Are You Confident of the Diagnosis?
What you should be alert for in the history
Carajal syndrome, a variant of Naxos disease (Naxos arrhythmogenic cardiocutaneous syndrome), associates woolly hair and palmoplantar keratoderma with an extreme type of left dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), initially characterized as dilated cardiomyopathy. Presentation of cutaneous abnormalities is that of Naxos disease (see chapter on Naxos disease). However, heart manifestations become apparent earlier in childhood with heart failure. Diffuse left ventricular involvement appears at 90% of patients during the second decade of life.
Deterioration of heart failure requiring heart transplantation is not uncommon, with the youngest reported candidate for heart transplantation being 4 years old.
Expected results of diagnostic studies
On cardiac histopathology, the features of ARVC/D are fullfilled with myocyte loss and mostly fibrous replacement of both right and left ventricular myocardium. Skin biopsy from affected areas usually reveals features of epidermolytic keratoderma. The syndrome is caused by mutations in the desmosomal protein desmoplakin largely trancating the C-terminal of the protein.
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Who is at Risk for Developing this Disease?
Woolly hair and palmoplantar kertoderma or similar skin defects in a child should alert for signs of cardiomyopathy (see chapter on Naxos disease).
What is the Cause of the Disease?
Etiology
A recessive mutation in desmoplakin gene (DSP 7901del1G) was originally reported to underlie this syndrome in three families from Ecuador. Other recessive desmoplakin mutations (R1267X and p.Gln1301X) or compound desmoplakin heterozygosity (Q1446X plus Q673X) largely trancating desmoplakin molecule at its C-terminal, have been reported.
Pathophysiology
Desmoplakin plays a major role in mechanical linking of desmin/keratin intermediate filaments to desmosomal plaque via its C-terminal. Mutations affecting the C-terminal of the protein have been associated with cardiac phenotype with severe left-dominant ARVC/D, that should be differentiated from dilated cardiomyopathy. Immunohistology of myocardium in a patient from Ecuador revealed the absence of desmoplakin, plakoglobin and desmin from intercalated disks (for more information see chapter on Naxos disease).
Systemic Implications and Complications
Heart failure
Death from heart failure
Sudden death
Treatment Options
Usually heart disease is severe, requiring early medical treatment for heart failure and consideration for heart transplantation. However, every patient is at increased risk for sudden cardiac death; therefore, ICD implantation should be considered as first step.
Optimal Therapeutic Approach for this Disease
Implantable cardioverter-defibrillator (ICD) implantation
Medical treatment for heart failure
Heart transplantation
Palmar plantar keratoderma can be treated with lactic acid 5-12% cream or urea 10-20% cream on a daily basis if symptomatic. If asymptomatic emollients are all that is required.
No therapy for the wooly hair is needed.
Patient Management
Once a case is diagnosed the whole family should be clinically screened by physical examination, 12-lead resting ECG, signal averaged ECG, 24-hour holter monitoring, and two-dimensional echocardiography. Genetic investigation of the family is required. Recessive mutations in desmoplakin gene have been related to Carvajal syndrome.
Upon identification of a pathogenic mutation in the proband, screening for this mutation is indicated in every relative who shows the cutaneous phenotype regardless of age, since desmoplakin mutations have been related to early heart disease with biventricular involvement.
The key to management is to have those who show the cutaneous anormalities followed up by a cardiologist who is familiar with the disease. Restriction of athletic activity is required for all individuals with Carvajal phenotype.
Unusual Clinical Scenarios to Consider in Patient Management
Carvajal syndrome is a variant of Naxos cardiocutaneous syndrome due to recessive desmoplakin mutations, its principal sign being the early and severe left ventricular involvement, with ventricular arrhythmias and premature heart failure. Dental anomalies have been reported in cases of compound heterozygosity in desmoplakin mutation.
What is the Evidence?
Protonotarios , N, Tsatsopoulou , A, Patsourakos , P, Alexopoulos , D, Gezerlis , P, Simitsis , S. “Cardiac abnormalities in familial palmoplantar keratosis”. Br Heart J . vol. 56. 1986. pp. 321-6. (First description of a recessive syndrome associating ARVC/D with woolly hair and palmoplantar keratoderma; familialARVC/D; left ventricular involvement in ARVC/D.)
Carvajal-Huerta , L. “Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy”. J Am Acad Dermatol . vol. 39. 1998. pp. 418-21. (Description of palmoplantar keratoderma and woolly hair in in association with dilated cardiomyopathy in families from Ecuador.)
McKoy , G, Protonotarios , N, Crosby , A, Tsatsopoulou , A, Anastasakis , A, Coonar , A. “Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease)”. Lancet. vol. 355. 2000. pp. 2119-24. (Study that showed Naxos disease was caused by a genetic mutation in the gene that encodes plakoglobin; first gene identified for ARVC/D, a mutation in desmosomal protein was the first reported as causing a cardiomyopathy.)
Norgett , EE, Hatsell , SJ, Carvajal-Huerta , L, Cabezas , JC, Common , J, Purkis , PE. “Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma”. Hum Molec Genet . vol. 9. 2000. pp. 2761-66. (Identification of a recessive desmoplakin mutation causing phenotype of woolly hair, palmoplantar keratoderma and cardiomyopathy of dilated type.)
Krotonotarios , N, Tsatsopoulou , A, Fontaine , G. “Naxos disease: Keratoderma, scalp modifications, and cardiomyopathy”. J Am Acad Dermatol . vol. 44. 2001. pp. 309-10. (Article indicating that the cardiomyopathy of Carvajal patients is ARVC/D rather than a dilated cardiomyopathy; therefore, the described cardiocutaneous phenotype is a subtype of Naxos disease.)
Protonotarios , N, Tsatsopoulou , A, Gatzoulis , K. “Arrhythmogenic right ventricular cardiomyopathy caused by a deletion in plakoglobin (Naxos disease)”. Card Electrophysiol Rev . vol. 6. 2002. pp. 72-80. (Electrocardiographic spectrum and natural history of ARVC/D iIn patients with Naxos disease.)
Protonotarios , N, Tsatsopoulou , A. “Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy”. Cardiovasc Path . vol. 13. 2004. pp. 185-94. (Discussion of the clinical phenotype and pathogenesis of Naxos and Carvajal syndrome with emphasis on the cardiac disease.)
Kaplan , SR, Gard , JJ, Carvajal-Huerta , L, Ruiz-Cabezas , JC, Thiene , G, Saffitz , JE. “Structural and molecular pathology of the heart in Carvajal syndrome”. Cardiovasc Pathol. vol. 13. 2004. pp. 26-32. (Pathologic and immunohistologic findings on cell-cell junctions in the myocardium of a patient with Carvajal syndrome, leading to the diagnosis to ARVC/D.)
Protonotarios , N, Tsatsopoulou , A, Marcus, Nava, Thiene. “Recessive forms of ARVC/D”. Arrhythmogenic right ventricular cardiomyopathy/dysplasia. 2007. pp. 15-20. (Analytical description and natural history of syndromic recessive ARVC/D.)
Tsatsopoulou , A, Protonotarios , N, Cirillo , N, Lanza , A, Gombos, F. “Desmosomes outside the epidermis. Desmosomes and myocardium: A pivotal role of desmosomes in myocardial degeneration, ventricular arrhythmias and sudden death”. Pathophysiology of the Desmosome. 2009. pp. 105-119. (Insights into desmosomal function in relation to clinical phenotypes with respect to arrhythmogenesis in ARVC/D.)
Tsatsopoulou , AA, Protonotarios , NI, McKenna , WJ. “Arrhythmogenic right ventricular dysplasia, a cell-adhesion cardiomyopathy: insights into disease pathogenesis from preliminary genotype-phenotype assessment”. Heart. vol. 92. 2006. pp. 1720-3. (Comprehensive review on the role of desmosomal defects on ARVC/D pathogenesis and arrhythmogenesis; contribution of studies on Naxos disease.)
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