Postnatal Growth Restriction Research Articles

Growth Restriction and Systemic Immune Development in Preterm Piglets.

Background: Many preterm infants are born with growth restriction (GR) following maternal or fetal complications before birth. Such infants may continue to grow slowly after birth, regardless of birth weight (BW), due to morbidities related to their immature organs. Severe GR increases the susceptibility to infections, but it is not clear if this is a consequence of impaired systemic immunity or other factors, such as prolonged hospital stay or poor mucosal barrier function. Using preterm pigs as models for preterm infants, we hypothesized that moderate GR, exerting limited clinical effects, does not influence systemic immune development.Methods: Preterm pigs were delivered by cesarean section and fed bovine milk diets until 19 d. Piglets with fetal growth restriction (F-GR, the lowest 25% of BW, n = 27, excluding those with BW <350 g) and postnatal growth restriction (P-GR, the lowest 25% of postnatal growth rate, n = 24) were compared with their corresponding controls (F-CON, n = 92, and P-CON, n = 85, respectively). Organ weights were determined and blood collected for assessment of clinical status (blood chemistry and hematology). For a subgroup (n = 58), in depth analyses of neutrophil function, T cell counts, plasma cytokine levels, and leucocyte gene expression were performed.Results: For F-GR pigs, adrenal gland weight was increased and bone mineral content decreased at 19 d. Total leucocyte levels were lower at birth and interleukin-10 levels increased at d 8–10. In P-GR pigs, total leucocyte, neutrophil, monocyte, and eosinophil counts along with helper T cell fractions were elevated at 8–19 d of age, while the fraction of neutrophils with phagocytic capacity was reduced. Diarrhea and all remaining organ weights, blood chemistry, and immune variables were not affected by F-GR or P-GR.Conclusion: Moderate GR before and after preterm birth has limited effect on systemic immune development in preterm pigs, despite marginal effects on immune cell populations, adrenocortical function, and body composition. Similar responses may be observed for preterm infants with moderate fetal and postnatal growth restriction.

Bifidobacterium Supplementation of Colostrum and Breast Milk Enhances Weight Gain and Metabolic Responses Associated with Microbiota Establishment in Very-Preterm Infants

Background: Postnatal growth restriction in very-preterm infants (VPIs) may have long-lasting effects. Recent evidence suggests that developmental problems in VPIs are related to abnormalities in intestinal microbial communities. Objective: To investigate the effect on growth outcomes in VPIs of supplementation with Bifidobacterium along with mother’s colostrum and breast milk. Methods: A randomized controlled study was performed on 35 VPIs, born between 24 and 31 weeks of gestation with birth weights <1,500 g. The patients received either daily Bifidobacterium breve supplementation (Bifid group) or vehicle supplement only (placebo group). Parenteral nutrition was initiated with glucose, amino acids, and fatty acids for all of the infants soon after birth. Each infant received their own mother’s colostrum within 24 h of birth, and breast milk on subsequent days. Fecal bacteria, organic acids, pH, bile acids, and plasma fatty acids were analyzed. Results: Seventeen infants were allocated to the Bifid group and 18 to the placebo group; the birth weights and gestational ages did not differ significantly between the two groups. Compared to the placebo group, the Bifid group showed significantly greater and earlier weight gain by 8 weeks; significantly higher total fecal bacterial counts, including bifidobacteria; higher levels of total fecal short-chain fatty acids and nominally (but not significantly) higher concentrations of plasma n–3 fatty acids; and lower levels of total fecal bile acid. Conclusions: Bifidobacterial supplementation of maternal colostrum and breast milk yielded the establishment of a beneficial microbiota profile, leading to favorable metabolic responses that appeared to provide improved growth in VPIs.

The developing gut-lung axis: postnatal growth restriction, intestinal dysbiosis, and pulmonary hypertension in a rodent model.

BACKGROUND:Post-natal growth restriction (PNGR) in premature infants increases risk of pulmonary hypertension (PH). In a rodent model, PNGR causes PH, while combining PNGR and hyperoxia increases PH severity. We hypothesized that PNGR causes intestinal dysbiosis and that treatment with a probiotic attenuates PNGR-associated PH.METHOD:Pups were randomized at birth to room air or 75% oxygen (hyperoxia), to normal milk intake (10 pups/dam) or PNGR (17 pups/dam), and to probiotic Lactobacillus reuteri DSM 17938 or phosphate-buffered saline. After 14 d, PH was assessed by echocardiography and right ventricular hypertrophy (RVH) was assessed by Fulton’s index (right ventricular weight/left ventricle+septal weight). The small bowel and cecum were analyzed by high throughput 16S ribosomal RNA gene sequencing.RESULTS:PNGR with or without hyperoxia (but not hyperoxia alone) altered the microbiota of the distal small bowel and cecum. Treatment with DSM 17938 attenuated PH and RVH in pups with PNGR but not hyperoxia alone. DSM 17938 treatment decreased α-diversity. The intestinal microbiota differed based on oxygen exposure, litter size and probiotic treatment.CONCLUSION:PNGR causes intestinal dysbiosis and PH. Treatment with DSM 17938 prevents PNGR-associated RVH and PH. Changes in the developing intestine and intestinal microbiota impact the developing lung vasculature and RV.

Growth velocity in very preterm infants and body fat accrual at term-equivalent age

BACKGROUND To achieve ideal growth velocity rates and reduce the risk for postnatal growth restriction, clinicians often prescribe enriched postnatal diets for very preterm infants. However, high growth velocity rates might be associated with excessive body fat accrual early in life and a higher risk of obesity and metabolic syndrome later in life. Non-invasive methods to assess infant body composition are now available to evaluate the quality of weight gain (i.e. fat versus fat-free mass). OBJECTIVE The objective of this secondary …

Impact of histological chorioamnionitis on postnatal growth in very-low birth weight infants

Background Postnatal growth restriction remains one of the most common problems of very preterm infants (VPI). Chorioamnionitis is a frequent cause of prematurity. Both have been related to worse postnatal outcomes. Objectives To evaluate the influence of histological chorioamnionitis (CA) on postnatal growth in very premature infants. Methods Retrospective one-to-one matched cohort study assessing growth in infants born at or below 32.0 weeks gestation from mothers for whom histological examination of the placenta was available. Newborns with histological CA were matched and compared with those without it. Postnatal growth was recorded at admission, 14 days of life, 28 days of life and 36 weeks postmenstrual age (PMA). Nutritional support and clinical outcomes were used as covariables. Results Eighty-eight patients were included: 44 with fetal or/and maternal placental inflammation, and 44 without histological CA (41% with vasculopathy findings and 59% without). Baseline characteristics were similar between the groups. Change in weight z-scores at 14 days of life, 28 days of life, 36 weeks PMA or at discharge were similar in both groups, with a steady fall and no signs of catch-up. No differences were found in enteral and parenteral nutritional intakes between groups. Conclusions Histological CA did not affect postnatal growth of very preterm infants after matching for birth weight z-scores with non-CA newborns.

Cohort study showed that growth rate increment has not been enough to prevent growth retardation of preterm infants and raised concerns about unbalanced growth

We describe the postnatal weight gain, linear and head growth trends of surviving preterm infants from 2005 to 2017. Multicentre cohort study, including surviving preterm infants <32weeks (n=21084), from the Spanish Neonatal Network database, without major congenital malformations who were less than 50weeks postmenstrual age at discharge. Outcomes were weight gain (g/kg/day), linear and head growth (cm/week) and changes in weight, length and head circumference z-scores from birth to discharge. The study period was divided into 2005-8, 2009-11, 2012-14 and 2015-17. Weight gain, linear growth and head growth were slightly higher in 2015-2017 than in 2005-2008: 12.2±2.6 to 13.1±2.5g/kg/day, 0.98±0.6 to 1.03±0.6cm/week and 0.76±0.2 to 0.77±0.3cm/week, respectively. It was associated with a decreased fall in weigh, length and head circumference z-scores from birth to discharge (-1.32±0.9 to -1.01±0.84, -1.38±1.2 to -1.18±1.2 and -0.41±1.2 to -0.33±1.3, respectively). Postnatal growth restriction remained a common complication of prematurity despite some increment over the last years. Growth disproportionality seemed to be worsening as weight gain was increased more than linear growth.

Prevention of necrotizing enterocolitis in premature infants - an updated review.

Necrotizing enterocolitis (NEC) is among the most common and devastating diseases encountered in premature infants, yet the true etiology continues to be poorly understood despite decades of research. Recently, gut bacterial dysbiosis has been proposed as a risk factor for the development of NEC. Based on this theory, several best clinical practices designed to reduce the risk of NEC have been proposed and/or implemented. This review summarizes the results of recent clinical trials and meta-analyses that support some of the existing clinical practices for reducing the risk of NEC in premature infants. It is evident that human milk feeding can reduce the incidence of NEC. While most of the studies demonstrated that probiotic supplementation can significantly reduce the incidence of NEC in premature infants, there are still some concerns regarding the quality, safety, optimal dosage, and treatment duration of probiotic preparations. Antibiotic prophylaxis does not reduce the incidence of NEC, and prolonged initial empirical use of antibiotics might in fact increase the risk of NEC for high-risk premature infants. Lastly, standardized feeding protocols are strongly recommended, both for prevention of postnatal growth restriction and NEC.

Effects of milk fat globule membrane and its various components on neurologic development in a postnatal growth restriction rat model

BackgroundMilk fat globule membrane (MFGM) is a component of breast milk that consists of glycosylated membrane-bound proteins, polar lipids and carbohydrates originating from the mammary gland plasma membrane. A commercially available bovine MFGM added to infant formula has been shown to improve cognitive development in infants at 12 months of age. ObjectiveConsidering that MFGM is a complex mixture, our aim was to determine which component(s) may be leading to these cognitive outcomes. MethodsGrowth-restricted rat pups were supplemented with one of five treatments: (a) bovine MFGM, (b) bovine phospholipid concentrate (PL), (c) sialic acid (SIA) at 200 mg/kg body weight (bw) SIA100, (d) SIA at 2 mg/kg bw and (e) nonfat milk as control. Pups were randomized, cross-fostered into litters of 17 pups per dam and supplemented from postnatal day (PD) 2 to PD 21. The following behavioral tests were performed at adulthood: T-Maze Spontaneous Alternation, Novel Object Recognition and Morris Water Maze. Hippocampus was isolated at PD14 and PD21. Expression of four genes were measured including brain-derived neurotrophic factor (BDNF), dopamine receptor 1, (Drd1), glutamate receptor (GluR-1) and ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialytransferase 4 (St8Sia4). Following behavioral testing, brains were collected for nonbiased stereology. ResultsIncreased expression of genes due to supplementation was most pronounced at the PD14 time point. The MFGM group exhibited higher T-Maze scores compared to the SIA group (P=.01), whereas the SIA100 group visited the novel object more frequently than the MFGM group in the Novel Object test (P=.02). No differences due to supplementation were found in the Morris Water Maze or nonbiased stereology, ConclusionsIn this trial, MFGM, compared to its individual components, had the largest impact on neurodevelopment in rat pups through up-regulation of genes and improved T-Maze scores compared to the SIA group.

Characteristics of the Intestinal Microbiota in Very Low Birth Weight Infants With Extrauterine Growth Restriction.

Objective: Very low birth weight (VLBW) infants, which experience significant postnatal growth restriction at the time of discharge, are at high risk of later growth failure and long-term consequences. This study aims to characterize the structure of intestinal microbiome community in VLBW infants with extrauterine growth restriction (EUGR).Methods: Twenty-three VLBW infants appropriate for gestational age (GA) hospitalized at the neonatal intensive care unit of the BaoAn Maternal and Child Care Hospital (Shenzhen, China) were enrolled in this study, which were divided into the growth restriction group (EUGR; n = 12) and the normal growth group (AGA; n = 11). Meconium and fecal samples at postnatal day 28 were collected respectively during hospitalization. Total bacterial DNA was extracted and sequenced using the Illumina MiSeq Sequencing System based on the V3–V4 hyper-variable regions of the 16S rRNA gene.Results: The intestinal bacterial communities of preterm infants were dominated by the phylum Proteobacteria. Compared with the AGA group, the relative abundances of the genera Aeromicrobium and Serratia in meconium samples significantly decreased, whereas genera Parabacteroides, Ruminococcus, Blautia, and Aeromonas were more prevalent in the EUGR group. On postnatal day 28, the relative abundances of the genera Parabacteroides, Bacteroides, Eubacterium, Granulicatella, and Salinivibrio were significantly different between the two groups, where genus Salinivibrio decreased significantly in the EUGR samples. Among them, genus Parabacteroides was more abundant on both postnatal day 1 and 28. Further KEGG prediction analysis showed that there were many differences in functional genes and pathways between the two groups on postnatal day 28, but not on day 1, the majority of which were related to energy metabolism. And no statistical differences were observed in the clinical characteristics of infants.Conclusions: Overall, these findings showed that a distinct gut microbiota profile presented in preterm infants with EUGR. The role of intestinal microbiome in the extrauterine growth of preterm infants during hospitalization should be further investigated.

Growth Hormone Improves Short-Term Growth in Patients with Temple Syndrome

Background/Aims: Temple syndrome is an imprinting disorder caused by maternal uniparental disomy of chromosome 14 (mat UPD14), paternal deletion of 14q32 or paternal hypomethylation of the intergenic differentially methylated region (MEG3/DLK1 IG-DMR). Patients with Temple syndrome have pre- and postnatal growth restriction, short stature, hypotonia, small hands and feet and precocious puberty. We sought to determine whether treatment with growth hormone improves growth outcomes in patients with Temple syndrome. Methods: This was a retrospective observational study reviewing the medical records of 14 patients with Temple syndrome, 7 of whom were treated with growth hormone. Results: After 1 year of growth hormone treatment, the height standard deviation score (SDS) increased a median of 1.31 SDS with a median increased height velocity of 5.30 cm/year. Conclusions: These results suggest short-term improvement in height SDS with growth hormone treatment similar to the response in patients treated under the small for gestational age indication. We recommend considering growth hormone therapy in all patients with Temple syndrome who have short stature.

Mesenchymal &lt;i&gt;Igf2&lt;/i&gt; is a Major Paracrine Regulator of Pancreatic Growth and Function

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Here we demonstrate that many imprinted genes are highly expressed in the pancreatic mesenchyme, and explore the role of Igf2 in-vivo. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy. Surprisingly, mesenchymal mass is unaffected, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Furthermore, increased IGF2 activity specifically in the mesenchyme, through Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Ex-vivo exposure of primary acinar cells to exogenous IGF2 increases cell proliferation and amylase production through AKT signalling. We propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.

Somatic growth and the risks of bronchopulmonary dysplasia and pulmonary hypertension: connecting epidemiology and physiology 1.

In the premature infant, poor growth in utero (fetal growth restriction) and in the first weeks of life (postnatal growth restriction) are associated with increased risk for bronchopulmonary dysplasia and pulmonary hypertension. In this review, we summarize the epidemiologic data supporting these associations, present a novel rodent model of postnatal growth restriction, and review 5 promising mechanisms by which poor nutrition may affect the developing lung. These observations support the hypothesis that nutritional and (or) pharmacologic interventions early in life may be able to decrease risk of the pulmonary complications of extreme prematurity.

Prenatal and postnatal presentation of PRMT7 related syndrome: Expanding the phenotypic manifestations.

Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-l-methionine to nitrogen atoms on arginine residues. Arginine methylation is involved in multiple biological processes, such as signal transduction, mRNA splicing, transcriptional control, DNA repair, and protein translocation. Currently, 10 patients have been described with mutations in PRMT7. The shared findings include: hypotonia, intellectual disability, short stature, brachydactyly, and mild dysmorphic features. We describe the prenatal, postnatal, and pathological findings in two male sibs homozygote for a mutation in PRMT7. Both had intrauterine growth restriction involving mainly the long bones. In addition, eye tumor was found in the first patient, and nonspecific brain calcifications and a systemic venous anomaly in the second. The pregnancy of the first child was terminated and we describe the autopsy findings. The second child had postnatal growth restriction of prenatal onset, hypotonia, strabismus, sensorineural hearing loss, genitourinary and skeletal involvement, and global developmental delay. He had dysmorphic features that included frontal bossing, upslanting palpebral fissures, small nose with depressed nasal bridge, and pectus excavatum. Our patients provide additional clinical and pathological data and expand the phenotypic manifestations associated with PRMT7 homozygote/compound heterozygote mutations to include brain calcifications and delayed myelination, and congenital orbital tumor.

Extrauterine growth restriction among neonates with a birthweight less than 1500 grams

Abstract Introduction Growth restriction in preterm infants has been related to a poor neurodevelopment outcome. Objectives To define the incidence of postnatal growth restriction in premature babies ≤1500 g and to detect related clinical or biochemical markers. Methods Retrospective longitudinal observational study. Multivariate linear regression models were used to determine variables that can predict the change in weight z-score during admission. Results The study included 130 patients with a mean birthweight of 1161 ± 251 g and a gestational age of 29.9 ± 2.5 weeks. At hospital discharge, 59.2% had a weight below P10. During admission, the z-scores of weight and length decreased by −0.85 ± 0.79 and −1.09 ± 0.65, respectively. The largest decrease in z-score occurred during NICU admission, with a weight gain rate of 6.6 ± 8.8 g/kg/day, after which growth acceleration took place (16.7 ± 3.8 g/kg/day), but was insufficient to catch-up. Higher levels of urea were negatively correlated with the change in the z-score of weight (P Conclusions More than half of newborns ≤1500 g have a weight at discharge of

Extrauterine growth restriction among neonates with a birthweight less than 1,500grams

Growth restriction in preterm infants has been related to a poor neurodevelopment outcome. To define the incidence of postnatal growth restriction in premature babies ≤1,500 grams and to detect related clinical or biochemical markers. Retrospective longitudinal observational study. Multivariate linear regression models were used to determine variables that can predict the change in weight z-score during admission. The study included 130 patients with a mean birthweight of 1,161±251grams and a gestational age of 29.9±2.5 weeks. At hospital discharge, 59.2% had a weight below P10.During admission, the z-scores of weight and length decreased by -0.85±0.79 and -1.09±0.65, respectively.The largest decrease in z-score occurred during NICU admission, with a weight gain rate of 6.6±8.8g/Kg/day, after which growth acceleration took place (16.7±3.8g/Kg/day), but was insufficient to catch-up.Higher levels of urea were negatively correlated with the change in the z-score of weight (P<.001), and a weight <P10 at birth positively correlated (P=.013). More than half of newborns ≤1,500 grams have a weight at discharge of <P10. This growth restriction occurs during NICU admission, and affects low birth weight infants less frequently.Urea levels correlate negatively with weight gain, which requires further study of the relationship between growth and the protein compartment.

Postnatal Growth Restriction Is Reduced If Birth Weight Is Used for Nutritional Calculations in ELBW Infants.

Since fluid and nutrition needs and delivery in ELBW infants are calculated based on their body weights, there could be a measurable difference in fluid, nutrition, and protein intake calculations based on birth weight (BW) or current weight of the infant, especially in the first two weeks of life. Theoretically, the use of current daily weight (CW) for calculations may result in decreased fluid, nutrition, and protein delivery as well as a cumulative protein deficit (cPD) over the first two weeks of life until the infant regains birth weight. However, there have been no clinical studies comparing the clinical and nutritional impact of these two strategies is unknown. Aims. The aims of this study were to quantify the amount of protein intake and to compare growth parameters at hospital discharge (as measured by discharge weight and head circumference percentiles) when using two different methodologies (BW vesrsus current daily weight until BW is regained) for calculating fluid and protein intake in the first two weeks after birth in ELBW infants. Methods. A retrospective review of infants weighing ≤ 1kg at birth was conducted from January 2005 to December 2009 (Phase 1; P1) and January 2012 to December 2014 (Phase 2; P2) in a tertiary care NICU. At this center, in P1 (2005-09) CW was exclusively used for calculating fluid, calorie, and protein administration till BW was regained. In P2 (2012-14), BW was exclusively used for all calculations. Both P1 and P2 periods were compared and analyzed for differences in demographics, nutritional intake, comorbid conditions, and growth outcomes. Results. We studied 146 infants with 84 and 62 infants in P1 and P2 periods, respectively. The mean gestational age was lower during Phase 1 (25.74 ±1.32 vs. 26.47 ±1.82 weeks. P value =0.01). However, the birth weights were not different between the two periods. When the multiple-regression analysis was done using a discharge weight of >10th percentile as the dependent variable, protein intake before regaining of BW (OR of 4.126 with 95th CI of 2.03-8.36, a P value of 0.00) and AGA status at birth (OR of 8.37 with 95th CI of 2.67-26.24) remained significant factors. Compared to P1, babies in P2 received 1g/kg/day more protein till BW was regained. In P1, 27% of babies who were appropriate for gestational age (AGA) for head circumference at birth became microcephalic by discharge, compared to 15.6% in P2 (p=0.03). Similarly, 75.3% of the babies who were AGA for weight at birth in P1 became small for gestational age (SGA) by discharge, compared to 16.7% in P2 (p=<0.0001). The number of days it took to regain BW was 9.6 days in P1 vs. 7 days in P2 (p=<0.0001). Conclusions. Basing nutrition calculations in ELBW on birth weight rather than current daily weight until the birth weight is regained resulted in significantly greater protein delivery, a significant decrease in the incidence of failure to thrive and smaller head circumference percentiles at discharge in ELBW infants.

EP11.12: Antenatal diagnosis of Miller‐McKusick‐Malvaux (3‐M) syndrome: a case report

The Miller-McKusick-Malvaux (3-M) syndrome is a rare primordial growth disorder characterised by low birth weight, reduced birth length, severe postnatal growth restriction, and a spectrum of minor anomalies, including facial dysmorphism. Although individuals with 3-M syndrome have short stature, and skeletal abnormalities, their intelligence is not affected. 3-M syndrome is inherited in autosomal recessive manner, and to date, there are only about 100 cases of affected individuals that have been identified worldwide. In the antenatal period, individuals with 3-M syndrome typically have long bones which are below the 3rd centile, and they are generally small for gestational age. This slow growth continues throughout childhood and adolescence. They have low birth weight and length, and remain much smaller than others in their family, growing to an adult height of approximately 120-130 cm. The majority of 3-M cases are diagnosed postnatally. We present a case of 3-M syndrome which was diagnosed during the antenatal period. This is the first 3-M case diagnosed prenatally which led to a live birth. Due to the fact that 3-M syndrome is inherited via an autosomal recessive pattern, early diagnosis in a fetus can aid in the genetic counselling for the current and future pregnancies. Antenatal detection is possible by analysis of DNA extracted from fetal cells by chorionic villus sampling or amniocentesis but in the absence of a family history, prenatal diagnosis is often difficult, and 3-M joins a long list of possible causes of shortened long bones, such as include Silver–Russell syndrome, Bloom syndrome, Dubowitz syndrome, Rubistein-Taybi syndrome, Floating-Harbor syndrome, Mulibrey nanism and fetal alcohol syndrome. 3-M syndrome is a rare genetic disorder that should be considered in the differential diagnoses when assessing fetuses which present with intrauterine growth restriction and short long bones. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice

ObjectiveImprinted genes are crucial for the growth and development of fetal and juvenile mammals. Altered imprinted gene dosage causes a variety of human disorders, with growth and development during these crucial early stages strongly linked with future metabolic health in adulthood. Neuronatin (Nnat) is a paternally expressed imprinted gene found in neuroendocrine systems and white adipose tissue and is regulated by the diet and leptin. Neuronatin expression is downregulated in obese children and has been associated with stochastic obesity in C57BL/6 mice. However, our recent studies of Nnat null mice on this genetic background failed to display any body weight or feeding phenotypes but revealed a defect in glucose-stimulated insulin secretion due to the ability of neuronatin to potentiate signal peptidase cleavage of preproinsulin. Nnat deficiency in beta cells therefore caused a lack of appropriate storage and secretion of mature insulin. MethodsTo further explore the potential role of Nnat in the regulation of body weight and adiposity, we studied classical imprinting-related phenotypes such as placental, fetal, and postnatal growth trajectory patterns that may impact upon subsequent adult metabolic phenotypes. ResultsHere we find that, in contrast to the lack of any body weight or feeding phenotypes on the C57BL/6J background, deletion of Nnat in mice on 129S2/Sv background causes a postnatal growth restriction with reduced adipose tissue accumulation, followed by catch up growth after weaning. This was in the absence of any effect on fetal growth or placental development. In adult 129S2/Sv mice, Nnat deletion was associated with hyperphagia, reduced energy expenditure, and partial leptin resistance. Lack of neuronatin also potentiated obesity caused by either aging or high fat diet feeding. ConclusionsThe imprinted gene Nnat plays a key role in postnatal growth, adult energy homeostasis, and the pathogenesis of obesity via catch up growth effects, but this role is dependent upon genetic background.

Fetal growth restriction shortens cardiac telomere length, but this is attenuated by exercise in early life.

Fetal and postnatal growth restriction cause a predisposition to cardiovascular disease (CVD) in adulthood. Telomeres are repetitive DNA-protein structures that protect chromosome ends, and the loss of these repeats (a reduction in telomere length) is associated with CVD. As exercise preserves telomere length and cardiovascular health, the aim of this study was to determine the effects of growth restriction and exercise training on cardiac telomere length and telomeric genes. Pregnant Wistar Kyoto rats underwent bilateral uterine vessel ligation to induce uteroplacental insufficiency and fetal growth restriction ("Restricted"). Sham-operated rats had either intact litters ("Control") or their litters reduced to five pups with slowed postnatal growth ("Reduced"). Control, Restricted, and Reduced male rats were assigned to Sedentary, Early exercise (5-9 wk of age), or Late exercise (20-24 wk of age) groups. Hearts were excised at 24 wk of age for telomere length and gene expression measurements by quantitative PCR. Growth restriction shortened cardiac telomere length ( P < 0.001), but this was rescued by early exercise ( P < 0.001). Early and Late exercise increased cardiac weight index ( P < 0.001), but neither this nor telomere length was associated with expression of the telomeric genes Tert, Terc, Trf2, Pnuts, or Sirt1. Growth restriction shortens cardiac telomere length, reflecting the cardiac pathologies associated with low birth weight. Exercise in early life may offer long-term protective effects on cardiac telomere length, which could help prevent CVD in later life.

Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction

Autosomal recessive missense Rotatin (RTTN) mutations are responsible for syndromic forms of malformation of cortical development, ranging from isolated polymicrogyria to microcephaly associated with primordial dwarfism and other major malformations.We identified, by trio based whole exome sequencing, a homozygous missense mutation in the RTTN gene (c.2953A > G; p.(Arg985Gly)) in one Moroccan patient from a consanguineous family. The patient showed early onset primary microcephaly, detected in the fetal period, postnatal growth restriction, encephalopathy with hyperkinetic movement disorders and self-injurious behavior with sleep disturbance. Brain MRI showed an extensive dysgyria associated with nodular heterotopia, large interhemispheric arachnoid cyst and corpus callosum hypoplasia.