Clinical characteristics of 41 children with hypertrophic cardiomyopathy: A single-center retrospective study

Abstract

Objective

To analyze the clinical characteristics, etiological composition, genetic variations, and survival outcomes of children with hypertrophic cardiomyopathy.

Materials and methods

This retrospective study included 41 pediatric patients diagnosed with hypertrophic cardiomyopathy at The First Affiliated Hospital of Guangxi Medical University from 2013 to 2024. Clinical data were reviewed, including symptoms, echocardiography, electrocardiography, genetic testing, and follow-up outcomes. Comparisons were made between patients with primary and secondary hypertrophic cardiomyopathy.

Results

Among the 41 patients, 27 were men and 14 were women, with a median age at onset of 4 years and 3 months. Genetic testing was performed in 24 cases, identifying 13 cases of primary hypertrophic cardiomyopathy and 11 cases of secondary hypertrophic cardiomyopathy, most commonly associated with Noonan syndrome. The most frequent symptoms were fatigue (28.95%) and dyspnea (23.68%). Common pathogenic genes in primary hypertrophic cardiomyopathy included MYH7 and MYBPC3. Echocardiography revealed asymmetric interventricular septal hypertrophy in 61.0% of cases and left ventricular outflow tract obstruction in 22.0%. No statistically significant differences were observed between primary and secondary hypertrophic cardiomyopathy groups in clinical manifestations or imaging findings. During follow-up, seven patients died. Kaplan–Meier analysis showed a median survival time of 61.4 months, with no significant difference in survival between the two groups.

Conclusion

Pediatric hypertrophic cardiomyopathy demonstrates substantial heterogeneity in clinical presentation and genetic background. Enhanced early screening and genetic testing may improve diagnostic accuracy and facilitate individualized management strategies.

Introduction

Hypertrophic cardiomyopathy (HCM) is an inherited form of cardiomyopathy with an estimated prevalence of approximately 1 in 500 among adults. ¹ However, the epidemiology of pediatric HCM remains poorly defined, with an estimated annual incidence of 0.3–0.5 per 100,000 children.^2–5 Pediatric HCM is characterized by considerable etiological complexity and phenotypic heterogeneity and may progress rapidly to heart failure or sudden cardiac death during infancy or early childhood, posing significant diagnostic and therapeutic challenges.

Advances in genetic testing have prompted a re-evaluation of the etiological classification of HCM. Recent guidelines ⁶ propose excluding hypertrophic phenotypes caused by non-sarcomeric mutations—such as metabolic disorders or Noonan syndrome—from the definition of HCM. In contrast, earlier diagnostic frameworks^7,8 emphasized a morphologic approach, distinguishing between primary and secondary forms of HCM based on myocardial structural characteristics.

To provide a more comprehensive understanding of pediatric HCM, we conducted a retrospective analysis of 41 children diagnosed with HCM using broad diagnostic criteria. We examined their clinical characteristics, underlying etiologies, imaging findings, genetic results, and survival outcomes to refine classification and facilitate early individualized intervention for this rare and heterogeneous population.

Materials and methods

Patients and study design

This retrospective clinical study included pediatric patients diagnosed with HCM at The First Affiliated Hospital of Guangxi Medical University between 1 January 2013 and 1 October 2024. The study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. ⁹ Patients were enrolled according to broad diagnostic criteria for HCM and were classified into primary and secondary subtypes based on etiological characteristics.

Inclusion and exclusion criteria

The inclusion criteria were as follows: (a) age <18 years at initial diagnosis; (b) confirmed diagnosis of HCM based on clinical presentation, imaging findings, genetic testing, and metabolic screening of blood and urine; (c) fulfillment of diagnostic criteria for pediatric HCM as defined by current international guidelines, i.e. left ventricular wall thickness exceeding the mean value for age, sex, and body surface area by more than two standard deviations (Z-score >2); ⁷ and (d) classification into primary HCM (ventricular hypertrophy caused by sarcomere gene mutations) or secondary HCM (ventricular hypertrophy associated with inherited metabolic disorders, syndromic malformations, or neuromuscular diseases). ¹⁰

The exclusion criteria were as follows: (a) left ventricular hypertrophy secondary to increased afterload (e.g. hypertension, aortic stenosis, or coarctation of the aorta); (b) physiological hypertrophy in athletes; (c) infants born to diabetic mothers; (d) hypertrophy related to long-term corticosteroid use; and (e) incomplete clinical data.

Data collection and genetic testing

Clinical data were collected from medical records, including demographic information, clinical symptoms, electrocardiography (ECG), chest radiography, echocardiography, laboratory results, and genetic findings. Among the 41 patients, 24 underwent genetic testing, including whole-exome sequencing and targeted cardiovascular gene panel analysis. All genetic variants were interpreted according to the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, with reference to ClinGen gene–disease validity curation for HCM (https://search.clinicalgenome.org/kgb/conditions/MODO:0005045). Variants were classified into five categories (pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign), and the supporting evidence codes (e.g. PS1, PM2, PP3) were documented in Supplementary Table 1. Family co-segregation testing was performed in a small subset of cases when parental samples were available; however, the data were insufficient for systematic analysis. The remaining 17 patients did not undergo genetic testing because of limited compliance or financial constraints.

Follow-up

Follow-up data were obtained through outpatient visits and telephone interviews. Follow-up content included clinical status at discharge, treatment modality (medical therapy or surgical intervention), and the occurrence of cardiovascular-related death, which was defined as the study endpoint. Additional information was collected regarding whether the patient underwent procedures such as catheter-based ablation, septal myectomy, heart transplantation, or implantation of an implantable cardioverter–defibrillator (ICD). The final follow-up date was 1 October 2024.

Statistical analysis

All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software version 26.0 (IBM Corp., Armonk, NY, USA). Categorical variables were expressed as frequencies and percentages and compared between groups using the chi-squared test or Fisher’s exact test. Non-normally distributed continuous variables were expressed as median (interquartile range) and compared using the Mann–Whitney U test. Kaplan–Meier survival analysis was used to estimate cumulative survival, and differences between groups were assessed using the log-rank test. A two-sided P-value <0.05 was considered statistically significant. Cases with missing data were excluded from corresponding subgroup analyses without imputation, while patients lost to follow-up were treated as right-censored at their last known clinical contact.

Results

General patient characteristics

Among the 41 pediatric patients with HCM, 27 were men and 14 were women, with a male-to-female ratio of 1.93:1. The age at first diagnosis ranged from 12 days to 14 years and 3 months, with a median age of 4 years and 3 months. A total of 19 patients (46.3%) were diagnosed during infancy (<1 year), 10 patients (24.4%) during early childhood (≥1 and ≤3 years), 4 patients (9.8%) during the preschool period (>3 and ≤6 years), and 8 patients (19.5%) were older than 6 years at the time of diagnosis.

Family history

Among the 41 patients, 7 (17.1%) had a confirmed family history of cardiovascular disease. Two patients had family members diagnosed with HCM: one patient’s mother and maternal grandmother were both diagnosed with HCM—the mother was stable under oral medication, while the grandmother died of heart failure at the age of 89. Another patient’s mother was initially diagnosed with HCM, which later progressed to dilated cardiomyopathy (DCM); she underwent heart transplantation 2 years ago and recovered well. In addition, the father of one patient had been diagnosed with “cardiomyopathy” and was found to carry a known pathogenic genetic mutation. Furthermore, four patients had a family history of sudden unexplained death or heart failure.

Etiological classification

Of the 41 patients, 24 underwent genetic testing. Among them, 13 were diagnosed with primary HCM and 11 with secondary HCM. The secondary HCM group included eight patients with Noonan syndrome, two with mitochondrial disorders, and one with a carbohydrate metabolism-related disease. The remaining 17 patients did not complete genetic testing, and the etiology remained undetermined.

In the 13 patients with primary HCM, the identified pathogenic or likely pathogenic variants involved genes such as MYBPC3, MYH7, MYH6, and TPM1, based on the interpretation standards of the ACMG. Missense mutations were the most common type, followed by splice site and nonsense mutations. Detailed information on mutation sites, variant types, and familial origins is summarized in Table 1.

Table 1.

Genetic variants and follow-up data of 24 pediatric patients with hypertrophic cardiomyopathy.

No.	Sex	Age at diagnosis (years)	Gene	Nucleotide change	Protein change	Zygosity	Variant type	Inheritance pattern	Family segregation	Pathogenicity (ACMG classification)	Heart failure classification	Family history	Follow-up outcome
1	M	13.0	MYBPC3	c.530G>A	p.Arg177His	Het	Missense	AD	Mother heterozygous, father negative	LP (PM2+ PP1+PP2 +PP5)	NYHAII	Mother diagnosed with cardiomyopathy; underwent heart transplant	Survived (post heart transplant)
			MYH7	c.2156G>A	p.Arg719Gln	Het	Missense	AD	Mother heterozygous, father negative	LP (PM2 + PM5 + PP1 + PP2)
2	M	11.7	MYH7	c.2156G>A	p.Arg719Gln	Het	Missense	AD	Father, uncle, and cousin heterozygous; mother negative	LP (PM2 + PM5 + PP2 + PP5)	NYHAII	Father diagnosed with dilated cardiomyopathy	Deceased
			TTN	c.15313C>T	p.Arg5105Ter	Het	Nonsense	AD	Father heterozygous; mother, uncle, and cousin negative	VUS (PVS1_Moderate + PM2)
3	M	1.7	RIT1	NA	NA	Het	NA	NA	De novo mutation (confirmed)	LP (PS2 + PP4)	NYHAI	Negative	Survived
4	F	0.5	RAF1	c.770C>T	p.S257L	Het	Missense	AD	De novo mutation (confirmed)	P (PS1 + PS2 + PM2)	NYHAII	Negative	Survived
5	M	1.0	RAF1	c.766A>G	p.R256G	Het	Missense	AD	De novo mutation (confirmed)	LP (PS2 + PM2 + PP3)	NYHAII	Negative	Survived
6	M	6.6	RAF1	c.770C>T	p.S257L	Het	Missense	AD	De novo mutation (confirmed)	P (PS1 + PS2 + PM2 + PP3)	NYHAII	Negative	Survived
			TTN	c.67513G>A	p.V22505I	Het	Missense	AD	Father heterozygous	VUS (PM2 + PP3)
7	F	0.8	TTN	c.50782T>C	p.Y16928H	Het	Missense	AD	Father heterozygous	VUS (PP3 +PM2_Supporting)	NYHAI	Negative	Survived
			TTN	c.21862C>T	p.R7288C	Het	Missense	AD	Father heterozygous	VUS (PM2 + PP3)
			MYH6	c.5410C>A	p.Q1804K	Het	Missense	AD	Father heterozygous	VUS (BS1 + PP3)
8	M	0.5	RAF1	c.781C>A	p.P261T	Het	Missense	AD	De novo mutation (confirmed)	P (PS1 + PS2 +PM2 + PP3)	NYHAI	Negative	Survived
9	F	1.6	TNNI3	c.292C>T	p.R97X	Het	NA	AD	Mother and brother heterozygous	VUS (PM2_Supporting)	NYHAI	Negative	Survived
			MYBPC3	c.1625-29G>A	splicing	Het	NA	AD	Mother and brother heterozygous	LB (BS2 )
			MYLK2	c.1292G>A	p.R431Q	Het	NA	AD	Mother and brother heterozygous	VUS (PM2)
10	M	1.1	GAA	c.1316T>A	p.M439K	Het	Missense	AR	Mother and sister heterozygous; father negative	LP (PM3_Strong + PM1 + PM2 + PP3)	NYHAI	Negative	Deceased
			GAA	c.1549A>T	p.I517F	Het	Missense	AR	Father heterozygous; mother and sister negative	LP (PM3 + PM1 +PM2 + PP3)
11	M	0.2	PTPN11	c.1391G>C	p.G464A	Het	Missense	AD	De novo mutation (confirmed)	P (PS2 + PS4 + PM1 + PM2 + PP3)	NYHAI	Negative	Survived
12	F	14.2	LAMP2	c.222T>A	p.Y74X	Het	Nonsense	XLR	Father not tested, mother negative	LP (PVS1 + PM2)	NYHAIII	Father sudden death at 28 (unknown cause)	Deceased
			SDHA	c.223C>T	p.R75X	Het	NA	AR	NA	P (PSU)
13	M	0.4	RAF1	c.770C>T	p.S257L	Het	Missense	AD	De novo mutation (confirmed)	P (PS2 + PS4 + PM1 + PM2)	NYHAII	Negative	Survived
14	M	0.03	JPH2	c.1975G>A	p.A659T	Het	NA	AD	Father heterozygous	VUS (PM2 + BP4)	NYHAII	Negative	LTFU
15	F	1.0	ACAD9	c.1237G>A	p.Glu413Lys	Het	NA	AR	Mother heterozygous	P (PS4 + PM2 + PP3 + PP4 + PP5)	NYHAI	Negative	Survived
16	M	2.5	TTN	c.13121C>T	p.A4374V	Het	NA	AD	NA	VUS (PM2_Supporting)	NYHAI	Negative	Survived
			TTN	c.10163G>A	p.R3388Q	Het	NA	AD	NA	LB (BS1 + BP4)
17	M	5.2	TPM1	c.787C>T	p.Q263*	Het	Nonsense	AD	De novo mutation (presumed)	LP (PVS1_Strong + PM2 + PM6 + PP4)	NYHAI	Negative	Deceased
18	F	2.7	TTN	c.27328 + 1G>T	NA	Het	Splice site	NA	Mother and sister heterozygous; father negative	VUS (PVS1_Moderate + PM2_Supporting)	NYHAII	Negative	LTFU
			TTN	c.54148C>T	p.Arg18050Cys	Het	Missense	NA	Father and sister heterozygous; mother negative	VUS (PM2_Supporting)
19	F	8.0	TTN	c.107707C>T	p.Pro35903Ser	Het	NA	NA	Mother heterozygous, father negative	LB (BS1)	NYHAII	Negative	Survived
			TTN	c.1537-4G>A	NA	Het	NA	NA	Father heterozygous; mother negative	LB (BS1)
20	M	6.8	PTPN11	NA	NA	NA	NA	NA	NA	P (presumed)	NYHAI	Negative	Survived
21	M	6.9	MYBPC3	c.2441243del	p.Plys814del	Het	Missense	AD	Mother heterozygous, father negative	LP (PM2 + PP1 + PP3 + PP5)	NYHAI	Negative	Survived
22	M	7.4	MYH7	c.2707G>A	p.Gln903Lys	Het	Missense	AD	De novo mutation (confirmed)	LP (PS2 + PM2_Supporting + PP3)	NYHAI	Negative	Survived
23	F	12.4	MYBPC3	c.2241-2243del	p.Lys814del	Het	Missense	AD, AR	Father heterozygous; mother negative	LP (PM4 + PM2 + PP1)	NYHAI	Negative	Survived
24	F	0.5	CSRP3	c.265G>T	p.G89C	Het	Missense	NA	Mother, brother, and sister heterozygous; father negative	VUS (PM2_Supporting + PP3)	NYHAI	Maternal grandfather with cardiovascular abnormality	Survived
			MPZL2	c.220C>Tp.Q74X	NA	Het	NA	AR	Mother, brother, and sister heterozygous; father negative	NA
			TTN	c.32867G>A	p.R10956K	Het	NA	NA	Mother, brother, and sister heterozygous; father negative	VUS (PM2 + PP3)
			TTN	c.22489A>G	p.k7497E	Het	NA	NA	Mother, brother, and sister heterozygous; father negative	LB (BS1)

Heart failure classification in patients under 3 years was assessed using the modified Ross scoring system, converted to NYHA functional class: 0–2 = Class I, 3–6 = Class II, 7–9 = Class III, and 10–12 = Class IV. Genes: TTN (titin), PTPN1 (protein tyrosine phosphatase non-receptor type 1), MYBPC3 (myosin-binding protein C, cardiac type), MYH7 (myosin heavy chain 7), CSRP3 (cysteine and glycine-rich protein 3), MPZL2 (myelin protein zero-like 2), RAF1 (proto-oncogene serine/threonine–protein kinase Raf-1), TNNI3 (troponin I type 3, cardiac), MYLK2 (myosin light chain kinase 2), PTPN11 (protein tyrosine phosphatase non-receptor type 11), LAMP2 (lysosome-associated membrane protein 2), SDHA (succinate dehydrogenase complex flavoprotein subunit A), JPH2 (junctophilin 2), ACAD9 (acyl-CoA dehydrogenase family member 9), TPM1 (tropomyosin alpha-1 chain), and GAA (acid alpha-glucosidase, associated with glycogen storage disease). P (presumed): Based on clinical history and phenotypic presentation; sequencing data not available. P (PSU): Pathogenic, but significance for this phenotype is uncertain. To ensure consistency across all age groups, the modified Ross scoring system was applied to children under 3 years. In silico predictions from multiple algorithms—including REVEL, SIFT, PolyPhen-2, MutationTaster, and GERP+—were incorporated into the ACMG/AMP evidence framework (e.g. PP3) to support variant classification, and these results are summarized in the table where available.

Het: heterozygous; AD: autosomal dominant; AR: autosomal recessive; XLR: X-linked recessive; NA: data not available or not tested; NYHA: New York Heart Association functional class; LP: likely pathogenic; P: pathogenic; VUS: variant of uncertain significance; LB: likely benign; ACMG: American College of Medical Genetics and Genomics.

Clinical manifestations

The clinical presentations at initial diagnosis were diverse. Common symptoms included dyspnea, fatigue, and respiratory tract infections. The most frequently observed symptoms and signs were concurrent respiratory tract infection at first visit (39.47%), fatigue or reduced exercise tolerance (28.95%), history of recurrent respiratory infections (28.95%), dyspnea (23.68%), excessive sweating (18.42%), chest tightness (15.79%), and chest pain (15.79%). Less frequent symptoms, such as syncope, cyanosis, and embolism, were observed in fewer than 5.26% of patients.

Diagnostic findings at initial presentation

Echocardiographic findings

All patients underwent transthoracic echocardiography. Asymmetric septal hypertrophy was the most common pattern, observed in 25 patients (61.0%). Left ventricular wall thickening was found in 10 patients (24.4%). Left atrial enlargement was present in 12 patients (29.3%), while right atrial enlargement was noted in only 1 patient (2.4%). Left ventricular outflow tract obstruction (LVOTO) was identified in nine patients (22.0%). Detailed echocardiographic data are shown in Table 2.

Table 2.

Echocardiographic measurements in 41 pediatric patients with hypertrophic cardiomyopathy (values presented as median (IQR) or mean ± SD).

Variable	Value
Left atrial diameter (mm)	22.00 (18.00, 28.00)
Left ventricular end-diastolic diameter (mm)	30.10 ± 8.78
Left ventricular end-systolic diameter (mm)	18.02 ± 6.87
Interventricular septal thickness (mm)	14.22 ± 5.43
Left ventricular posterior wall thickness (mm)	8.00 (7.00, 10.00)
Right ventricular diameter (mm)	13.86 ± 3.91
Left ventricular ejection fraction (%)	74.00 (64.00, 80.00)
Left ventricular fractional shortening (%)	40.46 ± 9.41

Data are presented as median (IQR) for non-normally distributed variables or mean ± SD for normally distributed variables, based on the Shapiro–Wilk test.

SD: standard deviation; IQR: interquartile range.

Chest X-ray and electrocardiogram findings

Chest radiography revealed cardiomegaly in 29 patients (70.7%), with pulmonary congestion present in 3 patients (7.3%). On ECG, ST-T changes were found in 15 patients (36.6%), including ST-segment elevation or depression in 11 patients (26.8%). Abnormal Q waves were present in 13 patients (31.7%), and left ventricular high voltage was noted in 5 patients (12.2%). Additionally, some patients exhibited conduction or rhythm abnormalities, including first-degree atrioventricular block, premature atrial contractions, bundle branch block, QT interval prolongation, and supraventricular tachycardia.

Comparison between primary and secondary HCM

This study compared the clinical characteristics and auxiliary examination findings between children with primary HCM and those with secondary HCM. No statistically significant differences were found between the two groups in terms of age at diagnosis, presenting symptoms, family history, cardiac imaging parameters, or laboratory test results (Tables 3 and 4).

Table 3.

Comparison of clinical characteristics between the primary and secondary HCM groups.

Variable	Primary HCM group (n = 13)	Secondary HCM group (n = 11)	P-value
Age ≤ 1 year, n (%)	6 (46.2%)	3 (27.3%)	0.423
Age > 1 year, n (%)	7 (53.8%)	8 (72.7%)
Male sex, n (%)	9 (69.2%)	6 (54.5%)	0.675
Positive family history, n (%)	5 (38.5%)	1 (9.1%)	0.166
Acute respiratory infection at diagnosis, n (%)	4 (30.8%)	6 (54.5%)	0.408
Recurrent respiratory infections, n (%)	6 (46.2%)	3 (27.3%)	0.423
Heart failure at initial visit, n (%)	7 (53.8%)	3 (27.3%)	0.240
Developmental delay, n (%)	8 (61.5%)	6 (54.5%)	1.000
Dyspnea, n (%)	3 (23.1%)	2 (18.2%)	1.000
Chest pain or tightness, n (%)	3 (23.1%)	3 (27.3%)	1.000
Fatigue or reduced exercise tolerance, n (%)	3 (23.1%)	4 (36.4%)	0.659
Dysmorphic features or hypotonia, n (%)	5 (38.5%)	1 (9.1%)	0.166
Cardiac murmur ≥ grade 3/6, n (%)	4 (30.8%)	3 (27.3%)	1.000
Cardiac murmur < grade 3/6, n (%)	9 (69.2%)	8 (72.7%)

Data are presented as number (percentage). P-values were calculated using Fisher’s exact test. “–” indicates no statistical comparison was made for subgroup pairs within the same variable.

HCM: hypertrophic cardiomyopathy.

Table 4.

Comparison of auxiliary examinations between the primary and secondary HCM groups.

Variable	Primary HCM (n = 13)	Secondary HCM (n = 11)	P-value
Cardiomegaly on chest X-ray, n (%)	9 (69.2%)	7 (63.6%)	1.000
ST-T changes on ECG, n (%)	4 (30.8%)	5 (45.5%)	0.675
Abnormal Q waves on ECG, n (%)	6 (46.2%)	2 (18.2%)	0.211
Prolonged QT interval on ECG, n (%)	8 (61.5%)	5 (45.5%)	0.682
Left ventricular hypertrophy on ECG, n (%)	4 (30.8%)	2 (18.2)	0.649
LA diameter (mm)	25.0 (18.0, 32.0)	18.0 (17.5, 24.5)	0.399
LVEDd (mm)	31.0 (24.0, 36.0)	27.0 (20.5, 31.5)	0.283
LVESd (mm)	19.0 (15.0, 22.0)	15.0 (12.0, 19.5)	0.232
IVSd (mm)	15.0 (9.0, 20.5)	12.0 (10.0, 14.5)	0.367
LVPWd (mm)	8.25 (6.75, 11.25)	8.0 (6.5, 9.5)	0.467
RV diameter (mm)	15.0 (13.75, 16.0)	13.0 (10.5, 16.5)	0.749
Right ventricular outflow tract (mm)	21.0 (15.5, 23.5)	16.0 (14.5, 19.0)	0.211
LVEF (%)	71.0 (64.0, 77.0)	78.0 (67.0, 83.0)	0.434
LVFS (%)	40.0 (33.0, 45.0)	45.0 (35.0, 49.5)	0.561
CK (U/L)	124.0 (100.4, 145.0)	91.0 (65.5, 148.0)	0.311
CK-MB (U/L)	29.0 (23.0, 33.0)	24.0 (19.0, 31.0)	0.368
LDH (U/L)	230.0 (212.0, 408.0)	271.0 (232.0, 374.5)	0.543
cTnI (ng/ml)	0.020 (0.0125, 0.049)	0.0055 (0.003, 0.04625)	0.274
Urea (mmol/L)	5.71 (3.96, 6.30)	5.01 (4.10, 5.56)	0.469
Creatinine (μmol/L)	30.0 (23.0, 39.0)	24.0 (21.0, 29.0)	0.384
Creatinine clearance (mL/min)	87.0 (78.875, 100.5)	81.2 (64.15, 86.75)	0.103
GGT (U/L)	18.0 (13.5, 23.5)	12.0 (10.0, 15.65)	0.075
AST (U/L)	32.0 (25.3, 39.0)	37.0 (24.5, 46.0)	0.602
ALT (U/L)	17.3 (12.0, 38.0)	19.0 (16.0, 28.0)	0.794

Data are presented as median (interquartile range). P-values were calculated using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables.

HCM: hypertrophic cardiomyopathy; ECG: electrocardiogram; LA: left atrium; LVEDd: left ventricular end-diastolic diameter; LVESd: left ventricular end-systolic diameter; IVSd: interventricular septal thickness; LVPWd: left ventricular posterior wall thickness; RV: right ventricle; LVEF: left ventricular ejection fraction; LVFS: left ventricular fractional shortening; CK: creatine kinase; CK-MB: creatine kinase-MB; LDH: lactate dehydrogenase; cTnI: cardiac troponin I; GGT: gamma-glutamyl transpeptidase; AST: aspartate aminotransferase; ALT: alanine aminotransferase.

Treatment and outcomes

Of the 41 patients, 25 (60.98%) received pharmacological treatment. Among them, 22 patients (53.66%) were treated with β-blockers. This included 18 patients (43.90%) who received β-blockers alone, 3 who received combination therapy with angiotensin-converting enzyme inhibitors (ACEIs) and/or calcium channel blockers, and 1 who also received anticoagulants and cardiotonic agents. Two patients with heart failure were treated with digoxin and diuretics, and one patient with cardiac enlargement was treated with captopril. Patients with genetic metabolic disorders received disease-specific treatments accordingly.

Regarding surgical or device interventions, two patients (4.88%) underwent septal myectomy. One of these had a preoperative diagnosis of severe LVOTO, and postoperative pathology showed myocardial hypertrophy with interstitial collagen fiber proliferation; the other underwent surgery at an outside institution. One patient (2.44%) received an ICD at age 18 and underwent heart transplantation at age 19, with good postoperative recovery. The patient’s mother had also been diagnosed with HCM, which progressed to DCM and required heart transplantation.

Thirteen patients (31.71%) did not receive any treatment due to the absence of clinical symptoms and a negative family history during both the initial visit and follow-up.

By the end of the follow-up period (October 2024), seven patients had died and five were lost to follow-up. Kaplan–Meier survival analysis revealed a median survival time of 61.4 months (range: 0.4–183.6 months). Although survival curves differed between the primary and secondary HCM groups, the difference did not reach statistical significance (Figure 1).

Figure 1.

Kaplan–Meier survival curves of pediatric patients with HCM. (a) Overall survival of all 41 patients. (b) Comparison of survival between primary and secondary HCM groups (P = 0.487). HCM: hypertrophic cardiomyopathy.

Discussion

HCM is a common inherited cardiomyopathy, with an estimated prevalence of approximately 1 in 500 adults. ¹ In contrast, the overall incidence of pediatric HCM remains unclear, with an estimated annual incidence of approximately 0.3–0.5 per 100,000 children.^2–5 The main pathological features include left ventricular hypertrophy, reduced ventricular chamber size, impaired diastolic function, and decreased ventricular compliance, which may ultimately lead to congestive heart failure, malignant arrhythmias, or even sudden cardiac death. ¹¹

Unlike adult HCM, pediatric HCM exhibits a more complex etiology and highly heterogeneous clinical phenotypes. Some patients present with overt heart failure symptoms during infancy or early childhood and experience rapid disease progression, posing significant challenges for early diagnosis and intervention. Previous studies have shown that pediatric HCM has distinct patterns in symptom presentation, disease progression, and risk factors for mortality, suggesting that management strategies used for adults cannot be directly applied to children.

With advances in molecular genetics, the etiological classification and diagnostic criteria for HCM have continued to evolve. The most recent guidelines recommend excluding cases of left ventricular hypertrophy caused by non-sarcomeric gene mutations—such as inherited metabolic disorders, mitochondrial diseases, and Noonan syndrome—from the definition of HCM and reclassifying them as secondary cardiomyopathies. ⁶ In contrast, traditional guidelines define HCM primarily based on cardiac morphology and further classify cases into primary and secondary subtypes.^7,8 This morphology-based classification remains particularly applicable in pediatric populations, as it allows for the inclusion of a broader range of clinically encountered HCM cases. In this study, we adopted the broader diagnostic criteria by including all children with left ventricular hypertrophy and categorizing them based on etiology, aiming to present a more comprehensive clinical spectrum of pediatric HCM.

In this study, 41 children diagnosed with HCM were followed up until October 2024. During the follow-up period, seven patients died and five were lost to follow-up. The median overall survival time was 61.4 months (range: 0.4–183.6 months), reflecting the highly heterogeneous disease course of pediatric HCM. While some patients maintained long-term clinical stability, others experienced rapid progression to end-stage disease early in the course. Previous studies have indicated that outcomes in pediatric HCM are influenced by multiple factors, including the underlying etiology, cardiac functional status at initial presentation, and the timeliness of medical intervention.^12–15 Although the median survival time in our cohort was relatively long, the occurrence of early deaths underscores the need for improved early identification and intervention strategies, particularly in high-risk subgroups such as younger patients or those with complex etiological backgrounds.

Among the 24 patients who underwent genetic testing, 11 (45.8%) were diagnosed with secondary HCM. The most common etiology was Noonan syndrome (eight cases), followed by mitochondrial disorders (two cases) and a carbohydrate metabolism-related disease (one case). Noonan syndrome, a RASopathy, is characterized by high clinical variability, including distinctive facial features, congenital heart defects, developmental delays, and growth retardation. The subtype with HCM as the predominant cardiac manifestation is relatively rare and often involves multisystem abnormalities, making early diagnosis challenging. ¹⁶ In addition, metabolic disorders such as glycogen storage disease and mitochondrial diseases are important causes of secondary HCM in children. These patients frequently exhibit skeletal muscle involvement, energy metabolism defects, or pathological accumulation of metabolic byproducts, often presenting with muscle weakness and reduced exercise tolerance.

In our cohort, one patient carrying a pathogenic variant in GAA died due to myocardial damage resulting from glycogen accumulation. Glycogen storage diseases are known to cause multisystem dysfunction, particularly involving the myocardium. Another patient who died during follow-up was found to carry a likely pathogenic variant in LAMP2 (c.222T>A, p.Y74X) and a VUS in SDHA. Given the established role of LAMP2 mutations in Danon disease, which is characterized by multisystem involvement and progressive cardiomyopathy, the LAMP2 variant is most likely responsible for the clinical phenotype. As LAMP2 mutations cause Danon disease in an X-linked manner, the clinical expression in heterozygous women can be variable. This variability is thought to be influenced by X-chromosome inactivation, where skewing toward inactivation of the normal allele may lead to earlier onset and more severe disease, while skewing toward the mutant allele may result in milder or delayed phenotypes. Although X-inactivation analysis was not performed in our cohort, this mechanism should be considered when interpreting the heterogeneous presentations of female carriers. SDHA mutations, commonly found in mitochondrial disorders, impair cardiac energy metabolism and have been associated with severe heart failure; however, the contribution of the SDHA variant in this patient remains uncertain. This case highlights the genetic and clinical complexity of secondary HCM and suggests that comprehensive genetic testing should be considered, particularly for patients suspected of having multiple gene variants.

In this study, seven patients (17.1%) had a confirmed family history of cardiovascular disease, including familial HCM, sudden cardiac death, and heart failure. Notably, familial clustering was observed in some cases. For example, one patient had both a mother and maternal grandmother diagnosed with HCM, while another patient’s mother experienced phenotypic progression from HCM to DCM and eventually underwent heart transplantation. These findings suggest a potential phenotypic continuum between HCM and DCM. Although HCM and DCM differ in their pathophysiological mechanisms, clinical overlap and transitions between the two phenotypes are increasingly recognized. This phenotypic plasticity reflects the complexity of cardiomyopathies and highlights the broader disease spectrum of HCM.^17–20

In our cohort, multiple pathogenic genes were identified, including MYH7 and MYBPC3. Among them, MYH7 mutations are among the most common genetic causes of HCM and have been closely associated with disease severity.^21–23 One patient with an MYH7 mutation died during follow-up, while another MYH7-positive patient, although surviving long term, required ICD implantation and ultimately heart transplantation. Although these limited observations are consistent with prior reports suggesting that MYH7 mutations may be linked to more severe clinical manifestations, the small sample size in our study precludes any definitive conclusions regarding prognosis.

In addition, TTN variants were also detected in some patients. TTN mutations have traditionally been associated with DCM but have also been increasingly reported in patients with HCM and other cardiovascular conditions. ²⁴ TTN variants are relatively common in the general population, and pathogenic TTN variants related to DCM are typically truncating mutations rather than missense variants. Accordingly, in our cohort, the majority of TTN variants were interpreted as VUS, rather than pathogenic or likely pathogenic. Further research, including family segregation and functional studies, will help clarify whether these variants contribute directly to HCM or act as genetic modifiers. These observations underscore the importance of early genetic screening and family cascade testing in children with a positive family history.

In this study, segregation analysis was performed whenever samples from relevant family members were available, although this was feasible only in a limited number of families. For pathogenic or likely pathogenic variants, the available family data suggested possible co-segregation with similar phenotypes, providing limited supportive evidence for classification. For VUS, although some cases showed co-segregation, the absence of functional or population data meant that segregation alone was insufficient to reclassify these variants. In HCM, segregation analysis has important clinical relevance for guiding family screening, genetic counseling, and early intervention; however, its utility is limited by small family size, variable penetrance, and incomplete phenotypic information in relatives.

In terms of clinical symptoms, initial presentations varied widely. Common complaints included dyspnea, fatigue, and recurrent respiratory tract infections, which may be associated with diastolic dysfunction and elevated pulmonary circulation pressures. Some patients also exhibited atypical symptoms such as excessive sweating, chest pain, cyanosis, and syncope. Although the incidence of syncope, cyanosis, and embolic events was low in our cohort, previous studies have shown that these symptoms are not uncommon in pediatric HCM and may be closely related to arrhythmias, LVOTO, or autonomic dysfunction. ²⁵

Transthoracic echocardiography remains the preferred modality for the diagnosis, monitoring, and treatment evaluation of pediatric HCM due to its high sensitivity, reproducibility, and noninvasive nature. In this study, all patients showed varying degrees of left ventricular hypertrophy, with asymmetric septal hypertrophy being the most common pattern. Some patients also had LVOTO, atrial enlargement, or ventricular dilation. Recent studies have reported that concentric left ventricular hypertrophy is more commonly observed in secondary HCM, possibly due to widespread intracellular deposition of metabolic substrates.^10,26,27 In contrast, primary HCM is typically caused by sarcomeric gene mutations, leading to extreme myocyte hypertrophy and disarray, which results in an asymmetric pattern of hypertrophy.

In our study, we further compared clinical characteristics and auxiliary examination findings between primary and secondary HCM. No statistically significant differences were found. This result is not entirely consistent with previous reports, which suggest that secondary HCM often presents earlier in life, typically in infants, and is more frequently associated with multisystem involvement, such as dysmorphic features, developmental delay, and reduced exercise tolerance.^28–30 At presentation, these patients are more likely to have concurrent heart failure. Imaging and laboratory features in some secondary HCM patients have also shown a higher incidence of cardiomegaly, increased left ventricular posterior wall thickness (LVPWd), reduced left ventricular ejection fraction (LVEF), and increased occurrence of LVOTO. This single-center retrospective study with a small sample size may not fully capture intergroup differences, and factors such as age at diagnosis, disease severity, and treatment strategies could act as confounders. Multivariate analysis was not performed to avoid overfitting. Moreover, only 24 patients (58.5%) underwent genetic testing, which may have introduced selection bias in classifying primary and secondary HCM and reduced the power of comparisons. Thus, the findings should be interpreted with caution and validated in larger multicenter studies.

In this study, the majority of patients received pharmacological therapy, with β-blockers being the most commonly prescribed agents. The use of ACEis, calcium channel blockers, or anticoagulants in combination was relatively limited. This treatment pattern is consistent with previous studies,^31–33 in which β-blockers have been widely used as first-line agents to relieve symptoms and improve hemodynamic stability in children with HCM, although their efficacy was not specifically evaluated in the present study. Surgical interventions were rare and mainly limited to patients with severe LVOTO or rapidly progressive disease, which aligns with current pediatric guidelines that advocate a cautious approach to surgical indications. ⁶

Although a few patients in our cohort underwent ICD implantation or heart transplantation due to disease severity, the majority remained clinically stable during follow-up. Notably, some patients who received no treatment showed no significant progression, suggesting that certain pediatric HCM cases may follow a relatively benign course. While no statistically significant difference in survival was observed between the primary and secondary HCM groups, the separation trend observed in the Kaplan–Meier curves suggests a potential prognostic impact of underlying etiology. Syndromic HCM tends to present earlier, with more severe phenotypes and multisystem involvement, which may contribute to poorer outcomes. Given the limited sample size and the inherent heterogeneity of secondary HCM, larger studies are needed to validate this trend and further explore genotype–phenotype correlations.

In conclusion, pediatric HCM represents a clinically and genetically heterogeneous disease with variable progression and outcomes. Our single-center retrospective study highlights the complexity of its etiological spectrum, including a considerable proportion of secondary forms such as RASopathies and metabolic disorders. Genetic testing played a key role in clarifying diagnoses and uncovering overlapping or coexisting pathogenic variants, which in some cases were associated with poor prognosis. The presence of a family history, particularly involving cardiomyopathy or sudden cardiac death, underscores the importance of early genetic screening and cascade testing.

Despite clinical variability, many patients remained clinically stable during follow-up while receiving pharmacological therapy, most commonly β-blockers. However, severe cases may still require ICD implantation or heart transplantation. While survival differences between primary and secondary HCM were not statistically significant, trends in the survival curves suggest a potential etiological influence on prognosis. The lack of significant group differences may be attributed to the small sample size and the single-center nature of this cohort, which may limit the generalizability of the findings. Therefore, future large-scale, multicenter studies are warranted to further validate these findings, explore genotype–phenotype correlations, and optimize individualized management strategies for children with HCM.

Data availability statement

The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and ethical restrictions but are available from the corresponding author upon reasonable request.

Ethics statement

This study was approved by the Ethics Committee of Hainan Provincial People’s Hospital (approval no. 2022(404); Haikou, China) and the Ethics Committee of The First Affiliated Hospital of Guangxi Medical University (approval no. 2022(KY-E-007); Nanning, China). All procedures involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committees and with the Declaration of Helsinki of 1975, as revised in 2024. The requirement for informed consent was waived by both committees owing to the retrospective nature of the study. All patient information was anonymized to ensure that individual identities could not be identified.

Supplemental material

Supplemental material for this article is available online.