CID-07396; No of Pages 15 Clinics in Dermatology (xxxx) xx, xxx Sclerodermalike syndromes: The great imitator Cecília Varjú, MD, PhD a, Gábor Kumánovics, MD, PhD a, László Czirják, MD, PhD a, Marco Matucci-Cerinic, MD, PhD b, Tünde Minier, MD, PhD a,⁎ aDepartment of Rheumatology and Immunology, University of Pécs Clinical Center, Pecs, Hungary bDepartment of Experimental and Clinical Medicine, Division of Rheumatology, Florence, Italy Abstract Sclerodermalike syndromes (SLSs) comprise diseases with mucin deposition (eg, scleromyxe- dema, scleredema), with eosinophilia (eg, eosinophilic fasciitis), metabolic or biochemical abnormalities (eg, nephrogenic systemic fibrosis), or endocrine disorders (eg, POEMS syndrome, or polyneuropathy, organomegaly, endocrinopathy, monoclonal lymphoproliferative disorder, and hypothyroidism). Chronic graft-versus-host disease may also show sclerodermalike skin changes. Inherited progeria syndromes with early aging (eg, Werner syndrome) and a heterogeneous group of hereditary disorders with either skin thickening (eg, stiff skin syndrome) or atrophy and tightening (eg, acrogeria) can also imitate classic systemic sclerosis (SSc). In addition, SLSs can be provoked by several drugs, chemicals, or even physical injury (eg, trauma, vibration stress, radiation). In SLSs, the distribution of skin involvement seems to be atypical compared with SSc. The acral skin involvement is usually missing, and lack of Raynaud phenom- enon, scleroderma-specific antinuclear antibodies, the absence of scleroderma capillary pattern, and inter- nal organ manifestations indicate the presence of an SLS. Skin involvement is sometimes nodular, and the underlying tissues can also be affected. For the differential diagnosis, a skin biopsy of the deeper layers including fascia and muscle is required. Histology does not always allow differentiation between SSc and SLSs; therefore, the diagnosis is often based on the distribution, quality of cutaneous involvement, and other accompanying clinical features. © 2019 Elsevier Inc. All rights reserved. Introduction collagen and intercellular matrix formation in the dermis and by edema probably caused by both microvascular injury fl Systemic sclerosis (SSc) is characterized by vascular ab- and some in ammation. With the accumulation of collagen fl normalities, fibrosis, inflammatory changes, and late stage and uid, the skin becomes thickened, making it impossible tissue atrophy. The pathology of SSc is complex and includes to pinch it into a normal skin fold. In the next indurative as a hallmark of disease skin fibrosis called scleroderma.1 phase, the skin also becomes shiny, taut, and adherent to The distribution of the skin involvement in SSc is very char- the subcutis, whereas in the late stage, the skin appears thin, acteristic, and the acral regions including the digits are almost atrophic, and often tightly tethered to the underlying tissue. fi always involved.2,3 Skin thickness is caused by increased Apart from the characteristic skin brosis, additional clin- ical manifestations are also suggestive of SSc. Raynaud phe- ⁎ Corresponding author. Tel.: +36 72536802. nomenon is present in almost all patients with SSc, although E-mail address: [email protected] (T. Minier). it may be missing in some early diffuse SSc cases at disease https://doi.org/10.1016/j.clindermatol.2019.10.010 0738-081X/© 2019 Elsevier Inc. All rights reserved. 2 C. Varjú et al. onset.2 Another hallmark of SSc is the presence of involvement and organ involvement is also crucial in the dis- scleroderma-specific antinuclear antibodies (anticentromere, tinction of idiopathic scleroderma that forms from scleroder- anti–topoisomerase 1, anti–RNA polymerase III). Patients malike diseases. A biopsy, involving deep skin layers, fascia, with SSc usually exhibit characteristic nailfold capillaro- and even muscle, is almost mandatory for the differential scopy findings, including capillary dropout and giant capil- diagnosis. laries.4 Scleroderma nailfold capillary pattern is present in approximately 90% of the SSc cases.2 In the majority of pa- tients, fibrosis, vasculopathy, and inflammation also lead to typical organ manifestations, including interstitial lung SLSs with mucin deposition disease, pulmonary hypertension, scleroderma renal crisis, heart involvement, digital ulcers, synovitis, and variable Scleromyxedema gastrointestinal involvements, which define the prognosis of the disease.2,5 Scleromyxedema is an orphan disease14 which belongs to Sclerodermalike syndromes (SLSs) mimic idiopathic SSc, the inflammatory mucinoses. It is often associated with other because they exhibit skin findings that include either the clas- diseases including hematologic malignancies,15 hepatitis C, or sic early skin thickening or late skin tethering and atrophy HIV infection16,17 and with connective tissue disorders18,19 in- present in SSc.6–13 Several important signs may also indicate cluding scleroderma.20 The affected patients are middle aged that the patient does not have SSc, but rather another SSc-like without any sex or race predominance.21 Scleromyxedema is disorder. The lack of Raynaud phenomenon, a negative characterized by waxy indurated papules with marked skin screening test for antinuclear antibodies, or the absence of sclerosis and induration.21–23 Initially clusters of papules and scleroderma pattern on nailfold videocapillaroscopy may be diffuse plaques appear symmetrically on the face, neck, upper a valuable indicator of the presence of a sclerodermalike part of the trunk, forearms, and hands. These particular erup- disease. Lack of typical internal organ manifestations may tions may be erythematous or hyperpigmented. As the disease also indicate the presence of a sclerodermalike disorder. progresses, a diffuse, symmetric skin involvement appears. The skin involvement in SLSs tends to begin superficially The presence of diffuse, waxy papules in linear arrays and in andprogressesintothedeeptissues,oftenaffectingthe a characteristic distribution that includes the glabella and poste- deeper layers including subcutaneous tissue and fascia. rior auricular area are the leading clinical manifestations of The nature, quality, and distribution of skin involvement scleromyxedema.14 The extensive facial mucin deposition and are pivotal elements in the differential diagnosis of these par- involvement of the glabella may cause an appearance of the ticular disorders (Figure 1). The presence of musculoskeletal so-called leonine face.24 The deep furrowing is also classically Fig. 1 Predilection sites of skin involvement in sclerodermalike syndromes. Reproduced with permission from L. Czirják. Scleroderma 3 palpable on the trunk and extremities, being known as the Scleroderma adultorum of Buschke “Shar-Pei sign.”21 The palms, scalp, and mucous membranes are spared. Scleroderma adultorum of Buschke is characterized by Myopathy of the proximal muscles, esophageal dysmoti- firm, nonpitting edema that typically begins at the neck and lity, polyarthritis, pulmonary involvement, central and pe- spreads to the back, shoulders, and face (Figure 2). The hands ripheral nervous system clinical manifestations, and rarely and feet are characteristically spared.12,23 Scleredema has Raynaud phenomenon, may also occur.21,25,26 Cases with also been described in association with various infections, severe acute central nervous system syndrome and encepha- paraproteinemia, or diabetes mellitus54; however, sclere- lopathyhavebeenreportedmanytimes.27,28 The disease dema may also be idiopathic.55 course in most of the cases is progressive,21 and a lethal Type 1 scleredema is an acute disease usually developing course has been also described.29,30 a few weeks after a bacterial or a viral respiratory infection, – Monoclonality in the serum is a common finding,31 36 mainly in childhood, and completely resolves within a few which is predominantly immunoglobulin G (IgG), lambda months to 2 years.23,56 Skin involvement develops quickly type.15,37 Occasionally, IgG kappa, IgM lambda, or IgA on the neck, then symmetrically spreads distally to the whole lambda and kappa types may be present.38,39 There can be trunk and around the shoulders. About 60% of this type of both improvement and remission both in monoclonality and scleredema is triggered by Streptococcal infections, with ele- clinical findings in a patient after an autologous stem cell vated anti–streptolysin O titer in the serum, and mild anemia. transplantation, perhaps indicating a potential causative role One pathogenetic hypothesis suggests that scleredema may of paraproteinemia in skin clinical manifestations and other develop due to direct actions of bacterial toxins and adrenal organ manifestations.40 The paraprotein levels may not cor- steroids released in response to the infection.56,205 Ultraso- relate with the severity or progression of the disease or the re- nography examination with a high-frequency linear array sponse to treatment in a multicenter study.21 transducer of 12.0 to 15.0 MHz is able to identify the thick- With regard to pathogenesis, it is very likely that the fibro- ened skin in a prone position, owing to the anatomic location blasts are active and produce large amounts of mucin.41,42 It is also widely accepted that the circulating cytokines (tumor necrosis factor alfa, transforming growth factor beta, and in- terleukin [IL] 1) may also play a role in the pathogenesis of scleromyxedema. These are proinflammatory cytokines and have a stimulatory effect on fibroblasts to produce glycos- aminoglycans,21