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Clinical Pediatric Endocrinology : Case... 2021Gain-of-function variants in , which resides on chromosome 7, cause MIRAGE syndrome that is associated with congenital adrenal insufficiency and gonadal dysgenesis. We...
Gain-of-function variants in , which resides on chromosome 7, cause MIRAGE syndrome that is associated with congenital adrenal insufficiency and gonadal dysgenesis. We previously reported a Japanese patient with MIRAGE syndrome carrying a heterozygous variant (p.Ala1479Ser). In this study, we confirmed the pathogenicity of Ala1479Ser-SAMD9 . Genetic study results revealed an atypically low variant allele frequency (26%) and we suspected of genomic rearrangement(s) involving chromosome 7. Single nucleotide polymorphism (SNP) array and short tandem repeat analysis showed presence of mosaic maternal isodisomic uniparental disomy 7 (UPD7). Deep sequencing using DNA samples obtained at 0, 6, 10, and 25 mo of age revealed that the percentage of cells with UPD7 increased constantly from 6% to 82% over 25 mo, and this increase coincided with a decrease in the percentage of cells with p.Ala1479Ser from 94% to nearly undetectable levels. We further screened for low-allele-frequency and rare variants in eight patients with Silver-Russel syndrome and maternal UPD7; however, none of the patients harbored such a variant. In conclusion, our case demonstrates that genetic findings can vary considerably in patients with MIRAGE syndrome and that a comprehensive diagnostic approach, including SNP array and deep sequencing, is important in such cases.
PubMed: 34629738
DOI: 10.1297/cpe.30.163 -
Frontiers in Pediatrics 2020Adrenal insufficiency (AI) is a potentially life-threatening condition that can be difficult to diagnose, especially if it is not considered as a potential cause of a... (Review)
Review
Adrenal insufficiency (AI) is a potentially life-threatening condition that can be difficult to diagnose, especially if it is not considered as a potential cause of a child's clinical presentation or unexpected deterioration. Children who present with AI in early life can have signs of glucocorticoid deficiency (hyperpigmentation, hypoglycemia, prolonged jaundice, poor weight gain), mineralocorticoid deficiency (hypotension, salt loss, collapse), adrenal androgen excess (atypical genitalia), or associated features linked to a specific underlying condition. Here, we provide an overview of causes of childhood AI, with a focus on genetic conditions that present in the first few months of life. Reaching a specific diagnosis can have lifelong implications for focusing management in an individual, and for counseling the family about inheritance and the risk of recurrence.
PubMed: 33381483
DOI: 10.3389/fped.2020.619041 -
Circulation Research May 2017
Review
Topics: Aortic Dissection; Animals; Aortic Aneurysm; Humans; Marfan Syndrome; Mutation; Transforming Growth Factor beta
PubMed: 28546355
DOI: 10.1161/CIRCRESAHA.116.310371 -
Frontiers in Immunology 2022Almost all solid tumors display hypoxic areas in the tumor microenvironment associated with therapeutic failure. It is now well established that the abnormal growth of... (Review)
Review
Almost all solid tumors display hypoxic areas in the tumor microenvironment associated with therapeutic failure. It is now well established that the abnormal growth of malignant solid tumors exacerbates their susceptibility to hypoxia. Therefore, targeting hypoxia remains an attractive strategy to sensitize tumors to various therapies. Tumor cell adaptions to hypoxia are primarily mediated by hypoxia-inducible factor-1 alpha (HIF-1α). Sensing hypoxia by HIF-1α impairs the apoptotic potential of tumor cells, thus increasing their proliferative capacity and contributing to the development of a chaotic vasculature in the tumor microenvironment. Therefore, in addition to the negative impact of hypoxia on tumor response to chemo- and radio-therapies, hypoxia has also been described as a major hijacker of the tumor response by impairing the tumor cell susceptibility to immune cell killing. This review is not intended to provide a comprehensive overview of the work published by several groups on the multiple mechanisms by which hypoxia impairs the anti-tumor immunity and establishes the immunosuppressive tumor microenvironment. There are several excellent reviews highlighting the value of targeting hypoxia to improve the benefit of immunotherapy. Here, we first provide a brief overview of the mechanisms involved in the establishment of hypoxic stress in the tumor microenvironment. We then discuss our recently published data on how targeting hypoxia, by deleting a critical domain in HIF-1α, contributes to the improvement of the anti-tumor immune response. Our aim is to support the current dogma about the relevance of targeting hypoxia in cancer immunotherapy.
Topics: Humans; Hypoxia; Immunosuppressive Agents; Immunotherapy; Neoplasms; Syndrome; Tumor Microenvironment
PubMed: 35795658
DOI: 10.3389/fimmu.2022.880810 -
Blood Purification 2011The recent interest in the role of the intestine in the cardiovascular stability of uremic patients, specifically on dialysis, but potentially also in chronic kidney...
The recent interest in the role of the intestine in the cardiovascular stability of uremic patients, specifically on dialysis, but potentially also in chronic kidney disease, must be seen against the background of the recent great interest in the role of the gut in chronic heart failure [Curr Opin Clin Nutr Metab Care 2008;11:632-639]. There has been a long-standing interest in the role of the intestine in renal failure, mainly concerning the role of metabolites of bacterial metabolism in the gut as potential uremic toxins. This area has recently been given a new twist by the finding that increased endotoxin concentrations in the blood of dialyzed patients are associated with hypotensive episodes and myocardial 'stunning'. Recent studies suggest that intradialytic underperfusion of myocardial areas, the so-called stunning, may be related to the entry of bacterial endotoxin and/or cytokines across the mucosal barrier into the circulation, where they have a negative impact on myocardial function (and presumably beyond the negative cardiac side effect also contribute to catabolism and malnutrition). Entry of bacterial endotoxin during dialysis sessions is presumably the result of intermittent underperfusion of the intestine if the effective blood volume is rapidly reduced causing breakdown of the mucosal barrier. Apart from the impact on myocardial perfusion, the entry of bacterial endotoxin and/or cytokines across the mucosal barrier may also contribute to malnutrition, wasting and reduced life expectancy in hemodialyzed patients. Such a causal relationship is absolutely plausible in view of an extensive literature on congestive heart failure where clinical and experimental evidence indicates that bacterial endotoxin and/or cytokines may escape from a hypoperfused edematous gut, entering the circulation, triggering an inflammatory response, upregulating circulating cytokines and interfering with the function of the heart through several pathogenic mechanisms.
Topics: Endotoxins; Heart Failure; Humans; Intestinal Mucosa; Intestines; Kidney Failure, Chronic; Myocardial Stunning; Renal Dialysis; Uremia
PubMed: 21228570
DOI: 10.1159/000321848 -
Stem Cell Research Jul 2021MIRAGE syndrome is a multisystem disorder caused by mutations in SAMD9 (sterile α motif domain-containing protein 9) with a high mortality in the first decade of life....
MIRAGE syndrome is a multisystem disorder caused by mutations in SAMD9 (sterile α motif domain-containing protein 9) with a high mortality in the first decade of life. We generated 2 human induced pluripotent stem cell lines from male children diagnosed with MIRAGE syndrome. The cell lines were generated from fibroblasts by integration-free reprogramming using the Sendai virus. Both cell lines were fully characterized regarding their pluripotent identity and differentiation potential, and quality controlled for karyotypic integrity, cell line identity and clearance of reprogramming vectors. The generated cell lines represent a valuable tool to study the disease mechanism of MIRAGE syndrome.
Topics: Cell Differentiation; Cell Line; Cellular Reprogramming; Child; Fibroblasts; Humans; Induced Pluripotent Stem Cells; Intracellular Signaling Peptides and Proteins; Male; Sendai virus
PubMed: 34119956
DOI: 10.1016/j.scr.2021.102417 -
Clinical Pediatric Endocrinology : Case... 2019Aspiration pneumonia is a common complication of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE)...
Aspiration pneumonia is a common complication of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome. However, the detailed clinical course of aspiration pneumonia in neonates and infants diagnosed with this disorder remains unclear. We report a case of a 2-yr-old girl diagnosed with MIRAGE syndrome during the early neonatal period. The patient developed 3 episodes of aspiration pneumonia until 4 mo of age, and this complication was attributed to esophageal hypoperistalsis secondary to achalasia and gastroesophageal reflux. Enteral feeding via a duodenal tube effectively prevented further episodes of aspiration pneumonia in this patient.
PubMed: 31666768
DOI: 10.1297/cpe.28.147 -
Frontiers in Endocrinology 2019MIRAGE (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, Enteropathy) syndrome is a severe multisystem disorder with high...
MIRAGE (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, Enteropathy) syndrome is a severe multisystem disorder with high mortality. It is caused by a heterozygous gain of function mutation in the growth repressor gene . The increasing number of reported cases displays a spectrum of phenotypes that may be explained by an adaptation mechanism, with appearance of a somatic second hit mutation with revertant effects. To determine the genetic basis of the MIRAGE syndrome rapidly corrected in a living and healthy 46,XY patient. A 46,XY patient born with growth restriction and disorders of sex development had thrombocytopenia and necrotizing enterocolitis during the neonatal period suggestive of the syndrome. Faced with the rapid improvement of the patient's phenotype, an adaptation mechanism was sought by repeating genetic analysis at different ages; her parents also underwent genetic analysis. The previously described p.(Thr778Ile) mutation was identified and surprisingly transmitted by the asymptomatic mother in this usually syndrome. To explain the rapid improvement of the patient's phenotype and absence of symptoms in the mother, an adaptation mechanism was sought. For the mother, a non-sense mutation was found (p.(Arg221)) in , and most likely appeared . It was not transmitted to her child. The child harbored a different non-sense mutation (p.(Arg285)) that most likely appeared near day 20. We show that pathogenic variants can be inherited from a healthy parent as the adaptation mechanism may arise early in life and mask symptoms. Presence of revertant mosaicism mutations could explain "incomplete penetrance" in other disease. For a better management and outcomes in patients, appearance of this natural gene therapy should be sought by repeating genetic analysis.
PubMed: 31572304
DOI: 10.3389/fendo.2019.00625 -
Human Genome Variation 2020MIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and...
MIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by a gain-of-function variant in the gene, but there is limited knowledge regarding the genotype-phenotype correlation. We herein report a Japanese patient with MIRAGE syndrome carrying a novel de novo heterozygous missense variant in the gene (c.4435 G > T; p.Ala1479Ser).
PubMed: 32194975
DOI: 10.1038/s41439-020-0091-5 -
BMJ Open May 2022In the UK, alcohol use is the main driver of chronic liver disease and each year results in over 1 million unplanned hospital admissions and over 25 000 deaths from...
INTRODUCTION
In the UK, alcohol use is the main driver of chronic liver disease and each year results in over 1 million unplanned hospital admissions and over 25 000 deaths from alcohol-related liver disease (ArLD). The only effective treatment to prevent progression of liver damage is reducing or ceasing alcohol consumption. Psychological and pharmacological therapies for alcohol misuse are ineffective in patients with ArLD. Functional imagery training (FIT) is a novel psychological therapy that builds on motivational interviewing techniques with multisensory imagery. This pilot trial aims to test the feasibility of training alcohol liaison nurses to deliver FIT therapy and of recruiting and retaining patients with ArLD and alcohol dependence to a randomised trial of FIT and treatment as usual (TAU) versus TAU alone.
METHODS AND ANALYSIS
This is a randomised pilot trial of FIT and TAU versus TAU alone in 90 patients with ArLD and alcohol dependence admitted to one of four UK centres. The primary objectives are to estimate rates of screening, recruitment, randomisation, retention, adherence to FIT/TAU and a preliminary assessment of the FIT intervention in the ArLD population. Data from the pilot study will be used to finalise the design of a definitive randomised controlled trial to assess the effectiveness and cost-effectiveness of FIT. The proposed primary outcome measure for the definitive trial is self-reported alcohol use assessed using timeline follow-back.
ETHICS AND DISSEMINATION
Research ethics approval was given by the Yorkshire and Humber-Bradford Leeds Research Ethics Committee (reference: 21/YH/0044). Eligible patients will be approached and written informed consent obtained prior to participation. Results will be disseminated through peer-reviewed open access journals, international conferences and a lay summary published on the Trials Unit website and made available to patient groups.
TRIAL REGISTRATION NUMBER
ISRCTN41353774.
Topics: Alcoholism; Cost-Benefit Analysis; Humans; Liver Diseases, Alcoholic; Pilot Projects; Randomized Controlled Trials as Topic; Syndrome
PubMed: 35584873
DOI: 10.1136/bmjopen-2021-060498