Overgrowth of oral mucosa and facial skin, a novel feature of aspartylglucosaminuria.

Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by deficiency of aspartylglucosaminidase (AGA). The main symptom is progressive mental retardation. A spectrum of different mutations has been reported in this disease, one missense mutation (Cys163Ser) being responsible for the majority of Finnish cases. We were able to examine 66 Finnish AGU patients for changes in the oral mucosa and 44 of these for changes in facial skin. Biopsy specimens of 16 oral lesions, 12 of them associated with the teeth, plus two facial lesions were studied histologically. Immunohistochemical staining for AGA was performed on 15 oral specimens. Skin was seborrhoeic in adolescent and adult patients, with erythema of the facial skin already common in childhood. Of 44 patients, nine (20%) had facial angiofibromas, tumours primarily occurring in association with tuberous sclerosis. Oedemic buccal mucosa (leucoedema) and gingival overgrowths were more frequent in AGU patients than in controls (p<0.001). Of 16 oral mucosal lesions studied histologically, 15 represented fibroepithelial or epithelial hyperplasias and were reactive in nature. Cytoplasmic vacuolisation was evident in four. Immunohistochemically, expression of AGA in AGU patients' mucosal lesions did not differ from that seen in corresponding lesions of normal subjects. Thus, the high frequency of mucosal overgrowth in AGU patients does not appear to be directly associated with lysosomal storage or with alterations in the level of AGA expression.

Bullous pemphigoid antigens (BPAGs): identification of RFLPs in human BPAG1 and BPAG2, and exclusion as candidate genes in a large kindred with dominant epidermolysis bullosa simplex.

Bullous pemphigoid antigens (BPAGs) are defined as autoantigens in a blistering skin disease, bullous pemphigoid. Two of the BPAGs, a 230-kD (BPAG1) and a 180-kD (BPAG2) protein, have been localized to hemidesmosomes, attachment structures at the basal keratinocyte-basement membrane interphase. We have recently cloned cDNAs corresponding to human BPAG1 and BPAG2, and mapped the corresponding genes to human chromosomes 6p and 10q, respectively. These cDNAs have now been used in a search for RFLPs in the corresponding genes. Southern hybridizations of genomic DNA from normal unrelated individuals with a BPAG1 cDNA detected an informative MspI RFLP, and similar hybridizations with a BPAG2 cDNA revealed an informative TaqI RFLP. These RFLPs were applied to a large kindred with epidermolysis bullosa simplex (EBS), generalized (Koebner) type, consisting of 14 affected and 12 unaffected individuals in three generations. Linkage analysis excluded the EBS locus in this pedigree approximately 9 cM and approximately 5 cM on either side of the BPAG1 and BPAG2 loci, respectively, when a lod score of -2.0 was taken as the limit of exclusion. This study demonstrates that mutations in the BPAG1 or BPAG2 genes are not the primary genetic defect in this family with EBS.

Type VII collagen is expressed but anchoring fibrils are defective in dystrophic epidermolysis bullosa inversa.

A patient with dystrophic epidermolysis bullosa inversa was studied using electron microscopy and indirect immunofluorescence using antibodies to matrix macromolecules of the dermoepidermal junction zone. There was splitting below the lamina densa with an apparently normal basement membrane, but a lack of intact anchoring fibrils and with a disarranged papillary connective tissue. Indirect immunofluorescence examination with antibodies to type VII collagen, the major structural protein of anchoring fibrils, showed a normal linear staining pattern. Synthesis of type VII collagen which is unable to form stable, resistant anchoring fibrils may be a distinct feature of this subtype of recessive dystrophic epidermolysis bullosa.

Epidermolysis bullosa simplex associated with muscular dystrophy with recessive inheritance.

Epidermolysis bullosa with unusually severe clinical features was associated with progressive muscular dystrophy in two siblings. Light and electron microscopic examination revealed an intraepidermal cleavage confirming that this mechanobullous disease belonged to the epidermolysis bullosa simplex group. This may represent a new disease entity inherited in an autosomal-recessive fashion.

Collagen metabolism in two rare forms of epidermolysis bullosa.

The collagenase activity in skin fibroblast cultures from three patients with rare forms of epidermolysis bullosa was assayed before and after proteolytic activation of the medium. Two of the patients had the recessive dystrophic form of the disease (REBD), which is generally associated with abnormal collagenase activity. The other patient had an atrophic mitis form of the disease (REBA), which has not previously been associated with defective collagen metabolism. However, a similar increase in collagenase activity was found in all three cases. The total collagen production of EB fibroblasts was also enhanced, being two to five times that of control cell lines, and the intracellular hydroxylases of collagen biosynthesis were higher in the case of two EB-cell lines. These changes reflect the compensatory increase in collagen synthesis which follows the increased degradation caused by excessive free collagenase activity. Diphenylhydantoin treatment of one REBD patient for 9 months improved her condition.

Occurrence of epidermolysis bullosa in Finland.

Cases of epidermolysis bullosa (EB) were gathered from the hospital files of dermatological clinics and university pediatric clinics in Finland over a period of 10 years. 40 families were identified, containing 121 live sufferers from this condition, after which genealogical analysis revealed a further 55 patients. 11 out of the 17 subtypes of EB (1) were diagnosed in these families. The diseases found in two families were difficult to type according to the present classification, and were therefore handled separately. No regional accumulation was found and it seems that there is no type of EB which represents a peculiarly Finnish form. The most significant difference compared with the Norwegian material was the very much lower incidence of the recessive dystrophic subtype in Finland.

Epidermolysis bullosa in Finland. Clinical features, morphology and relation to collagen metabolism.

The inheritance and occurrence of various subtypes of epidermolysis bullosa (EB), the clinical and ultrastructural features of the disease (I) and its connections with possible defects in collagen metabolism were studied in the population of Finland. Information was obtained on 40 families with 121 diseased members alive. Genealogical analysis of these revealed 55 additional cases of probable EB. The series probably includes all the subjects affected by the recessively inherited types living in Finland in 1971-1980. Subjects with dominant types often have such a mild disease that they cannot all be included in a retrospective study. Eleven of the subtypes of epidermolysis bullosa were represented, and two families were found not to belong to any previous subgroup and were regarded as so far unclassified. The largest morphological group among the intraepidermal types, with seventeen families altogether, represented the pattern of cytolysis, acantholysis and dyskeratosis corresponding to EB simplex Köbner and Weber-Cockayne. In six families tonofilament clumping was the main morphological finding and the clinical picture in these cases was EB herpetiformis Dowling-Meara (I, II). Tonofilament deficiency, found in one family with congenital skin defects, was classified as EB Bart, and in one family a deficiency in one enzyme of collagen synthesis, galactosylhydroxylysine glucosyltransferase activity in skin and serum, was found to correlate significantly with severity of EB simplex Köbner (VI). In three other EB simplex families no such deficiency could be shown, suggesting that it may be of aetiological significance in some but not all EB simplex cases. In the junctional group three families with six dead infants were classified as EB atrophicans gravis-Herlitz and one live member with a hemidesmosome defect as EB atrophicans mitis. There were also two unclassified cases with junctional splitting and normal hemidesmosomes. This suggests greater heterogeneity in this group than has hitherto been thought. Among the dermal forms of EB there were eight families with dominant EB dystrophica Cockayne-Touraine and Pasini with 55 patients altogether. In one family both of these clinical expressions were found, suggesting a common gene source. Two families represented recessive EB dystrophica and one also contained a patient with acquired EB (III). In this last case the disease broke out in connection with parturition. Active collagenase and compensatory collagen production were increased in the cases of recessive EB dystrophica and in that of recessive EB atrophicans mitis (V).(ABSTRACT TRUNCATED AT 400 WORDS)

Epidermolysis bullosa simplex. A new histologic subgroup.

Two patients with a new mechanobullous disease are described. The trauma-induced bullae were present at birth. The nails were deformed in both cases. Both patients were isolated cases; so far, the inheritance pattern is not known. The histologic picture was unique. The keratinocytes were dyskeratotic, enlarged, and had atypical mitoses on light microscopy of neonatal biopsy specimens. Electron microscopically the defect occurred in the tonofilaments, which formed round clumps. The blister formation took place in the lower part of the epidermis.

Pregnancy as a trigger of epidermolysis bullosa acquisita.

A 38-year-old woman developed epidermolysis bullosa acquisita (A-EBD) in connection with her third pregnancy. The activity of visible blistering disappeared at menopause. Direct immunofluorescence examination showed linear deposition of IgG and C'3 in the basement membrane zone. The light and electron microscopical findings of the disease were consistent with A-EBD. We assume that the bullous scarring eruption was triggered by a hormonal mechanism.

Immunohistological localization of three basement membrane components in various forms of epidermolysis bullosa.

The skin biopsies of eight epidermolysis bullosa (EB) patients, representing epidermolytic, junctional and dermolytic forms of the disease were studied immunohistochemically using antibodies against collagen Types IV and V, and a proteoglycan. All these molecules are either basement membrane components or closely associated substances. In two types of EB simplex (subtype of the epidermolytic form) the splicing took place above the basement membrane, whereas the staining with all three antibodies remained localized to the floor of the blister. The herpetiform variant of EB simplex proved to be junctional, i.e. the separation occurred within the lamina lucida. One patient clinically classified as belonging to the junctional EB group, was found to have the epidermolytic form of the disease. In this case all antibodies were localized only on the floor of the blister. In the patients with the dermolytic form of EB, all the antibodies stained the roof of the blister. The immunofluorescence techniques are rapid and easy to perform and are therefore proposed as useful for routine clinical diagnosis.

Deficiency of galactosylhydroxylysyl glucosyltransferase, an enzyme of collagen synthesis, in a family with dominant epidermolysis bullosa simplex.

Members of a family with dominant epidermolysis bullosa simplex were found to have a deficiency of galactosylhydroxylysyl glucosyltransferase (GGT), an enzyme catalyzing the glucosylation of galactosylhydroxylysyl residues in the biosynthesis of collagen. The enzyme's activity was low in serum, skin tissue, and cultured skin fibroblasts, although no abnormality was found in three other intracellular enzymes of collagen biosynthesis. Mixtures of serum samples from patients and healthy controls gave the expected GGT activity, indicating that the low values were not due to inhibitors. GGT deficiency was accompanied by decreased product formation in vivo, as shown by a markedly decreased urinary excretion of glucosylgalactosylhydroxylysine. Six of 12 affected members had definite GGT deficiency, and five had some evidence suggestive of this abnormality; 13 of 15 unaffected members had no such manifestations. No similar GGT deficiency was found in three other families with the same disease. We conclude that GGT deficiency may be etiologically related to this disease in some families, but that different defects must be the cause in other cases.

Guinea pig maximization test, open epicutaneous test and chamber test in induction of delayed contact hypersensitivity.

A comparison was made between the guinea pig maximization test (GPMT), open epicutaneous test (OET) and chamber test (CT), and the allergens were neomycin sulphate and propylene glycol (PG). The sensitization rate for neomycin in petrolatum was 35% in GPMT, 25% in OET and 25% in CT. The corresponding figures for neomycin in PG were 30% in GPMT, 45% in OET and 32% in CT. PG caused no hypersensitivity in 118 guinea pigs. The results suggested that as a hygroscopic, irritant and penetrating vehicle PG facilitates the induction of delayed contact allergy, especially in OET.

Enzymes of collagen biosynthesis in skin and serum in dermatological diseases. I. Enzymes of the skin.

Immunoreactive prolyl hydroxylase protein, prolyl hydroxylase activity and galactosylhydroxylysyl glucosyltransferase activity were measured in skin biopsies from 54 patients with various dermatological disorders and compared with results from 15 control samples; The mean prolyl hydroxylase activity was significantly elevated in case of keloids (P less than 0.001) and lichen ruber planus (P less than 0.02) and the mean galactosylhydroxylysyl glucosyltransferase activity in keloids (P less than 0.005), lichen ruber planus (P less than 0.02) and psoriasis (P less than 0.05), and high activities of these two enzymes were also occasionally found in other skin diseases and active systemic connective tissue diseases. These two enzyme activities correlated highly significantly (P less than 0.001) with each other in the total disease material. Immunoreactive prolyl hydroxylase protein was significantly elevated in psoriasis (P less than 0.02) lichen ruber planus (P less than 0.005), but not in keloids, where very high activities of the corresponding enzyme were found. Active prolyl hydroxylase constituted about 1.3% of total immunoreactive prolyl hydroxylase protein in normal skin, but as much as 10% in cases of keloids.

Primary irritant dermatitis from topical clioquinol.

During the 2-year period 1976--1977, seven patients were studied with primary irritant dermatitis from topical preparations containing clioquinol. During the same period contact hypersensitivity to the compound was recorded in 35 eczema patients. Six of the seven patients with clioquinol irritancy had used creams containing 3% large crystal clioquinol and fluorinated steroids. One patient had used 6% small crystal clioquinol cream. Challenge tests with 3% small crystal and large crystal clioquinol creams showed that crystal size did not affect the appearance of irritant dermatitis.

Nail changes as the first manifestation of the HLA-B27 inheritance. A case report.

A 6-year-old boy with nail changes compatible with those seen in Reiter's disease, and his father with chronic arthritis, recurrent anterior uveitis and amyloidosis, and a transplanted kidney are described. Both of them had HLA combination A2, B27 and neither had any of the antigens associated with psoriasis.