What are the causes of severe left-sided cardiomegaly (enlargement of the heart) in a 17-year-old female patient?

Severe Left-Sided Cardiomegaly in a 17-Year-Old Female

In a 17-year-old girl with severe left-sided cardiomegaly, the most likely causes are hypertrophic cardiomyopathy (HCM), congenital left-sided obstructive lesions (particularly aortic stenosis or coarctation), or infiltrative/storage diseases including Fabry disease, with HCM being the most common primary cardiac cause in this age group. 1

Primary Differential Diagnoses

Hypertrophic Cardiomyopathy (Most Common)

• HCM is the leading genetic cause of left ventricular hypertrophy in adolescents and young adults, characterized by LV wall thickness ≥15 mm (or 13-14 mm with positive family history or genetic testing) in the absence of other causes. 1
• The disease results from sarcomeric protein mutations (most commonly MYBPC3 and MYH7 genes) and presents with asymmetric septal hypertrophy, though any pattern of LV thickening can occur. 1
• Adolescent females may be asymptomatic or present with exertional dyspnea, chest pain, palpitations, or syncope—with syncope during high-intensity exercise being particularly ominous for sudden cardiac death risk. 1, 2
• The ECG is abnormal in 75-95% of cases, showing LV hypertrophy, deep Q waves, or T-wave inversions that may precede echocardiographic evidence of hypertrophy. 1

Congenital Left-Sided Obstructive Lesions

• Aortic stenosis causes pressure overload leading to compensatory concentric LV hypertrophy, with severity stratified by mean Doppler gradient (severe ≥40 mmHg). 3, 2
• Coarctation of the aorta produces systemic hypertension and LV hypertrophy through increased afterload, even after repair. 1, 3
• These lesions may have been undiagnosed if mild in childhood but progressive over time, particularly with bicuspid aortic valve variants. 2

Infiltrative and Storage Diseases

• Fabry disease should be strongly considered in adolescent females with unexplained LV hypertrophy, as carrier females can develop substantial cardiomyopathy in late adolescence and adulthood. 1
• Fabry disease presents with concentric LV hypertrophy, often accompanied by angiokeratomas, corneal whorls on slit-lamp examination, and neuropathic pain. 1
• Other storage diseases include Pompe disease, Danon disease, and mitochondrial disorders, though these typically present earlier in childhood. 3

Systemic Conditions

• Chronic systemic hypertension from any cause (including renal disease, endocrine disorders, or coarctation) produces concentric LV hypertrophy as a compensatory mechanism. 1, 4
• Acromegaly, though rare in adolescents, causes biventricular hypertrophy through GH/IGF-1 excess and should be considered if clinical features suggest growth hormone excess. 5, 6, 7

Critical Diagnostic Approach

Initial Imaging

• Transthoracic echocardiography is the primary diagnostic modality and must assess LV wall thickness (measure all segments), chamber dimensions, systolic and diastolic function, presence of left ventricular outflow tract obstruction, and valvular abnormalities. 1
• Measure maximal end-diastolic wall thickness in all LV segments, as HCM can have focal or asymmetric patterns. 1
• Assess for systolic anterior motion of the mitral valve and dynamic LVOT gradients with Valsalva maneuver. 1

Cardiac MRI Indications

• CMR should be performed when echocardiography is inadequate for defining anatomy, to evaluate for late gadolinium enhancement (suggesting fibrosis in HCM or infiltrative disease), or to precisely quantify LV mass and wall thickness. 2
• CMR has superior sensitivity for detecting focal hypertrophy and characterizing tissue composition compared to echocardiography. 2

Essential Laboratory Testing

• Measure alpha-galactosidase A activity in plasma or leukocytes to screen for Fabry disease, particularly in females where enzyme levels may be normal despite disease. 1
• Check IGF-1 levels if acromegaly is suspected based on clinical features. 5, 6
• Obtain BNP/NT-proBNP to assess for heart failure and disease severity. 1
• Screen for systemic hypertension with ambulatory blood pressure monitoring if office readings are elevated. 1, 4

Electrocardiographic Evaluation

• 12-lead ECG is mandatory and abnormal in 75-95% of HCM cases, showing LV hypertrophy, deep Q waves, T-wave inversions, or left axis deviation. 1
• 24-hour Holter monitoring is essential to detect nonsustained ventricular tachycardia (≥3 beats at ≥120 bpm), which identifies patients at higher risk for sudden cardiac death. 1

Genetic Testing

• Genetic testing for sarcomeric protein mutations should be performed in all patients with unexplained LV hypertrophy meeting HCM criteria, as identification of pathogenic variants confirms diagnosis and enables family screening. 1
• If Fabry disease is suspected, molecular testing of the GLA gene is required for definitive diagnosis in females, as enzyme activity may be normal. 1

Critical Pitfalls to Avoid

• Do not attribute LV hypertrophy to "athlete's heart" without excluding pathologic causes—physiologic hypertrophy in athletes rarely exceeds 13 mm wall thickness and is associated with normal diastolic function and proportional chamber enlargement. 1
• Avoid missing Fabry disease in young females, as this is a treatable condition with enzyme replacement therapy that can prevent progression if started early. 1
• Do not overlook coarctation of the aorta—always measure four-limb blood pressures and assess for radio-femoral pulse delay. 3
• Recognize that normal ECG does not exclude HCM, though it makes the diagnosis less likely; echocardiography remains essential. 1

Family Screening Implications

• If HCM is diagnosed, first-degree relatives require clinical screening with ECG and echocardiography, with adolescents screened every 12-18 months until physical maturity is achieved. 1
• Genetic testing of the proband enables cascade screening of family members for the specific pathogenic variant. 1