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Hereditary predispositions are responsible for more than 30% of or paraganglioma. Their identification is essential to optimize medical care and to offer an appropriate screening to relatives. To date, there are more than 15 known paraganglioma/pheochromocytoma predisposing genes. The most frequently involved are those encoding the succinate dehydrogenase (SDHx), accounting for half of cases and the VHL gene, causing the Von Hippel Lindau syndrome and representing approximately 20% of genetically determined cases. Patients with SDHB genes mutations have a higher risk of metastatic disease. An oncogenetic counseling is recommended to all patients developing one or several paragangliomas, isolated or associated with other tumors. Apart from the clinical presentation and in particular the syndromic forms characterized by specific tumor spectra, there is no validated morphological criterion allowing to suspect a hereditary form. On the other hand, pathologists have now access to several immunohistochemical tools allowing the identification of some hereditary forms, in particular those linked to the SDHx, VHL and FH genes. Thus, the loss of expression in immunohistochemistry of the SDHB or FH proteins orientates respectively, towards SDHx and FH genes, while the membrane expression of carbonic anhydrase IX (CA-IX) is a sensitive and specific tool pointing towards a VHL anomaly. Other immunohistochemical markers are under evaluation. A systematic SDHB immunohistochemical staining is recommended on all paragangliomas/pheochromocytomas in order to allow an early detection of the most common hereditary forms and to contribute to the interpretation of the genetic results in these patients seen in oncogenetics consultation.

Palindromic rheumatism is characterized by episodes of arthritis or para-arthritis leaving no residual or radiographic changes. Several diseases should be ruled out in the differential diagnosis. Evolution to rheumatoid arthritis is common, especially in patient with positive rheumatoid factor and anticitrullinated peptides. In seronegative patients, palindromic rheumatism could be part of the spectrum of autoinflammatory diseases because of a high frequency of MEFV mutations. Treatment remains discussed. The use of antimalarials could delay the development of rheumatoid arthritis or another connective tissue disease.

The medical treatment of renal-cell carcinoma, and of its most frequent subtype, clear cell renal-cell carcinoma, has recently been drastically changed by the emergence of targeted therapies. The development of these drugs has been made possible by more precise knowledge of molecular mechanisms involved in the carcinogenesis of these tumors. We present in this article the molecular pathways linked to targeted therapies for clear cell renal-cell carcinoma: VHL/HIF/VEHF and PI3K/AkT/mTOR pathways. We also describe succinctly the EGFR pathways, and the molecular mechanisms involved in other histological subtypes. Then, we briefly describe how these targeted therapies work. We finally discuss how biology could improve the use of these therapies, by developing new prognostic factors, and predictive factors of response to treatment.

Pemphigoid gestationis (PG) is a rare autoimmune bullous dermatosis associated with pregnancy. Its previous designation, herpes gestationis, is obsolete. PG is characterized by a subepidermic separation induced by the presence of peripheral blood autoantibodies against two hemidesmosomal antigens: BPAG1 and BPAG2. Clinical diagnosis is confirmed by histology and positive cutaneous immunofluorescence tests. The most discriminant examination for other pruritic dermatoses of pregnancy is the enzyme-linked immunosorbent assay (Elisa) NC16A BP 180. First-line treatment is local corticosteroid therapy; if local treatment fails, general corticosteroid therapy should be administered. The prognosis is good for mother and child, except that there is a risk of preterm delivery and of moderate fetal growth restriction. Management in a specialized setting is therefore necessary. Recurrence is possible during subsequent pregnancies.

Leber congenital amaurosis (LCA) is a the earliest and most severe form of retinal dystrophy responsible for congenital blindness. LCA has genetic heterogeneity and the study of this disease is elucidating the genetics and molecular interactions involved in the development of the retina. To date, 11 LCA genes have been mapped, ten of which have been identified. The CEP290 gene has been shown to account for Joubert and Senior-Loken syndromes and to be a frequent cause of nonsyndromic LCA. We report here the first Arab patient, born to consanguineous parents, with Leber congenital amaurosis attributable to mutation of the CEP290 gene.

Nephronophthisis is a chronic tubulo-interstitial nephritis which progress to terminal renal failure. It is an heterogeneous entity at the clinical as well as at the genetic level. There are three main clinical forms of nephronophtisis which have been associated with five gene defects. Juvenile nephronophtisis, the most frequent, progress to end stage renal failure before age 15. It is an autosomal recessive disease which is responsible for a urine concentration defect starting after age 2, failure to thrive and a progressive deterioration of renal function without signs of glomerular disease. Kidney size is normal. Histologic lesions concern tubular basement membranes which are thickened and multilayered or thinned. There is an associated interstitial fibrosis. Some children present with extrarenal symptoms: tapetoretinal degeneration (Senior-Loken syndrome), mental retardation, cerebellar ataxia, bone anomalies or liver involvement. Infantile nephronophtisis is a recessive autosomic tubulo-interstitial nephritis with cortical microcysts which progress to end stage renal failure before age 5. Adolescent nephronophtisis is a less frequent form of nephronophtisis. Medullary cystic disease is transmitted as an autosomic dominant trait. Clinical and histological signs are similar to nephronophthisis, but the disease progress later to terminal renal failure and is not accompanied by extra-renal symptoms. Several genes which are involved in nephronophtisis, encode proteins that localize in different cell compartments, in particular to the primary apical cilia, as it is the case for many other cystic kidney diseases.

X-linked mental retardation (XLMR) affects 1.8 per thousand male births and is usually categorized as "syndromic" (MRXS) or "non-specific" (MRX) forms according to the presence or absence of specific signs in addition to the MR. Up to 60 genes have been implicated in XLMR and certain mutations can alternatively lead to MRXS or MRX. Indeed the extreme phenotypic and allelic heterogeneity of XLMR makes the classification of most genes difficult. Therefore, following identification of new genes, accurate retrospective clinical evaluation of patients and their families is necessary to aid the molecular diagnosis and the classification of this heterogeneous group of disorders. Analyses of the protein products corresponding to XLMR genes show a great diversity of cellular pathways involved in MR. Common mechanisms are beginning to emerge : a first group of proteins belongs to the Rho and Rab GTPase signaling pathways involved in neuronal differentiation and synaptic plasticity and a second group is related to the regulation of gene expression. In this review, we illustrate the complexity of XLMR conditions and present recent data about the FMR1, ARX and Oligophrenin 1 genes.

Bullous pemphigoid (BP) is the most frequent autoimmune blistering skin disease of the elderly. It is mediated by circulating antibodies directed against two hemidesmosomal proteins of the dermal epidermal junction: BPAG1 and BPAG2. Clinical features consist of pruritus and tense blisters usually surrounded by erythema. Blisters sometimes evolve to erosions, become haemorrhagic or even large erosive areas. Lesions heal without scarring. Lesions are symmetrically located on the thighs, legs, trunck and arms. Mucous membranes are usually uninvolved. Histological examination of a skin biopsy specimen shows a subepidermal blister with eosinophils within the blister and the superficial dermis. Direct immunofluorescence shows linear IgG and/or C3 deposits along the dermal epidermal junction. In France and in Europe, most patients are now treated using topical steroid therapy (clobetasol propionate).

To study and compare the expression of p63 protein and smooth muscle actin in breast tubular carcinoma (TC) and its main differential diagnoses, radial scar (RS)/complex sclerosing lesion (CSL).Immunohistochemistry techniques were used to search for p63 protein and smooth muscle actin antibodies in 10 patients with TC and fifteen with RS/CSL.Myoepythelial cells were diffusely positive for both actin and p63 protein with a cytoplasmic (actin) or nuclear (p63) pattern in all patients with RS/CSL. Inversely, all TC were negative for p63. Actin antibodies failed to label myoepithelial cells in TC, but both vessels and stromal myoblasts were actin-positive, creating difficult interpretation situations. By contrast, p63 was consistently negative in these structures.For the differential diagnosis between TG and CR/LSC, smooth muscle actin and p63 protein demonstrate equivalent sensitivity for the detection of myoepithelial cells. However, the nuclear pattern of p63 labeling gives a "cleaner" stain. In addition, p63 enables distinction between myoepithelial cells and myofibroblasts/vascular smooth muscle cells, offering increased specificity.

Familial Mediterranean Fever (FMF) is an hereditary disease that especially affects people living around the Mediterranean sea. It is characterized by recurring fever and abdominal pain, eventually associated with localised pleuritis, synovitis or skin inflammation. The most serious complication is amyloidosis, which can lead to terminal renal failure. The attacks and complications can be avoided by life long administration of colchicine. Two independent French and American teams discovered the gene responsible for the disease in 1997. It encodes for a protein named pyrin/marenostrin involved in the homeostasis the inflammatory mechanisms. The main mutations have been identified and are henceforth accessible for molecular screening.

Duchenne muscle dystrophy results from the absence of dystrophin, a cytoskeletal protein of the muscle fibre. Dystrophin plays an essential role in the integrity of the membrane-associated protein complexes connected to the extracellular matrix. On chromosome 6 is located the gene of a protein presenting 80 % homology with dystrophin : utrophin, which is expressed at the neuromuscular junction. The review examines if utrophin can replace dystrophin and correct the structural and functional characteristics of the myopathy, and how the improvements can be quantitatively expressed. In transgenic mice, deficient in dystrophin, but overexpressing large quantities of utrophin, the latter is found on structures where dystrophin is normally located, histological signs of necrosis disappear and the recovery of functional disorders, specially affecting the mechanical properties of the muscle fibres, can be complete. The review examines also several ways of obtaining overexpression of utrophin in adult mdx mice, such as conditioned expression of the utrophin transgene (using a tetracycline-sensitive transactivator), transfection with viral vectors containing the utrophin cDNA (complete or truncated), actions on factor(s) controlling utrophin expression at the neuromuscular junction (heregulin, 4 N-acetylgalactosamine), and pharmacological ways of inducing expression (NO, arginine). Though partial improvements of the myopathy status have been obtained by these various approaches, they remain limited by their localized action and/or by the moderate level of utrophin expression obtained. Further researchs to overcome these limitations are urgently needed in order to transform the very promising effect of utrophin overexpression into a real treatment of Duchenne myopathy.

Ischaemic or haemorrhagic cerebral vascular accidents (CVA) are the second cause of premature death in Western countries. Their pathophysiological mechanisms are very heterogeneous and implicate environmental and genetic factors. The recent identification of several genes implicated in the rare monogenic forms of CVA, such as hereditary cerebral amyloid angiopathy, cerebral cavernous angioma or CADASIL, has had immediate diagnostic applications for patients and their relatives, and has opened new insights into the mechanisms governing angiogenesis and/or vascular homeostasis. In the multifactorial forms of CVA, by far the most frequent, the role of a genetic factor is much more moderate, making identification of the implicated genes difficult. A very great number of association studies have been performed in order to examine the possible implication of candidate genes due to their known or supposed functions, but very few genetic variants have been associated with an increased risk of CVA, this increase being modest moreover. Quite recently an approach combining genetic linkage analysis and a haplotypic association study has allowed the localisation and identification of a new gene, phosphodiesterase 4D, implicated in ischaemic CVA, and the localisation on chromosome 7 of a gene implicated in the occurrence of cerebral aneurysms, thus raising new hopes in these multifactorial form.

Periodic disease is the prototype of a group of hereditary disorders characterised by recurrent inflammatory attacks. Since the discovery of the causing gene (MEFV) in 1997, three hospital laboratories in France, and around 20 throughout the world, propose a specific genetic test, based on the search of the common MEFV mutations on DNA extracted from a simple blood sample. This strategy allows definitive confirmation of periodic disease if one mutation is detected on each of the two chromosomes (around 30 mutations are reported today), but do not exclude the diagnosis in the other cases (one or no mutation detected). A non-contributive test shows the existence of rare MEFV mutations, or the involvement of another gene responsible for inflammatory hereditary syndrome; important differential diagnosis to be done, because their mode of management may be different from that of periodic disease.

The aim of this study was to evaluate the histological findings observed in patients with bullous pemphigoid in whom the diagnosis of bullous pemphigoid could be confirmed by direct immunofluorescence and immunoblot serum analysis. Seven histological criteria were considered for selection of skin biopsy specimens: 1) cleavage of dermal epidermal junction; 2) migration of eosinophils along dermal epidermal junction; 3) presence of intra epidermal eosinophils (with or without associated spongiosis); 4) absence of keratinocyte necrosis; 5) absence of acantholysis; 6) absence of dermal fibrosis; 7) absence of vasculitis. Depending on the number of criteria observed the histological picture was considered as: highly suggestive, suggestive or poorly suggestive of bullous pemphigoid. The histological picture was considered as highly suggestive in 50% of cases, suggestive or poorly suggestive in 37% and 13% of cases respectively. Migration of eosinophils along dermal epidermal junction was observed in 23 biopsy specimens (50%). Histological findings considered as poorly suggestive of bullous pemphigoid consisted of a prurigo-like or an eczematous-like or a drug induced-like picture or no specific cutaneous erosions. An histological picture highly suggestive of bullous pemphigoid was observed in 67% of patients whose serum contained anti-BPAG2 antibodies and in only 36% patients of without anti-BPAG2 antibodies (p=0,04). On the contrary, only one bullous pemphigoid patient (4%) with circulating anti-BPAG2 antibodies had a histological picture poorly suggestive of bullous pemphigoid. These findings are in accordance with the pathogenic properties of anti-BPAG2 antibodies demonstrated in animal models. This study showed that: 1) typical histological findings of bullous pemphigoid are only observed in 50% of skin biopsy specimens. 2) The diagnosis of bullous pemphigoid should be considered in elderly patients even when a poorly specific prurigo-like or eczematous-like histological picture is observed. Moreover, it underlines the usefulness of direct immunofluorescence of skin biopsy specimens and indirect immunofluorescence and immunoblot analysis of serum in such atypical cases of bullous pemphigoid.

A 9 year old boy suffering from migraines, vomiting and exercise intolerance was hospitalized. Clinical examination revealed calf hypertrophy only. There was no muscular deficit and cardiac examination was normal. Creatine kinase and transaminase were elevated. Muscle biopsy revealed fibers of various sizes, centrally located nuclei, occasional necrotic and regenerative fibers. Interstitial tissue was normal. Immunohistochemistry with various antibodies directed against the membranous dystrophin complex was normal. Western Blot analysis revealed dystrophin of abnormal size, and multiplex PCR confirmed the dystrophinopathy showing an absence of exon 43 and 44. This observation highlights the occurrence of unusual dystrophinopathies revealed by exercise intolerance and pseudo-metabolic syndrome. Normal anti-dystrophin immunostaining does not rule out the diagnosis which may only be made by Western Blot analysis or genetic studies.

The normal hair development requires WNT signalling pathways. A constitutive activation of beta-catenin, one of the components of this cascade, induces an abnormal proliferation of hair matrix cells. This activation is observed in a human skin tumours called pilomatricoma. Mutations of the beta-catenin gene are detected in 75% of the tumours analysed.

The APC gene is mutated both in familial adenomatous polyposis (FAP) and sporadic colorectal cancers. It had been previously shown that the APC gene product interacts with beta-catenin, a key element in the Wnt-1 signaling pathway. This pathway is initiated by the growth factor Wnt-1 and ends up in the nucleus where it activates transcription factors of the Lef/Tcf family although the targets of the latter were still unknown. This has just been accomplished by the identification of the c-MYC oncogene as the relevant target of the Wnt-1/APC pathway in the development of human colorectal cancers. Indeed, under appropriate conditions (presence of growth factors, for example), c-MYC is an essential determinant of cell proliferation.

Periodic disease is a hereditary disorder. Until recently its diagnosis was essentially based on clinical criteria. When the clinical picture was incomplete or atypical, it often required elimination of other diagnoses which sometimes involved extensive and useless investigations. Diagnosis was consequently delayed or irrelevant, with the risk of renal failure when the patient was not treated (or tardily treated).Efforts of molecular geneticists have allowed to track and recently to identify the gene (MEFV) responsible for this disease. Today blood sampling enables identification of the causative mutations, sometimes even before the onset of symptoms.Four mutations clustered on exon 10 already account for 74% of cases in patients originating from the most affected populations and presenting with complete clinical picture. Identification of rare mutations should progressively allow improvement of the test sensitivity, especially in patients with a less typical form of the disease.

The adenomatous polyposis coli (APC) gene has been found to be mutated during the development of sporadic colorectal cancers as well as in familial adenomatous polyposis (FAP). These conditions result from initially somatic and germ line mutations respectively. In both cases, the expressed protein is truncated at its carboxyterminal region. Investigations into the role of wild-type APC have led to a better understanding of the importance of mutations in the genesis and progression of adenomas. APC was shown to regulate cell growth and cell death, to bind beta-catenin, and to colocalize with microtubules. APC truncation was therefore hypothesized to alter cell multiplication and cells are no longer able to undergo apoptosis. Owing to its beta-catenin binding, APC can modify the pool of beta-catenin which is in part utilized in the assembly of adherens junctions and in nuclear signalling. Truncated APC is unable to regulate this pool thereby altering adhesion and cell signalling. Finally, APC involvement in microtubule-dependent locomotion may explain some changes in cell movement which are observed in adenomas. The establishment of murine mutants and of normal and malignant intestinal cell cultures have allowed to assess biochemical and physiological properties of APC and its putative role in the genesis of colorectal carcinogenesis. Moreover, these experimental models have suggested a variety of possible therapeutic approaches.

At the present time more is known about barriers to transmission of infectious agents between species than barriers to transmission within the same species. However differences in resistance to infection have been well-established within given species of various plants and domestic farm animals. Unsurprisingly several similar mechanisms have been observed in humans. A well-known human example of genetic protection is resistance to malaria in endemic areas which has been associated with polymorphism in alpha and beta chain globulin genes, cytoskeleton proteins, and protein/receptors on the surface of red blood cells. Studies regarding infection by Schistosoma mansoni show that the extent of infection depends largely on each individual's intrinsic resistance under the control of a single major gene which has now been located on q31-33 locus of the long arm of chromosome 5. This locus harbors several genes involved in differentiation of auxiliary T lymphocytes. With regard to HIV infection it has been known for several years that a small but significant number of individuals are relatively resistant. This resistance has been attributed to deletion of the gene coding for the chemokine receptor used by the virus as a co-receptor to infect macrophage.

Among the cellular adhesion molecules, the integrin family, more particularly the VLA (Very late antigen) integrins, is currently the subject of numerous investigations in pathology. These integrins are involved in cell-cell contact or cell-matrix adhesions. During neoplastic diseases, cellular expression of integrins changes and a study of the modifications could allow a new etiopathogenic approach carcinogenesis and metastatic phenomena. New prognostic factors may be defined in tumor pathology. We describe the general structure of integrins and the mechanisms of their binding with matricial ligands and with cytoskeleton. The expression of VLA integrins and the alpha6beta4 heterodimer on normal and neoplastic human tissues is then described. Finally, we describe the involvement of these proteins in tumor progression and tissue invasion.

The essential function of the skin is that of a barriere against the outside. The epidermis is the tissue which assures the solidity and the resistance of the skin against forces of traction. The desmosomes, allowing the adhesion of epidermal cells, the keratinocytes, between them, are the structures of resistance of the epidermis. This adhesion function is possible thanks to the interactions between the desmosomial molecules and cytosqueletal filaments. Currently fifteen desmosomal proteins implicated in this process have been characterized. The role of desmosome in integrity of epidermis is demonstrated by the existence of the auto immune dermatosis, the pemphigus, in which the inflammatory reaction against desmosomal proteins results in the loss of the cohesion of keratinocytes.