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American Journal of Medical Genetics.... Dec 2019Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate... (Review)
Review
Congenital hyperinsulinism (HI) is the most frequent cause of persistent hypoglycemia in infants and children. Delays in diagnosis and initiation of appropriate treatment contribute to a high risk of neurocognitive impairment. HI represents a heterogeneous group of disorders characterized by dysregulated insulin secretion by the pancreatic beta cells, which in utero, may result in somatic overgrowth. There are at least nine known monogenic forms of HI as well as several syndromic forms. Molecular diagnosis allows for prediction of responsiveness to medical treatment and likelihood of surgically-curable focal hyperinsulinism. Timely genetic mutation analysis has thus become standard of care. However, despite significant advances in our understanding of the molecular basis of this disorder, the number of patients without an identified genetic diagnosis remains high, suggesting that there are likely additional genetic loci that have yet to be discovered.
Topics: Child; Congenital Hyperinsulinism; Epigenesis, Genetic; Genetic Testing; Humans; Infant; Mutation; Philadelphia; Syndrome
PubMed: 31414570
DOI: 10.1002/ajmg.c.31737 -
International Journal of Molecular... May 2020Small intestinal bacterial overgrowth (SIBO) is a condition hallmarked by an increase in the concentration of colonic-type bacteria in the small bowel. Watery diarrhea,... (Review)
Review
Small intestinal bacterial overgrowth (SIBO) is a condition hallmarked by an increase in the concentration of colonic-type bacteria in the small bowel. Watery diarrhea, bloating, abdominal pain and distension are the most common clinical manifestations. Additionally, malnutrition and vitamin (B12, D, A, and E) as well as minerals (iron and calcium) deficiency may be present. SIBO may mask or worsen the history of some diseases (celiac disease, irritable bowel disease), may be more common in some extra-intestinal disorders (scleroderma, obesity), or could even represent a pathogenetic link with some diseases, in which a perturbation of intestinal microbiota may be involved. On these bases, we performed a review to explore the multiple links between SIBO and digestive and extra-intestinal diseases.
Topics: Animals; Blind Loop Syndrome; Disease; Humans; Intestine, Small
PubMed: 32429454
DOI: 10.3390/ijms21103531 -
The Veterinary Clinics of North... Jul 2019Large offspring syndrome (LOS) is a fetal overgrowth condition in bovines most often observed in offspring conceived with the use of assisted reproductive technologies... (Review)
Review
Large offspring syndrome (LOS) is a fetal overgrowth condition in bovines most often observed in offspring conceived with the use of assisted reproductive technologies (ART). Phenotypes observed in LOS include, overgrowth, enlarged tongues, umbilical hernias, muscle and skeleton malformations, abnormal organ growth and placental development. Although LOS cases have only been reported to be associated with ART, fetal overgrowth can occur spontaneously in cattle (S-LOS). S-LOS refers to oversized calves that are born at normal gestation lengths. ART-induced LOS has been characterized as an epigenetic syndrome, more specifically, a loss-of-imprinting condition. We propose that S-LOS is also a loss-of-imprinting condition.
Topics: Animals; Beckwith-Wiedemann Syndrome; Cattle; Cattle Diseases; Female; Growth Disorders; Humans; Pregnancy; Reproductive Techniques, Assisted
PubMed: 31103180
DOI: 10.1016/j.cvfa.2019.02.007 -
Journal of Pediatric Genetics Sep 2015Numerous multiple malformation syndromes associated with pathologic overgrowth have been described and, for many, their molecular bases elucidated. This review describes... (Review)
Review
Numerous multiple malformation syndromes associated with pathologic overgrowth have been described and, for many, their molecular bases elucidated. This review describes the characteristic features of these overgrowth syndromes, as well as the current understanding of their molecular bases, intellectual outcomes, and cancer predispositions. We review syndromes such as Sotos, Malan, Marshall-Smith, Weaver, Simpson-Golabi-Behmel, Perlman, Bannayan-Riley-Ruvalcaba, PI3K-related, Proteus, Beckwith-Wiedemann, fibrous dysplasia, Klippel-Trenaunay-Weber, and Maffucci.
PubMed: 27617124
DOI: 10.1055/s-0035-1564440 -
American Journal of Human Genetics May 2017To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with...
To explore the genetic architecture of human overgrowth syndromes and human growth control, we performed experimental and bioinformatic analyses of 710 individuals with overgrowth (height and/or head circumference ≥+2 SD) and intellectual disability (OGID). We identified a causal mutation in 1 of 14 genes in 50% (353/710). This includes HIST1H1E, encoding histone H1.4, which has not been associated with a developmental disorder previously. The pathogenic HIST1H1E mutations are predicted to result in a product that is less effective in neutralizing negatively charged linker DNA because it has a reduced net charge, and in DNA binding and protein-protein interactions because key residues are truncated. Functional network analyses demonstrated that epigenetic regulation is a prominent biological process dysregulated in individuals with OGID. Mutations in six epigenetic regulation genes-NSD1, EZH2, DNMT3A, CHD8, HIST1H1E, and EED-accounted for 44% of individuals (311/710). There was significant overlap between the 14 genes involved in OGID and 611 genes in regions identified in GWASs to be associated with height (p = 6.84 × 10), suggesting that a common variation impacting function of genes involved in OGID influences height at a population level. Increased cellular growth is a hallmark of cancer and there was striking overlap between the genes involved in OGID and 260 somatically mutated cancer driver genes (p = 1.75 × 10). However, the mutation spectra of genes involved in OGID and cancer differ, suggesting complex genotype-phenotype relationships. These data reveal insights into the genetic control of human growth and demonstrate that exome sequencing in OGID has a high diagnostic yield.
Topics: Adolescent; Amino Acid Sequence; Child; Child, Preschool; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; DNA-Binding Proteins; Developmental Disabilities; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Female; Gene Expression Regulation; Genetic Loci; Genome-Wide Association Study; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Infant; Intellectual Disability; Intracellular Signaling Peptides and Proteins; Linkage Disequilibrium; Male; Mutation; Neoplasms; Nuclear Proteins; Sequence Analysis, DNA; Transcription Factors
PubMed: 28475857
DOI: 10.1016/j.ajhg.2017.03.010 -
The Journal of Clinical Endocrinology... Jan 2024Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature,... (Review)
Review
Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged. Multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome, respectively, variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome, and variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth. In addition, very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder. In this review, we discuss the genetics of these overgrowth disorders and explore possible common underlying mechanisms by which epigenetic pathways regulate human body size.
Topics: Humans; Autism Spectrum Disorder; Abnormalities, Multiple; Syndrome; Histone Methyltransferases; Intellectual Disability; Epigenesis, Genetic
PubMed: 37450557
DOI: 10.1210/clinem/dgad420 -
Alimentary Pharmacology & Therapeutics Mar 2017Small intestinal bacterial overgrowth (SIBO) is a heterogeneous syndrome, characterised by an increased number and/or abnormal type of bacteria in the small bowel. Over... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Small intestinal bacterial overgrowth (SIBO) is a heterogeneous syndrome, characterised by an increased number and/or abnormal type of bacteria in the small bowel. Over the past decades, rifaximin has gained popularity for this indication despite its use is not evidence based.
AIM
To perform a systematic review and meta-analysis to summarise evidence about the efficacy and safety of rifaximin to eradicate SIBO in adult patients.
METHODS
MEDLINE, EMBASE, CCRCT, Scopus and Web of Science were searched from inception to March 16, 2015 for RCTs and observational studies. Furthermore, abstract books of major European, American and Asian gastroenterological meetings were also examined.
RESULTS
Thirty-two studies involving 1331 patients were included. The overall eradication rate according to intention-to-treat analysis was 70.8% (95% CI: 61.4-78.2; I = 89.4%) and to per protocol analysis 72.9% (95% CI: 65.5-79.8; I = 87.5%). Meta-regression identified three covariates (drug dose, study design and co-therapy) independently associated with an increased eradication rate. The overall rate of adverse events was 4.6% (95% CI: 2.3-7.5; I = 63.6%). In the subset of studies (n= 10) allowing the analysis, improvement or resolution of symptoms in patients with eradicated SIBO was found to be 67.7% (95% CI: 44.7-86.9; I = 91.3%).
CONCLUSIONS
Rifaximin treatment seems to be effective and safe for the treatment of SIBO. However, the quality of the available studies is generally poor. Well-designed RCTs are needed to substantiate these findings and to establish the optimal regimen.
Topics: Adult; Bacteria; Bacterial Infections; Female; Gastroenterology; Humans; Intestine, Small; Rifamycins; Rifaximin; Syndrome
PubMed: 28078798
DOI: 10.1111/apt.13928