An 11-year-old girl of Indian origin born out of 3rd degree consanguineous marriage presented with 2 transient epi-sodes of syncope during exertion within a period of three months. Both the times she recovered spontaneously before reaching the hospital. She was previously asymptomatic except for thickening of palmar and plantar skin with fissures noticed since early childhood. None of her family members had a similar illness. General examination revealed woolly hair and hyperkeratosis of palms and soles. In the palms, hyperkeratosis was most marked in the subungual areas. There were fissures on the plantar aspect of big toe. In addition, distal phalanges of hands appeared shorter than normal (Fig. 1). Rest of the general examination including anthropometry was normal. Clinical examination of cardiovascular system revealed a resting pulse rate of 80/minute with normal volume and character of the peripheral pulses. Blood pressure was 96/44 mm Hg in the left upper limb in the sitting position. Cardiac apex was in the 5th left intercostal space in the midclavicular line with normal character, indicating cardiomegaly. First and second heart sounds were normal and there were no additional sounds or murmur.

Fig. 1 Palmoplantar keratosis. Note the subungual keratosis in the hands and fissures in the sole. Short distal phalanges of fingers are also obvious.

She was evaluated further to find out the etiology of syncope. Baseline electrocardiogram (ECG) showed complete right bundle branch block with left posterior hemiblock indicating advanced myocardial disease. Transthoracic echocardiogram showed mild ventricular dysfunction. Left ventricle (LV) was predominantly involved with significant chamber dilatation and the ejection fraction was 45%. ECG obtained during subsequent episode showed ventricular tachycardia (VT) at a rate of 150/ minute (regular wide QRS tachycardia with north-west axis and deep S in V5 and V6) suggesting VT as the etiology of syncope. Magnetic resonance imaging did not reveal any fat deposits in the myocardium.

The phenotypical features and cardiac manifestations along with history of consanguinity are suggestive of arrhythmogenic cardiomyopathy with autosomal recessive inheritance. These features are consistent with Naxos disease, probably Carvajal variant. Family was counseled regarding the disease and poor prognosis. She is being managed with amiodarone and antifailure medications including carvedilol. Two years from the initial diagnosis, her disease continues to worsen with recurrent refractory episodes of ventricular tachycardia and progressive cardiac failure.

Naxos disease was first reported in 1986 by Protonotarios, et al. [1] in patients from the Greek island of Naxos. Apart from Naxos, cases have also been reported from Italy, Turkey, Israel, Saudi Arabia and India. The variant with more pronounced left ventricular involvement and clinical overlap with dilated cardiomyopathy has been described in families from Ecuador (Carvajal syndrome) [2].

Genetic studies have located two causative genes, encoding for the desmosomal proteins plakoglobin and desmoplakin. Homozygous mutation of the plakoglobin gene truncating the C terminal of the protein causes Naxos disease which maps to 17q21 [3]. Homozygous mutations of another desmosomal component, desmoplakin which truncates the C terminal of the protein and maps to 6p24 is identified in involved patients from Ecuador [4]. The disease pathogenesis is linked to the specific tissue characteristics of cardiac muscle. Cardiac muscle consists of single myocytes connected by complex intercellular contact sites called intercalated discs. Three different types of intercellular junctions are located in intercalated discs, namely adherence junctions, gap junctions and desmosomes. Adherence junctions and desmosomes secure mechanical coupling enabling synergistic contraction while gap junctions serve electrical coupling allowing rapid spread of action potentials. Plakoglobin is a common component of both adherence junctions and desmosomes. At the adherence junctions, it is connected to the actin cytoskeleton and at desmosomes to the intermediate filaments of desmin. Desmoplakin is another desmosomal protein that interlinks plakoglobin or plakophilin with desmin intermediate filaments. Defects in linking sites (C terminal) of these proteins interrupts cell to cell adhesion, particularly under conditions of increased mechanical stress leading to cell isolation and death. The result is progressive loss of myocardium and fibro-fatty replacement. Surviving myocardial fibers within fibro-fatty tissue provide a slow conduction substrate inducing re-entrant ventricular arrhythmias [5]. The degree of fatty replacement is variable.

Desmosomes are abundant in epidermis too, explaining the cutaneous manifestations. Cutaneous disease is confined to areas most exposed to pressure like the palmar and plantar surfaces, indicating the role of mechanical stress in disease expression.

In patients with Naxos-Carvajal disease, woolly hair was apparent from birth while palmoplantar keratoderma developed during the first year of life [5]. The symptomatic presentation was usually with syncope and/or sustained ventricular tachycardia during adolescence. Disease is progressive with death occurring from arrhythmia or congestive heart failure [6]. Treatment options are limited and include antiarrhythmic therapy, medical therapy for congestive heart failure, implantable cardioverter defibrillator (ICD) implantation and cardiac transplantation.

There are a few reports of Naxos disease from India earlier [7-10]. Features of this patient including presentation at younger age and left ventricular involvement are more suggestive of the Carvajal variant. However, hypoplasia of distal phalanges seen in our patient is not reported earlier.

10. Sajeev CG, Francis J, Sankar V, Vasudev B ,Venugopal K. Ventricular tachycardia. The spectrum continues to broaden. The report of Naxos disease. Circulation. 2006;114:e60-e61.