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Syndromic disorders with skin fragility belong to different groups of genodermatoses: epidermolysis bullosa (EB), Ehlers-Danlos syndrome and porphyria. The genetic defects mainly concern structural proteins which assure the mechanical stability of the skin and other tissues. Depending on the expression pattern of the affected protein in the skin, cutaneous fragility may manifest as superficial erosions, blisters, wounds, wound healing defects or scars. Extracutaneous manifestations are manifold and involve the heart, skeletal muscles, intestine, kidneys, blood vessels or the skeleton. Syndromic types of EB include in addition to skin blistering: (i) cardiomyopathy in case of desmoplakin, plakoglobin, or kelch-like protein mutations; (ii) muscular dystrophy in case of plektin mutations; (iii) pyloric atresia in case of integrin α6β4 or plectin mutations; (iv) nephrotic syndrome in case of CD151 or integrin α3 mutations. Lysyl hydroxylase 3 mutations affect posttranslational modifications of collagens and lead to a dystrophic epidermolysis bullosa-like multisystemic disorder. Ehlers-Danlos syndromes are due to defects of dermal collagens or their processing and affect the skin, joints and blood vessels. Finally porphyrias are complex metabolic disorders with photosensitivity and sometimes skin fragility, liver or neurologic problems. Their pathogenesis relies on the accumulation of precursors in the tissues. Although these syndromes are rare in clinical practice, knowledge of the syndromic constellation contributes to early diagnosis and detection of complications.

A 59-year-old Caucasian man suffered from persistent disseminated necrolytic skin lesions for 8 months. They failed to respond to a variety of therapeutic regimens but then cleared spontaneously within a few days. After one week an invasive squamous cell carcinoma of the hypopharynx became clinically apparent. At autopsy, the expected glucagonoma often associated with necrolytic migratory erythema was not found.

Subepidermal bullous dermatoses are a heterogenous group of disorders characterized by loss of tissue adhesion in the dermoepidermal junction and formation of a vesicle or bulla in the lamina lucida or under the lamina densa. These diseases can be classified into the following: 1. Subepidermal autoimmune bullous dermatoses. These are characterized by circulating autoantibodies against normal constituents of the basement membrane zone and include the following: Epidermolysis bullosa acquisita, bullous pemphigoid, dermatitis herpetiformis Duhring, linear IgA disease, herpes gestationis, cicatricial pemphigoid and bullous systemic lupus erythematosis (SLE). II. Subepidermal bullous dermatoses, due to mutation of the basement membrane zone proteins. These are epidermolysis bullosa junctionalis and epidermolysis bullosa dystrophicans. III. Subepidermal bullous dermatoses due to metabolic disorders: Porphyria cutanea tarda (PCT). IV. Drug induced Lyell-Syndrome Due to space limitation it is not possible to discuss the histology of all these dermatoses. I will therefore choose the most important of them and display their histology in detail.

A four-week-old Simmental x Red Holstein calf had lesions of skin and oral mucosa since its first days of life. Where skin or mucosa was exposed to minimal trauma as in oral cavity or over joints, it broke off, forming blisters and erosions. The diagnosis of epidermolysis bullosa, a hereditary disease, was based on clinical and histological findings. Histology pointed to the epidermal form of epidermolysis bullosa, comparable to epidermolysis bullosa simplex in humans.

Publications on the subject of conjunctiva in 1991 have been reviewed. Clinical relevant topics have been stressed. In the field of conjunctival affections caused by microorganisms a spectrum of bilateral squamous conjunctival tumors associated with human papillomavirus type 16 were first documented. Chlamydial antibodies cause proliferation of lymphocytes. The peripheral lymphocyte proliferative response to whole chlamydial elementary bodies seems to have a strong correlation between the responses to the Chlamydia trachomatis serotypes B and L1. In the field of impression cytology of the conjunctiva the topographical distribution of ocular surface cells was described. In patients with glaucoma using long-term topical medication, there seem to be significant degrees of conjunctival metaplasia associated with the number of glaucoma medications. These changes in the conjunctival surface may be related to the preservatives in the preparations (benzalkonium compounds). An ultrastructural defect in conjunctiva in recessive dystrophic epidermolysis bullosa may increase the susceptibility of the conjunctiva to minor mechanical trauma. Thus resulting in the bullous and cicatrical changes seen clinically.

Epidermolysis bullosa acquisita is a rare acquired mechanobullous disorder which in contrast to the other types of epidermolysis bullosa is not hereditary. Skin lesions and, for the first time, lesions of the mucous membranes of the upper respiratory tract and oesophagus were studied by light and electron microscopic and immunofluorescence and immunoelectron microscopic methods. Immunofluorescence studies demonstrated linear IgG and complement deposits along the basement membrane zone. Electron microscopy of skin and mucosa revealed a dermolytic subbasal-lamina type of blister formation, diminished and rudimentary anchoring fibrils, and a zone of amorphous material beneath the basal lamina (lamina densa). Immunoelectron microscopic studies demonstrated the deposition of immunoglobulins in the amorphous zone beneath the basal lamina along the dermal-epidermal junction. The results are discussed in terms of current immunological findings.

Since the first description in 1976, epidermolysis bullosa atrophicans generalisata mitis has been recognized as a seperate entity, based on clinical and electron microscopical findings, and has been differentiated from epidermolysis atrophicans generalisata gravis Herlitz. Our own observations on a patient are presented by clinical documentation.

Dermatological conditions characterized by dermo-epidermal separation, basal lamina discontinuity, multiplication, and thickness variability, and/or irregularity of the subepidermal space are discribed. Pathological changes of the dermo-epidermal junction are considered to be destructive or reproductive. Both may appear in combination. Destructive processes may be relfected by dermo-epidermal separation. Epidermal cells and/or dermal connective tissue appear degenerated. Thickening of the lamina may occur by reactive hyperproduction or by precipitation of pathological materials. Reproductive processes of the junction originate in the epidermal cells and are reflected in multilayering of the basal lamina. Interruption of the lamina and irregularity of the subepidermal space often precede these phenomena.

Junctional blister formation is the common feature of four clinically different types of inherited epidermolyses with atrophies but lack of scarring which, as a group, have been termed epidermolysis bullosa atrophicans. The Herlitz type is the most common one among them. Based on a material of 24 cases aged 2 days to 42 years at the time of biopsy, ultrastructural data on the pathomorphogenesis are reported. Blisters form in the dermo-epidermal junction area between the basal lamina and the basal cell plasma membrane. A well-developed basal lamina-anchoring fibrils complex covers the blister floor. Hypoplasia of hemidesmosomes precedes blister formation and is a constant finding in intact junction area without any other signs of disturbances. It is, therefore, regarded as a causal factor in the pathogenesis. Nail loss as a result of junctional separation within the nail bed, secondary changes in older blisters and formation of slowly healing granulation tissues are also reported.--Early diagnosis is made available by electron microscopy as shown in out early childhood cases. Genes coding for junctional epidermolyses seem to be far more frequent than those coding for the scarring or dystrophic types.

Epidermolysis bullosa acquisita is an immunologically mediated mechano-bullous dermatosis presenting with a variety of clinical appearances. In mild cases the skin lesions, serous blisters, erosions and scars are restricted to the extremities. Scarring alopecia, dystrophy and even loss of nails as well as extensive erosions of mucous membranes may complicate severe cases. The characteristic histopathological feature is a subepidermal blister, which is located within the dermis by electron microscopy. Linear deposits of IgG and C3 along the basement membrane zone have been found on the dermal side of the lamina densa by immunoelectron microscopy. This close anatomical relationship with anchoring fibrils strongly suggests a functional disturbance of these anatomical structures, leading to dermolytic blistering. Treatment with sulphones, in combination with cortico-steroids in the more severe cases, has resulted in long-term improvement in two of our three patients.

A Turkish family with four children is described, two boys suffering from Cockayne's syndrome and a girl from recessive dystrophic epidermolysis bullosa (Hallopeau-Siemens). The outstanding features in the brothers are a pronounced delay in growth which began in both children at the age of about 1.5 years, progeria-like facial features, and a high degree of light sensitivity noticed very soon after birth. The daughter died of septicemia at the age of 4 years. Both diseases are rare and probably the consequence of extremely high consanguinity.

In a patient with epidermolysis bullosa acquisita the characteristic dermolytic cleavage was demonstrated by electron microscopy and by mapping of antigenic determinants (type IV collagen, laminin, bullous pemphigoid antigen) of the dermal-epidermal junction. The latter method represents a rapid and reliable way to determine the cleavage plane in diseases which display subepidermal blister formation at the light-microscopic level. The classification of epidermolysis bullosa acquisita is still under dispute. Due to its highly characteristic clinical, ultrastructural, and immunologic features and pending further experimental data, epidermolysis bullosa acquisita should be regarded as a separate disease entity; its lumping together with cicatricial pemphigoid, as proposed by some authors appears speculative. Therapy of epidermolysis bullosa acquisita is generally regarded as difficult; following a 3-year course of high dose vitamin E therapy our patient underwent complete clearing; the possibility of a spontaneous remission, on the other hand, cannot be unequivocally ruled out.

A case of epidermolysis bullosa acquisita associated with colitis granulomatosa (Crohn's disease) is reported. Although the cutaneous lesions of this unusual disease resemble in their clinical, histological and ultrastructural features to those of the hereditary epidermolysis bullosa dystrophica, the epidermolysis bullosa acquisita has to be regarded as a separate entity among the blistering epidermolysis because of its late manifestation in adults without evidence of hereditary disorders. The deposits of immunoglobulins in the involved skin of the acral areas demonstrated fluorescentmicroscopically are discussed in regard of a possible etiopathogenic relation with the primary irritated intestinal disease.

Bullous changes in the oral mucosa are often the first signs of a general dermatological disease. Successful diagnosis of such diseases is largely dependent upon the use of complex laboratory methods. Clinical and ultrastructural changes are described and discussed with particular reference to a case of parapemphigus. Atypical intracellular vacuolation and marked acantholysis observed in electron micrographs is interpreted as a secondary phenomenon of direct blistering.

Report on the epidermolytic hyperkeratosis (congenital bullous ichthyosiform erythroderma) by means of a family suffering from this hyperkeratosis. Diagnostic advices are given. Classification and nomenclature are discussed criticly.

Chronic blister-forming dermatosis can lead to conjunctival and corneal involvement. Taking one such case as an example, the authors show that while disorders of this kind can be classified as a form of bullous dermatosis, the differential diagnostic classification is not unequivocal, regardless of the examination method adopted. The term "overlay syndrome" has been introduced into the dermatologic literature to cover clinical pictures of this kind.

The report details possible haematological and dermatological side effects due to co-trimoxazole: agranulocytosis and epidermiolysis bullosa (Lyell) respectively developed after short-term therapy with co-trimoxazole in two women treated for tonsillitis and acute relapse of chronic obstructive bronchitis respectively. The clinical findings, therapeutical management and clinical outcome of both patients are described. Reviewing the literature the relevance of co-trimoxazole induced side effects is discussed.

A case of junctional epidermolysis bullosa (Herlitz) is reported. The patient has been treated with high doses of Dapson. The result is encouraging.

A 70-year-old Caucasian patient is described, who presented with a bullous dermatosis on an amputation stump. The bullous lesions had developed after practice with a Kondylen-Bettung-Münster (KBM) prosthesis. The lesions disappeared completely after prednisone therapy and replacement of the prosthesis with a Thomas splint. The patient has remained free of symptoms ever since, even though prednisone was completely withdrawn after 9 months. According to skin immunofluorescence criteria, the patient suffered from pemphigoid, rather than epidermolysis bullosa acquisita as strongly suggested by the anamnesis. In particular, the presence of linear IgG at the level of the lamina lucida of the epidermal basement membrane zone and the localization of laminin antigen at the blister floor are highly suggestive of pemphigoid.

Two sister cases of epidermolysis bullosa dystrophica inversa are reported. This type, first described by Gedde-Dahl (1971), is characterized by the inverse site of skin involvement, the intermittent course, frequent traumatic corneal erosions, retarded development of skin atrophy and absence of milia formation. Our present cases had all these characteristics except the corneal involvement. The pedigree of this family favors an autosomal recessive mode of inheritance; no consanguinity is demonstrable in the ancestors over four generations. Electron microscopic examination in one of the patients reveals the blistering beneath the basal lamina, which suggests that the pathogenesis may be similar to the Hallopeau-Siemens type rather than to the junctional type of epidermolysis bullosa.

We report on a 72-year-old man suffering from transient acantholytic dermatosis (TAD). The histologic pattern resembled that of Darier's disease. The disorder first set on after an episode of intensive exposure to sunlight and persisted for 6 years. The only drug the patient took during this period was the prophylactic antimaterial preparation, Fansidar. His sensitivity to UVB radiation was markedly increased. After Fansidar was replaced by Resochin, the skin cleared up. After one year the sensitivity to UVB had normalized.

A 10-year old girl with generalized benign atrophic epidermolysis bullosa (EB) developed large nevomelanocytic nevi over a period of 1 year. Since such nevoid lesions have been repeatedly observed in other patients with generalized benign atrophic EB they should be regarded as a characteristic clinical feature of this type of mechanobullous disease. Regular observation of such patients will demonstrate the significance of these pigmented lesions as precursors of malignant melanoma.

In reviewing the literature, we made an attempt to expand the term "transient acantholytic dermatosis" (TAD) beyond the criteria of classical Grover's disease to a broader spectrum of diseases and to systematically categorize the variety of reported clinical pictures. Moreover, we endeavoured to separate these conditions from Darier's and Hailey-Hailey's disease and from immunofluorescence-positive acantholytic dermatoses. Three patients of our own are presented with a heretofore undescribed bullous exanthematic variant.

Electronmicroscopical examination on skin lesions of epidermolysis bullosa dystrophica recessiva (E.b.d.r.) and epidermolysis bullosa acquisita (E.b.a.) associated with Crohn's disease have demonstrated that blistering occurs between epidermis and dermis beneath the basal lamina. The structural defect concerns the anchoring fibrils only which are missing in the junctional zone of the involved skin. All other junctional structures are intact. Beneath the basal lamina a band-like zone of a moderate electrondense, amorphous material is seen in the skin-lesions of epidermolysis bullosa acquisita, less marked in epidermolysis bullosa dystrophica. Direct immunofluorescent investigation of involved skin of E.b.a. shows a pemphigoid-like fluorescent pattern at the basal lamina with antihuman IgG-, -IgM-, beta1c/beta1a and antihuman C1q-component. In epidermolysis bullosa dystrophica, however, a fluorescent pattern at the basal lamina was found only with anti-human IgG and Anti-C3. The pathogenetic importance of the immunoglobuline-deposits at the basal lamina is discussed in regard of the loss of anchoring fibrils and the subsequent vesication in these types of epidermolytic diseases.

The clinical symptomatology of epidermolysis bullosa atrophicans generalisata gravis (Herlitz' disease), epidermolysis bullosa atrophicans generalisata mitis (typus Disentis) and epidermolysis bullosa atrophicans localisata is described. These types belong to the non-scarring epidermolyses and show ultrastructurally junctional blistering.

The aetiological and pathogenic relation between junctional epidermolysis bullosa (Herlitz) and prepyloric and pyloric obstruction in newborns with junctional epidermolysis bullosa is still unknown. There are two different hypotheses; one suggesting two distinct genetically related disorders (namely junctional epidermolysis bullosa and congenital pyloric atresia), the other suggesting an intrauterine mucosal damage in junctional epidermolysis bullosa. We report two infants suffering from junctional epidermolysis bullosa, Herlitz-type, verified by electron microscopy, and from connatal prepyloric and pyloric obstruction. In both cases we could demonstrate proliferative inflammation at the prepyloric antrum and pylorus as the cause of the obstruction but no complete obliteration of the pyloric channel. These findings point to an intrauterine event impacting the mucosa of the gastrointestinal tract in patients with junctional epidermolysis bullosa of the Herlitz-type and don't comply with the hypothesis of two different but genetically related diseases.

An additional case of epidermolysis bullosa dystrophica inversa is reported. A review of the literature shows that until now reports about probably 15 patients from seven families were published, although the first 13 patients were not investigated by electron microscope [3]. By blistering beneath the basal lamina similar to the Hallopeau-Siemens type these patients develop bullae predominantly at the trunk and the inverse sites of the axillar and genitoanal regions continuously or at close intervals starting shortly after birth. The mucous membranes of the mouth, the esophagus, and the cornea and conjunctiva of the eye are very often involved. By bacterial infection of the skin lesions the patients develop hpochrome anemia. The web-like structures in the esophagus following blistering can be successfully treated by careful dilatation because of the low tendency to scar formation. An autosomal recessive mode of inheritance seems to be most likely.

A new born girl perinatally suffered from a generalized blistering disease of the skin. By means of histological, in particular ultrastructural methods the diagnosis of Epidermolysis bullosa herpetiformis Dowling Meara could be confirmed in the first weeks of life. The Dowling Meara type is one of the epidermal variants of this group of inherited blistering diseases with a relative benign course. The early diagnosis is helpful in the prognostic assessment of the disease and in the medical and genetic advice for the parents.