Naxos syndrome

Overview

Naxos syndrome is a rare inherited disorder that primarily affects the heart, skin, and hair. It is classified as a cardiocutaneous syndrome, meaning it involves both cardiac and dermatologic features. The condition was first identified in families on the Greek island of Naxos, from which it gets its name. The most serious complication of Naxos syndrome is arrhythmogenic right ventricular cardiomyopathy (ARVC), a type of heart disease that can lead to sudden cardiac death, especially in young adults and athletes.

The hallmark triad of Naxos syndrome includes:

• Woolly hair from birth

• Palmoplantar keratoderma (thickened skin on the palms and soles)

• ARVC, typically developing during adolescence or early adulthood

Because of its potentially life-threatening cardiac complications, early recognition and intervention are critical for individuals with Naxos syndrome.

Causes

Naxos syndrome is caused by mutations in the JUP gene, which encodes plakoglobin—a key component of desmosomes. Desmosomes are structures that help bind cells together, especially in tissues that experience mechanical stress such as the heart and skin. When plakoglobin is defective due to a gene mutation, it impairs the structural integrity of both cardiac muscle and the epidermis.

The condition follows an autosomal recessive inheritance pattern. This means an individual must inherit two copies of the mutated gene (one from each parent) to develop the syndrome. Parents of an affected child are typically carriers and usually show no symptoms.

Symptoms

The clinical features of Naxos syndrome typically manifest in a specific timeline, with skin and hair abnormalities apparent from infancy, and cardiac involvement developing during adolescence or early adulthood.

Cutaneous Features

• Woolly hair: Present from birth; hair is tightly curled, coarse, and sparse, particularly on the scalp

• Palmoplantar keratoderma: Thickening and hardening of the skin on the palms and soles, often appearing in the first few years of life and worsening with age

Cardiac Features

• Arrhythmogenic right ventricular cardiomyopathy (ARVC): Progressive replacement of right ventricular muscle with fibrofatty tissue

• Ventricular arrhythmias, which can cause palpitations, fainting (syncope), or sudden cardiac arrest

• Heart failure symptoms in advanced cases

• Risk of sudden death, especially during intense physical activity

Other Features

• Occasional left ventricular involvement in later stages

• Electrocardiographic abnormalities, such as T-wave inversions and epsilon waves

Diagnosis

Early diagnosis of Naxos syndrome is crucial to manage the risk of sudden cardiac death and provide appropriate interventions. The following diagnostic tools are typically used:

• Clinical examination: Observation of woolly hair and palmoplantar keratoderma, especially in infants and young children from high-risk families

• Electrocardiogram (ECG): May show abnormal heart rhythms, especially ventricular arrhythmias

• Echocardiogram: Used to evaluate heart structure and function

• Cardiac MRI: Provides detailed imaging of fibrofatty replacement in the right ventricle

• Genetic testing: Confirms the diagnosis by identifying mutations in the JUP gene

• Family history: Important for identifying asymptomatic carriers or affected relatives

Treatment

There is no cure for Naxos syndrome, but treatments focus on managing cardiac risk and improving quality of life. A multidisciplinary team including cardiologists, dermatologists, and genetic counselors is typically involved.

Cardiac Management

• Antiarrhythmic medications: To control irregular heart rhythms and reduce the risk of sudden death

• Implantable cardioverter-defibrillator (ICD): Recommended for individuals at high risk of life-threatening arrhythmias

• Heart failure treatment: In advanced stages, standard therapies like ACE inhibitors, beta-blockers, and diuretics may be used

• Activity modification: Patients are advised to avoid strenuous exercise, which can exacerbate cardiac damage

Dermatologic Management

• Use of keratolytic creams and moisturizers for palmoplantar keratoderma

• Dermatologic follow-ups to manage skin thickening and cracking

Genetic and Family Counseling

• Genetic testing and counseling for family members

• Prenatal diagnosis or carrier testing for at-risk couples

Prognosis

The prognosis of Naxos syndrome largely depends on the severity and management of the cardiac involvement. While the dermatologic and hair features are not life-threatening, the development of ARVC significantly increases the risk of sudden cardiac death, particularly in young adults engaged in physical activity.

With early diagnosis, avoidance of high-risk activities, and appropriate cardiac interventions such as ICD placement, many individuals with Naxos syndrome can live into adulthood and maintain a relatively stable quality of life. Lifelong cardiac monitoring is essential. Ongoing research into gene therapy and targeted treatments may offer more options in the future.