Cell Communication & Adhesion, 21: 3–11, 2014 © 2014 Informa Healthcare USA, Inc. ISSN: 1541-9061 print / 1543-5180 online DOI: 10.3109/15419061.2013.876415

REVIEW ARTICLE

When Rare Illuminates Common: How Cardiocutaneous Syndromes Transformed Our Perspective on Arrhythmogenic Cardiomyopathy Srijita Sen-Chowdhry1,2 and William J. Mckenna1,3 1 Inherited Cardiovascular Disease Group, Institute of Cardiovascular Science, University College London, UK, Department of Epidemiology, Imperial College, St Mary’s Campus, Norfolk Place, London, UK, and 3Division of Cardiology, Yale School of Medicine, New Haven, CT, USA

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Abstract The classic cardiocutaneous syndromes of Naxos and Carvajal are rare. The myocardial disorder integral to their pathology – arrhythmogenic cardiomyopathy – is arguably not uncommon, with a prevalence of up to 1 in 1,000 despite almost certain under-recognition. Yet the study of cardiocutaneous syndromes has been integral to evolution of the contemporary perspective of arrhythmogenic cardiomyopathy – its clinical course, disease spectrum, genetics, and cellular and molecular mechanisms. Here we discuss how recognition of the association of hair and skin abnormalities with underlying heart disease transformed our conception of a little-understood but important cause of sudden cardiac death. Keywords: cardiomyopathy, genetics, desmosome, sudden cardiac death, cardiocutaneous syndrome

INTRODUCTION

result in parallel susceptibility to disease. Examples abound. Anderson–Fabry disease, for instance, is an X-linked dominant lysosomal storage disease with ocular, cutaneous (angiokeratomas and punctate telangiectases), cardiovascular (left ventricular hypertrophy, valvular dysfunction, hypertension and coronary artery disease), renal, and neurological manifestations. What all affected organ systems have in common is a need for the deficient enzyme, alpha-galactosidase A, for which replacement therapy is now available, underscoring the importance of timely recognition of the disease (Hoffmann, 2009). The neural crest serves as an illustration of shared embryological development, giving rise to smooth muscle cells, connective tissue, melanocytes, neurons and the chromaffin cells of the adrenal medulla. Cardiac neural crest cells contribute to development of the outflow tract, proximal great vessels, interventricular septum and semilunar valves. The neurocristopathies, so-named because they result from anomalous development of the neural crest, are therefore multi-system disorders. CHARGE syndrome, for example, is characterised by coloboma of the eye, heart disease (commonly tetralogy of Fallot), choanal atresia, growth retardation, genital hypoplasia and ear abnormalities or deafness (Abdelmalek et al., 2002).

Traditional clinical diagnosis is based on recognising associations between external physical ‘signs’ and internal disease states. Sometimes there is an obvious relationship between the physical sign and the underlying defect, such as heart murmurs and valve disorders; but quite often, the association has long been observed but never fully elucidated. Nor is an explanation necessary to ensure the utility of a physical sign. Previous generations of physicians were often able to establish a diagnosis from the history and examination alone, aided by instinct, experience, and familiarity with their patients and their environments (DeMaria, 2006). The modern clinician may reach the same conclusion only after extensive investigations, which at best merely exacerbate patient anxiety and at worst involve invasive procedures or exposure to ionising radiation. Yet just as clinical examination skills are waning, the field of genomics and proteomics has taken a quantum leap. New insights are emerging into the cellular and molecular mechanisms underlying the coexistence of abnormalities in apparently disparate systems. Any overlap between two or more organ systems in either genomic expression or embryologic development may Received 12 December 2013; accepted 13 December 2013.

CARDIOCUTANEOUS SYNDROMES

Address correspondence to Professor William J. McKenna, Institute of Cardiovascular Science, University College London, The Heart Hospital, 16-18 Westmoreland Street, London W1G 8PH, UK. Tel: ⫹ 0203-4564040. E-mail: [email protected]

Strictly, cardiocutaneous syndrome is a collective term that encompasses any disease state incorporating both 3

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cardiac and cutaneous manifestations, with or without involvement of other organ systems. Anderson-Fabry disease, Marfan syndrome, homocystinuria, CHARGE, and even foetal alcohol syndrome can be considered examples (Abdelmalek et al., 2002). Also falling under the same umbrella are the related cardiofaciocutaneous, Noonan and Costello syndromes. The manifestations of cardiofaciocutaneous syndrome include failure to thrive; developmental delay; distinctive facial features; dry, hyperkeratotic, scaly skin; sparse and curly hair; cavernous haemangiomata; and cardiovascular disease, commonly congenital pulmonic stenosis and hypertrophic cardiomyopathy. Implicated in cardiofaciocutaenous syndrome are gain-of-function mutations in four different genes (BRAF, KRAS, mitogen-activated protein/ extracellular signal-regulated kinase MEK1 and MEK2). There is both phenotypic resemblance and genetic affiliation to two better known syndromes: Noonan, caused by mutations in the protein tyrosine phosphatase SHP-2 gene (PTPN11) and occasionally KRAS; and Costello, caused by mutations in HRAS. The protein products of all the causal genes identified in this trio of syndromes act in the RAS– extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis (Roberts et al., 2006). In this issue of Cell Communication and Adhesion, the focus is on the classic cardiocutaneous syndromes, caused by defects in desmosomal and related proteins, and manifesting primarily (if not exclusively) in the skin and heart. Retracing the discovery of cardiocutaneous syndromes and identification of genes responsible highlights the continued relevance of physical signs in modern medicine.

NAXOS SYNDROME FIRST DESCRIBED In 1984, two newly qualified physicians – Drs Protonotarios and Tsatsopoulou – were in practice on the Greek island of Naxos, when they encountered a patient with sustained ventricular tachycardia (VT). Rather than confining themselves to examination of the cardiovascular system, they also observed hyperkeratosis of the palms and soles, and distinctive ‘woolly’ hair. There was every reason to presume dual pathology until they encountered a second individual with near-identical clinical profile (palmoplantar keratoderma, woolly hair and recurrent VT) on a visit to Athens. Upon returning to Naxos, they were presented a case of a 17-year-old girl who had died suddenly, and thought to enquire about her hands, feet and hair. It was subsequently confirmed that her death had been arrhythmic and that she, too, had palmoplantar keratoderma and woolly hair. The association could no longer be ascribed to mere coincidence. Family studies were the foundation of human genetics and it is this approach that they adopted to investigate further (Protonotarios et al., 1986).

Two brothers of the 17-year-old girl had the same cutaneous phenotype; echocardiography revealed cardiac involvement. Identification of three more affected families confirmed the hereditary basis of the syndrome – a triad of palmoplantar keratoderma, woolly hair and myocardial disease – while pedigree analysis was consistent with an autosomal recessive transmission. The results were compiled and published in 1986, together with a detailed account of the cardiac phenotype. Six of the nine affected cases had symptoms of arrhythmia, such as palpitation and syncope; frequent ventricular extrasystoles were a common finding, while three cases had documented episodes of VT. Of note, the ventricular arrhythmia had a left bundle branch block (LBBB) morphology, suggesting a right ventricular origin. Other clinical abnormalities of note included inverted T-waves in the right precordial leads (V1-3) on electrocardiography (ECG), right ventricular enlargement and increased right to left ventricular diameter ratio. The right ventricular preponderance had led to an earlier misdiagnosis of Ebstein’s anomaly in two patients, one of whom had undergone tricuspid valve replacement. Nevertheless, left ventricular dilation and dysfunction were also observed in two cases (Protonotarios et al., 1986). The differential diagnoses proposed for the cardiac phenotype were dilated cardiomyopathy with a predilection for the right ventricle and arrhythmogenic right ventricular dysplasia. The absence of heart failure argued against dilated cardiomyopathy, while the ECG changes and ventricular arrhythmia of LBBB configuration were strongly suspicious of arrhythmogenic right ventricular dysplasia. So it was that nine years before the proposal of the Task Force criteria for the disease, Drs Protonotarios and Tsatsopoulou identified arrhythmogenic right ventricular dysplasia (now cardiomyopathy) as the cardiac component of Naxos syndrome (McKenna et al., 1994; Protonotarios et al., 1986).

NAXOS SYNDROME SHEDS LIGHT ON THE GENETICS OF ARRHYTHMOGENIC CARDIOMYOPATHY In its more common, non-syndromic form, arrhythmogenic right ventricular cardiomyopathy (ARVC) may have a prevalence of up to 1 in 1,000 (Peters et al., 2004). Preliminary descriptions from 1965 to 1982 – when the disease was still known as dysplasia – highlighted fibrofatty replacement of the right ventricular myocardium, right ventricular dysfunction in the setting of normal pulmonary vasculature, ventricular tachyarrhythmia and a predisposition to sudden cardiac death (Dalla Volta et al., 1965; Frank et al., 1978; Marcus et al., 1982). Familial clustering was confirmed in 1988, leading to reclassification as a cardiomyopathy; ARVC is most commonly inherited as a Mendelian autosomal dominant trait (Nava et al., 1988). Yet the first disease-causing gene was not isolated until more than a decade later.

HOW CARDIOCUTANEOUS SYNDROMES TRANSFORMED OUR PERSPECTIVE ON ARRHYTHMOGENIC CARDIOMYOPATHY The difficulty in elucidating the genetics of ARVC lay in the nature of the disease itself. In its overt form, ARVC is relatively easy to diagnose, particularly with the aid of the Task Force diagnostic criteria (Marcus et al., 2010; McKenna et al., 1994). The disease does, however, have an early ‘concealed’ phase, during which individuals may be at risk of arrhythmia, but clinical abnormalities are minimal or absent, hindering diagnosis (Sen-Chowdhry et al., 2010). Identifying genetically affected family members is further complicated by reduced penetrance and incomplete phenotypic expression (Sen-Chowdhry et al., 2007). There are two standard means of gene identification in Mendelian disorders: linkage mapping and candidate gene screening. Both approaches are most readily applied to disorders with high penetrance, low lethality, and a clearly defined clinical phenotype. The ideal substrate is a large kindred with multiple affected members, who can be easily distinguished clinically from genetically unaffected relatives: a stark contrast from the typical family with ARVC seen in clinical practice (Sen-Chowdhry et al., 2010). The strategy that ultimately proved successful was to return to the form of the disease that is fully penetrant and easy to identify: Naxos syndrome, in which homozygous individuals show the cutaneous phenotype from early childhood and cardiac manifestations from young adulthood. The genetic locus for Naxos syndrome was mapped to 17q21 in 1998; two years later, the causal mutation was identified as a 2 base pair deletion in the gene encoding plakoglobin (JUP2157del2), which leads to frameshift and premature termination of the protein (Coonar et al., 1998; McKoy et al., 2000). The armadillo protein plakoglobin is a major constituent of desmosomes, adhesive structures that bridge the intermediate filament cytoskeletons and cytoplasmic membranes of adjacent cells. Skin and heart share the need for both mechanical strength and flexibility, dual functioning that is supported by the desmosomal complex. A desmosomal gene mutation may compromise either cell–cell adhesion or intermediate filament function or both, depending on its precise location and impact on protein structure and function. Desmosomes also function in signalling pathways, differentiation and tissue morphogenesis (Bolling & Jonkman, 2009; Sen-Chowdhry et al., 2007, 2010). The implication of plakoglobin in Naxos syndrome stimulated a search for mutations in other desmosomal components in the cardiac-restricted form of the disease. Desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2 (DSC2) have since been implicated in ARVC (Sen-Chowdhry et al., 2007, 2010). Recognition of an association between the external physical finding of palmoplantar keratoderma and underlying myocardial disease in Naxos syndrome thereby revolutionised our understanding of ARVC. CLINICAL COURSE OF NAXOS SYNDROME Although the presence of palmoplantar keratoderma in a child from a family with Naxos disease is a harbinger of

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future myocardial disease, children are typically asymptomatic from a cardiac standpoint (Protonotarios et al., 2001). Findings on cardiac evaluation of homozygous children range from minimal to high-volume ventricular ectopy and characteristic ECG changes; one 5-year-old was found to have more than 14,000 ventricular extrasystoles/24 hours and developed progressive depolarisation abnormalities on the 12-lead ECG, including epsilon waves (Kaplan et al., 2004; Protonotarios et al., 2001). Following her death from leukaemia at the age of 7, extensive examination of her heart revealed no fibrofatty replacement or features suggestive of ARVC, no leukaemic infiltrates, and no evidence of chemotherapyrelated injury. In short, there was no apparent histological substrate for the ventricular arrhythmia and ECG changes observed in vivo. A combination of electron microscopy and immunohistochemistry suggested an alternative basis for her arrhythmia: smaller and fewer gap junctions at the intercalated discs and reduced expression of the gap junction protein connexin 43. Dysfunction at the mechanical desmosomal junction may be sufficient, per se, to effect remodelling at the electrical junction (Kaplan et al., 2004). Once again, the study of Naxos syndrome had shed light on a key conundrum in ARVC: the occurrence of ventricular arrhythmia in the early, ‘concealed’ phase. Subsequent investigations of the common, autosomal dominant form suggest that myocyte necrosis, accompanied by an inflammatory response, may be the initiator of histological injury, with fibrofatty replacement a later sequela (Pilichou et al., 2009). For homozygotes with Naxos syndrome, the onset of cardiac symptoms characteristically occurs at adolescence or beyond [31 ⫾ 18 years (range: 12–68 years)]; 4.6% per year develop arrhythmic events and 2.7% heart failure. In one of the largest studies of Naxos patients to date, the annual disease related and sudden death mortality rates were 3% and 2.3%, respectively. By the age of 35 years, cumulative and event-free survival were 74% and 53%, respectively (Protonotarios et al., 2001). Although the death rate was marginally higher than that observed in non-syndromic ARVC, the clinical course was typical, including the early predilection for the right ventricle and the onset of left ventricular involvement with disease progression. Of the 40 heterozygotic carriers of the Naxos mutation included in the above study, five had woolly hair, but none had palmoplantar keratoderma. Eight heterozygotes had features consistent with ARVC, ranging from right precordial T-wave inversion to mild right ventricular dilation (Protonotarios et al., 2001). The cardiac abnormalities were not sufficient to satisfy the 1994 Task Force criteria in use at the time, although it is conceivable that at least some of this subgroup would fulfil the more sensitive 2010 guidelines (Marcus et al., 2010; McKenna et al., 1994; Protonotarios et al., 2001). The possible presence of mild cardiac disease among heterozygotic carriers of Naxos syndrome was one of the

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first clues to a gene-dose effect in ARVC, which has since been definitively demonstrated in cardiac-restricted disease. In one study, 28% of probands and 10% of genetically affected relatives harboured more than one desmosomal gene mutation, which was associated a 5-fold increased risk of developing penetrant disease among family members (odds ratio, 4.7; 95% confidence interval, 1.1–20.4) (Quarta et al., 2011). More recently, 16% of affected individuals in a typical ARVC cohort were found to be compound or double heterozygotes. Over a median follow-up period of 39 years, the presence of multiple desmosomal gene mutations conferred a hazard ratio of 3.71 (95% CI ⫽ 1.54–8.92) for life-time arrhythmic events (Rigato et al., 2013). Early onset heart failure, which is rare in ARVC, has also been anecdotally observed among in multiple mutation carriers (Bauce et al., 2010). CARVAJAL SYNDROME EXPANDS THE DISEASE SPECTRUM A further paradigm shift in ARVC began with the study of the related cardiocutaneous syndrome of Carvajal, which bears similarities to Naxos disease but is also different in at least two key respects. It was first described in 1996 by BH Rao et al. in an Indian family with palmoplantar keratoderma, woolly hair and apparent dilated cardiomyopathy (Rao et al., 1996). Dr Luis Carvajal-Huerta subsequently observed a similar phenotype in Ecuadorean families (Carvajal-Huerta, 1998). From a cardiac standpoint, the clinical course included an asymptomatic phase during which abnormalities were electrocardiographic, including inverted T-waves in V1–3, extending in some cases to V5, and frequent and complex ventricular arrhythmia. Subsequent echocardiographic findings in 10 patients from the original Carvajal series ranged from mild left ventricular enlargement to severe dilation and systolic impairment; right ventricular appearances were not reported. There were four hospital deaths, all of which were attributed to probable congestive heart failure; one case died from confirmed refractory heart failure (CarvajalHuerta, 1998). In the single post-mortem heart so far examined, the left ventricle was grossly dilated with aneurysms in the posterior and anteroseptal walls. The right ventricle showed more modest dilation and aneurysms. Extensive myocyte loss and replacement fibrosis, with a predilection for the subepicardium, were apparent on histology (Kaplan et al., 2004). Shortly after plakoglobin was implicated in Naxos syndrome, the Carvajal mutation was identified as a homozygous deletion in desmoplakin (DSP6901delG), which results in a premature stop codon and a truncated protein product lacking the C-domain of the tail region (Norgett et al., 2000). Carvajal syndrome, it seemed, was genetically related to both Naxos disease and non-syndromic ARVC, spurring re-examination of the cardiac phenotype.

Although the cardiac component of Carvajal syndrome was originally considered dilated cardiomyopathy, many of its features are more in keeping with ARVC (Kaplan et al., 2004; Protonotarios & Tsatsopoulou, 2004). Consistent with the reported Carvajal cases, the early manifestations of ARVC are electrical and out of proportion to the extent of structural abnormality; clinical heart failure is a late complication. The deaths from heart failure in the Carvajal series may well have been cases of endstage disease; available evidence suggests a frequently malignant, rapidly progressing clinical course. Appearances on histopathology, particularly the presence of aneurysms and subepicardial pattern of fibrosis, were also typical of ARVC, with two caveats. First, the adipose component of the myocyte replacement process was lacking, but this is likely non-specific and inconsequential, particularly as only one heart has been available for examination. Second, instead of the early right ventricular preponderance that originally defined ARVC, there was predominant involvement of the left ventricle. Nor was the cardiac phenotype of Carvajal syndrome an isolated peculiarity. The same time period saw a spate of reports of a non-syndromic cardiac disorder that mirrored ARVC in every respect, but preferentially affected the left ventricle. It was variously termed ‘left sided arrhythmogenic ventricular dysplasia’, ‘left side right ventricular cardiomyopathy’, ‘arrhythmogenic left ventricular dysplasia,’ and ultimately left dominant arrhythmogenic cardiomyopathy (LDAC) (De Pasquale & Heddle, 2001; Collett et al., 1994; Michalodimitrakis et al., 2002; Okabe et al., 1995; Sen-Chowdhry et al., 2008). Identification of the phenotype in a large family with a heterozygous mutation in desmoplakin (DSP1755insA) underscored the genetic affiliation to ARVC (Norman et al., 2005). Although DSP is commonly implicated among families with LDAC, the phenotype has also been recognised in conjunction with mutations in DSG2, phospholamban (PLN), and possibly TMEM43 in the Newfoundland founder population (Groeneweg et al., 2013; Merner et al., 2008; Sen-Chowdhry et al., 2008). The clinical profile of LDAC includes T-wave inversion in the (infero)lateral leads on the 12-lead ECG, arrhythmia of left ventricular origin, and regional and later global left ventricular dilation and dysfunction (Table 1) (Sen-Chowdhry et al., 2008). Concomitant right-sided abnormalities are also common, but the right ventricle is consistently affected less severely than the left. Pathologists described fibrous or fibrofatty replacement of the left ventricle with a subepicardial or midmyocardial distribution, and sometimes occurring as a circumferential band in the outer one-third of the myocardium and the right side of the interventricular septum. In vivo diagnosis has been facilitated by the demonstration of cognate findings on cardiovascular magnetic resonance, using late gadolinium enhancement for tissue characterisation (Figure 1) (Sen-Chowdhry et al., 2008).

HOW CARDIOCUTANEOUS SYNDROMES TRANSFORMED OUR PERSPECTIVE ON ARRHYTHMOGENIC CARDIOMYOPATHY

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Table 1. Clinical Profile of Arrhythmogenic Cardiomyopathy∗ [After ref (Sen-Chowdhry et al., 2010)]. Subtype 12-lead ECG

Classic right dominant

Normal Poor R-wave progression† Intraventricular conduction delay in V1-3 Leftward QRS axis (⫺30° ⬍ QRS axis ⬍ 0) or left axis deviation (QRS axis ⬍ 30°) Incomplete RBBB Early transition RBBB LBBB Epsilon waves in V1-3 Epsilon waves in inferior (II, III, aVF) and/or lateral leads (V5–V6 ⫾ V4, I, aVL) Inverted/flat T-waves in V1-3, extending to V4-6 with LV Inverted/flat T-waves in (infero)lateral leads, extending to involvement V1-3 with RV involvement

Signal-averaged ECG

Late potentials

Arrhythmia

Ventricular volumes RV/LV Volume ratio Other imaging abnormalities

Cardiocutaneous Syndrome Prototype

Left dominant

Both supraventricular tachycardia and atrial fibrillation/flutter are observed in arrhythmogenic cardiomyopathy, but are not contributory to diagnosis Frequent PVCs or VT of LBBB morphology (right ventricular origin) Mild, moderate, or severe RV dilation ⫾ dysfunction ⱖ 1.2, increases with disease progression

Frequent PVCs or VT of RBBB morphology (left ventricular origin) Mild, moderate, or severe LV dilation ⫾ dysfunction ⬍ 1, diminishes with disease progression

Localised dilation, WMA, and/or aneurysms in RV, preferentially affecting triangle of dysplasia and mid-free wall Fat/late enhancement in RV myocardium

Localised dilation, WMA, and/or aneurysms in LV

Naxos syndrome

Late enhancement in LV myocardium in a subepicardial/ midwall distribution Carvajal syndrome

ECG, electrocardiogram; RBBB, right bundle branch block; LBBB, left bundle branch block; PVC, premature ventricular complex; VT, ventricular tachycardia; RV, right ventricular; LV, left ventricular; WMA, wall motion abnormality ∗The clinical picture in the Biventricular subtype is generally a composite of right-dominant and left-dominant features. Both ventricles are affected to the same extent, with RV/LV volume ratio remaining ≈ 1 throughout the disease course. † Poor R-wave progression is the primary ECG abnormality observed in the Newfoundland founder population, in which LV structural abnormalities are prominent (Merner et al., 2008). It has also been reported in ∼ 10% of patients in a cohort including all three subtypes of arrhythmogenic cardiomyopathy.

A third (‘biventricular’) variant of ARVC is characterised by parallel involvement of both ventricles. In milder cases, localised structural abnormalities are often present in both ventricles, with progression to biventricular dilation and/or systolic dysfunction in advanced disease. Arrhythmia of both right and left ventricular origin may be observed, with at least 15% of cases

Figure 1. Late gadolinium enhancement of the left ventricular myocardium in left-dominant arrhythmogenic cardiomyopathy. Cardiovascular magnetic resonance images from a 19-yearold boy with a heterozygous chain termination mutation in desmoplakin. There is late gadolinium enhancement of the septum in a midwall distribution (arrows in left panel; box in right panel), likely representative of fibrous tissue. Ventricular volumes and function were normal and wall motion abnormalities inconspicuous, highlighting the importance of late gadolinium enhancement imaging in establishing the diagnosis. In this family, the majority of affected individuals had left-dominant arrhythmogenic cardiomyopathy, but the biventricular subtype was also present in a few.

show both types, underscoring the presence of arrhythmogenic substrate in both ventricles (Sen-Chowdhry et al., 2007). In both the left dominant and biventricular subtypes, initial presentation is with arrhythmia, not heart failure, and the propensity to ventricular arrhythmia exceeds the degree of ventricular impairment throughout the clinical course, underscoring the distinction from dilated cardiomyopathy (Sen-Chowdhry et al., 2007, 2008). Accumulating evidence of the breadth of disease expression in ARVC has led to calls for adoption of the broader term arrhythmogenic cardiomyopathy, with classic (right dominant), biventricular, and left-dominant subtypes (Sen-Chowdhry et al., 2008). The cardiac component of Carvajal syndrome is left dominant (or possibly biventricular) arrhythmogenic cardiomyopathy; and its description was one of the first pointers to this under-recognised part of the disease spectrum. GENOTYPE–PHENOTYPE ASSOCIATIONS IN THE DESMOSOMAL CARDIOCUTANEOUS SYNDROMES There are many other documented cases of cardiocutaneous syndromes secondary to homozygous, double heterozygous or compound heterozygous mutations in

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plakoglobin, desmoplakin and desmocollin (Asimaki et al., 2009; Delmar & McKenna, 2010; Bolling & Jonkman, 2009; Simpson et al., 2009; Alcalai et al., 2003; Erken et al., 2011; Uzumcu et al., 2006). Woolly hair is a prevalent feature, but alopecia has also been observed (Asimaki et al., 2009; Bolling et al., 2010; Erken et al., 2011). Skin involvement ranges from extremely dry skin to the well-known palmoplantar keratoderma; vesicular lesions at the extremities, knees, palms and soles; and lethal acantholytic epidermolysis bullosa (Bolling & Jonkman, 2009; Delmar & McKenna, 2010). Severe fragility of the mucous membranes and loss of teeth and nails are documented (Bolling et al., 2010; Mahoney et al., 2010). The cardiac phenotype is typically one of arrhythmogenic cardiomyopathy, although the subtype varies, and the severity of the disease may lead to early onset heart failure, which is rare in cardiac-restricted disease (Delmar & McKenna, 2010; Uzumcu et al., 2006). Each case report and family study contributes to gradual unravelling of the complex genotype–phenotype associations in desmosomal disease. In the Carvajal series (DSP6901delG) and the cases described by Asimaki et al. (DSP-Q1446X, DSP-Q683X) and Bolling et al. (DSP2874del5), for example, the mutations resulted in truncation of the desmoplakin protein (Asimaki et al., 2009; Carvajal-Huerta, 1998; Bolling et al., 2010). The C-terminus of desmoplakin binds to desmin intermediate filaments in the cytoplasm. The cardiac phenotype in all cases was characterised by severe, perhaps even predominant, left ventricular involvement. Naxos syndrome (JUP2157del2), on the other hand, can be considered a prototype for classic right ventricular cardiomyopathy (Table 1) (Protonotarios et al., 2001). It has been proposed that disrupted binding of desmosomal proteins to intermediate filaments confers susceptibility to disease in the high-pressure left ventricle. This may be analogous to the loss of cytoskeletal integrity considered central to the development of dilated cardiomyopathy (Sen-Chowdhry et al., 2007). In contrast, the right ventricle may be particularly vulnerable to desmosomal defects that impair cell adhesion, owing to its thin walls and high distensibility, an adaptation to wide physiological variations in preload. Mutations leading to truncation of desmosomal proteins are also associated with prominent left ventricular involvement in autosomal-dominant arrhythmogenic cardiomyopathy (Bauce et al., 2005; SenChowdhry et al., 2005, 2007). Nevertheless, the finding that more than one disease subtype can coexist within the same kindred suggests a role for modifier genes and/or environmental influences in determining the final phenotype (Sen-Chowdhry et al., 2007). In general, disease involving both the skin and the heart suggests the presence of more than one desmosomal mutation, while single (dominant) mutations tend to affect one or the other. Nevertheless, biventricular

cardiomyopathy, palmoplantar keratoderma, woolly hair and oligodontia have also been reported in conjunction with heterozygous mutations in desmoplakin (Chalabreysse et al., 2011; Norgett et al., 2006). At the milder end of the spectrum, families with arrhythmogenic cardiomyopathy secondary to dominant DSP mutations have self-reported dry skin and curly hair. The genetic and environmental basis of the myriad phenotypic variations in the cardiocutaneous syndromes remains to be resolved. BEYOND THE DESMOSOME: CARDIOCUTANEOUS SYNDROMES IN ANIMALS Cardiocutaneous syndromes also occur spontaneously in animals. Two notable examples have been observed in wa3 mice and Poll-Hereford cattle, both inherited as autosomal recessive traits. The mice have wavy coats and a cardiac phenotype typical of arrhythmogenic cardiomyopathy (Herron et al., 2005). Myocyte necrosis arises first in the right ventricular free wall and subsequently progresses to the septum, accompanied by inflammation, fibrosis and chamber dilation. Cardiomyopathy and woolly haircoat in Poll-Hereford cattle is similar, with affected calves identifiable at birth by their fuzzy coat; a proportion also develop ulcerative ocular keratitis. Myocardial involvement develops during the foetal period and is rapidly progressive, often causing death within the first three months of life. Abnormalities on histopathology of affected hearts include subepicardial fibrosis of the right ventricular free wall, and myocyte necrosis and replacement fibrosis in both ventricles (Simpson et al., 2009). The clinical profile in both mice and cattle is therefore typical of a desmosomal cardiocutaneous syndrome; yet no desmosomal mutation has been implicated. Rather, both are the result of homozygous mutations in the gene encoding NFkB interacting protein1 (PPP1R13L, also known as NKIP1) (Herron et al., 2005; Simpson et al., 2009). The NFkB group of transcription factors control inflammatory and immune responses, cellular proliferation, growth, development and apoptosis, many of which are dysregulated in arrhythmogenic cardiomyopathy. The putative mechanism by which defects in NKIP1 might lead to cardiocutaneous syndrome, however, invokes the canonical Wnt/β-catenin pathway, already implicated in ARVC. Irrespective of the causal mutation, reduction of immunodetectable plakoglobin at the intercalated disc is a recurrent feature in ARVC. Animal, cell-line and induced pluripotent stem cell models have shown translocation of plakoglobin from cell–cell junctions to the cytosolic pool (Garcia-Gras et al., 2006; Kim et al., 2013). From there, plakoglobin (also known as γ-catenin) may diffuse into the nucleus and compete with β-catenin, leading to suppression of canonical

HOW CARDIOCUTANEOUS SYNDROMES TRANSFORMED OUR PERSPECTIVE ON ARRHYTHMOGENIC CARDIOMYOPATHY Wnt/β-catenin-Tcf/Lef1 signalling (Delmar & McKenna, 2010). Since the β-catenin signalling cascade is also known to interact with NFkB, it is a plausible (albeit unproven) final common pathway in arrhythmogenic cardiomyopathy. The study of cardiocutaneous syndromes in animals has therefore provided another piece of the puzzle that is the molecular underpinning of arrhythmogenic cardiomyopathy. CONCLUSION In tandem with declining clinical examination skills have come rapid advancements in the fields of imaging, genomics and proteomics. Once-unimaginable windows into the macroscopic, microscopic and molecular workings of living organisms have opened. Invaluable as they are, these emerging insights are no substitute for the proficiency of traditional physicians in observing external physical signs and associating them with underlying clinical dysfunction. The recognition that certain hair and skin abnormalities were related to a poorly understood myocardial disorder fostered the concept of cardiocutaneous syndromes. The study of cardiocutaneous syndromes, in turn, has facilitated understanding of the clinical course, disease spectrum, genetics and cellular and molecular underpinning of arrhythmogenic cardiomyopathy. Just as the rare can illuminate the common, traditional clinical skills remain a necessary complement to cutting-edge technologies. ACKNOWLEDGEMENTS We are grateful to Dr Sripurna Das for her constructive comments on the manuscript. Declaration of interest: The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper. The authors were supported by the British Heart Foundation (SSC, WJM), the EU 5th Framework Program Research and Technology Development (QLG1CT-2000-01091), and the Department of Health’s NIHR Biomedical Research Centres funding scheme. REFERENCES Abdelmalek NF, Gerber TL, Menter A (2002). Cardiocutaneous syndromes and associations. J Am Acad Dermatol. 46: 161–183; quiz 183–186. Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T (2003). A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J Am Coll Cardiol. 42: 319–327. Asimaki A, Syrris P, Ward D, Guereta LG, Saffitz JE, McKenna WJ (2009). Unique epidermolytic bullous

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