What is the difference in diagnosis and management between Naxos syndrome and Carvajal syndrome?

Naxos Syndrome vs Carvajal Syndrome: Key Differences

Both Naxos disease and Carvajal syndrome are autosomal recessive cardiocutaneous disorders caused by desmosomal protein mutations, but they differ critically in their cardiac phenotype: Naxos disease predominantly affects the right ventricle (arrhythmogenic right ventricular cardiomyopathy), while Carvajal syndrome predominantly affects the left ventricle (dilated cardiomyopathy), with Carvajal syndrome presenting earlier in childhood with more severe heart failure and worse prognosis. 1, 2, 3, 4

Genetic Basis

Naxos Disease

• Caused by mutations in the plakoglobin (JUP) gene that truncate the protein at the C-terminal domain 1, 2, 4
• Autosomal recessive inheritance with 100% penetrance by adolescence 2, 5

Carvajal Syndrome

• Caused by mutations in the desmoplakin (DSP) gene, specifically a homozygous mutation in exon 24 (c.4297C > T, p.Gln1433*) that truncates the intermediate filament-binding site 1, 3, 6, 4
• Also autosomal recessive inheritance 1

Cutaneous Manifestations (Identical in Both)

• Woolly hair: Present from birth in all patients 2, 3, 6, 5
• Palmoplantar keratoderma: Develops during the first year of life 2, 5
• These cutaneous findings should immediately prompt cardiac evaluation 5, 4

Cardiac Phenotype (Critical Distinguishing Feature)

Naxos Disease

• Arrhythmogenic right ventricular cardiomyopathy (ARVC) with predominant right ventricular involvement 1, 2
• Fibro-fatty replacement of right ventricular myocardium, particularly in the "triangle of dysplasia" (inferior, apical, and infundibular walls) 1
• Left ventricular involvement occurs in >50% of cases but is typically less severe 1, 4
• Clinical manifestation by adolescence 2, 5

Carvajal Syndrome

• Dilated cardiomyopathy with predominantly left ventricular involvement 1, 3, 6, 4
• Biventricular dilatation with significantly impaired left ventricular systolic function 6
• Clinical manifestation during childhood (earlier than Naxos disease) 2, 5
• More frequent progression to heart failure 2, 4

Clinical Presentation

Naxos Disease

• Syncope, sustained ventricular tachycardia, or sudden cardiac death as presenting features 2, 5
• Right heart failure symptoms appear during end stages 2
• Ventricular tachycardia typically shows left bundle branch morphology (originating from right ventricle) 1

Carvajal Syndrome

• Heart failure symptoms (weakness, tachycardia, tachypnea, shortness of breath) as primary presentation 3, 6, 5
• Hepatomegaly from congestive heart failure 6
• Moderate to severe mitral and tricuspid regurgitation 6
• Earlier morbidity and mortality compared to Naxos disease 2, 4

Diagnostic Approach

Electrocardiography

• Both conditions show ventricular arrhythmias on ambulatory ECG monitoring 1, 2
• Task Force Criteria used for diagnosis of cardiomyopathy in both syndromes 1, 3

Echocardiography

• Naxos disease: Right ventricular dilatation, wall motion abnormalities, reduced RV fractional area change and ejection fraction 1
• Carvajal syndrome: Biventricular dilatation with severely reduced left ventricular ejection fraction (can be as low as 22%) 6

Genetic Testing

• Molecular genetic evaluation is essential for confirming diagnosis 3, 6, 5
• Identifies specific desmosomal gene mutations (plakoglobin for Naxos, desmoplakin for Carvajal) 2, 3, 6
• Enables genetic counseling for familial cases 5

Management Differences

Naxos Disease

• Implantable cardioverter-defibrillator (ICD) is primary intervention for prevention of sudden cardiac death 1, 2, 5
• Antiarrhythmic drugs (beta-blockers, sotalol, amiodarone) for preventing recurrent ventricular tachycardia 1, 2
• Heart transplantation considered at end stages 2

Carvajal Syndrome

• Aggressive heart failure management is the priority given predominant left ventricular dysfunction 3, 6
• ICD evaluation still warranted given arrhythmogenic potential 1
• Earlier consideration for heart transplantation due to more rapid progression 2, 4
• Pharmacological treatment for congestive heart failure with guideline-directed medical therapy 2

Prognosis

• Carvajal syndrome has worse prognosis with earlier morbidity and mortality, often presenting in childhood rather than adolescence 2, 4
• Three of six patients in one case series died during follow-up, highlighting the severity of both conditions 5
• Early diagnosis through recognition of cutaneous findings may increase life expectancy through timely treatment of heart failure and arrhythmias 5

Critical Clinical Pitfall

• Any child presenting with woolly hair and palmoplantar keratoderma from birth must be evaluated for cardiomyopathy, as cardiac involvement is inevitable with 100% penetrance 2, 3, 5
• Failure to recognize these cutaneous manifestations delays cardiac diagnosis and increases risk of sudden cardiac death 3, 5