Abstract
Background
Acute myocarditis, often linked to viral infections and autoimmune processes, significantly contributes to sudden cardiac death in young adults. Recurrent episodes can result from genetic mutations, particularly involving desmosomal proteins like desmoplakin ( DSP ). An accurate genetic diagnosis is essential for proper patient management.
Case summary
We present a case of a 14-year-old Caucasian male with recurrent chest pain and elevated troponin. His maternal history was notable for recurrent myocarditis. Genetic testing revealed a novel DSP variant c.2917G > T p.Glu973* in heterozygosity, classified as likely pathogenic and associated with cardiomyopathy, woolly hair, keratoderma, and tooth agenesis (MIM: 615821 ). Initial treatment with colchicine, prednisolone, and azathioprine managed to control symptoms but failed to prevent recurrence. Mycophenolate mofetil was later introduced, leading to a more sustained improvement.
Discussion
Recent literature linked DSP mutations to cardiomyopathies with high risks of arrhythmias and heart failure. While current management focuses on optimizing the underlying cardiovascular hemodynamic burden, this case highlights the potential utility of immunosuppressive therapy. Further research is needed to clarify its role in modifying disease progression.
Conclusion
DSP mutations should be considered in recurrent myocarditis. Early molecular diagnosis and tailored immunosuppressive strategies may help mitigate fibrosis and improve long-term outcomes.
Graphical abstract
Highlights
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Recognizing the importance of conducting genetic testing in cases of recurrent myocarditis
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Highlighting the value of family history assessment in cases of recurrent myocarditis
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Appreciating the role of cardiac MRI in evaluating myocarditis patients
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Acknowledging the limited understanding regarding preventive measures for recurrent myocarditis
1
History of presentation
A 14-year-old Caucasian male presented with his 7th episode of intense retrosternal oppressive pain, unresponsive to acetaminophen. Occasionally, he experienced nocturnal chest pain, palpitations, and diarrhea. He denied concurrent fever, respiratory symptoms, joint pain, skin changes, or weight loss. Throughout, he remained hemodynamically stable, with no respiratory distress. Blood work showed a troponin I of 6842 ng/L and NT-proBNP of 96 pg/mL, with normal inflammatory markers. The electrocardiogram (ECG) revealed incomplete right bundle branch block (RBBB) and two premature ventricular contractions (PVCs). Transthoracic echocardiography was normal. Based on the clinical and analytical findings, these episodes were interpreted as recurrent myocarditis/myopericarditis. Due to a similar maternal past medical history, both were referred to a genetics consultation.
2
Past personal and family medical history
In addition to the previous six episodes spanning from July 2021 to February 2024 ( Table 1 ), a 24-h Holter revealed a period of non-sustained ventricular tachycardia and frequent PVCs (a total of 1183 events). He was started on bisoprolol 2.5 mg, which was suspended due to symptomatic bradycardia. His 41-year-old mother was diagnosed with ulcerative colitis at the age of 20 and has had 29 episodes of myocarditis/myopericarditis since then.
| Year | Age | Symptoms | Duration of symptoms | Maximum troponin I/at discharge | ECG findings | Echocardiographic findings | Treatment | Length of hospital stay | |
|---|---|---|---|---|---|---|---|---|---|
| 1st episode | 2021 | 11 yr + 6 mths | Chest pain, palpitations, occasional vomiting | 5 days | 25,259 ng/L/15192 ng/dL | Negative T wave in avR, mild ST segment depression in V1 to V3, RBBB | Mild alterations in contractility in the posterior and lateral basal walls (GLS -16.9 %), thin layer of pericardial effusion | Ibuprofen Esomeprazole | 4 days |
| 2nd episode | 2022 | 12 yr + 1 mth | Chest pain, occasional diarrhea | 7 days | 10,632 ng/L/163 ng/dL | Mild ST segment depression in V3, RBBB | No abnormalities | Ibuprofen Esomeprazole | 9 days |
| 3rd episode | 2022 | 12 yr + 6 mths | Chest pain | 5 days | 4732 ng/L/144 ng/L | ST segment elevation in V1 to V3 and PR segment depression in DI and DII | Pericardial effusion (more anterior) | Ibuprofen Esomeprazole Colchicine | 4 days |
| 4th episode | 2022 | 12 yr + 7 mths | Chest pain | 3 days | 16,528 ng/L/70 ng/L | Intraventricular conduction disturbance (notch) in leads DII, DIII, avF. Negative T waves in V1 toV3, RBBB | No abnormalities | Ibuprofen Esomeprazole Colchicine | 9 days |
| 5th episode | 2022 | 12 yr + 8 mths | Chest pain, occasional vomiting | 3 days | 21,265 ng/L/287 ng/L | Intraventricular conduction disturbance (notch) in leads DII, DIII, avF. Negative T waves in DII, avF and V1 toV2, RBBB | No abnormalities | Ibuprofen Esomeprazole Colchicine Azathioprine | 9 days |
| 6th episode | 2023 | 13 yr + 2 mths | Chest pain | 3 days | 4363 ng/L/268 ng/L | Intraventricular conduction disturbance (notch) in leads DII, DIII, avF. Negative T waves in V1 toV3, RBBB | No abnormalities | Ibuprofen Esomeprazole Colchicine Azathioprine | 4 days |
| 7th episode | 2024 | 14 yr + 1 mth | Chest pain, palpitations | 3 days | 6842 ng/L/24 ng/L | 2 PVCs, RBBB | No abnormalities | Ibuprofen Esomeprazole Colchicine Prednisolone | 9 days |
3
Differential diagnosis
Considering its incidence, a viral infection was considered as a possible cause. Autoimmune conditions, such as systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis, as well as autoinflammatory syndromes like familial Mediterranean fever [ ] and Behçet’s disease [ ], were also contemplated due to their potential to cause recurrent chest pain and their relative familial associations. These diseases can present with various types of cardiac involvement, including serositis, myocarditis, pericarditis, valvular disease, and arrhythmias. Additionally, although unlikely given the patient’s age, coronary artery disease was also considered in the differential diagnosis.
4
Investigations
Chest X-rays routinely performed during each episode were consistently normal. Serological tests and Polymerase Chain Reaction (PCR) analysis of peripheral blood for various viral pathogens, including parvovirus B19, adenovirus, enteroviruses, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and herpesvirus type-6, were negative. Similarly, respiratory secretions PCR, as well as virus stool testing for rotavirus, adenovirus, and norovirus, were also negative. Autoimmunity studies, including antinuclear antibodies (ANA), anti-double stranded DNA (anti-dsDNA), anti-Ro/La antibodies, and antineutrophil cytoplasmic antibodies (ANCA), were normal. Additionally, levels of serum complement components C3 (0.96 g/L) and C4 (0.19 g/L), as well as serum amyloid A (0.1 mg/dL), were within normal ranges.
A cardiac magnetic resonance imaging (MRI) conducted after the second episode revealed, on the T2-weighted images, edema in the mid-antero and mid-infero septal walls, along with late intramural enhancement at the same locations ( Fig. 2 a). The extent of these findings was not quantified, as it is a feature not routinely available in the protocol utilized. A second MRI performed six months later showed, in T2-weighted images with and without fat suppression, an extensive intramyocardial hyperintensity, encompassing a larger area involving the basal segment (anterior, septal, and posterior walls), midventricular segment (anterior, antero-septal, and posterior walls), and apical segment (postero-septal and posterior walls) ( Fig. 2 a).
Given the low likelihood of coronary artery disease, supported by normal ECG and echocardiogram, cardiac catheterization was not performed. Likewise, due to the risks associated with endomyocardial biopsy and the uncertainty that its findings would alter the treatment approach, this procedure was not conducted. At the age of 39, the patient’s mother presented an echocardiogram showing preserved biventricular function and the left ventricle’s dimensions to be at the upper limit of normal. As found in her offspring, a cardiac MRI displayed myocardial edema and fibrosis.
Genetic testing initially identified a variant of uncertain significance (c.1016C > T; p.[Ser339Phe]) in heterozygosity in the MEFV gene. To further investigate, duo whole exome sequencing (WES) was performed on the patient and the patient’s mother. This analysis revealed a shared heterozygous variant, c.2917G > T; p.(Glu973*), in the DSP gene (NM_004415.3). This variant was classified as pathogenic according to ClinVar (Variation ID: 2033289). Furthermore, based on CENTOGENE’s implementation of guidelines from the American College of Medical Genetics and Genomics (ACMG), the Association for Molecular Pathology (AMP), and the Clinical Genome Resource (ClinGen), there is strong evidence supporting the association of this variant with disease. The identified variant is linked to dilated cardiomyopathy, woolly hair, palmoplantar keratoderma, and tooth agenesis (DCWHKTA, MIM: 615821 ). Segregation studies were subsequently performed on the patient’s maternal grandfather and uncle. Both were found to carry the same DSP variant and exhibit phenotypes, including woolly hair and keratoderma; however, neither presented with cardiac manifestations.
5
Management
Initial treatment with ibuprofen proved effective; however, subsequent recurrences required colchicine (1.5 mg once daily) and prednisolone (0.5 mg per kilogram per day). Despite the introduction of azathioprine during the fifth episode as a steroid-sparing immunosuppressant and in order to prevent further recurrences of myopericarditis [ ], two additional episodes occurred. The mother initially received azathioprine therapy primarily for the inflammatory bowel disease. However, ongoing chest pain episodes, recognized as uncontrolled extra-intestinal manifestations, prompted a transition to infliximab and colchicine. This resulted in a favorable response for both the intestinal and cardiac manifestations, with only one subsequent myocarditis episode in the last two years.
Following the seventh episode, a multidisciplinary evaluation involving the pediatric cardiology and rheumatology teams led to the introduction of mycophenolate mofetil (MMF) at a dose of 250 mg once daily, with a plan for a slow progressive increase until reaching a target dosage of 667 mg per m 2 per day. Concurrently, the patient began tapering off oral prednisolone, which was discontinued three months after MMF initiation. Due to the arrhythmogenic risk associated with the identified genetic condition, treatment with bisoprolol 2.5 mg was reinstated and well-tolerated.
6
Discussion
DSP gene encodes desmoplakin, a key protein constituent of desmosomes, essential for maintaining cellular structural integrity, particularly in tissues subjected to mechanical stress like the heart and skin. DSP is a crucial cardiac protein involved in force transmission within the myocardium. The described variant c.2917G > T p.(Glu973*) in the DSP gene is a nonsense variant that introduces a premature stop codon, leading to the early truncation of the protein and resulting in a non-functional protein. Variants causing DSP loss of function lead to alterations in intercellular adhesion and are more likely to result in severe forms of cardiomyopathy. However, the precise impact of these mutations and their molecular pathology often remain elusive due to a lack of expression and functional studies. Besides cardiac phenotypes, missense and loss-of-function variants have been linked to rare cardiocutaneous phenotypes with both autosomal recessive and autosomal dominant inheritance patterns [ ]. These conditions can manifest as skin fragility, palmoplantar keratoderma, various hair anomalies from complete alopecia to woolly hair, cardiac anomalies, and, in some instances, tooth agenesis varying from a single missing tooth to marked oligodontia. Hair anomalies are typically present in neonates, while palmoplantar keratoderma develops gradually. Notably, both our patient and his mother exhibited tightly woolly hair ( Fig. 1 b ), and the adolescent was already under dental care for still having deciduous teeth. Upon examination, the adolescent showed only minor thickening of the skin on the soles ( Fig. 1 a), although the patient’s mother mentioned that her brother had substantial thickening of the skin on the palms and soles.
