Cardiomyopathy, Dilated, With Woolly Hair, Keratoderma, And Tooth Agenesis

A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy with woolly hair, palmoplantar keratoderma, and tooth agenesis (DCWHKTA) is caused by heterozygous mutation in the desmoplakin gene (DSP; 125647).

Carvajal syndrome (DCWHK; 605676), which has overlapping features but no abnormalities of dentition, is caused by homozygous mutation in DSP.

Clinical Features

Norgett et al. (2006) reported a father and daughter with palmoplantar keratoderma, woolly hair, and cardiomyopathy. The proband presented at 3 years of age with hyperkeratosis and fissuring of the skin of the palms and soles, which also extended over the Achilles tendon, and she had woolly, unmanageable hair. One month after her birth, her father, who apparently had similar hair and skin, died suddenly from arrhythmogenic right ventricular dysplasia. There were no other affected family members. Examination of the proband at 14 years of age showed psoriasiform hyperkeratosis of the knees, elbows, and shins, with prominence around hair follicles. She had striate keratoderma of the palms and focal keratoderma of the soles, which spread over the Achilles tendon. Her hair was kinky and woolly, with short sparse hairs in the frontal scalp. She also had absent molars and premolar teeth but normal nails and normal hearing. Echocardiography (ECG) suggested biventricular cardiomyopathy, and 24-hour electrocardiography showed nonsustained ventricular tachycardia which, together with the history of sudden death in her father, prompted implantation of a cardiac defibrillator. Repeat echocardiograms showed progression of left ventricular dilation with severe global impairment of systolic function, and she died at age 18 years due to persistent dysrhythmia despite activation of the defibrillator.

Chalabreysse et al. (2011) described a father and 2 sons with palmoplantar keratoderma, woolly hair, tooth agenesis ranging from 1 missing tooth to oligodontia, and mild to severe dilated cardiomyopathy. The mother and another son and daughter were unaffected, as were the parents and sibship of the father. The proband had episodes of loss of consciousness that had begun in his teens as well as electrocardiographic abnormalities, including incomplete right bundle branch block and nonsustained ventricular tachycardia; he required heart transplantation in his 20s due to severe cardiomyopathy. He also had marked oligodontia, with only 4 permanent molars and several persisting primary teeth. His older brother and father had milder dilated cardiomyopathy and fewer missing teeth. The proband's explanted heart showed biventricular enlargement with no hypertrophy; microscopic examination revealed fatty and fibrofatty replacement in the anterior and posterior walls of the right ventricle, most severe in the epicardial layer, as well as in the interventricular septum. The left ventricle had no fatty replacement, but showed areas of mutilating fibrosis.

Boule et al. (2012) studied a father and son with dilated cardiomyopathy who also exhibited woolly hair, palmoplantar keratoderma, and tooth agenesis. The 29-year-old father had been diagnosed with dilated cardiomyopathy and left ventricular dysfunction at 12 years of age after the incidental finding of an enlarged heart on chest x-ray. Woolly hair, palmoplantar keratoderma, leukonychia, and absence of third molars (agenesis of 4 teeth) were noted. The patient had no history of syncope or palpitations; electrocardiogram showed QRS prolongation and depolarization abnormalities. ECG showed biventricular dilation and hypokinesia, with apical aneurysm and excessive trabeculations of the right ventricle. Holter electrocardiogram registered more than 500 premature ventricular beats per day. A diagnosis of arrhythmogenic right ventricular cardiomyopathy was made, and a cardioverter-defibrillator was implanted. His 10-year-old son had woolly hair, palmoplantar keratoderma, brittle nails without leukonychia, and agenesis of 10 teeth. At 5 years of age his echocardiogram was normal, but at age 10 years, after an episode of chest pain with significant elevation of cardiac troponin, electrocardiography showed multiple isolated premature ventricular beats with epsilon wave in V1, and ECG showed dilation of the right ventricular infundibulum.

Clinical Variability

Boyden et al. (2016) described 3 unrelated children, 1 girl and 2 boys, who had erythrokeratodermia at birth or shortly thereafter and also exhibited scant woolly hair, sparse or absent eyebrows and eyelashes, enamel defects with multiple caries of primary teeth and variable tooth agenesis of secondary dentition, palmoplantar keratoderma, onychodystrophy of all nails, and moderate to severe dilated cardiomyopathy. One of the boys died at age 3 years from heart failure, whereas the remaining 2 children had relatively preserved ventricular function. All 3 exhibited marked erythema of the skin, associated with ichthyotic fine white scaling and pruritus that was unresponsive to oral or systemic therapy. Skin histopathology showed psoriasiform hyperplasia and a reduced granular cell layer, as well as compact orthohyperkeratosis in 2 patients and parakeratosis in 1 patient. Serum IgE and eosinophil counts were normal. Boyden et al. (2016) designated the phenotype 'erythrokeratodermia-cardiomyopathy (EKC)' syndrome.

Molecular Genetics

In a DNA sample from a girl who died at age 18 years with dilated cardiomyopathy, palmoplantar keratoderma, woolly hair, and tooth agenesis, Norgett et al. (2006) analyzed the candidate gene desmoplakin (DSP; 125647) and identified a heterozygous 30-bp insertion (125647.0015). The mutation was not present in her unaffected mother or 160 control chromosomes; no DNA was available from her deceased, similarly affected father.

Chalabreysse et al. (2011) screened the DSP and plakoglobin (JUP; 173325) genes in the proband of a family with DCWHKTA and identified a heterozygous missense mutation in the DSP gene (S597L; 125647.0016); no mutations were found in the JUP gene. The proband's affected father was also heterozygous for the DSP missense mutation, but his affected older brother declined genetic testing. The mutation was not found in the unaffected mother, paternal grandparents, or 2 unaffected sibs.

In a father and son with DCWHKTA, Boule et al. (2012) analyzed the desmosomal genes DSP, JUP, PKP2 (602861), DSG2 (125671), and DSC2 (125645), and identified heterozygosity for a missense mutation in the DSP gene (T564I; 125647.0017). No mutations were detected in the other genes, and the DSP mutation was not found in 600 control chromosomes.

Boyden et al. (2016) analyzed exome data from a cohort of 496 kindreds with disorders of keratinization and identified 3 unrelated children with dilated cardiomyopathy, woolly hair, erythrokeratoderma, and tooth agenesis who were heterozygous for de novo tightly clustered missense mutations in the DSP gene: Q616P (125647.0021), H618P (125647.0022), and L622P (125647.0023).