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.