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Background: Extensive keratinization appears to play a major role in the dysfunction of the Meibomian gland. This article presents the potential impact of androgens on limiting keratinization in this tissue, thus, contributing to normal Meibomian gland function and a healthy ocular surface., Materials and Methods: Orchidectomized mice were systemically treated with either testosterone or placebo for 2 weeks. The mRNA was then extracted from the Meibomian glands and differential gene expression was investigated by microarray hybridization and evaluation with GeneSifter software as well as gene ontology information from the Gene Ontology (GO) Consortium., Results: By z-score calculations, keratinization was the most significantly gene ontology term influenced by testosterone based on down-regulated genes in the mouse Meibomian gland. In particular, under the influence of testosterone the genes coding for small proline-rich protein (Sprr) 2a, Sprr 2b, Sprr 3, keratins 6a and 17 and periplakin were significantly down-regulated, while Sprr 1a and Sprr 2f were significantly up-regulated., Conclusions: Testosterone down-regulates the expression of genes promoting keratinization in the Meibomian gland. This may help to prevent Meibomian gland dysfunction by limiting excessive keratinization of this tissue and the adjacent lid margins. The findings elucidate, at least in part, the beneficial impact of androgens on Meibomian gland function and thus on th e health of the ocular surface.

"Cancer of unknown primary (site)" (CUP) represents a frequent and often difficult task for diagnostic histopathology. In the initial CUP situation, immunohistochemistry, which is relatively cost-efficient and non-burdensome for the patient, contributes substantially to the targeted search for and identification of the primary tumor. It may be performed in a two-step algorithm (keratins as the first step, group and selective markers as the second step). However, in true CUP syndrome--a heterogeneous disease whose etiology and pathogenesis is still poorly understood--the primary tumor is rarely identified, and the immunohistochemical marker profile is often anomalous. Nevertheless, immunohistochemistry remains the most important special method, aiming at the phenotypical classification and particularly the identification of certain favorable therapy-responsive subsets. Novel methods for subtyping of CUP based on the analysis of gene expression profiles need to be further evaluated before their possible diagnostic application. Future basic and clinical research is required to unravel the still enigmatic tumor biology of the CUP syndrome and to improve the hitherto very unfavorable prognosis by developing new efficient therapy regimens.

The definition of atypical ductal hyperplasia (ADH) encompasses qualitative and quantitative criteria. Qualitative criteria include cytological and architectural features similar to those of low grade ductal carcinoma in situ (DCIS), the quantitative criteria are characterized by metric features (2 mm or 2 ductules) or by the confines of lobules. In this article we discuss the morphology of ADH, the status of ADH in the low grade pathway of breast carcinoma development and its clinical significance. Furthermore, we comment some special forms of atypical epithelial proliferations of the ductal type.

Background: Meesmann's corneal dystrophy (OMIM 122,100) is a rare autosomal dominant disorder of the corneal epithelium. It manifests in early childhood and affects both eyes. The disease is characterized by variable patterned dot-like corneal opacities and intraepithelial vesicles, which can be seen by slit-lamp examination and retro-illumination. Further signs include punctate erosions, lacrimation, photophobia, and blepharospasm. Vision is usually only slightly diminished. By histology, the corneal epithelium is irregularly thickened. It shows vacuolated epithelial cells and intraepithelial formation of vesicles. By electron microscopy fibrogranular aggregates are seen in the cytoplasm of epithelial cells., Results: Linkage analyses in descendants of the family described by Meesmann and Wilke and other affected kinships showed that the putative genetic defect locates within the keratin type I gene cluster on chromosome 17 (17q12-21). Molecular genetic analyses in more than ten affected families showed that mutations in the cornea-specific keratin genes K3 and K12 represent the causative genetic defects of the disease phenotype., Conclusion: Comparative studies in autosomal dominant skin disorders of cornification suggest that the mutations identified in patients with Meesmann's corneal dystrophy exert dominant negative effects on keratin filament assembly. Disturbed filament formation results in intracellular keratin clumping, identifiable as fibrogranular aggregates. As a result the mechanical resilience of the affected cells and the epithelial tissue appears markedly reduced. Whether abnormalities of functionally related structural proteins, e.g. desmosomal components, could result in a phenotype similar to Meesmann and Wilke's corneal dystrophy remains to be seen.

The histopathologic diagnosis of odontogenic cysts is based mainly on the morphological nature of the epithelial lining of cysts and their origin. We used the international histologic classification set up by the World Health Organisation in 1992. The aim of this study was to investigate the differentiation of various types of cyst using an immunohistochemical technique rather than by conventional morphological assessment. A standard immunocytochemical method (APAAP method), applying anticytokeratin monoclonal antibodies and a p53 antibody, was used for the diagnosis of odontogenic cysts. A total of 57 jaw cysts were diagnosed according to clinical, radiological and pathological criteria as radicular cysts (20), dentigerous cysts (20) and keratocysts (17). The results proved that cyst type can be distinguished by the pattern of staining using the monoclonal antibodies CK7, CK19, CK20 for cytokeratins and the clone DO-7 for the p53 protein. Staining with the monoclonal antibodies CK7 and CK20 did not distinguish type. CK19 was not detected in keratocysts and p53 was only expressed in keratocysts. This may prove to be diagnostically useful for the more precise distinction between different cyst types.

Pachyonychia congenita (PC) comprises a heterogeneous group of autosomal dominantly inherited conditions showing characteristic nail thickening and associated signs such as palmoplantar keratoderma, follicular keratoses, and mucosal leukokeratoses. Less frequently epidermal cysts, hairshaft abnormalities, natal teeth and laryngeal involvement may be seen. Phenotypically and genetically two major forms of PC are recognized, pachyonychia congenita Jadassohn-Lewandowsky/PC type I (Medelian inheritance in man-MIM-167200) and pachyonychia congenita Jackson-Lawler/PC type II (MIM 167210). Both conditions show nail deformities, focal palmoplantar keratoderma, and follicular hyperkeratoses. Diagnostically relevant are leukokeratoses of the oral mucosa in patients with PC type I. In contrast individuals affected with PC type II show premature dentition and multiple pilosebaceous cysts predominantly affecting the upper trunk. The latter closely resemble eruptive vellus hair cysts and steatocystoma multiplex. By mutational analysis keratin K6a and K16 gene mutations have been detected in patients with PC type I, and keratin K6b and K17 gene mutations have been shown to be the underlying genetic defect in patients with PC type II.

Background: Lattice dystrophy is an autosomal-dominantly inherited disease. A mutation of the gene coding for kerato-epithelin has been found in patients with this stromal dystrophy. In codon 124 a Guanine to Adenine mutation of the nucleotide 417 has been described. We looked for this mutation in a family with lattice dystrophy treated in our clinic., Patients and Methods: Using primers specific for kerato-epithelin gene, we amplified the cDNA extracted from lymphocytes of two patients suffering from lattice dystrophy. The polymerase chain reaction (PCR) products were subcloned and sequenced., Results: Guanine to Adenine mutations, as published were detected in both of our patients at codon 124., Conclusion: We found the published mutation in both of our patients, indicating that this Guanine to Adenine exchange is pathognomonic for lattice dystrophy.

Background: Pachyonychia congenita is considered to be a genodermatosis of autosomal inheritance. It is characterized by nail hypertrophy, shortly present after birth. Later on follicular keratosis of the extremities and hyperkeratosis of palms and soles can be found., History and Clinical Findings: We report a child with pachyonychia congenita type-I (Jadassohn-Lewandowsky). Shortly after birth nail hypertrophy of all finger- and toenails and leukoplakia of the palate and tongue were found. At the age of 3 years follicular keratosis of the extremities and plantar bullae could be found additionally., Conclusion: The underlying disturbance is a mutation within genes for keratin 6, 16 and 17 which leads to formation of abnormal tonofilaments. In adult patients retinoids can be used for symptomatic treatment especially of the palmoplantar keratosis.

In 1901, Vörner described a diffuse keratoderma of palms and soles with autosomal dominant inheritance. Histopathologically, this disease has the typical features of epidermolytic hyperkeratosis. Clinical examination does not allow differentiation between keratoderma of the Vörner type and the keratoderma described by Thost in 1880 and Unna in 1883. Reexamination of the family originally seen by Thost revealed histopathological signs of epidermolytic hyperkeratosis, confirming that keratoderma of the Vörner type is present in this family. The clinical features and variability of this palmoplantar keratoderma were demonstrated on the basis of an examination of 22 families (46 patients). In addition to diffuse hyperkeratosis of palms and soles with a sharp demarcation and erythematous margin, some less well-known features, such as knuckle pad-like keratoses on the finger joints and clubbing of the nails were observed. A genetic analysis of the pedigrees suggests that new mutations causing this disorder rarely occur. Point mutations in the keratin 9 gene, which has been mapped to chromosome 17q21, can be a cause of epidermolytic keratoderma of palms and soles. Five different keratin 9 gene mutations were identified. All these mutations are localized in the highly conserved coil 1A region of the rod domain, which is thought to be relevant for dimer formation in intermediate filaments.

We report on an 11-year-old female patient with anhidrotic ectodermal dysplasia (AED) showing the following characteristics: (1) reduced number of hair follicles and incomplete formation of sweat glands; (2) disturbed hair growth with shortening of anagen and anhidrosis; (3) disturbed cytokeratin expression pattern of CK 13, 14, 19 (follicular epithelium) and of CK 18 (eccrine sweat glands); (4) reduction of cystine and increase in sulphonic cysteine acid. Thus, we demonstrated pathological differentiation on the immunomorphological and on the biochemical level, leading to disturbed keratinization that could be visualized by transmission and scanning electron microscopical studies of the hair shafts. According to these findings AED is a developmental defect that involves not only incomplete formation of hair follicles and sweat glands but also a disordered differentiation and follicular keratinization with disturbed cytokeratin pattern and pathological amino acid composition of the terminal hairs produced.

A cDNA clone, encoding for a major component of the cornified cell envelope now termed loricrin, was isolated by cross-hybridization with the end domains of keratin 1 and 10. Loricrin is expressed very late in terminal epidermal differentiation in the upper stratum granulosum and is identical to the sulfur-rich component of the single type keratohyaline granule. Moreover, loricrin appears later to become cross-linked by the formation of glutamyl-lysyl-isopeptide bonds and thereby incorporated as a major component into the cornified cell envelope. In vivo, loricrin is expressed in all mammalian stratified epithelia tested so far. However, the highest levels of expression are found in humid tissues such as newborn epidermis, the epithelia of oral and anal mucosa, esophagus, foreskin, vagina and the epidermal parts of sweat ducts.