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

Dilated cardiomyopathy with woolly hair and keratoderma (DCWHK) is characterized by the presence of woolly or sparse hair from birth. Some patients exhibit fragile skin with blisters/erosions after minor mechanical trauma, with hyperkeratosis and epidermolytic keratoderma developing in early childhood. Cardiomyopathy may become apparent in the first decade of life, and early death due to heart failure has been reported, but patients may remain asymptomatic into the fourth decade of life. Some patients exhibit an arrhythmogenic form of cardiomyopathy, with sudden death in early adulthood (Carvajal-Huerta, 1998; Whittock et al., 2002; Alcalai et al., 2003; Uzumcu et al., 2006).

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. An isolated form of striated PPK (PPKS2; 612908) is also caused by heterozygous mutation in DSP.

Reviews

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 607450). 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.

Carvajal-Huerta (1998) described 18 patients from 6 Ecuadoran families with woolly hair, palmoplantar keratoderma, and dilated cardiomyopathy. Patients were born with woolly hair, and developed palmoplantar keratoderma (PPK) and other keratotic signs around 1 year of age. All patients exhibited a striate form of PPK, with keratotic lines beginning on the wrists and extending radially and centrifugally towards the fingers. In addition, all patients had plantar keratoderma at pressure sites, striated lichenoid keratoses in flexural folds, follicular keratosis on the elbows and knees, and clubbing of the fingernails. Psoriasiform keratoses were observed in 10 patients, on knees, extensor surfaces of legs, and dorsal feet; and 8 patients also experienced transient pruritic vesicles and blisters on the trunk, abdomen, and limbs. Cardiac evaluation was performed in 12 patients, most of whom initially showed asymptomatic electrocardiographic abnormalities beginning in the second decade of life, with later left ventricular dilation and abnormal contractility on echocardiogram. Five patients developed severely impaired systolic function and died between 12 to 17 years of age, of presumed congestive heart failure. Two brothers who developed cardiac abnormalities late, at 32 and 34 years of age, were lost to follow-up. Histology of skin lesions showed epidermolytic hyperkeratosis, dyskeratosis, and spongiosis.

Norgett et al. (2000) studied 3 families from the same region of Ecuador who were originally described by Carvajal-Huerta (1998), with woolly hair, PPK, and dilated cardiomyopathy, and mutation in the DSP gene. The skin disease presented as a PPK with some nonvolar involvement particularly at sites of pressure or abrasion. All epidermal lesions had the characteristic longitudinal hyperkeratosis of striated PPK. The hair was curly and woolly in texture. Cardiac investigation including electrocardiographic and echocardiographic examinations of a number of the affected family members were previously reported to show left ventricular dilated cardiomyopathy, often resulting in heart failure during adolescence. Histology of affected patient skin revealed large intercellular spaces between suprabasal keratinocytes supporting the finding of a cell adhesion defect underlying the disease.

Whittock et al. (2002) reported 2 unrelated girls (probands A and B) with focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, woolly hair with varying degrees of alopecia, and mutation in the DSP gene. Both patients exhibited skin blistering and fragility after birth that improved over time. The authors referred to this disorder as skin fragility-woolly hair syndrome. Proband A was said to have developed some teeth, which appeared to be abnormally formed; dentition of proband B, who was 17 years old, was not described. Proband B also had progressively worsening nail dystrophy, and reduced body hair with near-absent eyebrows and eyelashes. Both patients experienced painful keratoderma on the hands and feet with recurrent secondary infection and occasional more widespread trauma-induced sloughing of the skin; both required a wheelchair for mobility. Immunohistochemistry of patient skin biopsies revealed that desmoplakin was located not only at the cell periphery but also in the cytoplasm. In addition, electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network. The authors noted that there were no apparent cardiac anomalies in the 2 probands, but stated that the patients would be at risk for dilated left ventricular cardiomyopathy, as had been observed in previous patients with biallelic DSP mutations.

Alcalai et al. (2003) reported a 16-year-old girl from a large multiply consanguineous Muslim Arab family who had woolly hair, pemphigus-like epidermolytic skin abnormalities, cardiac arrhythmias, and mutation in the DSP gene. She presented with recurrent syncope and was found to have ventricular tachycardia originating from the midseptal area of the right ventricle. Echocardiography revealed a mildly dilated right ventricle, normal left ventricle, and no significant valvular defects. MRI was not performed and CT imaging was not informative, due to her implantable cardioverter/defibrillator device. She was diagnosed with arrhythmogenic right ventricular cardiomyopathy. There were 8 additional family members with woolly hair and blistering skin in childhood, particularly on the palms, soles, and knees, who had died suddenly in young adulthood, at ages ranging from 15 to 30 years; none had major cardiac symptoms before death and none underwent cardiac evaluation. Skin biopsy from the proband's deceased brother, who died at age 23, showed histology similar to pemphigus foliaceous.

Uzumcu et al. (2006) reported a Turkish boy who died at age 4 years of heart failure, who also had woolly hair and PPK and mutation in the DSP gene. The patient presented at age 3.5 years with chronic fatigue and cardiac arrhythmias. He had biventricular dilated cardiomyopathy with thinning of the ventricular walls, severe reduction in left ventricular ejection fraction (less than 25%), and mitral valve regurgitation. Holter monitor showed frequent runs of ventricular tachycardia with couplets and bigeminal early ventricular beats, and he was diagnosed with arrhythmogenic dilated cardiomyopathy. The authors noted that this was an unusually severe cardiac phenotype with early onset and rapid progression; autopsy was not permitted.

Al-Owain et al. (2011) reported 3 sibs and 2 cousins from a consanguineous Saudi family with woolly hair, PPK, skin fragility, and dystrophic nails, and mutation in the DSP gene. The index patient was a 14-year-old girl with woolly hair and patchy alopecia, who experienced excessive blistering of the skin after minor mechanical trauma. She also had PPK with fissuring, and thickened nails with subungual hyperkeratosis and wedging. The 4 other affected children, including the proband's 2 younger brothers and 2 affected cousins, all had woolly hair, skin fragility, PPK, and dystrophic nails. All had normal teeth. No cardiac symptoms were reported and there was no family history of sudden death. The proband's 2 affected brothers, who were 4 and 7 years of age, had normal echocardiograms; formal cardiac evaluation was declined for the proband and her 2 affected cousins, aged 3 and 16 years. Although the authors designated the patients as having skin fragility-woolly hair syndrome, they noted that cardiomyopathy sometimes occurs later in life in patients with DCWHK.

Rasmussen et al. (2013) studied a Turkish girl with congestive heart failure, woolly hair, and palmoplantar keratoderma, and mutation in the DSP gene. She presented at age 8 years with symptoms 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.

Vahlquist et al. (2014) reported a 4-year-old Swedish girl with skin fragility, alopecia, cardiomyopathy, and mutation in the DSP gene. She was born with erythematous fragile skin and sparse scalp hair. In the neonatal period, she developed focal hyperkeratosis on her neck, knees, and feet, and her nails thickened. Upon examination at age 2 years, she had sparse thin hair, widespread skin erosions, and focal keratoderma on her soles and around her thickened nails. A punch biopsy of clinically uninvolved skin showed a pathologic cytoskeleton throughout the epidermis, with keratin intermediate filaments clumped around the nucleus and ending abruptly at some distance from the desmosomes. Cardiac examination at 3 years of age showed an end-diastolic left ventricular diameter at the upper range of normal, with a normal shortening fraction of 30%. At 4.5 years of age, although she still had no overt cardiac symptoms, her left ventricle was pathologically dilated and showed severely impaired systolic function, with a shortening fraction of 13% and ejection fraction of 33%.

The transmission pattern of DCWHK in the Ecuadoran families reported by Carvajal-Huerta (1998) was consistent with autosomal recessive inheritance.

Both DCWHK and Naxos disease are autosomal recessive, whereas most of the hereditary dilated cardiomyopathies are autosomal dominant (Schonberger and Seidman, 2001).

In a large consanguineous Saudi family in which 5 children (3 sibs and 2 cousins) had woolly hair, skin fragility, and PPK, Al-Owain et al. (2011) performed multipoint parametric linkage analysis under assumption of a recessive model of inheritance with complete penetrance, obtaining a maximum lod score of 4.7 on chromosome 6, between regions 6p25.1-p24.1.

In a Muslim Arab family in which 8 members with woolly hair and an epidermolytic skin disorder died suddenly during young adulthood, and a 16-year-old girl with similar hair and skin was diagnosed with arrhythmogenic right ventricular cardiomyopathy, Alcalai et al. (2003) performed haplotyping with microsatellite markers and found linkage to chromosome 6p24, near the DSP gene.

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. In affected members of 3 Ecuadoran families with generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair, and dilated left ventricular cardiomyopathy, originally described by Carvajal-Huerta (1998), Norgett et al. (2000) identified the first recessive human desmoplakin gene mutation, a homozygous 1-bp deletion (125647.0002). The deletion segregated with disease in all 3 families and was not found in 100 unrelated normal controls. 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 2 unrelated girls with woolly hair, skin fragility, and PPK, Whittock et al. (2002) performed mutation screening of desmoplakin and identified compound heterozygosity for a missense/nonsense combination of mutations in both patients: N287K (125647.0004) and C809X (125647.0005) in proband A, and R2366C (125647.0006) and Q664X (125647.0007) in proband B. The authors noted that there were no apparent cardiac anomalies in the 2 probands, but stated that the patients would be at risk for dilated left ventricular cardiomyopathy.

In a 16-year-old Muslim Arab girl with woolly hair, an epidermolytic skin disorder, and arrhythmogenic right ventricular cardiomyopathy, Alcalai et al. (2003) identified homozygosity for a missense mutation in the DSP gene (G2375R; 125647.0025). The mutation segregated fully with disease in the family and was not found in 90 unrelated controls. DNA was unavailable from 8 additional family members with woolly hair and skin abnormalities who had died suddenly in young adulthood.

In a Turkish boy with woolly hair, PPK, and arrhythmogenic biventricular dilated cardiomyopathy, who died from heart failure at age 4 years, Uzumcu et al. (2006) sequenced the candidate gene DSP and identified homozygosity for a nonsense mutation (R1267X; 125647.0010). The mutation segregated fully with disease in the family and was not present in 100 ethnically matched control chromosomes.

In a large consanguineous Saudi family in which 3 sibs and 2 cousins had woolly hair, skin fragility, and PPK mapping to chromosome 6p25.1-p24.1, Al-Owain et al. (2011) sequenced the candidate gene DSP and identified homozygosity for a missense mutation (R2366H; 125647.0013). The parents in both sibships were heterozygous for the mutation, which was not found in 200 unrelated ethnically matched healthy controls. None of the children had cardiac symptoms, and 2 had normal echocardiograms at ages 4 and 7 years; cardiac evaluation was declined for the remaining 3 children, aged 3, 14, and 16 years. Although the authors designated the patients as having skin fragility-woolly hair syndrome, they noted that cardiomyopathy sometimes occurs later in life in patients with DCWHK.

In a Turkish girl with Carvajal syndrome, who underwent cardiac transplantation at age 12 years, 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.

In a 4-year-old Swedish girl with alopecia, skin fragility, focal keratoderma, and dilated cardiomyopathy, Vahlquist et al. (2014) sequenced the DSP gene and identified compound heterozygosity for a 13-bp deletion (125647.0026) and a 1-bp deletion (125647.0027). Her unaffected parents were each heterozygous for 1 of the mutations.