Does Ileus Represent the Forgotten End Organ Failure in Critical Illness?

PURPOSE OF REVIEW: This review evaluates the current literature on ileus, impaired gastrointestinal transit (IGT), and acute gastrointestinal injury (AGI) and its impact on multiple organ dysfunction syndrome. RECENT FINDINGS: Ileus is often under recognized in critically ill patients and is associated with significant morbidity and is potentially a marker of disease severity as seen in other organs like kidneys (ATN).

Institutional-specific smartphone application as a supplemental tool for an antimicrobial stewardship program in 2 large community-based hospitals: Acceptance of physicians and pharmacists.

PURPOSE: Antimicrobial stewardship programs (ASPs) have been a challenge in less resourceful health care settings. Medical smartphone applications (apps) can be accessible tools to support ASPs under such circumstances. A hospital-specific ASP app was prepared and the acceptance and usability of the study ASP app were evaluated by physicians and pharmacists in 2 community-based academic hospitals. METHODS: The exploratory survey was conducted 5 months following the implementation of the study ASP app. A questionnaire was developed, and the validity and reliability were analyzed using S-CVI/Ave (scale content validity index/Average) and Cronbach's alpha, respectively. The questionnaire consisted of demographics (3 items), acceptance (9 items), usability (10 items), and barriers (2 items). Descriptive analysis was conducted using a 5-point Likert scale, multiple selections, and free-text responses. RESULTS: Approximately 38.7% of 75 respondents (response rate, 23.5%) used the app. Most scored 4 or higher, indicating that the study ASP app was easy to install (89.7%), use (79.3%), and apply to clinical settings (69.0%). Frequently used contents were dosing (39.6%), the spectrum of activity (7.1%), and intravenous-to-oral conversion (7.1%). Barriers included limited time (38.2%) and insufficient content (20.6%). Users indicated that the study ASP app helped improve their knowledge on treatment guidelines (72.4%), antibiotic use (62.1%), and adverse reactions (69.0%). CONCLUSION: The study ASP app was well accepted by physicians and pharmacists and it can be useful to supplement ASPs activities in less resourceful hospitals with a large burden of patient care.

Iron overload-induced oxidative stress in myelodysplastic syndromes and its cellular sequelae.

The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders. MDS patients often require red blood cell transfusions, resulting in iron overload (IOL). IOL increases production of reactive oxygen species (ROS), oxygen free radicals. We review and illustrate how IOL-induced ROS influence cellular activities relevant to MDS pathophysiology. ROS damage lipids, nucleic acids in mitochondrial and nuclear DNA, structural proteins, transcription factors and enzymes. Cellular consequences include decreased metabolism and tissue and organ dysfunction. In hematopoietic stem cells (HSC), consequences of ROS include decreased glycolysis, shifting the cell from anaerobic to aerobic metabolism and causing HSC to exit the quiescent state, leading to HSC exhaustion or senescence. ROS oxidizes DNA bases, resulting in accumulation of mutations. Membrane oxidation alters fluidity and permeability. In summary, evidence indicates that IOL-induced ROS alters cellular signaling pathways resulting in toxicity to organs and hematopoietic cells, in keeping with adverse clinical outcomes in MDS.

Information Needs of Patients Diagnosed with Head and Neck Cancer Undergoing Radiation Therapy: a Survey of Patient Satisfaction.

Research suggests that the information needs of patients diagnosed with head and neck cancer can be particularly complex, given the frequent need for multidisciplinary treatments and resulting potential for profound functional impairments. This study was designed to identify head and neck cancer patients' reported informational needs and to evaluate their satisfaction with the written information they received. The study was divided into 2 phases: phase 1, prior to development of a new educational pamphlet, and phase 2, after its implementation. A survey was designed to evaluate several measures including content, amount, understanding, and timing of information delivery. It was distributed at two points during patients' treatment pathway for each phase: at their last radiation appointment and at their posttreatment follow-up appointment. Participant responses after the revised pamphlet indicated greater preparedness before their first treatment, as well as increased satisfaction with treatment option information. Most were satisfied with information timing, but about a third did indicate that additional information would have been helpful at variable time points. Open-ended responses demonstrated that overall, patients do still desire more information, particularly on side effect and self-care management information. While patients with head and neck cancer appear to be generally satisfied with the written information received, our findings suggest that there is still considerable variability in how the information is understood, when it should be delivered, and in which areas more would have been beneficial. These findings underscore the need to consider how best to balance available resources in order to provide more tailored yet comprehensive education for this group of patients.

Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

Examining Radiation Treatment Appointment Times at a Canadian Cancer Centre: A Timing Study.

INTRODUCTION: Technological advancements in radiation therapy have led to more complex treatment techniques such as volumetric modulated arc therapy, and in turn, more daily image verification. As treatment complexity increases, it is important to consider what effect this may have on treatment time. Additional factors that may influence treatment times are patient-centered care and mobility status. The aim of this study is to determine optimal radiation treatment appointment times based on site, technique, imaging requirements, and patient needs. METHODS: Data from 535 fractions of radiation treatments were collected and analyzed between June 2016 and July 2017 by a team of eight radiation therapists at BC Cancer Vancouver Centre. Data collectors documented a number of data points, including treatment unit, scheduled appointment time, scheduled appointment duration (booked in 12 minute increments), treatment site, treatment technique, imaging modality, pre-treatment-related and post-treatment-related activity time, patient mobility status, etc. Student's t-test was performed for each site/technique to determine if the mean total treatment time was significantly different from the standard appointment time for that site. A two-sample unpaired t-test assuming unequal variance was used to compare average treatment times of the same site with different imaging modalities. Student's t-test was also used to compare average treatment times for ambulatory patients versus patients requiring some form of mobility assistance. RESULTS: Average treatment times for 6 of the 10 sites used for data analysis were longer than standard booked times and showed statistical significance (prostate/prostate bed: n = 82, P < .001; chest: n = 32, P < .001, palliative 1 treatment site: n = 28, P < .05, gyne pelvis only treatment: n = 25, P < .001, head & neck: n = 56, P < .001, and rectum: n = 28, P < 0.05). The breast/chest wall + nodes site had a significantly shorter treatment time than the standard booked appointment time (n = 87, P < .001). Analysis of the prostate/prostate bed imaging showed a significant difference between daily cone beam computed tomography and daily kilovoltage treatment time, with cone beam computed tomography imaging taking 3.83 ± 1.36 (P < .001) minutes longer on average than kilovoltage imaging. Average treatment time for patients requiring mobility assistance was 20% longer than for patients requiring no assistance (P = .02). CONCLUSION: The majority of the most common sites and techniques treated at our centre were inappropriately booked. Radiation therapy appointment durations are influenced by several factors, including site, technique complexity, imaging, and patient care. It is recommended that radiation treatment centres evaluate appointment times regularly as technology, treatment delivery, and professional practice standards evolve to ensure high-quality patient care.

Genome-wide single nucleotide polymorphism-based autozygosity mapping facilitates identification of mutations in consanguineous families with epidermolysis bullosa.

Autozygosity mapping (AM) is a technique utilised for mapping homozygous autosomal recessive (AR) traits and facilitation of genetic diagnosis. We investigated the utility of AM for the molecular diagnosis of heterogeneous AR disorders, using epidermolysis bullosa (EB) as a paradigm. We applied this technique to a cohort of 46 distinct EB families using both short tandem repeat (STR) and genome-wide single nucleotide polymorphism (SNP) array-based AM to guide targeted Sanger sequencing of EB candidate genes. Initially, 39 of the 46 cases were diagnosed with homozygous mutations using this method. Independently, 26 cases, including the seven initially unresolved cases, were analysed with an EB-targeted next-generation sequencing (NGS) panel. NGS identified mutations in five additional cases, initially undiagnosed due to the presence of compound heterozygosity, deep intronic mutations or runs of homozygosity below the set threshold of 2 Mb, for a total yield of 44 of 46 cases (95.7%) diagnosed genetically.

Does the melatonin receptor 1B gene polymorphism have a role in postoperative delirium?

INTRODUCTION: Patients undergoing cardiac surgery are at high risk for postoperative delirium, which is associated with longer hospital and intensive care lengths of stays, increased morbidity and mortality. Because sleep disturbances are common in delirium, melatonin has been an area of interest in the treatment of delirium. The rs10830963 single nucleotide polymorphism of the melatonin receptor 1B gene can cause pathological dysfunction of this receptor and is associated with delayed morning offset of melatonin. We hypothesized patients undergoing aortic cardiac surgery who have the risk genotype of a melatonin receptor 1B polymorphism would have a higher incidence of postoperative delirium. METHODS: Ninety-eight patients undergoing aortic root or valve surgery underwent analysis for melatonin receptor 1B single nucleotide polymorphism, rs10830963. Using a validated method, CHART-DEL, all charts were retrospectively reviewed and scored for the presence of delirium while blinded to the results of the melatonin receptor 1B gene polymorphism. RESULTS: Genotyping for melatonin receptor 1B polymorphism was acceptable in 76 subjects of European descent of which 18 (23.7%) had delirium. Four of seven subjects with the risk genotype had delirium versus only 20.3% of subjects without the risk genotype. This carried an odds ratio of 5.2 (1.0, 26.1), p = 0.050. CONCLUSION: This observation suggests a role of the risk genotype of a melatonin receptor 1B polymorphism in the development of postoperative delirium. These hypotheses generating results warrant further prospective studies in a larger cohort group with delirium, circadian rhythm and melatonin assessments.

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage.

Background: Neuroprotection studies are generally unable to demonstrate efficacy in humans. Our specific hypothesis is that multiple pathophysiologic pathways, of variable importance, contribute to ischemic brain damage. As a corollary to this, we discuss the broad hypothesis that a multifaceted approach will improve the probability of efficacious neuroprotection. But to properly test this hypothesis the nature and importance of the multiple contributing pathways needs elucidation. Our aim is to demonstrate, using functional genomics, in human cardiac surgery procedures associated with cerebral ischemia, that the pathogenesis of perioperative human ischemic brain damage involves the function of multiple variably weighted proteins involving several pathways. We then use these data and literature to develop a proposal for rational design of human neuroprotection protocols. Methods: Ninety-four patients undergoing deep hypothermic circulatory arrest (DHCA) and/or aortic valve replacement surgery had brain damage biomarkers, S100ß and neurofilament H (NFH), assessed at baseline, 1 and 24 h post-cardiopulmonary bypass (CPB) with analysis for association with 92 single nucleotide polymorphisms (SNPs) (selected by co-author WAK) related to important proteins involved in pathogenesis of cerebral ischemia. Results: At the nominal significance level of 0.05, changes in S100ß and in NFH at 1 and 24 h post-CPB were associated with multiple SNPs involving several prospectively determined pathophysiologic pathways, but were not individually significant after multiple comparison adjustments. Variable weights for the several evaluated SNPs are apparent on regression analysis and, notably, are dissimilar related to the two biomarkers and over time post CPB. Based on our step-wise regression model, at 1 h post-CPB, SOD2, SUMO4, and GP6 are related to relative change of NFH while TNF, CAPN10, NPPB, and SERPINE1 are related to the relative change of S100B. At 24 h post-CPB, ADRA2A, SELE, and BAX are related to the relative change of NFH while SLC4A7, HSPA1B, and FGA are related to S100B. Conclusions: In support of the proposed hypothesis, association SNP data suggest function of specific disparate proteins, as reflected by genetic variation, may be more important than others with variation at different post-insult times after human brain ischemia. Such information may support rational design of post-insult time-sensitive multifaceted neuroprotective therapies.

Genetic Reduction in Left Ventricular Protein Kinase C-α and Adverse Ventricular Remodeling in Human Subjects.

BACKGROUND: Inhibition of PKC-α (protein kinase C-α) enhances contractility and cardioprotection in animal models, but effects in humans are unknown. Genotypes at rs9912468 strongly associate with PRKCA expression in the left ventricle, enabling genetic approaches to measure effects of reduced PKC-α in human populations. METHODS AND RESULTS: We analyzed the cis expression quantitative trait locus for PRKCA marked by rs9912468 using 313 left ventricular specimens from European Ancestry patients. The forward strand minor allele (G) at rs9912468 is associated with reduced PKC-α transcript abundance (1.7-fold reduction in minor allele homozygotes, P=1×10-41). This association was cardiac specific in expression quantitative trait locus data sets that span 16 human tissues. Cardiac epigenomic data revealed a predicted enhancer in complete (R2=1.0) linkage disequilibrium with rs9912468 within intron 2 of PRKCA. We cloned this region and used reporter constructs to verify cardiac-specific enhancer activity in vitro in cardiac and noncardiac cells and in vivo in zebrafish. The PRKCA enhancer contains 2 common genetic variants and 4 haplotypes; the haplotype correlated with the rs9912468 PKC-α-lowering allele (G) showed lowest activity. In contrast to previous reports in animal models, the PKC-α-lowering allele is associated with adverse left ventricular remodeling (higher mass, larger diastolic dimension), reduced fractional shortening, and higher risk of dilated cardiomyopathy in human populations. CONCLUSIONS: These findings support PKC-α as a regulator of the human heart but suggest that PKC-α inhibition may adversely affect the left ventricle depending on timing and duration. Pharmacological studies in human subjects are required to discern potential benefits and harms of PKC-α inhibitors as an approach to treat heart disease.

Common variants in MMP20 at 11q22.2 predispose to 11q deletion and neuroblastoma risk.

MYCN amplification and 11q deletion are two inversely correlated prognostic factors of poor outcome in neuroblastoma. Here we identify common variants at 11q22.2 within MMP20 that associate with neuroblastoma cases harboring 11q deletion (rs10895322), using GWAS in 113 European-American cases and 5109 ancestry-matched controls. The association is replicated in 44 independent cases and 1902 controls. Our study yields novel insights into the genetic underpinnings of neuroblastoma, demonstrating that the inherited common variants reported contribute to the origin of intra-tumor genetic heterogeneity in neuroblastoma.Chromosomal abnormalities such as 11q deletion are associated with poor prognosis in neuroblastoma. Here, the authors perform a genome-wide association study and identify an association between a variant within a Matrix metalloproteinase (MMP) gene member, MMP20, and 11q-deletion subtype neuroblastoma.

Erratum: A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.

We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10-7; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation.

Exome Sequencing Reveals Mutations in AIRE as a Cause of Isolated Hypoparathyroidism.

Context: Most cases of autosomal recessive hypoparathyroidism (HYPO) are caused by loss-of-function mutations in GCM2 or PTH. Objective: The objective of this study was to identify the underlying genetic basis for isolated HYPO in a kindred in which 3 of 10 siblings were affected. Subjects: We studied the parents and the three adult affected subjects, each of whom was diagnosed with HYPO in the first decade of life. Methods: We collected clinical and biochemical data and performed whole exome sequencing analysis on DNA from the three affected subjects after negative genetic testing for known causes of HYPO. Results: Whole exome sequencing followed by Sanger sequencing revealed that all three affected subjects were compound heterozygous for two previously reported mutations, c.967_979delCTGTCCCCTCCGC:p.(L323SfsX51) and c.995+(3_5)delGAGinsTAT, in AIRE, which encodes the autoimmune regulator protein that is defective in autoimmune polyglandular syndrome type 1 (APS-1). Each parent carries one mutation, and all of the children of the patients are either heterozygous for one mutation or wild type. The affected sister developed premature ovarian failure, but the two affected brothers have no other features of APS-1 despite elevated serum levels of anti-interferon-α antibodies. Conclusions: Our findings indicate that biallelic mutations in AIRE can cause isolated HYPO as well as syndromic APS-1. The presence of antibodies to interferon-α provides a highly sensitive indicator for loss of AIRE function and represents a useful marker for isolated HYPO due to AIRE mutations.

Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study.

BACKGROUND: Systemic sclerosis (SSc) is a rheumatologic disease with a multifactorial etiology. Genome-wide association studies imply a polygenic, complex mode of inheritance with contributions from variation at the human leukocyte antigen locus and non-coding variation at a locus on chromosome 6p21, among other modestly impactful loci. Here we describe an 8-year-old female proband presenting with diffuse cutaneous SSc/scleroderma and a family history of SSc in a grandfather and maternal aunt. METHODS: We employed whole exome sequencing (WES) of three members of this family. We examined rare missense, nonsense, splice-altering, and coding indels matching an autosomal dominant inheritance model. We selected one missense variant for Sanger sequencing confirmation based on its predicted impact on gene function and location in a known SSc genetic locus. RESULTS: Bioinformatic analysis found eight candidate variants meeting our criteria. We identified a very rare missense variant in the regulatory NODP domain of NOTCH4 located at the 6p21 locus, c.4245G > A:p.Met1415Ile, segregating with the phenotype. This allele has a frequency of 1.83 × 10-5 by the data of the Exome Aggregation Consortium. CONCLUSION: This family suggests a novel mechanism of SSc pathogenesis in which a rare and penetrant coding variation can substantially elevate disease risk in contrast to the more modest non-coding variation typically found at this locus. These results suggest that modulation of the NOTCH4 gene might be responsible for the association signal at chromosome 6p21 in SSc.

Genomic copy number variation association study in Caucasian patients with nonsyndromic cryptorchidism.

BACKGROUND: Copy number variation (CNV) is a potential contributing factor to many genetic diseases. Here we investigated the potential association of CNV with nonsyndromic cryptorchidism, the most common male congenital genitourinary defect, in a Caucasian population. METHODS: Genome wide genotyping were performed in 559 cases and 1772 controls (Group 1) using Illumina HumanHap550 v1, HumanHap550 v3 or Human610-Quad platforms and in 353 cases and 1149 controls (Group 2) using the Illumina Human OmniExpress 12v1 or Human OmniExpress 12v1-1. Signal intensity data including log R ratio (LRR) and B allele frequency (BAF) for each single nucleotide polymorphism (SNP) were used for CNV detection using PennCNV software. After sample quality control, gene- and CNV-based association tests were performed using cleaned data from Group 1 (493 cases and 1586 controls) and Group 2 (307 cases and 1102 controls) using ParseCNV software. Meta-analysis was performed using gene-based test results as input to identify significant genes, and CNVs in or around significant genes were identified in CNV-based association test results. Called CNVs passing quality control and signal intensity visualization examination were considered for validation using TaqMan CNV assays and QuantStudio® 3D Digital PCR System. RESULTS: The meta-analysis identified 373 genome wide significant (p < 5X10-4) genes/loci including 49 genes/loci with deletions and 324 with duplications. Among them, 17 genes with deletion and 1 gene with duplication were identified in CNV-based association results in both Group 1 and Group 2. Only 2 genes (NUCB2 and UPF2) containing deletions passed CNV quality control in both groups and signal intensity visualization examination, but laboratory validation failed to verify these deletions. CONCLUSIONS: Our data do not support that structural variation is a major cause of nonsyndromic cryptorchidism.

Early Infantile Epileptic Encephalopathy in an STXBP1 Patient with Lactic Acidemia and Normal Mitochondrial Respiratory Chain Function.

A wide range of clinical findings have been associated with mutations in Syntaxin Binding Protein 1 (STXBP1), including multiple forms of epilepsy, nonsyndromic intellectual disability, and movement disorders. STXBP1 mutations have recently been associated with mitochondrial pathology, although it remains unclear if this phenotype is a part of the core feature for this gene disorder. We report a 7-year-old boy who presented for diagnostic evaluation of intractable epilepsy, episodic ataxia, resting tremor, and speech regression following a period of apparently normal early development. Mild lactic acidemia was detected on one occasion at the time of an intercurrent illness. Due to the concern for mitochondrial disease, ophthalmologic evaluation was performed that revealed bilateral midperiphery pigmentary mottling. Optical coherence tomography (OCT) testing demonstrated a bilaterally thickened ganglion cell layer in the perifovea. Skeletal muscle biopsy analysis showed no mitochondrial abnormalities or respiratory chain dysfunction. Exome sequencing identified a de novo c.1651C>T (p.R551C) mutation in STXBP1. Although mitochondrial dysfunction has been reported in some individuals, our proband had only mild lactic acidemia and no skeletal muscle tissue evidence of mitochondrial disease pathology. Thus, mitochondrial dysfunction is not an obligate feature of STXBP1 disease.

Pathway-based Genome-wide Association Studies Reveal the Association Between Growth Factor Activity and Inflammatory Bowel Disease.

BACKGROUND: The inflammatory bowel diseases known as Crohn's disease (CD) and ulcerative colitis (UC) are related autoimmune conditions with a complex etiology composed of genetic and environmental factors. Genetic studies have revealed 200 susceptibility loci for inflammatory bowel diseases, but these only account for a small fraction of the genetic heritability of the disease. We employed pathway-based approaches to identify genes that cooperatively make contributions to the genetic etiology of CD. METHODS: We exploited the largest CD dataset (20,000 cases + 28,000 controls) and UC dataset (17,000 cases + 33,500 controls) to date. We conducted a meta-analysis of 5 CD cohorts of European ancestry using 3 pathway-based approaches and further performed replication studies in an independent cohort genotyped on the Immunochip and in another pediatric cohort of European ancestry. Similar meta-analysis was performed for UC cohorts. RESULTS: In addition to the multiple immune-related pathways that have been implicated in the genetic etiology of inflammatory bowel diseases before, we found significant associations involving genes in growth factor signaling for CD. This result was replicated in 2 independent cohorts of European ancestry. This association with growth factor activity is not unique to CD. We found a similar significant association with UC cohorts. CONCLUSIONS: Our findings suggest that genes involved in pathways of growth factor signaling may make joint contributions to the etiology of CD and UC, providing novel insight into the genetic mechanisms of these diseases.

Association of Mutations in SLC12A1 Encoding the NKCC2 Cotransporter With Neonatal Primary Hyperparathyroidism.

CONTEXT: Primary hyperparathyroidism with hypercalciuria has not been described in the newborn period. OBJECTIVE: Our objectives are to identify the genetic basis for neonatal primary hyperparathyroidism in a family with 2 affected children. SUBJECTS: An African American boy presenting with mild neonatal primary hyperparathyroidism and hypercalciuria was evaluated at The Children's Hospital of Philadelphia. His older brother with neonatal primary hyperparathyroidism had died in infancy of multiple organ failure. METHODS: We collected clinical and biochemical data and performed exome sequencing analysis on DNA from the patient and his unaffected mother after negative genetic testing for known causes of primary hyperparathyroidism. RESULTS: Exome sequencing followed by Sanger sequencing disclosed 2 heterozygous mutations, c.1883C>A, p.(A628D) and c.2786_2787insC, p.(T931fsX10), in the SLC12A1 gene, which was previously implicated in antenatal type 1 Bartter syndrome. Sanger sequencing confirmed the 2 mutations in the proband and his deceased brother; both parents were heterozygous for different mutations and an unaffected sister was homozygous for wild-type alleles. CONCLUSIONS: These results demonstrate a previously unrecognized association between neonatal primary hyperparathyroidism and mutation of SLC12A1, the cause of antenatal Bartter syndrome type 1, and suggest that the loss of sodium-potassium-chloride cotransporter-2 cotransporter activity influences parathyroid gland function.