Children’s Hospital investigators discovered two gene variants that raise the risk of the pediatric cancer neuroblastoma. The study broadened the understanding of how gene changes can make a child susceptible to this early childhood cancer and how those changes can cause a tumor to progress.

Affecting the peripheral nervous system, neuroblastoma usually appears as a solid tumor in the chest or abdomen. It accounts for 7 percent of all childhood cancers, and 10 to 15 percent of all childhood cancer deaths.

The study team performed a genome-wide association study, comparing DNA from 2,800 neuroblastoma patients with that of nearly 7,500 healthy children. They found two common gene variants associated with neuroblastoma, both in the 6q16 region of chromosome 6. One variant is within the HACE1 gene, the other in the LIN28B gene. They exert opposite effects: HACE1 functions as a tumor suppressor gene, hindering cancer, while LIN28B is an oncogene, driving cancer development.

The current study showed that low expression of HACE1 and high expression of LIN28B correlated with worse patient survival. To further investigate the gene’s role, the researchers used genetic tools to decrease LIN28B’s activity, and showed that this inhibited the growth of neuroblastoma cells in culture.

“In addition to broadening our understanding of the heritable component of neuroblastoma susceptibility, we think this research may suggest new therapies,” said first author Sharon J. Diskin, PhD.

As disease-causing microbes continue their worrisome trend of developing resistance to commonly used antibiotics, public health experts have called for more selective use of those medicines. A Children’s Hospital study suggests that educating pediatricians in their offices, and auditing their prescription patterns, encourages them to choose more appropriate antibiotics for children with common respiratory infections.

“Although much research has focused on improving how hospitals use antibiotics, there have been few studies of interventions in outpatient settings, where the vast majority of antibiotic use occurs,” said study leader and infectious diseases specialist Jeffrey S. Gerber, MD, PhD. “We focused on increasing appropriate antibiotic prescribing in primary care practices.”

Dr. Gerber and colleagues published their study of an “antimicrobial stewardship” program in Journal of the American Medical Association. Last year Dr. Gerber and his team presented their research at the IDWeek conference, a joint meeting of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, HIV Medicine Association, and the Pediatric Infectious Diseases Society.

Antimicrobial stewardship, pointed out Dr. Gerber, usually involves prospective audits of prescription patterns — comparing the prescription for a given diagnosis to the current recommendations of professional organizations (in the current study, as issued by the American Academy of Pediatrics). For this study, stewardship also included personalized, private feedback reports to practitioners, advising them of whether their prescriptions followed current recommendations.

The study concentrated on whether the pediatricians prescribed narrow-spectrum antibiotics, as recommended, or broad-spectrum antibiotics for acute bacterial respiratory infections such as pneumonia, acute sinusitis, and streptococcal pharyngitis (or “strep throat”). All are common conditions for which children receive antibiotics.

The study team randomized 18 pediatricians’ practices in CHOP’s primary care network into two groups: one that received the intervention (an hour-long clinician-education session at the practice office, followed by audit and feedback of antibiotic prescribing), and a control group that did not receive the educational session, audit and feedback. The study encompassed nearly 1.3 million office visits by some 185,000 patients to 162 clinicians over a study period of 32 months, from 2008 to 2011.

Among the intervention practices, broad-spectrum antibiotic prescribing decreased from 26.8 percent to 14.3 percent, or nearly half, compared to a decrease from 28.4 percent to 22.6 percent in the control group. For children with pneumonia, the inappropriate broad-spectrum prescriptions declined by 75 percent among practices receiving the intervention.

Obesity has doubled in children and tripled in adolescents in the past 30 years, according to the CDC, raising the risk for developing health problems later in life, including diabetes.

A study involving Children’s Hospital investigators found obese teenagers who reduced their body mass index (BMI) by 8 percent or more had improvements in insulin sensitivity, an important metabolic factor related to the later development of type 2 diabetes. The teens followed a family-based, lifestyle-modification weight loss program that offers the potential to become a broader model to reduce their BMI levels.

“This threshold effect that occurs at 8 percent suggests that obese adolescents don’t need to lose enormous amounts of weight to achieve improvements,” said pediatric endocrinologist Lorraine Levitt Katz, MD, of Children’s Hospital’s Diabetes Center for Children.

The findings were published in The Journal of Pediatrics. The article’s first author is Pamela Abrams, MD, a member of the study team while at Children’s Hospital. Children’s Hospital psychiatrist Robert I. Berkowitz, MD, who was the principal investigator of a clinical trial of weight loss treatments from which the researchers analyzed data for the current study, also contributed to the study.

The investigators looked at 113 primarily urban adolescents, aged 13 to 17, of whom 81 percent were female and 62 percent were African American. At the start of the study, their mean BMI was 37.1 — the severely obese range. Although none had type 2 diabetes, their obesity placed them at high risk for developing in the future.

An important goal of the study was to determine the threshold of weight loss that significantly impacted insulin sensitivity, glucose tolerance, and the presence of metabolic syndrome (MS). MS, as well as abnormal values in insulin sensitivity and glucose tolerance, is associated with the development of type 2 diabetes.

The research team found a significant improvement in all measures of insulin sensitivity. There was also a trend toward improvement in metabolic syndrome. And the threshold of 8 percent, the level at which a decreased BMI showed improved insulin sensitivity, was consistent with results found previously in adults.

Children’s Hospital researchers contributed to two studies showing that extending cardiopulmonary resuscitation (CPR) longer than previously thought useful saves lives in both children and adults. The teams analyzed the impact of duration of CPR in patients who suffered cardiac arrest while hospitalized.

“These findings about the duration of CPR are game-changing, and we hope these results will rapidly affect hospital practice,” said Robert A. Berg, MD, chief of Critical Care Medicine at Children’s Hospital. Dr. Berg is also chair of the Scientific Advisory Board of the American Heart Association’s Get With Guidelines-Resuscitation (GWTG-R), program a national registry that tracks and analyzes the resuscitation of patients after in-hospital cardiac arrests.

The investigators reported data from the GWTG-Resuscitation registry of CPR outcomes in thousands of North American hospital patients in two landmark studies, one of which was focused on children.

Dr. Berg was a co-author of the pediatric study, which was published in Circulation. After analyzing the hospital records of 3,419 children in the U.S. and Canada from 2000 through 2009, the investigators found that among children who suffered in-hospital cardiac arrest, more children than expected survived after prolonged CPR. Of those children who survived prolonged CPR — which is defined as lasting longer than 35 minutes — over 60 percent had good neurologic outcomes.

The conventional thinking has been that CPR is futile after 20 minutes, but these results challenge that, said Dr. Berg.

The pediatric results parallel those found in the second GWTG-R investigation, which examined 64,000 adult patients with in-hospital cardiac arrests between 2000 and 2008. That study showed patients at hospitals in the top quartile of median CPR duration (25 minutes), had a 12 percent higher chance of surviving cardiac arrest, compared to patients at hospitals in the bottom quartile of median CPR duration (16 minutes). Survivors of prolonged CPR had similar neurological outcomes to those who survived after shorter CPR efforts.

The American Heart Association and American Stroke Association named the Lancet study as the top finding of the year in heart disease and stroke research in its annual list of major advances.

Affecting an estimated 1 in 10,000 children, Cornelia deLange syndrome (CdLS) causes intellectual disability, limb deformations, and other disabilities resulting from impairments in early development. Researchers have identified a key gene that, when mutated, causes this rare multisystem disorder. By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control gene expression and cell division, the research sheds light on this disease.

The CdLS research team, led by Matthew A. Deardorff, MD, PhD, focused on the cohesin complex, a group of proteins that form a bracelet-like structure that encircles pairs of chromosomes, called sister chromatids. Mutations that perturb normal cohesin function can interfere with normal human development, Dr. Deardorff noted. Such is the case in CdLS, which exemplifies a newly recognized class of diseases called cohesinopathies.

In the current study, the scientists investigated both acetylation — how an acetyl molecule is attached to part of the cohesion complex — and deactylation, the removal of that molecule. Normally, deactylation helps recycle cohesin to make it available during successive rounds of cell division. The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.

Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of “recharged” cohesin available to properly regulate gene transcription. This, in turn, the researchers suggest, impairs normal embryonic development and gives rise to CdLS.

The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene. They also identified HDAC8 mutations in approximately 5 percent of patients with CdLS.

Because mothers of children with CdLS may carry mutations in the HDAC8 gene, identifying these mutations will be very useful in accurately counseling families of their recurrence risk — the likelihood of having a subsequent child with CdLS. And by providing details of the underlying defect in CdLS, the current research suggests future approaches to treating the genetic disease.

The United States has a weight problem: according to the CDC, more than one-third of American adults are obese. Moreover, as of 2010 one-third of children were either overweight or obese, with the rates of obesity doubling in children and tripling in adolescents in the past thirty years. And some groups are more inclined to be obese than others, with non-Hispanic blacks 51 percent more likely than whites to be obese, for example.

A recently published study may help researchers better understand why some populations are more susceptible to obesity than others. Struan Grant, PhD, associate director of the Hospital’s Center for Applied Genomics, co-authored a study that discovered new loci associated with body mass index (BMI) in adults of African ancestry.

Previous genome-wide association studies had identified 36 BMI-associated loci. While those studies mainly investigated individuals of European descent, in the current study the researchers conducted a meta-analysis to determine whether more than 3.2 million single nucleotide polymorphisms were associated with BMI in men and women of African ancestry. In all, more than 70,000 men and women of African descent were studied.

In addition to Dr. Grant, Children’s Hospital’s Hakon Hakonarson, MD, PhD, director of CAG, Brendan Keating, PhD, CAG lead clinical data analyst and faculty member in UPenn Pediatrics and Surgery, and CAG bioinformatics specialist Jonathan Bradfield, also contributed and co-authored the study. More than 200 researchers representing over 50 institutions took part in the investigation, which was published online recently in Nature Genetics.

The research group discovered two new loci — 5q33 and 7p15 — associated with BMI in people of African ancestry, while a third, 6q16, was found to be suggestive of an association. "These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations," the researchers say.

A team led by Marni J. Falk, MD, has expanded next-generation gene sequencing tools designed to unlock the secrets hidden in nuclear DNA to analyze a separate source of DNA — that found within mitochondria. Mitochondria, which contain their own DNA, are key suppliers of the energy needed for the multiple functions of our cells, and play a pivotal role in human health and disease.

“A first step in developing treatments for a disease is to understand its precise cause,” said Dr. Falk, director of the Mitochondrial-Genetic Disease Clinic at Children’s Hospital. “We have developed a one-step, off-the-shelf tool that analyzes both nuclear and mitochondrial DNA to help evaluate the genetic cause of suspected mitochondrial disease.”

The investigators described their customized, comprehensive test — which they call the “1:1000 Mito-Plus Whole-Exome” kit — in Discovery Medicine. To achieve their results, the study team adapted an existing whole-exome sequencing kit, expanding it to encompass the mitochondrial genome.

While individual mitochondrial diseases are rare, hundreds of causes of mitochondrial diseases are known. Some originate in mutations in DNA specific to the mitochondria, while many other mitochondrial diseases are based in nuclear DNA genes that affect mitochondrial function. The role of mitochondria in human disease has been recognized only since the 1980s, and is largely based on the pioneering research by CHOP’s Douglas C. Wallace, PhD, a co-author of the current study. However, many mitochondrial diseases remain poorly understood.

One complicating factor is heteroplasmy — a mixture of mutated and normal mitochondrial genomes within the same cells or tissues. In contrast to conventional gene sequencing, which can detect only heteroplasmic mutations that reach levels of at least 30 to 50 percent, Dr. Falk’s kit has the sensitivity to detect mitochondrial genome mutations present at levels as low as 8 percent.

A second study led by Dr. Falk reviews progress made in diagnosing mitochondrial disease at a single center over a rapidly changing three-year period before whole-exome sequencing was generally available. The retrospective review, published in Neurotherapeutics, covers 152 child and adult patients evaluated at CHOP’s Mitochondrial-Genetics Diagnostic Clinic from 2008 to 2011.

An international team of genetics researchers discovered four new gene regions that contribute to low birth weight. Three of those regions influence adult metabolism, and appear to affect longer-term outcomes such as adult height, risk of type 2 diabetes, and adult blood pressure.

“This large study adds to the evidence that genes have a strong influence on fetal growth,” said one of the co-authors, Struan F.A. Grant, PhD, associate director of the Center for Applied Genomics at Children’s Hospital. “The cumulative effect of the genes is surprisingly strong; it’s equivalent to the effect of maternal smoking, which is already recognized as lowering a baby’s weight at birth. We already know that a low birth weight increases the risk of health problems in adult life."

The article, published in Nature Genetics, was the second major study on birth weight by the Early Growth Genetics (EGG) Consortium, composed of groups of scientists from multiple countries, including the United Kingdom, Finland, the Netherlands, and the United States.

The meta-analysis and follow-up study encompassed nearly 70,000 individuals, of European, Arab, Asian, and African American descent, from across 50 separate studies of pregnancy and birth. In addition to confirming that three previously discovered genetic regions increased the risk of low birth weight, the consortium discovered four new regions: genes HMGA2, LCORL, ADRB1, and a locus on chromosome 5.

Two of the previously identified gene regions are connected to a risk of type 2 diabetes, while two of the newly found regions confer a risk of shorter adult stature. A third region, ADRB1, is associated with adult blood pressure — the first time that scientists have found a genetic link common to both birth weight and blood pressure.

A Children’s Hospital study verified the long-controversial belief that a few children, in exceptional cases, can “recover” from autism. The study, which included investigators from the Center for Autism Research, is the first solid science to confirm that, however rarely, with the help of behavioral therapy some children can make such great improvements that they no longer qualify as having autism.

The director of the Center for Autism Research Robert Schultz, PhD, served as one of the co-authors on the study published in the Journal of Child Psychology and Psychiatry.

The investigators sought to explore whether the autism-recovery phenomenon was the result of an initial misdiagnosis, or whether the children’s recovery was complete. For example, the investigators asked, could the recovered children have retained significant social impairments despite losing the technical diagnosis of autism?

To test and document children who were diagnosed with autism at a young age but who no longer were qualified as such, the research team compared three groups of patients. They examined a group with a history of autism and "optimal outcomes," a second group who had high-functioning autism, and a group of children who were developing typically.

The study’s results “clearly demonstrate” that some children who had previously been diagnosed with autism later recovered, to the point that their communication and social skills were comparable to those of typically developing children.

The researchers caution, however, that they don’t yet understand why some children recover and others don’t, and have no way to predict which patients will do well.

According to Dr. Schultz, this study “provides an important scientific opportunity to study why and how these particular children did so well — what is it about their past interventions, their initial profile of strengths and weaknesses and their brain that we can learn from in order to try to generalize this result to the great majority of youth who don’t achieve this optimal outcome?”

While investigating the biology of brain tumors in children, pediatric researchers are finding that crucial differences in how the same gene is mutated may call for different treatments. A study offers glimpses into how scientists will be using the ongoing flood of gene-sequencing data to customize treatments based on very specific mutations in a child’s tumor.

“By better understanding the basic biology of these tumors, such as how particular mutations in the same gene may respond differently to targeted drugs, we are moving closer to personalized medicine for children with cancer,” said the study’s first author, CHOP’s Angela J. Sievert, MD, MPH.

The study, of which Dr. Sievert was a co-first author with Children’s Hospital’s Shih-Shan Lang, MD, was published in the Proceedings of the National Academy of Sciences.

The study focused on a kind of astrocytoma, the most common type of brain tumor in children. When surgeons can fully remove an astrocytoma (also called a low-grade glioma), a child can be cured. However, many astrocytomas are too widespread or in too delicate a site to be safely removed. So pediatric oncologists have been seeking better treatment options.

The study focused on mutations in the BRAF gene, one of the most commonly mutated genes in human cancers. Because the same gene is also mutated in certain adult cancers, the pediatric researchers were able to make use of recently developed drugs known as BRAF inhibitors that were already being tested in adults.

And by examining the molecular mechanisms behind drug resistance and working with the pharmaceutical industry, the investigators identified a new, experimental second-generation BRAF inhibitor.

This work result lays a foundation for multicenter clinical trials to test the mutation-specific targeting of tumors by this class of drugs in children with astrocytomas, said Dr. Sievert. As this effort progresses, it will benefit from CHOP’s commitment to resources and collaborations that support data-intense research efforts.

Failing to address the emotional and behavioral problems of school-age children can have serious, life-changing ramifications — poor grades, suspension and expulsion, and problems with the law later in life. Studies show, however, that only 1 in 5 children with emotional and behavioral disorders receive mental health services, with low-income and ethnically diverse children lagging far behind their middle class, Caucasian counterparts.

At the heart of this disparity is a shortage of specialized services in low-income communities, the high cost of these services, and the stigma attached to using them. Underscoring the problem is the fact that evidence-based interventions are not successfully deployed in urban schools. These interventions are all too often derailed by inadequate training and poor implementation by service providers in schools.

The National Institute of Child Health and Human Development awarded Children’s Hospital a $3.1 million grant to study the level of support school personnel needed to effectively implement an intervention program called School-Wide Positive Behavioral Interventions and Supports (SW-PBIS) for typically developing students as well as students with, or at risk for, externalizing or anxiety disorders.

SW-PBIS is a comprehensive service delivery strategy that, by combining universal and targeted interventions to address students’ emotional and behavioral issues, can help improve overall school climate, perceived school safety, and student academic performance. The program focuses on preventing new cases of problem behaviors through school-wide discipline, classroom behavior management, and effective instructional practices.

The CHOP study, led by Ricardo Eiraldi, PhD, examines whether school personnel can implement the components of a two-tier SW-PBIS program with the same level of fidelity, integrity, and effectiveness when they receive a relatively low level of support from coaches and supervisors as they can with a high level of support. Dr. Eiraldi and his team partnered with the School District of Philadelphia to select six schools in North Philadelphia for participation in the project.

Ron Keren, MD, MPH, director of the Center for Pediatric Clinical Effectiveness, received nearly $2 million from the Patient-Centered Outcomes Research Institute to lead a study of treatments for serious bacterial infections in children.

The three-year award supports a project examining whether children who have a serious bacterial infection that requires prolonged antibiotic therapy (greater than one week) do as well taking the antibiotics by mouth as they would if they received them via an intravenous (IV) catheter — specifically a peripherally inserted central catheter, or PICC, line.

These two antibiotic treatment options have major implications for the overall experience of the child, families and caregivers, but there is a lack of real-world evidence on their benefits and drawbacks to help clinicians and patient families make an informed choice.

PICC lines also have some risks. They can clot, break, or become dislodged. And because they sit in large blood vessels directly above the heart, any bacteria that are inadvertently introduced into the catheter go directly to the heart and are pumped throughout the body, which can lead to a dangerous infection called sepsis.

Oral antibiotics, on the other hand, are much easier for patients to take and caregivers to manage. However, because oral medications must pass through the digestive system, to have the same efficacy as IV medications oral antibiotics must have high “bioavailability” — the percentage of the drug that reaches the blood. Drugs administered via PICC lines have, by definition, 100 percent bioavailability.

“If we find that the prolonged IV option is no better than the oral route, we think that most families would prefer for their child to take oral antibiotics,” Dr. Keren noted. “However, if IV antibiotics are marginally better than oral antibiotics, then that benefit will need to be weighed against any reduction in quality of life and complications that we anticipate with the PICC lines.”

Autism is typically diagnosed around age two or three, and a growing body of research shows that early intervention yields better outcomes for individuals with autism. A new research grant will allow CHOP researchers to study children’s brain development at even earlier ages, in the hope of finding an earlier starting point.

Supported by a grant through the National Institutes of Health’s Autism Centers of Excellence program, the Children’s Hospital of Philadelphia’s Center for Autism Research will continue to work to identify early signs of autism spectrum disorders. Children’s Hospital will share more than $100 million in NIH funding for autism research, which is distributed across nine Autism Centers of Excellence (ACE) grants.

Under the five-year, $2.2 million grant, CAR is part of a network of four research sites using advanced imaging techniques to study brain development in 200 infants beginning at three months of age. The researchers will follow infants every three months, through 24 months of age, to carefully chart brain development.

The research team plans to conduct follow-up behavioral and diagnostic testing of these children at 36 to 60 months, the age at which a diagnosis of autism is considered to be more stable. The study will also evaluate child and family-level characteristics to learn which are predictors for a later autism diagnosis.

The current grant is a continuation of an earlier ACE-funded brain imaging study conducted by CAR in collaboration with four other autism research centers throughout the country. This research network published a study earlier this year demonstrating significant differences in brain development as early as six months of age — well before the appearance of behavioral or “outward” symptoms of autism.

Muscular dystrophy is a group of genetic disorders that causes progressive loss of muscle structure and muscle contractility, strength, and function. The disease is characterized by chronic inflammation, muscle cell death, and increase and infiltration of fat and fibrous tissue. Current treatment options are limited to symptom management.

A new grant award is allowing a Children’s Hospital investigator to study the effectiveness of certain drugs — retinoid agonists — in slowing or preventing muscle degeneration in those with muscular dystrophy. Findings from the study could lead to a new, groundbreaking treatment.

With a $405,000, three-year grant from the Muscular Dystrophy Association (MDA), Masahiro Iwamoto, PhD, DDS, a research scientist of the Translational Research Program in Pediatric Orthopaedics and research associate professor of Orthopedics at the University of Pennsylvania School of Medicine, is testing his hypothesis that a retinoic acid receptor-gamma (RARg) agonist, a synthetic retinoid which selectively activates RARg, could be used to slow and even stop the disease progression of muscular dystrophy.

Retinoic acid, an active form of vitamin A, plays an important role in the functioning of numerous organs, including musculoskeletal systems. The clinical use of natural retinoids, however, is limited to the treatment of certain malignant tumors and skin conditions due to side effects. To improve drug effectiveness and reduce side effects, synthetic receptor-specific retinoid agonists have been developed.

Dr. Iwamoto and his team recently discovered that a class of selective RARg agonist block the formation of bone within muscle and prevents muscle degeneration. The findings were part of his research into heterotopic ossification (HO), the pathological formation of ectopic bone within soft tissue, primarily skeletal muscles.

With the MDA grant, Dr. Iwamoto builds upon his HO research to learn more about RARg properties and how the molecule contributes to the repair and maintenance of skeletal muscle. An RARg agonist known as R667 has already shown some promise in the lab and has been tested in humans for other conditions. Dr. Iwamoto is testing whether R667 has the potential for treating muscular dystrophy in mice without serious side effects.