Cardiocutaneous Syndrome: The Tale between Heart and Skin

Cardiocutaneous syndromes are rare, genetically determined disorders in which arrhythmogenic cardiomyopathy is accompanied by characteristic cutaneous phenotypes of woolly hair and palmoplantar keratoderma. Pattern of cardiac involvement differs in different cardiocutaneous syndromes; right ventricle (RV) is predominantly affected in the form of classical arrhythmogenic right ventricular cardiomyopathy/ dysplasia (ARVC/D) in Naxos disease whereas the left ventricle (LV) is mainly involved in the form of dilated cardiomyopathy in Carvajal syndrome. Both conditions are transmitted in autosomal recessive manner, and results from mutations in cell adhesion molecules compromising the integrity of desmosomal junctions of skin and myocardium. Naxos disease usually presents by adolescence with malignant ventricular arrhythmia or cardiac arrest whereas Carvajal syndrome is manifested earlier with heart failure. Cardiomyopathy is diagnosed by the 2010 Task Force Criteria. Implantation of automated implantable cardioverter-defi brillator (AICD) forms the mainstays of treatment by preventing sudden cardiac death. Genetic testing is available. Several international databases and registries, often as a part of other genetically determined arrhythmogenic disorders, are directed to better characterize and manage these cardiocutaneous syndrome patients. Review Article Cardiocutaneous Syndrome: The Tale between Heart and Skin A K M Monwarul Islam*, Amiruzzaman Khan and Zakir Hossain Department of Cardiology, Sir Salimullah Medical College, Dhaka, Bangladesh Dates: Received: 16 January, 2017; Accepted: 25 January, 2017; Published: 27 January, 2017 *Corresponding author: AKM Monwarul Islam, MD, Assistant Professor, Department of Cardiology, Sir Salimullah Medical College, Mitford Road, Dhaka, 1100, Bangladesh, Tel: +8801712564487; E-mail:


Introduction
Naxos disease and Carvajal syndrome are the 2 closelyrelated genetically determined conditions where inherited cardiomyopathy is accompanied by characteristic cutaneous phenotype of palmoplantar keratoderma and woolly hair [1].
The cutaneous manifestations are similar in 2 conditions, but the pattern of cardiomyopathy differs; in Naxos disease,

Epidemiology
Naxos disease was fi rst described by Protonotarios et al. in 4 families originating from the Greek island of Naxos [8].
Carvajal syndrome with predominant LV involvement has been described from India and Ecuador [14][15][16]. Biventricular involvement has also been described [17]. Naxos disease is prevalent in Greek islands, and the prevalence may be up to 1:1000 [18].

Pathophysiology
Genetics: ARVC/D is a genetic disease of clinical and genetic heterogeneity with a familial background consistent with an autosomal-dominant trait of inheritance in most cases; only a minority are inherited as autosomal recessive manner, either or not associated with palmoplantar keratoderma and woolly hair. ARVC/D-causing genes encode cardiac desmosomes in majority and non-desmosomal structures in minority, the Citation: Islam  The ARVC/D of Naxos disease shows 100% penetrance [20].
Pathology: Woolly hair is one of the telltale signs of Naxos disease and Carvajal syndrome. This is the fi rst of the triad of phenotypes to appear, and is present since birth. The peculiar hair is readily evident in the scalp, and is extremely curly, thin, grows slowly, often fragile, and is diffi cult to comb. However, woolly hair is not specifi c to Naxos disease and Carvajal syndrome; woolly hair can be autosomal dominant (hereditary form), autosomal recessive (familial wooly hair), and localized nonhereditary woolly hair in the form of woolly hair nevus [28]. (Figure 1).
Like the woolly hair, palmoplantar keratoderma is a characteristic feature of Naxos disease and Carvajal syndrome.
Palmoplantar keratoderma is characterized by thickening of the skin on the palms and soles. This feature is not present at birth, rather develops during the fi rst year of life when the infant starts using the hands and feet [19]. Palmoplantar keratoderma of Naxos disease and Carvajal syndrome is of striate type, however, is not specifi c to them, and can be seen in other acquired and inherited conditions ( Figure 2).
Cardiomyopathy is the most clinically important feature of Naxos disease and Carvajal syndrome. The cardiomyopathy of both the conditions constitutes the relatively rare, recessivelytransmitted variant of ARVC/D, which can affect either ventricle. In Naxos disease, the RV is affected, and usually presents by adolescence with arrhythmia manifested as syncope and/or ventricular tachycardia (VT) of left bundle branch block (LBBB) morphology. In contrast, in case of Carvajal syndrome, the LV is predominantly affected, the presentation is in earlier ages, may be in childhood, and the usual presentation is heart failure rather than arrhythmia. Presence of myocardial noncompaction [29] and absence of signifi cant myocardial fi brofatty replacement [30], also differentiate cardiomyopathy in Carvajal syndrome from that in Naxos disease.

Diagnosis
The diagnosis of Naxos disease and Carvajal syndrome is often straight forward in presence of telltale features usually in childhood or adolescence. Woolly hair and palmoplantar keratoderma are recognized clinically. No single diagnostic test exists for ARVC/D. The diagnosis is made using a combination of clinical, electrocardiographic and radiological features, as defi ned by the 2010 Task Force Criteria (TFC) [31].   an epsilon wave just after the QRS in lead V1 [32]. Complete and incomplete right bundle branch block (RBBB) may also be observed [33,34]. The epsilon waves are reproducible small defl ections seen just beyond the QRS complex in lead V1 or V2. (Figure 3 CMR fi ndings associated with ARVC/D include RV wall thinning, RVOT enlargement, trabecular disarray, fi brofatty replacement, ventricular dilation, and global or regional systolic dysfunction [37][38][39]. These abnormalities typically occur in predilection sites including the RV base and LV lateral wall. Like RV evaluation, CMR is useful in evaluation of LV cardiomyopathy in Carvajal syndrome as well. The CMR picture of Carvajal syndrome often mimics that of LV non-compaction [30]. Cardiac computed tomography (CT) scanning is not  [20]. Sustained or non-sustained VT and decreased LV function have recently been identifi ed as risk factors for subsequent arrhythmic death in patients with ARVC/D [42]. Endocardial voltage mapping (EVM) has been found to be useful in stratifying the arrhythmia risk in ARVC/D patients. The extent of negative T-waves across the 12-lead ECG was found to correlate with the amount of RVelectroanatomic scar (RV-EAS) and predict EAS-related arrhythmic risk [43]. Also, the extent of bipolar RV endocardial low-voltage area detected by EVM was shown to be a powerful predictor of arrhythmic outcome in ARVC/D, independently of history and RV dilatation/dysfunction; a normal bipolar EVM characterized a low-risk subgroup of ARVC/D patients [44]. Anti-arrhythmics like sotalol and amiodarone are used.  primary prevention remain a matter of debate [45]. For Naxos disease and Carvajal syndrome, AICD is probably indicated in those who develop symptoms and/or structural progression before the age of 35 years [17,20,46,47]. Anti-arrhythmic drugs are used as an adjunct after AICD implantation. The wearable cardioverter-defi brillators (WCDs) may have a role as a bridging therapy before the scheduled AICD implantation or heart transplantation in Naxos disease and Carvajal syndrome [48,49].
Diuretics and angiotensin converting enzyme inhibitors are indicated in heart failure, anti-thrombotics may prevent thrombus formation in high-risk patients. Heart transplantation remains the only option for the end-stage cardiomyopathy patients [12]. Ventricular assist device (VAD) has been used before cardiac transplantation in a patient with Carvajal syndrome [50]. Emollients, topical keratolytics, tazarotene 0.05%, and tretinoin 0.1% can be tried for palmoplantar keratoderma [51].

Prevention
So far, 13 disease genes have been identifi ed, responsible for around 60% of all ARVC/D cases [52]. Most of mutations in dominant forms have been identifi ed in desmosomal genes including DSP, plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and JUP [53]. Being genetic diseases, ARVC/D is at present incurable. So, early detection and prevention may be attractive options. Clinical genetic testing is already available worldwide for the common ARVC/ D-associated genes, e.g., plakophilin-2 (PKP2), desmoplakin In an attempt to control Naxos disease, systematic genetic screening of the populations at risk has been carried out to identify the heterozygous carriers of the plakoglobin gene mutation [1]. Several registries are dealing with ARVC/D patients around the globe. A multidisciplinary collaborative European study has been designed with the aim to investigate the clinical, pathological and genetic features of ARVC/D [55].
One of the missions is the study of Naxos disease (participating unit: Yannis Protonotarios Medical Center, Naxos, Greece).
Simultaneously, another major registry in North America worked in collaboration with European expertise [56]. The

Johns Hopkins Arrhythmogenic Right Ventricular Dysplasia
(Cardiomyopathy) Program of USA [54], the Australian Genetic Heart Disease Registry [57], the Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Program at the University Hospital Zurich [58] and the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry [59], are also active.

Conclusion
The liaison between skin and heart may be dangerous. The clinicians should have appropriate preparedness to recognize the rare but often lethal cardiocutaneous syndromes including Naxos disease and Carvajal syndrome. Any child presenting with woolly hair at birth should be evaluated and followed up regularly. The mainstay of treatment is to prevent sudden cardiac death. AICD should be offered to the high risk cases.
Early diagnosis, proper risk stratifi cation, timely treatment, and regular follow up can lessen the morbidity and mortality of the patients.