What are the other Names for this Condition? (Also known as/Synonyms)

• Arrhythmogenic Right Ventricular Cardiomyopathy with Skin, Hair, and Nail Abnormalities
• Diffuse Non-Epidermolytic Palmoplantar Keratoderma with Woolly Hair and Cardiomyopathy
• Palmoplantar Keratoderma with Arrhythmogenic Right Ventricular Cardiomyopathy and Woolly Hair

What is Naxos Disease? (Definition/Background Information)

• Naxos Disease may be described as a form of hereditary diffuse palmoplantar keratoderma that is transmitted in an autosomal recessive manner. The condition manifests during early infancy and is characterized by woolly hair (short and kinked hair) along-with arrhythmogenic right ventricular cardiomyopathy (ARVC). Thus, it is also known as Diffuse Non-Epidermolytic Palmoplantar Keratoderma with Woolly Hair and Cardiomyopathy
• Hereditary diffuse palmoplantar keratoderma is a type of palmoplantar keratoderma (PPK) caused by genetic mutations. PPK is a benign skin condition, wherein there is thickening of skin (keratoderma) of the palms and/or soles. PPK is considered to be a pattern of skin findings and not a condition in itself. The abnormal skin thickening can be focal (localized), widespread (diffused), or punctate type (appearing as tiny bumps)
• Naxos Disease is a cardio-cutaneous condition that presents both skin and heart related symptoms. Woolly hair and skin symptoms are observed in early childhood, while heart symptoms are observed during adolescence. This can lead to severe heart complications that may be fatal without early and appropriate intervention
• Apart from addressing the skin presentations, managing, and treating dilated cardiomyopathy that causes the heart muscles to weaken is a priority. Depending on the severity, it may be treated with prescription medications, non-surgical procedures, and through surgical implants. An early diagnosis is important to improve overall prognosis of individuals with Naxos Disease

Who gets Naxos Disease? (Age and Sex Distribution)

• Naxos Disease is an extremely rare congenital disorder; and, the initial signs and symptoms are noted in neonates and infants
• The condition affects both males and females
• Only a few cases are reported from the nations of Ecuador, Greece, India, Israel, Italy, and Turkey. According to medical literature, the prevalence of the condition in some of the Greek islands is very high at 1:1,000

What are the Risk Factors for Naxos Disease? (Predisposing Factors)

• The risk factor for Naxos Disease includes a positive family history of the condition
• Children born to consanguineous partners or spouses have a high risk for the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Naxos Disease? (Etiology)

• Naxos Disease is caused by genetic abnormalities which are passed down (through families) in an autosomal recessive manner
• It is caused by homozygous mutations involving the JUP gene, which regulates the protein piakoglobin that is responsible for cell adhesion
• Naxos Disease is considered by some research experts as a variant of Carvajal Syndrome, another form of palmoplantar keratoderma

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents are carriers of the gene causing an autosomal recessive condition, there is a 25 % chance that a child will get the defective recessive gene from both parents. They will therefore have the disease.   If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of not receiving the gene from either parent, and will not have the disease and will not pass the gene on to their offspring. In the rare situation where both parents have the actual autosomal recessive condition, all their offspring will have two disease carrying genes and the disease is manifested.

What are the Signs and Symptoms of Naxos Disease?

The signs and symptoms associated with Naxos Disease may vary from one individual to another and may include:

• Presence of woolly hair (coarse hair) and skin symptoms at birth
• The presence of abnormally-thickened skin on the palms of the hands and soles of the feet
• The skin thickening involves the entire palm and sole (diffused presentation)
• Sometimes, involvement of the skin on the hands and feet (and of the wrists and ankles, in some cases) may be noted
• Skin lesions on the fingers and toes
• Increased sweating
• Secondary infections, mostly of the feet, may take place
• Normal activities that involve the use of one’s hands and feet may be severely affected

Arrhythmogenic right ventricular cardiomyopathy (ARVC) may not be apparent during the initial years (early childhood), due to absence of significant signs and symptoms. ARVC is usually an incidental finding. Heart signs and symptoms, due to ARVC, may be noted during adolescence, which may include:

• Fainting
• Shortness of breath during physical activities or while lying down
• Fatigue
• Palpitations
• Swelling of legs
• Heart murmurs

How is Naxos Disease Diagnosed?

The diagnosis of Naxos Disease may involve the following tests and procedures:

• A complete evaluation of medical history along with a thorough examination of the skin lesions by a dermatologist
• The healthcare provider may also ask many questions related to the individual’s age, family medical history, current medications, cosmetics, body lotions used, other medical conditions, infections, etc.
• Blood tests that may include complete blood count (CBC) test, basic metabolic panel, liver function test (LFT), and biomarkers for heart disorders
• Dermoscopy: It is a diagnostic tool where a dermatologist examines the skin using a special magnified lens
• Wood’s lamp examination: In this procedure, the healthcare provider examines the skin using ultraviolet light. It is performed to examine the change in skin pigmentation
• Chest X-ray to check for heart size, contour, and fluid build-up in lungs
• Other imaging tests of the heart using techniques, such as computed topography (CT) scan and magnetic resonance imaging (MRI) scan
• Electrocardiogram (EKG) to check the heart’s electrical activity
• Echocardiography (ECG or echo) uses sound waves to create a moving picture of the heart. This helps to check the size, shape, and pumping function of the heart
• Stress test: This test places stress on the heart by making it work harder and beat faster to determine, if the cardiac muscles can cope with the increased workload
• Molecular genetic testing to identify the gene involved
• Skin biopsy: A skin tissue biopsy is performed and sent to a laboratory for a pathological examination. The pathologist examines the biopsy under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Naxos Disease?

The complications associated with Naxos Disease may include:

• Emotional stress
• Cosmetic concerns
• Disruption of normal life and activities if the condition is severe
• Heart related complications due to arrhythmogenic right ventricular cardiomyopathy may include:
  • Involvement of the left ventricle such that there is abnormal functioning of this chamber
  • Heart valve regurgitation: It causes the heart to pump ineffectively such that blood flows back into the heart
  • Arrhythmias: Abnormal heart rhythm, which can be triggered by physical exertion
  • Sudden cardiac arrest (which can be unexpected)
  • Embolism: Development of blood clots in the heart which may get into the bloodstream and obstruct blood supply to many important organs
  • Edema: Fluid build-up in the lungs, abdomen, legs, and feet
  • Stroke
• Treatment complications including a lack of treatment response

How is Naxos Disease Treated?

There is no cure for Naxos Disease. The condition is managed through symptomatic treatments, which may involve the following measures:

• Skin treatments may include:
  • Use of moisturizing creams and lotions; use of ointments containing vitamin D
  • Use of oral and systemic retinoids
  • Administration of keratolytics (topical medicine containing salicylic acid)
  • Phototherapy
  • Surgical debridement (removal of thickened skin)
• Heart treatments for arrhythmogenic right ventricular cardiomyopathy may include:
  • Prescription medications such as anti-arrhythmic medications, beta blockers, ACE inhibitors, blood thinners, etc.
  • Pain management with radiofrequency ablation
  • Surgical treatments may include implantation of automatic cardioverter defibrillator and heart transplantation

Regular follow up visits with the healthcare provider is important and recommended.

How can Naxos Disease be Prevented?

Currently, Naxos Disease is a genetic disorder that cannot be prevented. However, the following may be considered:

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited genetic disorders such as hereditary palmoplantar keratoderma

What is the Prognosis of Naxos Disease? (Outcomes/Resolutions)

The prognosis of Naxos Disease may vary from one individual to another and is dependent on the severity of the condition.

• An early detection of the heart abnormality (arrhythmogenic right ventricular cardiomyopathy) can ensure prompt intervention thereby minimising the risk of mortalities
• Unrecognised ARVC can be life-threatening and may lead to death due to left ventricular dysfunction or cardiac arrest (which may cause sudden death)

Additional and Relevant Useful Information for Naxos Disease:

Cleaning the skin too hard with strong chemicals or soaps may aggravate the skin condition. Care must be taken avoid strong soaps and chemicals that could potentially worsen the condition.