Naxos disease

What is Naxos disease?

Naxos disease is a rare, autosomal recessive cardiocutaneous syndrome characterised by the triad of palmoplantar keratoderma (PPK), woolly hair, and arrhythmogenic right ventricular cardiomyopathy (ARVC).

Naxos disease is also known as Naxos syndrome.

Who gets Naxos disease?

Naxos disease was first reported in 1986 in patients originating from the Greek island of Naxos. The estimated prevalence in the Greek Cyclades islands may be as high as 1 in 1000 people. Cases have also been reported in Turkey, Israel, and Saudi Arabia.

Naxos disease is an autosomal recessive condition, meaning an individual must inherit the mutated gene from both parents to develop the disease. However, sporadic cases caused by somatic mutations have also been reported.

What causes Naxos disease?

Naxos disease most commonly results from a homozygous 2-base-pair deletion in the JUP gene, which encodes plakoglobin. Plakoglobin is a key component of desmosomes and adherens junctions:

• Desmosomes are intercellular adhesion complexes critical to the structural integrity of skin and heart muscle by resisting shear forces
• Adherens junctions are also adhesional proteins that, along with desmosomes, facilitate mechanical coupling between cardiac myocytes (heart muscle cells).

Research also implicates plakoglobin in intracellular signalling pathways involved in the development of the heart, skin, and hair.

What are the clinical features of Naxos disease?

Cutaneous features

• Woolly hair: Apparent from birth.
• Diffuse palmoplantar keratoderma: Thickening of the skin on the palms and soles, usually manifesting during the first year of life after infants begin to use their hands and feet.
• Acanthosis nigricans: Occasionally reported, presenting as hyperpigmented skin in intertriginous areas.

Wooly hair in Naxos disease (ND-patient1)

Striate keratoderma in Naxos disease (ND-patient1)

Marked hyperkeratosis over the forefoot in Naxos disease (ND-patient1)

Plantar keratoderma in Naxos disease 

Cardiac features

In all patients with Naxos disease, the clinical manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) – also known as arrhythmogenic right ventricular dysplasia (ARVD) — become apparent by adolescence.

Patients may present with syncope or sustained ventricular tachycardia. Furthermore, over 90% of patients display abnormal findings on ECG (eg, T-wave inversion in leads V1-3) and echocardiogram (eg, right ventricular dilatation, hypokinesia, and aneurysms).

Cardiac histopathology reveals replacement of myocardium with fibro-fatty tissue. Immunohistochemistry studies show reduced plakoglobin expression in both cutaneous and cardiac tissues.

How do clinical features vary in differing types of skin?

The clinical features of Naxos disease do not appear to differ according to skin type.

What are the complications of Naxos disease?

• Progression to biventricular disease
• Congestive heart failure
• Sudden cardiac death

How is Naxos disease diagnosed?

A diagnosis of Naxos disease is considered when a patient presents with PPK and woolly hair from early childhood, along with clinical and investigational findings consistent with ARVC during adolescence or early adulthood.

A definitive diagnosis is confirmed through genetic testing by identifying a homozygous pathogenic variant of the JUP gene.

What is the differential diagnosis for Naxos disease?

• Carvajal syndrome:
  • Considered by some to be a rare variant of Naxos disease
  • Described in patients from Ecuador and India
  • Caused by a homozygous mutation of the desmoplakin gene
  • Also presents with woolly hair, palmoplantar keratoderma, and cardiomyopathy
  • Differs from Naxos disease by presenting with a predominant left ventricular involvement and early morbidity.
• Dilated cardiomyopathy
• Other forms of palmoplantar keratoderma.

What is the treatment for Naxos disease?

There is currently no cure for Naxos disease, and the primary objective of treatment is to prevent sudden cardiac death. Emerging research into gene therapy for genetic cardiomyopathies may offer future therapeutic options.

General measures

• Multidisciplinary care, including access to psychosocial support
• Genetic counselling for patients and family members
• Regular cardiac monitoring
• Avoid sports or other strenuous activities that may worsen heart failure or trigger ventricular arrhythmias, or where a loss of consciousness may be dangerous.

Specific measures

Cutaneous

Management of palmoplantar keratoderma focuses on symptom relief, typically through the use of emollients and keratolytic agents to soften and reduce thickened skin. For more information, see: palmoplantar keratoderma.

Cardiac

As with other forms of arrhythmogenic right ventricular cardiomyopathy (ARVC), the cardiac manifestations of Naxos disease require specialist cardiologist care.

Interventions include:

• Implantable cardioverter defibrillator (ICD)
• Beta-blockers and antiarrhythmic drug therapy
• Radiofrequency catheter ablation
• Heart transplantation in end-stage heart failure.

How do you prevent Naxos disease?

• Prenatal genetic testing for couples known to carry pathogenic variants in the JUP gene
• Genetic screening of at-risk populations to identify carriers and offer genetic counselling

What is the outcome for Naxos disease?

The prognosis for Naxos disease is broadly comparable to that of other genetic forms of arrhythmogenic right ventricular cardiomyopathy (ARVC).

With early identification and appropriate management, individuals with Naxos disease can lead relatively normal lives. However, the risk remains for serious cardiac events, including sustained ventricular tachycardia and sudden death.