Hypertrophic cardiomyopathy in children: Clinical manifestations and diagnosis

INTRODUCTION — Hypertrophic cardiomyopathy (HCM) is one of the most common forms of inherited cardiomyopathy in both adults and children. It is characterized by hypertrophy of the left ventricle (LV) (image 1A-B and image 2A-B). 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 (SCA) and sudden cardiac death (SCD) in children".)

This topic will review the epidemiology, clinical manifestations, and diagnosis of HCM in children. The management and prognosis of pediatric HCM and other related topics are discussed separately.

●(See "Hypertrophic cardiomyopathy in children: Management and prognosis".)

●(See "Sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in children".)

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

●(See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

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

●(See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death".)

●(See "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction".)

●(See "Hypertrophic cardiomyopathy: Management of patients with outflow tract obstruction".)

DEFINITIONS — The terms HCM and left ventricular hypertrophy (LVH) are applied broadly to a number of different clinical presentations:

●Genetically determined HCM – Genetically determined HCM includes sarcomeric and nonsarcomeric (or syndromic) HCM; the term specifically excludes LVH due to secondary influences (eg, athletic training, hypertension, other systemic illnesses).

•Sarcomeric HCM – Sarcomeric HCM (sometimes referred to as "true HCM") is a condition caused by pathologic variants in genes encoding sarcomeric proteins (figure 1). (See 'Genetics' below and "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Sarcomeric gene mutations causing HCM'.)

•Nonsarcomeric (syndromic) HCM – Increasingly, variants in nonsarcomeric genes encoding proteins with a wide range of functions have been shown to cause HCM [1]. There are a number of genetic syndromes and neuromuscular disorders that present with morphologic characteristics similar to sarcomeric HCM (sometimes called "HCM phenocopies"). These include inborn errors of metabolism, multiple congenital anomaly syndromes (eg, Noonan syndrome), mitochondrial disorders, and neuromuscular disorders (table 1). The most common of these syndromes is Noonan syndrome, with other examples including Danon disease, Friedreich ataxia, Fabry disease, LEOPARD syndrome, Pompe disease, and mitochondrial diseases [2]. Mutations of PRKGA2 are another rare cause of nonsarcomeric HCM.

•Preclinical HCM – The term preclinical HCM (also called genotype-positive/phenotype-negative [G+ P-]) describes individuals who are known to carry a pathologic variant in a gene associated with HCM but who lack current clinical evidence of HCM (ie, no LVH on echocardiography). G+ P- individuals are typically identified through cascade testing after a family member is diagnosed with HCM. (See 'Evaluation of first-degree relatives' below.)

●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 diabetes), rheumatic disease, immunological disease, and cardiotoxic exposures are not considered HCM. (See 'Differential diagnosis' below.)

There is debate over whether syndromic causes of HCM should be included when describing pediatric HCM. The approach to therapy is often the same, though it is worth noting that patients with syndromic causes of HCM are often excluded from studies of medical and implantable cardioverter-defibrillator therapy. In addition, the prognosis is generally worse for syndromic HCM, as discussed separately. (See "Hypertrophic cardiomyopathy in children: Management and prognosis", section on 'Prognosis'.)

In this topic review, nonsyndromic and syndromic causes of HCM are considered together under the broad term "HCM" unless otherwise specified.

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, syndromic forms, and idiopathic) is approximately 0.3 to 0.5 cases per 100,000 children [3-7]. 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 [4,5]. 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'.)

GENETICS — Genes encoding sarcomeric proteins account for the majority of known pathogenic variants in HCM (figure 1) [8]. Increasingly, variants in nonsarcomeric genes encoding proteins with a wide range of functions have also been shown to cause HCM [1]. Genetic syndromes and neuromuscular disorders that present with morphologic characteristics similar to sarcomeric HCM (sometimes called "HCM phenocopies") are summarized in the table (table 1). These conditions account for approximately 15 to 25 percent of pediatric HCM [3,4,7,9].

●Nonsyndromic HCM – In studies of pediatric patients with nonsyndromic HCM who underwent genetic testing, approximately 50 to 70 percent were found to have pathogenic or likely pathogenic variants, mostly in genes encoding sarcomeric proteins (figure 1) [10-12]. The diagnostic yield of genetic testing varies depending on the specific genes included in the testing panel and whether the child has a family history of cardiomyopathy (the yield is generally higher in children with familial cardiomyopathy) [10,12]. Disease expression among first-degree family members with sarcomeric HCM can be dramatically different [8,13,14].

In a study of 337 pediatric patients with nonsyndromic HCM who had disease-causing variants identified through genetic testing, the relative frequencies of genetic variants were as follows [12]:

•Single variant in a sarcomeric gene – 91 percent (variants in MYBPC3 or MYH7 accounted for 74 percent)

•Single variant in a nonsarcomeric gene – 4 percent

•Multiple variants identified – 5 percent

Approximately 30 to 50 percent of pediatric patients with phenotypically determined HCM will have no identified pathogenic variant (referred to as phenotype-positive/genotype-negative) [11]. In the absence of clinical signs of a syndrome or systemic disease as the underlying cause, the assumption is that such patients are genetically determined with a yet undiscovered mutation or gene. However, simple mendelian inheritance alone is insufficient to explain inheritance patterns, and some nonsarcomeric mutations and genetic polymorphisms are known to work in a polygenic manner [15]. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Renin-angiotensin system polymorphisms'.)

●Syndromic HCM – Approximately 15 to 25 percent of children with HCM have underlying genetic syndromes (table 1) [3,4,7,9]. In a report from the from the Pediatric Cardiomyopathy Registry that included 855 children with HCM (nonsyndromic HCM in 75 percent and syndromic in 25 percent), identified causes among patients with syndromic HCM included [3]:

•Multiple congenital abnormality (MCA) syndromes – MCA syndromes accounted for 9 percent of all HCM cases and 36 percent of syndromic HCM. Noonan syndrome was the most common syndrome, accounting for 78 percent of cases in this category. (See "Noonan syndrome".)

•Inborn errors of metabolism (IEM) – IEMs accounted for 9 percent of all HCM cases and 34 percent of syndromic HCM. Pompe disease was the most common IEM, accounting for 34 percent of cases in this category. (See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)".)

•Neuromuscular disorders – Neuromuscular disorders accounted for 7 percent of all HCM cases and 30 percent of syndromic HCM. Friedreich ataxia was the most common neuromuscular disorder, accounting for 88 percent of cases in this category. (See "Friedreich ataxia".)

Additional details regarding the genetics of HCM are provided separately. (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing".)

CLINICAL MANIFESTATIONS — Clinical findings associated with HCM can develop in infants and prepubertal 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 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, LV systolic dysfunction (LV ejection fraction [LVEF] <50 percent) has been reported in approximately 5 to 8 percent of patients with HCM [16,17]. This group of patients is at higher risk for atrial fibrillation, stroke, symptomatic heart failure, and SCD [16,17]. 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 LV 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 preambulatory 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 [18]:

●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 [18,19]. (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 to have symptoms of congestive heart failure (24 versus 9 percent of infants with sarcomeric HCM) [2,18,19]. (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 (IEM) and malformation syndromes, and is primarily due to heart failure rather than sudden death [3]. (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 [20]; however, children with IEM have a higher rate of presenting with symptomatic heart failure. Among those who come to clinical attention, symptoms may include [21]:

•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 exertional chest pain (angina) in children with HCM is myocardial bridging. (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 an LV 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 syndromic disorder, 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 [21]. Once a family history of HCM has been identified, the diagnostic evaluation usually includes a three-generation pedigree, ECG, and echocardiogram [22]. (See 'Evaluation of first-degree relatives' below.)

In patients without a positive family history or syndromic findings, 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:

●Establish the diagnosis of HCM

●Identify the presence or severity of LV outflow tract (LVOT) obstruction

●Identify the presence or severity of mitral regurgitation

●Assess the risk for arrhythmia (both supraventricular and ventricular) and to risk stratify for SCD

●Assess overall LV diastolic and systolic function

●Offer genetic testing and identify other affected family members

Electrocardiography — An ECG should be performed in all children when considering a diagnosis of HCM [22]. 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 syndromic causes of HCM, 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 [22]. Echocardiography can demonstrate cardiac morphology (image 2A-B), systolic and diastolic function, the presence and severity of an LVOT gradient, and the degree of mitral regurgitation (movie 1 and movie 2) [23-28].

●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 [3].

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 [29]. Other online calculators are also available [30].

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 to have concentric hypertrophy, whereas those with sarcomeric HCM more commonly have asymmetric septal hypertrophy, but this is not always the case (image 2A-B) [3].

●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 [18,31]. 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 with no LVOT obstruction at rest who are old enough to cooperate with exercise testing, exercise stress echocardiography should be performed to assess for inducible LVOT obstruction. Performing a Valsalva maneuver (if the child is able to cooperate with the instructions) can also elicit a gradient across the LVOT and may assist with the diagnosis, particularly if exercise testing is not feasible.

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.

Genetic testing serves the following purposes:

●It informs testing of other family members ("cascade testing"). (See 'Evaluation of first-degree relatives' below.)

●For patients with syndromic HCM, characterizing the underlying syndrome can help identify noncardiac issues. If the child has clinical features suggestive of a specific syndromic cause of HCM (eg, Noonan syndrome, glycogen storage disease, mucopolysaccharidosis) (table 1), focused genetic testing for the specific disorder(s) 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 metabolic or storage disorders since these can be easy to miss. (See "Inborn errors of metabolism: Identifying the specific disorder".)

●Genetic testing can also aid in the diagnosis of sarcomeric HCM; however, 30 to 50 percent of children with phenotypically-determined HCM do not have identified mutations [8,10-12]. (See 'Genetics' above and 'Diagnosis' below.)

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" [32]. 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'.)

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 cardiovascular magnetic resonance [CMR] imaging without need for sedation).

●Ambulatory ECG monitoring – Ambulatory ECG monitoring should be performed in all pediatric patients diagnosed with HCM as part of the risk assessment for ventricular arrhythmias and SCD [22]. 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 "Ambulatory ECG monitoring" and "Hypertrophic cardiomyopathy in children: Management and prognosis", section on 'Prevention of sudden cardiac death (ICD placement)'.)

●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 to assess 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 [33]. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and evaluation", section on 'Exercise testing' and "Exercise testing in children and adolescents: Principles and clinical application".)

●Cardiovascular 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 and there are no other contraindications to magnetic resonance imaging. In addition, in patients with HCM being considered for surgical myectomy in whom the mitral valve and papillary muscle anatomy are not well defined with echocardiography, CMR can be performed to aid in preoperative surgical planning.

Late gadolinium enhancement (LGE) on CMR reflects fibrosis (image 1A-B), and studies in adult patients suggest that LGE is a risk factor for SCD independent of other traditional risk factors. (See "Hypertrophic cardiomyopathy: Risk stratification for sudden cardiac death", section on 'Risk modifiers'.)

Among a cohort of 195 patients ≤21 years of age with HCM (155 with phenotypically-determined HCM and 40 genotype-positive/phenotype-negative [G+ P-] patients) who underwent CMR, LGE was present in 70 of 155 patients (46 percent) with phenotypic HCM, but in none of the G+ P- carriers [34]. Although this represents lower incidence of fibrosis compared with studies in adults with HCM, in a subset of patients with serial imaging, there was evidence of progressive fibrosis over time. In a smaller study of children and adolescents with HCM, diffuse fibrosis on CMR correlated with symptoms and elevated serum B-type natriuretic peptide levels [35].

These data are insufficient to firmly establish LGE as a major risk factor for SCD in pediatric patients with HCM. However, when considered together with the data on LGE in adults with HCM, it is reasonable to consider extensive LGE as a potential risk modifier when assessing the overall SCD risk profile. (See "Hypertrophic cardiomyopathy in children: Management and prognosis", section on 'Prevention of sudden cardiac death (ICD placement)'.)

●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 nonsarcomeric 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 CMR. The hallmark finding is increased LV wall thickening (image 1A-B and image 2A-B) without an identifiable hemodynamic cause (eg, hypertension, valve disease) [36]. 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 LV hypertrophy 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

●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".)

●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 LV hypertrophy (LVH) in infants and children include:

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

•Athlete's heart (in adolescents). (See "Definition and classification of the cardiomyopathies", section on 'Athlete's heart'.)

•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 mothers with diabetes (IMD)", section on 'Ventricular hypertrophy'.)

•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, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

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. 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 noninvasive 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 nonconcentric LVH, maximal LV wall thickness >15 mm, nondilated LV cavity (LV end-diastolic diameter ≤55 mm), LV outflow tract obstruction at rest, and late gadolinium enhancement patterns on CMR [37].

EVALUATION 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 [22,38]. (See 'Society guideline links' below.)

●Clinical evaluation – First-degree relatives of the proband should undergo screening that includes history, physical examination, ECG, and echocardiography or other appropriate imaging modality. 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 three to five years. There may be a role for tissue Doppler echocardiography in such patients, where abnormalities in contraction and relaxation velocities can suggest preclinical 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:

•Index case has an HCM-causing variant – If the index case has a pathogenic or likely pathogenic variant, we proceed with targeted genetic testing in all first-degree relatives of the proband ("cascade testing"). (See "Hypertrophic cardiomyopathy: Gene mutations and clinical genetic testing", section on 'Screening of family members for HCM'.)

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 LV hypertrophy (referred to as genotype-positive/phenotype-negative [G+ P-]), are considered at risk for developing HCM and require regular repeated clinical evaluations, as detailed above.

In a study of 119 children who were identified through cascade genetic testing to have pathogenic sarcomere mutations 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 [14]. In another study of 285 adult and pediatric patients with identified sarcomeric protein mutations, reported penetrance for developing HCM was almost 50 percent at 15 years of follow-up [43].

These studies suggest that some G+ P- individuals 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.

Another point to make when counseling patients before cascade testing is that results of genetic testing can be accessed by life and disability insurers. However, in the United States and many other countries, it is illegal to discriminate against patients for health insurance based on a preexisting genetic diagnosis. This issue is discussed separately. (See "Genetic testing", section on 'Genetic discrimination'.)

•Index case does not have an HCM-causing variant – If the index case or relatives do not have a definite HCM-causing mutation, 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 5^th to 6^th 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 10^th to 12^th 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

●Definitions and prevalence – Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) (image 1A-B and image 2A-B). The term HCM is applied broadly to a number of different clinical presentations, including sarcomeric HCM as well as HCM occurring as part of a broader genetic syndrome or neuromuscular disorder (table 1). HCM is one of the most common forms of inherited cardiomyopathy, with a prevalence of approximately 0.3 to 0.5 cases per 100,000 children. (See 'Definitions' above and 'Epidemiology' above.)

●Clinical manifestations – Clinical findings associated with HCM can develop at any time from infancy to adolescence or early adulthood. Patients who are diagnosed with HCM in infancy are more likely to have a symptoms of heart failure at presentation, while children diagnosed at age ≥1 year of age are most commonly asymptomatic. An isolated heart murmur is another common presenting finding. Other presenting symptoms may include chest pain, presyncope/syncope, palpitations, heart failure symptoms, and/or sudden cardiac arrest/death. The physical examination may be normal or may reveal nonspecific abnormalities such as a systolic murmur, fourth heart sound, and/or a left ventricular (LV) lift. (See 'Clinical manifestations' above.)

●Diagnostic evaluation – When HCM is suspected, the diagnostic evaluation includes (see 'Diagnostic evaluation' above):

•A three-generation pedigree.

•ECG. (See 'Electrocardiography' above.)

•Echocardiogram. (See 'Echocardiography' above.)

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

•Additional selective testing – This may include ambulatory monitoring, exercise testing, cardiac magnetic resonance imaging, and/or cardiac catheterization with endomyocardial biopsy. These tests may be warranted for diagnostic purposes, and for prognostic purposes or risk assessment. (See 'Additional testing' above.)

●Diagnosis – The hallmark finding of HCM is increased LV wall thickening without an identifiable hemodynamic cause (eg, hypertension, valve disease) (image 1A-B 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 LVH is diagnostic for HCM; however, 30 to 50 percent of children with phenotypically-determined HCM will have no identified mutation. (See 'Diagnosis' above.)

●Evaluation of first-degree relatives – Once the diagnosis of HCM is made, all first-degree relatives of the proband should undergo a clinical evaluation that includes history, physical examination, ECG, and echocardiography. In addition, 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. (See 'Evaluation of first-degree relatives' above.)

●Differential diagnosis – 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.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John L Jefferies, MD, MPH, FACC, FAHA, who contributed to earlier versions of this topic review.