Introduction
Stiff skin syndrome (SSS) was initially described by Esterly and McKusick in 1971 [1]. It is a rare congenital disease that may resemble scleroderma-like disorders, thereby posing a significant diagnostic challenge. The onset of SSS is typically in childhood or early adolescence [2–5]. Skin areas affected by SSS have a unique texture, often compared to stone or rock-hard, and frequently display hypertrichosis or hyperpigmentation. Skin fibrosis occurs without underlying inflammation. The patients usually present with bilateral lesions favoring areas with abundant fascia, such as the lower back or thighs [5]. SSS does not involve internal organs and is not associated with immunologic or vascular aberrations [2]. However, skin induration may lead to limited joint mobility, contractures, scoliosis, and in extreme cases, thoracic restriction with ensuing respiratory distress [3].
Most cases of SSS are due to heterozygous genetic variations of FBN1, leading to decreased expression of fibrillin-1 which controls fibrosis by means of interactions with transforming growth factor-β (TGF-β) [6–8].
Recently, a segmental form of SSS has been proposed [4]. It is distinguished by a later onset, primarily unilateral involvement, and milder disease course without progression to widespread disease. Histopathology is consistent with generalized SSS. However, genetic studies usually display no FBN1 alterations [2, 9, 10]. It is considered a form of cutaneous mosaicism whose molecular background is still being elucidated.
While other scleroderma-like disorders, such as morphea or systemic sclerosis, are more commonly encountered in clinical practice, SSS should not be overlooked in the differential diagnosis. Although rare, SSS presents with unique clinical features that distinguish it from these more prevalent conditions. Recognizing the subtle differences between SSS and other scleroderma-like disorders is crucial for ensuring accurate diagnosis and appropriate management.
Objective
In this review, we aimed to summarize the extent, range and nature of the literature relating to SSS with a focus on differences between SSS and other scleroderma-like disorders. Summarizing the existing evidence may help other physicians better understand the distinct characteristics of SSS, guide accurate diagnosis, and result in more effective treatment strategies for patients affected by this rare condition. In this work, we also presented our experiences based on a new case of segmental SSS diagnosed in the Department of Dermatology, Medical University of Warsaw.
Methods
All data were collected from publicly available sources. Two bibliographic databases: PubMed and Embase were screened in August 2024 using the key word: stiff skin syndrome. Filters included studies on humans and the English language. No time restriction was set. Conference abstracts and poster sessions were excluded. The reference lists of identified studies were searched for additional articles. Duplicate studies were removed using Rayyan – a web and mobile app for systematic reviews [11]. The full text of each study was then assessed by the first author (BR). The studies were first screened based on the title and abstract and then selected for full-text review. Decisions were also recorded in Rayyan. In the “Results” section, we added a subsection entitled “Authors’ experiences”, where we presented a case report of a patient with a segmental variation of SSS and our management of this condition.
Results
In the initial search, we identified 165 records. After the automated selection of duplicates, one of the researchers (BR) manually screened the results, leading to the removal of 64 duplicate entries. This process left 101 studies for further assessment by the first author. Applying the predefined inclusion and exclusion criteria, 57 reports were selected for retrieval and further evaluated for eligibility. Ultimately, 50 articles were deemed suitable and included in this review.
The reviewed literature primarily comprises case reports/series [2–6, 8–10, 12–50], and retrospective cohort studies [51–53], underscoring the infrequency of SSS within clinical practice. A comprehensive analysis of the available data has led to the identification of 144 previously published cases of SSS. The demographic analysis reveals that females constitute a slight majority, accounting for 53% (76/144) of the documented cases. A consistent finding across many reports is the presence of joint immobility, which often occurs as a concomitant feature of the syndrome. The onset of SSS exhibits considerable variability, with cases reported as early as birth and as late as the fifth decade of life. This wide range in the age of onset reflects the heterogeneity of the disorder and suggests that SSS can manifest across a broad spectrum of life stages.
Authors’ experiences
An additional case of segmental SSS ultimately diagnosed in the Department of Dermatology, Medical University of Warsaw is reported below.
A 34-year-old patient presented with disseminated areas of skin fibrosis associated with mild hyperpigmentation and hypertrichosis (fig. 1). The lesions started approximately at 2 years of age and were initially unilateral, located on the right shoulder, arm, lumbar region, hip, and thigh (fig. 2). The patient had been treated with oral and subcutaneous methotrexate (at a maximum dose of 25 mg/week), oral chloroquine, prednisone, trimethoprim/sulfamethoxazole and penicillamine with no improvement. After approximately 20 years of spontaneous disease stabilization, the patient developed contralateral lesions located on the left arm, hip and thigh. The skin lesions were accompanied by restricted shoulder mobility (fig. 3) and fixed contractures in the hip, knee, and ankle joints, more prominent on the right side.
Capillaroscopy was normal. Indirect immunofluorescence initially demonstrated antinuclear antibodies with a speckled pattern at the titer of 1 : 160, but two subsequent tests were negative. The immunoblot assay for systemic sclerosis also produced a negative result. The patient underwent two magnetic resonance imaging (MRI) scans of the left and subsequently the right thigh, respectively. The first test did not demonstrate any alterations. The second MRI revealed slight fatty remodeling of the muscles, degenerative and proliferative changes in the hip joints predominantly on the right side, and slightly increased amount of fluid in the right knee joint. Chest X-ray was normal aside from a slightly higher position of the left hemidiaphragm and small triangular opacities adjacent to the right diaphragmatic outline possibly corresponding to pleural adhesions or fibrous bands. Abdominal and skin ultrasound was normal.
Several cutaneous biopsies were performed. The first biopsy displayed normal epidermis and thickened dermis with a normal number of skin appendages. In the subcutaneous tissue, significantly thickened connective tissue septa devoid of inflammatory infiltrate and single sclerotic vessels were noted, accompanied by fascial sclerosis. Two subsequent skin biopsies of the right lumbar area exhibited prominent undulating and basal hyperpigmentation of the epidermis (fig. 4 A). The dermis displayed swollen collagen bundles, normal vasculature and preserved skin appendages. There were signs of adipose tissue entrapment between collagen fibers up to the level of sebaceous glands (fig. 4 B). Staining with Alcian blue and PAS did not reveal increased mucin deposition in the dermis (fig. 4 C). Genetic testing for FBN1 alterations was negative.
Based on the clinical picture, histology and negative genetic assay, a diagnosis of segmental SSS was made.
The patient was started on systemic losartan 50 mg/day due to his reproductive plans, followed by mycophenolate mofetil 2 g/day with a slight improvement in joint mobility and cutaneous sclerosis.
Discussion
SSS is a congenital, noninflammatory scleroderma-like disorder [4]. Clinical features differentiating SSS from similar entities involve the presence of lesions on the areas with abundant fascia, ensuing joint contractures and hypertrichosis [3]. These features are crucial for establishing a correct diagnosis. Based on Varju et al. article [54], we made a table with differential diagnoses of SSS and other scleroderma-like conditions (table 1). In this context, the presented patient had been initially misdiagnosed with late-stage morphea.
Widespread SSS has been associated with a genetic variation of the FBN1 gene, restricting the activation and signaling of TGF-β which leads to fibroplasia [7]. However, this abnormality has not been confirmed in the recently distinguished segmental form, characterized by predominantly unilateral lesions and a milder disease course [2, 9]. Based on several reports, it seems that IL-17C abnormalities as well as other mechanisms associated with impaired TGF-β signaling may be involved [6, 10].
Therapeutic options for SSS remain limited. Physical therapy is crucial to prevent joint contractures and preserve overall quality of life [35, 36]. Pharmacological treatment is used to limit the profibrotic activity of TGF-β [45]. In line with this, several papers demonstrated efficacy of mycophenolate mofetil (MMF) and losartan [9, 35, 45]. The mechanism of action of MMF involves reducing the proliferation of fibroblasts by inhibiting the formation of guanine nucleosides [55]. Losartan probably acts through preventing increase in thrombospondin-1 levels by disrupting the binding of angiotensin II to its receptor, which helps to reduce the activation of TGF-β [56]. Other treatment modalities including methotrexate, cyclosporine, penicillin-G, D-penicillamine, glucocorticosteroids, intravenous immunoglobulin and narrowband ultraviolet B light therapy were found to be ineffective in treating SSS [36]. With respect to segmental SSS, beneficial effects of secukinumab, a fully humanized anti-IL-17A antibody, were reported in the aforementioned case with underlying IL-17C mutations [10]. However, due to elusive disease background, it is uncertain whether other patients without confirmed IL-17C mutations would benefit from such treatment.
Conclusions
Stiff skin syndrome should be considered in individuals with early-onset non-inflammatory skin sclerosis on the areas with abundant fascia, joint contractures and hypertrichosis. Segmental form may have an indolent course, which particularly often leads to misdiagnoses. At the same time, segmental stiff skin syndrome is not associated with FBN1 gene alterations causing the widespread phenotype. Therefore, the diagnosis should be based on the clinico-pathological correlation. There are limited data on the efficacy of various therapeutic interventions, but physical therapy and medications inhibiting TGF-β-induced skin sclerosis such as losartan and mycophenolate mofetil have been demonstrated to alleviate joint contractures and disease progression in some individuals.
Funding
No external funding.
Ethical approval
Not applicable.
Conflict of interest
The authors declare no conflict of interest.
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