Cardiomyopathy, Dilated, With Woolly Hair And Keratoderma

A number sign (#) is used with this entry because dilated cardiomyopathy with woolly hair and keratoderma (DCWHK) is caused by homozygous mutation in the DSP gene (125647), which encodes desmoplakin, on chromosome 6p24.

Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (Naxos disease; 601214) is caused by mutation in the plakoglobin gene (JUP; 173325). Also see 610476 for a similar disorder caused by homozygous mutation in the DSC2 gene (125645).

Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (DCWHKTA; 615821) is caused by heterozygous mutation in DSP.

Clinical Features

Carvajal-Huerta (1998) described 18 patients with a confirmation of epidermolytic palmoplantar keratoderma, woolly hair, and dilated cardiomyopathy, examined clinically and histologically in Ecuador between 1970 and 1997. Cardiologic examinations were performed in 12 of the patients. The patients were born with woolly hair. Around the first year, palmoplantar keratoderma and other keratotic signs appeared. The first cardiac abnormalities were exclusively electrocardiographic and occurred in asymptomatic patients. In these patients, dilation of the left ventricle, together with alterations in muscle contractility, was observed. The dilated cardiomyopathy sometimes led to congestive heart failure and death.

Rasmussen et al. (2013) studied a Turkish girl who presented at 8 years of age with congestive heart failure, woolly hair, and palmoplantar keratoderma, consistent with a diagnosis of Carvajal syndrome. Transthoracic echocardiogram showed biventricular dilation and a left ventricular ejection fraction of 15%, and she underwent cardiac transplantation at age 12 years. The explanted heart showed severe dilation of all 4 chambers, thinned myocardium, extensive interstitial replacement fibrosis, and hypertrophy of cardiomyocytes, without fatty infiltrations or inflammatory changes. Her first-cousin parents and 2 sibs were unaffected.

In a review of cardiocutaneous syndromes and arrhythmogenic cardiomyopathy, Sen-Chowdhry and McKenna (2014) stated that although the cardiac component of Carvajal syndrome was originally considered dilated cardiomyopathy, many of its features resemble those of arrhythmogenic cardiomyopathy (see 107970). In addition, they noted that different disease subtypes have been found to coexist within the same kindred, suggesting a role for modifier genes and/or environmental influences.

Inheritance

Autosomal recessive inheritance was considered likely in the Ecuadorian families examined by Carvajal-Huerta (1998). The patients were distributed in 6 families; in 2 families, parental consanguinity was documented.

Both Naxos disease and dilated cardiomyopathy with woolly hair and keratoderma are autosomal recessive, whereas most of the hereditary dilated cardiomyopathies are autosomal dominant (Schonberger and Seidman, 2001).

Molecular Genetics

Desmosomes are major cell adhesion junctions, particularly prominent in the epidermis and cardiac tissue and are important for the rigidity and strength of the cells (Green et al., 1990; for a review, see the entry for desmoplakin, 125647). The desmosome consists of several proteins, of which desmoplakin (DSP) is the most abundant. Mutations in the DSP gene can cause isolated autosomal dominant palmoplantar keratoderma (Armstrong et al., 1999). Norgett et al. (2000) described the first recessive human desmoplakin gene mutation, 7901delG (125647.0002), which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair, and a dilated left ventricular cardiomyopathy. All tested affected members of 3 families from Ecuador were homozygous for this mutation, which produces a premature stop codon leading to a truncated desmoplakin protein missing the C domain of the tail region. Cardiologic investigation, including electrocardiographic and echocardiographic examinations, of a number of the affected family members was reported by Carvajal-Huerta (1998). A number of the patients with this syndromic disorder suffered heart failure in their teenage years, resulting in early morbidity. Histology of the skin revealed large intercellular spaces and clustering of desmosomes at the infrequent sites of keratinocyte adhesion. Immunohistochemistry of skin from the patients showed a perinuclear localization of keratin in suprabasal keratinocytes, suggesting a collapsed intermediate filament network. The study demonstrated the importance of desmoplakin in the attachment of intermediate filaments to the desmosome. Desmoplakin-null mice die in early development (Gallicano et al., 1998); in contrast, the truncated protein due to the homozygous 7901delG mutation in humans is not embryonic lethal. The authors hypothesized that the tail domain of desmoplakin is not required for establishing tissue architecture during development.

In a Turkish girl with Carvajal syndrome, Rasmussen et al. (2013) identified homozygosity for a 1-bp deletion in the DSP gene (125647.0014). Her unaffected first-cousin parents and 2 sibs were heterozygous for the mutation.