Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall–Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.     

Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid‐type fibromatosis by whole‐exome sequencing and genomic analysis

CTNNB1 mutations or APC abnormalities have been observed in ～85% of desmoids examined by Sanger sequencing and are associated with Wnt/β‐catenin activation. We sought to identify molecular aberrations in “wild‐type” tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild‐type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A‐derived gene expression profiles, wild‐type and mutated tumors clustered together. Whole‐exome sequencing of eight of the wild‐type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild‐type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low‐frequency CTNNB1 mutation or APC loss in wild‐type desmoids was validated in the remaining eight wild‐type desmoids; directed miSeq identified low‐frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild‐type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild‐type tumors (determined by next‐generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/β‐catenin activation as the common pathway governing desmoid initiation. © 2015 Wiley Periodicals, Inc.     

Does clinical outcome of birch pollen immunotherapy relate to induction of blocking antibodies preventing IgE from allergen binding? A pilot study monitoring responses during first year of AIT

Background

The clinical benefit of allergen-specific immunotherapy (AIT) involves induction of blocking antibodies. It is not clear if these antibodies function via steric hindrance alone or a combination of levels, avidities, and epitope specificities, and clinical outcome cannot be predicted. We aim to in-depth characterize serum antibody profiles during birch pollen AIT, investigate therapy-induced antibodies for their capacity to block IgE binding to Bet v 1 and correlate data with clinical outcomes.

Methods

Immune responses of five birch pollen allergic patients were monitored during the first year of AIT by nasal provocation tests (NPTs), ImmunoCAP, immunoblots, direct and avidity enzyme-linked immunosorbent assays, mediator release assays, facilitated antigen binding (FAB) assays, and inhibition mediator release assays.

Results

There was no correlation between NPT results and therapy-induced changes in levels (IgE, IgG, IgA, IgM), avidities, or mediator release potency of Bet v 1-specific antibodies. In FAB assays, blocking antibodies initiated upon AIT were shown to prevent formation of Bet v 1-IgE complexes of an indicator serum pool and significantly correlated with clinical readout. Inhibition mediator release assays using patient-specific IgE for passive sensitization revealed therapy-induced blocking capacities with very good correlation to NPT results. Notably, this assay was the only one to detect a non-responder during treatment in this pilot study.

Conclusions

Clinical outcome of AIT depends on induction of blocking antibodies able to prevent the patient’s own IgE from allergen binding. Monitoring of clinical efficacy seems to be best achieved using the inhibition mediator release assay, as development of relevant blocking antibodies can be verified in a patient-tailored manner.

     

Application of the ISTH bleeding score in hemophilia

Background

Hemophilia is an inherited bleeding disorder. With proper treatment and self-care, persons with hemophilia can maintain an active, productive lifestyle. Hemophilia can be mild, moderate, or severe, depending on the degree of plasma clotting factor deficiency. The aim of the study was to assess the utility of ISTH-BAT in diagnosis, determining severity of the bleeding condition in newly diagnosed and known hemophilia patients, compare the bleeding score (BS) in adult and pediatric groups and investigate its association with plasma factor levels.

Prevalence and Correlates of the Use of Prefilled Syringes Among Persons Who Inject Drugs in San Diego,CA

Persons who inject drugs (PWID) are at increased risk for blood-borne virus (BBV) infections and overdose resulting from high-risk injecting practices. Studies of prefilled syringe use ([PFSU] using a syringe that already contained drug solution when it was obtained by the user), an injection practice previously described in Eastern Europe, suggest that it increases susceptibility to BBV. However, little is known about this practice in the USA. Data were obtained from an ongoing cohort study of PWID to determine the prevalence and assess correlates of PFSU in San Diego, CA. Baseline interviews assessed socio-demographics and drug use behaviors. Logistic regression was used to identify factors independently associated with ever using a prefilled syringe (yes/no). Participants (n = 574) were predominately males (73.9 %) and white (50.9 %) with a mean age of 43.4 years (range 18–80); 33.3 % reported ever using prefilled syringes, although only 4.9 % reported use in the past 6 months. In multivariable analyses, PFSU was independently associated with ever having a rushed injection due to police presence [adjusted odds ratio (AOR) = 2.51, 95 % CI 1.66, 3.79], ever being in prison (AOR = 1.80, 95 % CI 1.23, 2.63), injecting most often in public versus private places in the past 6 months (AOR = 1.66, 95 % CI 1.11, 2.48), and injecting drugs in Mexico (AOR = 1.70, 95 % CI 1.16, 2.49). Results indicate that a history of PFSU is common and associated with environmental factors that may also increase risk for adverse health outcomes. Studies are needed to better understand PFSU in order to develop interventions to prevent adverse outcomes associated with their use.     

Shape-controlled synthesis of magnetic Fe3O4 nanoparticles with different iron precursors and capping agents

This paper describes a modified method to prepare monodisperse Fe₃O₄ magnetic nanoparticles with different shapes (cube, octahedron, and sphere). The shape of the magnetic nanoparticles could be conveniently controlled by changing the types of precursor/capping agent and concentration of capping agent. The prepared samples were characterized using scanning electron microscopy, X-ray diffraction and vibrating sample magnetometry. Cubes and octahedra were formed using ferrous sulfate heptahydrate as an iron source, ethylene glycol as a solvent and potassium hydroxide (KOH) as a capping agent while spheres were formed by using ferric chloride hexahydrate as an iron source, ethylene glycol as a solvent and ammonium acetate as a capping agent. By varying KOH concentration (0.5 M, 1 M, 1.5 M, and 5 M), the shape was transformed from cubes to octahedra because octahedra are developed dominantly at higher concentration of KOH within the reaction mixture. The magnetic studies show superparamagnetic behavior for all samples at room temperature. The Fe₃O₄ nanoparticles show the magnetic saturation values of 87 emu g⁻¹, 85 emu g⁻¹, and 82 emu g⁻¹ for spheres, cubes, and octahedrons, respectively.

This paper describes a modified method to prepare monodisperse Fe₃O₄ magnetic nanoparticles with different shapes (cube, octahedron, and sphere).     

Fecal microbiota transplantation and Clostridioides difficile infection among privately insured patients in the United States

Journal of Gastroenterology - Clostridioides difficile infection (CDI) may be rising in severity in the US over the past decade and its treatment landscape is changing given the recent adoption of...