Discussion
Scleredema adultorum, also known as Buschke disease, is a rare skin disease with characterized by thickened, nonpitting sclerosis and hard skin nodules [6-8]. It is typically found on the face, neck, shoulders, and trunk, and rarely affects the hands and feet. The etiology of scleredema adultorum is currently unclear, and histopathological findings include a thickened dermis with mucin deposits between thickened collagen bundles [9]. There are three types of scleredema, including post-infection, associated with blood dyscrasias (e.g., paraproteinemia), and connected with diabetes mellitus, which is the most typical cause [10]. Chronic obesity, hyperglycemia, and a dysfunctional metabolism may all contribute to scleredema diabeticorum, the etiology of which remains unspecified. Blood glucose plays a critical role in scleredema diabeticorum, and dermal collagen is irreversibly glycosylated, leading to excessive accumulation of mucin and collagen [11]. This patient was diagnosed with diabetes mellitus at our hospital, and significant dermal thickening and mucin deposition were observed (Figure 3B, Figure 6). His diagnosis of scleredema diabeticorum was clearly established. Unlike previous cases, the skin lesions in this patient were detected prior to developing diabetes mellitus. Early detection of diabetes is therefore critical for the diagnosis and prevention of scleredema in patients.
In addition to affecting the skin, scleredema may also affect the heart, joints, tongue, bone marrow, and eyes [12]. In early reports of scleredema, myocardial involvement has been identified by focusing on alterations in the ECG [13,14]. Cardiac involvement can manifest in various ways, including cardiomyopathy and heart failure. Leinwand et al. [15] reported a case of a middle-aged female patient with scleredema. The results of the heart autopsy revealed that the patient had a rubbery rigidity in the ventricular wall. A 2001 case report described typical histologic features of sclerosing edema in a myocardial biopsy from an elderly male patient [4]. In our patient, although no myocardial biopsy was performed, cardiac involvement was evaluated by CMRI, and CMRI shows lamellar delayed enhancement of the inter-apical septum and inferior lateral wall. A previous case report [5] used CMRI to evaluate myocarditis in a patient with scleredema, but its results did not show delayed enhancement. There were few reports of cardiomyopathy associated with scleredema, and the causes of cardiomyopathy were variable. Since scleredema in our case occurred before the patient’s cardiac involvement, it should be further determined whether the patient’s cardiomyopathy resulted from a delayed start of scleredema. We will continue to follow up with the patient and complete the myocardial biopsy examination.
Notably, whole exome sequencing for hereditary cardiovascular disease was performed on our patient. The results indicated that the cysteine and glycine-rich protein 3 (CSRP3) gene pathogenicity for this patient was categorized as a Variant of Uncertain Significance (VUS). Mutations in the CSRP3, which encodes the muscle Lim Protein (MLP), are key contributors to cardiomyopathy. Previous studies have found that mutations in the human CSRP3 gene are associated with hypertrophic cardiomyopathy (HCM) [16,17]. However, as a gene classified at an intermediate level among HCM genes, there is insufficient evidence for the pathogenicity of CSRP3 and its pathogenicity remains unclear [18]. According to a study from 2020[19], the CSRP3 p. (Cys150Tyr) variant was associated with the pathogenicity of HCM, but it was different from the present case variant locus CSRP3c.301T>C (p. Ser101Pro).
Although this VUS result suggests that the gene involved is associated with the patient’s clinical indication, there is currently insufficient information to determine whether the variant itself is pathogenic. It can still complicate clinical diagnosis. We further carried out genetic tests on the patient’s family tree to clarify the pathogenicity of the gene. The results of the test revealed that no one else in the patient’s family carried the CSRP3 gene. Therefore, it is still not possible to determine whether the gene variant is pathogenic or not. We will conduct VUS and negative cases at intervals reanalysis to obtain evidence supporting the disease association.
In conclusion, it is unclear which factors contribute to cardiomyopathy in our patients. This might result from both the CSRP3 mutation and scleredema, rather than just one or the other. Further follow up on the patient’s condition to clarify the etiology of cardiomyopathy. Scleredema has an insidious onset and a good prognosis with aggressive treatment. Early detection and notification of the associated cardiomyopathy in a scleredema patient are crucial to prevent adverse outcomes. Recognition and treatment of scleredema associated cardiomyopathy are still lacking in clinical practice. Therefore, collaboration with multidisciplinary departments is essential for comprehensive understanding and treatment.