Scleroderma-like disorders

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Autoimmunity Reviews 7 (2008) 331 – 339 www.elsevier.com/locate/autrev

Scleroderma-like disorders R. Foti a , R. Leonardi a , R. Rondinone b , M. Di Gangi a , C. Leonetti a , M. Canova b , A. Doria b,⁎ a

Rheumatology Unit. Azienda Ospedaliera Universitaria V. Emanuele, Ferrarotto, S. Bambino Catania, Italy b Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128—Padova—Italy Received 2 December 2007; accepted 20 December 2007 Available online 11 January 2008

Abstract Fibrosing disorders comprise a wide spectrum of heterogeneous diseases characterized by sclerosis of the dermis, subcutis, and sometimes the underlying soft tissues and bone. The hallmark of this group of diseases is skin thickening as in systemic sclerosis with a different distribution pattern and for this reason they have also been referred to as “sclerodermalike” disorders. These diseases may have a different clinical course ranging from a benign disease with a localized cutaneous involvement, to a widespread, systemic, life-threatening disease. Some of them are associated with autoantibodies and/or autoimmune conditions. An accurate recognition of these scleroderma-like diseases is important for the institution of the most appropriate treatment. © 2007 Elsevier B.V. All rights reserved. Keywords: Scleroderma-like; Systemic sclerosis; Skin thickening

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Localized scleroderma . . . . . . . . . . . . . . . . . . Scleromyxedema . . . . . . . . . . . . . . . . . . . . . Buschke scleredema . . . . . . . . . . . . . . . . . . . Nephrogenic fibrosing dermopathy/nephrogenic systemic POEMS syndrome . . . . . . . . . . . . . . . . . . . . Myeloma with scleroderma-like changes . . . . . . . . . Diffuse fasciitis with eosinophilia (eosinophilic fasciitis) Eosinophilia–myalgia syndrome (EMS) . . . . . . . . . Toxic oil syndrome (TOS) . . . . . . . . . . . . . . . . Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . Carcinoid syndrome . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author. Tel.: +39 049 8212202; fax: +39 049 8212191; (Mobile) +39 338 8072644, (Mobile) +39 335 1425825. E-mail address: [email protected] (A. Doria). 1568-9972/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2007.12.004

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R. Foti et al. / Autoimmunity Reviews 7 (2008) 331–339

12. Porphyria cutanea tarda (PCT) . . . . . . . 13. Phenylketonuria (PKU) . . . . . . . . . . . 14. Chronic graft-versus host disease (GVHD) . 15. Vinyl chloride disease, organic solvents and 16. Drug induced scleroderma-like illnesses . . 17. Werner's syndrome . . . . . . . . . . . . . 18. Melorheostosis and stiff skin syndrome . . 19. Restrictive dermopathy . . . . . . . . . . . 20. Atrophoderma of Pasini-Pierini . . . . . . . 21. Scleroatrophic Huriez syndrome . . . . . . Take-home messages . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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Scleroderma-like disorders (SLD) encompass a wide range of diseases characterized by cutaneous hardening and thickening as in systemic sclerosis (SSc), with histologic features of an excessive local accumulation of collagen and other extracellular matrix components. A correct diagnosis is very important since SLD are very different diseases in terms of pathogenesis, clinical course, treatment, and outcome. Histological examination does not always allow the differentiation among the various subtypes of scleroderma and SLD, and therefore the diagnosis is often based on the pattern of cutaneous involvement and other clinical features. The treatment is primarily based on the aetiology, when it is known, and depends on the extension of the disease, the rate of progression and measures of disease activity. SLD can be classified according to many variables like histopathologic features or anatomical localization and extension [1,2]. However, a clinical-pathogenetic classification seems to be more useful for primary care clinicians to recognize the manifestations of the SLD and to understand the diagnostic and prognostic differences between the various subtypes Table 1. 1. Localized scleroderma Localized scleroderma, otherwise called morphea, is characterized by circumscribed areas of cutaneous sclerosis with different shapes, in the absence of Raynaud's phenomenon or visceral involvement. Localized scleroderma has been subdivided into plaque, generalized, linear, bullous, and deep morphea. Plaque morphea occurs as a single or multiple circumscribed oval area of cutaneous sclerosis with an ivory-white colour and a smooth surface, asymmetrically distributed on the trunk, or, less commonly, on the extremities; the face and fingers are generally spared. When the lesions are

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smaller than 10 mm in diameter, they are referred to as guttate morphea. Generalized morphea is a widespread variant in which the trunk and limbs may be extensively involved. Linear morphea is most common in children and adolescents and involves the lower and upper extremities with a band-like distribution; the linear lesions are usually single and unilateral but may sometimes be bilateral. Rarely the head may be involved with the socalled “coup de sabre” pattern.

Table 1 Classification of scleroderma-like disorders –Localized scleroderma. –Disorders with mucin deposition: scleromyxedema, Buschke scleredema, nephrogenic fibrosing dermopathy. –Disorders with monoclonal gammopathy: scleromyxedema, POEMS syndrome, myeloma with scleroderma-like changes, Buschke scleredema. –Disorders with eosinophilia: diffuse fasciitis with eosinophilia, eosinophilia-myalgia syndrome, toxic oil syndrome. –Disorders with defined metabolic/biochemical/endocrine abnormalities: insulin dependent diabetes mellitus (IDDM), noninsulin dependent diabetes mellitus (NIDDM), carcinoid syndrome, porphyria, phenylchetonuria, nephrogenic fibrosing dermopathy. –Chronic graft-versus host disease. –Chemically induced scleroderma-like disorders: eosinophilia-myalgia syndrome, toxic oil syndrome, polyvinyl-chloride disease, organic solvents, epoxy resins exposure. –Drug induced scleroderma-like disorders: bleomycin, injections of pentazocine, progestin, vitamin B12, vitamin K, cocaine, D-penicillamine, peplomycin, interferon-β1a, uracil-tegafur, paclitaxel, methysergide, gemcitabine. –Physical injury (trauma, vibration stress, radiation) –Inherited progeroid syndromes (Werner's syndrome) –Heterogeneous group of hereditary disorders with skin thickening (melorheosthosis, stiff skin syndrome, porphyria cutanea tarda, phenylketonuria), or tight skin (restrictive dermopathy, scleroatrophic Huriez syndrome).


It can frequently involve the deeper layers of the skin with the possible extension to the underlying structures such as the tendons and joints with resulting ankylosis. Deep morphea is characterized by the involvement of the subcutaneous tissue, fascia, and muscles. Localized scleroderma, in contrast to SSc, is in most instances a self-limited condition, although variants such as linear morphea can persist for longer periods (Table 2). The diagnosis of morphea is based on clinical findings, although histopathologic confirmation is sometimes needed to rule out other diseases [1,3−6]. Morphea can be differentiated from SSc by the distribution of the sclerotic plaques, the absence of sclerodactyly, perioral involvement, Raynaud's phenomenon, periungual telangiectasia, and severe systemic involvement. 2. Scleromyxedema Scleromyxedema, also known as lichen myxedematosus or papular mucinosis, is a rare chronic disease of unknown etiology characterized by the presence of infiltrative and confluent skin induration with the formation of papules, due to an increased deposition of glycosaminoglycans within the dermis [4,5]. The papular lesion are typically not pruritic and are most frequently localized to the face, neck, distal forearms, and back of the hands, with sparing of the palms, scalp and mucous membranes. The wide mucin deposition within the forehead and the glabella causes the appearance of the so-called leonine facies. The progressive thickening and hardening of the skin may determine a decreased range of motion of the hands and wrists and a reduced opening of the mouth. When the lesions are diffuse, scleromyxedema can clinically mimic SSc, particularly in those cases in which there is a significant visceral involvements such as esophageal dysmotility and inflammatory myopathy. Skin biopsy may help in differentiating scleromyxedema from SSc showing a diffuse mucin depositions within the upper and mid reticular dermis, which can be easily identified using colloidal iron, toluidine blue or Alcian blue stains [3,4,9]. Fibroblasts from patients with scleromyxedema have been found to synthesize a greater amount of hyaluronic acid and mucin than normal fibroblast [4]. Scleromyxedema is almost always associated with a benign gammopathy (Table 2), mainly IgG lambda type [9]. Reported treatment protocols include retinoids, PUVA, plasmapheresis, dermabrasion, total body electron beam irradiation, extracorporeal photopheresis [5], IVIG [7], melphalan [5] and other immunosuppressive

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drugs such as cyclophosphamide, cyclosporine or methotrexate. 3. Buschke scleredema Buschke scleredema is a rare connective tissue disease of unknown aetiology, characterized by the sudden onset of a marked, symmetrical induration of the skin of the posterior and lateral aspects of the neck, then gradually extending to the upper back, shoulders and face. The mobility of the affected joints is reduced. The fingers are always spared and Raynaud's phenomenon or visceral involvement are infrequent. Graff [8] described 3 types of scleredema. Type 1 usually involves pediatric patients and is often preceded by an acute febrile illness including streptococcal infection, influenza, scarlet fever, measles and mumps. Type 2 has no preceding febrile or underlying illness but it tends to follow a slow progressive course with an increased risk of developing paraproteinemia including multiple myeloma. Type 3 occurs in diabetic patients and is also know as scleredema diabeticorum. Usually the disease regresses in several months to 2 years. The skin histology is characterised by a thickened dermis with increased spaces between large collagen bundles due to increased deposition of mucopolysaccharide which can be identified using special stains like toluidine blue or colloidal iron. Numerous therapies have been tried with contradictory results including corticosteroids, Dpenicillamine, immunosuppressants, photopheresis and phototherapy with psoralen (Table 2). Physiotherapy may help preventing the restrictive effects on the muscles and joints. [9–11]. 4. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis Nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis is a progressive fibrotic disorder occurring in patients with end-stage renal disease who received haemodialysis, peritoneal dialysis, or underwent renal transplantation. The pathogenesis of the disease is unknown, but many observations suggest a close association with exposure to gadolinium-containing contrast agents and recently gadolinium has been detected in skin tissue samples of affected patients. [12]. The fibrotic process affects the cutis, subcutaneous tissue, fascia, striated muscles, but also internal organs such as the heart and lungs [13]. The skin becomes hard and thick with erythematous or hyperpigmented papules that coalesce into plaques, with a “peau d'orange” appearance, symmetrically distributed on the limbs and the trunk, with

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Table 2 Scleroderma-like disorders Diseases

Age

Localized scleroderma

Skin involvement

Musculoskeletal involvement

Systemic involvement

Laboratory findings

Treatment

Ref.

A, P Unknown

Trunk, extremities, face, neck, scalp

Arthralgias, arthritis, ankylosis

Rare, if any

ANA, anti-ssDNA

[1]

Scleromyxedema

A

Face, glabella, neck, forearms, hands

Pulmonary, neurologic involvement dysphagia

IgG lambda paraproteinemia

Buschke scleredema

A, P Unknown

Myositis, arthralgias, arthritis, flection cotractures Neck, shoulder girdle, Reduction of range face, upper extremities of motion

Nephrogenic systemic fibrosis POEMS syndrome

A, P Gadolinium

Trunk, limbs

Muscle fibrosis

Heart and lung fibrosis

None

A

Unknown

Diffuse

Osteosclerotic bone lesion

IgG or IgA monoclonal gammopathy

Eosinophilic A fasciitis Eosinophilia-myalgia A syndrome

Unknown

Extremities

Joint contractures

Peripheral neuropathy, organomegaly, endocrinopathy, multiple myeloma Rare, if any

D-penicillamine, systemic steroids, methotrexate, hydroxychloroquine Melphalan, systemic steroids, plasmapheresis, retinoids, PUVA, IVIG Systemic steroids, D-penicillamine, colchicine, photophoresis, PUVA Plasmapheresis, interferon, IVIG Radiation therapy, alkylatorbased therapies, steroids.

Prednisone, methotrexate

[3]

Contaminants in

Diffuse

Severe myalgia

Stopping ingestion of preparations

[3]

ICA, IAA, anti-GAD

Correction of hyperglycemia

[20,21]

Increased daily excretion of 5-HIAA Increased urinary excretion of porphyrins

Surgical removal of tumor, octreotide Avoid alcohol and estrogens; phlebotomy; hydroxychloroquine Low phenylalanine diet

[22]

Carcinoid syndrome Porphyria cutanea tarda Phenylchetonuria

Chronic graft-versus host disease

Unknown

Iper gamma globulinemia, eosinophilia Eosinophilia

Hands, forearms

Finger joint contractures

Face, chest, legs

None

Neurological and gastrointestinal symptoms, dyspnea Cardiovascular, renal and neurologic involvement Endocardial fibrosis

Diffuse

None

None

Diffuse

None

CNS involvement

Increased urinary excretion of phenylalanine metabolites

Trunk

Myositis

Gastrointestinal, liver, lymphoid tissue and lung involvement

Anti-Scl, anti-PM-Scl, aPL, ANCA

L-tryptophan

preparations Enzymatic glycosilation of collagen A Serotonin and other mediators A Uroporphyrinogen decarboxylase deficiency P Phenylalanine hydroxylase deficiency A, P Donor T-lymphocytes

A

Rare: cardiomyopathy Possible and pericardial effusion paraproteinemia

[4]

[10,11]

[14] [17]

L-tryptophan

[23]

[24]

Corticosteroid, extracorporeal [26] photo-pheresis, tacrolimus, thalidomide, rituximab

A Adult; P Paediatric; IDDM Insulin dependent diabetes mellitus; CSN central nervous system; NIDDM Non insulin dependent diabetes mellitus; ANA antinuclear antibodies; anti-ssDNA anti-single stranded DNA antibodies; aPL antiphospholipid antibodies; ICA Islet cell autoantibodies; IAA Insulin autoantibodies; GAD Glutamic acid decarboxylase; 5-HIAA 5-hydrossindolacetic acid; ANCA anti-neutophil cytoplasmic antibodies; IVIG intravenous Ig.


Diabetes mellitus

Etiology


sparing of the face. Skin biopsies demonstrate a marked thickening of the dermis, fascia, and the septa within the subcutaneous fat due to the accumulation of thick collagen bundles separated by large clefts due to the deposition of mucin, as demonstrated by alcian blue or colloidal iron stains. Numerous spindle-shaped and elongated fibroblasts are present throughout the dermis and fascia. Histopatology of the muscles shows pronounced infiltration of the perimysium and endomysium with fibrotic tissue and muscle fiber atrophy. The disease runs a chronic course and the prognosis depends on the extent and the severity of the cutaneous and systemic involvement [14] (Table 2). There is no proven effective therapy. Plasmapheresis has been the most extensively used treatment though the reported results are inconsistent. In a few patients, local administration of interferon or treatment with IVIG has proven to be partially effective. Photopheresis and other treatments such as corticosteroids, cyclosporine and methotrexate have failed to show significant clinical improvement [14].

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skin changes are the result of the infiltration of the skin by neoplastic cells [18]. 7. Diffuse fasciitis with eosinophilia (eosinophilic fasciitis)

POEMS syndrome is a rare multisystemic disease occurring in the setting of a plasma cell dyscrasia which is characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes [15]. Moreover, other important clinical features have been described, such as sclerotic bone lesions, Castleman's disease, papilledema, pleural effusion, oedema, ascites, and thrombocytosis. The most common cutaneous abnormalities are hyperpigmentation and thickening with sclerodermoid changes which may sometimes limit joint excursion. The histopathologic changes seen in the sclerodermoid lesions are nonspecific, and consist in hyperpigmentation of the basal layer, an inflammatory infiltrate and dermal fibrosis. Sweat glands and collagen are normal, and this permits the differentiation from scleroderma. POEMS syndrome may mimic SSc; in the case report described by Toussaint et al. [15], Raynaud's phenomenon, skin thickening, and facial telangiectasia were present for 6 months prior to the diagnosis of POEMS and were initially suggestive of systemic scleroderma. The treatment relies on the control of the underlying plasma cell disorder [16,17].

Eosinophilic fasciitis (EF) is an idiopathic SLD characterized by the inflammation and sclerosis of the fascia and the subcutaneous tissue of the limbs with sparing of the hands, feet, and the face [1,3]. EF has an acute onset with symmetric painful oedema 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 illdefined induration of the underlying tissues. In advanced stages the “groove sign” may be seen due to the cutaneous induration. Venous furrowing or vertically linear depressions following the course of the blood vessels occur between muscle groups. Joint contractures are common. Visceral organ involvement is rare and in contrast to SSc (Table 2), there is no Raynaud's phenomenon, abnormal nail fold capillaries, and sclerodactyly. EF may be associated with hematological abnormalities, including malignant lymphoproliferative diseases, myelodysplastic syndromes, aplastic anemia, haemolytic anemia, thrombocytopenia, and some cases have been reported following the administration of statins and other drugs. The diagnosis of EF can be established by clinical, laboratory and histological findings. A full-thickness incisional biopsy specimen should be obtained, to include the skin, fat, fascia, and superficial muscle as the fibrotic process also extends upwards into the lower dermis and also downwards to the muscles below the fascia. The cellular infiltrate consists of lymphocytes, plasma cells, histiocytes, and eosinophils which may be focally distributed within the fascia. Magnetic resonance imaging can assist with the diagnosis, help in the identification of an appropriate site for tissue sampling, and provide information on treatment response [19]. Although skin induration may improve spontaneously, most patients require therapy (Table 2). No consensus on the treatment of eosinophilic fasciitis exists; nevertheless, prednisone frequently induces softening of the skin [1,3].

6. Myeloma with scleroderma-like changes

8. Eosinophilia–myalgia syndrome (EMS)

Sclerodermatous processes coexisting with multiple myeloma or monoclonal gammopathy have been reported in literature, without deposits of mucin or amyloid. The

EMS was first described in 1989 in patients who had ingested preparations containing high amounts of L-tryptophan, and is characterized by marked

5. POEMS syndrome

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eosinophilia, myalgia, joint pain, pruritus, oedema, and sclerodermoid cutaneous manifestations, which constitute the most striking and consistent clinical features [20]. In mice the injection of 1,1'-ethylidenebis[Ltryptophan], a contaminant of L-tryptophan preparations, induces inflammation in the dermis, fascia and perimysium. Dermal fibroblasts from affected patients are activated and produce increased amount of collagen and other extracellular matrix components in vitro. Moreover, they have been demonstrated to over-express transforming growth factor-beta (TGFβ), a powerful inducer of collagen synthesis which has been implicated in the pathogenesis of several fibrotic conditions. Eosinophils probably contribute to the fibrotic process through the stimulation of fibroblast-activating agonists, particularly TGFβ. Patients may develop skin tightening with a “peau d'orange” appearance, and sclerodermoid changes. This process tends to start in the distal part of the lower and upper extremities and gradually extends proximally but, unlike SSc, the fingers and toes are almost always spared, and Raynaud's phenomenon is absent. Biopsy samples of the skin and the underlying fascia reveal thickening of the fascia with homogenization of collagen accompanied by an inflammatory cell infiltrate in the fascia, subcutaneous tissue, interlobular septa, and deep reticular dermis. This infiltrate is primarily composed of lymphocytes, with few eosinophils and plasma cells [3]. The association between EMS and autoantibodies such as ANA and antiphospholipid antibodies has been described (Table 2); however, the clinical significance of these antibodies remains unclear [21]. 9. Toxic oil syndrome (TOS) Toxic oil syndrome is a devastating disease that occurred in Spain in 1981 following the consumption of aniline-denatured and refined rapeseed oil that had been illegally sold as olive oil [20]. The disease is characterized by a great variety of symptoms and sclerodermiform cutaneous changes presenting initially as slightly indurated oedematous areas, with subsequent progressive hardening. The skin lesions were similar in some cases to a localized myxedema or a plaque of morphea, and in others to an eosinophilic fasciitis on the trunk or to generalized morphea. The most severe cases resembled SSc, with generalized involvement of the arms and legs, oedematous fingers, sclerodactyly and muscle atrophy of the hands. No particular treatment (e.g. corticosteroids, azathioprine, penicillamine, plasmapheresis, vitamin E, superoxide dismutase, vasodilators, analgesics, anti-inflammatory) produced any convincing therapeutic effect [20].

10. Diabetes mellitus Various skin changes may be seen in 10% to 50% of patients with insulin dependent diabetes mellitus (IDDM) and among these, sclerodermatous skin changes are relatively common, sometimes with resultant joint contractures. Non-enzymatic glycosilation of collagen may be responsible for the stimulation of skin fibroblasts to produce abundant amounts of matrix proteins [22]. Scleroderma-like skin changes are found to affect also non insulin dependent diabetes mellitus (NIDDM) patients [23]. Clinically they develop a symmetric, bilateral thickening and induration of the skin on the dorsum of the fingers with subsequent progressive contractures of finger joints known as “prayer” sign [23]. The differentiation from SSc relies on the absence of telangiectasia, oedema, and Raynaud's phenomenon. Histological studies have revealed thickening of the dermis and accumulation of collagen with small amount of mucin. Only anecdotal reports are available about the treatment; the therapeutic control of glucose metabolism may determine an improvement of the joint contractures or at least stop the progression of skin changes (Table 2). Physical therapy may be important in severe cases to preserve the range of motion [23]. 11. Carcinoid syndrome Carcinoid tumors are the most common type of neuroendocrine tumors. They may release hormones, serotonin, and other mediators such as substance P and neurokinin A, thereby causing the so-called carcinoid syndrome [24]. The syndrome classically involves the gastrointestinal tract, cardiovascular system, respiratory system, and the skin with resulting diarrhoea, tachycardia, hypotension, fibrotic right-sided heart disease, bronchospasm, flushing, telangiectasia, and rarely a sclerodermalike cutaneous manifestation. Carcinoid-associated scleroderma can be differentiated from SSc because the lower limbs are more often involved before the upper limbs, and by the absence of an acral distribution and of Raynaud's phenomenon. Visceral involvement is limited to the endocardial fibrosis observed in carcinoid heart disease (Table 2). 12. Porphyria cutanea tarda (PCT) PCT is caused by a defect of the heme biosynthetic pathway and is associated with the excretion of large amounts of uroporphyrin in urine [25]. PCT includes familial types and acquired types that may occur in


individuals with a genetic predisposition after exposure to hepatotoxins or in the context of hepatic tumors. The most common manifestations of PCT are due to increased mechanical skin fragility after sunlight exposure, and consist of vesicles and bullae on the exposed areas of the skin, i.e. the face, hands and the V-shaped area of the neck, that heal with hyperpigmented patches, hypopigmented atrophic scars and milia (Table 2). Sclerodermoid plaques may also be observed on exposed areas and may resemble morphea both clinically or histologically, or SSc when the hands are involved with contractures and sclerodactyly [9,25]. 13. Phenylketonuria (PKU) PKU is a rare autosomal recessive metabolic disease resulting from the deficiency of phenylalanine hydroxylase. The untreated state is characterized by mental retardation, microcephaly, delayed speech, seizures, eczema. Scleroderma-like changes may also be observed [26]; these alterations usually appear within the first 2 years of life and have a predisposition for the proximal areas of the extremities, sparing the hands and feet, and are usually limited to the skin and subcutaneous tissue (Table 2). The severity of the skin changes usually regresses upon introduction of a low-phenylalanine diet [26]. 14. Chronic graft-versus host disease (GVHD) The cutaneous manifestations of chronic GVHD may be classified into a lichenoid and a sclerodermoid form [27]. The early sclerodermoid lesions appear as circumscribed firm plaques often favouring the lower aspect of the trunk that may slowly spread to become more generalized. Patients with extensive truncal involvement may develop a progressive restrictive lung disease due to diminished chest wall compliance (Table 2). Occasionally sclerodermoid lesions may present with clinical features resembling eosinophilic fasciitis or deep morphea [27]. Sometimes the cutaneous lesions may be accompanied by dystrophic changes of the nails, including vertical ridges, onycholysis and telangiectasia of the nail fold [28]. Skin sclerosis may be the product of excessive tissue repair resulting from immunologic injury by effector lymphocytes. Raynaud's phenomenon is rare. A variety of autoantibodies have been reported in patients with GVHD, particularly when sclerodermatous skin changes are present, including anti-Scl-70, anti-PM-Scl, aCL, or ANCA, although their significance and clinical utility is unclear [21].

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15. Vinyl chloride disease, organic solvents and epoxy resins exposure Vinyl chloride is a gas used in the manufacture of a variety of plastics. Chronic inhalation exposure to lower levels of vinyl chloride has been found to cause Raynaud's syndrome, circulatory disturbances in the extremities, thrombocytopenia, dermatitis, sclerodermalike skin changes, pseudo-clubbing of the fingers, lytic lesions across the distal phalanges in hands and feet (acroosteolysis) with the radiological feature of a transverse line of osteolysis [29]. Skin changes in vinyl chloride disease resemble morphoea clinically and histologically while vascular changes often present with luminal narrowing and subtotal occlusion of the digital arteries. Several cases of scleroderma-like illness have been reported in patients exposed to a variety of other solvents such as toluene, benzene, xylene and white spirits. Epoxy resins are also associated with a disorder characterised by marked skin sclerosis and muscle weakness [20,29]. 16. Drug induced scleroderma-like illnesses In some rare cases a scleroderma-like disease has been described as a consequence of the administration of drugs such as bleomycin, pentazocine, cocaine, D-penicillamine, vitamin K [9], vitamin B12 [30], peplomycin [31], interferon-β1a [32], uracil-tegafur [33], paclitaxel [34], methysergide [35], gemcitabine [36]. The cutaneous manifestations vary in shape and extension and can be easily differentiated from SSc because of the absence of scleroderma-specific autoantibodies or visceral involvement. 17. Werner's syndrome Werner's syndrome is a rare autosomal recessive disorder that affects connective tissue and is characterized by precocious aging and various endocrine disturbances [9]. The main clinical features of the disease are: bird-like face, short stature with stocky trunk, very thin extremities; cushingoid appearance, disproportion between the patient's real age and the physical appearance due to premature senescence (grey hair, alopecia, bilateral juvenile cataract, hoarseness). The cutaneous lesions consist of skin atrophy and tightening, with sclerosis most prominent on the distal extremities, especially on the legs and feet. [9] The skin and subcutaneous tissue of the extremities shows epidermal thinning and dermal fibrosis with or without collagen hyalinization; newly synthesized hyalinized collagen tends to replace subcutaneous fat. No inflammatory infiltrate is usually evident.

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18. Melorheostosis and stiff skin syndrome

20. Atrophoderma of Pasini-Pierini

Melorheostosis is a rare mesodermal disease characterized by linear hyperostosis of the bone and sclerotic changes of the overlying skin. The cutaneous manifestations are usually divided in two groups: (I) vascular and lymphatic and (II) scleroderma and fibrotic contractures [37]. Melorheostosis may be seen in children and adults. The condition is often asymptomatic but joint pain, stiffness and deformity may be present, with limitations of motion. Skin biopsy is not needed because the diagnosis is usually made by plain radiograph or in equivocal cases, by bone scintigraphy [37]. Stiff skin syndrome (SSS) is a connective tissue disease of unknown origin, characterized by pronounced skin induration, mild hypertrichosis and limited joint mobility, predominantly in areas with abundant fascia, such as the buttocks and thighs [38]. The disease is present at birth or develops early in infancy. Two types of SSS have been defined, i.e. an autosomal recessive type, also known as Parana syndrome, and an autosomal dominant type. The disease is also characterized by the lack of visceral or musculoskeletal involvement and the absence of immunologic abnormalities. Histologically, the epidermis is normal. The interstitial ground substance of the upper dermis appears slightly granular and eosinophilic. No significant irregularity is noted in the deeper dermis. In some cases, mucopolysaccharide depositions may be detected. The differential diagnosis includes morphea, scleroderma and eosinophilic fasciitis. SSS generally has a good prognosis. The best management of these patients is through rehabilitation exercises to prevent contractures and restrictive pulmonary changes that may develop over time [38].

Atrophoderma of Pasini-Pierini (APP) is a benign localized form of dermal atrophy of unclear etiology, most frequently affecting young women. It begins with asymptomatic, discrete, slightly erythematous lesions, characteristically localized on the trunk, especially on the back and lumbosacral region. The face, hands and feet are generally spared. With time, the lesions develop a superficial atrophy and appear as slightly depressed areas of thin, slate-coloured or violet brown skin. The patches extend very slowly and may become confluent. Histopathologic changes are often minimal, consisting of slight sclerosis of the dermis and some collagen proliferation in the subcutis, with scarce inflammatory infiltrates. Sclerodermatous induration may be observed within the plaques during their evolution, and the association with morphea suggests that APP should be considered as an atrophic variant or an abortive form of morphea rather than a distinct entity [9]. 21. Scleroatrophic Huriez syndrome Scleroatrophic Huriez syndrome also know as Palmoplantar Keratoderma with Sclerodactyly is a rare congenital genodermatosis of autosomal dominant inheritance, characterized by scleroatrophy of the hands and feet, nail hypoplasia, palmoplantar keratoderma and hypohidrosis [40]. The development of aggressive squamous cell carcinoma of the affected skin is a distinctive feature of the syndrome, occurring in N 15% of affected individuals, mostly in the third or fourth decade of life, with a high risk of metastasis [40]. Take-home messages

19. Restrictive dermopathy Restrictive dermopathy (RD) is a rare and lethal autosomal recessive disease characterized by a thin, taut, translucent skin [39] that encases the fetus causing an intrauterine fetal akinesia deformation sequence (FADS) with multiple joint contractures. Polyhydramnios with reduced fetal movements results in premature delivery due to the anticipated rupture of the membranes. Most infants with RD die within the first days or weeks of life because of respiratory insufficiency due to thoracic stiffness. The characteristic histologic abnormalities of the skin are located in the dermis, and consist of compactly arranged collagen fibres, scant elastic fibers, and poorly developed skin appendages. The epidermal rete ridges are flattened and the dermal-hypodermal border is remarkably straight [39].

• The finding of skin thickening does not necessarily mean scleroderma/systemic sclerosis. • The etiology and pathogenesis, with the exception of a few cases, is generally unknown. • A clinical-pathological correlation may be necessary for the correct classification and diagnosis of scleroderma-like disorders. • Accurate differentiation among scleroderma-like diseases is essential for the understanding of the clinical course, prognosis, and the appropriate management. • There is no gold standard therapy: many different treatments have been reported in the literature, with sometimes contradictory results. • Physical therapy such as active and passive range of motion therapy is sometimes useful, especially in the case of joint contractures.


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