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Background: We have encountered repeated cases of recessive lethal generalized severe (Herlitz-type) junctional epidermolysis bullosa (JEB gen sev) in infants born to Hungarian Roma parents residing in a small region of Hungary., Objectives: To identify the disease-causing mutation and to investigate the genetic background of its unique carrier group., Methods: The LAMB3 gene was analysed in peripheral-blood genomic DNA samples, and the pathological consequences of the lethal defect were confirmed by cutaneous LAMB3cDNA sequencing. A median joining haplotype network within the Y chromosome H1a-M82 haplogroup of individuals from the community was constructed, and LAMB3 single-nucleotide polymorphism (SNP) patterns were also determined., Results: An unconventional intronic splice-site mutation (LAMB3, c.1133-22G>A) was identified. Thirty of 64 voluntarily screened Roma from the closed community carried the mutation, but none of the 306 Roma from other regions of the country did. The age of the mutation was estimated to be 548 ± 222 years. Within the last year, more patients with JEB gen sev carrying the same unusual mutation have been identified in three unrelated families, all immigrants from the Balkans. Two were compound heterozygous newborns, in Germany and Italy, and one homozygous newborn died in France. Only the French family recognized their Roma background. LAMB3SNP haplotyping confirmed the link between the apparently unrelated Hungarian, German and Italian male cases, but could not verify the same background in the female newborn from France., Conclusions: The estimated age of the mutation corresponds to the time period when Roma were wandering in the Balkans., (© 2016 British Association of Dermatologists.)

Background: Health-related quality of life (HRQoL) in pemphigus has been widely investigated; nevertheless, utility values for economic evaluations are still lacking., Objectives: To estimate health utilities for hypothetical pemphigus vulgaris (PV) and pemphigus foliaceus (PF) health states in a general population sample., Methods: Three health states (uncontrolled PV, uncontrolled PF and controlled pemphigus) were developed based on a systematic literature review of HRQoL studies in pemphigus. Utilities were obtained from a convenience sample of 108 adults using a visual analogue scale (VAS) and 10-year time trade-off (TTO). Lead-time TTO was applied for health states regarded as worse than dead with a lead time to disease time ratio of 1 : 1., Results: The mean VAS utility scores for PV, PF and controlled pemphigus were 0·25 ± 0·15, 0·37 ± 0·17 and 0·63 ± 0·16, respectively. Corresponding TTO utilities were as follows: 0·34 ± 0·38, 0·51 ± 0·32 and 0·75 ± 0·31. Overall, 14% and 6% judged PV and PF as being worse than dead. For both VAS and TTO values, significant differences were observed between all health states (P < 0·001). VAS utilities were rated significantly lower compared with TTO in each health state (P < 0·001)., Conclusions: This is the first study that reports health utility values for PV and PF. Successful treatment of pemphigus might result in significant utility gain (0·24-0·41). These empirical findings with respect to three health states in pemphigus may serve as anchor points for further utility studies and cost-effectiveness analyses., (© 2016 British Association of Dermatologists.)

Bullous pemphigoid is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or generalized bullous lesions. In up to 20% of affected patients, bullae may be completely absent, and only excoriations, prurigo-like lesions, eczematous lesions, urticated lesions and/or infiltrated plaques are observed. The disease is significantly associated with neurological disorders. The morbidity of bullous pemphigoid and its impact on quality of life are significant. So far, a limited number of national treatment guidelines have been proposed, but no common European consensus has emerged. Our consensus for the treatment of bullous pemphigoid has been developed under the guidance of the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology. It summarizes evidence-based and expert-based recommendations., (© 2015 British Association of Dermatologists.)

Women with skin conditions may need topical corticosteroids during pregnancy. However, little is known about the effects of topical corticosteroids on the fetus. A guideline subcommittee of the European Dermatology Forum was organized to develop an evidence-based guideline on the use of topical corticosteroids in pregnancy (http://www.euroderm.org/edf/images/stories/guidelines/EDF-Guideline-on-Steroids-in-Pregnancy.pdf). The evidence from a Cochrane Review suggested that the major possible adverse effects on the fetus of topical corticosteroids were orofacial clefts when used preconceptionally and in the first trimester of pregnancy, and fetal growth restriction when very potent topical corticosteroids were used during pregnancy. To obtain robust evidence, a large population-based cohort study (on 84,133 pregnant women from the U.K. General Practice Research Database) was performed, which found a significant association of fetal growth restriction with maternal exposure to potent/very potent topical corticosteroids, but not with mild/moderate topical corticosteroids. No associations of maternal exposure to topical corticosteroids of any potency with orofacial cleft, preterm delivery and fetal death were found. Moreover, another recent Danish cohort study did not support a causal association between topical corticosteroid and orofacial cleft. The current best evidence suggests that mild/moderate topical corticosteroids are preferred to potent/very potent ones in pregnancy, because of the associated risk of fetal growth restriction with the latter., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Benign familial chronic pemphigus (Hailey-Hailey disease, HHD) is a rare hereditary condition characterized by development of blisters at sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene, which encodes the human secretory pathway calcium ATPase 1 (hSPCA1), have been identified as possible causative mutations. Studying Hungarian patients with HHD, we found two novel, distinct, heterozygous mutations. In a 65-year-old man with a 41-year history of severe recurrent symptoms, a single nucleotide insertion, 1085insA, was detected. In a patient whose symptoms were induced by environmental contact allergens, we found a nonsense mutation, Q506X, in exon 17. Our study further illustrates the diversity of mutational events in the pathogenesis of HHD.

Background: Mutations in the type VII collagen gene (COL7A1) are responsible for dominant and recessive forms of dystrophic epidermolysis bullosa (DEB). These mutations are usually specific for individual families; only a few cases of recurring mutations have been identified., Objectives: Forty-three unrelated Hungarian and German patients with different DEB phenotypes were screened for novel and recurrent COL7A1 mutations., Methods: All patients were classified based on clinical and genetic findings, skin immunofluorescent antigen mapping, and electron microscopic studies. Mutation analysis was performed by amplification of genomic DNA with polymerase chain reaction using COL7A1-specific primers, heteroduplex analysis, and direct nucleotide sequencing. Restriction endonuclease digestion was used for family screening and mutation verification. Results In this group of patients, the splice-site mutation 425A-->G was observed frequently, in 11 of 86 alleles (12.8%), once in homozygous form and in nine cases in heterozygous form. One of 100 control alleles from clinically unaffected individuals also carried the mutation. We also identified three novel mutations: the 976-3C-->A splice-site mutation, and the 4929delT and 8441-15del20 deletions., Conclusions: High recurrence of the splice-site mutation 425A-->G in central European patients with DEB should be taken into account when designing COL7A1 mutation detection strategies. Reporting of three novel COL7A1 mutations in this study further emphasizes the molecular heterogeneity of DEB and provides more information for studies on genotype-phenotype correlations in different DEB subtypes.

A 48-year-old woman with a follicular, grade III, B-cell non-Hodgkin lymphoma developed clinical, immunopathological and histological features of paraneoplastic pemphigus. The skin symptoms flared after repeated cyclophosphamide infusions, and were preceded and accompanied by a progressive dyspnoea. Although the skin and oral mucosal disease went into remission with high-dose steroid and intravenous immunoglobulin therapy, the severe alveolitis led to death. Immunoblotting of human epidermal extracts showed that the patient's serum IgG reacted with the 210-kDa envoplakin, 190-kDa periplakin, as well as the recombinant protein of BP180 NC16a domain. IgG and IgA enzyme-linked immunosorbent assays for desmoglein 3 were positive, too. Indirect immunofluorescence studies on COS-7 cells transiently transfected with desmocollin 1-3 cDNAs showed that the patient's serum contained IgG and IgA antibodies to desmocollin 3 as well as IgG antibodies to desmocollin 2. Serum IgG and IgA strongly stained rat bronchial epithelium, corresponding to autoantibodies possibly involved in the pathomechanism of the severe lung disease. In this case, which was characterized by a mixed IgA/IgG antibody panel displaying known and unique antigenicity, the serious episodes of paraneoplastic pemphigus flared after cyclophosphamide treatment.

A 25-year-old woman with Hallopeau-Siemens recessive dystrophic epidermolysis bullosa had generalized blistering, scarring and milia since birth. In the course of the disease, acral pseudosyndactyly developed, and the patient suffered from corneal erosions, oesophageal strictures, malabsorption, recurrent severe pneumonias and nephrotic syndrome. In addition, she had severe anaemia, sideropaenia, hypocalcaemia, heavy proteinuria and hypoalbuminaemia. A rapidly growing skin squamous cell carcinoma developed on the neck that spread to axillary and cervical lymph nodes. Recurrent hypocalcaemic tetanic convulsions and dyspnoea and a pneumonia refractory to antibiotics led to the premature demise of the patient. Autopsy revealed extensive amyloidosis of the renal, hepatic and splenic tissues. AA type amyloid deposits were detected in the renal glomeruli and in the lung, explaining the patient's unusually severe pulmonary infections. In essence, the patient had severe recessive dystrophic epidermolysis bullosa, complicated by squamous cell carcinoma, recurrent pneumonias and nephrotic syndrome due to secondary amyloidosis of the kidney and lung. The possibility of secondary pulmonary amyloidosis should be considered in severe dystrophic epidermolysis bullosa patients with recurrent pulmonary infections.

Background: Tissue transglutaminase (TGc) has recently been identified as the major, if not the sole, autoantigen of gluten-sensitive enteropathy (GSE). We developed and validated an ELISA based on the human recombinant antigen and compared it to existing serological tests for GSE [guinea pig TGc ELISA and endomysium antibody (EMA) test]., Methods: Human TGc was expressed in the human embryonic kidney cell line 293-EBNA as a C-terminal fusion protein with the eight-amino acid Strep-tag II allowing one-step purification via streptavidin affinity chromatography. We carried out ELISA assays for IgA antibodies against TGc using calcium-activated human and guinea pig TGc. The sera were also tested on monkey esophagus sections by indirect immunofluorescence for IgA EMA. We examined 71 serum samples from patients with GSE (38 with celiac disease, 33 with dermatitis herpetiformis), including 16 on therapy, and 53 controls., Results: The human TGc could be expressed and purified as an active enzyme giving a single band on a Coomassie-stained gel. The mean intra- and interassay CVs for the human TGc ELISA were 3.2% and 9.2%, respectively. The area under the ROC curve was 0.999. The specificity and sensitivity were 98.1% (95% confidence interval, 95.7-100%) and 98.2% (95.9-100%), respectively., Conclusions: The human TGc ELISA was somewhat superior to the guinea pig TGc ELISA, and was as specific and sensitive as the EMA test. The human TGc-based ELISA is the method of choice for easy and noninvasive screening and diagnosis of GSE.

It has been suggested that patients with homogeneous linear IgA deposits at the basement membrane zone constitute a distinct bullous disorder called linear IgA dermatosis (LAD) of adults or children. The results of the present ultrastructural immunogold study in two patients with LAD suggest that LAD is not a single disease entity. LAD in a 10-year-old girl was found to be ultrastructurally similar to an IgA-type pemphigoid. IgA was detected in the uppermost lamina lucida underlying the basal cell plasma membrane. In a second patient, an 86-year-old man, IgA deposits were present within the lamina densa and the anchoring plaques. The distribution of IgA in this patient was ultrastructurally identical with that of IgG in epidermolysis bullosa acquisita skin and with that of the non-collagenous globular terminus of collagen VII within the basement membrane zone of normal skin. By using the immunogold technique, we could distinguish two distinct types of LAD according to the IgA binding sites in the diseased skin. We suggest that different labelling patterns may correspond to different clinical pictures.