Hypertrophic cardiomyopathy associate with a PLN gene mutation in a child: a case report

Introduction

Background

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease caused primarily by mutations in genes encoding sarcomere proteins and related sarcomere components (1,2). While, mutations in genes involved in calcium metabolism, such as the calpain gene phospholamban (PLN), are rare and are found in less than 1% of patients (3). The pathophysiological mechanism of the disease is complex, and the clinical manifestations and disease progression of different patients are significantly different (4,5).

Rationale and knowledge gap

Despite the low prevalence (<1%) of PLN mutations affecting calcium metabolism in HCM patients (3), and the absence of documented pediatric cases, investigating these rare variants remains essential for elucidating core pathophysiological mechanisms. It is critical to clarify the role of PLN mutations in early-onset cardiomyopathy to improve diagnosis and management in pediatric patients.

Objective

By analyzing the PLN gene mutation, the pathogenesis and treatment strategies are explored, aiming to enhance pediatricians’ understanding of the disease and promote early diagnosis and treatment. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-264/rc).

Case presentation

The 13-year-old male patient was admitted to the hospital for the first time due to “skin pallor” for more than 1 year and 5 months. The child presented with microcytic hypochromic anemia, occasional cough, no hemoptysis, and no shortness of breath. The child was preliminarily diagnosed as mild thalassemia complicated with iron deficiency anemia, and was given iron supplementation. Hemoglobin can gradually rise, reticulocytes are normal. During hospitalization, the child complained of chest pain, and 12-lead electrocardiogram (ECG), echocardiogram and cardiac magnetic resonance (CMR) were completed. Echocardiogram (Figure 1A,1B) showed: thickening of the anterior septal basal segment, with the maximum thickness of 14 mm and a Z-score of 5.6 (Boston standard); obstruction of left ventricular outflow tract (dynamic); moderate mitral regurgitation [considered to be caused by systolic anterior motion (SAM) sign]; mild regurgitation of tricuspid valve, aortic valve and pulmonary valve; normal systolic function of left ventricle and right ventricle; tissue Doppler imaging (TDI) spectrum of mitral annular septum showed: e'>a', e'=10 cm/s, left ventricular diastolic function was normal. Holter ECG showed sinus rhythm, heart rate (HR): 51–158 bpm, mean: 79 bpm, with occasional sinus arrhythmia; 17 single premature atrial beats were detected, show early repolarization. The result of CMR (3.0 T) (Figure 1C,1D) showed: thickening of the anterior septal basal segment, with 14 mm in large diameters, and the size of the left atrium and ventricle were within the normal range, normal range of left ventricular global systolic motor function, the size of right atrium and ventricle is within normal range, normal range of right ventricular global systolic motor function, and mild mitral regurgitation. The possibility of diagnosis of “hypertrophic cardiomyopathy” was added. A 12-lead ECG (Figure 1E) showed sinus arrhythmia, high left ventricular voltage, and early repolarization changes. After treatment with metoprolol (12.5 mg/bid) and captopril (6.25 mg/q8h), the child’s symptoms of pallor, cough and chest pain were improved. After discharge, the child continued to take metoprolol and captopril orally. The child was admitted for the second time 10 months later due to “repeated chest pain and elevated troponin”. The quantitative level of troponin I (0.111 µg/L) was significantly elevated, and cardiac markers creatine kinase isoenzyme, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were normal. Whole exome gene sequencing of the child (Figure 2A): The subject was detected to carry a missense mutation of PLN gene on chromosome 6, which was NM_002667.5:c.106T>C (p.Cys36Arg), heterozygous mutation. The phenotype (HCM, etc.) of the subject was generally consistent with that of diseases such as HCM 18 (OMIM# 613874) caused by pathogenic variations in the PLN gene. The patient was diagnosed with “hypertrophic cardiomyopathy and myocardial damage”, and continued to receive metoprolol and captopril, and was additionally treated with vitamin C, fructose diphosphate (1 g/tid), levocarnitine (1 g/bid) and coenzyme Q10 (10 mg/bid) for cardiac protection; meanwhile, captopril and metoprolol were continued to improve cardiac function, and the dose of metoprolol was increased to 16.7 mg/bid. Leflunomide (10 mg/qd) and total glucosides of white paeony capsules (0.3 g/qd) were added to regulate immunity, supplemented with adenosine triphosphate (ATP) tablets (20 mg/tid) to improve metabolism and calcium supplement; the frequency of chest pain decreased, the troponin I value (0.031 µg/L) was declining compared with previous result, while the value was still slightly high. During hospitalization, the child had good compliance during medication. No obvious adverse reactions were observed during the treatment period.

Figure 1 The patient’s examinations, including echocardiogram, CMR, and ECG. (A,B) The echocardiograms of a pediatric patient with thickening of the anterior basal septal segment, demonstrating a maximum thickness of 14 mm and a Z-score of 5.6. (C,D) CMR images of the same patient, in which interventricular septal thickening is visible on both four-chamber and short-axis views, with a maximum thickness of approximately 14 mm. (E) A 12-lead ECG, revealing sinus arrhythmia, left ventricular high voltage, and early repolarization changes. CMR, cardiac magnetic resonance; ECG, electrocardiogram.

Figure 2 Genetic testing of the patient and his father. (A) The whole gene analysis of the patient, which identified a heterozygous missense variant in the PLN gene on chromosome 6: NM_002667.5:c.106T>C (p.Cys36Arg). (B) The patient’s father carries the same mutation locus. PLN, phospholamban.

The mother of the child had a history of mild anemia, and the father had a history of similar chest pain and palpitation. It was verified that the mutation of PLN gene of the child originated from the father (Figure 2B), and the mother did not carry the mutation of PLN gene locus.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Patient perspective

Since I became ill, I have been feeling weak, chest tightness and later chest pain. After diagnosis, doctors confirmed that I had thalassemia and HCM, and I started medication and regular monitoring. After several weeks of treatment, my chest tightness and chest pain decreased from frequent to occasional, and my breathing became much smoother.

Discussion

Key findings

According to recent studies and guidelines, HCM is an inherited heart disease characterized by cardiac hypertrophy, particularly left ventricular hypertrophy, asymmetry of hypertrophy, and early left ventricular outflow tract obstruction. In our clinical observations, children with HCM tended to exhibit elevated troponin I levels, which were associated with myocardial damage. After early diagnosis, the timely use of β-blockers, angiotensin converting enzyme inhibitors and other treatment methods can effectively reduce the degree of myocardial hypertrophy, restore the level of troponin I to normal, and control clinical symptoms.

Early studies have shown that certain mutations in the PLN gene may be associated with the development of HCM, mutations at amino acid residue 9 (p.Arg9Cys and p.Arg9Leu) of the PLN gene have been found to be associated with cardiac hypertrophy in HCM patients (6). These mutations may affect the regulation of intracellular calcium by changing the phosphorylation state of PLN, which may lead to cardiac hypertrophy. Patients with HCM due to mutations in the PLN gene often present with cardiac hypertrophy, especially in the apex. Clinical symptoms in these patients may include dyspnea, chest pain, and syncope. Patients with PLN mutations may exhibit more pronounced diastolic dysfunction in cardiac function than other types of HCM. In addition, patients with PLN gene mutations may also develop cardiac arrhythmias, particularly non-sustained ventricular tachycardia (7). This suggests that mutations in the PLN gene may be different from other types of HCM and have a higher risk of disease progression.

Strengths and limitations

Strengths is identifying PLN mutations in the child’s HCM and providing valuable treatment of cardiac function, avoiding serious cardiovascular outcomes. Limitations of our study include a lack of long-term follow-up data on HCM and thalassemia treatment outcomes.

Comparison with similar researches

Gao et al. reported one adult female patient with HCM has previously been reported to carry the same PLN mutation (p.Cys36Arg), while no more details have been documented (8). Haghighi et al. first described the p.Leu39Ter mutation in the PLN gene (9). Two families with hereditary heart failure. In this study, a pair of brothers and sisters carrying the homozygous state of the PLN gene p.Leu39Ter variant developed dilated cardiomyopathy and heart failure and required heart transplants at the age of 16 and 27 years, respectively. Landstrom et al. (10) reported a PLN mutation in HCM in a 58-year-old man with a positive family history, diagnosed at the age of 51 years with septal and apical hypertrophy, maximum left ventricular wall thickness of 24 mm, Wolf-Parkinson-White syndrome, left atrial enlargement, sinus bradycardia, conduction block, ventricular ectopia with symptomatic non-sustained ventricular tachycardia, and paroxysmal atrial fibrillation/flutter.

Explanations of findings

The most common electrocardiographic change in HCM is the presence of left ventricle hypertrophy, Q-and T-wave abnormalities as a voltage criterion, and in our case, the presence of left ventricle high voltage, early repolarization-like changes in the electrocardiographic pattern is consistent with this typical change. ST-T changes gradually appeared in the child, confirming myocardial damage in the child.

In HCM, abnormal hypertrophy of cardiomyocytes occurs due to genetic or other causes. Hypertrophy of cardiomyocytes leads to the stretching and distortion of intracellular structure, which destroys the original normal cytoskeleton structure and cell membrane integrity of cardiomyocytes (1). Troponin I, as an important component of cardiac contractile protein, forms actin-tropomyosin complex together with actin and tropomyosin, and participates in cardiac contractile process. When cardiac muscle cells are structurally damaged, the structure and function of this complex are also affected, resulting in the release of troponin I from damaged cardiac muscle cells into the bloodstream, resulting in elevated serum troponin I levels (11). Children with HCM are often associated with left ventricular outflow tract obstruction, which causes the left ventricle to overcome greater resistance to ejection (12). In this case, the patient had left ventricular outflow tract obstruction. Prolonged left ventricular outflow tract obstruction can lead to abnormal mechanical stress on cardiomyocytes, resulting in hypertrophy, degeneration and injury of cardiomyocytes. This mechanical stress can directly destroy the structure and function of cardiomyocytes, resulting in the release of troponin I (12). In addition, mechanical stress can also induce apoptosis and inflammation of cardiomyocytes by activating mechanosensitive signaling pathways in cardiomyocytes, further aggravating myocardial injury and troponin I elevation. At the same time, the increase of ventricular wall tension also activates many signaling pathways in cardiomyocytes, such as RhoA/ROCK signaling pathway, and the abnormal activation of these signaling pathways will further aggravate the injury of cardiomyocytes and the increase of troponin I (4).

Although echocardiography is a first-line imaging modality in cardiology practice, it has limited sensitivity to complex structural changes occurring in the myocardium. In contrast, CMR imaging, as a non-invasive technique, provides a more accurate assessment and can be more effectively differentiated from other cardiac disorders. Current guidelines emphasize the role of genetic counseling, genetic testing, and cascade screening in HCM (13,14), and since HCM is often autosomal dominant, identifying pathogenic or potentially pathogenic variants can help to better predict disease outcomes, provide a basis for prenatal planning, and determine the need for follow-up of future relatives.

Implications and actions needed

Children with chronic chest pain should have a comprehensive workup, including imaging and genetic testing. In clinical practice, HCM children should be routinely detected myocardial enzymes, early identification of myocardial damage, reasonable heart care treatment.

Conclusions

Management of patients with unexplained left ventricle hypertrophy, particularly young children with cardiomyopathy, demands multimodal imaging coupled with molecular genetic analysis, genetic testing facilitates early HCM diagnosis and treatment by identifying patients pre-symptomatically, thereby enabling prompt intervention.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-264/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-264/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-264/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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