Tag Archives: #childhood

How Dynamic Changes in Early Childhood Development May Lead to Changes in Autism Diagnosis? (Psychiatry)

Researchers from the Center for Autism Research (CAR) at Children’s Hospital of Philadelphia (CHOP) found that difficulties in diagnosing toddlers with autism spectrum disorder (ASD) might be due to the dynamic nature of the disorder during child development. Children with clinical characteristics that put them on the diagnostic border of autism have an increased susceptibility to gaining or losing that diagnosis at later ages. The findings were published online by The Journal of Child Psychology and Psychiatry.

While most children diagnosed with ASD at early ages retain their diagnosis, a significant number of children have more dynamic presentations of clinical features associated with autism and may show changes as they develop, particularly around the time they are between two and three years old. These changes may lead a minority of children to actually lose or gain their ASD diagnosis over time. Recent studies have introduced the notion that this change in diagnosis is the result of intermediate cases of ASD, where children are neither clearly affected nor clearly unaffected.

Robert T. Schultz, PhD
Robert T. Schultz, PhD © CHOP

Although researchers have been aware of these intermediate cases and possible diagnostic shifts, no prior studies have quantitatively evaluated the transition region between these ASD and non-ASD cases. Using a data-driven approach, the study team wanted to explore the links between early diagnostic shifts in ASD and the “fuzzy nature” of the diagnostic boundary.

“This study is the first to really develop a quantitative understanding of how each person is unique and how some of their core attributes change in small ways over the third year of their life,” said Robert T. Schultz, PhD, director of CAR and senior author of the study. “Past studies called attention to diagnostic instability at early ages without understanding why this was happening for each child and that these changes are gradual. Children grow in a continuous manner, and we now have a principled way to measure this steady growth and how it may push these children into and out of the diagnostic category of autism.”

Study participants and findings

The researchers used a cohort of children with high risk of developing ASD, since all participants had an older sibling diagnosed with autism. The cohort included 222 participants assessed at 24 months of age and then at 36 months of age. Using machine learning, the team was able to empirically characterize the classification boundary between ASD and non-ASD participants by quantifying developmental and adaptive skills.

The study found that most children who switched diagnostic labels (dynamic group) – either from ASD to non-ASD or vice versa – had intermediate clinical feature profiles. They were, on average, closer to the classification boundary compared with children who had stable diagnoses, both at 24 and 36 months of age. The magnitude of the shift was similar for both the dynamic and stable diagnostic groups, suggesting that diagnostic shifts were not associated with a large change in clinical profiles.

Birkan Tunç, PhD
Birkan Tunç, PhD © CHOP

However, when children were examined at an individual level, a few children in the dynamic group showed substantial change. There were also substantial improvements in some children with severe impairments, suggesting that not all diagnostic shifts are due to having an intermediate clinical profile. Diagnostic shifts could be due to a variety of factors, including different causes of ASD, varying timing of the onset of ASD, and different treatment histories.

“Our study clearly shows the inherently dynamic nature of early diagnoses of autism,” said Birkan Tunç, PhD, a computational scientist with CAR and lead author of the study. “If we can identify predictive behavioral or neurobiological patterns of children who might have a change in their diagnosis, we may advance current clinical practices and better tailor individualized intervention strategies. Our findings call for more vigilant surveillance and faster initiation of intervention rather than waiting for a categorical diagnosis to begin treatment.”

This work was supported by grants from the National Institutes of Health (R01-HD055741, U54-HD086984, U54-HD087011, R01-HD088125, R01-MH073084, R01-MH118362, R01-MH121462, R01-MH116961, R01-ES026961) and the Pennsylvania Department of Health (SAP 4100047863, SAP 4100042728).


Reference: Tunç et al, “Diagnostic shifts in autism spectrum disorder can be linked to the fuzzy nature of the diagnostic boundary: a data-driven approach.” J Child Psychol Psychiatry, online April 7, 2021. DOI: 10.1111/jcpp.13406.


Provided by Children’s Hospital of Philadelphia

Traumatic Stress In Childhood Can Lead to Brain Changes in Adulthood (Psychiatry)

New findings an important step toward developing potential new treatments for mental health disorders.

A groundbreaking new study has shown that traumatic or stressful events in childhood may lead to tiny changes in key brain structures that can now be identified decades later.

The study is the first to show that trauma or maltreatment during a child’s early years—a well-known risk factor for developing mental health conditions such as major depressive disorder in adulthood—triggers changes in specific sub-regions of the amygdala and the hippocampus.

Once these changes occur, researchers believe the affected regions of the brain may not function as well, potentially increasing the risk of developing mental health disorders as adults during times of stress.

“Now that we can actually identify which specific sub-regions of the amygdala or the hippocampus are permanently altered by incidents of childhood abuse, trauma or mistreatment, we can start to focus on how to mitigate or even potentially reverse these changes,” said Peter Silverstone, interim chair of the Department of Psychiatry and one of a team of eight U of A researchers who conducted the study.

A total of 35 participants with major depressive disorder were recruited for the study, including 12 males and 23 premenopausal females aged 18 to 49 years. Researchers also recruited 35 healthy control subjects, including 12 males and 23 females who were matched by age, sex and education.

“This may help shed some light on how promising new treatments such as psychedelics work, since there is mounting evidence to suggest they may increase nerve regrowth in these areas. Understanding the specific structural and neurochemical brain changes that underlie mental health disorders is a crucial step toward developing potential new treatments for these conditions, which have only increased since the onset of the COVID-19 pandemic,” said Silverstone, who is also a member of the U of A’s Neuroscience and Mental Health Institute.

The study noted that previously “most of the work on the effect of stress on the amygdala and hippocampal substructures has been conducted in animals,” and direct testing of preclinical stress models in humans has been impossible to date. However, “recent advances in high-resolution MRI (magnetic resonance imaging) of the hippocampal subfields and amygdala subnuclei have allowed researchers to test these models in vivo in humans for the first time.”

Once these biological changes occur in stress-related brain structures, researchers say the affected regions of the brain may become “maladaptive” or dysfunctional when people deal with adult stresses, making them “more vulnerable” to developing depression or other psychiatric disorders as adults.

The amygdala and hippocampus are regarded as targets of childhood adversity “because they exhibit protracted postnatal development, a high density of glucocorticoid receptors and postnatal neurogenesis,” the study notes. “(This) study confirmed the negative effects of childhood adversity on the right amygdala and suggested that these effects might also affect the basolateral amygdala.”

The study, “Effects of childhood adversity on the volumes of the amygdala subnuclei and hippocampal subfields in individuals with major depressive disorder,” was published in the current issue of the Journal of Psychiatry & Neuroscience. Co-author Arash Aghamohammadi-Sereshki, now a post-doctoral research associate at the University of Calgary, contributed to the research while completing his PhD in neuroscience at the U of A. The senior author was Nikolai Malykhin, an associate professor in the Department of Psychiatry.


Reference: Aghamohammadi-Sereshki A, Coupland NJ, Silverstone PH, Huang Y, Hegadoren KM, Carter R, Seres P, Malykhin NV. Effects of childhood adversity on the volumes of the amygdala subnuclei and hippocampal subfields in individuals with major depressive disorder. J Psychiatry Neurosci. 2021 Jan 21;46(1):E186-E195. doi: 10.1503/jpn.200034. PMID: 33497169.


Provided by University of Alberta

New Evidence: Effects of Huntington’s Disease Mutation May begin in Childhood (Medicine)

The neurodevelopmental hypothesis of Huntington’s disease (HD) suggests its origins are rooted in childhood when the mutant gene that causes HD begins to affect both brain and body growth and development, reports the Journal of Huntington’s Disease.

There is growing evidence to support the hypothesis that there is a neurodevelopmental component to the late-onset neurodegeneration occurring in the brain of huntingtin gene (HTT gene) mutation carriers, and that this increased susceptibility to brain cell death begins during childhood. Experts discuss the evidence that the HTT gene mutation affects brain and body growth based on a unique study of children at risk for HD, the Kids-HD study, in a review paper and accompanying research article published in the Journal of Huntington’s Disease.

Theories of the etiology of Huntington’s disease. © Journal of Huntington’s Disease.

The classic concept is that Huntington’s disease is caused by toxic mutant huntingtin (mHTT) acting over time on mature brain cells. However, there is growing evidence for an alternative theory in which mHTT has an effect on brain development and that this altered development plays a vital role in the later degenerative process. This theory is based on the notion that wild-type huntingtin (HTT) function plays a role in normal brain development.

“Although the gene was discovered in 1993, we still don’t have a good understanding of what causes HD – how does the mutant gene cause brain cells to become ‘sick’ then die?” noted lead investigator Peg C. Nopoulos, MD, Department of Psychiatry, Department of Pediatrics, and Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. “The neurodevelopmental hypothesis is a relatively new way of thinking about the disease and can help focus research efforts in a new direction. This review and the accompanying study are important in reshaping our ideas about how we view the nature and timing of preventive treatment for HD and the factors that contribute to disease.”

The neurodevelopmental hypothesis of HD posits that the disease-causing gene mutation affects development of a specific region or specific brain circuit. These cells are abnormal in their growth; however, they are compensated for early in life. Therefore, despite abnormal development, there are no overt symptoms. The abnormally developed cells remain in a “mutant steady state.” These cells are then vulnerable to dysfunction and degeneration later in life when they are subjected to stresses and strains, either normal (programmed synaptic elimination during puberty or through the aging process) or pathological (toxic effects of mHTT). In the end, the disease pathology results in neural degeneration with its accompanying cognitive and motor deficits.

The two papers focus on the most recent findings from Kids-HD, a unique brain imaging study of children aged six to 18 years old at risk for HD because they have a parent or grandparent with HD. The review discusses the effects of mHTT on brain development and the study evaluates the effect of mHTT on body development.

According to the authors, there is evidence in children as young as 6 who carry a mutation in the HTT gene, that production of mHTT alters the growth and development of the striatum and related circuitry. The gene contains a sequence of three DNA bases – cytosine-adenine-guanine (CAG) – repeated multiple times. The developmental changes appear to be influenced by the CAG repeat length and occur well before onset of symptoms of the disease. Deficits may then be compensated for by increased activity in other brain circuits, particularly those involving the cerebellum, and are manifest only when compensatory systems are no longer working.

The body development analysis used data from the 186 children in the Kids-HD study. Investigators applied simple measures of growth – height, weight, and the combined BMI measure – to compare changes in two groups – those who carried the CAG repeat expansion mutation in the HTT gene and those who did not.

Around puberty the study began to show an altered trajectory of growth in HTT gene mutation carriers. The pace at which their BMI increased slowed over time so that at by about 17 years old, that group had substantially lower BMI than the group without the gene mutation. Boys with the gene mutation tended to be taller than the control group, but with lower weight; girls with the gene mutation tended to be around the same height, but lower in weight.

Importantly, although the gene mutation carriers were roughly 30 years from the expected time of onset of the disease, the mutant HTT gene had already affected their growth and development. This work is important because it suggests that the mutation is altering the body even before the onset of neurological disease in midlife.

Gene therapy trials are currently underway to evaluate the effectiveness of drugs to slow disease progression in affected individuals, and future trials will ultimately aim to prevent disease onset by delivery of gene therapy to gene mutation carriers – those with mHTT, but no symptoms.

“Gene therapy trials are finally here. However, interfering with a gene responsible for brain development early in life must be done with an abundance of caution,” commented Dr. Nopoulos. “Understanding how mHTT affects brain development is vital in the context of planning disease prevention therapies.”

HD is a fatal genetic neurodegenerative disease that causes the progressive breakdown of nerve cells in the brain. An estimated 250,000 people in the United States are either diagnosed with, or at risk for, the disease. Symptoms include personality changes, mood swings and depression, forgetfulness and impaired judgment, unsteady gait, and involuntary movements (chorea). Every child of an HD parent has a 50% chance of inheriting the gene. Patients usually survive 10 – 20 years after diagnosis.

Reference: Tereshchenko, Alexander et al. ‘Developmental Trajectory of Height, Weight, and BMI in Children and Adolescents at Risk for Huntington’s Disease: Effect of mHTT on Growth’. 1 Jan. 2020 : 245 – 251. https://content.iospress.com/articles/journal-of-huntingtons-disease/jhd200407

Provided by IOS Press

Stroke In Childhood And Adolescence: Outcome Influenced by Parental Education And Income (Neuroscience)

Children from educationally deprived, low-income families are much more likely to face long-term cognitive impairment following a stroke. Such is the main finding of a recent study conducted at MedUni Vienna’s Department of Pediatrics and Adolescent Medicine under the supervision of Lisa Bartha-Doering and Rainer Seidl.

© Medical University of Vienna

With an incidence of between 2 and 5 cases per 100,000 children, stroke in childhood is a rare occurrence. Nonetheless, this still means that up to 75 children in Austria suffer a stroke every year. Nearly half of these are left with long-term neurological impairment following a stroke. Apart from physical and motor deficits, they are often left with impaired speech, attention span, working speed, perception and memory. The working group led by Lisa Bartha-Doering and Rainer Seidl has now shown that children from educationally deprived and low-income families are more likely to suffer long-term cognitive impairment following a stroke.

Says Lisa Bartha-Doering: “Not all children have an equal chance of growing up healthy. The correlation between socioeconomic background, which encompasses the social and economic circumstances of the children, and their health has been documented for many years now. The recognition that socioeconomic status affects the outcome following a neurological disease is therefore not new but it is important to keep reminding ourselves of it. However, what did surprise us was the extent to which the variation in the cognitive outcome for children following a stroke can be explained by their socioeconomic background.”

In fact, the study showed that nearly half of the differences in cognitive abilities were attributable to the children’s socioeconomic status. Rainer Seidl, Head of the neuropediatric out-patient clinic in Vienna General Hospital/MedUni Vienna explains: “The opportunity for early rehabilitation after the acute phase has improved over the last few years, due to the creation of children’s rehabilitation centres and children’s access to rehabilitation. However, the financial status of their families continues to influence access to important ongoing outpatient therapies, as well as their frequency and duration. Since therapists with statutory health insurance contracts often have long waiting lists, access to free physiotherapy, speech therapy and occupational therapy is limited in Austria. In rural regions, there is even less availability of free therapy places. Neurocognitive training is not funded at all by the health insurance fund in Austria. Higher-income parents therefore often finance the necessary treatment privately or pay for additional treatment sessions. Therefore, children from low-income families often cannot have the same number of treatment sessions as children of higher socioeconomic status.”

The researchers also point to the cognitive reserve of the child (i.e. their individual flexibility for reorganising cognitive processes in the brain) as another important factor. When researching the cognitive reserve, it is assumed that this is determined by the interplay of genetic and environmental factors: In healthy children, this reserve is closely linked to their intellectual achievements. The capacity for neuronal reorganisation and its influence upon specific cognitive abilities play a major role, particularly following a stroke in childhood. The authors suppose a third important reason for the outcome of the study, which is the higher incidence of childhood strokes among educationally deprived and low-income classes. Although stroke in childhood and adolescence is less influenced by the typical adult risk factors such as diabetes, atherosclerosis, hypertension or smoking, low socioeconomic status is a risk factor for the incidence of stroke in childhood and its course, due to associated greater susceptibility to infection, poor diet and inadequately treated metabolic diseases.

“Our study shows that more attention needs to be given to the treatment of children from educationally deprived, low-income families. Free access to treatment, including physiotherapy, speech therapy, occupational therapy and neurocognitive therapy should be available to all children who have suffered a stroke. Teachers and caregivers should also be made aware of this particularly vulnerable patient group of children of lower socioeconomic status, so that they can create a learning-friendly, supportive environment for them,” conclude the authors in summary.

Reference: Bartha-Doering L, Gleiss A, Knaus S, Schmook MT, Seidl R. The influence of socioeconomic status on cognitive outcome after arterial ischemic stroke in childhood. Developmental Medicine and Child Neurology 2020. DOI: 10.1111/dmcn.14779.

Provided by Medical University of Vienna

New Drug Molecules Hold Promise For Treating Rare Inherited Terminal Childhood Disease (Medicine)

Scientists at the University of Exeter have identified a way to “rescue” cells that have genetically mutated, paving the way to a possible new treatment for rare terminal childhood illness such as mitochondrial disease.

Mitochondria. Credit: Wikipedia commons

The research, funded by the United Mitochondrial Disease Foundation in the U.S., was led by Professors Matt Whiteman and Tim Etheridge. In the study, published in the Journal of Inherited Metabolic Disease, the team used novel drugs being developed at the University of Exeter, which “metabolically reprogramme” mitochondria—the cellular energy production centers in cells, by providing them with an alternative fuel source to generate metabolic energy in the form of minute quantities of hydrogen sulfide.

The team used microscopic worms (C. elegans) with specific genetic mutations affecting energy production, that match mutations that cause human diseases such as Leigh Syndrome. The team found that administering the new compounds to these animals successfully normalized or improved energy production needed to keep them healthy and active.

Professor Tim Etheridge, of the University of Exeter, one of the study authors, said: “Worms are a very powerful genetic tool to study human health and disease and offer an ideal platform to quickly identify new potential therapeutics. The worms used in this study had genetic defects in how their mitochondria regulate cellular energy production to model different human mitochondrial diseases. The novel compounds we are developing at the University of Exeter are able to bypass some of these defects and keep the worms, and their mitochondria healthy. We know this because we saw improvements in physical activity and improvements in muscle and mitochondrial integrity. The animals also lived for longer after treatment but more importantly, they remained active for longer, because of metabolic reprogramming.”

The team had previously shown that the compounds had potent therapeutic effects in mammalian models with defective mitochondria. In those studies, the animals’ mitochondria became defective as result of a disease process. In the latest study however, the defective mitochondria were the direct cause of the disease, as in human mitochondrial disease and were still successfully treated with the Exeter compounds. The fact that the compounds could reverse some of these inherited defects in energy metabolism strongly suggest that their effect will translate to humans, and the team is confident this can be tested in the near future.

Lead author Professor Matt Whiteman, of the University of Exeter, said: “Mitochondrial diseases, and their related conditions, are areas of huge and desperate unmet clinical need. Our study is an important first step and a lot of work still needs to be done. For the first time, we have demonstrated that our new molecules have successfully metabolically reprogrammed, or rescued, cells in animals with genetic defects in their mitochondria. We’re currently testing newer and more potent molecules able to do the same task, through slightly different approaches, and we’re looking for commercial partners to help our efforts to progress our molecules through to clinical testing.”

The paper is titled “The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model.”

Reference: Bridget C. Fox et al. The Mitochondria‐targeted Hydrogen Sulfide Donor Ap39 Improves Health and Mitochondrial Function in A C. Elegans Primary Mitochondrial Disease Model, Journal of Inherited Metabolic Disease

Provided by University of Exeter

Lipid Identified In Human Breast Milk May Play An Important Role in Early Childhood Weight (Pediatrics / Medicine)

A lipid metabolite called 12,13-diHOME is in human breast milk and appears to be associated with beneficial infant weight gain and body composition in the early postnatal period.

A lipid metabolite called 12,13-diHOME is in human breast milk and appears to be associated with beneficial infant weight gain and body composition in the early postnatal period. Moreover, maternal fitness, specifically exercise, appears to boost levels of the metabolite in breast milk and so might benefit their offspring. This finding was published online by The Journal of Clinical Endocrinology and Metabolism.

Elvira Isganaitis, MD, is a staff physician at Joslin Diabetes Center and Assistant Professor of Pediatrics at Harvard Medical School © Joslin Communications

The authors of the study propose that 12,13-diHOME, as well as linked pathway metabolites from breast milk, have a protective effect against obesity development in offspring. They also suggest that a single bout of maternal exercise may boost levels of the metabolite in breast milk and that may translate into benefits for offspring in terms of healthy growth and development.

The metabolite is derived naturally from diet directly from linoleic acid, an essential fatty acid (Omega-6) found in many plant-derived oils as well as nuts and seeds.

The research was led by Elvira Isganaitis, MD, from Joslin Diabetes Center, staff physician at Joslin Diabetes Center and Assistant Professor of Pediatrics at Harvard Medical School; and David Fields PhD, who is Associate Professor and the CHF Chickasaw Nation Endowed Chair in Pediatric Diabetes at the University of Oklahoma Health Sciences Center.

“Although breast milk has long been promoted as a way to lower the risk of childhood obesity, the data have not been entirely consistent,” said Dr Isganaitis. “The literature is contradictory, and in many cases the protective effects of breastfeeding disappear after controlling for maternal factors such as education, obesity, smoking or socioeconomic status.”

“We propose that variations in milk composition between mothers may account for some of the discrepancies that have been observed in terms of childhood obesity and diabetes risk. In other words, some mothers may have greater amounts of protective factors in their milk.”

The main focus of the overall study was a prospective cohort study that involved initially 58 mother-singleton infant pairs recruited over the period of 2015-2019. The infants were assessed for various anthropometric parameters related to growth and body composition over a six-month period of follow-up.

The mothers meanwhile provided breast milk samples over the same period of assessment and these were analyzed with a variety of techniques including targeted mass spectrometry, lipidomics and metabolomics approaches. In a separate part of the study, as a pilot, the authors also recruited 16 mother-infant pairs to assess the effects of a mild session of exercise on milk abundance of 12,13-diHOME.

As well as identifying 12,13-diHOME in human breast milk, potentially for the first time, the authors report that the abundance of the metabolite was positively associated with BMI at birth but negatively associated with various measures of adiposity, BMI and fat mass six months post-partum. Crucially, they also identify largely the same patterns in metabolites in the same biosynthetic pathway, backing up the observations with respect to 12,13-diHOME.

All of the metabolites they identify are involved in the so-called ‘browning’ or ‘beigeing’ of fat cells, which is a process linked with increased energy expenditure in adipose tissue, and so, the thinking that infants receiving higher levels of the metabolites should benefit in terms of healthier growth patterns (and potentially avoid childhood obesity).

For the smaller pilot study, which was supported by the Harold Hamm Diabetes Center, the authors found that at 1-month postpartum, the overall increase in 12,13-diHOME in milk was 1.39-fold following a 90-minute period of acute exercise. The eight volunteers included who were normal weight experienced a 1.50-fold increase, while the eight individuals with obesity experienced a 1.32-fold increase following exercise.

“Although the underlying biological mechanisms are currently unclear, it seems that metabolites in breast milk associated with increased energy expenditure are present, but are also influenced by a single bout of exercise – this is inescapably exciting for this field” said Dr. Fields.

In terms of implications, Dr. Isganaitis added, “The fact that exercise resulted in measurable differences in breast milk composition adds to the growing literature about the multitude of effects that exercise has on the human body. The exciting implication for new parents is that when a mother exercises, it has the potential to improve not only her own health but may also result in metabolic benefits for her child.”

The authors do point towards some limitations with the study, not least, that the design precludes definitively proving causality between 12,13-diHOME and adiposity levels in infants.

Other contributors to the research, from the University of Oklahoma, the University of Minnesota, BERG and Harvard Medical School, include Danielle Wolfs, Matthew Lynes, Yu-Hua Tseng, Stephanie Pierce, Valerie Bussberg, Abena Darkwah, Vladimir Tolstikov, Niven Narain, Michael Rudolph, Michael Kiebish, Ellen Demerath and David Fields. Funding was provided by the National Institutes of Health, United States Army Medical Research, the Harold Hamm Diabetes Center and the Diabetes Research Center award.

Funding was provided by the National Institutes of Health, United States Army Medical Research, the Harold Hamm Diabetes Center and the Diabetes Research Center award.

The pilot study was funded by the Harold Hamm Diabetes Center, which oversees the world’s top research prize in the diabetes field, the Harold Hamm International Prize. Established in 2012, this award recognizes and promotes lasting achievements in diabetes research focused on progress toward a cure. Visit http://www.ouhealth.com/harold-hamm-diabetes-center or follow @HammDiabetesCtr.

References: Danielle Wolfs, Matthew D Lynes, Yu-Hua Tseng, Stephanie Pierce, Valerie Bussberg, Abena Darkwah, Vladimir Tolstikov, Niven R Narain, Michael C Rudolph, Michael A Kiebish, Ellen W Demerath, David A Fields, Elvira Isganaitis, Brown Fat–Activating Lipokine 12,13-diHOME in Human Milk Is Associated With Infant Adiposity, The Journal of Clinical Endocrinology & Metabolism, , dgaa799, https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaa799/5950351?redirectedFrom=fulltext https://doi.org/10.1210/clinem/dgaa799

Provided by Joslin Diabetes Center

About Joslin Diabetes Center

Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is an independent, non-profit institution affiliated with Harvard Medical School, and one of only 16 NIH-designated Diabetes Research Centers in the U.S.

For more information about the Joslin Diabetes Center, visit http://www.joslin.org or follow @joslindiabetes | One Joslin Place, Boston, MA 617-309-2400

Corresponding author: Elvira Isganaitis (elvira.Isganaitis@joslin.harvard.edu)

Birth Defects Linked to Greater Risk of Cancer in Later Life (Medicine)

Risk is greatest in childhood, but does persist into adulthood.

People born with major birth defects face a higher risk of cancer throughout life, although the relative risk is greatest in childhood and then declines, finds a study published by The BMJ today.

The researchers found a continued increased risk of cancer in people who had been born with both non-chromosomal and chromosomal anomalies, suggesting that birth defects may share a common cause with some forms of cancer, be that genetic, environmental, or a combination of the two.

It is generally accepted that people with major birth defects have a greater risk of developing cancer during childhood and adolescence, but it is less clear whether that risk persists into adulthood, so researchers set out to investigate.

They used health registries in Denmark, Finland, Norway, and Sweden to identify 62,295 people aged up to 46 years who had been diagnosed with cancer and matched them against 724,542 people without a cancer diagnosis (controls) by country and year of birth.

The data showed that 3.5% of cases (2,160 out of 62,295) and 2.2% of controls (15,826 out of 724,542) had a major birth defect, and that the odds of developing cancer was 1.74 times higher in people with major birth defects than in those without.

The odds of cancer in people with birth defects was greatest in children aged 0-14 (2.52 times higher) and then declined, but it was still 1.22-fold higher in adults aged 20 or more with major birth defects compared with those without.

In particular, people with congenital heart defects, defects of the genital organs or nervous system, skeletal dysplasia and chromosomal anomalies (too few or too many chromosomes or missing, extra or irregular portion of chromosomal DNA) continued to have a greater risk of cancer in later life.

The type of birth defect had a marked impact on the subsequent risk and type of cancer.

For example, the odds of cancer were highest (5.53-fold higher) in people with chromosomal anomalies such as Down’s syndrome. The most common type of cancer in people with birth defects caused by chromosomal anomalies was leukaemia.

Structural birth defects, such as defects of the eye, nervous system and urinary organs, were associated with later cancer in the same organ or location, although the researchers stress that some of these associations were based on small numbers.

This was a large study using robust Scandinavian national registry systems, but the authors do highlight some limitations. For example, the study only included diagnoses made in the first year of life and confirmed in hospital, so some less visible birth defects may have been missed.

And while factors such as in vitro fertilisation, maternal age and maternal smoking were taken into account, other potentially influential factors, such as parental income or education, could not be adjusted for.

Nevertheless, the researchers say: “Our study showed that birth defects are associated with risk of cancer in adulthood as well as in adolescence and childhood, a finding of clinical importance for healthcare workers responsible for follow-up of individuals with birth defects.”

They point out that surveillance for cancer in children with birth defects has been discussed, but thus far the absolute cancer risk has been regarded as too low.

“The most important implication of our results is to provide further rationale for additional studies on the molecular mechanisms involved in the developmental disruptions underlying both birth defects and cancer,” they conclude.

Few of the associations described in this study suggest that screening is either viable or desirable for most children or adults with birth defects, say US researchers in a linked editorial.

The relation between cancers and birth defects is likely to be complex, they write, and this study did not distinguish between genetic, environmental, and iatrogenic explanations for the observed associations.

As such, they say the clinical implications of this study are limited, but the findings should certainly trigger further research “that may offer important preventive opportunities and identify high risk patient groups for enhanced targeted surveillance.”

References: Dagrun Slettebø Daltveit, Kari Klungsøyr, Anders England, et al., “Cancer risk in individuals with major birth defects: large Nordic population based case-control study among children, adolescents, and adults”, BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4060 https://www.bmj.com/content/371/bmj.m4060

Provided by BMJ

Scientists Discover Bacterium Linked To Deadly Childhood Disorder (Medicine)

Scientists at the Center for Infection and Immunity (CII) at Columbia University Mailman School of Public Health have discovered bacteria linked to post-infectious hydrocephalus (PIH), the most common cause of pediatric hydrocephalus worldwide. Results of the study led by Pennsylvania State University with CII scientists and clinical colleagues in Uganda are published in the journal Science Translational Medicine.

Hydrocephalus is the most common indication for neurosurgery in children. Of the estimated 400,000 new cases each year, about half are estimated to be post-infectious, with the largest number of cases in low- and middle-income countries, especially sub-Saharan Africa. Neonatal sepsis often precedes PIH, although the manifestations of hydrocephalus typically emerge in the months following the neonatal period as cerebrospinal fluid accumulates so that cranial expansion garners medical attention. These infants typically die in early childhood without advanced surgical management.

Study co-first author Brent L. Williams, PhD, assistant professor of epidemiology at CII, examined cerebrospinal fluid (CSF) taken from 100 consecutive cases of PIH and control cases of non-post-infectious hydrocephalus (NPIH) in infants in Uganda, testing the samples for evidence of bacterial and fungal microorganisms. He found Paenibacillus species (bacteria) in CSF linked to cases of PIH, not controls. Williams further quantitated Paenibacillus species in infant CSF samples, finding a high burden of these bacteria in infected patients. The findings were subsequently independently confirmed, and a strain of Paenibacillus was isolated and characterized through further testing by Steven Schiff, MD, the study’s senior author, and colleagues at Pennsylvania State University. The researchers also found that Paenibacillus quantity was associated with clinical measures of hydrocephalus based on brain imaging scores, as well as potential signs of infection based on immune cell counts in patients.

Co-senior author W. Ian Lipkin, MD, John Snow Professor and CII Director, noted that “this discovery has the potential to reduce morbidity and mortality of this central nervous system disease in millions of children in sub-Saharan Africa by shifting treatment from surgery to antibiotics and vaccines.”

“Now that we have identified a pathogen that may be responsible for some cases of post-infectious hydrocephalus, we can develop new, more sensitive tests to quickly detect an infection, assess its severity, identify the source of such infections, and hopefully provide targeted treatments to prevent the development of hydrocephalus” added Brent Williams.

References: Joseph Paulson, Brent Williams et al., “Paenibacillus infection with frequent viral coinfection contributes to postinfectious hydrocephalus in Ugandan infants”, Science Translational Medicine, 2020, Vol. 12, Issue 563, eaba0565 DOI: 10.1126/scitranslmed.aba0565 link: https://stm.sciencemag.org/content/12/563/eaba0565

Provided by Columbia University’s Mailman school of public health