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AIMS/HYPOTHESIS: Our study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes. METHODS: In the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA1c, time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison. RESULTS: We included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (-0.52 [-0.54, -0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (-0.21 [-0.25, -0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management.
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Glucemia , Diabetes Mellitus Tipo 1 , Hemoglobina Glucada , Fenotipo , Humanos , Diabetes Mellitus Tipo 1/sangre , Femenino , Masculino , Glucemia/metabolismo , Adulto , Hemoglobina Glucada/metabolismo , Persona de Mediana Edad , Análisis por Conglomerados , AlgoritmosRESUMEN
PURPOSE: Recessive deficiency of proopiomelanocortin (POMC) causes childhood-onset severe obesity. Cases can now benefit from the melanocortin 4 receptor agonist setmelanotide. Furthermore, a phase 3 clinical trial is evaluating setmelanotide in heterozygotes for POMC. We performed a large-scale genetic analysis to assess the effect of heterozygous, pathogenic POMC variants on obesity. METHODS: A genetic analysis was performed in a family including 2 cousins with childhood-onset obesity. We analyzed the obesity status of heterozygotes for pathogenic POMC variants in the Human Gene Mutation Database. The association between heterozygous pathogenic POMC variants and obesity risk was assessed using 190,000 exome samples from UK Biobank. RESULTS: The 2 cousins carried a compound heterozygous pathogenic variant in POMC. Six siblings were heterozygotes; only 1 of them had obesity. In Human Gene Mutation Database, we identified 60 heterozygotes for pathogenic POMC variants, of whom 14 had obesity. In UK Biobank, heterozygous pathogenic POMC variants were not associated with obesity risk, but they modestly increased body mass index levels. CONCLUSION: Heterozygous pathogenic POMC variants do not contribute to monogenic obesity, but they slightly increase body mass index. Setmelanotide use in patients with obesity, which would only be based on the presence of a heterozygous POMC variant, can be questioned.
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Obesidad Infantil , Proopiomelanocortina , Niño , Humanos , Índice de Masa Corporal , Heterocigoto , Mutación , Obesidad/genética , Obesidad Infantil/genética , Proopiomelanocortina/genética , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/agonistas , Fármacos Antiobesidad/uso terapéuticoRESUMEN
BACKGROUND: The overall natural history, risk of death and surgical burden of patients with multiple endocrine neoplasia type 1 (MEN1) is not well known. METHODS: Patients with MEN1 from a nationwide cohort were included. The survival of patients with MEN1 was compared with that of the general population using simulated controls. The cumulative probabilities of MEN1-specific operations and postoperative mortality were assessed, and surgical sequences were analysed using sunburst charts and Venn diagrams. RESULTS: A total of 1386 patients with MEN1 were included. Life expectancy was significantly reduced in patients with MEN1 compared with simulated controls from the general population, with a lifetime difference of 15 years. Mutations affecting the JunD interaction domain had a significant negative impact on survival. Survival for patients with MEN1 compared with the general population improved over time. The probability of experiencing at least one specific MEN1 operation was above 95 per cent after 75 years, and most patients had surgery at least twice during their lifetime. Time to a 50 per cent risk of MEN1 surgery was 30.5 years for patients born after 1960, compared with 47.9 years for those born before 1960. Sex and mutations affecting the JunD interacting domain had no impact on time to first surgery. There was considerable heterogeneity in surgical sequences, with no specific clinical pathway. CONCLUSION: Life expectancy was significantly lower among patients with MEN1 compared with the general population, and further decreased in patients with mutations affecting the JunD interacting domain. Almost all patients underwent at least one MEN1-specific operation during their lifetime, but there was no standardized sequence of surgery.
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Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias Pancreáticas , Estudios de Cohortes , Humanos , Esperanza de Vida , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Mutación , Neoplasias Pancreáticas/cirugía , ProbabilidadRESUMEN
AIMS: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. METHODS: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c (IQR) and proportions of individuals with HbA1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. RESULTS: Median HbA1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c < 58 mmol/l (<7.5%) increased and proportions of people with HbA1c ≥ 75 mmol/mol (≥9.0%) decreased. CONCLUSIONS: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.
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Diabetes Mellitus Tipo 1 , Adulto , Glucemia , Niño , Estudios Transversales , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Hemoglobina Glucada/análisis , Control Glucémico , Humanos , MasculinoRESUMEN
We report here the first case of life-threatening hypomagnesemia in a Zollinger-Ellison syndrome patient with multiple endocrine neoplasia type 1 (MEN1) syndrome. The severe symptomatic hypomagnesemia proved to be due to proton pump inhibitors (PPIs), but withdrawal of PPIs led to early severe peptic complications despite a substitution by histamine H2-receptor antagonist therapy. Simultaneous management of life-threatening hypomagnesemia, severe gastric acid hypersecretion and MEN1-associated gastrinomas was complex. A total gastrectomy was performed in order to definitely preclude the use of PPIs in this frail patient who was not eligible for curative pancreatoduodenal resection.
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Gastrectomía/métodos , Deficiencia de Magnesio/inducido químicamente , Deficiencia de Magnesio/cirugía , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Inhibidores de la Bomba de Protones/efectos adversos , Síndrome de Zollinger-Ellison/cirugía , Fragilidad , Humanos , Masculino , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Úlcera Péptica/tratamiento farmacológico , Estómago/patología , Resultado del Tratamiento , Síndrome de Zollinger-Ellison/complicacionesRESUMEN
BACKGROUND: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. RESULTS: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. CONCLUSION: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.
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Anosmia/genética , Síndrome del Nevo Basocelular/diagnóstico , Síndrome del Nevo Basocelular/genética , Hipogonadismo/genética , Síndrome de Kallmann/diagnóstico , Síndrome de Kallmann/genética , Receptor Patched-1/genética , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , MutaciónRESUMEN
A post hoc analysis of the Diabeloop WP7 multicentre, randomized controlled trial was performed to investigate the efficacy of the Diabeloop Generation-1 (DBLG1) closed-loop system in controlling the hypoglycaemia induced by physical activity (PA) in real-life conditions. Glycaemic outcomes were compared between days with and without PA in 56 patients with type 1 diabetes (T1D) using DBLG1 for 12 weeks. After the patient announces a PA, DBLG1 reduces insulin delivery and, if necessary, calculates the amount of preventive carbohydrates (CHO). Daily time spent in the interstitial glucose range less than 70 mg/dL was not significantly different between days with and without PA (2.0% ± 1.5% vs. 2.2% ± 1.1%), regardless of the intensity or duration of the PA. Preventive CHO intake recommended by the system was significantly higher in days with PA (41.1 ± 35.5 vs. 21.8 ± 28.5 g/day; P < .0001), and insulin delivery was significantly lower (31.5 ± 10.5 vs. 34.0 ± 10.5 U/day; P < .0001). The time spent in hyperglycaemia and the glycaemic variation coefficient increased significantly on days with PA. In real-life conditions, the use of DBLG1 avoids PA-induced hypoglycaemia. Insulin adjustments and preventive CHO recommendation may explain this therapeutic benefit.
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Diabetes Mellitus Tipo 1 , Hipoglucemia , Glucemia , Estudios Cruzados , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Dieta , Ejercicio Físico , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Sistemas de Infusión de InsulinaRESUMEN
OBJECTIVE: Pregnancy in patients with macroprolactinomas has been associated with a higher risk of pituitary tumour growth. However, the incidence and risk factors remain unclear. We aimed to evaluate the evolution of macroprolactinomas during pregnancy and to identify potential risk factors. DESIGN, PATIENTS AND MEASUREMENTS: This is a two-centre, retrospective, observational study. All patients with macroprolactinomas, treated with a dopamine receptor agonist (DA), and who had at least one pregnancy were included. RESULTS: There were a total of 85 viable pregnancies in 46 patients with macroprolactinomas. At diagnosis, mean size of pituitary adenomas was 17.9 ± 8.2 mm (10-43 mm) and mean plasma prolactin level was 1012.2 ± 1606.1 µg/L (60-7804 µg/L). Tumour growth-related symptoms were identified 12 times in 9 patients (19.6%) including 3 cases of apoplexy. Restarting, changing and/or increasing DA treatment was effective in 10 cases. Emergency surgery had to be performed twice (due to pituitary apoplexy). Patients with tumour progression tended to present with larger tumours after initial treatment and before pregnancy (9.9 vs 5.9 mm; P = .0504 and 11.5 vs 7.3 mm; P = .0671, respectively), whereas adenoma size at diagnosis did not seem to be a significant factor. The obstetrical outcomes were comparable to the general population. CONCLUSIONS: Symptomatic growth of macroprolactinoma during pregnancy occurred in 19.6% of medically treated patients. This risk seems higher for patients with poor initial tumour response to the DA treatment. Tumour progression is generally well controlled with medical treatment during pregnancy.
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Neoplasias Hipofisarias , Prolactinoma , Estudios de Cohortes , Agonistas de Dopamina/uso terapéutico , Femenino , Humanos , Neoplasias Hipofisarias/tratamiento farmacológico , Embarazo , Prolactina , Prolactinoma/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Primary ovarian insufficiency (POI) is a frequently occurring disease affecting women under 40 years old. Recently, we have analyzed unrelated POI women via whole exome sequencing (WES) and identified NOTCH2 mutations underlying possible functional effects. The present study involved reanalyzing of WES assays. We used in the KGN granulosa-like cell model, a synthetic gene reporter construct driving luciferase gene expression to assess the functional effects of five NOTCH2 mutations identified in POI patients. We found that NOTCH2-p.Ser1804Leu, p.Ala2316Val, and p.Pro2359Ala mutations had a functional impact on the protein's transcriptional activity. The results have demonstrated for the first time that NOTCH2 mutations contribute to POI etiology. We therefore recommend sequencing NOTCH2's open reading frame in large panels of POI patients to establish an accurate genotype-phenotype correlation. We cannot rule out the fact that patients affected by Alagille syndrome carrying NOTCH2 mutations may suffer ovarian dysfunction.
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Predisposición Genética a la Enfermedad , Mutación Missense/genética , Insuficiencia Ovárica Primaria/genética , Receptor Notch2/genética , Secuencia de Aminoácidos , Femenino , Humanos , Receptor Notch2/química , Transcripción GenéticaRESUMEN
PURPOSE: Primary ovarian insufficiency (POI) is a frequent disorder that affects ~1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone (FSH), leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene variants, most cases remain idiopathic. The aim of the present study was to identify and validate functionally new sequence variants in ATG (autophagy-related genes) leading to POI. METHODS: We have reanalyzed, in silico, the exome sequencing data from a previously reported work performed in 69 unrelated POI women. Functional experiments using a classical hallmark of autophagy, the microtubule-associated protein 1 light chain 3ß (LC3), were then used to link these genes to this lysosomal degradation pathway. RESULTS: We venture a functional link between ATG7 and ATG9A variants and POI. We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve. CONCLUSION: Our results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.
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Proteína 7 Relacionada con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/genética , Autofagia/genética , Proteínas de la Membrana/genética , Insuficiencia Ovárica Primaria/genética , Proteínas de Transporte Vesicular/genética , Adulto , Femenino , Hormona Folículo Estimulante/genética , Predisposición Genética a la Enfermedad , Humanos , Mutación con Pérdida de Función/genética , Menopausia Prematura/genética , Insuficiencia Ovárica Primaria/patología , Secuenciación del ExomaRESUMEN
STUDY QUESTION: Does the phenotype of women with normosmic congenital hypogonadotrophic hypogonadism (nCHH) and pituitary resistance to GnRH caused by biallelic mutations in the GnRH receptor (GNRHR) (nCHH/bi-GNRHR) differ from that of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with nCHH/bi-GNRHR have variable pubertal development but nearly all have primary amenorrhea and an exaggerated LH response to GnRH stimulation, similar to that seen in women with PCOS. WHAT IS KNOWN ALREADY: Women with nCHH/bi-GNRHR are very rare and their phenotype at diagnosis is not always adequately documented. The results of gonadotrophin stimulation by acute GnRH challenge test and ovarian features have not been directly compared between these patients and women with PCOS. STUDY DESIGN, SIZE, DURATION: We describe the phenotypic spectrum at nCHH/bi-GNRHR diagnosis in a series of 12 women. Their reproductive characteristics and acute responses to GnRH were compared to those of 70 women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients and controls (healthy female volunteers aged over 18 years) were enrolled in a single French referral centre. Evaluation included clinical and hormonal studies, pelvic ultrasonography and GnRH challenge test. We also functionally characterized two missense GNRHR mutations found in two new consanguineous families. MAIN RESULTS AND THE ROLE OF CHANCE: Breast development was highly variable at nCHH/bi-GNRHR diagnosis, but only one patient had undeveloped breasts. Primary amenorrhea was present in all but two cases. In untreated nCHH/bi-GNRHR patients, uterine height (UH) correlated (P = 0.01) with the circulating estradiol level and was shorter than in 23 nulliparous post-pubertal age-matched controls (P < 0.0001) and than in 15 teenagers with PCOS under 20-years-old (P < 0.0001) in which PCOS was revealed by primary amenorrhea or primary-secondary amenorrhea. Unexpectedly, the stimulated LH peak response in nCHH/bi-GNRHR patients was variable, and often normal or exaggerated. Interestingly, the LH peak response was similar to that seen in the PCOS patients, but the latter women had significantly larger mean ovarian volume (P < 0.001) and uterine length (P < 0.001) and higher mean estradiol (P < 0.001), anti-Müllerian hormone (AMH) (P = 0.02) and inhibin-B (P < 0.001) levels. In the two new consaguineous families, the affected nCHH/bi-GNRHR women carried the T269M or Y290F GNRHR missense mutation in the homozygous state. In vitro analysis of GnRHR showed complete or partial loss-of-function of the T269M and Y290F mutants compared to their wildtype counterpart. LIMITATIONS, REASONS FOR CAUTION: The number of nCHH/bi-GNRHR patients reported here is small. As this disorder is very rare, an international study would be necessary to recruit a larger cohort and consolidate the phenotypic spectrum observed here. WIDER IMPLICATIONS OF THE FINDINGS: In teenagers and young women with primary amenorrhea, significant breast and uterine development does not rule out CHH caused by biallelic GNRHR mutations. In rare patients with PCOS presenting with primary amenorrhea and a mild phenotype, the similar exaggerated pituitary LH responses to GnRH in PCOS and nCHH/bi-GNRHR patients could lead to diagnostic errors. This challenge test should therefore not be recommended. As indicated by consensus and guidelines, careful analysis of clinical presentation and measurements of testosterone circulating levels remain the basis of PCOS diagnosis. Also, analysis of ovarian volume, UH and of inhibin-B, AMH, estradiol and androgen circulating levels could help to distinguish between mild PCOS and nCHH/bi-GNRHR. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the French National Research Agency (ANR) grant ANR-09-GENO-017 KALGENOPATH, France; and by the Italian Ministry of Education, University and Research (MIUR) grant PRIN 2012227FLF_004, Italy. The authors declare no conflict of interest.
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Amenorrea/fisiopatología , Hipogonadismo/fisiopatología , Fenotipo , Síndrome del Ovario Poliquístico/fisiopatología , Receptores LHRH/genética , Adolescente , Adulto , Amenorrea/etiología , Mama/crecimiento & desarrollo , Diagnóstico Diferencial , Femenino , Humanos , Hipogonadismo/complicaciones , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Mutación , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/diagnóstico , Reproducción/fisiología , Útero/crecimiento & desarrollo , Adulto JovenRESUMEN
BACKGROUND: Germline mutations in the SDHD tumour suppressor gene (11q23.1) predispose to phaeochromocytomas and paragangliomas (PPGL) mainly on a paternal transmission. However, PPGL have been recently reported in three carriers of a maternally inherited SDHD mutation. OBJECTIVE: To assess the risk of PPGL occurrence on maternal transmission of SDHD mutation. METHODS: Pedigrees of 80 SDHD-related families have been reviewed. 35 asymptomatic subjects carrying a maternally transmitted SDHD mutation were identified. 20 of them accepted to benefit from a PPGL imaging screening. RESULTS: A unique histologically proven biochemically negative phaeochromocytoma has been diagnosed in a 35-year-old woman. Molecular investigations carried out on tumour tissue revealed that the loss of heterozygosity encompassed the paternally derived q arm and the maternally derived p arm of chromosome 11. CONCLUSIONS: This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18â years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers.
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Neoplasias de las Glándulas Suprarrenales/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , Adolescente , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Cromosomas Humanos Par 11/genética , Femenino , Pruebas Genéticas , Mutación de Línea Germinal/genética , Heterocigoto , Humanos , Pérdida de Heterocigocidad/genética , Herencia Materna/genética , Paraganglioma/patología , Linaje , Feocromocitoma/patología , Medición de RiesgoRESUMEN
STUDY QUESTION: Is it possible to identify new mutations potentially associated with non-syndromic primary ovarian insufficiency (POI) via whole-exome sequencing (WES)? SUMMARY ANSWER: WES is an efficient tool to study genetic causes of POI as we have identified new mutations, some of which lead to protein destablization potentially contributing to the disease etiology. WHAT IS KNOWN ALREADY: POI is a frequently occurring complex pathology leading to infertility. Mutations in only few candidate genes, mainly identified by Sanger sequencing, have been definitively related to the pathogenesis of the disease. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study performed on 69 women affected by POI. PARTICIPANTS/MATERIALS, SETTING, METHODS: WES and an innovative bioinformatics analysis were used on non-synonymous sequence variants in a subset of 420 selected POI candidate genes. Mutations in BMPR1B and GREM1 were modeled by using fragment molecular orbital analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Fifty-five coding variants in 49 genes potentially related to POI were identified in 33 out of 69 patients (48%). These genes participate in key biological processes in the ovary, such as meiosis, follicular development, granulosa cell differentiation/proliferation and ovulation. The presence of at least two mutations in distinct genes in 42% of the patients argued in favor of a polygenic nature of POI. LIMITATIONS, REASONS FOR CAUTION: It is possible that regulatory regions, not analyzed in the present study, carry further variants related to POI. WIDER IMPLICATIONS OF THE FINDINGS: WES and the in silico analyses presented here represent an efficient approach for mapping variants associated with POI etiology. Sequence variants presented here represents potential future genetic biomarkers. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Universidad del Rosario and Colciencias (Grants CS/CIGGUR-ABN062-2016 and 672-2014). Colciencias supported Liliana Catherine Patiño´s work (Fellowship: 617, 2013). The authors declare no conflict of interest.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización Intercelular/genética , Modelos Moleculares , Mutación , Insuficiencia Ovárica Primaria/genética , Adulto , Sustitución de Aminoácidos , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/química , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Estudios de Cohortes , Biología Computacional , Sistemas Especialistas , Femenino , Francia , Estudio de Asociación del Genoma Completo , Humanos , Péptidos y Proteínas de Señalización Intercelular/química , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Simulación de Dinámica Molecular , Polimorfismo de Nucleótido Simple , Insuficiencia Ovárica Primaria/metabolismo , Estabilidad Proteica , Derivación y Consulta , Estudios Retrospectivos , Secuenciación del Exoma , Adulto JovenRESUMEN
Generalized glucocorticoid resistance is associated with glucocorticoid receptor (GR; NR3C1) mutations. Three novel heterozygous missense NR3C1 mutations (R477S, Y478C, and L672P) were identified in patients presenting with adrenal incidentalomas, glucocorticoid excess without Cushing syndrome. Dexamethasone (DXM) binding studies demonstrated that the affinity of GRR477S and GRY478C mutants, located in the DNA-binding domain (DBD) of GR, was similar to wild-type GR (Kd = 2-3 nM). In contrast, GRL672P mutant, located in the ligand-binding domain (LBD) of GR, was unable to bind glucocorticoids and was more sensitive to protein degradation. GR subcellular distribution revealed a marked decrease in DXM-induced nuclear translocation of GRR477S and GRY478C mutants, whereas GRL672P remained exclusively cytoplasmic. Chromatin immunoprecipitation demonstrated impaired recruitment of DBD mutants onto the regulatory sequence of FKBP5. Transactivation assays disclosed the lack of transcriptional activity of GRR477S and GRL672P , whereas GRY478C had a reduced transactivation capacity. Three-dimensional modeling indicated that R477S lost two essential hydrogen bonds with DNA, Y478C resulted in altered interaction with surrounding amino-acids, destabilizing DBD, whereas L672P altered the H8 helix folding, leading to unstructured LBD. This study identifies novel NR3C1 mutations with their molecular consequences on altered GR signaling and suggests that genetic screening of NR3C1 should be conducted in patients with subclinical hypercorticism.
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Neoplasias de las Glándulas Suprarrenales/genética , Resistencia a Antineoplásicos , Glucocorticoides/farmacología , Mutación Puntual , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Adulto , Animales , Sitios de Unión , Células COS , Núcleo Celular/metabolismo , Chlorocebus aethiops , Síndrome de Cushing/genética , Citoplasma/metabolismo , ADN de Neoplasias/metabolismo , Dexametasona/farmacología , Femenino , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Mutación Missense , Estructura Secundaria de Proteína , Transporte de Proteínas , Receptores de Glucocorticoides/metabolismoRESUMEN
OBJECTIVES: To quantify serum advanced glycation end-products (AGEs) at the onset of type 1 diabetes mellitus and to determine their potential usefulness as retrospective indicators of glycemic balance. STUDY DESIGN: Carboxymethyllysine (CML) and pentosidine concentrations were determined by liquid chromatography-tandem mass spectrometry in 3 groups of children with type 1 diabetes mellitus: group (Gr) 1, subjects included at disease onset (n = 36); Gr2, subjects with diabetes of 5 years duration (n = 48); Gr3, subjects with diabetes of 10 years duration and in control subjects (n = 33). Hemoglobin A1c (HbA1c) values were recorded over the entire course of treatment for assessing long-term glycemic balance. RESULTS: Serum AGE concentrations were increased in all groups of subjects with diabetes compared with control subjects, but were highest in Gr1 (for CML: 0.155, 0.306, 0.219, and 0.224 mmol/mol Lys in control, Gr1, Gr2, and Gr3 subjects, respectively; for pentosidine: 312, 492, 365, and 403 nmol/mol Lys, respectively). AGE concentrations were closely correlated with HbA1c values (r = 0.78 for CML; r = 0.49 for pentosidine). In Gr2 and Gr3, the overall glycemic balance estimated by average HbA1c values was positively correlated with CML and pentosidine concentrations, especially in the first year of follow-up. CONCLUSION: Our results indicate that AGE concentrations are elevated in serum at the time of diabetes mellitus diagnosis, suggesting that the deleterious role of AGEs in the development of long-term complications should be taken into account even at the initial stages of the disease. Moreover, in some circumstances, AGEs could serve as surrogate markers of HbA1c for monitoring glycemic control.
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Glucemia/análisis , Diabetes Mellitus Tipo 1/sangre , Hemoglobina Glucada/análisis , Productos Finales de Glicación Avanzada/sangre , Índice Glucémico/fisiología , Niño , Cromatografía Liquida , Estudios Transversales , Humanos , Espectrometría de Masas en TándemRESUMEN
STUDY QUESTION: What are the prevalence and the outcomes of spontaneous pregnancies (SP) in a large cohort of French women with Turner syndrome (TS)? SUMMARY ANSWER: Amongst 480 women with TS, 27 women (5.6%) had a total of 52 SP, with 30 full-term deliveries for 18 women. WHAT IS KNOWN ALREADY: Primary ovarian insufficiency is a classic feature of TS. So far, few studies have evaluated the rate of SP in these patients. STUDY DESIGN, SIZE, DURATION: The French Ministry of Health set up a National Reference Centre for Rare Growth Disorders (CRMERC), including TS. We studied a cohort of adult TS patients from seven endocrine units (Saint-Antoine, Pitié-Salpêtrière, Bicêtre, Lyon, Marseille, Brest, Reims Hospitals) belonging to this centre, between January 1999 and January 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 480 adult patients with TS were included. The patients' clinical characteristics, karyotypes and reproductive histories had been collected, after informed consent, in a web database called CEMARA. Our reference population was issued from a database belonging to the French Health Ministry, collecting pregnancy outcomes in the French general population. In order to find predictive characteristics of SP, TS with spontaneous pregnancies were compared with non-pregnant TS patients from our cohort. MAIN RESULTS AND THE ROLE OF CHANCE: There were 27 patients (5.6%) who had a total of 52 SP. The two predictive factors which correlated with occurrence of a SP were spontaneous menarche and mosaic karyotype. The median delay to conception was 6 months (range 0-84). Miscarriage occurred in 16 pregnancies, 30.8% versus 15% in the general French population (P < 0.01). The remaining pregnancy outcomes were legal abortion (n = 2), medical interruption (n = 3), intrauterine fetal death (n = 1) and delivery at term (n = 30). Caesarean section rates were higher than in the general population, respectively 46.7% versus 21% (P < 0.001). Pregnancy-induced hypertensive disorders (PHDs) occurred in four cases (13.3%), including two cases of mild pre-eclampsia (6.7%). Neither aortic root dilatation nor aortic dissection were observed. The median birthweight was 3030 g (range 2020-3460). Two cases of TS were identified in the 17 daughters issued from this cohort. LIMITATIONS, REASONS FOR CAUTION: It would have been interesting to evaluate AMH levels and SP occurrence, as a predictive factor. Unfortunately, hormonal measurements were missing for some patients. Prospective studies are necessary to display prognostic values of AMH for SP and thus better target fertility preservation programmes in TS patients. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that pregnancy outcomes in SPs are more favourable than those after oocyte donation in TS patients. However, the risk of fetal chromosomal abnormalities remains high. Our study will be useful in order to give patients with TS, their families, paediatricians and physicians involved in reproduction, better counselling concerning their fertility. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by the Association pour la recherche Claude Bernard, Paris France All authors claim no competing interests. TRIAL REGISTRATION NUMBER: NA.
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Fertilidad , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Insuficiencia Ovárica Primaria/etiología , Síndrome de Turner/fisiopatología , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Menarquia , Persona de Mediana Edad , Mosaicismo , Embarazo , Complicaciones Cardiovasculares del Embarazo/genética , Resultado del Embarazo , Índice de Embarazo , Sistema de Registros , Historia Reproductiva , Tiempo para Quedar Embarazada , Síndrome de Turner/genética , Adulto JovenRESUMEN
OBJECTIVES: To study linear and volumetric adrenal measurements, their reproducibility, and correlations between total adrenal volume (TAV) and adrenal micronodularity, age, gender, body mass index (BMI), visceral (VAAT) and subcutaneous adipose tissue volume (SAAT), presence of diabetes, chronic alcoholic abuse and chronic inflammatory disease (CID). METHODS: We included 154 patients (M/F, 65/89; mean age, 57 years) undergoing abdominal multidetector row computed tomography (MDCT). Two radiologists prospectively independently performed adrenal linear and volumetric measurements with semi-automatic software. Inter-observer reliability was studied using inter-observer correlation coefficient (ICC). Relationships between TAV and associated factors were studied using bivariate and multivariable analysis. RESULTS: Mean TAV was 8.4 ± 2.7 cm(3) (3.3-18.7 cm(3)). ICC was excellent for TAV (0.97; 95 % CI: 0.96-0.98) and moderate to good for linear measurements. TAV was significantly greater in men (p < 0.0001), alcoholics (p = 0.04), diabetics (p = 0.0003) and those with micronodular glands (p = 0.001). TAV was lower in CID patients (p = 0.0001). TAV correlated positively with VAAT (r = 0.53, p < 0.0001), BMI (r = 0.42, p < 0.0001), SAAT (r = 0.29, p = 0.0003) and age (r = 0.23, p = 0.005). Multivariable analysis revealed gender, micronodularity, diabetes, age and BMI as independent factors influencing TAV. CONCLUSIONS: Adrenal gland MDCT-based volumetric measurements are more reproducible than linear measurements. Gender, micronodularity, age, BMI and diabetes independently influence TAV. KEY POINTS: ⢠Volumetric measurements are more reproducible than linear measurements for adrenal glands. ⢠Inter-observer reproducibility of adrenal gland volume is excellent using semiautomatic software. ⢠Gender, age, BMI, and diabetes independently influence total adrenal gland volume. ⢠Adrenal micronodularity is associated with increased total adrenal gland volume.
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Glándulas Suprarrenales/anatomía & histología , Glándulas Suprarrenales/diagnóstico por imagen , Tomografía Computarizada Multidetector/métodos , Glándulas Suprarrenales/fisiología , Factores de Edad , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Diabetes Mellitus/fisiopatología , Femenino , Humanos , Imagenología Tridimensional/métodos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Tamaño de los Órganos , Estudios Prospectivos , Valores de Referencia , Reproducibilidad de los Resultados , Factores SexualesRESUMEN
BACKGROUND: This present retrospective case control study was designed to evaluate circadian disturbance in patients with chronic idiopathic central serous chorioretinopathy (ICSC). METHODS: Between January 1st, 2012, and November 30th, 2014, 29 consecutive patients with chronic ICSC examined in a referral setting were compared with a gender-matched and age-matched control group of 29 patients. A history of pharmacologic medication (including corticosteroid treatment), sleep disturbance, irregular working hours, cardiovascular risk factors, and depressive anxiety disorders was noted. RESULTS: The median age of the patients was 52, and in the control subjects it was 50. The male-female ratio for both groups was 4.8:1. Patients with chronic ISCS were more likely to be exposed to irregular working hours (p < 0.01, OR 9.3 [2.29-37.6]) and to present with overweight than the control subjects (p = 0.016). No significant differences were found for sleeping disturbances, pharmacological medication, cardiovascular risk factors, or depressive anxiety disorders. CONCLUSIONS: In this preliminary study, the exposition of irregular working hours as a risk factor for chronic ICSC was identified, which had not been previously reported. If further studies confirm these findings, then employment with regular working hours could be recommended for chronic ICSC patients.
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Coriorretinopatía Serosa Central/fisiopatología , Trastornos Cronobiológicos/complicaciones , Agudeza Visual , Adulto , Anciano , Coriorretinopatía Serosa Central/epidemiología , Coriorretinopatía Serosa Central/etiología , Trastornos Cronobiológicos/fisiopatología , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.
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Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/mortalidad , Mutación , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas/genética , Familia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasia Endocrina Múltiple Tipo 1/metabolismo , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Factores de RiesgoRESUMEN
BACKGROUND: DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated. METHODS: We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies. RESULTS: Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC). CONCLUSIONS: We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.