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1.
Eur J Hum Genet ; 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39085583

RESUMO

Four European Reference Networks (ERN-EYE, ERKNet, Endo-ERN, ERN-ITHACA) have teamed up to establish a consensus statement and recommendations for Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy with at least 26 genes identified to date. The clinical manifestations are pleiotropic, can be observed in utero and will progress with age. Genetic testing has progressively improved in the last years prompting for a revision of the diagnostic criteria taking into account clinical Primary and Secondary features, as well as positive or negative molecular diagnosis. This consensus statement also emphasizes on initial diagnosis, monitoring and lifelong follow-up, and symptomatic care that can be provided to patients and family members according to the involved care professionals. For paediatricians, developmental anomalies can be at the forefront for diagnosis (such as polydactyly) but can require specific care, such as for associated neuro developmental disorders. For ophthalmology, the early onset retinal degeneration requires ad hoc functional and imaging technologies and specific care for severe visual impairment. For endocrinology, among other manifestations, early onset obesity and its complications has benefited from better evaluation of eating behaviour problems, improved lifestyle programs, and from novel pharmacological therapies. Kidney and urinary track involvements warrants lifespan attention, as chronic kidney failure can occur and early management might improve outcome. This consensus recommends revised diagnostic criteria for BBS that will ensure certainty of diagnosis, giving robust grounds for genetic counselling as well as in the perspective of future trials for innovative therapies.

2.
Heliyon ; 9(7): e17750, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37539268

RESUMO

The objective of this study was to investigate the impact of the geographic and climatic conditions on laterites properties and on geopolymerization based-laterite. Four different laterite deposits in the four geographical zones of Cameroon were studied. This included the center, north, south and west corners of Cameroon, having chemical composition of SiO2 + Al2O3 + Fe2O3 = 88.94, 87.6, 89.13 and 78.97%, respectively. The center and south laterites from the black forest, with high pluviometry and relative humidity, show significant amounts of Fe2O3. While the west laterite from grass field - mountainous areas and the north-laterite from plain arid and semi-arid climate still show lower iron concentrations. The IR absorption bands of the different laterites appear between 1007 and 1047 cm-1; characteristic bands of aluminosilicate. The BET (Brunauer-Emmett-Teller) Specific surface area values are comprised in the range of [21.9, 24.1 m2/g] for non-calcined laterite and between [45.6 and 123.5 m2/g] for laterites calcined at 550 °C and 575 °C. The main particle size values are 5.71, 6.37, 7.43 and 8.45 µm for center-laterite, west-laterite, north laterite and south-laterite, respectively. Although, they differ in the degree of laterization, all the laterites present almost total conversion to geopolymers, due to the presence of amorphous kaolinite and reactive goethite. However, the iron content has significant impact on the globular microstructure. The particle size of laterites, their high values of BET surface area and their significant reactivity make them promising substitutes to metakaolin and other supplementary cementitious materials.

3.
Patient Prefer Adherence ; 17: 1393-1405, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37325587

RESUMO

Purpose: X-linked hypophosphatemia (XLH) is a rare, chronic, genetic condition characterized by renal phosphate wasting and abnormal bone and teeth mineralization. It represents a challenging and multifaceted disease that causes wide-ranging impacts on patients' lives. In this context, a scientific committee has designed a support initiative for patients treated for XLH: the aXess program. We sought to determine if a patient support program (PSP) could help XLH patients cope with their condition. Methods: During the 12 months of participation in the aXess program, XLH patients were contacted by phone by a nurse to coordinate their treatment, ensure treatment adherence, and provide motivational interviews. A Pediatric QOL inventory was conducted on all participants at enrollment (D0), at month 6, and month 12. Results: Altogether, a total of 59 patients were enrolled in the program. Most patients reported an improvement in QOL in all examined dimensions by month 12 (physical, emotional, social, and school, 85.4 ± 0.2 at month 12 versus 75.6 ± 0.3 at enrollment, p<0.05). Patients were very satisfied with the program, with a mean overall satisfaction score of 9.8 ± 0.6 (on a scale from 0 to 10) at month 6 and 9.2 ± 1.5 at month 12. Conclusion: Our findings indicate that this program might improve the QOL for patients with chronic conditions such as XLH through patient education, therapy adherence, motivational interviews, and frequent follow-up. It links the home environment and overall illness management, bringing patients, families, and caregivers together.

4.
Med Sci (Paris) ; 39(3): 271-280, 2023 Mar.
Artigo em Francês | MEDLINE | ID: mdl-36943125

RESUMO

Growth failure is a frequent complication observed in children with chronic kidney disease (CKD) and correlated to increased morbidity and mortality. To achieve a normal growth in children with CKD remains challenging for pediatric nephrologists. Growth failure in the setting of pediatric CKD is multifactorial and related to an impaired sensitivity to growth hormone and to a deficiency of IGF1 (insulin-like growth factor 1). Growth failure management has improved during the last two decades and consists of correcting any nutritional and metabolic abnormalities, of an improvement of dialysis for children on end-stage renal disease, and of an administration of a supraphysiologic dose of recombinant growth hormone to overcome GH insensitivity. This article summarizes the causes, outcomes and assessment tools of growth in children with CKD as well as the management of recombinant growth hormone.


Title: Maladie rénale chronique et retard de croissance - Indication et efficacité du traitement par l'hormone de croissance. Abstract: Le retard de croissance est une des complications les plus fréquentes chez l'enfant présentant une maladie rénale chronique. Il est corrélé à une morbi-mortalité importante, augmentée par les désordres métaboliques qui y sont associés. D'origine multifactorielle, une hypothèse régulièrement avancée est celle d'une résistance à l'hormone de croissance (GH), caractérisée par un déficit en IGF1 (insulin-like growth factor 1). L'obtention d'une croissance staturale satisfaisante reste un défi majeur pour les néphropédiatres. La prise en charge du retard statural comprend différents axes thérapeutiques : une nutrition adaptée aux besoins de l'enfant, une correction des troubles métaboliques avec optimisation de la dialyse, et un traitement par hormone de croissance recombinante à dose supra-physiologique, qui permet de lever la résistance.


Assuntos
Hormônio do Crescimento Humano , Falência Renal Crônica , Insuficiência Renal Crônica , Criança , Humanos , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/etiologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/complicações
5.
Sci Rep ; 12(1): 8454, 2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35589834

RESUMO

An optimized sol-gel protocol was carried out to produce an yttrium aluminum garnet (YAG) xerogel from aluminum alkoxide and an yttrium salt on a semi-pilot scale. This xerogel was successfully used without prior pyrolysis as a solid load with the aid of additives in the preparation of pastes. Thermal treatment of the green bodies, obtained by robocasting of the paste, led to cohesive single-phase YAG ceramics. Manufacturing ceramic pieces by additive methods will allow shaping complex forms, while the single step conversion/consolidation would simplify the technological process, reducing global energy costs. Since YAG possesses high strength and good creep behavior at high temperatures, these refractory pieces could replace the metal alloys used in turbine blades for deep space exploration. Structural, thermal and chemical characterizations were performed on xerogel powders, pastes, and YAG ceramics.

7.
Eur J Endocrinol ; 184(2): 347-355, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33361469

RESUMO

AIM: To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population. METHODS: Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018. RESULTS: Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, 'CaSR group'; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, 'cell proliferation group'; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in 'cell proliferation group' patients compared to those in the 'CaSR group' (P = 0.001 and 0.028, respectively). CONCLUSION: Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.


Assuntos
Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Feminino , França/epidemiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Hiperparatireoidismo Primário/epidemiologia , Hiperparatireoidismo Primário/patologia , Lactente , Recém-Nascido , Masculino , Biologia Molecular , Fenótipo , Estudos Retrospectivos
8.
Molecules ; 25(18)2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32937984

RESUMO

Dimension reduction, cost efficiency, and environmental sustainability are important factors in absorbent designs. Geopolymers represent an eco-friendly and cost-efficient solution for such applications, and the objective of this study is to develop new geopolymer-based composites with tailored dielectric properties. To develop such composites, different formulations based on three types of carbon and various surfactants are tested. The nonionic surfactant is preferred over the anionic surfactant. Dielectric investigations between 2 and 3.3 GHz are performed. The results reveal that the carbon content and its type (origin) have significant effects on the dielectric characteristics and less on the magnetic characteristics. Indeed, an increase in permittivity from 2 to 24 and an increase from 0.09 to 0.6 for loss tangent are shown with changes in the carbon content and type. A permittivity (ε) of 2.27 and loss (tan δ) of 0.19 are obtained for a pore size of 1.6 mm, for the carbon type with the lowest purity, and with a nonionic surfactant. Finally, it is shown that the addition of magnetite has little impact on the overall magnetic properties of the geopolymer.


Assuntos
Carbono/química , Polímeros/química , Tensoativos/química , Carvão Vegetal/química , Cinza de Carvão , Óxido Ferroso-Férrico/química , Metais/química , Microscopia Eletrônica de Varredura , Água/química , Difração de Raios X
9.
J Clin Endocrinol Metab ; 105(12)2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32835378

RESUMO

PURPOSE: Bardet-Biedl syndrome (BBS) is a ciliopathy with a wide spectrum of symptoms due to primary cilia dysfunction, including genitourinary developmental anomalies as well as impaired reproduction, particularly in males. Primary cilia are known to be required at the following steps of reproduction function: (i) genitourinary organogenesis, (ii) in fetal firing of hypothalamo-pituitary axe, (iii) sperm flagellum structure, and (iv) first zygotic mitosis conducted by proximal sperm centriole. BBS phenotype is not fully understood. METHODS: This study explored all steps of reproduction in 11 French male patients with identified BBS mutations. RESULTS: BBS patients frequently presented with genitourinary malformations, such as cryptorchidism (5/11), short scrotum (5/8), and micropenis (5/8), but unexpectedly, with normal testis size (7/8). Ultrasonography highlighted epididymal cysts or agenesis of one seminal vesicle in some cases. Sexual hormones levels were normal in all patients except one. Sperm numeration was normal in 8 out of the 10 obtained samples. Five to 45% of sperm presented a progressive motility. Electron microscopy analysis of spermatozoa did not reveal any homogeneous abnormality. Moreover, a psychological approach pointed to a decreased self-confidence linked to blindness and obesity explaining why so few BBS patients express a child wish. CONCLUSIONS: Primary cilia dysfunction in BBS impacts the embryology of the male genital tract, especially epididymis, penis, and scrotum through an insufficient fetal androgen production. However, in adults, sperm structure does not seem to be impacted. These results should be confirmed in a greater BBS patient cohort, focusing on fertility.


Assuntos
Síndrome de Bardet-Biedl/fisiopatologia , Doenças dos Genitais Masculinos/fisiopatologia , Adolescente , Adulto , Síndrome de Bardet-Biedl/complicações , Doenças dos Genitais Masculinos/etiologia , Genitália Masculina/fisiopatologia , Humanos , Masculino , Análise do Sêmen , Espermatozoides/ultraestrutura , Adulto Jovem
10.
J Med Genet ; 57(3): 160-168, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31586944

RESUMO

BACKGROUND: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro. METHODS: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients. RESULTS: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.


Assuntos
Anormalidades Múltiplas/genética , Desenvolvimento Fetal/genética , Retardo do Crescimento Fetal/genética , Transtornos do Crescimento/genética , Receptor IGF Tipo 1/genética , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Nanismo/genética , Nanismo/fisiopatologia , Feminino , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/fisiopatologia , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like II/genética , Masculino , Microcefalia/genética , Microcefalia/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptores de Somatomedina/genética
11.
Appl Spectrosc ; 73(12): 1361-1369, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31315423

RESUMO

Knowledge of alkaline silicate solutions is crucial in order to optimize geopolymer properties. Geopolymers are new binders resulting from the activation of an aluminosilicate by an alkaline solution. It is well established that the solution reactivity strongly affects the geopolymerization and therefore the geopolymer working properties. As a consequence, an evaluation of the reactivity degree of alkaline silicate solutions prior synthesis is of the utmost interest. However, the determination of the solution reactivity is currently tedious, and for geopolymer commercialization, it would be necessary to find an easy way to determine it. Therefore, Raman spectroscopy, combined with chemometric techniques, is proposed as a solution to easily determine the alkaline silicate solution reactivity. To conduct this investigation, 65 silicate solutions were characterized by Raman spectroscopy, and reference values of their reactivity degree were determined. Finally, principal component analysis and partial least squares regression were performed to build a statistical model able to predict the alkaline silicate solution reactivity from Raman spectra.

12.
Horm Res Paediatr ; 92(2): 133-142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31022718

RESUMO

BACKGROUND: The paradox of normal growth despite a lack of growth hormone (GH) is an unexplained phenomenon described in some pathological (sellar, suprasellar, and hypothalamic disorders) and overgrowth syndromes. It has been suggested that the paradoxical growth is due to other GH variants, GH-like moieties, prolactin, insulin, insulin-like growth factors (IGFs), and unidentified serum factors or growth mechanisms. The objective of this study was to determine the mechanism underlying this normal growth without GH. CASE DESCRIPTION: We describe here growth, hormonal, and genetic analyses for an adolescent boy with panhypopituitarism who achieved an adult height above his genetic potential. RESULTS: Normal growth was observed despite low serum GH, IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) concentrations, but the IGF-II/IGFBP-3 molar ratio was slightly high. Panhypopituitarism was associated with a heterozygous missense mutation of HESX1, with variable penetrance in heterozygous relatives. Exome analysis detected heterozygous missense mutations of various genes involved in intracellular signaling pathways. The growth-promoting activity of the patient's serum was unable to induce AKT phosphorylation in the MCF-7 cell line. CONCLUSION: The high IGF-II/IGFBP-3 molar ratio was not the cause of the sustained high growth velocity, due to the low affinity of IGF-II for IGF type 1 receptor. The key finding was the HESX1 mutation, as similar cases have been described before, suggesting a common mechanism for growth without GH. However, the variable penetrance of this variant in heterozygous relatives suggests that modifier genes or mechanisms involving combinations with mutations of other genes involved in intracellular signaling pathways might be responsible.


Assuntos
Proteínas de Homeodomínio/genética , Hormônio do Crescimento Humano/sangue , Hipopituitarismo , Mutação , Adolescente , Adulto , Proteínas de Homeodomínio/sangue , Hormônio do Crescimento Humano/genética , Humanos , Hipopituitarismo/sangue , Hipopituitarismo/genética , Hipopituitarismo/fisiopatologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Células MCF-7 , Masculino
13.
Environ Sci Pollut Res Int ; 26(14): 14473-14482, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30877539

RESUMO

The aims of this study correspond to (i) determine the feasibility of synthesize geomaterial from two main Pb-contaminated mining sediments (Sed1 and Sed2) without prior activation in substitution to metakaolin (MK), (ii) understand the mechanisms involved toward two types of silicate solution (Na and K one), and (iii) to evaluate the change in the Pb metallic element speciation and leaching after alkali treatment. The raw material as well as consolidated material were characterized by X-ray diffraction, infrared spectroscopy, and electron microscopy. The mechanical properties were evaluated, and the leaching behavior realized according to EN12457-2. The results evidence the limit of mining sediment incorporation by substitution near 50% whatever the sediments and the alkaline solution used. There is no difference in the mechanical properties up to 10% substitution then decrease with the increase of sediment content. The Pb-bearing phases are dissolved during alkaline treatment and redistributed in the geomaterial matrix. Finally, the leaching experiments clearly evidenced the possibility to stabilize Pb into MK-based geomaterial matrix up to 25-30% weight of mine waste.


Assuntos
Recuperação e Remediação Ambiental/métodos , Sedimentos Geológicos/química , Caulim/química , Chumbo/química , Mineração , Poluentes do Solo/química , Difração de Raios X
14.
Sci Adv ; 5(2): eaau9425, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30801013

RESUMO

Imprinting disorders (IDs) often affect growth in humans, leading to diseases with overlapping features, regardless of the genomic region affected. IDs related to hypomethylation of the human 14q32.2 region and its DLK1/MEG3 domain are associated with Temple syndrome (TS14). TS14 is a rare type of growth retardation, the clinical signs of which overlap considerably with those of Silver-Russell syndrome (SRS), another ID related to IGF2 down-regulation at 11p15.5 region. We show that 14q32.2 hypomethylation affects expression, not only for genes at this locus but also for other imprinted genes, and especially lowers IGF2 levels at 11p15.5. Furthermore, expression of nonimprinted genes is also affected, some of which are also deregulated in SRS patients. These findings highlight the epigenetic regulation of gene expression at the DLK1/MEG3 domain. Expression profiling of TS14 and SRS patients highlights common signatures, which may account for the clinical overlap observed between TS14 and SRS.


Assuntos
Proteínas de Ligação ao Cálcio , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Metilação de DNA , Epigênese Genética , Impressão Genômica , Proteínas de Membrana , Síndrome de Silver-Russell , Proteínas de Ligação ao Cálcio/biossíntese , Proteínas de Ligação ao Cálcio/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 11/metabolismo , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 14/metabolismo , Feminino , Humanos , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismo
16.
J Clin Endocrinol Metab ; 103(7): 2436-2446, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659920

RESUMO

Context: Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective: To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients: We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results: Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions: Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , Síndrome de Silver-Russell/genética , Adolescente , Adulto , Proteínas de Ligação ao Cálcio , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Metilação de DNA/genética , Diagnóstico Diferencial , Feminino , Impressão Genômica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Proteínas de Membrana/genética , Fenótipo , Puberdade Precoce/genética , RNA Longo não Codificante/genética , Estudos Retrospectivos , Síndrome de Silver-Russell/diagnóstico , Síndrome , Dissomia Uniparental , Adulto Jovem
17.
Hum Mutat ; 39(6): 790-805, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29637653

RESUMO

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications).


Assuntos
Arritmias Cardíacas/genética , Genes Ligados ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Glipicanas/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Arritmias Cardíacas/patologia , Códon sem Sentido/genética , Feminino , Mutação da Fase de Leitura/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/patologia , Masculino , Linhagem , Fenótipo
18.
Nat Rev Endocrinol ; 14(4): 229-249, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29377879

RESUMO

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/terapia , Consenso , Síndrome de Beckwith-Wiedemann/complicações , Síndrome de Beckwith-Wiedemann/genética , Variações do Número de Cópias de DNA , Metilação de DNA , Humanos , Técnicas de Diagnóstico Molecular , Neoplasias Embrionárias de Células Germinativas/etiologia , Polimorfismo de Nucleotídeo Único , Diagnóstico Pré-Natal , Técnicas de Reprodução Assistida
19.
J Med Genet ; 55(3): 205-213, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29223973

RESUMO

BACKGROUND: The 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex. OBJECTIVES: To report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations. METHODS: From a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain. RESULTS: Large duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C. CONCLUSIONS: The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Duplicação Gênica/genética , Impressão Molecular , Síndrome de Silver-Russell/genética , Adulto , Síndrome de Beckwith-Wiedemann/patologia , Centrômero/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Análise Citogenética , Feminino , Humanos , Fator de Crescimento Insulin-Like II/genética , Masculino , Mutação , Fenótipo , Síndrome de Silver-Russell/patologia , Telômero/genética
20.
J Am Med Dir Assoc ; 17(7): 671.e1-7, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27236544

RESUMO

OBJECTIVES: To determine the rate of inappropriate admissions to emergency departments (EDs) and to identify determinants of these admissions. DESIGN: Prospective multicenter study. SETTING: Burgundy (France), EDs and medical nursing homes (MNHs). PARTICIPANTS: 1000 Burgundy MNH residents admitted to EDs, from April 17 to June 20, 2013. MEASUREMENTS: For each subject, a questionnaire was completed. Data included age, gender, type of health professional who referred the resident to the ED (THP), whether or not a medical dispatcher organized the transfer to the ED, transport mode, reason for admission to the ED, level of independence according to the Groupes Iso-Ressource score (GIRS), and diagnosis made in the ED. The French version of the Appropriateness Evaluation Protocol grid was applied to each admission to the ED, and in some situations, the expert committee ruled on the appropriateness of the admission to the ED. MNH characteristics were also recorded. Two groups were constituted according to the appropriateness or not of admission to the ED. RESULTS: Mean age of the 1000 residents was 87. There were 706 women. Two-thirds were referred to the EDs by a physician, mainly a general practitioner. In 91.7%, the transfer to the ED was organized by a medical dispatcher, and 8.8% were transported by medicalized transport. More than 95% had a GIRS ≤4. Among the admissions to EDs, 18.1% were inappropriate. Female gender (P = .017), nonmedicalized transport (P = .002), public MNH (P = .044), and nonaccess to a geriatric opinion in an emergency (P = .043) were determinants of inappropriate admission to EDs. CONCLUSION: In this first study on admissions to EDs of MNH residents using French data, we found a lower rate of admissions to the ED than that reported in the literature. Female gender, nonmedicalized transport, public MNH, and nonaccess to a geriatric opinion in an emergency were associated with inappropriate admission to EDs.


Assuntos
Serviço Hospitalar de Emergência/estatística & dados numéricos , Mau Uso de Serviços de Saúde/tendências , Casas de Saúde , Admissão do Paciente/tendências , Idoso de 80 Anos ou mais , Feminino , França , Humanos , Masculino , Estudos Prospectivos
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