Patients with anorectal malformation and upper limb anomalies:genetic evaluation is warranted

Abstract The objective of this study was to compare the prevalence of genetic disorders in anorectal malformation (ARM) patients with upper limb anomalies to that in ARM patients with other associated anomalies. A retrospective case study was performed in two pediatric surgery centers. All patients born between 1990 and 2012 were included. VACTERL (vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula with esophageal atresia (TE), renal dysplasia (R), and limb anomalies (L)) was defined as at least three components present. We included 700 ARM patients: 219 patients (31 %) had isolated ARM, 43 patients (6 %) had a major upper limb anomaly, and 438 patients (63 %) had other associated anomalies. The most prevalent upper limb anomalies were radial dysplasia (n=12) and hypoplastic thumb (n= 11). Ten of the 43 patients (23 %) with an upper limb anomaly were diagnosed with a genetic disorder—nine also met the V

Patients with anorectal malformation and upper limb anomalies: genetic evaluation is warranted

The objective of this study was to compare the prevalence of genetic disorders in anorectal malformation (ARM) patients with upper limb anomalies to that in ARM patients with other associated anomalies. A retrospective case study was performed in two pediatric surgery centers. All patients born between 1990 and 2012 were included. VACTERL (vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula with esophageal atresia (TE), renal dysplasia (R), and limb anomalies (L)) was defined as at least three components present. We included 700 ARM patients: 219 patients (31 %) had isolated ARM, 43 patients (6 %) had a major upper limb anomaly, and 438 patients (63 %) had other associated anomalies. The most prevalent upper limb anomalies were radial dysplasia (n = 12) and hypoplastic thumb (n = 11). Ten of the 43 patients (23 %) with an upper limb anomaly were diagnosed with a genetic disorder—nine also met the VACTERL criteria—vs. 9 % of ARM patients with other anomalies (p = 0.004, chi-squared test). Conclusion: Genetic disorders are twice as frequently diagnosed in ARM patients with upper limb anomalies than in those with other anomalies. As they also frequently meet the VACTERL criteria, it is important to consider VACTERL as a diagnosis per exclusionem. Genetic counseling is certainly warranted in these patients.What is Known:• Anorectal malformations (ARMs) often co-occur with other congenital anomalies, including upper limb anomalies, mainly of pre-axial origin.• Co-occurrence of ARMs and upper limb anomalies is seen in disorders such as Townes-Brocks syndrome, Fanconi anemia, and VACTERL association.What is New:• ARM patients with a major upper limb anomaly—with or without other congenital anomalies—have a twofold greater chance of a genetic disorder than have non-isolated ARM patients without upper limb anomalies.• Not all upper limb anomalies in ARM patients are part of the VACTERL association; a workup for genetic evaluation is proposed

VACTERL association etiology: The impact of de novo and rare copy number variations

Copy number variations (CNVs), either DNA gains or losses, have been found at common regions throughout the human genome. Most CNVs neither have a pathogenic significance nor result in disease-related phenotypes but, instead, reflect the normal population variance. However, larger CNVs, which often arise de novo, are frequently associated with human disease. A genetic contribution has long been suspected in VACTERL (Vertebral, Anal, Cardiac, TracheoEsophageal fistula, Renal and Limb anomalies) association. The anomalies observed in this association overlap with several monogenetic conditions associated with mutations in specific genes, e.g. Townes Brocks (SALL1), Feingold syndrome (MYCN) or Fanconi anemia. So far VACTERL association has typically been considered a diagnosis of exclusion. Identifying recurrent or de novo genomic variations in individuals with VACTERL association could make it easier to distinguish VACTERL association from other syndromes and could provide insight into disease mechanisms. Sporadically, de novo CNVs associated with VACTERL are described in literature. In addition to this literature review of genomic variation in published VACTERL association patients, we describe CNVs present in 68 VACTERL association patients collected in our institution. De novo variations (>30 kb) are absent in our VACTERL association cohort. However, we identified recurrent rare CNVs which, although inherited, could point to mechanisms or biological processes contributing to this constellation of developmental defects

Predictors of allergen sensitization in Singapore children from birth to 3 years

10.1186/s13223-016-0161-xAllergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology121Article number 56GUSTO (Growing up towards Healthy Outcomes

Modeling the emission line sequence of H II galaxies

Using a sample of unprecedented size (about 400 objects) of H II galaxies in which the oxygen abundances have been obtained using the temperature derived from the [OIII] 4363/5007 line ratio, we confirm that the H II galaxies form a very narrow sequence in many diagrams relating line ratios and Hbeta equivalent width. We divide our sample in three metallicity bins, each of which is compared with sequences of photoionization models for evolving starbursts with corresponding metallicity. Our aim is to find under what conditions a theoretical sequence can reproduce all the observed trends. Taking into account the presence of an older, non-ionizing stellar population, for which independent indications exist, we find that the simple model of an adiabatic expanding bubble reproduces the observational diagrams very well if account is taken of an aperture correction and the covering factor is assumed to decrease with time exponentially with an e-folding time of 3 Myr. We find that the He II 4686 nebular line emission occurs too frequently and in too wide a range of EW(Hbeta) to be attributable to either the hard radiation field from Wolf-Rayet stars or the X-rays produced by the latest stellar generation. Assuming that the He II 4686 line is due to photoionization by a hot plasma at a temperature of 10^6 K, a total X-ray luminosity of 10^40 - 4x10^40 erg/s is required for at least half of the sources. We find evidence for self-enrichment in nitrogen on a time scale of several Myr, and argue for a possible self-enrichment in oxygen as well.Comment: 15 pages, 6 Postscript figures, to appear in Astronomy & Astrophysic

Overlap functions in correlation methods and quasifree nucleon knockout from 16^{16}O

The cross sections of the ($e,e'N$) and ($\gamma,p$) reactions on $^{16}$O are calculated, for the transitions to the $1/2^{-}$ ground state and the first $3/2^{-}$ excited state of the residual nucleus, using single-particle overlap functions obtained on the basis of one-body density matrices within different correlation methods. The electron-induced one-nucleon knockout reaction is treated within a nonrelativistic DWIA framework. The theoretical treatment of the ($\gamma,p$) reaction includes both contributions of the direct knockout mechanism and of meson-exchange currents. The results are sensitive to details of the different overlap functions. The consistent analysis of the reaction cross sections and the comparison with the experimental data make it possible to study the nucleon--nucleon correlation effects.Comment: 26 pages, LaTeX, 5 Postscript figures, submitted to PR

Legius Syndrome in Fourteen Families

Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome. © 2010 Wiley-Liss, Inc

Infantile hypertrophic pyloric stenosis in patients with esophageal atresia

Background: Patients born with esophageal atresia (EA) have a higher incidence of infantile hypertrophic pyloric stenosis (IHPS), suggestive of a relationship. A shared etiology makes sense from a developmental perspective as both affected structures are foregut derived. A genetic component has been described for both conditions as single entities and EA and IHPS are variable components in several monogenetic syndromes. We hypothesized that defects disturbing foregut morphogenesis are responsible for this combination of malformations. Methods: We investigated the genetic variation of 15 patients with both EA and IHPS with unaffected parents using exome sequencing and SNP array-based genotyping, and compared the results to mouse transcriptome data of the developing foregut. Results: We did not identify putatively deleterious de novo mutations or recessive variants. However, we detected rare inherited variants in EA or IHPS disease genes or in genes important in foregut morphogenesis, expressed at the proper developmental time-points. Two pathways were significantly enriched (p < 1 × 10−5): proliferation and differentiation of smooth muscle cells and self-renewal of satellite cells. Conclusions: None of our findings could fully explain the combination of abnormalities on its own, which makes complex inheritance the most plausible genetic explanation, most likely in combination with mechanical and/or environmental factors. As we did not find one defining monogenetic cause for the EA/IHPS phenotype, the impact of the corrective surgery could should be further investigated

On the evolutionary status of Be stars. I. Field Be stars near the Sun

A sample of 97 galactic field Be stars were studied by taking into account the effects induced by the fast rotation on their fundamental parameters. All program stars were observed in the BCD spectrophotometric system in order to minimize the perturbations produced by the circumstellar environment on the spectral photospheric signatures. This is one of the first attempts at determining stellar masses and ages by simultaneously using model atmospheres and evolutionary tracks, both calculated for rotating objects. The stellar ages ($\tau$) normalized to the respective inferred time that each rotating star can spend in the main sequence phase ($\tau\_{\rm MS}$) reveal a mass-dependent trend. This trend shows that: a) there are Be stars spread over the whole interval 0 \la \tau/\tau\_{\rm MS} \la 1 of the main sequence evolutionary phase; b) the distribution of points in the ($\tau/\tau\_{\rm MS},M/M\_{\odot}$) diagram indicates that in massive stars (M \ga 12M\_{\odot}) the Be phenomenon is present at smaller $\tau/\tau\_{\rm MS}$ age ratios than for less massive stars (M \la 12M\_{\odot}). This distribution can be due to: $i$) higher mass-loss rates in massive objets, which can act to reduce the surface fast rotation; $ii$) circulation time scales to transport angular momentum from the core to the surface, which are longer the lower the stellar mass.Comment: 18 pages, 6 figures, A&A, in pres