Naxos disease (ORPHA:34217)
A rare arrhythmogenic right ventricular cardiomyopathy (ARVC) and a cutaneous phenotype, characterized by peculiar woolly hair and palmoplantar keratoderma.
Epidemiology
Naxos disease was first described in families originating from the Greek island of Naxos. Moreover, affected families have been identified in other Aegean islands, Turkey, Israel, Saudi Arabia, India, Argentina and French-Canadian families. A syndrome with the same cutaneous phenotype and predominantly left ventricular involvement has been described in families from India and Ecuador (carvajal syndrome).
Clinical description
Woolly hair appears from birth, palmoplantar keratoderma develop during the first year of life and cardiomyopathy is clinically manifested by adolescence with 100% penetrance. Patients present with syncope, sustained ventricular tachycardia or sudden death. Symptoms of right heart failure appear during the end stages of the disease.
Etiology
Mutations in the JUP gene encoding the desmosomal proteins plakoglobin and desmoplakin have been identified as the cause of Naxos disease. Defects in the linking sites of these proteins can interrupt the contiguous chain of cell adhesion, particularly under conditions of increased mechanical stress or stretch, leading to cell death, progressive loss of myocardium and fibro-fatty replacement.
Diagnostic methods
Diagnosis is suspected on clinical presentation based on palmoplantar keratoderma with hair shaft abnormalities, mostly of woolly hair type present from infancy, fulfilling the diagnostic criteria of ARVC later in adolescence or early adulthood. It is confirmed by the presence of a JUP variant in homozygosity on genetic testing.
Differential diagnosis
Naxos disease should be differentiated from carvajal syndrome that is caused by homozygous variants in desmoplakin (DSP), clinically manifested during childhood and leading more frequently to heart failure. It presents with similar cutaneous features as those of Naxos disease, in infancy, but the cardiac phenotype is compatible with arrhythmogenic cardiomyopathy with left ventricular predominance.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Naxos disease transmission is autosomal recessive. If both individuals are carriers of the disease-causing variant, there is a 25% risk of having an affected child at each pregnancy. Therefore it is recommended that genetic counseling be offered to at-risk couples.
Management and treatment
Implantation of an automatic cardioverter defibrillator is indicated for prevention of sudden cardiac death. Antiarrhythmic drugs are used for preventing recurrences of episodes of sustained ventricular tachycardia and classical pharmacological treatment for congestive heart failure, while heart transplantation is considered at the end stages.
Prognosis
Prognosis in Naxos disease tracks that of other genetic cases of ARVC (Arrhythmogenic Right Ventricular Cardiomyopathy). Patients are at risk of developing life-threatening arrhythmias and heart failure.

                            Last update: 
                            August 2023


                            - Expert reviewer(s): 
                            Dr Alexandros PROTONOTARIOS  - Dr Adalena TSATSOPOULOU