PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

A longitudinal study of serial BODE indices in predicting mortality and readmissions for COPD

Introduction: BODE index comprises Body mass index, Obstruction of the airway [FEV1], Dyspnoea score [modified Medical Research Council questionnaire] and Exercise capacity [6 min walk test]. This study assessed the role of serial changes in BODE index in predicting mortality and readmissions of COPD patients. Methods: A prospective cohort study involving 243(208males) COPD patients hospitalized for acute exacerbations of COPD [AECOPD]. BODE index was assessed at 6 weeks(baseline), 6, 12, 18 and 24 months post hospital discharge. Mortality and readmissions in the subsequent 3 years were recorded. All the patients were managed by usual care without additional intervention. Results: The mean (SD) age and FEV1% predicted were 74.2(7.8) yrs and 51.7(21.6)% respectively. Over the 3 years, 25.1% died whereas 76.5% had at least 1 readmission for AECOPD. Baseline BODE index was predictive of both the survival and readmissions to hospital for AECOPD by Cox regression analysis (p 1point), no change, and decreased in BODE (>1point) index respectively. Serial changes in BODE index at 6 month was marginally associated with mortality, but not at 12-, 18- and 24-month. The 6-, 12- and 24-month BODE indices were predictive of the readmissions for AECOPD when compared to baseline. Conclusion: Baseline BODE index could predict both survival and readmissions for AECOPD, whereas serial BODE indices were not predictive of survival at 3 years. Single rather than serial measurements of BODE index is sufficient for prediction of survival and readmissions for patients treated with usual care. © 2010 Elsevier Ltd. All rights reserved.link_to_subscribed_fulltex

Prenatal cerebral imaging features of a new syndromic entity related to KIAA1109

Our goal was to describe and illustrate prenatal cerebral imaging features of the most severe form of a new syndromic entity related to KIAA1109 pathogenic variants based on a retrospective multicentric study of seven cases. All cases demonstrated a similar complex severe cerebral malformative pattern. This pattern included, within the supratentorial space, major cerebral parenchymal thinning with a lissencephalic cortical pattern, voluminous germinal matrices, severe ventriculomegaly, and corpus callosum agenesis. Within the infra-tentorial space, cerebellar hypoplasia was associated with characteristic brainstem dysgenesis including elongation of the pons, as well as a variable degree of kinking of the brainstem. This cerebral pattern, which was suggestive of the more severe phenotypes related to disrupting variants of tubulin-encoding genes, was associated in all cases with clubfoot and/or arthrogryposis, and in most cases with cardiac and ophthalmologic anomalies. In all cases, exome sequencing led to the identification of KIAA1109 pathogenic variants

Prenatal cerebral imaging features of a new syndromic entity related to KIAA1109 pathogenic variants mimicking tubulinopathy.

Our goal was to describe and illustrate prenatal cerebral imaging features of the most severe form of a new syndromic entity related to KIAA1109 pathogenic variants based on a retrospective multicentric study of seven cases. All cases demonstrated a similar complex severe cerebral malformative pattern. This pattern included, within the supratentorial space, major cerebral parenchymal thinning with a lissencephalic cortical pattern, voluminous germinal matrices, severe ventriculomegaly, and corpus callosum agenesis. Within the infra-tentorial space, cerebellar hypoplasia was associated with characteristic brainstem dysgenesis including elongation of the pons, as well as a variable degree of kinking of the brainstem. This cerebral pattern, which was suggestive of the more severe phenotypes related to disrupting variants of tubulin-encoding genes, was associated in all cases with clubfoot and/or arthrogryposis, and in most cases with cardiac and ophthalmologic anomalies. In all cases, exome sequencing led to the identification of KIAA1109 pathogenic variants

Plasma glycemic measures and fecundability in a Singapore preconception cohort study

Fertility and Sterility1151138 - 147FEST