Michael J. Tidman

The prevalence of epidermolysis bullosa in Scotland

The prevalence of epidermolysis bullosa (EB) in Britain and most other countries is unknown. Patients suffering from the inherited forms of EB and living in Scotland have been traced. Two hundred and fifty‐nine affected people from 76 families have been identified, of whom 211 were clinically assessed. One‐third of these Scottish EB sufferers had never been seen by a dermatologist. In Lothian, where there appears to be a relatively high prevalence of EB, 75% of patients were unknown to their general practitioners.

Epidermolysis bullosa simplex (Dowling-Meara). A clinicopathological review.

The clinicopathological features of 22 cases of the Dowling‐Meara form of epidermolysis bullosa simplex (DM‐EBS) (11 males. 11 females: aged 5 days‐46 years) were reviewed using data collected over a 10‐year period. All cases presented clinically within the first 5 days of life. Early blisters were often large (up to 5 cm in diameter), and were mostly acral and particularly periungual. Some cases presented with more widespread erosive skin changes, and two neonates with extensive skin involvement died as a result of overwhelming sepsis. After the neonatal period a different pattern of blistering occurred with more proximal haemorrhagic, herpetiform clusters of blisters. Central healing with recurrent blistering at the margins of these areas was frequently noted. Other physical signs included varying degrees of intra‐oral blistering, nail shedding, nail dystrophy, minor scarring, palmo‐plantar keratoderma, a lack of seasonal variation and improvement during later childhood. The underlying pathological mechanism in DM‐EBS is basal cell cytolysis, or rarely acantholysis, in association with tonofilament (TF) clumping. TF clumping was found in lesional, perilesional and some non‐lesional skin, suggesting that the tonofilament abnormality may be of primary aetiological significance in DM‐EBS. TF clumping may be due to specific keratin abnormalities because the altered TF were found in a distribution similar to the known distribution of the basal cell keratins. K5 and K14. The level of blistering was invariably very low within the epidermal basal layer and often less than 0·5 μm above the basement membrane. We conclude that DM‐EBS is a distinct, and probably under‐recognized genodermatosis which tends to have a good prognosis. However, the disease can occasionally be severe, especially during the neonatal period, when it may be confused with junctional or severe recessive dystrophic EB. Electron microscopy is the best means for demonstrating the characteristic cytoskeletal disorder and confirming the diagnosis.

Abnormal expression of hemidesmosome‐like structures by junctional epidermolysis bullosa keratinocytes in vitro

Hemidesmosomes are frequently rudimentary in junctional epidermolysis bullosa (JEB), and JEB keratinocytes display abnormal attachment to the substrate in culture. Our aim was to determine whether this abnormality reflects defective hemidesmosome synthesis in vitro. Keratinocytes from five JEB patients were cultured under standard conditions. Control cultures, from four healthy males, three patients with dystrophic EB (DEB), and one patient with the simplex variant (EBS), were also examined. Post‐confluent cultures were processed for transmission electron microscopy. Hemidesmosome‐like structures were counted in electron micrograph montages. The number of hemidesmosome‐like structures in JEB cultures (0.97±0.57, per 10±m of basal cell membrane) was approximately 17% of the value for normal controls (5.81±3.08, P <0.02). The values for EBS (3.72) and DEB (3.28±1.44) were not statistically different from normal controls. In addition hemidesmosome‐like structures in JEB cultures were morphologically ill‐defined, compared with those from controls. This correlated with the loose apposition between JEB keratinocytes and the substrate, which appeared tight in controls. JEB keratinocytes continue to express in vitro a major phenotypic abnormality which characterizes the disease in vivo. Therefore, this model should prove useful in studies determining the pathogenesis and possible new treatments of JEB.

Laryngeal involvement in the Dowling-Meara variant of epidermolysis bullosa simplex with keratin mutations of severely disruptive potential

The clinical features of the Dowling–Meara variant of epidermolysis bullosa simplex (EBS‐DM) can, in an infant, be indistinguishable from other severe forms of epidermolysis bullosa (EB). Two unrelated infants with no family history of skin disease are described who, within hours of birth, developed extensive blistering of skin and oral mucosae and who both subsequently developed hoarse cries. Despite this superficial resemblance to other forms of EB, electron microscopy revealed a basal cell rupture and keratin aggregates characteristic of EBS‐DM in the skin of both infants and in the vocal cord epithelium of one. Molecular analysis confirmed the diagnosis by identification of mis‐sense point mutations in basal cell keratin genes in both cases. One patient carries a point mutation in keratin 14 (converting arginine at position 125 to histidine) and the other has a novel point mutation in keratin 5 (converting serine at position 181 to proline). Hoarseness is not a well documented feature of EBS‐DM and is usually associated with junctional EB. These two patients demonstrate that the presence of a hoarse cry in an infant affected by severe EB does not necessarily indicate a poor prognosis.

Junctional epidermolysis bullosa

In 1935, Herlitz [1] recognized the existence of a distinct hereditary blistering disease that was lethal in early infancy. Since then, the ‘hereditary lethal’ form of epidermolysis bullosa (EB) has borne his name, but there was no certain means of delineating Herlitz disease from the more common dystrophic forms, which could be clinically confusing, especially in the neonatal period, until Pearson [2] showed by electron microscopy that the level of blistering, in the various types of EB, was at different layers in or around the dermo—epidermal zone. In Herlitz disease blistering is at the level of the lamina lucida of the epidermal basement membrane (EBM). Thus we were introduced to the term junctional bullous epidermatosis or junctional EB (JEB), which could now be clearly distinguished from simplex (epidermolytic) and dystrophic (dermolytic) forms.

Epidermolysis bullosa: preliminary observations of blister formation in keratinocyte cultures

Keratinocytes from patients with different types of epidermolysis bullosa (EB) demonstrated an abnormal tendency to blister or bleb formation after 14–22 days in culture. The changes were most marked in samples from cases of junctional EB and were not observed in control cultures of normal skin. These findings suggest the possibility of a primary abnormality of keratinocyte adhesion in different varieties of EB and that keratinocyte culture should provide a useful model for further studies on disorders of adhesion in EB.

Diagnosis and diagnostic techniques

The development of a blistering eruption in a neonate or infant is a potentially serious situation. Some of the genetically determined bullous diseases are life-threatening conditions and others are associated with chronic disability and pain. Parents of affected children may be committed to dedicated nursing care and subject to all the frustrations of having a disabled child. They may also have to live with anxiety over the risk of having further afflicted offspring. Genetic counselling and prenatal diagnosis rely on establishing a correct diagnosis, which may be difficult at the onset of an inherited bullous disorder without resorting to special investigative techniques.