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The therapeutic potential of bone marrow mesenchymal stromal cells (bmMSCs) to address heart failure needs improvement for better engraftment and survival. This study explores the role of metabolic sorting for human bmMSCs on coculture in vitro and on doxorubicin-induced heart failure mice models. Using functional, epigenetic and gene expression approaches on cells sorted for mitochondrial membrane potential in terms of their metabolic status, we demonstrated that bmMSCs selected for their glycolytic metabolism presented proliferative advantage and resistance to oxidative stress thereby favoring cell engraftment. Therapeutic use of glycolytic bmMSCs rescued left ventricular ejection fraction and decreased fibrosis in mice models of acute heart failure. Metabolic changes were also related to epigenetic histone modifications as lysine methylation. By targeting LSD1 (lysine-specific demethylase 1) as a conditioning agent to enhance the metabolic profile of bmMSCs, we deciphered the interplay between glycolysis and bmMSC functionality. Our study elucidates novel strategies for optimizing bmMSC-based treatments for heart failure, highlighting the metabolic properties of bmMSCs as a promising target for more effective cardiovascular regenerative therapies.
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Background: 177Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical, biological, and imaging parameters may be used to establish a relative disease prognosis but none is able to predict early efficacy or toxicities. We investigated expression levels for mRNA and miRNA involved in radiosensitivity and tumor progression searching for correlations related to patient outcome during LuPRRT therapy. Methods: Thirty-five patients received LuPRRT for G1/G2 midgut NETs between May 2019 and September 2021. Peripheral blood samples were collected prior to irradiation, before and 48 h after the second and the fourth LuPRRT, and at 6-month follow-up. Multiple regression analyses and Pearson correlations were performed to identify the miRNA/mRNA signature that will best predict response to LuPRRT. Results: Focusing on four mRNAs and three miRNAs, we identified a miRNA/mRNA signature enabling the early identification of responders to LuPRRT with significant reduced miRNA/mRNA expression after the first LuPRRT administration for patients with progressive disease at 1 year (p < 0.001). The relevance of this signature was reinforced by studying its evolution up to 6 months post-LuPRRT. Moreover, nadir absolute lymphocyte count within the first 2 months after the first LuPRRT administration was significantly related to low miRNA/mRNA expression level (p < 0.05) for patients with progressive disease. Conclusion: We present a pilot study exploring a miRNA/mRNA signature that correlates with early hematologic toxicity and therapeutic response 12 months following LuPRRT. This signature will be tested prospectively in a larger series of patients.
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Neoplasias Intestinales , MicroARNs , Tumores Neuroendocrinos , ARN Mensajero , Humanos , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/sangre , Tumores Neuroendocrinos/terapia , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/patología , Masculino , Femenino , MicroARNs/sangre , MicroARNs/genética , Persona de Mediana Edad , Neoplasias Intestinales/sangre , Neoplasias Intestinales/patología , Neoplasias Intestinales/genética , Neoplasias Intestinales/tratamiento farmacológico , ARN Mensajero/genética , ARN Mensajero/sangre , Anciano , Estudios de Seguimiento , Adulto , Pronóstico , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Receptores de Péptidos/genética , Radiofármacos/uso terapéutico , Radiofármacos/administración & dosificación , Lutecio , RadioisótoposRESUMEN
CONTEXT: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear. OBJECTIVE: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients. DESIGN: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment. PATIENTS: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database. RESULTS: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis. CONCLUSION: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families.
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Neoplasia Endocrina Múltiple Tipo 1 , Humanos , Estudios Retrospectivos , Francia/epidemiología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 1/genética , Neoplasia Endocrina Múltiple Tipo 1/epidemiología , Anciano , Mutación de Línea Germinal , Fenotipo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Prevalencia , Neoplasia Endocrina Múltiple/genética , Neoplasia Endocrina Múltiple/epidemiología , Proteínas Proto-OncogénicasRESUMEN
BACKGROUND: The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in VHL tumour suppressor gene. The identification of VHL variants requires accurate classification which has an impact on patient management and genetic counselling. METHODS: The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected VHL genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing VHL genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (http://www.umd.be/VHL/). RESULTS: Here we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11. CONCLUSION: Consequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review.
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Neoplasias Renales , Enfermedad de von Hippel-Lindau , Humanos , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Pruebas Genéticas , Predisposición Genética a la Enfermedad , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/patología , Estudios de Asociación Genética , Neoplasias Renales/genética , Mutación de Línea GerminalRESUMEN
Background: Embryonal rhabdomyosarcomas (ERMS) of the uterine cervix and corpus are rare pediatric tumors usually associated with a late age of onset and frequent somatic DICER1 mutation. It may also develop in the context of a familial predisposition such as DICER1 syndrome requiring specific medical care for children and young adults at risk for a broad range of tumors. Case presentation: This is a case of a prepubescent 9-year-old girl who was presented to our department for metrorrhagias due to a vaginal cervical mass, initially classified as a müllerian endocervical polyp on negative myogenin immunostaining. The patient subsequently manifested growth retardation (-2DS) and learning disabilities leading to genetic explorations and the identification of a germline pathogenic DICER1 variant. The family history revealed thyroid diseases in the father, aunt and paternal grandmother before the age of 20. Conclusion: Rare tumors such as cervical ERMS associated with a family history of thyroid disease during infancy could be related to DICER1 syndrome. Identifying at-risk relatives is challenging but necessary to detect early DICER1 spectrum tumors in young patients.
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Congenital iodide transport defect is an uncommon autosomal recessive disorder caused by loss-of-function variants in the sodium iodide symporter (NIS)-coding SLC5A5 gene and leading to dyshormonogenic congenital hypothyroidism. Here, we conducted a targeted next-generation sequencing assessment of congenital hypothyroidism-causative genes in a cohort of nine unrelated pediatric patients suspected of having a congenital iodide transport defect based on the absence of 99mTc-pertechnetate accumulation in a eutopic thyroid gland. Although, unexpectedly, we could not detect pathogenic SLC5A5 gene variants, we identified two novel compound heterozygous TG gene variants (p.Q29* and c.177-2A>C), three novel heterozygous TG gene variants (p.F1542Vfs*20, p.Y2563C, and p.S523P), and a novel heterozygous DUOX2 gene variant (p.E1496Dfs*51). Splicing minigene reporter-based in vitro assays revealed that the variant c.177-2A>C affected normal TG pre-mRNA splicing, leading to the frameshift variant p.T59Sfs*17. The frameshift TG variants p.T59Sfs*17 and p.F1542Vfs*20, but not the DUOX2 variant p.E1496Dfs*51, were predicted to undergo nonsense-mediated decay. Moreover, functional in vitro expression assays revealed that the variant p.Y2563C reduced the secretion of the TG protein. Our investigation revealed unexpected findings regarding the genetics of congenital iodide transport defects, supporting the existence of yet to be discovered mechanisms involved in thyroid hormonogenesis.
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Hipotiroidismo Congénito , Tiroglobulina , Niño , Hipotiroidismo Congénito/genética , Oxidasas Duales/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Yoduros/metabolismo , Mutación , Tiroglobulina/genéticaRESUMEN
The release of excessive amounts of catecholamine by pheochromocytoma-paragangliomas (PPGL) can lead to life-threatening catecholamine-induced cardiomyopathy (CIC). Single-nucleotide polymorphisms of the beta1 and alpha-2c adrenergic receptors alter myocyte receptor function and enhanced norepinephrine release. We tested the hypothesis that such genetic variations may impact the risk of developing CIC in the context of PPGL. Thirty-one patients with PPGL, including nine with a history of CIC, were analyzed for alpha-2-adrenergic receptors: ADRA2C, beta-1 and beta-2 adrenergic receptors: ADRB1 and ADRB2 genotyping. CIC was defined either by a history of heart failure or cardiogenic shock associated with dilated or Takotsubo cardiomyopathy. Subjects were genotyped for ADRA2C (rs61767072 for del322_325), ADRB1 (rs1801252 for Ser49Gly and rs1801253 for Arg389Gly) and ADRB2 (rs1042713 for Arg16Gly and rs1042714 for Gln27Glu). Single-locus analysis revealed that variant in ADRA2C (alpha 2CDel322-325) was more common among patients with CIC than among controls (allele frequency, 0.44 vs 0.05; P< 0.001). The lack of alpha 2CDel322-325 polymorphism has a negative predictive value of 95% for the onset of CIC. In a replication cohort including 26 patients with PPGL whom eight have developed a CIC, the association between Alpha 2CDel322-325 and CIC was confirmed (allele frequency, 0.33 vs 0.; P= 0.0001). In conclusion, Alpha 2CDel322-325 through the identification of patients at low risk of developing CIC can help physicians to better determine the most appropriate therapeutic approach, notably in patients at high risk of surgical complications.
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Neoplasias de las Glándulas Suprarrenales , Cardiomiopatías , Paraganglioma , Feocromocitoma , Receptores Adrenérgicos alfa 2 , Receptores Adrenérgicos beta 1 , Receptores Adrenérgicos beta 2 , Neoplasias de las Glándulas Suprarrenales/genética , Biomarcadores , Catecolaminas , Genotipo , Humanos , Feocromocitoma/genética , Polimorfismo de Nucleótido Simple , Receptores Adrenérgicos alfa 2/genética , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 2/genéticaRESUMEN
INTRODUCTION: Iodothyronine deiodinases are selenoproteins with the amino acid selenocysteine (Sec) introduced into the position of a TGA stop codon by a complex machinery involving tRNA[Ser]Sec when a cis-acting Sec-insertion sequence element is present in the 3' end of the mRNA. Recently, a variant in the TRU-TCA1-1 gene encoding for tRNA[Ser]Sec was reported, which resulted in reduced expression of stress-related selenoproteins. The proband presented with multisystem symptoms, euthyroid hyperthyroxinemia, and selenium deficiency. Here, we describe 2 new members of a family harboring the same tRNA[Ser]Sec variant. CASE PRESENTATION: A 13-year-old patient was seen for Hashimoto's disease with high FT3 (4.6 pg/mL, normal range 2-4.2 pg/mL) and normal FT4 and TSH concentrations. He had no clinical complaints. During a 6-year clinical and hormonal follow-up, the index patient was not treated, FT3 decreased, FT4 increased, and serum TSH stayed in the normal range resulting in a euthyroid hyperthyroxinemia. Reverse T3 concentration was significantly increased at the last visit (19 years and 4 months). At the last evaluation, the total selenium level was low (91 µg/L, normal range 95-125). DNA sequencing identified a germinal homozygous variant (C65G) in the TRU-TCA1-1 gene. During follow-up, no additional clinical symptom was observed in the absence of any treatment. The same germinal tRNA[Ser]Sec variant was identified at heterozygous state in his father, who had normal thyroid function tests except a moderately increased reverse T3 concentration, with increased total selenium (143 µg/L) level. In both patients, the expression of stress-related selenoprotein GPX3 was in the low-normal range (168 and 180 IU/L, respectively, normal range: 150-558 IU/L). We did not find any significant biological abnormalities evocative of other selenoprotein deficiencies. DISCUSSION/CONCLUSION: We report on 2 members of a family with a variant in the TRU-TCA1-1 gene encoding for tRNA[Ser]Sec. Our study suggests that this tRNA[Ser]Sec variant is not exclusively causative of disruption in selenoprotein synthesis.
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Context: Congenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis. Objective: We explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype. Patients Design and Setting: Using the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed in silico for pathogenicity. Results: Among the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the TG, DUOX2, TPO, or SLC5A5 genes in 10 infants and heterozygous variants in DUOX2, TG, TPO, and TSHR in 19 others. In seven cases, a heterozygous variant in the TG gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them. Conclusion: The systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.
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Hipotiroidismo Congénito/genética , Autoantígenos/genética , Oxidasas Duales/genética , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Yoduro Peroxidasa/genética , Proteínas de Unión a Hierro/genética , Masculino , Receptores de Tirotropina/genética , Simportadores/genéticaRESUMEN
CONTEXT: Although 24-hour urinary 5-hydroxyindolacetic acid (24u5HIAA) is a key biomarker in midgut neuroendocrine tumors (NETs), it may be inaccurate and inconvenient. OBJECTIVE: We compared the diagnostic performances of 24u5HIAA, overnight urinary 5HIAA (Ou5HIAA), and plasmatic 5HIAA (p5HIAA) in midgut NETs. METHODS: This prospective, multicenter study included 80 patients with metastatic midgut NETs and 17 control patients with irritable bowel syndrome. 24u5HIAA, Ou5HIAA, and p5HIAA were measured in urine and plasma collected on 2 consecutive days following a specific recommended diet. Reproducibility of the biomarkers was evaluated by the Spearman test. Diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUROC). Correlations with the main clinical features and declared observance to the specific diet were assessed using AUROC and logistic regression models. RESULTS: The reproducibility of 24u5HIAA, Ou5HIAA, and p5HIAA were excellent (ρâ =â 0.916; 0.897; 0.978, respectively, Pâ <â .001) with significant discrimination between patients and controls (AUROCâ =â 0.795, Pâ <â .001; 0.757, Pâ =â .001; 0.717, Pâ =â .005, respectively). All 3 markers were correlated with the presence of carcinoid syndrome (AUROCâ =â 0.702, Pâ =â .006; 0.701, Pâ =â .006; 0.697, Pâ =â .007, respectively), carcinoid heart disease (AUROCâ =â 0.896; 0.887; 0.923, Pâ <â .001, respectively, Pâ <â .001), and liver metastatic involvement greater than 30% (AUROCâ =â 0.827; 0.807; 0.849, Pâ <â .001, respectively, Pâ <â .001), independent from other traditional prognostic factors. Biomarker levels were similar between patients with optimal or suboptimal diet observance. CONCLUSION: Ou5HIAA and p5HIAA could be used as more convenient alternatives to 24u5HIAA in patients with metastatic midgut NETs. Prospective long-term studies with repeated dosages are needed.
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Neoplasias Gastrointestinales/sangre , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/orina , Ácido Hidroxiindolacético/sangre , Ácido Hidroxiindolacético/orina , Tumores Neuroendocrinos/sangre , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/orina , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
Adult human cardiac mesenchymal progenitor cells (hCmPC) are multipotent resident populations involved in cardiac homeostasis and heart repair. Even if the mechanisms have not yet been fully elucidated, the stem cell differentiation is guided by the mitochondrial metabolism; however, mitochondrial approaches to identify hCmPC with enhanced stemness and/or differentiation capability for cellular therapy are not established. Here we demonstrated that hCmPCs sorted for low and high mitochondrial membrane potential (using a lipophilic cationic dye tetramethylrhodamine methyl ester, TMRM), presented differences in energy metabolism from preferential glycolysis to oxidative rates. TMRM-high cells are highly efficient in terms of oxygen consumption rate, basal and maximal respiration, and spare respiratory capacity compared to TMRM-low cells. TMRM-high cells showed characteristics of pre-committed cells and were associated with higher in vitro differentiation capacity through endothelial, cardiac-like, and, to a lesser extent, adipogenic and chondro/osteogenic cell lineage, when compared with TMRM-low cells. Conversely, TMRM-low showed higher self-renewal potential. To conclude, we identified two hCmPC populations with different metabolic profile, stemness maturity, and differentiation potential. Our findings suggest that metabolic sorting can isolate cells with higher regenerative capacity and/or long-term survival. This metabolism-based strategy to select cells may be broadly applicable to therapies.
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Potencial de la Membrana Mitocondrial , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Biomarcadores , Diferenciación Celular , Metabolismo Energético , Regulación de la Expresión Génica , Humanos , Inmunofenotipificación , Mitocondrias/genética , Mitocondrias/metabolismo , Desarrollo de Músculos/genética , Osteogénesis/genéticaRESUMEN
OBJECTIVES: Only two mutations at the lysine 183 amino acid in the extracellular N-terminal domain of human TSH receptor (hTSHR) have been associated with hypersensitivity to hCG and familial gestational hyperthyroidism. DESIGN: Describe a new variant of the TSHR gene with hCG hypersensitivity found in two women of the same family diagnosed with gestational hyperthyroidism. PATIENTS: A 38-year-old woman was seen during the first trimester of her second pregnancy for thyrotoxicosis with increased fT3 and fT4 concentrations and low TSH levels without anti-TSH receptor antibody. Thyrotoxicosis improved spontaneously during the 2nd trimester and persisted at the 3rd trimester. Similar clinical symptoms (weight loss, nausea, vomiting) were also reported during the first trimester of her first pregnancy and the first pregnancy of her mother. RESULTS: DNA sequencing of the hTSHR gene of this woman and her mother identifies a heterozygous variant changing valine to isoleucine residue at codon 597 in the transmembrane domain (TMD) of this receptor. In vitro functional studies of this variant showed increased constitutive activity in regard to the basal level of cAMP and IP3 production and to the low cell-surface expression, while response to TSH was reduced compared to that of the wild-type receptor. The Val597Ile variant presented a dose-dependent increase in cAMP response to hGC and human luteinizing hormone (hLH). Simulation of the protein dynamics showed a high structural impact of the Val597Ile variant on helices 3 (TMH3) and 5 (TMH5) of the transmembrane domain participating to constitutive activity and hCG sensitivity. CONCLUSION: We describe a new variant in the transmembrane region of the hTSHR gene with increased constitutive activity and hCG hypersensitivity in familial gestational hyperthyroidism.
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Hipertiroidismo , Complicaciones del Embarazo , Tirotoxicosis , Adulto , Gonadotropina Coriónica , Femenino , Humanos , Hipertiroidismo/genética , Embarazo , Receptores de Tirotropina/genética , TirotropinaRESUMEN
Inactivating germline pathogenic variants of the DICER1 gene are responsible for a spectrum of rare diseases, which expanded a lot in recent years. The constitution of an U.S. registry with these patients and their families as well as the registration of patients in European databases of rare tumors helped to better identify diseases encountered in this syndrome but also to study its pathophysiology (major role in miRNA maturation and recently discovered functions, e.g. in genome integrity maintenance). Most encountered disorders are pediatric malignancies, mainly the pulmonary pneumoblastoma and Sertoli-Leydig tumours. However, benign pathologies such as thyroid goiters, cystic nephromas or pulmonary cystic lesions are also frequently reported. Homogeneous guidelines regimens written by the European groups working on very rare pediatric tumors are proposed but it is important to underscore that they rely on rare scientific data; therefore overall consensus remains precarious. The genetic counseling to families is still difficult due to the large observed spectrum of tumors and the incomplete penetrance. In this article, the authors update current knowledge on the DICER1 syndrome.
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ARN Helicasas DEAD-box/genética , Neoplasias/genética , Enfermedades Raras/genética , Ribonucleasa III/genética , ARN Helicasas DEAD-box/metabolismo , Femenino , Asesoramiento Genético , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Enfermedades Raras/diagnóstico , Enfermedades Raras/metabolismo , Ribonucleasa III/metabolismo , SíndromeRESUMEN
INTRODUCTION: Excess catecholamine stimulates heat production in brown adipose tissue (BAT). Activation of BAT can be detected in patients presenting pheochromocytoma. CASE STUDY: A 58-year-old female patient sought medical advice due to 13 kg weight loss over 2 years accompanied by sweating and high blood pressure. Thoracic-abdominal-pelvic CT-scan revealed a solid 40 mm mass in the left adrenal compartment with peri-adrenal nodules and a solid 80 mm mass at the lower end of the right kidney. 18FDG-PET scan exhibited intense uptake in the supraclavicular, intercostal, mediastinal, peri-renal, mesenteric, iliac and inguinal spaces. Renal tumor with locoregional infiltration and remote metastases was initially considered. Diagnosis of pheochromocytoma was subsequently confirmed by a 10-fold increase in urinary catecholamine, metanephrine and normetanephrine levels. Left adrenalectomy confirmed the diagnosis of pheochromocytoma, with 3 lymph-node metastases in the adjacent adipose tissue surrounded by brown fat. The patient was clinically asymptomatic with normal blood pressure at 3 months post-surgery. A weight gain of 6 kg was recorded, with normalisation of catecholamines/metanephrine/normetanephrine levels. Bilateral peri-renal infiltration (including the right renal mass) disappeared on CT-scan, and TEP-18-FDG no longer showed hypermetabolism. Recurrent mediastinal metastases were diagnosed 6 months after surgery. CONCLUSION: Brown fat activation may mislead diagnosis of pheochromocytoma, suggesting multi-metastatic extra-adrenal tumor, if clinicians are not aware of it.
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Tejido Adiposo Pardo/fisiología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Feocromocitoma/diagnóstico , Pérdida de Peso , Tejido Adiposo Pardo/patología , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/fisiopatología , Adrenalectomía , Catecolaminas/orina , Femenino , Humanos , Hipertensión , Metástasis Linfática/patología , Persona de Mediana Edad , Metástasis de la Neoplasia/diagnóstico , Feocromocitoma/patología , Feocromocitoma/fisiopatología , Tomografía de Emisión de Positrones , Sudoración , Tomografía Computarizada por Rayos XRESUMEN
Background Acquired von Willebrand's syndrome (aVWS) associated with hypothyroidism is rare in children and more often diagnosed during the peripubertal period in the context of Hashimoto's thyroiditis. Case presentation A 5-year-old girl was referred to the paediatric haematology unit for rectal bleeding, anaemia and prolonged activated partial thromboplastin time (aPTT). Her developmental and learning skills were normal. The physical examination revealed severe short stature (height SDS: -3.6) with overweight (body mass index SDS: 1.8) and clinical sign of hypothyroidism. Laboratory investigation revealed aVWS type 1 associated with severe primary hypothyroidism. Anti-thyroid antibodies were negative and thyroid ultrasound found thyroid hypoplasia in favour of congenital hypothyroidism. Restoration of euthyroidism was associated with increased growth velocity and normalisation of coagulation parameters. Conclusion This report highlights the importance of excluding an underlying pathology (including hypothyroidism) in children with suspected VWS, even in young age.
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Hipotiroidismo/complicaciones , Enfermedades de von Willebrand/etiología , Enfermedades de von Willebrand/patología , Preescolar , Femenino , Humanos , PronósticoRESUMEN
BACKGROUND: DICER1 syndrome is an autosomal dominant disorder that predisposes individuals to develop benign or malignant tumours from infancy to adulthood. There is low-to-moderate penetrance of tumour development, which is sex- and age-dependent. Multinodular goitre (MNG) is among the most highly penetrant phenotype of the disorder, especially in females. PATIENTS AND METHODS: We report a series of eight families referred for childhood-onset of MNG or DICER1-related tumours with familial history of MNG in relatives. No additional families with these criteria stated were identified during the same date. We screened DNA samples from the probands and members of their family (40) for constitutional DICER1 variants using Next Generation Sequencing tools. RESULTS: Germline pathogenic DICER1 gene variants were identified in all probands and several of their relatives: 64% presented with MNG/thyroidectomy as the phenotypic expression of the syndrome. DICER1 gene variants were identified in the RNAseIII and the PAZ domains. All tumour tissues studied presented clonal pathogenic variants in hotspot regions. Early identification of DICER1 variant carriers has permitted diagnosis and therapeutic scheme correction for two patients and cascade testing in relatives. CONCLUSIONS: Multinodular goitre is uncommon in children. Childhood-onset MNG, multiple occurrences of the disease within the same family, or its association with rare benign or malignant tumours should raise suspicions of anomalies in the DICER1 gene, as proposed by recent international recommendations. Early detection of DICER1 pathogenic variants has important consequences in terms of therapeutic strategy, early tumour screening, and genetic counselling.
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ARN Helicasas DEAD-box/genética , Bocio Nodular/metabolismo , Bocio Nodular/patología , Ribonucleasa III/genética , Adolescente , Niño , Femenino , Predisposición Genética a la Enfermedad , Bocio Nodular/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación/genética , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/metabolismo , Síndromes Neoplásicos Hereditarios/patología , LinajeRESUMEN
BACKGROUND: Pleuroblastoma (PPB) is a rare pediatric tumor which, in 30% of cases, is associated with cystic nephroma. It has been recently linked to the DICER1 mutation as part of a predisposition syndrome for various tumors. However, if DICER 1 anomalies have been reported in patients with Wilms tumor (WT), to date, no cases of PPB, WT, and DICER1 mutations have been reported in the same patient. CASE PRESENTATION: We report the case of a 3-year-old patient, initially managed for metastatic WT. During his clinical course, the diagnosis of a PPB was made after detecting the DICER1 mutation and subsequent management was therefore modified. CONCLUSION: This case highlights that in case of simultaneous discovery of a renal tumor and a pulmonary lesion in a child, the DICER 1 mutations should be looked for as these could help adapt management and schedule the surgical procedures.
Asunto(s)
ARN Helicasas DEAD-box/genética , Neoplasias Renales/genética , Neoplasias Pulmonares/genética , Blastoma Pulmonar/genética , Ribonucleasa III/genética , Tumor de Wilms/genética , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/cirugía , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/cirugía , Pronóstico , Blastoma Pulmonar/diagnóstico por imagen , Blastoma Pulmonar/cirugía , Tumor de Wilms/diagnóstico por imagen , Tumor de Wilms/cirugíaRESUMEN
The PGC-1 (Peroxisome proliferator-activated receptor Gamma Coactivator-1) family of coactivators (PGC-1α, PGC-1ß, and PRC) plays a central role in the transcriptional control of mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) processes. These coactivators integrate mitochondrial energy production into cell metabolism using complementary pathways. The XTC.UC1 cell line is a mitochondria-rich model of thyroid tumors whose biogenesis is almost exclusively dependent on PRC. Here we aim to propose an integrative view of the cellular pathways regulated by PRC through integration of cDNA and miRNA microarray data and chromatin immunoprecipitation results obtained from XTC.UC1 cells invalidated for PRC. This study showes that PRC induces a complex network of cellular functions interacting with at least one to five of the studied transcription factors (Estrogen Related Receptor alpha, ERR1; Nuclear-Respiratory Factors, NRF1 and NRF2; cAMP Response Element Binding, CREB; and Ying Yang, YY1). Our data confirm that ERR1 is a key partner of PRC in the regulation of mitochondrial functions and suggest a potential role of this complex in RNA processing. PRC is also involved in transcriptional regulatory complexes targeting 12 miRNAs, five of which are involved in the control of the OXPHOS process. Our findings demonstrate that the PRC coactivator can act in complex with several transcription factors and regulate miRNA expression to control the fine regulation of main metabolic functions in the cell. Therefore, in PGC-1α/ß-associated pathologies, PRC, as a metabolic sensor, may ensure mitochondrial homeostasis.