The clinical and echocardiographic spectrum of pediatric hypertrophic cardiomyopathy in North Africa: a Moroccan case series

¹Laboratory of Medical Genetics and Oncogenetics, Hassan II University Hospital, Fez, Morocco, ²Faculty of Sciences and Techniques, Sidi Mohamed Ben Abdellah University, Fez, Morocco, ³Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco, ⁴Department of Pediatrics, Medico-Surgical Unit of Pediatric Cardiology, Hassan II University Hospital, Fez, Morocco

^&Corresponding author
Oussama Ech Charady, Laboratory of Medical Genetics and Oncogenetics, Hassan II University Hospital, Fez, Morocco

Introduction    

Pediatric hypertrophic cardiomyopathy (HCM) is a rare and complex cardiac disorder characterized by unexplained left ventricular hypertrophy (LVH), often asymmetric and most frequently involving the interventricular septum (IVS). It is defined by myocardial hypertrophy in the absence of secondary causes such as arterial hypertension, aortic stenosis (AS), or metabolic disease. This hypertrophy can lead to dynamic left ventricular outflow tract (LVOT) obstruction, primarily due to systolic anterior motion (SAM) of the mitral valve, which may cause subaortic gradients and secondary valvular regurgitation [1]. In adults, HCM is relatively common, with a prevalence of approximately 1 in 500 individuals, but in children, the condition is significantly rarer and often more severe [2]. It represents the second most frequent form of cardiomyopathy in pediatric populations, following dilated cardiomyopathy (DCM), and is a major cause of sudden cardiac death (SCD) in young individuals [3].

Unlike adult-onset HCM, pediatric forms are characterized by greater clinical heterogeneity, varying from isolated sarcomeric mutations to syndromic and metabolic etiologies. Syndromic cases, especially those related to RASopathies such as Noonan syndrome (NS), frequently present with additional congenital heart defects, most commonly pulmonary stenosis (PS), atrial septal defects, and dysplastic valves [4,5]. These structural abnormalities complicate the clinical spectrum and management of pediatric HCM. Echocardiography remains the first-line diagnostic modality, providing accurate characterization of the different pathological profiles, particularly in identifying dynamic subaortic obstruction related to SAM of the mitral valve, as well as associated valvular malformations. Given the risk of malignant arrhythmias, progressive obstruction, and SCD, early diagnosis and comprehensive evaluation are crucial. The integration of clinical, echocardiographic, and molecular data improves phenotypic characterization, disease management, and guides genetic counseling. In this context, we report a Moroccan pediatric case series of six patients, illustrating the diversity of clinical and echocardiographic presentations of pediatric HCM.

Methods     

We conducted a prospective descriptive study at the Medical Genetics and Oncogenetics Unit (MGOU) of Hassan II University Hospital in Fez, Morocco, between May 2025 and September 2025, including pediatric patients presenting with clinical and echocardiographic features suggestive of HCM and referred for genetic evaluation. Clinical evaluation included a detailed physical examination, assessment of cardiac symptoms (dyspnea, syncope, chest pain, cyanosis, feeding difficulties in infants), and screening for extra-cardiac anomalies suggestive of syndromic disease, such as facial dysmorphism, short stature, or congenital anomalies. A three-generation pedigree was systematically obtained to identify family history of cardiomyopathy, SCD, or consanguinity. All patients underwent a standard 12-lead electrocardiogram (ECG) to assess rhythm disturbances, conduction abnormalities, and signs of LVH.

Transthoracic echocardiography was performed following international pediatric guidelines, with strict application of echocardiographic Z-scores to objectively quantify the severity of myocardial hypertrophy and structural anomalies according to current standards. Patients with secondary causes of LVH (severe hypertension, aortic stenosis, athlete's heart, or metabolic/endocrine disease) were excluded. From the broader cohort, six patients were selected for this case series based on the richness and diversity of their clinical and echocardiographic presentations. The study was conducted in accordance with the Declaration of Helsinki. The local Ethics Committee waived formal ethical approval due to the observational and descriptive nature of this case series. All data were fully anonymized to ensure patient confidentiality. Written informed consent for publication was obtained from the patients' legal guardians. For molecular investigations, whole-genome sequencing (WGS) has been performed for all patients; however, the comprehensive genomic data and bioinformatics analysis will be detailed in a forthcoming molecular study.

Results     

Case 1: the first patient was an 8-month-old male infant presenting with a dysmorphic phenotype suggestive of NS, associated with cryptorchidism and a harsh systolic murmur detected during routine evaluation. Transthoracic echocardiography showed severe valvular PS with a maximum Doppler gradient of 110 mmHg, caused by a thickened, rigid, and dysplastic pulmonary valve. The pulmonary artery branches were of normal caliber, but there was dilatation of the right pulmonary artery compared with the left. The right ventricle (RV) was moderately dilated and hypertrophied, with preserved systolic function. The left ventricular (LV) size and systolic function were normal, with no evidence of hypertrophy or dilation. A patent foramen ovale (PFO) measuring 3-5 mm with a bidirectional shunt was also noted. Additionally, fine intracavitary fibrous structures were observed, raising suspicion of incipient sarcomeric HCM. Regarding patient management, the infant was scheduled for percutaneous balloon pulmonary valvuloplasty to alleviate the severe right ventricular outflow tract (RVOT) obstruction. Furthermore, a neuropediatric consultation was requested, and a comprehensive genetic evaluation was initiated to investigate the suspected syndromic etiology.

Case 2: the second case involved a 3-month-old female infant who presented with persistent neonatal bradycardia (resting heart rate of 71 bpm) and feeding difficulties. Her heart rate increased only minimally during crying (85-90 bpm). Electrocardiogram revealed a third-degree complete atrioventricular (AV) block. Echocardiography demonstrated a non-dilated LV with moderate hypertrophy, including an IVS thickness of 20 mm, along with features suggestive of left ventricular noncompaction (LVNC). Systolic function was preserved. A parachute mitral valve was identified, associated with posterior papillary muscle hypoplasia and a restrictive inflow pattern. A persistent ductus arteriosus (PDA, 1 mm) was also present. Doppler evaluation revealed severe pulmonary arterial hypertension (PAH) estimated at two-thirds of systemic systolic pressure. The management plan included close clinical surveillance and a Holter ECG to monitor the complete AV block, alongside the initiation of diuretic therapy. Given the congenital heart block (CHB), an underlying maternal autoimmune etiology was suspected; therefore, comprehensive autoimmune screening was ordered, and the mother was referred to an internist for specialized evaluation. Concurrently, a pediatric genetic assessment was initiated.

Case 3: the third patient was a 13-year-8-month-old male followed for sarcomeric HCM, who presented with stage II exertional dyspnea. The ECG showed marked LVH with repolarization abnormalities. Echocardiography revealed a non-dilated LV with severe myocardial hypertrophy, including an IVS thickness of 17 mm and posterior wall thickness of 16 mm, with preserved systolic function. A dysplastic mitral valve exhibited a prominent SAM, generating moderate mitral regurgitation (grade 2-3). An ectopic muscular chordae inserting into the septum was also identified. The RV was normal in size and function. The pulmonary arterial pressure (PAP) was estimated at 40 mmHg based on mild tricuspid regurgitation. There was marked left atrial (LA) dilation and mild-moderate aortic regurgitation. A subaortic fibromuscular ridge produced a severe LVOT obstruction, with a peak systolic gradient of 140 mmHg (mean 70 mmHg). Clinical follow-up revealed a slow progression of the sarcomeric cardiomyopathy with stabilization of the mitral regurgitation. However, a recurrence of the subaortic obstruction was noted, driven by persistent geometric anomalies of the mitral valve. The patient was maintained on medical therapy with a non-selective beta-blocker (propranolol). A comprehensive surgical intervention is planned, which includes the resection of the subaortic fibromuscular structure and surgical correction of the mitral valve insertions.

Case 4: the fourth patient was a 2-month-old girl referred for a systolic murmur. Echocardiography revealed a large PFO (10 mm) and moderate LVH with an IVS thickness of 10 mm and preserved LV function. A severely dysplastic aortic valve was noted, associated with a subaortic fibromuscular ridge producing a peak subaortic gradient of 85 mmHg (mean 45 mmHg), without aortic regurgitation. The mitral valve was dysplastic, with SAM linked to an ectopic muscular chordae in the LVOT. The LA was normal, whereas the right atrium (RA) was dilated (10 mm). The RV was hypertrophied, non-dilated, and functionally preserved. A severe PS was also present, due to a severely dysplastic pulmonary valve, with a maximum gradient of 100 mmHg. Given the severity of the biventricular outflow tract (BVOT) obstruction, the patient was placed under strict clinical and echocardiographic surveillance pending further therapeutic decisions.

Case 5: the fifth patient was a 5-month-old female infant with clinically suspected NS, presenting with a grade 4/6 systolic murmur and laryngeal stridor with suprasternal retractions. Echocardiography demonstrated septal hypertrophy (8 mm) with normal LV systolic function, RA dilation, and a normal-sized LA. The mitral valve was dysplastic with SAM of the anterior leaflet, associated with fibrous attachments on the IVS, generating minimal mitral regurgitation. The aortic valve was dysplastic without regurgitation. A severe mixed PS (valvular + subvalvular) was present, with a peak gradient of 110 mmHg, and a small posterior atrial septal defect. Given the complex double outflow tract obstruction (aortic and pulmonary) and the underlying sarcomeric cardiomyopathy, the management plan included close clinical surveillance and consideration for percutaneous balloon dilatation. Furthermore, a karyotype and targeted genetic testing for NS were requested to formally confirm the syndromic presentation.

Case 6: the sixth patient was a 10-year-4-month-old girl with a known diagnosis of sarcomeric HCM, presenting with mild exertional dyspnea (stage I). Electrocardiogram showed LVH with a borderline PR interval. Transthoracic echocardiography revealed markedly asymmetric septal hypertrophy, particularly in the subaortic region, with measurements ranging from 14 to 25 mm, associated with abnormal septal angulation. This anatomical configuration resulted in a moderate LVOT obstruction, with a peak gradient of 25 mmHg, and mild SAM of the mitral valve. The aortic valve was bicuspid, without stenosis or regurgitation. A PFO was present, and the LA was dilated. The RV was non-dilated and functionally preserved, with moderate tricuspid regurgitation allowing estimation of a PAP of 30 mmHg. Regarding patient management, the clinical plan consisted of regular clinical and echocardiographic surveillance, alongside the initiation of medical therapy with a non-selective beta-blocker (propranolol) to manage the symptomatic HCM and mitigate the dynamic outflow tract obstruction. The echocardiographic findings of all six patients are summarized in Figure 1, illustrating the wide spectrum of morphological and functional cardiac abnormalities observed in this case series. The results presented in both tables highlight the clinical and paraclinical heterogeneity of pediatric HCM in our series. The demographic, clinical, and biological data (Table 1) characterize the initial patient profiles, while the echocardiographic and electrocardiographic findings (Table 2) demonstrate the variability of morphological and functional impairments in our cohort. These elements provide a crucial foundation for contextualization with the existing literature in the discussion.

Discussion     

Pediatric HCM is a rare condition characterized by significant clinical, etiological, and prognostic heterogeneity. Several recent studies corroborate this observation, highlighting that Pediatric HCM encompasses a wide spectrum of presentations, ranging from syndromic forms with neonatal or infantile onset, often linked with RASopathies, to sarcomeric forms diagnosed later in childhood or adolescence. Overlap phenotypes, such as the association between HCM and LVNC or the coexistence of valvular abnormalities, further illustrate this diversity [4,6,7]. In our series, this diversity was reflected through various diagnostic contexts including isolated sarcomeric forms, syndromic forms, as well as cases associated with valvular abnormalities or LVNC features. The age at diagnosis, ranging from 2 months to 13 years 8 months, reflects the temporal spectrum described in the literature. Norrish et al. reported a bimodal distribution, with an early peak in syndromic forms, often detected within the first months of life and a later peak corresponding to sarcomeric forms [5]. Three of our patients (cases 1, 4, and 5) presented with severe PS, illustrating the well-documented association between this defect and RASopathies, particularly NS. In syndromic forms of pediatric HCM, especially RASopathy-associated HCM (R-HCM), PS often coexists with LVH, complicating the clinical presentation and requiring tailored management. Biventricular hypertrophy may serve as a useful clinical clue ("red flag") for R-HCM, as it can indicate coexisting RVOT obstruction.

In this subgroup, the prevalence of PS ranges between approximately 25% and 70%, and the pulmonary valve is frequently dysplastic with commissural fusion. Emerging genotype-phenotype data also suggest that specific RAS-MAPK variants are associated with a higher propensity for recurrent LVOT obstruction and multivalvular involvement during childhood, underscoring the value of targeted genetic testing and multidisciplinary follow-up in NS spectrum-related cardiomyopathy [8]. In our cohort, cases 1 and 5 displayed typical phenotypic features including heart murmur, laryngeal stridor and facial dysmorphism, which are consistent with patterns described in the literature [6]. According to Roberts et al. up to 30% of children diagnosed with HCM before the age of one have a RASopathy, with hallmark features such as PS, facial dysmorphism, and other valvular abnormalities, which was also observed in our cohort [7]. In these syndromic forms, the combination of PS and HCM constitutes a major component of the cardiac phenotype. Tartaglia et al. demonstrated that PS is nearly ubiquitous in patients with PTPN11 mutations, making it the most characteristic cardiac defect of this genotype [8]. This combined phenotype (HCM and PS) aligns with the classic profile of PTPN11-related RASopathies.

The phenotypic variability of obstructive and non-obstructive forms observed in our series reflects the classic heterogeneity of pediatric HCM. For example, Case 3 presented with a maximal subaortic gradient of 140 mmHg, indicating severe obstruction, associated with moderate mitral regurgitation and LVH on ECG. This configuration is linked to an increased risk of cardiovascular events, as demonstrated by pediatric echocardiography studies, showing that a gradient ≥30 mmHg (at rest or with provocation) correlates with worse outcomes and warrants careful surveillance [9]. Risk-stratification models, such as SCAR-C4 and PRIMaCY, incorporate LVOT gradient among other predictors to estimate the 5-year SCD risk. However, recent external evaluations indicate only moderate discrimination, suggesting these tools should complement rather than replace clinical judgment, ECG/arrhythmic data, and imaging markers [10]. In contrast, case 6 showed severe myocardial hypertrophy (septal thickness 14-25 mm), a moderate subaortic gradient (25 mmHg), and SAM associated with a bicuspid aortic valve. As originally described by Wigle et al. [11], the degree of LVOT obstruction does not depend solely on myocardial wall thickness but also on dynamic interactions involving the mitral valve apparatus and blood flow. Contemporary pediatric imaging has further refined this concept by demonstrating the central role of SAM biomechanics, papillary muscle position, and LV geometry in modulating dynamic LVOT obstruction [12,13]. These studies also highlight the influence of genetic factors, notably PTPN11 mutations, which may increase susceptibility to obstruction even in the presence of severe myocardial hypertrophy [14].

Another notable feature in our cohort is the universal presence of valvular abnormalities, including dysplastic mitral, pulmonary and aortic valves, as well as frequent SAM. While previous literature typically reports valvular abnormalities in 30-50% of pediatric HCM cases, our findings suggest a higher prevalence in this Moroccan cohort [15]. A larger cohort would be highly recommended to confirm these findings. These structural anomalies reinforce the concept that, in children, HCM often combines primary myocardial disease with developmental valvular defects. Furthermore, in alignment with current international consensus for the management of cardiomyopathies, our findings underscore the necessity of rigorous phenotypic profiling. While our echocardiographic evaluation utilized strict Z-scores, the incorporation of advanced imaging modalities, particularly cardiac Magnetic Resonance Imaging (MRI), remains a critical next step for tissue characterization and refined risk stratification. Compared to large international registries, our Moroccan cohort exhibits a notably high prevalence of associated valvulopathies, emphasizing a potentially distinct phenotypic presentation in this regional context that warrants further large-scale investigation. Case 2 warrants particular attention due to its unusual presentation: HCM associated with LVNC, complete AV block, and PAH. Although rare, HCM-LVNC overlap has been repeatedly reported and is thought to reflect complex or multiple genetic mechanisms [16,17]. Conduction disease, including high-grade AV block, is exceptional in HCM but has been described in isolated pediatric reports, justifying extended genetic testing (including non-sarcomeric and conduction-system genes) when LVNC traits or conduction abnormalities are present [18,19]. Case 6, characterized by massive septal hypertrophy, multiple valvular abnormalities, LVH on ECG and a moderate intraventricular gradient, illustrates a key pathophysiological principle in HCM.

The severity of LVOT obstruction is not determined solely by septal thickness, but also strongly influenced by valvular and subvalvular dynamics. In particular, SAM of the mitral valve plays a central role in LVOT obstruction. Studies report that, in up to 60-70% of obstructive HCM cases, the mechanism involves a combination of septal hypertrophy and SAM, even in the absence of a resting gradient [20]. Recent pediatric imaging and surgical reviews further confirm the significant role of dynamic mechanisms, such as papillary muscle malposition, anomalous leaflet or chordal insertion and accessory papillary muscles, in generating LVOT obstruction, independently of isolated septal hypertrophy [13]. The literature underscores early diagnosis and multidisciplinary management to mitigate risks, particularly SCD, which remains a major concern in children with severe obstruction, arrhythmias, or high-risk genotypes. Our series reflects this reality, with several high-risk features or complex syndromic associations. In this context, integrating clinical, imaging, and genetic data facilitates precise counseling, cascade family screening, and therapeutic decisions (including implantable cardioverter-defibrillator (ICD) when appropriate). Evolving pediatric evidence highlights additional markers, such as left atrial stiffness (LAS) and global longitudinal strain (GLS), that may refine risk beyond conventional indices, and supports exercise-stress echocardiography to unmask latent obstruction in borderline cases.

Therapeutically, beta-blockers remain the first-line option in obstructive forms, while disopyramide has re-emerged as a safe and effective adjunct in children to reduce gradients and symptoms, potentially delaying septal reduction therapy. Surgical septal myectomy remains the gold standard for refractory obstruction in experienced centers, with careful consideration of age and anatomy. Although cardiac myosin inhibition is a promising strategy in adults with obstructive HCM, pediatric evidence is still limited, and current recommendations favor trial enrollment rather than off-label use in children pending adolescent data. Overall, management should be phenotype and genotype informed, combining medical therapy, surveillance of LVOT dynamics, and timely consideration of invasive strategies when needed. On the genetic level, WGS has been performed for our cohort. The detailed bioinformatics analysis and definitive genotype-phenotype correlations will be reported in a separate upcoming article. This comprehensive approach aligns with pediatric consensus statements advocating systematic genetic testing and cascade family screening, as genotype influences penetrance, age at onset, arrhythmic risk, and recurrence of obstruction, and guides precision surveillance (visit frequency, imaging, exercise testing, and thresholds for ICD or intervention). Precise mutation identification will refine etiological diagnosis, improve genetic counseling, and enable personalized longitudinal care in our setting. Case 2 warrants particular attention due to its unusual presentation: HCM associated with LVNC, complete AV block, and PAH. Although rare, HCM-LVNC overlap has been repeatedly reported and is thought to reflect complex or multiple genetic mechanisms [16,17]. Conduction disease, including high-grade AV block, is exceptional in HCM but has been described in isolated pediatric reports, justifying extended genetic testing (including non-sarcomeric and conduction-system genes) when LVNC traits or conduction abnormalities are present [18,19]. Case 6, characterized by massive septal hypertrophy, multiple valvular abnormalities, LVH on ECG and a moderate intraventricular gradient, illustrates a key pathophysiological principle in HCM. The severity of LVOT obstruction is not determined solely by septal thickness, but also strongly influenced by valvular and subvalvular dynamics. In particular, SAM of the mitral valve plays a central role in LVOT obstruction. Studies report that, in up to 60-70% of obstructive HCM cases, the mechanism involves a combination of septal hypertrophy and SAM, even in the absence of a resting gradient [20].

Limitation: the primary limitation of this study is the small sample size of six patients, which restricts the generalizability of our findings. Furthermore, as a descriptive case series originating from a single specialized center (the MGOU of Hassan II University Hospital), there may be a selection bias toward more severe, complex, or syndromic phenotypes referred specifically for genetic evaluation. Finally, while WGS has been completed, these molecular results are reserved for a separate dedicated study. Consequently, the current report focuses strictly on clinical and echocardiographic phenotyping, preventing firm genotype-phenotype correlations at this stage. As noted, studies with a larger multicenter cohort would be highly recommended to confirm these clinical and echocardiographic observations.

Conclusion     

This Moroccan pediatric case series highlights the marked clinical, morphological, and genetic heterogeneity of HCM in children. Pediatric HCM may occur as an isolated sarcomeric disease or within syndromic contexts, particularly Noonan spectrum disorders. From an educational perspective, this report provides crucial clinical lessons for pediatricians and cardiologists: it demonstrates that the presence of pediatric HCM, particularly when associated with pulmonary stenosis or valvular anomalies, must immediately prompt screening for underlying RASopathies. Furthermore, it teaches that the severity of LVOT obstruction depends strongly on dynamic mechanisms, such as SAM of the mitral valve, rather than myocardial thickness alone. Comprehensive echocardiographic evaluation remains the cornerstone for early diagnosis, paving the way for targeted genetic testing, the specific findings of which will be detailed in our future molecular report.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Study conception and design: Oussama Ech Charady, Ihssane El Bouchikhi, Karim Ouldim, Laila Bouguenouch, Samir Atmani. Data collection: Oussama Ech Charady, Samir Atmani. Analysis and interpretation of results: Oussama Ech Charady, Ihssane El Bouchikhi, Nadia Maazouzi, Karim Ouldim, Laila Bouguenouch, Samir Atmani. Draft manuscript preparation: Oussama Ech Charady. Critical revision of the manuscript for important intellectual content: Ihssane El Bouchikhi, Nadia Maazouzi, Karim Ouldim, Laila Bouguenouch, Samir Atmani. All the authors have read and agreed to the final version of the manuscript.

Acknowledgments     

The authors would like to express their sincere gratitude to the patients and their families for their trust and cooperation. We also extend our thanks to the medical and paramedical staff of the MGOU at Hassan II University Hospital for their daily dedication and support in patient care.

Tables and figure     

Table 1: demographic and clinical features of the studied pediatric hypertrophic cardiomyopathy patients

Table 2: echocardiographic and electrocardiographic characteristics of the studied patients

Figure 1: representative echocardiographic findings in six pediatric patients with hypertrophic cardiomyopathy; panels (a-f) correspond to cases 1-6, respectively

References