Epidermolysis bullosa simplex with muscular dystrophy an mutation in PLEC Q81.0

The first description of an affected Finnish sibling was in 1988 by Niemi et al. The affected individuals had a combination of epidermolysis bullosa and muscular dystrophy affecting the limb-girdle muscles (OMIM: 253600). During the course of the disease, contractures and muscle shortening, postural abnormalities and deformities are expected. Two male siblings died early from severe skin disease.

Rare autosomal recessive form of epidermolysis bullosa simplex with epidermal basal cleft formation and mutations in the PLEC gene, first described in 1988 (Niemi KM et al. 1988). Clinically, there is an obvious traumatic blistering that heals with scarring and a progressive muscular dystrophy that begins in early childhood (Fine et al. 1989). The PLEC gene is located at gene locus 8q24.3. Due to truncating or null mutations, there is reduced or absent expression of plectin in skin and lesional muscle.

Autosomal recessive inheritance of mutations in the PLEC gene mapped to gene locus 8q24. The result is disruption of the cytoskeleton (plectin reduced or absent) of basal keratinocytes. Gap formation occurs between the nucleus and the hemidesmosomes (basal gap formation) as well as blistering after mechanical stress.

Generalized blistering from birth. Progressive muscle weakness only at a later age (2nd year of life until 30th year of life).

Integument: Serous or hemorrhagic blisters of various sizes, induced by mechanical stimuli and heal with scarring. Mucous membranes are free of appearance except for the oral mucosa traumatized by ingestion.

Extracutaneous manifestations: Characteristic is the development of severe, slowly progressive muscular dystrophy involving the shoulder girdle in childhood or adulthood. Growth retardation and anemia frequently exist.

In detail:

Abanmi et al (1994) reported growth retardation and anemia associated with autosomal recessive epidermolysis bullosa simplex in a Saudi family with 5 affected siblings.

Gache et al (1996) reported on 2 unrelated families. Two of his brothers had bullous skin disease at birth that was fatal in early infancy.

McLean et al (1996) described a 24-year-old Hispanic man with MD-EBS and a mutation in the PLEC gene. He developed blisters on his feet, back, thighs, and face at 10 days of age. The blisters recurred at sites of mechanical trauma and healed with atrophic scarring. He also had nail dystrophy and dental anomalies. Development was normal until the age of 10 years. From that time, climbing stairs became difficult and he stopped walking. At the age of 13, he was permanently confined to a wheelchair. His intelligence was normal. Electron microscopy showed poorly formed hemidesmosomes along the bladder roof, with part of the hemidesmosome adhering to the base of the bladder. Tonofilaments were not in contact with the hemidesmosomes. Electromyography showed long-standing neuromuscular disease, and muscle biopsy revealed group atrophy of muscle fibers.

Bolling et al (2010) reported a 40-year-old man who was heterozygous for a missense mutation (R323Q) and a nonsense mutation (E1614X) in the PLEC1 gene. The patient suffered from lifelong traumatic skin blistering as well as nail dystrophy. In the third decade of life, weakness of the shoulder girdle and upper extremities occurred. At age 30, left ventricular dilated cardiomyopathy was diagnosed and septal biopsy confirmed (fibrosis and atrophic fibers).

Shimizu et al (1999) were able to draw on a clinical collective of 10 patients and observed the following clinical symptoms:

generalized blistering at birth (100% of patients).

• nail dystrophies (100% of patients)
• marked muscle weakness in 8 patients (older than 9 years; 2 patients were younger than 9 years), which forced them to use a wheelchair in later years (100% of patients)

Other symptoms were:

• carious teeth (50% of patients)
• urethral strictures (30% of patients)
• mild palmoplantar keratoses (20% of patients)
• infantile respiratory complications (10% of patients)
• alopecia (10% of patients)
• laryngeal stenosis (10% of patients)

Epidermolytic blister formation.

Electron microscopy: Cleft formation above the hemidesmosomes. Often misdiagnosed as EB junctionalis.

Antigen mapping: Typically, staining with pectin antibodies is reduced or negative.

Immunofluorescence microscopy reveals a lack of plectin expression that correlates with impaired interaction of the keratin cytoskeleton with hemidesmosomes in affected skin. Consistent with the lack of reactivity of MD-EBS skin to plectin antibodies, plectin is not detected in skeletal muscle of affected individuals. The impaired expression of plectin in muscles correlated with an altered labeling pattern of the muscle intermediate filament protein desmin.

Gache et al (1996) also observed deficient immunoreactivity for plectin as well as for the hemidesmosomal protein HD1. The colocalization of HD1 and plectin in normal skin and muscle and their decreased expression in MD-EBS tissues strongly suggested that plectin and HD1 are closely related proteins.

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