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Journal of Clinical Research in... Dec 2017Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder due to mutations in the insulin receptor gene (INSR) which is mapped to 19p13.2. RMS is characterized...
Rabson-Mendenhall syndrome (RMS) is an autosomal recessive disorder due to mutations in the insulin receptor gene (INSR) which is mapped to 19p13.2. RMS is characterized by acanthosis nigricans, generalized lanugo, tooth and nail dysplasia, high nasal bridge, and growth retardation. A 5-year-old female patient was referred due to acanthosis nigricans and generalized lanugo. On her physical examination, severe acanthosis nigricans of the neck, axillae, the external genitalia and antecubital regions, generalized lanugo, mildly decreased subcutaneous fat, dysmorphic facial features, and polydactyly on her left hand were noted. Insulin resistance and impaired glucose tolerance were found. Sequence analysis of the INSR in the patient revealed c.3529+5G>A mutation in homozygous state. RMS should be suspected in a patient with characteristic physical features and insulin resistance.
Topics: Acanthosis Nigricans; Antigens, CD; Child, Preschool; Donohue Syndrome; Female; Humans; Mutation, Missense; Receptor, Insulin; Severity of Illness Index
PubMed: 28663160
DOI: 10.4274/jcrpe.4577 -
Cytometry. Part B, Clinical Cytometry Jul 2018Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder that has not been well-documented in children, particularly those with...
Standardized high-sensitivity flow cytometry testing for paroxysmal nocturnal hemoglobinuria in children with acquired bone marrow failure disorders: A single center US study.
BACKGROUND
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder that has not been well-documented in children, particularly those with acquired bone marrow failure disorders (ABMFD)-acquired aplastic anemia (AAA) and myelodysplastic syndrome (MDS). Therefore, we sought to determine the prevalence of PNH populations in children with ABMFD.
METHODS
PNH testing was performed in children with an ABMFD diagnosis using high sensitivity (≥0.01%) fluorescent aerolysin (FLAER)-based assay according to 2010 International Clinical Cytometry Society (ICCS) PNH Consensus Guidelines and 2012 Practical PNH Guidelines. FLAER/CD64/CD15/CD24/CD14/CD45 and CD235a/CD59 panels were used for white blood cell and red blood cell testing, respectively.
RESULTS
Thirty-seven patients with ABMFD (34 AAA, 3 MDS) were included (17M/20F, age 2-18 years, median 9 years). PNH populations were identified in 17 of 37 (46%) patients. Of the 17 patients with PNH populations identified, 7 were PNH clones (>1% PNH population), and 10 had minor PNH population or rare cells with PNH phenotype (≤1% PNH population).
CONCLUSIONS
This is the first study to use a standardized high-sensitivity FLAER-based flow cytometry assay and the recommended cutoff of 0.01% to identify cells with PNH phenotype in pediatric patients with ABMFD in the United States. The identification of a PNH population in 46% of ABMFD supports the recommendation for high sensitivity PNH testing in children with these disorders. As a less sensitive assay using a cutoff of ≥ 1% PNH population would have missed 10 (27%) patients with minor PNH population or rare cells with PNH phenotype. © 2017 International Clinical Cytometry Society.
Topics: Adolescent; Anemia, Aplastic; Child; Child, Preschool; Female; Flow Cytometry; Hemoglobinuria, Paroxysmal; Humans; Male; Myelodysplastic Syndromes; Prevalence; Retrospective Studies; Sensitivity and Specificity
PubMed: 28574201
DOI: 10.1002/cyto.b.21536 -
Experimental and Molecular Pathology Feb 2017This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25,... (Review)
Review
This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.
Topics: Alcoholism; Congresses as Topic; Cytochrome P-450 CYP2E1; Hepatitis, Alcoholic; Humans; Life Style; Liver Diseases, Alcoholic; Microbiota; Non-alcoholic Fatty Liver Disease; Polymorphism, Genetic
PubMed: 28077318
DOI: 10.1016/j.yexmp.2017.01.003 -
BioMed Research International 2016Single-nucleotide polymorphisms (SNPs) associated with complex disorders can create, destroy, or modify protein coding sites. Single amino acid substitutions in the...
Single-nucleotide polymorphisms (SNPs) associated with complex disorders can create, destroy, or modify protein coding sites. Single amino acid substitutions in the insulin receptor (INSR) are the most common forms of genetic variations that account for various diseases like Donohue syndrome or Leprechaunism, Rabson-Mendenhall syndrome, and type A insulin resistance. We analyzed the deleterious nonsynonymous SNPs (nsSNPs) in gene based on different computational methods. Analysis of INSR was initiated with PROVEAN followed by PolyPhen and I-Mutant servers to investigate the effects of 57 nsSNPs retrieved from database of SNP (dbSNP). A total of 18 mutations that were found to exert damaging effects on the INSR protein structure and function were chosen for further analysis. Among these mutations, our computational analysis suggested that 13 nsSNPs decreased protein stability and might have resulted in loss of function. Therefore, the probability of their involvement in disease predisposition increases. In the lack of adequate prior reports on the possible deleterious effects of nsSNPs, we have systematically analyzed and characterized the functional variants in coding region that can alter the expression and function of gene. characterization of nsSNPs affecting gene function can aid in better understanding of genetic differences in disease susceptibility.
Topics: Amino Acid Substitution; Computational Biology; Donohue Syndrome; Humans; Insulin Resistance; Mutation; Polymorphism, Single Nucleotide; Protein Conformation; Receptor, Insulin
PubMed: 27840822
DOI: 10.1155/2016/2023803 -
The Annals of Thoracic Surgery Aug 2016Understanding the seminal complications leading to death after pediatric cardiac surgical procedures may provide opportunities to reduce mortality. This study analyzed...
BACKGROUND
Understanding the seminal complications leading to death after pediatric cardiac surgical procedures may provide opportunities to reduce mortality. This study analyzed all deaths at two pediatric cardiac surgical programs and developed a method to identify the seminal complications and modes of death.
METHODS
Trained nurses abstracted all cases of in-hospital mortality meeting inclusion criteria from each site over 5 years (2008 to 2012). Complication definitions were consistent with those of a multicenter clinical registry. An adjudication committee assigned a seminal complication in each case (the complication initiating the cascade of events leading to death). Seminal complications were grouped into categories to designate "mode of death." The epidemiology of seminal complications and of mode of death was described.
RESULTS
In 191 subjects, low cardiac output syndrome (71% of all subjects), cardiac arrest (52%), and arrhythmia (48%) were the most common complications. The committee assigned low cardiac output syndrome (30%), failure to separate from bypass (16%), and cardiac arrest (12%) most frequently as seminal complications. Seminal complications occurred a median 2 hours (interquartile range [IQR], 0 to 35 hours) postoperatively. Patients experienced a median of seven (IQR, 3 to 12) additional complications before death at a median of 15 days (IQR, 4 to 46). Systemic circulatory failure was the most common mode of death (51%), followed by inadequate pulmonary blood flow (13%) and cardiac arrest (12%).
CONCLUSIONS
Seminal complications occurred early postoperatively, and systemic circulatory failure was the most common mode of death. Our classification system is likely scalable for subsequent multicenter analysis to understand cause-specific mortality variation across hospitals and to drive quality improvement.
Topics: Cardiac Surgical Procedures; Cause of Death; Female; Heart Defects, Congenital; Hospital Mortality; Humans; Infant; Infant, Newborn; Male; Postoperative Complications; Registries; Survival Rate; United States
PubMed: 27154145
DOI: 10.1016/j.athoracsur.2016.02.043 -
Medicine Feb 2016Donohue syndrome ([DS]; leprechaunism) describes a genetic autosomal recessive disorder that results from the presence of homozygous or compound heterozygous mutations...
Donohue syndrome ([DS]; leprechaunism) describes a genetic autosomal recessive disorder that results from the presence of homozygous or compound heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2).Donohue syndrome is associated with a fatal congenital form of dwarfism with features of intrauterine and postnatal growth retardation, exaggerated hyperglycemia with hyperinsulinism and dysmorphic abnormalities.We present a case of DS owing to the rarity of this syndrome (1 case in every million births). We discuss how the disease presents, its genetic underpinning, and its prevention.The case was encountered in an Arab male born on 1 September, 2014, for consanguineous parents. The delivery was via cesarean section at 37 weeks gestation due to severe intrauterine growth restriction and nonprogress labor term. The patient was admitted to the Neonatal Intensive Care Unit due to infection, and jaundice. Dysmorphic features, abnormalities of the craniofacial region, low birth weight, skin abnormalities, abdominal distension and hypertrichosis were observed. Laboratory examinations showed, hyperinsulinism, increased C-peptide, thrombocytopenia, leucopenia, and anemia.The diagnosis of DS was done based on the combinations of typical dysmorphic characteristics, clinical evaluation, supported by genetic analysis and exaggerated biochemical results. Genetic diagnosis of DS was performed through analysis of DNA via polymerase chain reaction (PCR). A qualitative real-time PCR was used, to monitor the amplification of a targeted DNA molecule during the PCR. Other technique using sequencing of the INSR gene, which permits genetic diagnosis, counseling, and antenatal diagnoses in subsequent pregnancies, were also performed.Treatment of DS is supportive and requires the combined efforts of a multidisciplinary team, which include pediatricians, endocrinologists, dermatologists, and other health care professionals. Currently, treatment with recombinant insulin-like growth factor 1 demonstrates effectiveness, and a combination treatment with insulin-like growth factor binding protein 3 resulted in an increased lifespan.There is a scarcity of genetic information on DS among the Arab population. Consanguinity is one of underlying reasons for the appearance of rare genetic disorders. Inbreeding has long been considered a controversial phenomenon. Genetic counseling and overwhelming the alertness of the negative consequences of consanguinity on public health are warranted.
Topics: Consanguinity; Donohue Syndrome; Fatal Outcome; Humans; Infant; Infant, Newborn; Male
PubMed: 26871809
DOI: 10.1097/MD.0000000000002710 -
BMJ Case Reports Oct 2015Donohue syndrome is a rare autosomal recessive condition caused by severe loss-of-function mutations in the insulin receptor (INSR) gene. The diagnosis is made on...
Donohue syndrome is a rare autosomal recessive condition caused by severe loss-of-function mutations in the insulin receptor (INSR) gene. The diagnosis is made on clinical, biochemical and genetic grounds. Mutations are found on chromosome 19p13.2, and code for mutations in the INSR gene. Treatment is challenging and often unsuccessful, and relies on maintaining normoglycaemia and avoiding fasting; in some patients, recombinant human insulin-like growth factor (rhIGF-1) has been trialled. The prognosis is poor, with most babies dying in infancy. Ethically, it is important to consider the benefit versus burden of treatment, the quality of life of the surviving patient and the parents' wishes, when making decisions regarding withholding or withdrawing care.
Topics: Clinical Decision-Making; Donohue Syndrome; Humans; Hyperglycemia; Infant, Newborn; Insulin Infusion Systems; Male; Mutation; Palliative Care; Prognosis; Quality of Life; Receptor, Insulin
PubMed: 26508115
DOI: 10.1136/bcr-2015-210019 -
Frontiers in Behavioral Neuroscience 2015To gain further knowledge on the preclinical phase of Alzheimer's disease (AD), we sought to characterize cognitive performance, neuroimaging and plasma-based AD...
To gain further knowledge on the preclinical phase of Alzheimer's disease (AD), we sought to characterize cognitive performance, neuroimaging and plasma-based AD biomarkers in a cohort of non-demented adults with down syndrome (DS). The goal of the down syndrome biomarker Initiative (DSBI) pilot is to test feasibility of this approach for future multicenter studies. We enrolled 12 non-demented participants with DS between the ages of 30-60 years old. Participants underwent extensive cognitive testing, volumetric MRI, amyloid positron emission tomography (PET; 18F-florbetapir), fluorodeoxyglucose (FDG) PET (18F-fluorodeoxyglucose) and retinal amyloid imaging. In addition, plasma beta-amyloid (Aβ) species were measured and Apolipoprotein E (ApoE) genotyping was performed. Results from our multimodal analysis suggest greater hippocampal atrophy with amyloid load. Additionally, we identified an inverse relationship between amyloid load and regional glucose metabolism. Cognitive and functional measures did not correlate with amyloid load in DS but did correlate with regional FDG PET measures. Biomarkers of AD can be readily studied in adults with DS as in other preclinical AD populations. Importantly, all subjects in this feasibility study were able to complete all test procedures. The data indicate that a large, multicenter longitudinal study is feasible to better understand the trajectories of AD biomarkers in this enriched population. This trial is registered with ClinicalTrials.gov, number NCT02141971.
PubMed: 26441570
DOI: 10.3389/fnbeh.2015.00239 -
Indian Pediatrics Aug 2015
Topics: Donohue Syndrome; Fatal Outcome; Female; Humans; Infant, Newborn
PubMed: 26388649
DOI: No ID Found -
Expert Opinion on Pharmacotherapy 2015Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary... (Review)
Review
INTRODUCTION
Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary disease (COPD), outside their labeled indications and recommended treatment strategies and guidelines, despite having the potential to cause significant side effects.
AREAS COVERED
Although the existence of asthma in patients with asthma-COPD overlap syndrome (ACOS) clearly supports the use of anti-inflammatory treatment (typically an ICS/LABA combination, as ICS monotherapy is usually not indicated for COPD), the current level of ICS/LABA use is not consistent with the prevalence of ACOS in the COPD population. Data have recently become available showing the comparative efficacy of fixed bronchodilator combinations (long-acting muscarinic antagonist [LAMA]/LABA with ICS/LABA combinations). Additionally, new information has emerged on ICS withdrawal without increased risk of exacerbations, under cover of effective bronchodilation.
EXPERT OPINION
For patients with COPD who do not have ACOS, a LAMA/LABA combination may be an appropriate starting therapy, apart from those with mild disease who can be managed with a single long-acting bronchodilator. Patients who remain symptomatic or present with exacerbations despite effectively delivered LAMA/LABA treatment may require additional drug therapy, such as ICS or phosphodiesterase-4 inhibitors. When prescribing an ICS/LABA, the risk:benefit ratio should be considered in individual patients.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Disease Management; Drug Therapy, Combination; Glucocorticoids; Humans; Muscarinic Antagonists; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Syndrome
PubMed: 26194213
DOI: 10.1517/14656566.2015.1067682