“Sporadic” dystrophic epidermolysis bullosa: a new dominant or mitis recessive mutation?

ARTICLE

Dystrophic epidermolysis bullosa (DEB) is a heterogeneous group of inherited mechanobullous disorders clinically characterised by trauma-induced mucocutaneous blisters, leading to atrophic scarring, milia and nail dystrophy. The phenotypic appearance, characterised by varying degrees of skin and mucous fragility, in fact, may vary between affected individuals or families, including at least 10 distinct forms of DEB [1]. Electron microscopy shows a cleavage beneath the lamina densa with distinct abnormalities in the anchoring fibrils (AFs) which appear morphologically altered, reduced in number, or entirely absent in different variants of DEB [2].

This disorder occurs in dominant and recessive forms and has been closely linked to the type VII collagen gene (COL7A1) that encodes the major component of AFs [3, 4].

This paper describes a "sporadic" case of dominant dystrophic epidermolysis bullosa (DDEB), although a mitis case of recessive dystrophic epidermolysis bullosa (RDEB) cannot be excluded on the basis of clinical, immunofluorescent and ultrastructural examination; it also emphasises the importance of molecular technology so as to define the mode of inheritance in cases of DEB with clinically normal parents and no other family members affected.

Case report

A 16-year old white boy came to our outpatients institute complaining of nail dystrophy. The boy was the first-born of unrelated parents, after an uneventful pregnancy, and a spontaneous and uncomplicated delivery. The family medical history was negative for blistering disease for four generations. The mother reported that eight days after the birth, some blisters were noted on the fingers, feet, knees, elbows and a diagnosis of epidermolysis bullosa, without specific classification, was made. On these sites, such mechanical fragility continued during infancy with improvement after puberty. At the time of presentation, physical examination revealed: thickened and dystrophic nails both on the hands and feet, atrophic skin with some milia on the hands (dorsal side) and both elbows and knees, some large bullae on the hands and ankles (Figs. 1, 2, 3). Albopapuloid lesions were not found and the rest of the skin was normal. He had normal teeth and hair and his musculoskeletal growth appeared strong and harmonious.

Transmission electron microscopy, performed using standard procedures on normal-appearing skin of the lateral side of the arm (in spite of the mechanical friction no cleavage was obtained), revealed intact hemidesmosomes, a normal indented dermal-epidermal junction with recognisable AFs, but reduced in number (Fig. 4); a careful examination of the lamina densa also displayed areas of few or even absent AFs.

Immunostaining with monoclonal antibody to human type VII collagen (LH7: 2) demonstrated a reduction of staining with a linear pattern along the basement membrane (Fig. 5).

Discussion

The diagnosis of DDEB was made on a clinical, ultrastructural and immunofluorescence basis. The mild localised blisters, the atrophic scars with milia, the nail dystrophy and the absence of albopapuloid lesions suggest a dystrophic mild type of epidermolysis bullosa ­ Cockayne-Touraine type.

Currently electron microscopic evaluation remains the gold standard for diagnostic classification of epidermolysis bullosa [2]: several ultrastructural changes in anchoring fibrils have previously been reported in DEB, although AFs abnormalities specific to each subtype of DEB have not been defined. According to the literature data [5, 6] in DDEB, AFs have been shown to be diminished in number and abnormal in structure or reduced in number but qualitatively normal. However, the relevance of these abnormalities remains difficult to interpret due to the known variability in the number and morphology of AFs in different body regions of normal subjects, making controlled ultrastructural morphometric analysis necessary. Thus, morphometric analysis of AFs alone seems unable to distinguish between the different subtypes of DDEB and even some types of localised RDEB. Moreover, in our case, the bright linear immunofluorescent staining at the dermal-epidermal junction with type VII collagen antibody (LH7: 2) was similar to previously-reported findings in different forms of dominant dystrophic epidermolysis bullosa [7, 8].

Although most cases of "sporadic" DEB have been shown to be autosomal recessive in nature [9-11], our case has clinical, ultrastructural and immunofluorescence features more in keeping with an autosomal dominant subtype; future mutational analysis will be necessary to determine the precise molecular genetics of this case.

This problem has been brought out by recent publication of Christiano and colleagues [12] of a series of seemingly sporadic cases which turned out, in many instances, to be shown to have inherited two mutant alleles from their clinically unaffected parents. This implies that "mild" RDEB is commoner than once thought.

Type VII collagen, the major protein of AFs, is synthesised by keratinocytes and by fibroblasts [13, 14]. Several COL7A1 mutations have recently been demonstrated both in DDEB and RDEB [15, 16]. In particular, mutations in dominant subtypes of DEB usually comprise glycine substitutions in the triple helix of COL7A1. Such changes lead to dominant negative disruption of the type VII collagen, perturbation in AFs and relatively mild clinical phenotype. In contrast, in the recessively inherited forms of DEB a premature termination codon and non-sense mutations have been demonstrated in both COL7A1 alleles. As a result of mutation, no type VII collagen polypeptides are synthesised and no functional AFs are assembled, leading to a more severe clinical phenotype. Moreover mitis forms of RDEB mutations may arise from the combination of a premature termination codon mutation in one COL7A1 allele.

This evidence has important implications for genetic counselling to the families: in particular, the risk for the mitis RDEB affected individual of having an affected offspring is extremely small, while that of an individual with a de novo dominant mutation is 1:2. Furthermore, the risk of recurrence in subsequent pregnancies in the clinically- unaffected parents of the mitis RDEB patient is 1:4, by contrast, in cases of the clinically unaffected parents having an affected offspring with a de novo dominant mutation, the risk is more difficult to predict: small if the mutation arose during the early embryonic development, significant if the mutation is derived from a parental germ-line mutation [9, 11].

Finally, although electron microscopy together with immunohistopathology remain the gold standard for diagnostic classification of epidermolysis bullosa (EB), it is often insufficient in those families having one mildly affected individual and clinically normal parents (as in our case). In view of the immense progress made in elucidating the molecular mechanism in this disease, it would be desirable to set up established and appropriately accredited molecular diagnostic laboratories in order to further understand the different variants of EB, the basic aspects of the disease and the precise mode of inheritance, for better genetic counselling in families at risk.

Article accepted on 7/4/00

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