A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1.

Sarcoidosis is a complex systemic inflammatory disease of unknown aetiology that is influenced by a variety of genetic and environmental factors. To identify further susceptibility loci for sarcoidosis, a genome-wide association study (GWAS) was conducted in 381 patients and 392 control individuals based on Affymetrix 100k GeneChip data. The top 25 single-nucleotide polymorphisms (SNPs) were selected for validation in an independent study panel (1,582 patients versus 1,783 controls). Variant rs10484410 on chromosome 6p12.1 was significantly associated, with a Bonferroni-corrected p-value of 2.90 × 10⁻² in the validation sample and a nominal p-value of 2.64 × 10⁻4 in the GWAS. Extensive fine mapping of the novel locus narrowed down the signal to a region comprising the genes BAG2, C6orf65, KIAA1586, ZNF451 and RAB23. Verification of the sarcoidosis-associated nonsynonymous SNP rs1040461 in a further independent case-control sample and quantitative mRNA expression studies point to the RAB23 gene as the most likely risk factor. RAB23 is proposed to be involved in antibacterial defence processes and regulation of the sonic hedgehog signalling pathway. The identified association of the 6p12.1 locus with sarcoidosis implicates this locus as a further susceptibility factor and RAB23 as a potential signalling component that may open up new perspectives in the pathophysiology of sarcoidosis.

Neuron-specific enolase concentrations in blood as a prognostic parameter in cerebrovascular diseases.

BACKGROUND AND PURPOSE: To investigate the clinical relevance of plasma concentrations of neuron-specific enolase (NSE) in patients with severe cerebrovascular diseases, serial analyses were performed during the first 10 days after the acute event. METHODS: Plasma samples taken from 61 patients (30 with brain infarction, 13 with intracerebral hemorrhage, 11 with cardiogenic hypoxia-ischemia, and 7 with myocardial infarction [as control group]) were analyzed for NSE concentration using an enzyme immunoassay. The time course of plasma NSE was correlated with clinical findings, clinical outcome, cranial computed tomography, intracranial pressure, and other laboratory data. RESULTS: In cases of hypoxia-ischemia there was close correlation between plasma NSE values during the first 72 hours and the clinical outcome. In brain infarction and intracerebral hemorrhage, high plasma NSE mostly indicated an unfavorable outcome, but low values did not permit a reliable prognostic estimation. In cases of cerebral infarction and intracerebral hemorrhage with secondary neuronal destruction (for example, due to malignant edema), increasing NSE concentrations in plasma preceded the change of clinical or other diagnostic parameters. CONCLUSIONS: The course of plasma NSE levels is seen as a relevant parameter for assessing the prognosis of cerebral hypoxia-ischemia. Additionally, it may prove to be a useful tool for monitoring space-occupying brain infarctions and intracerebral hemorrhages and therefore may contribute to improved therapeutic management of severe cerebrovascular diseases.

[Nail diseases as a symptom of ectodermal dysplasia and related syndromes]. / Nagelerkrankungen als Symptom ektodermaler Dysplasien und verwandter Syndrome.

The nails are often involved in complex dysplasias. The present paper reviews nail manifestations of complex dysplasias, ectrodactylia and selected palmoplantar keratoses with associated symptoms. Some of these are of early diagnostic importance, while others are rare symptoms of complex dysplasias. Mono- and oligosymptomatic syndromes are drawn to the reader's attention.

[Monosymptomatic Melkersson-Rosenthal syndrome with subsequent vulvitis and perivulvitis granulomatosa]. / Monosymptomatisches Melkersson-Rosenthal-Syndrom mit nachfolgender Vulvitis und Perivulvitis granulomatosa.

We report on an 40-year-old woman with granulomatous facial swelling followed by vulvitis and perivulvitis granulomatosa. The characteristic histopathology with epitheloid cell granulomas was seen in samples from both the face and the vulva. By immunohistochemistry the lesions were characterized as consisting mainly of histiocytic and CD-30-positive T cells. The possible aetiology is discussed briefly.

Dermal cylindroma. Expression of intermediate filaments, epithelial and neuroectodermal antigens.

We report on immunohistochemical staining patterns in so-called apocrine tumors of skin with special emphasis on the dermal cylindroma. The results were compared with apocrine tubular adenoma, syringocystadenoma papilliferum and the normal eccrine sweat gland. A relationship of dermal cylindroma to the apocrine gland is suggested by expression of lysozyme and alpha 1-antichymotrypsin. The tumor shares keratin, epithelial membrane antigen (EMA) and EGF-receptor expression with eccrine and apocrine glands. The presence of intermingled cells with a coexpression of keratin and vimentin argues for a partial myoepithelia-like differentiation. Neuroectodermal antigens are missing. Therefore, dermal cylindroma is classified as an adnexal tumor of skin with a variable rate of cells of apocrine secretory, myoepithelial and undifferentiated phenotypes.

[Hutchinson-Gilford syndrome]. / Hutchinson-Gilford-Syndrom.

A case report on a 6-year-old boy suffering from the extremely rare Hutchinson-Gilford syndrome (progeria) is presented. The results of histopathological and immunohistological examination of the scar-like skin lesions are reported. Subcutaneous amorphous nodules were eosinophilic, PAS- und elastica-negative und remained unstained with antibodies against collagen type IV, vimentin, and collagenase. The dense perivascular infiltration consisted of CD4+, CD8-, alpha-1-antichymotrypsin-, MAC 387-, and some vimentin-positive cells. Perinodular blood vessels were more abundant and had a thickened wall. Collagen bundles were swollen. The epidermis appeared atrophic with focal basal cell degeneration.

[Hidrotic ectodermal dysplasia syndrome--trichooculodermatovertebral syndrome]. / Hidrotisches ektodermales Dysplasie-Syndrom--Trichooculodermovertebral-Syndrom.

We report on a 23-year-old women suffering from a hidrotic ectodermal dysplasia with baldness, xerodermia, kyphosis of the chest, hypopigmented mamillae, disturbances of the menstrual cycle, dysphonia and keratitis punctata superficialis recidivans. The complex condition is classified as a tricho-oculo-dermo-vertebral syndrome. Immunohistological findings suggest a combined alteration of epithelial differentiation of hair follicles and interfollicular epidermis.

[Nevus spongiosus et albus mucosae]. / Naevus spongiosus et albus mucosae.

An 8-year-old girl with a non-familial case of white sponge nevus (WSN) is presented. The differential diagnosis is discussed with reference to anamnestic, clinical and histopathological data. In keratin expression, WSN resembles the epithelia of the hard palate and the tongue.

[Unilateral systematic linear porokeratosis. Immuno- and lectin histochemistry]. / Unilaterale systematische lineäre Porokeratose. Immun- und Lektinhistochemie.

An uncommon case of unilateral systemic linear porokeratosis in a women aged 22 years is reported in this paper. The results obtained from frozen-section investigations into lectin binding were indicative of reduced epidermal fucosylation and sialinization beneath the cornoid lamella. The basal stratum failed to react with a polyclonal antibody against calmodulin. Epidermal reaction, with AS-6 staining against urokinase, was of higher intensity. The above findings, as a whole, are likely to suggest accelerated keratinocyte migration to the stratum corneum in cases of linear porokeratosis and and should actually support assignment of the latter to the group of dermatoses with transepidermal elimination.

Sweat gland tumors of skin - immunohistochemistry with common antibodies in the paraffin section.

Adnexal tumors of skin are a group of relatively uncommon tumors. Their differential diagnosis is complicated by the fact, that in one lesion different lines of differentiation may be present, i.e. eccrine, apocrine or pilosebaceous. Immunohistochemistry can provide additonal informations on the cellular phenotype. In the present paper fifty-three sweat gland tumors have been investigated by immunohistochemistry in the paraffin section. The usefulness of commonly used 'marker antibodies' (S-100, CEA, Cam 5.2, Vim9(1)) has been challenged by the use of routine material and a comparison to other adnexal, vascular and epidermal tumors of skin (n = 22). Tumors with lumen formations, which express at least Cam 5.2 and CEA are highly suggestive for a differentiation related to the secretory coils of eccrine or to apocrine glands. Lumen forming tumors with the phenotype CEA-positive/ Cam 5.2-negative more closely resemble the eccrine duct. A myoepithelial phenotype is more suggestive, when cells are expressing vimentin and S-100. The histopathology, however, is an essential for the interpretation of immunohistochemical findings.

The initial steps of tumor progression in melanocytic lineage: a histochemical approach.

Antigen expression was studied by immunohistochemistry in 133 human melanocytic skin lesions to gain insight into the initial steps of tumor development, i.e. in particular the change from melanocytes to benign nevi. We refer to the proposed progression model of Clark and co-workers. The following types of antigens were investigated: (i) intermediate filament antigens (vimentin), (ii) melanoma-associated antigens (HMB-45, NKI/C3, MA-930, LS59), (iii) proliferation-associated antigens (S-100, Ki67, Ro/SSA, calmodulin), (iv) progression-associated antigens (HLA-DR, ICAM-1), and (v) basal membrane antigens (bullous pemphigoid antigen, laminin, fibronectin, collagen type IV). The intensity of expression and the topography of immunoreactive pigment cells were compared with the stage of tumor progression. Special attention was paid to the early steps of this process, i.e. the disturbance of the epidermal melanin unit and the development of melanocytic ("nevocellular")nevi. A dramatic shift of antigen expression (antigen types [i] to [v]) was noted in benign nevi compared with melanocytes. Nevi with cellular atypia disclosed a tendency towards an increased percentage of tumor cells reactive for melanoma- and progression-related antigens (types [ii] and [iv]). However, there was no clear cut level of distinction of antigen expression (types [i] to [v]) between benign and primary malignant melanocytic tumors. So-called dysplastic nevi resembled benign tumors or melanocytes rather than malignant melanoma. Metastatic melanoma of skin showed a relatively high number of Ki67-positive, cycling melanoma cells. The results have a bearing on the concepts of melanocytic nevus ontogenesis and "maturation". It appears that melanocytes lose maturity on their way down to the dermis in contrast to traditional concepts (Abtropfung); this might be of importance for our understanding of melanoma development in association with melanocytic nevi. Our findings are discussed with regard to Clark's model of tumor progression.

[Nevoid bundle hairs]. / Nävoide Bündelhaare.

We report on two cases of naevoid bundle hair of the scalp. The clinical picture is characterized by an abnormal grouping of hairs emerging from one follicle ostium. The hairs arise from separate follicles but fuse into a common outer hair root sheath in the above the sebaceous gland. The outer hair root sheath is characterized by its abnormal reactivity with monoclonal antibodies against keratin but normal reactivity with anti-filaggrin. Naevoid bundle hair is thought to be an atavistic hair growth pattern.

Pachyonychia congenita. Immunohistologic findings.

Pachyonychia congenita (PC) is a very rare hereditary disorder of keratinization. Immunohistological findings has so far been lacking. Reported in this paper is a case of Jadassohn-Lewandowsky type PC in a woman aged 18 years on which immunohistological investigations could be performed. Several monoclonal antibodies to filaggrin and keratin were used to stain tissue sections of lesional plantar skin, with a view to studying impairment of epidermal differentiation. While staining patterns comparable to those of normal skin were exhibited by anti-filaggrin and some antikeratins (RPN 1161, A51-B/H4), substantially altered immunostaining was recordable from other anti-keratins. Only superficial vital keratinocytes were stained by RKSE 60 against keratin 10 and K 8.12 against keratins 13 and 16. The authors, in other words, obtained information on expression of keratin 10, normally occurring in all suprabasal keratinocytes, as well as of the basal proliferation keratin 16 in the uppermost vital cell positions of PC lesion. The above results are likely to suggest impairment of keratin expression in cases of PC.

Human eccrine sweat glands--a histochemical approach.

Histogenesis of eccrine sweat glands is incompletely understood. Histochemistry of the human eccrine sweat gland of adult skin by the use of lectins as well as antibodies to neuroglandular antigen (NGA) and urokinase was in favour of a relative independent differentiation from interfollicular epidermis. Expression of NGA by sweat glands is a feature unique among skin appendages. The possible impact of our findings for sweat gland histogenesis is briefly discussed.

[Pachyonychia congenita. Presentation of a case and histological-histochemical findings]. / Pachyonychia congenita. Falldarstellung und histologisch-histochemische Befunde.

We report on two cases of pachyonychia congenita, Jadassohn-Lewandowsky type, in a father and daughter. Histopathological examination revealed thickened, aggregated bundles of tonofilaments and an increased number of atypical keratohyalin granula, which is suggestive of an altered keratinization. Immunohistological staining with antibodies to cytokeratins (A45-B/B3, A51-B/H4, A53-B/A2, RPN 1161) was unchanged. Filaggrin could not be detected. Basal cells immunoreactive for calmodulin were markedly reduced or even absent in the rete ridges. Staining with a monoclonal antibody against Ki67 made epidermal cell hyperproliferation seem unlikely. The epidermal lectin binding was normal. C3 was detectable in vessel walls mainly of the stratum reticulare. The findings are discussed with reference to pachyonychia pathogenesis.

[A combination of psoriasis vulgaris and nevus cell nevus--clinical, histopathologic and histochemical findings]. / Kombination von Psoriasis vulgaris und Nävuszellnävus--Klinische, histopathologische und histochemische Befunde.

In a study on 76 patients suffering from psoriasis, we found melanocytic nevi (MCN) within psoriatic lesions in 7%, and in perilesional areas of about 2 cm in 13% of the patients. Under magnification (operating microscope), we failed to detect any signs of psoriasis in both the epidermis covering the MCN and the adjacent epidermis. Histopathologically, 6 out of 7 MCN examined did not show any psoriatic alterations of the epidermis, and in all the 7 cases, the adjacent epidermis was free of psoriasis. Using unfixed frozen sections in histochemistry, we studied the lectin binding of FITC-labeled ConA and UEA I in 5 MCN. The epidermal reaction was comparable to that of psoriatic lesions. In contrast to psoriatic lesions, there was no staining of the spinous layer with a polyclonal antiserum against calmodulin, but only the staining of basal cells as in non-lesional psoriasis. We discuss possible 'protective' factors against psoriasis.

[Acquired acral fibrokeratoma]. / Das erworbene akrale Fibrokeratom.

A 33-year-old man with an acral fibrokeratoma of the finger. Clinical, anamnestic, histopathologic and immunohistological findings suggest a traumatically induced connective tissue hyperproliferation with secondary epidermal hyperplasia in this benign fibroepithelial tumour.

[Immunohistologic studies of the distribution of proliferative compartments in the appendages of adult human skin]. / Immunhistologische Untersuchungen zur Verteilung proliferativer Kompartimente in den Anhangsgebilden humaner adulter Haut.

Both, calmodulin (CaM) as well as the antigen Ki67 show a close relationship to cell proliferation. By means of specific antibodies against them, it has become possible to study the spatial distribution of proliferative compartments in tissues. We performed an indirect immunofluorescence study on unfixed frozen sections of human adult skin to gain more informations about the spatial distribution of immunoreactive CaM and Ki67 in skin appendages, i.e. anagen hair follicle, sebaceous and eccrine sweat gland. Two major patterns of immunoreactivity were seen: Type (1) or epidermis-like, which was present in the interfollicular epidermis and the pilosebaceous unit. Type (2) or sweat gland type, which was seen in eccrine sweat glands. Both types disclosed significant differences in the relative number of proliferative cells in S-phase, which might be a consequence of a quiet different tissue architecture. Furthermore, myoepithelial cells of secretory coils were likely to represent mainly SQ-cells. Their immunoreactivity in human skin was quiet different from other parts of eccrine sweat glands suggesting another ontogenetic pathway.