Exon 87 skipping of the COL7A1 gene in dominant dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is a rare, inherited, blistering disorder resulting from mutations in the COL7A1 gene, which encodes the anchoring fibrils, type VII collagen. We herein describe a further Japanese girl diagnosed with dominant DEB (DDEB). She had blisters sporadically and erosions healed with mild scarring and milia on the knees and pretibial regions. Severe pruritus was present at this time. Direct nucleotide sequencing of genomic DNA disclosed a heterozygous same splice-site mutation c.6900G>A in the COL7A1, which causes in-frame exon 87 skipping. So far, five different COL7A1 mutations leading to exon 87 skipping have been identified in rare forms of DEB: four DDEB pruriginosa and one pretibial DDEB. Therefore, a recent study suggested that exon 87 skipping in COL7A1 was related to the phenotype of DDEB pruriginosa. When she was 18 years old, however, the blister formation and pruritus markedly decreased. Therefore, her clinical symptoms were consistent to very mild DDEB but not to DDEB pruriginosa. Taken together, in-frame exon 87 skipping through c.6900G>A mutation may account for the mild skin features, rather than DDEB pruriginosa, in the present case.

Pretibial myxedema is associated with polymorphism in exon 1 of CTLA-4 gene in patients with Graves' ophthalmopathy.

Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is a well-known molecule that regulates T cell activity, with polymorphisms at different regions of this gene having been associated with autoimmune conditions. Pretibial myxedema (PTM), also called Graves' dermopathy, is an autoimmune extrathyroidal manifestation of Graves' disease. We opted to investigate the relationship between three single nucleotide polymorphisms of the CTLA-4 gene (+49A/G, and -318C/T and -1147C/T) and PTM in Iranian patients with Graves' ophthalmopathy (GO). A total of 105 unrelated Iranian patients with GO from the outpatient endocrine clinic of a large university general hospital as well as 103 healthy controls were studied. The genomic DNA was extracted from venous blood samples by a salting out method, and the polymorphisms at +49, -318 and -1147 positions of the CTLA-4 gene were determined using the polymerase chain reaction-restriction fragment length polymorphism method. The GG genotype (OR = 6.000, 95% CI = 1.805-19.940, P = 0.005) and the G allele (OR = 2.653, 95% CI = 1.314-5.357, P = 0.009) at position +49 were significantly associated with PTM in the patient group. The same genotype and allele were also significantly more common among patients (with or without PTM) than controls. No significant association was found for the other two polymorphisms. In conclusion, the +49G allele is associated with increased risk of PTM in patients with GO. Studies with larger sample sizes are needed to confirm the results of the present study.

Epidermólisis ampollar distrófica dominante generalizada severa / Dominant dystrophic epidermolysis bullosa severe generalized

La epidermólisis ampollar distrófica (EAD) es una genodermatosis que se caracteriza por la aparición de ampollas en respuesta al trauma friccional, que luego dejan cicatrices extensas y milia. En ella, la formación de ampollas ocurre por alteraciones morfológicas y cuantitativas en las fibrillas de anclaje en la sublámina densa, cuyo principal componente es el colágeno tipo VII. Comunicamos un caso de EAD en un niño de 7 años que presentaba múltiples cicatrices atróficas, erosiones sobre base eritematosa, algunas con costras en su superficie y numerosas ampollas con contenido serohemorrágico en todo el tegumento. En la cavidad oral se evidenciaban múltiples erosiones, caries y microstomía. Además, el niño presentaba pérdida completa de las uñas y pseudosindactilia de manos y pies. El estudio histopatológico de una lesión ampollar mostró piel desprovista de revestimiento epidérmico. El resultado del inmunomapeo evidenció fluorescencia en el lado epidérmico para todos los anticuerpos testeados: antígeno del penfigoide ampollar, laminina, colágeno IV y colágeno VII; patrón sugestivo de EAD dominante.

Dystrophic epidermolysis bullosa (DEB) is an inherited disease characterized by blistering of the skin following minor trauma that heals with extensive scars and milia. In this disease there are morphologic and quantitative alterations in the anchoring fibrils composed mostly by collagen type VII. We report a case of a 7-year-old boy with multiple atrophic scars, erosions covered by crusts and several serum-hemorrhagic blisters affecting all of tegument. There were multiple oral erosions, caries and microstomia. All nails were missing and presented pseudosyndactyly on the hands and feet. The histopathological exam of a blister revealed skin with absence of the epidermis. The immunomapping study showed positive fluorescence of antibodies against bullous pemphigoid antigen, laminin, collagen IV and collagen VII in the top of the blister (epidermis); suggestive of dominant DEB.

Familial pigmented purpuric dermatoses.

Pigmented purpuric dermatoses (PPD) are chronic, asymptomatic dermatoses characterized by petechiae, pigmentation and rarely telangiectasias. Familial occurrence of PPD is very rare. We report four individuals in a family over three generations. The inheritance is suggestive of an autosomal dominant pattern.

A case of primary cutaneous anaplastic large cell lymphoma with variant anaplastic lymphoma kinase translocation.

Anaplastic lymphoma kinase (ALK) is frequently observed in systemic anaplastic large cell lymphoma (ALCL), mostly in childhood or adolescence, but only rarely in primary cutaneous cases. We report a case of primary cutaneous ALCL (pcALCL) with cytoplasmic ALK expression. A 54-year-old woman with an ulcerative tumour on her forehead was admitted to our hospital. Histologically, there was an infiltrate consisting of atypical large lymphocytes and small lymphocytes in the dermis and fat tissue. Southern blot analysis showed monoclonal T-cell receptor Cbeta1 gene rearrangement. Atypical large lymphocytes were positive for CD30, CD4 and CD25, and negative for CD3 and CD79a. They were also positive for ALK only in the cytoplasm, and neurophosmin (NPM)-ALK fusion transcript was not detected by reverse transcription-polymerase chain reaction. This suggested that the translocation partner of the ALK gene in this case was different from NPM (variant translocation). The tumour on the forehead resolved in 1 month after biopsy. Nodular lesions recurred on the right knee, and were histologically identical with the forehead lesion. Our case suggests the existence of a subgroup with variant ALK translocation in pcALCL; examining NPM-ALK translocation in each case with ALK expression should be useful to characterize the disease further.

Familial dyskeratotic comedones.

We report a 49-year-old white woman having asymptomatic hyperkeratotic comedone-like lesions on her legs, arms and trunk. Her sister is similarly affected, but less severely. The clinical and histopathological features indicated a diagnosis of familial dyskeratotic comedones, a rare autosomal dominant condition.

T-cell restriction in thyroid eye disease.

Infiltrating immunocompetent cells act to establish and perpetuate the orbital autoimmune process in thyroid eye disease (TED). Until recently, it has remained unclear whether T cells infiltrating the orbital connective/fatty tissue and extraocular muscles represent a primary immune response that is specifically directed against orbital antigens. In addition, despite a close clinical and temporal association of the thyroidal and extrathyroidal manifestations in Graves' disease (GD), it has not been proven whether T cells infiltrating thyroid, orbital, and pretibial tissue in patients with TED and pretibial dermopathy (PTD) are directed against certain antigenic determinants shared between these anatomically distinct tissues. Using polymerase chain reaction (PCR)-based molecular analysis of T-cell antigen receptor (TcR) variable (V) region genes, we have demonstrated marked restriction of orbital and pretibial TcR Valpha and Vbeta genes in patients with active TED and PTD. In addition, molecular analysis of T cells in paired samples of extraocular muscle and orbital connective/fatty tissue revealed usage of similar TcR V genes. In contrast, TcR V gene restriction was either absent or much less pronounced in patients with longstanding TED and PTD. Comparison of TcR V genes in T cells obtained from thyroid gland, orbital tissue, pretibial tissue, and peripheral blood of three individual patients with active GD, TED, and PTD also revealed marked restriction and, in addition, striking similarities of TcR V gene usage. Sequencing of complementarity determining regions 3 (CDR3) and junctional domains of TcR Vbeta genes confirmed oligoclonality of intrathyroidal, orbital, and pretibial T cells. Moreover, several conserved junctional motifs were shared by T cells infiltrating the thyroid gland and the extrathyroidal sites. Taken together, these data suggest that, in patients with GD and extrathyroidal manifestations, similar antigenic determinants may be responsible for recruitment and oligoclonal expansion of T cells both within the thyroid gland and in the involved extrathyroidal sites.

Analysis of T-cell antigen receptor variable region gene usage in patients with thyroid-related pretibial dermopathy.

It is unknown whether T cells infiltrating the pretibial skin of patients with thyroid-related pretibial dermopathy represent a primary immune response or participate in a nonspecific inflammatory process. To characterize these T cells at the molecular level, we examined the T-cell antigen receptor variable region gene usage in pretibial skin biopsy specimens obtained from patients with early and late stages of pretibial dermopathy and from individuals with unrelated inflammatory conditions of the pretibial skin. RNA extracted from pretibial biopsy specimens and peripheral blood lymphocytes was reverse transcribed and amplified with the polymerase chain reaction and 22 V alpha and 23 V beta gene-specific oligonucleotide primers. The resulting T-cell receptor (TcR) V alpha and V beta transcripts were verified by Southern hybridization analysis using TcR C-region-specific, digoxigenin-labeled oligonucleotide probes. Compared with matched peripheral blood lymphocytes, the pretibial TcR V alpha and V beta gene repertoire expressed was heterogeneous but revealed marked restriction of V alpha and V beta gene usage in samples derived from patients with active inflammatory pretibial dermopathy of recent onset. In contrast, greater diversity of the TcR V alpha gene repertoire and loss of TcR V beta gene restriction were noted in patients with long-standing, clinically inactive pretibial dermopathy. TcR V gene usage in pretibial tissue and peripheral blood lymphocyte samples obtained from control subjects was unrestricted. Limited variability of TcR V gene usage in early pretibial dermopathy may reflect a primary immune response of antigen-specific T lymphocytes infiltrating the pretibial skin in thyroid-related pretibial dermopathy.

Genetic linkage between the collagen type VII gene COL7A1 and pretibial epidermolysis bullosa with lichenoid features.

Pretibial epidermolysis bullosa is a rare form of dominant dystrophic epidermolysis bullosa. The disease was diagnosed after considerable delay in a large Belgian family and was remarkable for its late age at onset and its misleading clinical presentation in the proband, which strongly resembled keratosis lichenoides chronica. Both recessively and dominantly inherited forms of dystrophic epidermolysis bullosa have been shown to be linked to the collagen type VII gene, COL7A1. Two-point linkage analysis with two intragenic polymorphisms (PvuII, AluI) in COL7A1 was performed. Strong genetic linkage between the disease in this family and COL7A1 was demonstrated by a lod score of 4.45 (theta = 0) for the AluI polymorphism. The observed intrafamilial variability of clinical phenotypes contradicts the presently proposed classification of dominantly inherited dystrophic epidermolysis bullosa.

A case of pretibial dystrophic epidermolysis bullosa: decreased expression of the non-helical domain of type VII collagen molecule.

A 27-year-old man with an ataxic gait due to infantile cerebral paralysis exhibited recurrent blistering caused by mechanical stimuli on the pretibial area of both legs from the age of 20. His parents were not consanguineous, and he had no relatives who suffered from blistering. The histology showed a subepidermal bulla due to dermolytic epidermal-dermal separation. The anchoring fibrils were sparse and rudimentary in the predilection area. An LH 7:2 monoclonal antibody against the non-helical domain of the type VII collagen molecule stained the basement membrane zone of the patient's skin at a weaker intensity than the staining of normal human skin, but at a distinctively stronger intensity than the staining of skin from a patient with recessive dystrophic epidermolysis bullosa. Immunoelectron microscopy revealed that LH 7:2-immunoreactants were distributed irregularly within the lamina densa and sparsely in the sublamina densa region. The patient was diagnosed with pretibial dystrophic epidermolysis bullosa.

Porokeratosis with large skin lesions. Histologic, cytologic and cytogenetic study of three cases.

Three porokeratosis patients with large skin lesion(s) are reported. The histopathology of the large lesions revealed that the epidermis 1) frequently presented slight or marked acanthosis and/or elongation of the rete ridge, and 2) contained abnormal cells, e.g. hyperchromatic, large, multinucleated, and/or irregular shaped nuclei. The DAPI-DNA microfluorometric study revealed DNA polyploidy and/or an increased population of epidermal cells with hyperdiploid and/or tetraploid DNA content. These results indicate the proliferating potential of the epidermis and the existence of a neoplastic clone or clones therein. This finding may explain the enlargement of skin lesions and possibly the development of malignancy, as sometimes occurs in large skin lesions. Furthermore, cultured skin fibroblasts from a patient's skin lesion or its surrounding skin revealed various kinds of chromosomal structural abnormalities, which may serve as a basis for the development of abnormal neoplastic clones in the porokeratotic epidermis.

Unusual presentation of porokeratosis palmaris, plantaris et disseminata.

Porokeratosis plantaris, palmaris et disseminata is an autosomal dominant genodermatosis characterized by multiple lesions on the palms and soles, and later on other areas, both sun-exposed and non-sun-exposed. We report a 66-year-old man with porokeratosis plantaris, palmaris et disseminata whose disease had an unusual evolution. To our knowledge this is the first case of the disease in which the lesions first appeared on the trunk and extremities and later involved the palms and soles.