[An illustrative case of the POEMS syndrome]. / Cas clinique. Un cas illustratif de POEMS syndrome.

POEMS syndrome is a rare and invalidating entity characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and dermatoses. The diagnosis of this condition is often late and challenging due to the heterogeneity of clinical forms. The light chains secreted by the clonal plasmocytes cause overproduction of VEGF (Vascular Endothelial Growth Factor) responsible for the appearance of the clinical manifestations of POEMS. The diagnostic approach is based on different clinical and biological criteria. Patients with a solitary plasmacytoma are candidates for radiotherapy treatment. Patients with diffuse bone involvement or bone marrow infiltration are best treated by systemic drugs. The response to treatment may take several months before clinical and biological improvement. Early diagnosis and dedicated management limit the clinico-functional impact of POEMS.

Le POEMS syndrome est une entité rare et invalidante caractérisée par une polyneuropathie, une organomégalie, une endocrinopathie, une gammapathie monoclonale et des atteintes dermatologiques. Le diagnostic de cette infection est souvent tardif et représente un véritable défi au vu de l'hétérogénéité des formes cliniques. Les chaînes légères sécrétées par les plasmocytes clonaux entraînent une surproduction de VEGF (Vascular Endothelial Growth Factor) responsable de la plupart des manifestations cliniques du POEMS. La démarche diagnostique repose, en pratique, sur des critères cliniques dont les principaux sont la polyneuropathie et la gammapathie monoclonale. Le bilan d'extension reprend le dosage du VEGF, l'électrophorèse et l'mmunofixation des protéines sériques. Un bilan radiologique permet d'objectiver des lésions osseuses ostéosclérotiques ou des adénopathies et l'électromyogramme la polyneuropathie. Les patients qui souffrent d'un plasmocytome en l'absence d'une infiltration médullaire de plasmocytes clonaux sont des candidats au traitement par radiothérapie. Les patients avec une atteinte osseuse diffuse ou une localisation médullaire recevront un traitement systémique. La réponse au traitement peut prendre plusieurs mois avant une amélioration clinique et biologique. Un diagnostic précoce et une prise en charge spécifique limitent l'impact clinico-fonctionnel du POEMS.

[Unilateral pigmentary retinopathy : about 2 cases]. / Le cas clinique du mois. Rétinopathie pigmentaire unilatérale.

We present the case of two patients in whom unilateral retinal involvement with pigmentary lesions on the fundus examination was observed. Apart from the unilateral nature of the lesions, a diagnosis of retinitis pigmentosa could have been made in view of the morphological and functional aspects of the retina. However, in these two clinical cases, an association between retinal lesions and Bartonella in one case, and pre-existing multiple sclerosis in the other case, has been proposed with a final diagnosis of unilateral pigmentary retinopathy. Nevertheless, a sufficiently long period of patient follow-up is necessary to rule out delayed onset in the unaffected eye, suggesting an asymmetrical bilateral retinitis pigmentosa.

Nous présentons le cas de deux patientes chez qui une atteinte rétinienne unilatérale comportant des lésions pigmentaires à l'examen du fond de l'œil a été observée. Malgré le caractère unilatéral des lésions, un diagnostic de rétinite pigmentaire d'origine génétique aurait pu être évoqué au vu des aspects morphologiques et fonctionnels de la rétine. Cependant, une origine infectieuse (infection à Bartonella) a pu être proposée pour un cas, alors que, pour l'autre cas, une atteinte inflammatoire secondaire à une sclérose en plaques a été retenue. Pour cette raison, le diagnostic final est celui d'une rétinopathie pigmentaire unilatérale. Néanmoins, un suivi à long terme est obligatoire de façon à écarter une apparition retardée des lésions dans l'œil indemne, ce qui pourrait indiquer la présence d'une rétinite pigmentaire bilatérale asymétrique.

Efficacy of an agonist of α-MSH, the palmitoyl tetrapeptide-20, in hair pigmentation.

OBJECTIVE: Hair greying (i.e., canities) is a component of chronological ageing and occurs regardless of gender or ethnicity. Canities is directly linked to the loss of melanin and increase in oxidative stress in the hair follicle and shaft. To promote hair pigmentation and reduce the hair greying process, an agonist of α-melanocyte-stimulating hormone (α-MSH), a biomimetic peptide (palmitoyl tetrapeptide-20; PTP20) was developed. The aim of this study was to describe the effects of the designed peptide on hair greying. METHODS: Effect of the PTP20 on the enzymatic activity of catalase and the production of H2 O2 by Human Follicle Dermal Papilla Cells (HFDPC) was evaluated. Influence of PTP20 on the expression of melanocortin receptor-1 (MC1-R) and the production of melanin were investigated. Enzymatic activity of sirtuin 1 (SIRT1) after treatment with PTP20 was also determined. Ex vivo studies using human micro-dissected hairs allowed to visualize the effect of PTP20 on the expression in hair follicle of catalase, TRP-1, TRP-2, Melan-A, ASIP, and MC1-R. These investigations were completed by a clinical study on 15 human male volunteers suffering from premature canities. RESULTS: The in vitro and ex vivo studies revealed the capacity of the examined PTP20 peptide to enhance the expression of catalase and to decrease (30%) the intracellular level of H2 O2 . Moreover, PTP20 was shown to activate in vitro and ex vivo the melanogenesis process. In fact, an increase in the production of melanin was shown to be correlated with elevated expression of MC1-R, TRP-1, and Melan-A, and with the reduction in ASIP expression. A modulation on TRP-2 was also observed. The pivotal role of MC1-R was confirmed on protein expression analysed on volunteer's plucked hairs after 3 months of the daily application of lotion containing 10 ppm of PTP20 peptide. CONCLUSION: The current findings demonstrate the ability of the biomimetic PTP20 peptide to preserve the function of follicular melanocytes. The present results suggest potential cosmetic application of this newly designed agonist of α-MSH to promote hair pigmentation and thus, reduce the hair greying process.

[Ocular vascular pathologies : keep an eye open!] / Les pathologies vasculaires oculaires : ouvrez l'œil !

Vascular ocular pathologies are common and usually diagnosed in the emergency department by the ophtalmologist. However, it is very important for the physicians and the general practitioners to know these different diseases for improving the visual and vital prognosis. This paper describes the most important ocular and cerebrovascular pathologies.

Les pathologies vasculaires oculaires sont fréquentes et leur diagnostic est souvent posé aux urgences ophtalmologiques. Néanmoins, pour les médecins traitants et les médecins spécialistes, il est important de les reconnaitre afin d'améliorer le pronostic visuel et vital du patient. Cet article décrit les pathologies vasculaires oculaires et cérébrovasculaires les plus importantes.

[Vogt-Koyanagi-Harada syndrome]. / Le syndrome de Vogt-Koyanagi-Harada.

We present the case of a patient who had a decrease of the visual acuity associated with headaches, diagnosed as vogt-koyanagi-harada syndrome. This is a rare multisystemic pathology that affects organs with high concentration of melanocytes. This syndrome needs to be identified on time as corticotherapy has to be administrated urgently. This paper also summarizes the literature on this disease.

Nous présentons le cas d'une patiente souffrant d'une baisse d'acuité visuelle associée à des céphalées. L'investigation a permis de mettre en évidence un syndrome de vogt-koyanagi-harada. Il s'agit d'une pathologie multi-systémique rare, affectant les organes présentant une haute concentration de mélanocytes. Il est important d'en poser rapidement le diagnostic pour administrer une corticothérapie. L'étude de ce cas est complétée par une revue de la littérature sur le sujet.

The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia.

Recurrent chromosomal abnormalities and gene mutations detected at the time of diagnosis of acute myeloid leukemia (AML) are associated with particular disease features, treatment response and survival of AML patients, and are used to denote specific disease entities in the World Health Organization classification of myeloid neoplasms and acute leukemia. However, large studies that integrate cytogenetic and comprehensive mutational information are scarce. We created a comprehensive oncoprint of mutations associated with recurrent cytogenetic findings by combining the information on mutational patterns of 80 cancer- and leukemia-associated genes with cytogenetic findings in 1603 adult patients with de novo AML. We show unique differences in the mutational profiles among major cytogenetic subsets, identify novel associations between recurrent cytogenetic abnormalities and both specific gene mutations and gene functional groups, and reveal differences in cytogenetic and mutational features between patients younger than 60 years and those aged 60 years or older. The identified associations between cytogenetic and molecular genetic data may help guide mutation testing in AML, and result in more focused application of targeted therapy in patients with de novo AML.

Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia.

Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a 'second hit' to initiate leukemogenesis. Mutation assessment of 177 adults with CBF-AML, including 68 with t(8;21) and 109 with inv(16)/t(16;16), identified not only mutations well known in CBF-AML but also mutations in the CCND1 and CCND2 genes, which represent novel frequent molecular alterations in AML with t(8;21). Altogether, CCND1 (n=2) and CCND2 (n=8) mutations were detected in 10 (15%) patients with t(8;21) in our cohort. A single CCND2 mutation was also found in 1 (0.9%) patient with inv(16). In contrast, CCND1 and CCND2 mutations were detected in only 11 (0.77%) of 1426 non-CBF-AML patients. All CCND2 mutations cluster around the highly conserved amino-acid residue threonine 280 (Thr280). We show that Thr280Ala-mutated CCND2 leads to increased phosphorylation of the retinoblastoma protein, thereby causing significant cell cycle changes and increased proliferation of AML cell lines. The identification of CCND1 and CCND2 mutations as frequent mutational events in t(8;21) AML may provide further justification for cell cycle-directed therapy in this disease.

Crystal Structures of Group B Streptococcus Glyceraldehyde-3-Phosphate Dehydrogenase: Apo-Form, Binary and Ternary Complexes.

Glyceraldehyde 3-phosphate dehydrogenase or GAPDH is an evolutionarily conserved glycolytic enzyme. It catalyzes the two step oxidative phosphorylation of D-glyceraldehyde 3-phosphate into 1,3-bisphosphoglycerate using inorganic phosphate and NAD+ as cofactor. GAPDH of Group B Streptococcus is a major virulence factor and a potential vaccine candidate. Moreover, since GAPDH activity is essential for bacterial growth it may serve as a possible drug target. Crystal structures of Group B Streptococcus GAPDH in the apo-form, two different binary complexes and the ternary complex are described here. The two binary complexes contained NAD+ bound to 2 (mixed-holo) or 4 (holo) subunits of the tetrameric protein. The structure of the mixed-holo complex reveals the effects of NAD+ binding on the conformation of the protein. In the ternary complex, the phosphate group of the substrate was bound to the new Pi site in all four subunits. Comparison with the structure of human GAPDH showed several differences near the adenosyl binding pocket in Group B Streptococcus GAPDH. The structures also reveal at least three surface-exposed areas that differ in amino acid sequence compared to the corresponding areas of human GAPDH.

Heterogeneous distribution in sediments and dispersal in waters of Alexandrium minutum in a semi-enclosed coastal ecosystem.

Within the framework of research aimed at using genetic methods to evaluate harmful species distribution and their impact on coastal ecosystems, a portion of the ITS1rDNA of Alexandrium minutum was amplified by real-time PCR from DNA extracts of superficial (1-3cm) sediments of 30 subtidal and intertidal stations of the Bay of Brest (Brittany, France), during the winters of 2013 and 2015. Cell germinations and rDNA amplifications of A. minutum were obtained for sediments of all sampled stations, demonstrating that the whole bay is currently contaminated by this toxic species. Coherent estimations of ITS1rDNA copy numbers were obtained for the two sampling cruises, supporting the hypothesis of regular accumulation of A. minutum resting stages in the south-eastern, more confined embayments of the study area, where fine-muddy sediments are also more abundant. Higher ITS1rDNA copy numbers were detected in sediments of areas where blooms have been seasonally detected since 2012. This result suggests that specific genetic material estimations in superficial sediments of the bay may be a proxy of the cyst banks of A. minutum. The simulation of particle trajectory analyses by a Lagrangian physical model showed that blooms occurring in the south-eastern part of the bay are disconnected from those of the north-eastern zone. The heterogeneous distribution of A. minutum inferred from both water and sediment suggests the existence of potential barriers for the dispersal of this species in the Bay of Brest and encourages finer analyses at the population level for this species within semi-enclosed coastal ecosystems.

[Posterior scleritis]. / La sclérite postérieure : cas clinique.

Posterior scleritis, a severe and painful inflammation of the sclera, is an often misdiagnosed pathology due to its clinical polymorphism. An accurate diagnosis is however needed in order to propose an appropriate treatment of the ophthalmologic symptoms and to exclude an associated systemic inflammatory or auto-immune pathology.

La sclérite postérieure est une inflammation sévère et douloureuse localisée au niveau de la sclère. Cette pathologie méconnue est souvent sous-diagnostiquée en raison de son polymorphisme clinique. Il est néanmoins important de la reconnaître de façon à proposer un traitement adéquat des symptômes oculaires et de rechercher les différentes pathologies systémiques inflammatoires ou auto-immunes pouvant lui être associées.

Structure of Streptococcus agalactiae glyceraldehyde-3-phosphate dehydrogenase holoenzyme reveals a novel surface.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a conserved cytosolic enzyme, which plays a key role in glycolysis. GAPDH catalyzes the oxidative phosphorylation of D-glyceraldehyde 3-phosphate using NAD or NADP as a cofactor. In addition, GAPDH localized on the surface of some bacteria is thought to be involved in macromolecular interactions and bacterial pathogenesis. GAPDH on the surface of group B streptococcus (GBS) enhances bacterial virulence and is a potential vaccine candidate. Here, the crystal structure of GBS GAPDH from Streptococcus agalactiae in complex with NAD is reported at 2.46 Šresolution. Although the overall structure of GBS GAPDH is very similar to those of other GAPDHs, the crystal structure reveals a significant difference in the area spanning residues 294-307, which appears to be more acidic. The amino-acid sequence of this region of GBS GAPDH is also distinct compared with other GAPDHs. This region therefore may be of interest as an immunogen for vaccine development.

MicroRNA-related sequence variations in human cancers.

MicroRNAs are emerging as a most promising field in basic and translational research, explaining the pathogenesis of numerous human diseases and providing excellent tools for their management. This review considers the effects of microRNA sequence variations and their implication in pathogenesis and predisposition to human cancers. Although the role of microRNAs still remains to be elucidated, functional, and populational studies indicate that microRNA variants are important factors underlying the process of carcinogenesis. Further understanding of the cellular and molecular basis of microRNA action will lead to the identification of their new target genes and microRNA-regulated pathways. As a consequence, novel models of cancer pathogenesis can be proposed, and serve as a basis for elucidation of new prognostic and diagnostic tools for human cancers.

The regulatory role of the tetrapeptide AcSDKP in skin and hair physiology and the prevention of ageing effects in these tissues--a potential cosmetic role.

The naturally occurring tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) recognized as a potent angiogenic factor was shown recently to contribute to the repair of cutaneous injuries. In the current article, we report the ability of AcSDKP to exert a beneficial effect on normal healthy skin and scalp and to compensate for the ageing process. In vitro AcSDKP at 10⁻¹¹-10⁻7 M significantly stimulates the growth of human keratinocytes, fibroblasts and follicle dermal papilla cells. Moreover, it enhances the growth of human epidermal keratinocyte progenitor and stem cells as shown in a clonogenic survival assay. Topical treatment of ex vivo cultured skin explants with 10⁻5 M AcSDKP increases the thickness of the epidermis and upregulates the synthesis of keratins 14 and 19, fibronectin, collagen III and IV as well as the glycoaminoglycans (GAGs). In the ex vivo-cultured hair follicles, AcSDKP promotes hair shaft elongation and induces morphological and molecular modifications matching the criteria of hair growth. Furthermore, AcSDKP at 10⁻¹¹-10⁻7 M was shown to improve epidermal barrier, stimulating expression of three protein components of tight junctions (claudin-1, occludin, ZO-1) playing an important role in connecting neighbouring cells. This tetrapeptide exercises also activation of SIRT1 implicated in the control of cell longevity. Indeed, a two-fold increase in the synthesis of SIRT1 by cultured keratinocytes was observed in the presence of 10⁻¹¹-10⁻7 M AcSDKP. In conclusion, these findings provide convincing evidence of the regulatory role of AcSDKP in skin and hair physiology and suggest a cosmetic use of this natural tetrapeptide to prevent skin ageing and hair loss and to promote the cutaneous regeneration and hair growth.

Recurrent and founder mutations in the PMS2 gene.

Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.

Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene.

Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene.

The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is the second most frequent cancer in developed countries. Newfoundland has the highest incidence of CRC in Canada and the highest rate of familial CRC yet reported in the world. To determine the impact of mutations in known CRC susceptibility genes and the contribution of the known pathways to the development of hereditary CRC, an incident cohort of 750 patients with CRC (708 different families) from the Newfoundland population was studied. METHODS: Microsatellite instability (MSI) testing was performed on tumours, together with immunohistochemistry analysis for mismatch repair (MMR) genes. Where indicated, DNA sequencing and multiplex ligation-dependent probe amplifications of MMR genes and APC was undertaken. DNA from all patients was screened for MUTYH mutations. The presence of the BRAF variant, p.V600E, and of MLH1 promoter methylation was also tested in tumours. RESULTS: 4.6% of patients fulfilled the Amsterdam criteria (AC), and an additional 44.6% fulfilled the revised Bethesda criteria. MSI-high (MSI-H) was observed in 10.7% (n=78) of 732 tumours. In 3.6% (n=27) of patients, CRC was attributed to 12 different inherited mutations in six known CRC-related genes associated with chromosomal instability or MSI pathways. Seven patients (0.9%) carried a mutation in APC or biallelic mutations in MUTYH. Of 20 patients (2.7%) with mutations in MMR genes, 14 (70%) had one of two MSH2 founder mutations. 17 of 28 (61%) AC families did not have a genetic cause identified, of which 15 kindreds fulfilled the criteria for familial CRC type X (FCCTX). CONCLUSIONS: Founder mutations accounted for only 2.1% of cases and this was insufficient to explain the high rate of familial CRC. Many of the families classified as FCCTX may have highly penetrant mutations segregating in a Mendelian-like manner. These families will be important for identifying additional CRC susceptibility loci.

Genetic predisposition to human disease: allele-specific expression and low-penetrance regulatory loci.

The two alleles of a gene can be expressed at different levels, the extreme example being imprinting, a condition in which one allele is totally suppressed. Recently, subtle differences in the expression of the two alleles have been detected in numerous human genes and in a few cases, have been associated with a genetic predisposition to disease. The underlying mechanisms are largely unexplored.

A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia.

BACKGROUND: Mutations in the sulfate transporter gene SLC26A2 (DTDST) cause a continuum of skeletal dysplasia phenotypes that includes achondrogenesis type 1B (ACG1B), atelosteogenesis type 2 (AO2), diastrophic dysplasia (DTD), and recessive multiple epiphyseal dysplasia (rMED). In 1972, de la Chapelle et al reported two siblings with a lethal skeletal dysplasia, which was denoted "neonatal osseous dysplasia" and "de la Chapelle dysplasia" (DLCD). It was suggested that DLCD might be part of the SLC26A2 spectrum of phenotypes, both because of the Finnish origin of the original family and of radiographic similarities to ACG1B and AO2. OBJECTIVE: To test the hypothesis whether SLC26A2 mutations are responsible for DLCD. METHODS: We studied the DNA from the original DLCD family and from seven Finnish DTD patients in whom we had identified only one copy of IVS1+2T>C, the common Finnish mutation. A novel SLC26A2 mutation was found in all subjects, inserted by site-directed mutagenesis in a vector harbouring the SLC26A2 cDNA, and expressed in sulfate transport deficient Chinese hamster ovary (CHO) cells to measure sulfate uptake activity. RESULTS: We identified a hitherto undescribed SLC26A2 mutation, T512K, homozygous in the affected subjects and heterozygous in both parents and in the unaffected sister. T512K was then identified as second pathogenic allele in the seven Finnish DTD subjects. Expression studies confirmed pathogenicity. CONCLUSIONS: DLCD is indeed allelic to the other SLC26A2 disorders. T512K is a second rare "Finnish" mutation that results in DLCD at homozygosity and in DTD when compounded with the milder, common Finnish mutation.