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Hypertrophic cardiomyopathy in children: Clinical manifestations and diagnosis

Hypertrophic cardiomyopathy in children: Clinical manifestations and diagnosis
Authors:
John L Jefferies, MD, MPH, FACC, FAHA
Thomas D Ryan, MD, PhD
Martin S Maron, MD
Section Editor:
John K Triedman, MD
Deputy Editors:
Todd F Dardas, MD, MS
Carrie Armsby, MD, MPH
Literature review current through: Jul 2022. | This topic last updated: Aug 20, 2020.

INTRODUCTION — Hypertrophic cardiomyopathy (HCM) is one of the most common forms of inherited cardiomyopathy in both adults and children, and it is characterized by hypertrophy of the left ventricle (LV) which sometimes involves the right ventricle. The disease course is highly variable, but it is well recognized that there is an increased risk of morbidity and sudden cardiac death (SCD). (See "Sudden cardiac arrest and death in children".)

In broad terms, the symptoms related to HCM can be categorized as those related to heart failure, chest pain, or arrhythmias. Patients with HCM are at an increased risk for SCD, representing the most common cause of SCD in young, athletic, seemingly healthy individuals. (See "Hypertrophic cardiomyopathy: Prevalence, pathophysiology, and management of concurrent atrial arrhythmias" and "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".)

Importantly, no medical treatments have been shown to alter disease progression. Management strategies are focused on symptom improvement, with utilization of potentially life-saving therapy in the form of implantable cardioverter defibrillators (ICDs) in patients deemed to be at high risk of SCD.

This topic will review the epidemiology, clinical manifestations, and diagnosis of HCM in children. The management an prognosis of HCM in children are discussed separately. (See "Hypertrophic cardiomyopathy in children: Management and prognosis".)

The clinical manifestations, diagnosis, management, and natural history of HCM in adults are discussed separately:

(See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation".)

(See "Hypertrophic cardiomyopathy: Medical therapy for heart failure".)

(See "Hypertrophic cardiomyopathy: Nonpharmacologic treatment of left ventricular outflow tract obstruction".)

(See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk".)

(See "Hypertrophic cardiomyopathy: Natural history and prognosis".)

DEFINITIONS — The term HCM is applied broadly to a number of different clinical presentations:

Sarcomeric HCM – True HCM is a genetically-determined condition attributed to mutations of sarcomeric proteins, and with no other explanation for the left ventricle hypertrophy (LVH). The terms "idiopathic" and "familial" HCM are sometimes used to describe patients who phenotypically have HCM in whom genetic testing is negative or was not performed, in the absence of evidence for a syndrome or systemic disease ("idiopathic HCM") or in the presence of a positive family history ("familial HCM"). The assumption is that such patients are genetically-determined with a yet undiscovered mutation or gene. Clinically, idiopathic and familial HCM follow the path of sarcomeric HCM.

HCM phenocopies – There are a number of HCM mimickers, or "phenocopies," which present similarly to sarcomeric HCM but that have different pathophysiologies. These include inborn errors of metabolism (IEM), multiple congenital anomaly syndromes (eg, Noonan syndrome), mitochondrial disorders, and neuromuscular disorders (table 1). Phenocopies account for approximately 25 percent of pediatric HCM cases reported in large registry studies [1-3]. The most common phenocopy is Noonan syndrome, with other examples including Danon disease, Friedreich ataxia, LEOPARD syndrome, Pompe disease, mitochondrial diseases, and mutation of PRKGA2 [4].

In a series of 855 patients in the Pediatric Cardiomyopathy Registry diagnosed with HCM between 1990 and 2007, the relative frequency of each cause was as follows [1]:

"Idiopathic" HCM (ie, sarcomeric HCM) – 74 percent

Malformation syndromes – 9 percent

IEM – 9 percent

Neuromuscular disorders – 7 percent

Adaptive or secondary LVH – Adaptive changes to stimuli such as athletic training or hypertension can occur in pediatric patients; however, LVH resulting from these adaptations is not considered HCM. In addition, secondary causes of LVH such as pulmonary parenchymal or vascular disease, endocrine disease (eg, maternal gestational diabetes), rheumatic disease, immunological disease, and cardiotoxic exposures are not considered HCM. (See 'Differential diagnosis' below.)

There is debate over whether the phenocopies should be included when describing HCM. While the approach to therapy is often the same, there may be differences in outcomes. In an analysis of a claims-based database queried for patients <18 years old with HCM, which identified 4460 patients over a four-year period, 789 (18 percent) had an associated genetic disorder. Patients with an associated genetic disorder had higher rates of hospital admission, heart failure diagnosis code, and death when compared with patients with HCM alone [5].

In this topic review, sarcomeric HCM and phenocopies are considered together under the broad term "HCM," unless otherwise specified. However, it is worth noting that HCM phenocopies are often excluded from studies of medical and ICD therapy.

EPIDEMIOLOGY — The prevalence of HCM in the general pediatric population is likely underestimated since many affected children have subclinical disease. Based on data from various pediatric cardiomyopathy registries, the annual incidence of HCM from all causes (including sarcomeric, phenocopies, and idiopathic) is approximately 0.3 to 0.5 cases per 100,000 children [1-3,6,7]. The peak incidence is in infants <1 year old, there is a slight male predominance, and in the US population, prevalence is higher in African American children than in White or Hispanic children. In total, HCM accounts for 25 to 40 percent of all pediatric cardiomyopathy cases [2,6]. In adult populations, the prevalence of HCM is estimated at approximately 1 in 500 persons. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Prevalence'.)

CLINICAL MANIFESTATIONS — Clinical findings associated with HCM can develop in infants and pre-pubertal children, but are more commonly seen in teenagers and young adults following the growth spurt and other changes associated with puberty. Because children with sarcomeric HCM often have no or minor symptoms, affected individuals are frequently diagnosed as a result of family screening, detection of a murmur during routine examination, or the identification of an abnormal electrocardiogram (ECG). Patients with syndromic or systemic disease may be brought to attention as part of screening, but only if providers appreciate the association.

A small subset of patients will progress to an advanced form of the disease that is characterized by relative left ventricle (LV) dilation and wall thinning and systolic dysfunction, the so-called "burned out HCM" phenotype. In a cohort which included both pediatric and adult patients, left ventricular systolic dysfunction (LV ejection fraction <50 percent) has been reported in approximately 5 to 8 percent of patients with HCM [8,9]. This group of patients was at higher risk for atrial fibrillation, stroke, and symptomatic heart failure [8], with higher reported mortality compared with patients with HCM and normal LV systolic function [9]. Such patients are managed according to the standard approach to patients with heart failure due to systolic dysfunction and may progress to the need for mechanical circulatory support or heart transplantation. (See "Heart failure in children: Management".)

Signs and symptoms — The signs and symptoms of HCM in pediatric patients vary based on age and associated conditions. Many pediatric patients with HCM are asymptomatic, and there is not a strong correlation between symptoms and the presence or magnitude of left ventricular outflow tract (LVOT) obstruction or the extent of LV hypertrophy. Age and developmental status play an important role in perception of and ability to express symptoms, particularly for pre-ambulatory and/or preverbal patients.

Presenting symptoms may include:

Chest pain

Presyncope/syncope

Palpitations

Heart failure symptoms (eg, poor feeding, failure to thrive, tachypnea, easy fatigability)

Sudden cardiac arrest/death

In a report of 80 children with HCM identified through a population-based cohort study, presenting clinical features that prompted cardiac evaluation included [10]:

Cardiac murmur (53 percent)

Family history of HCM (15 percent)

Underlying syndrome (6 percent)

Congestive heart failure (8 percent)

Arrhythmic symptoms (2 percent)

Nonspecific symptoms (16 percent)

The signs and symptoms of HCM vary somewhat according to age:

Infants <1 year – An isolated heart murmur is the most common presentation during the first year of life [10,11]. (See 'Physical examination' below.)

Symptomatic infants typically present with signs and symptoms of heart failure (eg, tachypnea, poor feeding, and poor growth). Patients with Noonan Syndrome are more likely to present prior to six months of age (51 percent versus 28 percent of infants with sarcomeric HCM ), and more likely with symptoms of congestive heart failure (24 versus 9 percent of infants with sarcomeric HCM) [4,10,11]. (See "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Mortality is high among patients diagnosed with HCM during infancy, particularly in those with inborn errors of metabolism and malformation syndromes, and is primarily due to heart failure rather than sudden death [1]. (See "Hypertrophic cardiomyopathy in children: Management and prognosis", section on 'Prognosis'.)

Children ≥1 year of age – Most older children (≥1 year of age) with HCM are asymptomatic [12]; however, children with inborn errors of metabolism have a higher rate of presenting with symptomatic heart failure. Among those who come to clinical attention, symptoms may include [13]:

Abdominal pain, decrease in appetite, or intolerance of feeds

Dyspnea on exertion

Fatigue

Atypical or anginal chest pain

Presyncope and syncope, particularly during or immediately following exertion

Palpitations

Sudden cardiac arrest/death

One possible cause for myocardial ischemia in children with HCM is myocardial bridging. However, the data are conflicting as to whether myocardial bridging is a predictor of ventricular tachyarrhythmias and sudden death [14-16]. (See "Myocardial bridging of the coronary arteries".)

Physical examination — The physical examination in a child with HCM may be normal or may reveal nonspecific abnormalities such as a systolic murmur, fourth heart sound, and/or a left ventricular lift. Many of the classically described physical examination findings in patients with HCM are associated with LVOT obstruction. Persons with minimal or no LVOT obstruction may have normal or nearly normal physical examinations. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Physical examination'.)

Murmurs – Patients with HCM may develop several types of systolic murmurs, but the two most common are related to LVOT obstruction and mitral regurgitation.

LVOT obstruction, often due to a combination of LV upper septal hypertrophy and systolic anterior motion (SAM) of the mitral valve, results in a harsh crescendo-decrescendo systolic murmur that begins slightly after S1 and is heard best at the apex and lower left sternal border. The murmur may radiate to the axilla and base, but usually not into the neck. Altering preload and afterload can change the intensity of the murmur, which increases during the Valsalva maneuver or standing abruptly, and decreases with hand grip or squatting. (See "Approach to the infant or child with a cardiac murmur", section on 'Left lower sternal border'.)

SAM of the mitral valve, or abnormal mitral valve anatomy related to papillary muscle or chordae tendineae abnormalities, can lead to impaired leaflet coaptation and mitral regurgitation. This usually results in a posteriorly directed mitral regurgitation jet, which produces a mid-late systolic murmur at the apex. Centrally directed mitral regurgitation, usually associated with primary mitral valve pathology, classically results in a holosystolic murmur heard loudest at the apex that radiates to the axilla. However, if the regurgitant jet is eccentrically directed, the murmur can radiate toward the base of the heart and may be confused with the murmur of LVOT obstruction. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Development of mitral regurgitation' and "Approach to the infant or child with a cardiac murmur", section on 'Apex'.)

Other cardiac findings – A number of other physical findings may be observed in children with HCM, although none is pathognomonic for HCM. These include:

Third and/or fourth heart sound (S3 or S4). (See "Approach to the infant or child with a cardiac murmur", section on 'Third and fourth heart sounds'.)

Paradoxic splitting of the second heart sound (S2) in patients with severe LVOT obstruction. (See "Approach to the infant or child with a cardiac murmur", section on 'Second heart sound'.)

Brisk and bifid arterial pulses.

Diffuse LV apical impulse on palpation. (See "Approach to the infant or child with a cardiac murmur", section on 'Palpation of the chest'.)

Parasternal lift.

Signs of congestive heart failure, including pulmonary congestion, peripheral edema, and/or elevation of the jugular venous pressure.

Noncardiac findings – Dysmorphic features and other noncardiac findings may suggest an underlying syndromic or genetic disorder associated with HCM (table 1) (eg, short stature, hypertelorism, downward eye slant, and low-set ears in Noonan syndrome; limb and gait ataxia in Friedreich ataxia; generalized muscle weakness in Pompe disease). (See "Causes of short stature", section on 'Noonan syndrome' and "Friedreich ataxia" and "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)".)

DIAGNOSTIC EVALUATION

Clinical suspicion — The signs and symptoms of HCM in children are nonspecific and, unless there is a positive family history or a commonly associated systemic disease, HCM is usually not the initial diagnostic consideration. (See 'Differential diagnosis' below.)

In approximately one-quarter of pediatric patients with HCM, a positive family history can be elicited [13]. Once a family history of HCM has been identified, the diagnostic evaluation usually includes a three-generation pedigree, electrocardiogram (ECG), and echocardiogram. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Screening of first-degree relatives' and 'Screening of first-degree relatives' below.)

In patients without a positive family history or suggestive systemic disease, a diagnosis of HCM may be suspected after an echocardiogram is obtained for evaluation of a heart murmur or other concerning cardiac symptoms. The evaluation of children with heart murmurs and suspected heart disease is reviewed more broadly in separate topic reviews. (See "Approach to the infant or child with a cardiac murmur" and "Suspected heart disease in infants and children: Criteria for referral".)

Aims of diagnostic testing — Diagnostic testing in children with suspected HCM has the following aims:

To establish the diagnosis of HCM

To identify the presence or severity of left ventricular outflow tract (LVOT) obstruction

To identify the presence or severity of mitral regurgitation

To assess the risk for arrhythmia (both supraventricular and ventricular) and to risk stratify for sudden cardiac death (SCD)

To assess overall LV diastolic and systolic function

To offer genetic testing and identify other affected family members

Electrocardiography — An ECG should be performed in all children when considering a diagnosis of HCM. ECG testing is the most sensitive routinely performed diagnostic test for HCM, but the ECG abnormalities are not specific to HCM and should prompt further diagnostic evaluation, usually with echocardiography.

The typical ECG findings in a patient with HCM include prominent voltages with localized or diffuse repolarization abnormalities (waveform 1). In certain phenocopies, such as Pompe disease, the markedly increased voltages can be pathognomonic (waveform 2). A more extensive discussion of the usual ECG findings in a patient with HCM is presented separately. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Electrocardiography'.)

Echocardiography — Comprehensive transthoracic echocardiography with two-dimensional, color Doppler, spectral Doppler, and tissue Doppler imaging should be performed in all patients when considering a diagnosis of HCM. Echocardiography can demonstrate cardiac morphology (image 1A-F), systolic and diastolic function, the presence and severity of an LVOT gradient, and the degree of mitral regurgitation (movie 1 and movie 2) [17-22].

LV hypertrophy – In pediatric patients, measurements of LV wall thickness must be adjusted for age and body surface area using z-scores (defined as the number of standard deviations from the population mean). According to the Pediatric Cardiomyopathy Registry criteria, HCM is considered if the LV wall thickness z-score is >2 [1].

Z-scores can be computed by several different methods. The Boston Children’s Hospital z-score system is based on data gathered over a 12-year period from normal children [23]. Other online calculators are also available [24].

In older adolescents and adults, a clinical diagnosis of HCM is confirmed when LV wall thickness ≥15 mm is imaged anywhere in the LV wall (measured at the thickest segment). A wall thickness of ≥13 mm may also be considered diagnostic of HCM, particularly when identified in a patient whose family member also has HCM.

Patients with inborn errors of metabolism and neuromuscular disorders tend toward concentric hypertrophy, whereas those with sarcomeric HCM more commonly have asymmetric septal hypertrophy, but this is not always the case (image 1A-F) [1].

Systolic anterior motion of the mitral valve – Pediatric patients with HCM may have systolic anterior motion (SAM) of the mitral valve, which positions the mitral valve within the LVOT. SAM of the mitral valve may result in LVOT obstruction when there is contact between the mitral valve and the septum. The greater the duration of mitral-septal contact, the higher the LVOT obstruction. The presence of SAM is not a requirement for a diagnosis of HCM.

LVOT obstruction – LVOT obstruction is present in 20 to 50 percent of pediatric patients with HCM [10,25]. Echocardiography can be used to accurately and noninvasively measure the presence and magnitude of LVOT gradients using continuous-wave Doppler techniques. LVOT gradients in HCM are dynamic, characterized by spontaneous variability on a day-to-day (or even hourly) basis, and are influenced by factors that alter myocardial contractility and loading conditions (eg, dehydration, heavy meals, etc). Therefore, for patients who do not have LVOT obstruction at rest (and who are able to cooperate with testing), exercise stress echocardiography should be performed to assess for inducible LVOT obstruction.

Genetic testing — We offer genetic testing to all patients with HCM, unless there is clinical suspicion for a secondary cause of LV hypertrophy (eg, hypertension). In most cases, referral to a clinical geneticist is warranted to guide the evaluation. The main purpose of genetic testing is to inform testing of other family members ("cascade testing"). (See 'Screening of first-degree relatives' below.)

In addition, genetic testing can aid in the diagnosis of HCM (see 'Diagnosis' below); however, 30 to 40 percent of children with phenotypically-determined HCM do not have identified mutations [26-28]. Genetic testing has little prognostic value because there is a substantial amount of genetic heterogeneity and it is not possible to classify mutations as being definitively "benign" or "malignant" [26]. Identifying patients with multiple mutations may have prognostic implications; however, this remains uncertain. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Predicting prognosis with mutations'.)

If the clinical evaluation raises suspicion for another genetic condition known to cause LV hypertrophy (eg, Noonan syndrome, glycogen storage diseases, mucopolysaccharidoses, other lysosomal storage diseases) (table 1), more focused testing is performed. All infants and young children (ie, <2 to 3 years old) with HCM should be referred to a clinical geneticist for consideration of systemic or metabolic diseases since these can be easy to miss. (See "Inborn errors of metabolism: Identifying the specific disorder".)

To date, over 1400 variants in 13 sarcomeric genes alone have been identified as disease causing in HCM [27]. Due to this substantial genetic heterogeneity, clinical genetic testing is currently able to identify a disease-causing sarcomere protein mutation in approximately 60 percent of patients with HCM not related to systemic disease, although disease expression among first-degree family members with sarcomeric HCM can be dramatically different [27-29]. For those patients with syndromes or systemic disease, referral to a geneticist is necessary for management of non-cardiac issues.

In a report of 84 children diagnosed with isolated unexplained LVH before 15 years of age who underwent genetic testing for mutations associated with HCM, mutations were identified in approximately half (25 of 51) of presumed sporadic cases and in nearly two-thirds (21 of 33) of familial cases [30]. In >75 percent of the children, mutations occurred in the cardiac beta-myosin heavy chain gene or the cardiac myosin binding protein-C gene. While the majority of mutations in HCM have been identified in sarcomeric proteins (figure 1), there are also reports of mutations in cytoskeletal proteins and other proteins such as the largest known protein, titin [31]. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Sarcomeric gene mutations causing HCM'.)

Approximately 30 percent of patients with suspected phenotypically-determined HCM will have no identified mutation, so-called phenotype-positive/genotype-negative. In the absence of data for a syndrome or systemic disease, the assumption is that such patients are genetically-determined with a yet undiscovered mutation or gene. Clinically, they follow the path of sarcomeric HCM.

Additional testing — Additional testing may be warranted for diagnostic purposes (eg, if the diagnosis of HCM remains uncertain following echocardiography) and for prognostic purposes (eg, assessment of exercise tolerance, risk assessment for ventricular arrhythmias with ambulatory ECG monitoring). The age and developmental level of the patient are key factors to consider when pursuing additional testing (ie, the child's ability to cooperate with exercise testing or to tolerate cardiac magnetic resonance [CMR] without need for sedation).

Ambulatory ECG monitoring – Ambulatory ECG monitoring should be performed for 24 to 48 hours in all pediatric patients diagnosed with HCM (based on clinical and imaging findings) as part of the risk assessment for ventricular arrhythmias and risk for sudden cardiac death. In addition, in patients with palpitations in whom the etiology is uncertain or if there is suspicion for atrial fibrillation/flutter, ambulatory monitoring should also be considered. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Ambulatory ECG monitoring'.)

Exercise testing – For all pediatric patients with known or suspected HCM (based on clinical and imaging findings) who are able to exercise on a treadmill, we proceed with exercise stress testing, usually combined with echocardiography, as part of the risk stratification (ie, abnormal blood pressure response to exercise) and for the assessment of LV outflow tract (LVOT) gradient. In a series of 91 children with HCM (median age 12 years, median LV wall thickness 12 mm) who underwent exercise testing, 40 patients (44 percent) had LVOT gradient <30 mmHg at rest but an inducible LVOT gradient >30 mmHg with exercise [32]. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Exercise testing' and "Exercise testing in children and adolescents: Principles and clinical application".)

Cardiac magnetic resonance imaging – We suggest performing CMR for diagnostic purposes in selected patients in whom the diagnosis of HCM remains uncertain following echocardiography. It is reasonable to consider performing CMR for additional risk stratification purposes in all patients with suspected or diagnosed HCM if expense is not an issue (ie, as part of a research protocol). In addition, in patients with HCM being considered for invasive septal reduction therapy in whom the mitral valve and papillary muscle anatomy are not well defined with echocardiography, CMR can be performed to clarify if a patient is better suited for alcohol septal ablation or surgical myectomy (image 2A-B). (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Cardiovascular magnetic resonance'.)

Late gadolinium enhancement (LGE) on CMR reflects fibrosis, and studies in adult patients suggest that LGE is a risk factor for SCD independent of other traditional risk factors. Among a cohort of 195 patients ≤21 years of age with HCM (155 with phenotypic expression and 40 genotype positive, phenotype negative patients) who underwent CMR, LGE was present (median 3.3 percent of myocardium) in 70 of 155 patients (46 percent) with phenotypic HCM, but in none of the genotype positive, phenotype negative carriers [33]. Although this represents lower incidence of fibrosis than seen in adults with HCM, in a subset of patients with serial imaging, there was evidence for an increase in fibrosis over time, suggesting a progressive disease process in this age group and need for repeat CMR imaging every two to three years. Additional data in a smaller cohort of children and adolescents with HCM showed diffuse fibrosis, assessed with CMR T1 mapping, correlates with symptoms and elevated serum brain natriuretic peptide levels [34]. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk modifiers'.)

Cardiac catheterization and biopsy – Invasive hemodynamic assessment via cardiac catheterization is not regularly required to confirm the diagnosis of HCM, but it may have utility if there is a question of restrictive cardiomyopathy or constrictive pericarditis. Endomyocardial biopsy is not regularly used for diagnosis but may be useful to exclude non-sarcomeric disease (eg, Fabry disease, amyloidosis, Danon disease). (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Cardiac catheterization' and "Endomyocardial biopsy".)

DIAGNOSIS — The diagnosis of HCM is established based on echocardiography and/or cardiac magnetic resonance (CMR). The hallmark finding is increased LV wall thickening (image 1A-F and image 2A-B) without an identifiable hemodynamic cause (eg, hypertension, valve disease) [35]. Other findings such as SAM of the mitral valve or hyperdynamic LV support the diagnosis but are not obligatory. (See 'Echocardiography' above.)

Identification of a known pathogenic mutation in the setting of otherwise unexplained LVH is diagnostic for HCM; however many children with phenotypically-determined HCM will have no identified mutation. In the case of a patient with no identified mutation or a variant of unknown significance, the diagnosis is based primarily on clinical findings, echocardiography, and family history. (See 'Genetic testing' above and "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

DIFFERENTIAL DIAGNOSIS

Children presenting with heart murmurs – Physical examination findings can help distinguish HCM from other causes of heart murmurs in children, though ultimately echocardiogram is necessary to confirm or exclude HCM as the diagnosis. (See "Approach to the infant or child with a cardiac murmur".)

Children presenting with chest pain, syncope, or symptoms of heart failure – There are many possible causes of chest pain (table 2), syncope (table 3), and heart failure (table 4) in children, including primary cardiac and noncardiac etiologies. The clinical course, physical examination findings, ECG, and echocardiogram distinguish HCM from other causes. (See "Causes of syncope in children and adolescents" and "Causes of nontraumatic chest pain in children and adolescents" and "Heart failure in children: Etiology, clinical manifestations, and diagnosis", section on 'Etiology and pathophysiology' and "Suspected heart disease in infants and children: Criteria for referral".)

LVH on echocardiogram – Other causes of LVH in infants and children include:

Hypertension. (See "Evaluation of hypertension in children and adolescents".)

Athlete’s heart (in adolescents).

Valvar, subvalvar, or supravalvar aortic stenosis. (See "Valvar aortic stenosis in children" and "Subvalvar aortic stenosis (subaortic stenosis)".)

Pulmonary parenchymal or vascular disease. (See "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

Endocrine disease (eg, maternal gestational diabetes). (See "Infants of women with diabetes", section on 'Cardiomyopathy'.)

Rheumatic and immunological disease (eg, systemic lupus erythematosus). (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Cardiac'.)

Cardiotoxic exposures (eg, anthracyclines). (See "Clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of anthracycline cardiotoxicity".)

These other causes of LVH can be distinguished from HCM on the basis of the echocardiogram, clinical history, family history including 3-generation pedigree, blood pressure measurements, and metabolic and/or genetic testing. Historical elements such as longstanding hypertension, rheumatological diagnosis, or history of cardiotoxic exposure can implicate secondary LVH over HCM. Family history of suspicious LVH in multiple family members suggests an inherited primary pathologic process. Although no single finding on non-invasive diagnostic testing can distinguish HCM from a secondary cause of LVH (eg hypertension, athlete's heart), HCM is more likely with lateral ECG changes and echocardiographic findings of non-concentric LVH, maximal LV wall thickness >15 mm, nondilated LV cavity (LV end diastolic diameter ≤55 mm) and certain abnormal diastolic parameters. In addition, CMR may offer further details supporting a diagnosis of HCM, such as the presence of myocardial fibrosis [36].

SCREENING OF FIRST-DEGREE RELATIVES — Hypertrophic cardiomyopathy is an autosomal dominant disorder, and most mutations have a high degree of penetrance. As a result, first-degree family members of an affected individual should be evaluated for possible inheritance of the disease (algorithm 1). Our approach is as follows, and is generally consistent with the recommendations of a variety of experts and professional societies [17,22,37,38]. (See 'Society guideline links' below.)

Clinical evaluation – First-degree relatives of the proband should undergo screening that includes history, physical examination, ECG, and echocardiography. We proceed with screening for all first-degree relatives regardless of age because limited data suggest that HCM may manifest prior to age 10 in approximately 30 percent of patients [38,39].

Family members who have a normal clinical evaluation should not necessarily be assumed to be free of risk:

If screening is normal in a child prior to puberty, clinical evaluation should be repeated every two to three years until the onset of puberty.

Because hypertrophy frequently develops during adolescence, clinical evaluation should be repeated annually from 12 to 18 years of age.

Due to the possibility of delayed-onset hypertrophy, it is recommended that adult family members with normal ECGs and echocardiograms who are over the age of 18 be reevaluated approximately every five years. There may be a role for tissue Doppler echocardiography in such patients, where abnormalities in contraction and relaxation velocities can suggest pre-clinical myocardial dysfunction [40-42]. However, these abnormalities are not considered diagnostic for HCM and rarely precede the development of ECG abnormalities.

Genetic testing – Genetic testing is based on whether an HCM-causing mutation has been identified in the index case:

If a definite HCM-causing mutation has been identified in the index case, we proceed with targeted genetic testing in all first-degree relatives of the proband ("cascade testing"). Relatives who test negative for the mutation are considered unaffected. Relatives testing positive for the same disease-causing mutation as the index case, but in whom there is no clinical evidence of LVH, are considered at risk for developing HCM and require regular re-evaluation, as previously discussed. In a study of 119 children who were identified through cascade genetic testing to have a pathogenic sarcomere mutation and who were followed for an average of 6.9 years, 7 percent developed increased LV wall thickness, consistent with a clinical diagnosis of HCM [29]. In another study of 285 adult and pediatric patients with an identified sarcomeric protein mutation, reported penetrance for developing HCM was almost 50 percent at 15 years of follow-up [43]. These studies suggest that some HCM family members who carry a pathogenic mutation may never develop a clinical diagnosis of HCM; however, the incidence is much higher than the general population, and persons with an identified sarcomeric mutation warrant lifelong follow-up. Both points should be raised when discussing genetic testing with families. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Screening of family members for HCM'.)

If a definite HCM-causing mutation has not been identified in the index case, we proceed only with clinical screening and do not perform genetic testing.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Hypertrophic cardiomyopathy in adults (The Basics)" and "Patient education: Hypertrophic cardiomyopathy in children (The Basics)")

Beyond the Basics topic (see "Patient education: Hypertrophic cardiomyopathy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Hypertrophic cardiomyopathy (HCM) is one of the most common forms of inherited cardiomyopathy in both adults and children, and is characterized by hypertrophy of the left ventricle (LV) which sometimes involves the right ventricle. The term HCM is applied broadly to a number of different clinical presentations, including sarcomeric HCM as well as HCM "phenocopies" that present similarly to sarcomeric HCM but that have different pathophysiologies (table 1). (See 'Introduction' above and 'Definitions' above.)

The prevalence of HCM in the general pediatric population is likely underestimated since many affected children have subclinical disease, with annual incidence of HCM from all causes of approximately 0.3 to 0.5 cases per 100,000 children. (See 'Epidemiology' above.)

Clinical findings associated with HCM can develop in infants and pre-pubertal children, but are more commonly seen in teenagers and young adults. An isolated heart murmur or signs and symptoms of heart failure are most common in infants <1 year of age, while children ≥1 year of age are most commonly asymptomatic. Presenting symptoms may include chest pain, presyncope/syncope, palpitations, heart failure symptoms, and/or sudden cardiac arrest/death, and the physical examination may be normal or may reveal nonspecific abnormalities such as a systolic murmur, fourth heart sound, and/or a left ventricular lift. (See 'Clinical manifestations' above.)

When HCM is suspected, the diagnostic evaluation should include a three-generation pedigree, electrocardiogram (ECG), and echocardiogram. Additional testing, which selectively may include ambulatory ECG monitoring, exercise testing, cardiac magnetic resonance imaging, and/or cardiac catheterization with endomyocardial biopsy, may be warranted for diagnostic purposes, and for prognostic purposes or risk assessment. All first-degree relatives of the proband should undergo screening. (See 'Diagnostic evaluation' above and 'Screening of first-degree relatives' above.)

We offer genetic testing to all patients with HCM, unless there is clinical suspicion for a secondary cause of LV hypertrophy (eg, hypertension). In most cases, referral to a clinical geneticist is warranted to guide the evaluation. (See 'Genetic testing' above.)

The hallmark finding of HCM is increased LV wall thickening without an identifiable hemodynamic cause (eg, hypertension, valve disease) (image 1A-F and image 2A-B). Other findings such as systolic anterior motion (SAM) of the mitral valve or hyperdynamic LV support the diagnosis but are not obligatory. Identification of a known pathogenic mutation in the setting of otherwise unexplained left ventricular hypertrophy (LVH) is diagnostic for HCM; however, 30 to 40 percent of children with phenotypically-determined HCM will have no identified mutation. (See 'Diagnosis' above.)

The differential diagnosis of HCM in children is broad and includes other causes of murmurs, chest pain, syncope, and heart failure, including primary cardiac and noncardiac etiologies. The clinical course, physical examination findings, ECG, and echocardiogram distinguish HCM from other causes. Other causes of LVH include hypertension; athlete's heart; valvar, subvalvar or supravalvar aortic stenosis; pulmonary parenchymal or vascular disease; endocrine disease (eg, maternal gestational diabetes); rheumatic and immunological disease (eg, systemic lupus erythematosus); and cardiotoxic exposures (eg, anthracyclines). These other causes of LVH can be distinguished from HCM on the basis of the echocardiogram, clinical history, family history including three-generation pedigree, blood pressure measurements, and metabolic and/or genetic testing. (See 'Differential diagnosis' above.)

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