Exploring the genetic causes of isolated short stature. What has happened to idiopathic short stature?

Statural growth is underpinned by development of the growth plate during the process of endochondral ossification, which is strongly regulated by numerous local factors (intracellular, paracrine and extracellular matrix factors) and systemic factors (nutrition, hormones, proinflammatory cytokines and extracellular fluids). This explains why growth retardation can be associated with numerous pathologies, particularly genetic syndromes, hormonal or inflammatory conditions, or gastrointestinal disorders having a nutritional impact. However, in most cases (80%), no specific aetiology is found after clinical investigation and conventional additional tests have been carried out. In such cases, "idiopathic" short stature is diagnosed, which includes patients presenting with constitutional delay of growth and development and familial short stature, but also patients with very subtle constitutional skeletal dysplasia which are not easily identifiable. In recent years, new methods of genetic investigation (e.g. gene panels, exome or genome sequencing) have made it possible to identify many genetic variants associated with apparently isolated short stature. Indeed, it is still difficult to estimate the proportion of patients presenting with idiopathic short stature for which a molecular diagnosis of monogenic conditions could be made. This estimate varies hugely depending on the thoroughness of the clinical, laboratory and radiological assessments performed prior to molecular analysis, since retrospective analysis of positive cases usually reveals subtle signs of underlying syndromes or rare skeletal disorders. Molecular diagnosis in children is important to be able to offer genetic counselling and to organise patient management. Moreover, improved understanding of the molecular basis of these cases of short stature opens up numerous possibilities for more specific treatments targeting the growth plate. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

The autoinflammatory diseases: a fashion with blurred boundaries!

Monogenic autoinflammatory diseases are defined as a group of conditions with a clinical and biological inflammatory syndrome but little or no evidence of autoimmunity. Over 17 years have passed since the discovery of the first autoinflammatory gene, MEFV, responsible for familial Mediterranean fever. Substantive progress has been made since then, highlighting the key role of the inflammasome in the maintenance of the cell homeostasis but also unravelling new pathophysiological pathways involved in these diseases. The history of autoinflammatory gene discovery demonstrates the powerfulness of next-generation sequencing approaches in linking inflammatory disorders with various overlapping phenotypes. It can be easily anticipated that new genes will be exponentially identified in the coming years. Integrating these new concepts should help to promote personalized patient care through novel therapeutic opportunities.

[Kabuki syndrome: Update and review]. / Le syndrome Kabuki : mise au point et revue de la littérature.

Kabuki syndrome (OMIM: 147920) is a rare condition, mainly associating intellectual deficiency, a polymalformative syndrome, and specific morphological changes in the face. It nevertheless has a strong clinical and biological heterogeneity with rarer but very different symptoms (endocrinological anomalies, autoimmune disorders, obesity, etc.). Clinical diagnosis is difficult because it is based on a spectrum of clinical, radiological, and biological factors. Complications are numerous, sometimes interpenetrating, and early diagnosis of the disease is essential for optimal management. The development of genetic testing is therefore essential for the diagnosis of this disease. Recently, exome sequencing has helped identify two genes responsible for the disease: KMT2D (lysine (K)-specific methyltransferase 2D, better known as MLL2 - mixed lineage leukemia), and KDM6A (lysine-specific demethylase 6A). Functional studies of these genes should help clarify their role in the pathogenesis of the disease, in particular to test the hypothesis of epigenetic changes during embryogenesis and development. Finally, understanding the interactions between KMT2D and its target genes could unravel other candidate genes for hitherto unexplained Kabuki syndrome cases.

[Neurobrucellosis: description of 5 cases in Setif Hospital, Algeria]. / Neurobrucellose: 5 observations à l'hôpital de Sétif, Algérie.

PURPOSE: Brucellosis is a major ubiquitous zoonosis transmitted from livestock to humans. It is a public health problem in developing countries. Between 2003 and 2005, the incidence of brucellosis in Algeria showed a 181% increase from 8.79 to 24.71. Between 2005 and 2007, the incidence remained almost stable. The estimated mean incidence of neurobrucellosis is 4% with clinical manifestations that are variable and often multi-focal in the same patient. The purpose of this retrospective study is to describe 5 cases of neurobrucellosis managed in our department between 2001 and 2007. MATERIALS AND METHODS: It was a retrospective study 5 patients. There were 2 women and 3 men with a mean age of 20 years. RESULTS: Neurological involvement occurred immediately in all patients. Clinical manifestations were variable with meningoencephalitis in 2, meningoencephalitis associated with a polyperipheral neuropathy in 1, meningomyeloradiculitis in 1, and acute diffuse encephalitis in 1. Definitive diagnosis was based on isolation of bacteria from a blood specimen in 1 case and detection of antibodies in blood and cerebrospinal fluid in 4. All patients were treated using a combination of 3 of the following 4 drugs: doxycycline, rifampicine, cotrimoxazole and aminoside. Treatment was associated with corticosteroid therapy in 3 cases. DISCUSSION: Neurobrucellosis can affect any part of the nervous system and can mimic any neurological disease. Early detection and treatment is the only predictor of favorable outcome of neurobrucellosis, but there is no standardized treatment protocol. Neurobrucellosis should be included in differential diagnosis for any patient presenting central or peripheral neurological manifestations especially in endemic zones.

Dynamic sorption of ionizable organic compounds (IOCs) and xylene from water using geomaterial-modified montmorillonite.

Adsorption of phenols and xylene onto composite material, Na-montmorillonite, activated carbon, cement and water mixture, 70%, 7%, 7% and 16% (w/w/w/w), respectively, was studied at pH values of 5.15, 4.55, 5.2 and 4.9, respectively, of phenol, 2-CP, 2-NP and xylene. Equilibrium isotherms and fixed-bed column studies were undertaken to evaluate the performance of clay-active coal-coated cement (CACC) in removing phenols from aqueous solution. Investigations revealed CACC to be a very efficient media for the removal of phenols from water. The suitability of the Langmuir adsorption model to the equilibrium data was investigated for all phenols-adsorbent systems. At the maximum sorption capacity of the composite material it was found that the uptake (mg phenols/g) of phenols increased in the order 2-CP>2-NP>phenol approximately m-xylene as do their solubilities. The LUB design approach was used to determine the equivalent length of unused bed. The lower LUB values imply a better utilization of CACC composite. A model, which considered the effect of axial dispersion, was successfully used to describe the fixed-bed operation, the axial dispersion coefficient increased significantly with solubility.

Gene expression profiling of Spodoptera frugiperda hemocytes and fat body using cDNA microarray reveals polydnavirus-associated variations in lepidopteran host genes transcript levels.

BACKGROUND: Genomic approaches provide unique opportunities to study interactions of insects with their pathogens. We developed a cDNA microarray to analyze the gene transcription profile of the lepidopteran pest Spodoptera frugiperda in response to injection of the polydnavirus HdIV associated with the ichneumonid wasp Hyposoter didymator. Polydnaviruses are associated with parasitic ichneumonoid wasps and are required for their development within the lepidopteran host, in which they act as potent immunosuppressive pathogens. In this study, we analyzed transcriptional variations in the two main effectors of the insect immune response, the hemocytes and the fat body, after injection of filter-purified HdIV. RESULTS: Results show that 24 hours post-injection, about 4% of the 1750 arrayed host genes display changes in their transcript levels with a large proportion (76%) showing a decrease. As a comparison, in S. frugiperda fat body, after injection of the pathogenic JcDNV densovirus, 8 genes display significant changes in their transcript level. They differ from the 7 affected by HdIV and, as opposed to HdIV injection, are all up-regulated. Interestingly, several of the genes that are modulated by HdIV injection have been shown to be involved in lepidopteran innate immunity. Levels of transcripts related to calreticulin, prophenoloxidase-activating enzyme, immulectin-2 and a novel lepidopteran scavenger receptor are decreased in hemocytes of HdIV-injected caterpillars. This was confirmed by quantitative RT-PCR analysis but not observed after injection of heat-inactivated HdIV. Conversely, an increased level of transcripts was found for a galactose-binding lectin and, surprisingly, for the prophenoloxidase subunits. The results obtained suggest that HdIV injection affects transcript levels of genes encoding different components of the host immune response (non-self recognition, humoral and cellular responses). CONCLUSION: This analysis of the host-polydnavirus interactions by a microarray approach indicates that the presence of HdIV induces, directly or indirectly, variations in transcript levels of specific host genes, changes that could be responsible in part for the alterations observed in the parasitized host physiology. Development of such global approaches will allow a better understanding of the strategies employed by parasites to manipulate their host physiology, and will permit the identification of potential targets of the immunosuppressive polydnaviruses.

Members of the Hyposoter didymator Ichnovirus repeat element gene family are differentially expressed in Spodoptera frugiperda.

BACKGROUND: The abundance and the conservation of the repeated element (rep) genes in Ichnoviruses genomes suggest that this gene family plays an important role in viral cycles. In the Ichnovirus associated with the wasp Hyposoter didymator, named HdIV, 10 rep genes were identified to date. In this work, we report a relative quantitative transcription study of these HdIV rep genes in several tissues of the lepidopteran host Spodoptera frugiperda as well as in the H. didymator wasps. RESULTS: The data obtained in this work indicate that, in the early phases of infection (24 hours), HdIV rep genes each display different levels of transcripts in parasitized 2nd instar or HdIV-injected last instar S. frugiperda larvae. Only one, rep1, is significantly transcribed in female wasps. Transcript levels of the HdIV rep genes were found as not correlated to their copy number in HdIV genome. Our results also show that HdIV rep genes display different tissue specificity, and that they are primarily transcribed in S. frugiperda fat body and cuticular epithelium. CONCLUSION: This work is the first quantitative analysis of transcription of the ichnovirus rep gene family, and the first investigation on a correlation between transcript levels and gene copy numbers in Ichnoviruses. Our data indicate that, despite similar gene copy numbers, not all the members of this gene family are significantly transcribed 24 hours after infection in lepidopteran larvae. Additionally, our data show that, as opposed to other described HdIV genes, rep genes are little transcribed in hemocytes, thus suggesting that they are not directly associated with the disruption of the immune response but rather involved in other physiological alterations of the infected lepidopteran larva.

Removal of sulfacid brilliant pink from an aqueous stream by adsorption onto surfactant-modified Ti-pillared montmorillonite.

A modified hydrophobic and organophilic pillared clay (CTAC-TiH-montm) was prepared by exchanging some Ti polymeric cations into the interlamellar space of one Algerian montmorillonite (montm) and then by co-adsorption of some surfactant molecules such as cetyltrimethylammonium chloride (CTAC). These new materials were used in adsorption of an anionic textile dye: Sulfacid brilliant pink (SAP). According to adsorption isotherms, the organic modification of Ti-montmorillonite clay by CTAC surfactant increases the amount of textile dye fixed to more than 1000 mg g(-1). The adsorption experiments showed that a ratio of 3 mmol of CTAC per g of clay and an acidic medium (pH = 4) were the optimal parameters necessary to obtain good adsorption uptake and colourless treated solutions. A comparative study proved the high adsorption capacity of the synthesised adsorbents; they can thus be considered as powerful competitors to activated carbon in the treatment of aqueous textile plants and industry effluents.

Using of surfactant modified Fe-pillared bentonite for the removal of pentachlorophenol from aqueous stream.

The first part of this work considers the preparing of the adsorbent type Montm-FeOH-CTAC. After purification of two types Algerian bentonites (Maghnia and Mostaghanem) and preparation of cationic polyhydroxy ferric solution, we have optimized following parameters: CTAC/Montm.-FeOH = 7 mmol.g-1 and pH = 3.4, in order to obtain the adsorbent with maximum uptake of PCP. The study of the different experimental equilibrium isotherms showed clearly the high efficiency of these new adsorbents toward PCP, with significant quantities adsorbed especially onto Maghnia samples in acidic environment. Using two mathematical models Langmuir and Freundlich was found to be the Freundlich the best fitted. A comparative study of PCP adsorption onto the two modified clays and an activated carbon in the same conditions has been done.

Linkage and association studies between the proopiomelanocortin (POMC) gene and obesity in caucasian families.

AIMS/HYPOTHESIS: The region 2p21-23, containing the proopiomelanocortin gene (POMC), was reported to be linked to leptin concentrations in Mexican-American, French and African-American cohorts. A polyhormone peptide, POMC is expressed in brain, gut, placenta and pancreas. The POMC mutations are responsible for rare cases of early-onset obesity. Thus we examined the contribution of the POMC locus to obesity in French families. METHODS: Single and multipoint linkage studies were done between obesity, obesity associated-phenotypes (leptin values and z-score of the body mass index) and three newly mapped markers surrounding POMC in 264 affected sib-pairs from French obese families. Mutation screening of the exons and intron/exon junctions of the POMC gene was realised by direct sequencing. Association studies were done in 379 unrelated obese patients and 370 non-obese non-diabetic subjects. RESULTS: Linkage analysis confirmed the trend towards linkage between polymorphic markers around POMC and variations of leptin concentrations and z-score (maximum lod score at D2S2337 = 2.03). Mutation screening of the POMC gene in the French Caucasian cohort identified two previously reported polymorphisms. None of these variants was associated with obesity, diabetes or serum leptin and lipid concentrations. CONCLUSION/INTERPRETATION: Our results indicate that mutations in the POMC gene do not contribute to the variance of obesity associated phenotypes, at least in French Caucasians. Given the replicated evidence of linkage between leptin values and the chromosome 2p21-23 region in different populations, it is likely that functional variant(s) in the POMC regulating sequences or in an unknown gene in this region explains this linkage.

A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10.

Obesity, a common multifactorial disorder, is a major risk factor for type 2 diabetes, hypertension and coronary heart disease (CHD). According to the definition of the World Health Organization (WHO), approximately 6-10% of the population in Westernized countries are considered obese. Epidemiological studies have shown that 30-70% of the variation in body weight may be attributable to genetic factors. To date, two genome-wide scans using different obesity-related quantitative traits have provided candidate regions for obesity. We have undertaken a genome-wide scan in affected sibpairs to identify chromosomal regions linked to obesity in a collection of French families. Model-free multipoint linkage analyses revealed evidence for linkage to a region on chromosome 10p (MLS=4.85). Two further loci on chromosomes 5cen-q and 2p showed suggestive evidence for linkage of serum leptin levels in a genome-wide context. The peak on chromosome 2 coincided with the region containing the gene (POMC) encoding pro-opiomelanocortin, a locus previously linked to leptin levels and fat mass in a Mexican-American population and shown to be mutated in obese humans. Our results suggest that there is a major gene on chromosome 10p implicated in the development of human obesity, and the existence of two further loci influencing leptin levels.