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Noonan syndrome [NS; Mendelian Inheritance in Men (MIM) #163950] and related syndromes [Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome; MIM #151100), Noonan-like syndrome with loose anagen hair (MIM #607721), Costello syndrome (MIM #218040), cardio-facio-cutaneous syndrome (MIM #115150), type I neurofibromatosis (MIM #162200), and Legius syndrome (MIM #611431)] are a group of related genetic disorders associated with distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was clinically described more than 50 years ago, and disease genes have been identified throughout the last 3 decades, providing a molecular basis to better understand their physiopathology and identify targets for therapeutic strategies. Most of these genes encode proteins belonging to or regulating the so-called RAS/MAPK signaling pathway, so these syndromes have been gathered under the name RASopathies. In this review, we provide a clinical overview of RASopathies and an update on their genetics. We then focus on the functional and pathophysiological effects of RASopathy-causing mutations and discuss therapeutic perspectives and future directions.

Context:LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism.Objective:The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4.Design and Patients:We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants.Results:We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant.Conclusion:This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.

Background Mutation in the FBN1 gene was common in the Marfan syndrome (MFS), and caused aortic dilatation that could be delayed by beta-blocker therapy. Aims This study evaluated the effect of beta-blockers therapy on aortic dilatation in the MFS patients with subtypes of FBN1 gene mutation. Methods A single center observational prospective study included 53 MFS patients less than 20-years-old with predicting-happlo insufficiency (PTC) or dominant-negative (DN) mutation of FBN1 gene. Among 41 patients used beta-blockers therapy, aortic diameter and aortic dilatation rate were evaluated by echocardiography. Results At the baseline, dimension of aortic sinus of Valsalva of PTC-MFS patients and DN-MFS patients were in the upper bound of normal range (Z-score: 1.76 ± 1.25 vs. 1.69 ± 0.87, P = 0.621, respectively). While, dimension of ascending aorta was in the normal range. After a mean follow-up 1.5 ± 0.71 years with beta-blockers therapy, the dilatation rate at aortic sinus of Valsalva decreased [PTC-MFS: −0.28 ± 0.85 mm/m2.year (95% CI: −0.82; 0.26) vs. DN-MFS: −0.32 ± 1.34 mm/m2.year (95% CI: −0.91; 1.34), P = 0.069]. The dilatation rate at ascending aorta decreased in PTC-MFS patients [−0.18 ± 1.19 mm/m2.year (95% CI: −0.96; 0.61)] and increased in DN-MFS patients [0.4 ± 1.82 mm/m2.year (95% CI: −0.43; 1.23)], P = 0.554. Conclusion Among the FBN1-MFS patients, beta-blockers therapy was effective to reduce the aortic dilatation rate, of which difference between PTC-MFS patients and DN-MFS patients was not significant.

Background Mutation of the fibrillin 1 (FBN1) gene was common in the Marfan syndrome (MFS) leading to aortic dilatation. Purpose This study aimed to evaluate the effect of beta-blocker therapy on aortic dilatation in the MFS patients with subtypes of FBN1 gene mutation. Methods An observational prospective study included 67 MFS patients with predicting-happloinsufficiency (PTC) or dominant-negative (DN) mutation of FBN1 gene who were followed up at 2.8 ± 1.8 years. Aortic diameters and the rate of aortic dilatation were evaluated by echocardiography. Results At the baseline, dimension of aortic sinus of Valsalva of PTC-MFS patients and DN-MFS patients were in the upper bound of normal-range [Z score: 2.3 ± 1.82 (95% CI: 1.69; 2.91) vs. 2.67 ± 1.58 (95% CI: 2.02; 3.32), respectively, P > 0.05]. While, dimension of ascending aorta of DN-MFS patients were in the upper bound of normal range and was higher than PTC-MFS patients [Z score: 2.8 ± 2.16 (95% CI: 2.05; 3.55) vs. 1.69 ± 2.32 (95% CI: 0.66; 2.72), respectively, P > 0.05]. With the beta-blocker therapy, the rate of aortic dilatation was delayed: at aortic sinus of Valsalva in PTC-MFS patients as 0.27 ± 0.69 mm/m2.year (95% CI: −0.19; 0.73) was higher than in DN-MFS patients as 0.05 ± 2.78 mm/m2.year (95% CI: −1.43; 1.54), P > 0.05; and at ascending aorta in PTC-MFS patients as 0.37 ± 0.93 mm/m2.year (95% CI: −0.35; 1.08) was lower than in DN-MFS patients as 1.65 ± 2.75 mm/m2.year (95% CI: −0.1; 3.4), P > 0.05. Conclusion With beta-blocker therapy, the rate of aortic dilatation for FBN1-MFS patients was delayed and not significantly different between subtypes of FBN1 gene mutation.

IF 5.451; International audience; Background Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation.Objectives Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases.Methods and results In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands.Conclusion Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.

BackgroundGrowth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified.ObjectiveThe goal of this study was to compare growth parameters according to genotype in patients with NS.Subjects and methodsThe study population included 420 patients (176 females and 244 males) harboring mutations in thePTPN11,SOS1,RAF1, orKRASgenes. NS-associatedPTPN11mutations (NS-PTPN11) and NS with multiple lentigines-associatedPTPN11mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes.ResultsPatients with NS were shorter at birth (mean birth length standard deviation score (SDS): –1.0 ± 1.4;P< 0.001) and throughout childhood than the healthy population, with height SDS being –2.1 ± 1.3 at 2 years, and –2.1 ± 1.2 at 5 and 10 years and adulthood (P< 0.001). At birth, patients withNS-PTPN11were significantly shorter and thinner than patients withNSML-PTPN11,SOS1, orKRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients withNSML-PTPN11andSOS1than in patients withNS-PTPN11(P< 0.001 andP= 0.002 respectively). Patients with NS had lower BMI at 10 years (P< 0.001). No difference between genotypes was demonstrated.ConclusionDetermining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients.

Puberty is a series of biological events that lead to sexual maturity. The first event is the initiation of pulsatile GnRH secretion from the hypothalamus. Physiological variability and multiple factors influence onset of puberty: ethnic, genetic, nutritional and environmental factors. We observe a secular trends of puberty in industrialized countries, but menarche is stabilized at 12 ½ years in these countries since 30 to 40 years

Background:Several studies suggest that 24,25-dihydroxyvitamin D [24,25(OH)2D] may have an effect on bone mass and metabolism.Objective:We evaluated the relationship between serum 24,25(OH)2D levels and bone density and bone metabolism in children with a primary bone disorder—osteogenesis imperfecta (OI).Materials and Methods:The study included 132 patients (age, 1.1 to 17.9 yr; 67 girls) with OI types I, III, or IV who had not received bisphosphonate treatment at the time of analysis.Results:Serum 24,25(OH)2D levels were significantly higher in OI type III than in OI type I or IV. Serum 24,25(OH)2D concentrations were positively correlated with serum 25-hydroxyvitamin D (25OHD) levels and negatively correlated with serum PTH levels, and were not correlated with serum 1α,25-dihydroxyvitamin D [1,25(OH)2D]. The ratio between serum 24,25(OH)2D and 25OHD was negatively correlated with age and was independent of serum 25OHD concentrations. Regression analysis revealed that OI severity (P = 0.04), serum 25OHD levels (P < 0.001), and serum PTH concentrations (P = 0.045), but not age, gender, or serum 1,25(OH)2D, were independent predictors of serum 24,25(OH)2D levels. No correlation was found between serum 24,25(OH)2D levels or the ratio between serum 24,25(OH)2D and 25OHD and lumbar spine bone mineral density z-scores or bone marker levels (serum osteocalcin and urinary collagen type I N-telopeptide) after adjusting for OI type, age, and gender.Conclusion:Patients with more severe OI type had higher 24,25(OH)2D serum levels and higher serum 24,25(OH)2D to 25OHD ratios, suggesting an increased 25OHD-24-hydroxylase activity.

A decrease in muscle mass, low motor performance, and normal lumbar spine bone mineral density (BMD) have been reported in children with Prader-Willi syndrome (PWS). However, these data are limited by the fact that PWS children (who have short stature) were compared to age-matched healthy or obese individuals of normal height.The goal of the present study was to compare bone and muscle characteristics in PWS children to sex- and age- or height-matched healthy subjects.The study population included 17 PWS children (ages 6.2 to 17.5 yr; nine girls) who were not treated with GH. The axial skeleton was analyzed at the lumbar spine using dual-energy x-ray absorptiometry, and the appendicular skeleton (radius and tibia) was evaluated using peripheral quantitative computed tomography. Muscle parameters (mass, size, and functional parameters) were measured by dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and jumping mechanography, respectively.Compared to height-matched controls, PWS patients had normal axial and appendicular BMD, as well as normal muscle size. Compared to age- or height-matched controls of normal weight, PWS patients had lower maximal muscle force and power relative to body mass during jumping. PWS patients had similar absolute maximal muscle force but lower absolute maximal power compared to age- or height-matched controls. Relationships between bone mass and muscle size and force were similar in PWS patients and in healthy subjects.Relative to their height, PWS patients not treated with GH had normal axial and appendicular BMD, muscle size, and muscle-bone relationships.

Thyroglobulin (TG) is a homodimeric glycoprotein synthesized by the thyroid gland. To date, 52 mutations of the TG gene have been identified in humans. The purpose of the present study was to identify and characterize new mutations in the TG gene. We report a French patient with congenital hypothyroidism, mild enlarged thyroid gland and low levels of serum TG. Sequencing of DNA, genotyping, expression of chimeric minigenes as well as bioinformatics analysis were performed. DNA sequencing identified the presence of compound heterozygous mutations in the TG gene: the paternal mutation consists of a c.3788-3789insT or c.3788dupT, whereas the maternal mutation consists of g.IVS19+3_+4delAT. Minigene analysis of the g.IVS19+3_+4delAT mutant showed that the exon 19 is skipped during pre-mRNA splicing or partially included by use of cryptic 5' splice site located to 100 nucleotides downstream of the wild type exon-intron junction. The c.3788-3789insT mutation results in a putative truncated protein of 1245 amino acids, whereas g.IVS19+3_4delAT mutation originates two putative truncated proteins of 1330 and 1349 amino acids. In conclusion, we show that the g.IVS19+3_+4delAT mutation promotes the activation of a cryptic donor splice site in the exon 19 of the TG gene. These results open up new perspectives in the knowledge of the mechanism of splicing for the TG pre-mRNA.

Tall stature is statistically defined as a height standard deviation score (SDS) above 2 for a given age, sex and population group. The most common cause of tall stature is constitutional (often familial) tall stature. However, underlying endocrine or genetic disorders must be considered as some of them may require specific treatment or management. In constitutional tall stature, healthy children are referred to discuss treatment aiming at reducing adult height. The indications of treatment are rare and usually discussed in girls with extremely tall stature (height SDS>4, corresponding to 185cm in girls). The treatment options for tall children are limited and concerns have been raised about their long-term safety. Indeed, recent studies have suggested that high-dose estrogens in adolescent girls may be associated with an increased risk of infertility, as well as increased risk of cancer. Surgical epiphysiodesis has also been reported to reduce adult height but this invasive procedure in healthy children can be questionable and further data on its safety profile are required.

The prevalence of vitamin D deficiency and its consequences on bone in pediatric bone fragility disorders is not well characterized. In the present study, we evaluated determinants of vitamin D status in children and adolescents with osteogenesis imperfecta (OI) and assessed the relationship between 25-hydroxyvitamin D (25OH D) serum concentrations and lumbar spine areal bone mineral density (LS-aBMD).This retrospective cross-sectional study comprised 315 patients with a diagnosis of OI type I, III, or IV (aged 1.1-17.9 yr; 161 girls) who had not received bisphosphonate treatment at the time of 25OH D analysis. In 282 patients (90%), LS-aBMD measurements were available at the same time.Serum concentrations of 25OH D ranged from 14 to 133 nmol/liter and were less than 50 nmol/liter in 86 patients (27%). Regression analysis revealed that age (P0.001), season (P0.001), and OI severity (P = 0.048), but not gender, were significant independent predictive factors of 25OH D levels. Serum 25OH D concentrations were negatively correlated with serum PTH levels (P = 0.003) and urinary cross-linked N-telopeptides of type I collagen to creatinine ratios (P = 0.005). Serum 25OH D levels were positively associated (P = 0.02) with LS-aBMD z-scores after accounting for OI severity, age, and gender.Serum 25OH D levels are positively associated with LS-aBMD z-scores in children and adolescents with OI types I, III, and IV.

Objectif Les mutations « gain de fonction » dans le gene Ptpn11 codant pour SHP2 sont responsables du syndrome de Noonan (SN), une maladie genetique rare caracterisee par de multiples defauts developpementaux, notamment un retard de croissance, des cardiopathies et des desordres myeloproliferatifs. SHP2 est une tyrosine phosphatase qui regule des voies de signalisation majeures (MAPK, PI3K), jouant ainsi des roles pleiotropiques dans le developpement, l’homeostasie et le metabolisme. Si les consequences developpementales induites par les mutations de SHP2 responsables du SN sont bien connues, leur impact sur le metabolisme n’a jamais ete etudie. Methode L’etude a ete realisee sur un modele murin du SN (Ptpn11D61G/+), portant a l’etat heterozygote la mutation D61G, frequemment retrouvee chez les patients, ainsi que sur une cohorte de patients. Resultats Nous avons mis en evidence un phenotype metabolique inattendu, associant une adiposite reduite et une intolerance au glucose/resistance a l’insuline, aussi bien dans le modele murin que chez les patients. Bien qu’elles ne presentent aucun signe de lipotoxicite, les souris SN developpent une inflammation de leurs tissus metaboliques. Une transplantation de moelle osseuse ou une depletion des macrophages par du clodronate permettent de normaliser l’intolerance au glucose. Conclusion Nous avons identifie un phenotype metabolique original qui decouple la resistance a l’insuline provoquee par l’inflammation de l’aspect adiposite. Ceci ouvre de nouvelles perspectives dans la physiopathologie du SN et, au-dela du contexte des maladies rares, dans la comprehension des mecanismes impliques dans les maladies metaboliques.

Polyvalvular heart disease has been reported in a handful of "private" syndromes that have been recently suggested to represent a single dominantly inherited condition, the polyvalvular heart disease syndrome. We report five cases in two unrelated families (one sporadic case in the first family and three siblings and their father in the second family) with the same association of polyvalvular heart disease, distinctive facial appearance, and, except the father in family 2, major joint hypermobility. Interestingly, in three of our patients (2 siblings and the sporadic case), electron microscopy revealed characteristic ultrastructural skin abnormalities with abnormal amorphous or microfibrillar deposits under the capillary basal membrane in the papillary dermis, suggestive of a connective tissue disorder, but different from Marfan syndrome or Ehlers-Danlos syndrome. Moreover, in family 2, three others sibs died in early infancy of their heart defect. Our two families and the other published cases might illustrate intrafamilial and interfamilial variability within a single condition. However, our two families disclose major joint hypermobility, normal stature, and ultrastructural skin abnormalities that were not described in the previous reports. These discrepancies let us to consider them as affected by a distinct disorder of the connective tissue.

The 3M syndrome is a rare autosomal recessive disorder recently ascribed to mutations in the CUL7 gene and characterized by severe pre- and postnatal growth retardation. Studying a series of 33 novel cases of 3M syndrome, we have identified deleterious CUL7 mutations in 23/33 patients, including 19 novel mutations and one paternal isodisomy of chromosome 6 encompassing a CUL7 mutation. Lack of mutations in 10/33 cases and exclusion of the CUL7 locus on chromosome 6p21.1 in six consanguineous families strongly support the genetic heterogeneity of the 3M syndrome.

Resume L’hormone de croissance (growth hormone [GH]), secretee par l’antehypophyse dans la circulation generale, se lie a des recepteurs membranaires au niveau des tissus cibles, ce qui active des voies de signalisation aboutissant, notamment a la stimulation de la croissance ; la plupart de ses effets sont medies par l’insulin-like growth factor 1 (IGF-1). En plus de ces effets sur la croissance, la GH a egalement une action metabolique importante. En 1966, Laron et al. evoquerent pour la premiere fois la notion d’insensibilite a GH (growth hormone insensitivity [GHI]) chez 3 enfants presentant un phenotype compatible avec un deficit complet en GH bien qu’associe a des concentrations seriques elevees de GH. Cette hypothese fut confirmee en 1989 par la mise en evidence de mutations du gene du recepteur de la GH (growth hormone receptor [GHR]). Plus recemment, des anomalies de molecules impliquees dans la signalisation en aval du GHR ont ete decrites, permettant d’elargir la notion de GHI. Ainsi, des mutations du gene codant signal transducer and activator of transcription 5b (STAT5b) ont ete retrouvees chez des enfants presentant un retard statural associe a un deficit immunitaire. De meme, des mutations du gene de la phosphatase Shp2 ont ete identifiees chez des enfants presentant un syndrome de Noonan caracterise par un retard statural, une cardiopathie et une predisposition tumorale. La decouverte de ces nouveaux mecanismes nous permet de mieux comprendre la croissance normale et pathologique. Enfin, ces connaissances physiopathologiques permettent d’eclairer certains mecanismes de la cancerogenese ou de la resistance a d’autres mediateurs comme les cytokines.

Resume Dix a 15 % des enfants nes avec une petite taille de naissance ( small for gestionnal age [SGA]) n’ont pas de rattrapage statural spontane dans les premieres annees de vie. Chez ces enfants, differentes etudes cliniques ont demontre l’efficacite du traitement par hormone de croissance ( growth hormone [GH]) selon des modalites qui ont evolue. En France, des 1997, le traitement par GH a recu l’autorisation de mise sur le marche (AMM) dans cette indication, a partir de l’âge de 3 ans pour une duree de 3 ans. Objectif Le but de ce travail est de decrire l’evolution de la croissance de ces enfants pendant les 3 premieres annees puis a l’arret du traitement. Methodes Nous avons analyse, de maniere retrospective, 33 enfants traites suivant cette indication et suivis dans l’unite d’endocrinologie de l’hopital des Enfants de Toulouse. Resultats Au debut du traitement, l’âge moyen etait de 6,5 ± 1,8 ans et la taille moyenne a −3,1 ± 0,5 deviations standards (DS) avec une difference par rapport a la taille cible de −1,8 ± 0,8 DS. Pendant les 3 premieres annees de traitement par GH, a la dose de 0,4 mg/kg par semaine, nous avons observe une augmentation de la vitesse de croissance avec un gain de taille moyen de 1,5 ± 0,5 DS et une taille moyenne superieure a –2 DS chez 25 enfants apres 3 ans. Parmi les 25 enfants dont la taille etait superieure a −2 DS apres 3 annees de traitement et dont le traitement avait ete arrete, le traitement a ete repris chez 15 d’entre eux du fait d’un ralentissement de la vitesse de croissance. Parmi les enfants qui n’avaient pas rattrape apres 3 ans, la poursuite du traitement par GH n’a pas ameliore la croissance. Conclusion Cette etude va dans le sens des nouvelles indications qui preconisent l’absence d’interruption du traitement par GH.

Phosphoinositide 3-kinase (PI3K) participates in extracellular signal-regulated kinase 1 and 2 (ERK1-2) activation according to signal strength, through unknown mechanisms. We report herein that Gab1/Shp2 constitutes a PI3K-dependent checkpoint of ERK1-2 activation regulated according to signal intensity. Indeed, by up- and down-regulation of signal strength in different cell lines and through different methods, we observed that Gab1/Shp2 and Ras/ERK1-2 in concert become independent of PI3K upon strong epidermal growth factor receptor (EGFR) stimulation and dependent on PI3K upon limited EGFR activation. Using Gab1 mutants, we observed that this conditional role of PI3K is dictated by the EGFR capability of recruiting Gab1 through Grb2 or through the PI3K lipid product PIP(3), according to a high or weak level of receptor stimulation, respectively. In agreement, Grb2 siRNA generates, in cells with maximal EGFR stimulation, a strong dependence on PI3K for both Gab1/Shp2 and ERK1-2 activation. Therefore, Ras/ERK1-2 depends on PI3K only when PIP(3) is required to recruit Gab1/Shp2, which occurs only under weak EGFR mobilization. Finally, we show that, in glioblastoma cells displaying residual EGFR activation, this compensatory mechanism becomes necessary to efficiently activate ERK1-2, which could probably contribute to tumor resistance to EGFR inhibitors.

Activating and inactivating mutations of SHP-2 are responsible, respectively, for the Noonan (NS) and the LEOPARD (LS) syndromes. Clinically, these developmental disorders overlap greatly, resulting in the apparent paradox of similar diseases caused by mutations that oppositely influence SHP-2 phosphatase activity. While the mechanisms remain unclear, recent functional analysis of SHP-2, along with the identification of other genes involved in NS and in other related syndromes (neurofibromatosis-1, Costello and cardio-facio-cutaneous syndromes), strongly suggest that Ras/MAPK represents the major signaling pathway deregulated by SHP-2 mutants. We discuss the idea that, with the exception of LS mutations that have been shown to exert a dominant negative effect, all disease-causing mutations involved in Ras/MAPK-mediated signaling, including SHP-2, might lead to enhanced MAPK activation. This suggests that a narrow range of MAPK signaling is required for appropriate development. We also discuss the possibility that LS mutations may not simply exhibit dominant negative activity.

Over the two past decades, mutations of the PTPN11 gene, encoding the ubiquitous protein tyrosine phosphatase SHP2 (SH2 domain-containing tyrosine phosphatase 2), have been identified as the causal factor of several developmental diseases (Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML), and metachondromatosis), and malignancies (juvenile myelomonocytic leukemia). SHP2 plays essential physiological functions in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a wide range of growth factors and hormones, notably the pleiotropic Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide-3 Kinase (PI3K)/AKT cascades. Analysis of the biochemical impacts of PTPN11 mutations first identified both loss-of-function and gain-of-function mutations, as well as more subtle defects, highlighting the major pathophysiological consequences of SHP2 dysregulation. Then, functional genetic studies provided insights into the molecular dysregulations that link SHP2 mutants to the development of specific traits of the diseases, paving the way for the design of specific therapies for affected patients. In this review, we first provide an overview of SHP2's structure and regulation, then describe its molecular roles, notably its functions in modulating the Ras/MAPK and PI3K/AKT signaling pathways, and its physiological roles in organism development and homeostasis. In the second part, we describe the different PTPN11 mutation-associated pathologies and their clinical manifestations, with particular focus on the biochemical and signaling outcomes of NS and NS-ML-associated mutations, and on the recent advances regarding the pathophysiology of these diseases.

International audience; Objectives Life expectancy of patients with Marfan syndrome has increased, due to earlier diagnosis, better familial screening, regular follow-up (FU) and prophylactic aortic surgery (PASu). Incidence of events in affected patients recognized during childhood is unknown. Methods 465 patients with Marfan syndrome, diagnosed before 18y.o. were included in the French multicenter database. Cardio-vascular events (death, aortic dissection or PASu) were recorded Results A cardio-vascular event occurred in 25 patients (5.4% 95CI 3.5- 7.8%), including PASu (n=20, 4.3% 95CI 2.5-6.2%), aortic dissection (n=3, 0.6% 95CI 0.0-1.4%) and deaths (n=2, 0.4% 95CI 0.0-1.0%). 16 events (64%) occurred before 19 year-old (Median 15.0, min 2.8, interquartile 11.7-16.3; PASu n=12, deaths n=2 and dissection n= 2). An aortic surgery was performed in 23 patients (4.9%, 95CI 3.0-6.9%), including a Bentall procedure with mechanical aortic valve in 10 (43.5%), a valve sparing surgery in the remaining 13 (56.5%) and a supra-coronary graft in 4 (17.4%, dissection: n=2 and PASu: n=2). Mean age at the date of PASu was 17.1±6.5 year-old. Events occurred before or at inclusion in the database in 8 patients (32.0%) (PASu n=5, dissection n=2, death n=1). Dissection was observed before inclusion in 2 patients and during pregnancy in 1 patient. Kaplan-Meier survival estimate indicates that 95% of patients remained free from events at eighteen and 78% at thirty year-old. Conclusion Prophylactic surgery for enlarged aorta is the main cause of cardiac events in patients with Marfan syndrome diagnosed during childhood. A quarter of them have a cardiac event before thirty year-old.

Background Patients with pituitary stalk interruption syndrome (PSIS) are initially referred for hypoglycemia during the neonatal period or growth retardation during childhood. PSIS is either isolated (nonsyndromic) or associated with extra-pituitary malformations (syndromic). Objective To compare baseline characteristics and long-term evolution in patients with PSIS according to the initial presentation. Study Design Sixty-seven patients with PSIS were included. Data from subgroups were compared: neonates (n = 10) versus growth retardation patients (n = 47), and syndromic (n = 32) versus nonsyndromic patients (n = 35). Results Neonates displayed a more severe hormonal and radiological phenotype than children referred for growth retardation, with a higher incidence of multiple hormonal deficiencies (100% versus 34%; P = 0.0005) and a nonvisible anterior pituitary lobe (33% versus 2%; P = 0.0017). Regular follow-up of growth might have allowed earlier diagnosis in the children with growth retardation, as decreased growth velocity and growth retardation were present respectively 3 and 2 years before referral. We documented a progressive worsening of endocrine impairment throughout childhood in these patients. Presence of extra-pituitary malformations (found in 48%) was not associated with more severe hormonal and radiological characteristics. Growth under GH treatment was similar in the patient groups and did not vary according to the pituitary MRI findings. Conclusions PSIS diagnosed in the neonatal period has a particularly severe hormonal and radiological phenotype. The progressive worsening of endocrine impairment throughout childhood justifies periodic follow-up to check for additional hormonal deficiencies.

Resume La biologie du metabolisme mineral osseux a connu ces dernieres annees des avancees importantes. Plusieurs syndromes pediatriques ont ete precises sur le plan moleculaire. Il existe une intrication etroite entre les composantes endocriniennes de la regulation metabolique et la trophicite du tissu osseux. L’accent est mis desormais sur l’impact anabolique sur l’os des traitements a visee osseuse, tels les biphosphonates, la parathormone (PTH) ou l’hormone de croissance. Ces elements sont importants pour le devenir de l’os a l’âge adulte. Nous analysons ici les composantes essentielles de la regulation du metabolisme osseux mineral au vu des donnees recentes de la biologie, telles que la signalisation liee au systeme PTH/PTHrP (PTH-related peptide), le role du FGF23 (Fibroblast growth factor 23) dans les hypophosphatemies et la regulation du metabolisme de la vitamine D par la 1α-hydroxylase. Ces elements de regulation sont intriques dans plusieurs pathologies genetiques et dans le syndrome de Mc Cune-Albright. L’interaction entre facteurs metaboliques et endocriniens sera analysee en evaluant son impact sur la secretion de PTH et sur l’osteogenese.

Objectif L’hypothyroidie congenitale est associee pour 30 % des cas a un trouble de l’hormonosynthese. Des mutations homozygotes dans les genes DUOX2, TPO, TG, NIS, Pendrine, DUOXA2 et DEHAL1 sont classiquement rapportees. Pour autant, l’analyse exhaustive de ces genes est delicate. Nous avons developpe l’approche NGS pour un panel de 18 genes associes aux dysthyroidies congenitales et rapportons une annee d’exploration des HC avec glande en place. Materiel et methodes Nous avons teste l’ADN leucocytaire de 30 enfants presentant une hypothyroidie congenitale avec glande en place (HCGP), (donnees hormonales et d’imagerie disponibles) sur la puce NGS diagnostique developpee. Resultats Sur les 30 enfants explores, 16 (55 %) presentaient une ou plusieurs anomalies dans les genes de l’hormonosynthese thyroidienne. Les mutations etaient retrouvees soit homozygotes soit heterozygotes composites dans les genes TG, DUOX2, TPO ou SLC5A5 pour 9 enfants (56 %). Pour 5 autres (31 %), des mutations heterozygotes dans deux genes differents de la voie de synthese hormonale etaient identifiees. Enfin, dans 2 cas, une mutation heterozygote dans le gene TG representait la seule anomalie de la voie de l’hormonosynthese. Discussion L’exploration exhaustive des genes de la voie de l’hormonosynthese thyroidienne par la technique NGS a permis de mettre en evidence des mutations dans les genes classiquement explores pour 55 % des enfants avec HCGP. Pour la moitie d’entre eux, nous avons identifie des mutations touchant 2 voies differentes de la synthese hormonale : ceci remet en cause nos connaissances sur les troubles de l’hormosynthese thyroidienne et explique peut-etre l’heterogeneite phenotypique observee chez ces enfants HCGP.

Introduction L’hyperthyroidie familiale non auto-immune (HFNA) est une pathologie rare liee a des mutations activatrices du recepteur de la TSH. Observations Nous rapportons une nouvelle famille d’HFNA avec des patients sur 3 generations : le cas index a ete diagnostique a 19 mois, devant une hyperthyroidie severe avec tachysystolie, avance staturale et hypotrophie, avance de maturation osseuse, craniostenose, agitation psychomotrice avec retard moteur, exophtalmie discrete, et goitre vasculaire. Les examens confirmaient l’hyperthyroidie (T3L > 20 pg/mL, T4L : 52 pg/mL, TSH : 0,005 μU/mL) sans Ac anti-recepteur de la TSH. Sa sœur ainee, âgee de 4 ans, presentait un tableau clinique et hormonal de thyreotoxicose moins severe. Des doses importantes de thiamazole ont permis de controler l’hyperthyroidie avant thyroidectomie totale chez les deux fillettes. Leur pere traite medicalement a 16 ans pour une hyperthyroidie recidivante, a ete opere a 21 ans revelant un carcinome papillaire in situ. La grand-mere paternelle avait eu une thyroidectomie partielle a 27 ans, puis une thyroidectomie totale devant une cardiothyreose. Une insuffisance mitrale moderee est retrouvee chez les 4 membres de cette famille. Discussion Une mutation germinale heterozygote de l’exon 10 du gene du recepteur a la TSH (7 domaines transmembranaire) a ete identifiee chez les 4 membres de cette famille : mutation C678 W avec substitution d’une cysteine par un tryptophane. Les etudes fonctionnelles in vitro ont permis de confirmer le role de cette mutation dans l’activation constitutive du recepteur de la TSH et donc responsable du phenotype thyroidien de ces patients.

The needs to produce "more", "better" and "cheaper" are today in line with a financial crisis which makes companies struggle with economical issues (related to the obligation to make profits), social issues (related to safety of men and machines) and environmental ones (related to the reduction of nuisance and pollution). At the equipment level, the system maintaining in operational conditions (SMOC) has to deal with these issues. Maintenance is the key process of the SMOC, and one of the most significantprocesses to lever up the global performances of the system when associated to a prognosis process. This defines predictive maintenance strategies. Those new forms of maintenance make numerous scientific as well as industrial issues rise, and some are tackled in the present document: When to perform a particular predictive maintenance action? How to group together several preventive maintenance actions? What is opportunity for maintenance?Answers to these questions make use of different mathematical tools, such as Bruss algorithm (in stochastic analysis) or equivalence relations (in algebra). Finally, an industrial application on TELMA platform is presented., Les besoins essentiels de produire " plus ", " mieux " et " moins cher " s'inscrivent aujourd'hui dans une crise financière qui conduit les entreprises industrielles à faire face à des enjeux économiques liés aux impératifs de gains de productivité, mais aussi à des enjeux sociaux liés aux impératifs de sécurité des hommes et des matériels, aux exigences de protection de l'environnement et de réduction des nuisances. Ces enjeux se déclinent au niveau des équipements par le concept de maintien en condition opérationnelle (MCO). La maintenance en est l'élément principal, et l'un des principaux leviers d'action sur la performance globale des systèmes de production lorsqu'elle est couplée à un processus de pronostic. On parle alors de stratégies de maintenance prévisionnelles.Ces nouvelles formes de maintenance posent de nombreux défis scientifiques et industriels, dont certains sont étudiés dans les présents travaux : Quel est le " meilleur " instant pour réaliser une intervention de maintenance préventive donnée ? Comment regrouper deux actions de maintenance préventive ? Qu'est-ce qu'une opportunité pour la maintenance ?Les réponses à ces questions mobilisent des outils mathématiques variés, allant de l'algorithme de Bruss en analyse stochastique aux relations d'équivalence en algèbre.Enfin, une application industrielle sur la plateforme TELMA est présentée.

Marfan syndrome (MFS) is a rare connective tissue disorder caused by mutation in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1), leading to transforming growth factor-beta (TGF-β) signaling dysregulation. Although decreased axial and peripheral bone mineral density (BMD) has been reported in adults with MFS, data about the evolution of bone mass during childhood and adolescence are limited. The aim of the present study was to evaluate bone and muscle characteristics in children, adolescents, and young adults with MFS. The study population included 48 children and young adults (22 girls) with MFS with a median age of 11.9 years (range 5.3 to 25.2 years). The axial skeleton was analyzed at the lumbar spine using dual-energy X-ray absorptiometry (DXA), whereas the appendicular skeleton (hand) was evaluated using the BoneXpert system (with the calculation of the Bone Health Index). Muscle mass was measured by DXA. Compared with healthy age-matched controls, bone mass at the axial and appendicular levels and muscle mass were decreased in children with MFS and worsened from childhood to adulthood. Vitamin D deficiency (50 nmol/L) was found in about a quarter of patients. Serum vitamin D levels were negatively correlated with age and positively correlated with lumbar spine areal and volumetric BMD. Lean body mass (LBM) Z-scores were positively associated with total body bone mineral content (TB-BMC) Z-scores, and LBM was an independent predictor of TB-BMC values, suggesting that muscle hypoplasia could explain at least in part the bone loss in MFS. Patients with a FBN1 premature termination codon mutation had a more severe musculoskeletal phenotype than patients with an inframe mutation, suggesting the involvement of TGF-β signaling dysregulation in the pathophysiologic mechanisms. In light of these results, we recommend that measurement of bone mineral status should be part of the longitudinal clinical investigation of MFS children.

LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.

(Numéro Spécial JD-JN-MACS'07 1ère partie). A été présenté le 09 juillet 2007 à Reims lors des 2èmes Journées Doctorales / Journées Nationales MACS; National audience; La planification d'actions de maintenance préventive opportuniste permet de minimiser le nombre d'arrêts de production superflus, et les décisions de maintenance doivent être synchronisées avec les exigences de la production, afin d'améliorer le plus possible la productivité et conserver la finalité attendue du produit manufacturé. Pour cela, une nouvelle approche basée sur l'algorithme de Bruss est proposée. L'objectif est de sélectionner, parmi les arrêts de production déjà prévus, une liste de ceux qui permettront de réaliser une action de maintenance donnée. La phase d'optimisation intègre notamment la durée des arrêts, la fiabilité et la maintenabilité du composant considéré.

6 pages; International audience; Today, a new role for maintenance exists to enhance the eco-efficiency of the product lifecycle. The concept of “lifecycle maintenance” has emerged to stress this role leading to push, at the manufacturing stage, an innovative culture wherein maintenance activities become of equal importance to actual production activities. This equivalence requires mainly to consider the integration of both the maintenance planning and the production strategy planning to develop opportunistic maintenance tasks guaranteeing conjointly the product – production – equipment performances. In this paper, a novel approach is proposed to synchronise the maintenance planning with the production planning. The approach uses the “odds algorithm” and is based upon the theory of optimal stopping. The objective is to select, among all the production stoppages already planned, those which will be optimal to develop maintenance tasks keeping the expected product conditions. It combines criteria such as product performance and component reliability. An approach evaluation is shown on a practical example.

Noonan syndrome (NS), a genetic disease caused in half of cases by activating mutations of the tyrosine phosphatase SHP2 ( PTPN11 ), is characterized by congenital cardiopathies, facial dysmorphic features, and short stature. How mutated SHP2 induces growth retardation remains poorly understood. We report here that early postnatal growth delay is associated with low levels of insulin-like growth factor 1 (IGF-1) in a mouse model of NS expressing the D61G mutant of SHP2. Conversely, inhibition of SHP2 expression in growth hormone (GH)-responsive cell lines results in increased IGF-1 release upon GH stimulation. SHP2-deficient cells display decreased ERK1/2 phosphorylation and rat sarcoma (RAS) activation in response to GH, whereas expression of NS-associated SHP2 mutants results in ERK1/2 hyperactivation in vitro and in vivo. RAS/ERK1/2 inhibition in SHP2-deficient cells correlates with impaired dephosphorylation of the adaptor Grb2-associated binder-1 (GAB1) on its RAS GTPase-activating protein (RASGAP) binding sites and is rescued by interfering with RASGAP recruitment or function. We demonstrate that inhibition of ERK1/2 activation results in an increase of IGF-1 levels in vitro and in vivo, which is associated with significant growth improvement in NS mice. In conclusion, NS-causing SHP2 mutants inhibit GH-induced IGF-1 release through RAS/ERK1/2 hyperactivation, a mechanism that could contribute to growth retardation. This finding suggests that, in addition to its previously shown beneficial effect on NS-linked cardiac and craniofacial defects, RAS/ERK1/2 modulation could also alleviate the short stature phenotype in NS caused by PTPN11 mutations.

Loeys-Dietz syndrome (LDS) is a rare autosomal-dominant connective tissue disorder caused by heterozygous mutations in the genes encoding transforming growth factor beta receptor 1 or 2 (TGFBR1 or TGFBR2). Although an association between LDS and osteoporosis has been reported, the skeletal phenotype regarding bone mass is not well characterized. Here, we report on two LDS patients with mutations in TGFBR2. Patient 1 was a 24-year-old man who had a total of three fractures involving the left radius, the left metacarpal, and the right femur. At the age of 14 years, lumbar spine areal bone mineral density Z-score was -4.0 and iliac bone histomorphometry showed elevated bone turnover (bone formation rate per bone surface: 91 µm³/µm²/year; age-matched control values 37 [10], mean [SD]) and mildly low trabecular bone volume per tissue volume (17.2%; age-matched control values 25.7 [5.3]). Bone mineralization density distribution (BMDD) in trabecular bone was increased (Ca(Peak) 22.70 wt% Ca; age-matched control values 21.66 [0.52]). Patient 2, a 17-year-old girl, suffered from diffuse bone pain but had not sustained fractures. At 14 years of age, her lumbar spine areal bone mineral density Z-score was -3.4. Iliac bone histomorphometry at that age confirmed low bone mass (bone volume to tissue volume 10.1%, same control values as above) and high bone turnover (bone formation rate per bone surface 70 µm³/µm²/year). BMDD in trabecular bone was significantly shifted toward increased mineralization (Ca(Peak) 22.36 wt% Ca). Thus, it appears that LDS can be associated with low bone mass and high bone turnover but increased matrix mineralization of trabecular bone.

Short stature (SS) is defined as height less than the third percentile or below –2 standard deviation score (SDS) with reference to chronological age according to standard growth curves. Children are born small for gestational age (SGA) when their birth height and/or birth weight are below or equal to –2 SDS using standards such as Usher and McLean. In patients presenting with SS associated with abnormal physical features, malformations, or delayed development, a syndromic growth disorder should be considered. Whilst individually rare, there are many syndromes with short stature as a component—in the London Dysmorphology Database (Winter and Baraitser), there are 873 such syndromes, 175 of which are of prenatal onset. In these patients, malformations and/or sensorineural abnormalities should be systematically screened by complementary exams (skeletal X-rays, cardiac and abdominal ultrasound, complete eye and hearing evaluations). In some cases, these abnormalities could help in making the diagnosis (e.g. pulmonary stenosis suggestive of Noonan’s syndrome). Different chromosome disorders may present with SS. For this reason, chromosome studies, preferably high-resolution analysis, should be performed to search for chromosome abnormalities in these children. Specific gene analysis may be requested when a specific syndrome is suspected. In these syndromes, growth failure may be due to a wide variety of mechanisms, including growth hormone deficiency (GHD), growth hormone resistance (Laron syndrome, bone dysplasia) or in combination with nutritional issues with, in many, the underlying mechanisms still being unknown. A complete evaluation of growth hormone/IGF-1 axis is necessary in these children. There are many classifications of short stature, each with specific advantages and disadvantages. Indeed, syndromes with SS could be classified according to clinical presentation and in particular auxological and anthropometrical parameters (SS with normal prenatal growth, SS with intrauterine growth retardation, SS with obesity), or to pathophysiology (GHD or growth hormone insensitivity, bone disorders and idiopathic SS). Here, a classification based on clinical presentation is used. Those syndromes with SS that are most common and are often followed by paediatric endocrinologists namely Silver–Russell, Noonan’s, Turner’s and Prader–Willi syndromes will be reviewed, as well as some rarer syndromes.

Generalized arterial calcification of infancy (GACI, MIM#208000) is a rare autosomal recessive disorder characterized by extensive calcifications in the media of large- and medium-sized muscular arteries. Most affected children die in early infancy because of cardiac failure. GACI is linked to mutations in the ENPP1 gene, which encodes for an enzyme that generates inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation. Treatment with bisphosphonates, which are synthetic PPi analogues, has been proposed as a means of reducing arterial calcifications in GACI patients, but no formalized treatment approach exists. We report on the long-term survival of a severe case of GACI linked to a novel homozygous missense mutation c.583T/C in the ENPP1 gene, diagnosed prenatally, and treated with bisphosphonates. Intravenous disodium pamidronate (three infusions at days 8, 15, and 18 of 0.25, 0.50, and 0.50 mg/kg, respectively) was changed to oral disodium etidronate (starting dose of 20 mg/kg daily, 50 mg die) at 3 weeks of age. Although the etidronate dose was maintained at 50 mg daily in our patient (corresponding to a progressive decrease from 20 to 5 mg/kg daily), the progressive resolution of arterial calcifications seen by 3 months of age was maintained until 2 years of age. Throughout the 2-year follow-up, our patient developed mild hypophosphatemia, due to renal phosphate wasting, without clinical, biochemical, or radiological sign of rickets. Conclusion: High-dose bisphosphonate therapy may not be necessary for an extended period of time in children with GACI.

The effect of low vitamin D levels in children with bone fragility disorders has not been examined in detail. In this study, we evaluated the relationship between vitamin D status and parameters of skeletal mineralization, mass, and metabolism in a group of pediatric osteogenesis imperfecta (OI) patients. This retrospective study consisted of 71 patients with a diagnosis of OI type I, III, or IV (ages 1.4 to 17.5 years; 36 girls) who had not received bisphosphonate treatment before iliac bone biopsy. Serum 25-hydroxyvitamin D [25(OH)D] levels ranged from 13 to 103 nmol/L and were less than 50 nmol/L in 37 patients (52%). None of the OI patients had radiologic signs of rickets or fulfilled the histomorphometric criteria for the diagnosis of osteomalacia (ie, elevated results for both osteoid thickness and mineralization lag time). Serum 25(OH)D levels were negatively correlated with age and serum parathyroid hormone levels but were not correlated with any parameter of bone mineralization (ie, osteoid thickness, mineralization lag time, or bone-formation rate per bone surface) or bone mass (ie, lumbar spine areal bone mineral density, iliac bone volume per tissue volume, or iliac cortical width). We found no evidence that serum 25(OH)D levels in the range from 13 to 103 nmol/L were associated with measures of bone mineralization, metabolism, or mass in children with OI. © 2011 American Society for Bone and Mineral Research

Publisher Summary Pseudo-vitamin D deficiency rickets (PDDR) is a rare autosomal recessive disorder caused by mutations in the gene encoding 1α-OHase (CYP27B1), leading to an inability to synthesize 1,25(OH)2D. This disease was the first described inborn error of vitamin D metabolism and has contributed in a major way to the understanding of vitamin D biology. Patients with PDDR are healthy at birth and the first symptoms usually appear within the first year of life. The distribution of presenting signs and symptoms seems to differ somewhat between PDDR and vitamin D deficiency rickets. Hypocalcemia is the cardinal feature in PDDR. Serum calcium concentration drops below 2 mmol/l (8 mg/ dl). This, particularly if the decrease is rapid, may give rise to tetany and convulsions, which may occur prior to any radiological evidence of rickets. The treatment of choice for PDDR patients is replacement therapy with small daily doses of calcitriol. Started in infancy, this treatment results in short- and long-term correction of all clinical, biochemical, and radiological abnormalities related to PDDR, without serious adverse events. Because of the easiness and efficacy of the replacement therapy, it is unlikely that any form of gene-based therapy will be considered anytime soon.

International audience; Today most conventional maintenance strategies are purely reactive, corrective (fixing or replacing equipment after it fails) or time-scheduled (Wang, 2002). These strategies are not well adapted to the control of the global performances of a manufacturing system (Gupta, et al., 2001). Therefore it is now necessary to move from traditional maintenance strategies towards condition-based maintenance performed only when a certain level of equipment deterioration occurs, or predictive maintenance which anticipates the appearance of a failure (Djurdjanovic, et al., 2003). This notion of anticipation becomes of true importance whenever a prognosis process is available (Iung, et al., 2005). Indeed the notion of anticipation allows the investigation of non-planned maintenance actions, which is part of what is called opportunistic maintenance. Opportunistic maintenance aims at answering the following questions: When to perform a particular maintenance action? What components should benefit from a preventive maintenance action? Which components should first benefit from a preventive maintenance intervention? The notion of opportunistic maintenance has been carefully reviewed in (Thomas, et al., 2008a). It was emphasized that the classical notion of opportunistic maintenance can cover up various realities and criteria. Moreover predictive vs. proactive maintenance strategies may generate numerous opportunities to perform non-previously-planned maintenance tasks. The notion of opportunistic maintenance currently does not allow taking advantage of those new opportunities-to-come, partly because of the lack of rigorous definitions and adapted formalisms of opportunistic maintenance

Pseudo-vitamin D deficiency rickets (PDDR; OMIM 264700) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to an inability to synthesize 1α,25-dihydroxyvitamin D(3) (calcitriol). The long-term (1 yr) effects of calcitriol replacement treatment have not been reported.Thirty-nine patients (20 females) with PDDR received calcitriol for periods of 2.0-26 yr. In 21 patients, data were available at diagnosis and during the first 2 yr of treatment with calcitriol. Twenty-five patients had reached their final height at the time of this analysis.The most common presenting features were active rickets, neurological signs, and short stature. Treatment with calcitriol resulted in the normalization of biochemical parameters and mean lumbar spine areal bone mineral density z-scores within 3 months, whereas height z-scores increased more gradually. As to long-term effects, adult patients who had received calcitriol before the pubertal growth spurt (n = 11) had normal height, whereas patients who were treated with calcitriol only after puberty (n = 14) on average were short (height z-score -2.2). Lumbar spine areal bone mineral density z-scores were normal in all patients who had achieved final height. Nine women had 19 pregnancies, which all were without complications. All newborns were eucalcemic at birth.Treatment with calcitriol started in infancy results in short- and long-term correction of all clinical, biochemical, and radiological abnormalities related to PDDR.

info:eu-repo/semantics/published

3-M syndrome is an autosomal recessive disorder characterized by severe pre- and postnatal growth retardation and minor skeletal changes. We have previously identified CUL7 as a disease-causing gene but we have also provided evidence of genetic heterogeneity in the 3-M syndrome. By homozygosity mapping in two inbred families, we found a second disease locus on chromosome 2q35-36.1 in a 5.2-Mb interval that encompasses 60 genes. To select candidate genes, we performed microarray analysis of cultured skin fibroblast RNA from one patient, looking for genes with altered expression; we found decreased expression of IGFBP2 and increased expression of IGFBP5. However, direct sequencing of these two genes failed to detect any anomaly. We then considered other candidate genes by their function/location and found nine distinct mutations in the OBSL1 gene in 13 families including eight nonsense and one missense mutations. To further understand the links between OBSL1, CUL7, and insulin-like growth factor binding proteins (IGFBPs), we performed real-time quantitative PCR (RT-PCR) analysis for OBSL1, CUL7, IGFBP2, and IGFBP5, using cultured fibroblast RNAs from two patients with distinct OBSL1 mutations (p.F697G; p.H814RfsX15). We found normal CUL7 mRNA levels but abnormal IGFBP2 and IGFBP5 mRNA levels in the two patients, suggesting that OBSL1 modulates the expression of IGFBP proteins.

From the time of its initial, informal meetings starting in 1980 to its formal creation in 1990, the IRSSD has met on a bi-annual basis to discuss all aspects of the spine and associated deformities. It has encouraged open discussion on all topics and, in particular, has tried to be the seed-bed for new ideas. The members are spread around the world and include people from all areas of academia as well as the most important people, the patients themselves. Most notably, application of the ideas and results of the research has always been at the forefront of the discussions. This paper was conceived with the idea of evaluating the impact made by the IRSSD over the last 30 years in the various areas and is intended to create discussion for the upcoming meeting in Montreal regarding future focus: "We are lost over the Atlantic Ocean but we are making good time."

Background/aims‘Primary IGF1 deficiency (IGFD)’ is defined by low levels of IGF1 without a concomitant impairment in GH secretion in the absence of secondary cause. The aims of this study were to evaluate the prevalence of non-GH deficient IGFD in prepubertal children with isolated short stature (SS) and to describe this population.MethodsThis retrospective study included all children with isolated SS seen in our Pediatric Endocrinology Unit from January 2005 to December 2007. Children were included based on the following criteria: i) SS with current height SDS ≤ −2.5, ii) age≥2 years, and iii) prepubertal status. Exclusion criteria were: i) identified cause of SS and ii) current or past therapy with rhGH. IGF1-deficient children were defined as children without GH deficiency and with IGF1 levels below or equal to −2 SDS.ResultsAmong 65 children with isolated SS, 13 (20%) had low IGF1 levels, consistent with a diagnosis of primary IGFD, four of which were born small for gestational age and nine were born appropriate for gestational age. When compared with non-IGFD children, IGFD children had higher birth weight (−0.7 vs −1 SDS, P=0.02) and birth height (−1.7 vs −2 SDS, P=0.04) and more delayed bone age (2.6 vs 1.7 years, P=0.03).ConclusionThe prevalence of primary IGFD was 20% in children with isolated SS. Concerning the pathophysiology, our study emphasizes that IGFD in some children may be secondary to nutritional deficiency or to maturational delay.

National audience; Une modélisation de la notion de proximité entre composants d'un même système industriel est proposée à l'aide d'outils issus de la logique floue, de la géométrie et de la CAO. Cette notion permet d'investiguer des actions de maintenance préventive opportuniste, en proposant des actions de maintenance non planifiées sur des composants ‘proches' d'un composant de référence. Un cas d'application est proposé.