en coup de sabre can have scleroderma lesions elsewhere. Neuroimaging abnormalities are common in patients with linear scleroderma of the face, although they are not always associated with clinical manifestations [35,38]. In patients with en coup de sabre, associated neurologic manifestations include seizures (particularly complex partial seizures), headaches, facial weakness or paralysis, dystonia, and neuropathy [7,35,39,40]. Sometimes, the neurologic symptoms may even occur before or concurrent with the skin manifestations [41].

An area of controversy is the relationship between en coup de sabre and PRS. Some evidence suggests that PRS represents the severe end of the spectrum of en coup de sabre or linear scleroderma, as supported by cases of patients who have definite linear lesions on the face and other parts of the body [37]. In patients with PRS, compared with those with en coup de sabre, there is usually greater involvement of the lower face, and the superficial skin is involved in a relatively minor fashion. Seizures and other neurologic abnormalities, uveitis, and dental and ocular abnormalities have been described in both conditions, as have electroencephalography (EEG) and central nervous system (CNS) imaging abnormalities ipsilateral to the affected side of face [42]. However, in other reports, there is no evidence of inflammation and/or induration preceding the severe atrophy seen in patients with PRS, suggesting that the two might be separate entities [43].

Circumscribed (plaque) morphea — Circumscribed morphea is characterized by oval or round circumscribed areas of induration with a central waxy, ivory color surrounded by a violaceous halo (the "lilac ring") (picture 3 and picture 4). In the superficial variety, the lesion is confined to the dermis with only occasional involvement of the superficial panniculus. In the deep variety, the primary site of involvement is the panniculus or subcutaneous tissue. In this case, the entire skin feels thickened, taut, and bound down (picture 5).

Plaques evolve through several stages (picture 5 and picture 10):

Initial erythematous inflammatory stage

Sclerotic indurated phase with surrounding inflammation

Softening and dermal atrophy phase with associated hypo- or hyperpigmentation

The superficial forms usually resolve within three to five years [44], although a patch may sometimes persist. New patches occasionally appear many years after the initial presentation.

Subtypes of circumscribed morphea, quite rare in children, include:

Guttate morphea – Guttate morphea frequently involves the shoulders and chest. Lesions are multiple, small (2 to 10 mm in diameter), hypopigmented and pigmented papules with minimal induration (picture 11). The epidermis is thin and atrophic, resembling lichen sclerosus et atrophicus.

Keloid morphea – Keloid morphea, also known as "nodular morphea," is characterized by indurated plaques that resemble posttraumatic scars. Keloid morphea can be several centimeters in diameter and is found either as a single lesion or as multiple lesions (picture 12).

Bullous morphea – In this rare form of morphea, the, bullous lesions probably result from localized trauma or lymphatic obstruction secondary to the fibrosing process [45].

Atrophoderma of Pasini and Pierini – This subtype usually involves the trunk and is characterized by hyperpigmented atrophic patches with well-demarcated borders. It may coexist with other types of sclerotic lesions or represent the involutionary phase of circumscribed morphea.

Morphea profunda – Sometimes, circumscribed deep induration of the skin involves subcutaneous tissue extending to fascia and underlying muscle. The skin appears bound down with a solitary or multiple indurated plaques. Histopathology is characterized by fibrosis associated with mononuclear cell infiltration and focal lymphoid follicles in the lower dermis (picture 13) [46,47].

Generalized morphea — Generalized morphea, which can be superficial or deep, is defined by the presence of four or more plaques involving at least two out of seven anatomic sites (head-neck, right upper extremity, left upper extremity, right lower extremity, left lower extremity, anterior trunk, posterior trunk) (picture 6) [1]. Usually, the trunk and legs are involved, and the acral (fingers, toes, or ears) areas are spared. Onset of induration is rapid, occurring over a period of several months, and the degree of the skin inflammation is greater than in other subtypes.

Pansclerotic morphea — Pansclerotic morphea is the least common but most disabling variant of JLS (picture 14) [1]. It is characterized by generalized full-thickness skin involvement of the trunk, extremities, face, and scalp that usually spares the fingertips and toes [48]. Often, a circumferential asymmetric involvement of a limb affecting the skin, subcutaneous tissue, muscle, and bone can be present. This aggressive disease has a poor prognosis due to the rapid progression of deep musculoskeletal atrophy resulting in cutaneous ulceration and severe joint contractures. Less than 40 case reports have been reported [49]. Most children require multimodal and high-dose immunosuppressive therapies to reduce the inflammation and arrest irreversible disability. Unlike SSc, pansclerotic morphea does not affect the internal organs and is not associated with Raynaud phenomenon, capillaroscopy changes, or positive autoantibodies. The progression of the disorder is unrelenting, and there have been reports of squamous cell carcinoma developing in affected patients [50]. The mean time interval between the onset of scleroderma and the development of squamous cell carcinoma ranges between 10 to 20 years; therefore, it is important to carefully check for skin tumors during follow-up examinations.

Mixed morphea — Mixed morphea is a condition in which a combination of two or more of the previous subtypes coexist [1]. This subtype, described for the first time in 2006, represents approximately one-fifth of the whole pediatric localized scleroderma cohort [7]. The most frequent association concerns circumscribed morphea and linear scleroderma, where patients may exhibit overlapping lesions. These changes of skin lesions over time should be carefully monitored because linear scleroderma is associated with greater morbidity and increased complication rates than the circumscribed subtype [51]. Adult-onset localized scleroderma presents a different subtype predominance, with generalized morphea (47 percent) the most common, followed by linear scleroderma (24 percent) and circumscribed morphea (18 percent) [52]. Mixed morphea has never been reported.

Overlap with lichen sclerosus — Patients with circumscribed morphea and generalized morphea sometimes may have surface changes of lichen sclerosus (picture 15A-B and picture 16A-B). In addition, these two groups of patients may have lichen sclerosus that affects the anogenital region (picture 17A-B) [53]. (See "Extragenital lichen sclerosus" and "Vulvar lichen sclerosus".)

Extracutaneous manifestations — Approximately 20 percent of patients with JLS present with extracutaneous manifestations [22]. Extracutaneous findings are most common in patients with linear scleroderma and consist essentially of arthritis, ocular and neurologic findings, or other autoimmune conditions. In these patients, organ impairment is milder and not life threatening, compared with systemic sclerosis (SSc) [18]. (See 'Disease course and prognosis' below.)

In a multicenter study of 750 children with JLS, the prevalence and the clinical features of extracutaneous findings in patients were determined [22]. There was at least one extracutaneous manifestation present in 22 percent of children, and 4 percent had multiple manifestations. Extracutaneous manifestations may occur with all subtypes of JLS, but the prevalence varies according with the subtypes.

Musculoskeletal involvement is the most frequent finding and accounts for one-half of the extracutaneous manifestations in patients with JLS. It is more prevalent in patients with linear scleroderma of the trunk/limb (40 to 51 percent), mixed morphea (23 percent), and pansclerotic morphea (33 to 100 percent) [54,55]. It includes joint manifestations such as arthralgia, arthritis, tenosynovitis, contractures, and muscle manifestations such as myositis, atrophy, and weakness [22,54,56-58]. Other musculoskeletal problems are fasciitis and growth defects that include limb girth and length differences. The joint involved sometimes is completely unrelated to the site of the skin lesion. Children with JLS who develop arthritis often have a positive rheumatoid factor (RF) and sometimes an elevated erythrocyte sedimentation rate (ESR) and circulating antinuclear antibodies (ANAs) [22]. These children tend to have an accelerated course with predominant musculoskeletal disease, including rapid development of contractures (picture 18).

Neurologic manifestations include headaches, seizures, Rasmussen encephalitis, movement disorders, peripheral neuropathy, intellectual deterioration, neuropsychiatric symptoms, and brainstem involvement [22,33,35,39,59-62]. Both seizures and headaches, including migraine headaches, can be presenting features of linear scleroderma of the face; therefore, clinicians should be aware of this association and perform a thorough cutaneous examination [60]. Seizures are most commonly complex partial or generalized and are often refractory to antiepileptic treatment [35]. Magnetic resonance imaging (MRI) of the brain may show focal and diffuse abnormalities, T2 hyperintense signals (mainly in subcortical white matter), brain atrophy, calcifications, and vascular abnormalities consistent with CNS vasculitis [35,37,61,62].

Oral manifestations include abnormal bone growth causing malocclusion (prognathia, retrognathia, or more localized defects) and tooth anomalies [36].

Ocular findings include abnormalities in adnexal structures (lacrimal glands, lid, lashes) and retina, uveitis, strabismus, orbital myositis, and pupillary mydriasis [63,64]. The Single Hub and Access Point for Paediatric Rheumatology in Europe (SHARE) guidelines for JLS recommend an ophthalmologic assessment, including screening for uveitis, at diagnosis for every patient with JLS, particularly those with skin lesions on the face/scalp [65].

The risk for developing oral, ocular, and neurologic manifestations is higher for linear scleroderma of the head than for other subtypes [22,54]. In these patients, oral problems have been reported in 41 to 100 percent [36,54], ocular in 9 to 47 percent [22,54,63,64], and neurologic in 27 to 47 percent [22,35,54].

Other autoimmune conditions are seen with greater frequency in patients with localized scleroderma, primarily in adult patients. In a large, retrospective case series of patients with morphea, 30 percent of adult patients and 5 percent of pediatric patients reported concomitant findings of other rheumatic or autoimmune disorders [17]. Raynaud phenomenon was the most common condition reported in a pediatric series [22].

Vascular findings include vasculitic rash and deep vein thrombosis [22].

Gastrointestinal findings, in particular esophageal motor function abnormalities with gastroesophageal reflux disease (GERD), have been reported both in children [22,66] and in adults [67] with localized scleroderma. In one study of 14 children with JLS, esophageal abnormalities were detected in eight patients, five of whom were symptomatic [66].

Overlap with SSc can rarely occur (overlap disease) [4-6]. One review reported 2.4 to 7.4 percent of coexistent cases of SSc and localized scleroderma in adult patients [68]. The coexistence with SSc is most prevalent in the circumscribed type of localized scleroderma, followed by generalized morphea. Raynaud phenomenon, scleroderma pattern on nailfold video capillaroscopy, and the presence of SSc-specific antibodies were commonly observed in coexistent cases and should alert clinicians to further explore the possible presence of SSc. The mean time interval between localized scleroderma and SSc diagnosis was 3.3 years, whereas between SSc and localized scleroderma diagnosis was longer (5.8 years).(See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis".)

LABORATORY TESTS — The diagnosis of JLS is not dependent on laboratory testing. Routine studies, such as complete blood count, blood chemistries, and urinalysis, are usually normal.

Autoantibodies are commonly observed in JLS, which reflects activation of the immune system. Although not as specific with regard to organ manifestation or scleroderma subtype as seen in systemic sclerosis (SSc), autoantibodies may help with assessing disease severity.

A high proportion of patients with JLS are antinuclear antibody (ANA) positive, ranging from 30 to 70 percent when tested by indirect immunofluorescence [3,7,18,54,69,70]. The presence of ANA in several studies seems to correlate to deeper disease involvement with features such as joint contractures, muscle atrophy, and extremity shortening, but not disease subtype or age of onset [7,18,54,69,70].

More classic SSc-specific autoantibodies, such as anti-centromere and anti-topoisomerase, occur in 2 to 14 percent and 3.2 to 10 percent of patients with JLS, respectively, but none were associated with particular localized scleroderma subtypes [22,71,72]. Other autoantibodies, such as anti-histone antibody (AHA) and anti–single-stranded DNA antibody (ssDNA Ab), were found to be positive in 10 to 50 percent of patients with JLS patients, and both correlated with severity features such as deep muscle involvement, joint contractures, and increased number of lesions [18,67,72-74]. In contrast, antibodies to double-stranded DNA (ds-DNA) are rarely found. In a large retrospective study, a positive test for ds-DNA was found only in 4.2 percent of tested patients, but none showed systemic lupus erythematosus (SLE) features [7].

When evaluated, rheumatoid factor (RF) was mildly elevated in approximately 50 percent of patients and correlated with the occurrence of generalized morphea subtype, presence of arthritis, and number of lesions [7,75]. Other markers of immune activation, such as immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) elevation, were found to be increased in approximately 20 percent of patients [7].

Other, more typical laboratory parameters tested in connective tissue diseases, such as elevated creatine phosphokinase and aldolase, were associated with muscle atrophy and extremity shortening in a North American JLS cohort, indicating muscle involvement [3].

There are no specific laboratory tests for measuring disease activity. One report found elevated soluble interleukin (IL) 2 receptor levels with active disease [73]. However, another study failed to confirm these findings [75].

DIAGNOSIS — The diagnosis of JLS is established on clinical grounds, usually by the characteristic physical appearance of the lesions (table 1). A biopsy of the skin and/or subcutaneous tissue may be useful for confirmation if there is doubt about the diagnosis (picture 10 and picture 7). During the early phase of the disease, there may be an intense inflammatory infiltrate with lymphocytes, plasma cells, macrophages, eosinophils, and mast cells. Subsequently, there is an increase in fibroblast activation with massive collagen deposition. In advanced stages, compact collagen fibers may replace the entire dermis.

The depth of involvement is important in differentiating the various subtypes of JLS. Circumscribed morphea is usually more superficial, with principal involvement of the dermis and occasionally the panniculus, whereas linear scleroderma tends to spare the superficial dermis and involves the deep dermis, subcutaneous tissue, fascia, and sometimes muscle and underlying bone. Those JLS patients with clinical evidence of lichen sclerosus have histopathologic changes that are identical to that seen in patients with lichen sclerosus without morphea (picture 19).

DIFFERENTIAL DIAGNOSIS — Although the lesions of JLS are fairly distinctive, the cutaneous manifestations of the following disorders may have a similar appearance:

Localized lipodystrophy is characterized by a loss of subcutaneous fat from small areas of the body. Drug-induced lipodystrophy at the site of injection was a frequent complication of insulin therapy before the availability of purified human insulin but is rare now. Other medications, such as injectable glucocorticoids and antibiotics (intramuscular penicillin, amikacin, etc), can also cause localized lipoatrophy.

Morphea-like lesions of phenylketonuria are more diffuse; affect the proximal areas of the extremities, sparing the hands and feet; and are usually limited to the skin and subcutaneous tissue. The severity of the skin changes usually regresses upon introduction of a low-phenylalanine diet.

Graft-versus-host disease (GVHD) (picture 20) lesions appear as circumscribed, firm plaques often favoring the lower aspect of the trunk that may slowly spread to become more generalized. Sometimes, the cutaneous lesions may be accompanied by dystrophic changes of the nails, including vertical ridges, onycholysis, and nail fold telangiectasias.

Borrelia infection (erythema migrans) (picture 21) may resemble circumscribed morphea in its early onset. The lesions usually are flat and without scale, may be pruritic or burning, but are rarely painful. Erythema migrans is annular, but the lesion can vary greatly in shape and rarely is perfectly round. Their migratory nature and the absence of central induration are the differentiating features.

Eosinophilic fasciitis (EF) (picture 22) is characterized by inflammation and sclerosis of the fascia and the subcutaneous tissue of the limbs with sparing of the hands, feet, and the face [1,76]. EF has an acute onset with symmetric, painful edema of the extremities, followed by progressive induration associated with the finding of a peripheral eosinophilia. The skin develops an irregular "peau d'orange" appearance, and, as the sclerotic process occurs predominantly at a deep level, the skin surface often feels normal, with ill-defined induration of the underlying tissues.

Acquired port-wine stains [77] usually develop slowly, never cause induration of the skin, and may occur in any location on the body. They can mimic the early presentation of localized scleroderma; therefore, patients should be closely monitored to early detect signs of incipient fibrosis.

Connective tissue nevi (picture 23) [78] are dermal hamartomas characterized by abnormal proliferation of components of the extracellular dermal matrix, specifically collagen and elastin, and/or proteoglycans. The lesions can be solitary or multiple, and their border is not well defined. Usually, the superficial skin has a normal appearance. A skin biopsy is needed to confirm the diagnosis.

REFERRAL — All pediatric patients with suspected or confirmed JLS should be referred to a clinician who is part of a multidisciplinary team, including pediatric rheumatology and dermatology, that is experienced in the diagnosis and management of this disorder [65]. Ideally, this team should be an integral part of a tertiary pediatric facility with access to additional subspecialists and services.

TREATMENT — Education of the patient and caregiver(s) is critical in the management of JLS. Undue anxiety often is created by confusion regarding localized (JLS) versus systemic (SSc) disease. Explanation of the difference between these conditions and their expected outcome should be emphasized.

Treatment may include general nonpharmacologic measures and/or pharmacologic therapy [79]. Care should include advice on skin care, an exercise schedule to maintain functional ability, psychologic and social support, and pharmacologic therapy. Surgical procedures are rarely necessary.

Nonpharmacologic measures — A carefully designed treatment program, including physiotherapy and massage, is beneficial in many children with JLS. Physiotherapy maintains functional ability, muscle strength, and joint movement while preventing flexion contractures.

The use of corrective splints and gait analysis also may be helpful. Attention to positive joint alignment and muscle development is particularly important in linear scleroderma.

Pharmacologic measures — Determining the optimal therapy for JLS has been challenging since only one controlled trial in children has been published (table 2) [80].

Single lesions/mild disease — Pharmacotherapy is usually not required for single-circumscribed lesions, such as superficial circumscribed morphea, other than emollients (any lanolin-based cream) and low-concentration topical corticosteroids or calcipotriene as needed [81] to help relieve dryness and itching.

Moderate-to-severe disease — Consistent with consensus-based recommendations both in children [65,82] and in adults [83,84], the author advises systemic treatment when there is a risk for disability, such as in deep pansclerotic morphea, progressive linear scleroderma, or generalized morphea. The new era for the treatment of localized scleroderma began in the late 1990s with the introduction of methotrexate. After the first experience in adult patients [85,86], more and more pediatric rheumatologists began treating JLS patients with methotrexate, with numerous case series [87-89]. Finally, a double-blind, randomized, placebo-controlled trial in 2011 clearly documented the safety and efficacy of methotrexate in JLS [80]. Later on, methotrexate treatment of localized scleroderma patients with severe skin or deeper tissue involvement was also recommended by European dermatologists including the European Dermatology Forum [83,90]. To improve care, pediatric rheumatology organizations in Europe (Paediatric Rheumatology European Society [PReS], via the Single Hub and Access Point for Paediatric Rheumatology in Europe [SHARE] initiative) and North America (Childhood Arthritis and Rheumatology Research Alliance [CARRA]) each led consensus-building efforts to generate standardized treatment regimens based upon best available evidence [65,82].

The European SHARE recommendations suggest a weekly regimen of methotrexate of 15 mg/m2, given as a single oral or subcutaneous dose per week (maximum dose 25 mg per week) for at least 24 months before tapering. Other dosing regimens range from 0.6 to 1 mg/kg/dose with the same maximum dose [82,89,91]. A course of systemic glucocorticoids is advised as adjunctive bridge therapy during the first two to three months of therapy [65].

A long-term follow-up study showed that prolonged remission off methotrexate can be achieved in patients treated for more than 24 months [92]. In fact, a relapse rate of 12.5 percent was reported in patients treated for less than 24 months, whereas no relapses were noted in those treated longer. Similar results were reported in a single-center study in which methotrexate was given subcutaneously for 24 months and then switched to oral administration for 12 additional months [91].

Methotrexate-resistant disease — Unfortunately, up to 6 to 10 percent of JLS cases are resistant to methotrexate [80,89,93,94]. Possible predictors of relapse include older age at onset and linear scleroderma affecting the limbs.

For patients with relapsing and/or methotrexate-refractory disease, mycophenolate mofetil is often used [95]. The use of this agent is supported by small case series both in children and in adult patients [96,97]. Mycophenolate mofetil efficacy was confirmed in a cohort of pediatric patients refractory or intolerant to methotrexate who received mycophenolate mofetil at a dose of 700 to 1000 mg/m2/day [98]. mycophenolate mofetil was effective in 77.3 percent of patients, and no difference was noted between mycophenolate mofetil treatment alone compared with combination treatment of methotrexate plus mycophenolate mofetil.

Thus, consistent with SHARE recommendations, patients who do not respond to at least six months of therapy with methotrexate with or without glucocorticoids or who are intolerant to methotrexate are usually treated with mycophenolate mofetil at a dose of 500 to 1000 mg/m2/day [65].

Experimental therapy — Therapies that have been studied in smaller numbers of patients include tocilizumab, abatacept, imiquimod, ultraviolet light, and vitamin D.

Biologic agents have been proposed as potential therapeutic options for refractory JLS. One drug under investigation is tocilizumab, a fully humanized antibody against interleukin (IL) 6. IL-6, a key player in the pathogenesis of scleroderma syndromes, is elevated in patients with localized scleroderma [14]. Two case series reported the effective use of tocilizumab for children with JLS, and included diffuse and pansclerotic forms as well as patients presenting with extracutaneous complications [99,100]. Therefore, tocilizumab may represent a possible choice for the treatment of patients with disease that is severe or refractory to methotrexate and mycophenolate mofetil.

Another potential drug of interest is abatacept, a cytotoxic T lymphocyte-associated protein 4 (CTLA4) fusion protein that modulates lymphocyte activity, since evidence from experimental mice models suggests that it has a role in limiting dermal fibrosis [101]. Two different, small, Danish case series reported promising results in adult patients with localized scleroderma [102,103]. A subsequent multicenter study evaluated the efficacy of abatacept in 18 children with JLS, the majority with linear subtype and musculoskeletal involvement. Patients experienced improvement in both skin and musculoskeletal activity. At 12 months, 61 percent of patients had responded to therapy, 22 percent had failed treatment, and 17 percent had discontinued abatacept for adverse events [104].

Small studies have reported efficacy of imiquimod, a Toll-like receptor 7 agonist that acts as an immune response modifier, for circumscribed morphea [105,106].

Other therapies that have been explored, particularly by dermatology specialists in Europe, include:

Ultraviolet (UV) light – The use of UV A1 phototherapy, with or without chemical agents, such as psoralen, was reported to be beneficial for localized or superficial lesions in adults [107,108]. This therapy has not been studied in children. UVA1 phototherapy is typically not used in children, due to the potential carcinogenic risk. Narrowband UVB phototherapy is preferred for treatment of other skin disorders in children, but it appears to be less effective than UVA1 in adult studies of localized scleroderma [109].

Vitamin D – Use of vitamin D or its analogs (topically and systemically) was also reported in adults with JLS [81,110], but results in the only controlled trial indicated that it was not more effective than placebo [111].

Surgery — Surgical reconstruction may be required at some point for functional and aesthetic issues but should only be performed after the disease has reached complete, stable remission off medication and when the child's growth is complete [112]. Facial contouring is a surgical treatment option that was shown to improve quality of life in adolescents with facial asymmetry due to linear scleroderma of the face [113].

Orthopedic problems can occur and may require complex corrective surgery [114].

EVALUATION OF PROGRESSION OR RESPONSE TO THERAPY — Evaluating the progression or response to therapy of JLS may be difficult, although various methods are available.

Localized Scleroderma Cutaneous Assessment Tool (LoSCAT) - Scoring methods, such as the Localized Scleroderma Severity Index (LoSSI) [115] and the Localized Scleroderma Damage Index (LoSDI) [116] that together form the LoSCAT, divide the body surface area into 18 anatomic sites, and skin thickness, inflammation, lesion extension, and damage are scored on a 0- to 3-point scale. Another skin activity measure that expands upon the LoSSI included additional skin lesion features that are associated with disease activity [117]. In particular, the combination of erythema, disease extension, violaceous color, abnormal skin texture, and skin thickening provide the best correlation to clinician global assessment of activity in multiple regression models [117]. Absolute and percent changes in scores correlate with meaningful change, corresponding with improved or worsened disease activity or damage [118].

Patient-reported outcome measures (PROMs) - PROMs for JLS are aimed at capturing the status of a patient's health as the patient experiences it, without interpretation by a clinician. This proposed instrument, termed Localized Scleroderma Quality of Life Instrument (LoSQI), consists of 32 items for four theoretical domains (skin sensations, physical functioning and musculoskeletal sequelae, body image and social support, medication side effects) with a 4-point response scale (0 to 3) [119]. In addition, for older patients (≥10 years old and adolescents), anchoring vignettes (AVs) were shown to be a potential complementary measurement technique to reduce bias in patient-reported outcome by helping clinicians understand differences in how individuals and groups interpret response options [120].

Other clinical assessments - Arthritis should be monitored clinically with a complete joint examination including the temporomandibular joint [65]. Patients with JLS involving the face should also have regular orthodontic and maxillofacial evaluation and ophthalmologic assessment every three to four months during the first two years and then yearly [65]. Laboratory studies (usually a complete blood count, aspartate aminotransferase [AST], alanine aminotransferase [ALT], erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and urinalysis) are performed periodically (usually every four months) to check for drug toxicity.

Noninvasive technology, including infrared thermography, ultrasonography, and magnetic resonance imaging (MRI), may be helpful in following the extent of disease in selected patients [44,65]:

Infrared thermography – Infrared thermography, which measures the radiation of infrared heat from the body, is of value in the detection of active JLS lesions in children, with high sensitivity (92 percent) but moderate specificity (68 percent) [121,122]. This procedure is noninvasive and usually well tolerated. It allows for easy interpretation and rapid results that are helpful in decision making. However, there are false-positive results in cases of atrophic or old lesions, particularly in the scalp region, because old lesions lead to a marked atrophy of skin, subcutaneous fat, and muscle, with increased heat conduction from deeper tissues [121]. In these cases, a careful clinical examination is needed to confirm doubtful active lesions.

Ultrasonography – Ultrasonography is a noninvasive tool that also may be helpful in the evaluation of JLS patients and monitoring of disease activity [123,124]. The penetration depth of the 13 MHz probe reaches 60 mm, allowing for quantitative assessment of JLS lesions. Hypodermis echogenicity and deep tissue layer vascularity are the most sensitive indicators of disease activity. Being an operator-dependent technique, ultrasonography is not widely used in routine clinical practice.

Computerized skin score (CSS) – CSS method allows the measurement of single-target skin lesions and follows them over time [125]. The indurate borders of the lesions are demarcated upon an adhesive transparent film, which is transferred to a computer as a scanned image. The dimensions of the scanned image are converted to a CSS. This technique is applicable in day-to-day practice, is not time consuming, and does not need specialized equipment.

Laser Doppler flowmetry (LDF) – LDF is a noninvasive tool that measures cutaneous microcirculation and has been used in dermatology and microvascular surgery. In one study of 41 children with JLS, LDF was more accurate in detecting active lesions than thermography [126]. CSS and LDF are still under validation; therefore, their use is still limited.

Magnetic resonance imaging – MRI is indicated in the linear subtype when central nervous system (CNS) or orbital involvement is suspected [127]. All patients with JLS involving the face and head, with or without signs of neurologic involvement, should have an MRI of the head at the time of the diagnosis [65]. In the other forms involving the limbs, MRI is able to demonstrate the extent and depth of soft tissue lesions. It is therefore indicated in the assessment of musculoskeletal involvement, particularly in pansclerotic morphea and linear scleroderma where sarcopenia is frequent [128,129]. The two main disadvantages are the need for sedation in younger patients and the presence of possible artifacts.

Emerging techniques of assessment – Additional techniques for the assessment of JLS have been proposed but still need proper validation for wider use.

Cone beam computed tomography (CBCT) – CBCT is a reliable and relatively safe technique to assess and quantify the disease involvement in linear scleroderma of the face. The radiation dose is considerably less than a traditional computed tomography. It is indicated not only for disease assessment but also for issues related to facial reconstructive procedures [130].

Sonoelastography (SE) – SE is a noninvasive ultrasound application that evaluates tissue stiffness by the determination of shear wave (SW) velocity, a biologic parameter considered analogous to tissue elasticity. SE is able to discriminate between healthy skin and localized scleroderma lesions by determination of skin elasticity, showing a significant increase in skin stiffness in JLS lesions compared with healthy skin control sites in both the dermis and the hypodermis [131].

DISEASE COURSE AND PROGNOSIS — The outcome for most children with JLS depends upon the type and extent of the lesion. The major problem in most untreated patients is not survival, as it is with systemic sclerosis (SSc), but morbidity as a result of skin, muscle, and bone atrophy; growth defects; and deformities of varying severity, mostly seen in patients with linear scleroderma and pansclerotic morphea. This supports the consensus of early, aggressive treatment with systemic therapy and tight monitoring until full remission [65,82]. (See 'Linear scleroderma' above and 'Pansclerotic morphea' above.)

The mean disease duration of JLS in one series including both adult and pediatric patients was 13 years [54]. A small number of patients had active disease for more than 20 years, and 44 percent of those with deep linear or circumscribed morphea developed significant disability. In one study of 133 patients with JLS, most achieved complete remission [55]. Only 12.5 percent, all with linear scleroderma, still had active disease after >10 years of follow-up. Mild tissue damage was observed in more than half of patients, moderate in 25.4 percent, and severe in 23 percent, with a functional limitation reported in 19.8 percent. As expected, delay in the start of systemic treatment was associated with longer disease activity and higher relapse rate. Patients with linear scleroderma, pansclerotic morphea, and mixed subtype presented with more severe aesthetic and functional damage [55].

JLS is associated with higher global damage than adult-onset localized scleroderma and shows a trend towards a higher frequency of impairment [52]. The difference in subtype patterns is a major contributor since JLS is associated with a higher frequency of linear scleroderma than adult-onset localized scleroderma, which means a higher frequency of extracutaneous manifestations. Additional differences between JLS and adult-onset localized scleroderma include a higher relapse rate (27 versus 17 percent) and longer duration of active disease for JLS (13 to 13.5 years versus 4.4 to 5.8 years) [30,52,54]. The main factor associated with relapse in one study was the linear scleroderma subtype [30], while subtype differences are thought to influence duration. Early diagnosis and methotrexate treatment as well as long‐term monitoring are crucial to improve outcome and promptly identify flares [132].

Regarding psychological issues, the stress of living with linear scleroderma of the face was studied in a cohort of Canadian patients with JLS [133]. Patient self-perception was mainly based upon the visibility of the lesion, the different phases of life transitions, and the social reactions of peers, including intrusive questioning and/or bullying. To face these issues, children and their parents/caregivers used strategies to normalize the experience by hiding physical signs of the illness, constructing explanations about what is morphea, and by connecting with their peers.

Although patients may experience long periods of disease inactivity, studies of adults with childhood-onset disease, mostly treated with just topical drugs, demonstrate the risk of persistent disease activity. In one study, 56 percent had permanent damage, with 89 percent having ongoing disease activity as adults [134]; whereas, in another study, 31 percent of patients reported active disease, and 38 percent functional limitations after 10 years [29].

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: Morphea (localized scleroderma)".)

SUMMARY AND RECOMMENDATIONS

The predominant form of scleroderma in childhood is juvenile localized scleroderma (JLS). It is classified into five types based upon lesion appearance and extent of disease: linear scleroderma (trunk, limbs, or face), circumscribed morphea, generalized morphea (superficial or deep), pansclerotic morphea, and mixed morphea (table 1). (See 'Classification' above and 'Clinical manifestations' above.)

Localized disease principally involves the skin, subcutaneous fascia, muscle, and bone, although extracutaneous findings are common. (See 'Clinical manifestations' above and 'Extracutaneous manifestations' above.)

The diagnosis of JLS is established on clinical grounds, usually by the physical appearance of the lesions (table 1). A biopsy of the skin and/or subcutaneous tissue may be useful for confirmation if there is doubt about the diagnosis. (See 'Diagnosis' above.)

Treatment is individualized and matched to both the type of JLS and stage of disease (table 2). Care should include advice on skin-softening agents, exercise to maintain functional ability, pharmacologic therapy, and, if indicated, surgery. (See 'Treatment' above.)

We suggest not treating a single circumscribed lesion with systemic therapy, unless it crosses a joint line and produces contracture (Grade 1C). Emollients (any lanolin-based cream) and low-concentration weak topical corticosteroids (1% hydrocortisone cream) may relieve dryness and itching. (See 'Pharmacologic measures' above.)

For moderate-to-severe JLS, including pansclerotic morphea, progressive linear scleroderma (particularly if crossing joint lines or involving the face), or generalized morphea, we recommend treatment with methotrexate for at least 24 months, in combination with glucocorticoids (oral or parenteral) for the first three months (table 2) (Grade 1B). (See 'Pharmacologic measures' above.)

Evaluation of progression or response to therapy can be assessed by clinical scoring methods, such as the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT) or, more objectively, by instruments such as computerized scoring (CSS), infrared thermography to detect active "hot" lesions, magnetic resonance imaging (MRI) to evaluate their depth, and high-frequency ultrasound. (See 'Evaluation of progression or response to therapy' above.)

The outcome for most children with JLS depends upon the type and extent of the lesion. The major problem in most untreated patients is not survival, as it is with systemic sclerosis (SSc), but morbidity due to functional-esthetic damage and growth problems. (See 'Disease course and prognosis' above.)

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Topic 6399 Version 25.0

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