Epidermolysis Bullosa, Lethal Acantholytic

A number sign (#) is used with this entry because of evidence that lethal acantholytic epidermolysis bullosa (EBLA) is caused by homozygous or compound heterozygous mutation in the desmoplakin gene (DSP; 125647) on chromosome 6p24.

Clinical Features

Jonkman et al. (2005) described a male infant with severe fragility of skin and mucous membranes in whom rapidly progressive generalized epidermolysis had begun during delivery. The area of epidermolysis progressed from 30% to 70% within the first day and to 90% by the fifth day. Large sheets of skin were detached, leaving superficial, not bleeding, dull, intense red wound surfaces. The child lost profuse amounts of fluid from the extensive skin erosions. The skin fragility was accompanied by universal alopecia. Three triangular neonatal teeth were present in the mandible, and the oral cavity and conjunctivae were erosive. All 20 nails had recently shed; the impressions of the nail plates in the nail beds were still visible. Death occurred at 10 days of age due to immense transcutaneous fluid loss. Histopathology of the skin showed suprabasal clefting, leaving basal cells attached to the blister floor like a row of tombstones. The spinous layer showed spongiosis (widening of the intercellular space) and acantholysis, looking like a 'dilapidated brick wall,' which extended into hair follicles and eccrine ducts. The histopathology mimicked that of pemphigus vulgaris (169610). Electron microscopic examination of the skin revealed that the level of cleavage was intracellular, between the inner dense plaque of the desmosome and the cytoskeleton. Immunofluorescence staining of desmosomal proteins showed a distinct punctate intercellular pattern in the patient's skin. Jonkman et al. (2005) designated the phenotype lethal acantholytic epidermolysis bullosa.

Bolling et al. (2010) reported a consanguineous Yemeni family in which the first child, a boy, died at 3 days of age from an erosive skin condition consistent with a lethal form of epidermolysis bullosa. Electron microscopy showed acantholysis in the entire epidermis. Keratinocytes were incompletely separated and showed swollen mitochondria, indicating cell distress. Desmosomes were reduced in number, and very hypoplastic; most were torn out of the cell membrane as a whole, with the outer dense plaques still glued together. Hemidesmosomes were also present. The inner dense plaque was completely absent, as was intermediate-filament insertion in all desmosomes. The tonofilament skeleton showed midcytoplasmic retraction. Basal keratinocytes were well connected to the basement membrane, although the hemidesmosomes appeared slightly smaller and had reduced tonofilament insertions as well. A second child was normal, but the third child, another boy, was also born with extensive cutaneous erosions. Examination revealed a scalded appearance with epithelial shedding over at least 50% of the body. Islands of pale necrotic epidermis were floating on the erosions, similar to observations in the original EBLA case described by Jonkman et al. (2005). In addition, the infant had universal alopecia, nail beds without nails, and mild 2-3, 3-4, and 4-5 syndactyly of the fingers with fifth-finger clinodactyly. He had extensive milia over the nose and lacked natal teeth, and the external ears showed mild unraveling of the superior helices and retroversion; Bolling et al. (2010) noted that the original EBLA patient exhibited dysmorphic ears as well, with prominent antihelices and squaring-off of the superior helices. The second affected brother died at 1 day of age from respiratory failure. Prenatal ultrasound had shown mild cardiac ventricular hypertrophy with reduced contractility; the family declined autopsy.

Hobbs et al. (2010) described an infant girl, born to consanguineous parents, who had almost complete denudement of skin and mucosae, absent fingernails and toenails, and total alopecia. Denuded sites reepithelialized within days without residual scarring, but blistering recurred rapidly and the airway filled with extensive sloughed mucosa. Chest x-rays and echocardiograms were normal. Histologic analysis showed suprabasal acantholysis or cell clusters in a single acantholytic basal cell layer. Immunofluorescence microscopy showed staining for all basement membrane zone markers, with plectin (601282) and cytokeratin (see 139350) staining a discontinuous single row of basal keratinocytes adherent to the basement membrane. The infant died at 26 days of age due to airway obstruction; the parents declined autopsy.

Molecular Genetics

The observation in their patient that the keratin intermediate filaments were disconnected from the inner dense plaque, similar to desmoplakin knockout mice and patients with skin fragility-woolly hair syndrome (607655), led Jonkman et al. (2005) to screen the DSP gene (125647) for mutations. Mutation screening of genomic DNA demonstrated compound heterozygosity for 2 mutations in exon 24 of the DSP gene. A premature termination mutation (R1934X; 125647.0008) was inherited from the father, and a 2-bp deletion (6370delTT; 125647.0009) was inherited from the mother. Aberrant mRNA transcripts that predicted premature termination of translation with loss of the 3 intermediate filament-binding subdomains in the desmoplakin tail were detected by RT-PCR. Protein analysis showed expression of truncated desmoplakin polypeptides.

In 2 brothers with lethal acantholytic epidermolysis bullosa (LAEB) from a consanguineous Yemeni family, Bolling et al. (2010) identified homozygosity for a 5-bp deletion in the DSP gene (125647.0018) that was not found in 100 control DNA samples.

In an infant girl with EBLA, Hobbs et al. (2010) identified homozygosity for a 1-bp deletion in the DSP gene (125647.0019) for which her consanguineous parents were heterozygous.