Increased abdominal fat mass and high fat consumption in young school children with congenital heart disease: results from a case-control study.

BACKGROUND: We have previously found that infants with complex congenital heart disease (CHD) experience growth failure despite high-energy dietary supplementation. This is a follow-up and comparison with healthy controls at 9 years of age regarding body composition and macronutrient intake, especially in relationship to the diet provided during infancy. METHODS: Anthropometric changes in 10 children with CHD at 12 months and at 4 and 9 years of age were analysed as Z-scores. To assess body composition and food intake at 9 years of age, a dual-energy X-ray absorptiometry scan and a 3-day food diary were completed and compared with age- and gender-matched controls using Wilcoxon's signed-rank test for matched pairs. RESULTS: Growth changes from 12 months to 9 years, converted to Z-scores for weight for height and height for age, were significantly different within the group of children with complex CHD, although no growth differences were seen in comparison with healthy controls at 9 years of age. However, the children with CHD had statistically higher abdominal fat mass index and higher daily intake of fat, particularly from saturated fatty acid in g kg-1 compared to controls. CONCLUSIONS: At 9 years of age, children with complex CHD with growth failure and high fat intake in infancy have normalised growth but increased abdominal fat mass and higher intake of saturated fatty acid compared to their peers. Nutritional monitoring in early childhood may detect unhealthy diet quality and prevent later health risks in this group.

Further delineation of CDC45-related Meier-Gorlin syndrome with craniosynostosis and review of literature.

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by the triad of short stature, microtia and absent or small patellae. We report on a patient with MGS secondary to biallelic mutations in CDC45 detected on whole exome sequencing (WES). Patients with MGS caused by mutations in CDC45 display a distinct phenotype characterized by craniosynostosis and anorectal malformation. Our patient had craniosynostosis, anorectal malformation and short stature, but did not have the microtia or patella hypoplasia. Our report also highlights the value of WES in aiding diagnosis of patients with rare genetic diseases. In conclusion, our case report and review of the literature illustrates the unique features of CDC45-related MGS as well as the benefits of WES in reducing the diagnostic odyssey for patients with rare genetic disorders.

Rate of gestational weight gain and adverse pregnancy outcomes in rural nulliparous women: a prospective cohort analysis from China.

Both inadequate and excessive gestational weight gain (GWG) have been shown to increase the risk of adverse pregnancy outcomes, but the risk profiles of GWG rate are unclear. We aimed to examine the associations between GWG rate in the second/third trimester and a spectrum of pregnancy outcomes. This study consisted of 14 219 Chinese rural nulliparous women who participated in a randomised controlled trial of prenatal micronutrient supplementation during 2006-2009. The outcomes included stillbirth, neonatal and infant death, preterm birth, macrosomia, low birth weight (LBW) and large and small for gestational age (LGA and SGA, respectively). GWG rate was divided into quintiles within each BMI category. Compared with women in the middle quintile, those in the lowest quintile had higher risks of neonatal death (adjusted OR 2·27; 95 % CI 1·03, 5·02), infant death (adjusted OR 1·85; 95 % CI 1·02, 3·37) and early preterm birth (adjusted OR 2·33; 95 % CI 1·13, 4·77), while those in the highest quintile had higher risks of overall preterm birth (adjusted OR 1·28; 95 % CI 1·04, 1·59), late preterm birth (adjusted OR 1·25; 95 % CI 1·00, 1·56), LBW (adjusted OR 1·48; 95 % CI 1·02, 2·15), macrosomia (adjusted OR 1·89; 95 % CI 1·46, 2·45) and LGA (adjusted OR 1·56; 95 % CI 1·31, 1·85). In conclusion, very low and very high GWG rates in the second/third trimester appear to be associated with adverse pregnancy outcomes in Chinese nulliparous women, indicating that an appropriate GWG rate during pregnancy is necessary for neonatal health.

Neu Laxova syndrome.

NeuLaxova syndrome (NLS) is a rare congenital abnormality involving multiple systems. Until date, only 60 cases of this syndrome have been reported in the literature. A stillborn fetus from a 23-year-old female with bad obstetrics history and consanguinity marriage, presented at 41 weeks gestation and not appreciating fetal movements for the past 3 days. Ultrasound examination revealed the absence of fetal cardiac activity and features of growth retardation. The fetus was sent for pathological examination. At autopsy, fetus had ichthyosis over the scalp and face, depressed nasal bridge, low set ears, microcephaly, slopping forehead, wide interdigital spaces, edema of hands and feet, hypoplastic penis, right leg showed congenital talipes equinovarus and left leg showed rocker bottom foot. On dissection, all organs were in situ. Both lungs were hypoplastic, brain was atrophied, and heart showed right ventricle hypertrophied. A diagnosis of NLS was made. Genetic counseling and early serial ultrasound examination should be performed at high-risk families because of its autosomal recessive mode of inheritance. Early diagnosis of the disease may offer termination of the pregnancy as an option. The prognosis is poor, and the affected newborns are either stillborn or die immediately after birth.

Tissue-specific and mosaic imprinting defects underlie opposite congenital growth disorders in mice.

Differential DNA methylation defects of H19/IGF2 are associated with congenital growth disorders characterized by opposite clinical pictures. Due to structural differences between human and mouse, the mechanisms by which mutations of the H19/IGF2 Imprinting Control region (IC1) result in these diseases are undefined. To address this issue, we previously generated a mouse line carrying a humanized IC1 (hIC1) and now replaced the wildtype with a mutant IC1 identified in the overgrowth-associated Beckwith-Wiedemann syndrome. The new humanized mouse line shows pre/post-natal overgrowth on maternal transmission and pre/post-natal undergrowth on paternal transmission of the mutation. The mutant hIC1 acquires abnormal methylation during development causing opposite H19/Igf2 imprinting defects on maternal and paternal chromosomes. Differential and possibly mosaic Igf2 expression and imprinting is associated with asymmetric growth of bilateral organs. Furthermore, tissue-specific imprinting defects result in deficient liver- and placenta-derived Igf2 on paternal transmission and excessive Igf2 in peripheral tissues on maternal transmission, providing a possible molecular explanation for imprinting-associated and phenotypically contrasting growth disorders.

Gestational Weight Gain: Association with Adverse Pregnancy Outcomes.

Background It is unclear how adherence to the Institute of Medicine's (IOM) guidelines for weight gain affects pregnancy outcomes. Objective We investigated how weight gain outside the IOM's recommendations affects the risks of adverse pregnancy outcomes. Study Design We performed a secondary analysis of a prospective cohort study including singleton, nonanomalous fetuses. The risks of small for gestational age (SGA), macrosomia, preeclampsia, cesarean delivery, gestational diabetes, or preterm birth were calculated for patients who gained weight below or above the IOM's recommendations based on body mass index category. A time-to-event analysis was performed to account for gestational age at delivery. A Cox proportional model was fit to estimate hazard ratios accounting for possible confounders. Results Women who gained weight below recommendations were 2.5 times more likely to deliver SGA and twice as likely to deliver preterm. Normal-weight patients who gained below recommendations were 2.5 times more likely to deliver SGA and twice as likely to deliver preterm. Obese patients who gained inadequate weight were 2.5 times more likely to deliver SGA. Conclusion Among normal-weight patients, adhering to IOM recommendations may prevent growth abnormalities and preterm delivery. Among obese patients, a minimum weight gain requirement may prevent SGA infants.

For Debate: Growth Hormone Treatment of Infants Born Small for Gestational Age should be Started at or before the First Year of Age.

Children born small for gestational age without early catch-up of somatic growth and head circumference subsequently remain short and suffer from various degrees of neurocognitive and psychological impairment. Based upon the role of growth hormone (GH) and insulin-like growth factor-I on early brain growth and maturation, we propose that GH treatment of these infants be instituted prior to their 2nd birthday.

Genetic Mutations, Birth Lengths, Weights and Head Circumferences of Children with IGF-I Receptor Defects. Comparison with other Congenital Defects in the GH/IGF-I axis.

BACKGROUND: In recent years more and more genetic defects along the GHRH-GH-IGF-I axis have been reported. Mutations of the IGF-I receptor (R) are a rare abnormality of whom only the heterozygote progenies survive. OBJECTIVES: To summarize, from the literature, data on birth length, weight and head circumference of neonates with IGF-I-R mutations, and to correlate the data with that of other types of mutations in the GH/IGF-I axis. SUBJECTS: Sixty seven neonates from 24 published articles were included and forty seven different mutations of the IGF-I (R) located on chromosome 15 have been identified. RESULTS: Mean (±SD) birth length (BL), available for 26, (10 M, 16F) neonates with a gestational age of 34-41weeks, was 44.2±4cm; one was premature (30cm at 31 weeks). There was a significant correlation between birth length and gestational age (GA) r=0.71 (p>.001). Mean birth weight (BW) of 41 neonates (18M, 23F) was 2388±743gr. Two premature neonates weighed 650gr and 950gr respectively. The BW correlated significantly with gestational age, (males: r=0.68; p=0.007, females: r=0.49; p=0.024). The BMI of 25 neonates ranged from 6 to 13. In 22 records marked microcephaly was ascertained or stated. Nine of 16 mothers were short (133 -148cm), m±SD = 150.5±7.3cm.

Gestational diabetes mellitus in sub-Saharan Africa: systematic review and metaregression on prevalence and risk factors.

OBJECTIVE: We systematically reviewed publications on prevalence and risk factors for gestational diabetes mellitus (GDM) in the 47 countries of sub-Saharan Africa. METHODS: We conducted a systematic search in PUBMED and reviewed articles published until June 2014 and searched the references of retrieved articles. We explored sources of heterogeneity among prevalence proportions with metaregression analysis. RESULTS: Of 1069 articles retrieved 22 studies were included. Half were from West Africa, specifically Nigeria, five from South Africa and six from East and Central Africa. There were differences in screening methods and diagnosis criteria used, even between studies carried out in the same country and same time period. Metaregression analysis indicated high heterogeneity among the studies (I(2) = 100, P < 0.001), which could not be sufficiently explained by study setting, population, diagnostic criteria or time trend, although we observed a relatively higher prevalence in studies carried out after 2000 (5.1% vs. 3.2%), when women at risk were selected (6.5% vs. 3.8%) and when more current diagnostic criteria were used (5.1% vs. 4.2%). Associations with risk factors were reported in six studies. Significant risk factors reported in more than one study were overweight and/or obesity, family history for type 2 diabetes, previous stillbirth, previous macrosomic child and age >30 years. CONCLUSIONS: There are few studies on prevalence and risk factors for GDM in Sub-Saharan Africa and heterogeneity is high. Prevalence was up to about 14% when high-risk women were studied. Preventive actions should be taken to reduce the short- and long-term complications related to GDM in Sub-Saharan Africa.

Radiological and clinical analysis of Madelung's deformity in children.

INTRODUCTION: Madelung's deformity is a bone dysplasia that occurs predominantly in adolescent females, characterized by early epiphyseal growth arrest in the medial part of the distal radius. This leads to an upward and medial displacement of the radial joint surface, restricting range of motion. OBJECTIVES: The objective of this study was to determine whether there was a link between clinical and radiological data in children with Madelung's deformity and to test the hypothesis of a relation between the deformity and a genetic mutation. METHODS: A retrospective study recruited 13 patients with Madelung's deformity, with a mean age of 13.2 years (range, 8-18 years). Assessment comprised level of pain, range of motion and grip force, with standard AP and lateral wrist X-rays. Every patient except one underwent molecular genetic screening, adhering to current recommendations. RESULTS: Pronation-supination, radial inclination and grip force were significantly impaired compared to normal results. All X-ray measurements were significantly abnormal, except for the lunate-covering ratio. Genetic mutation (SHOX) was systematic in the 12 patients screened. DISCUSSION: Radiological deformity did not correlate with functional disturbance or pain. Non-acquired Madelung's deformity requires molecular screening for SHOX or XO mutation, which definitively diagnoses Léri-Weill dyschondrosteosis or Turner syndrome. CONCLUSION: A larger series is necessary to confirm these preliminary results, which nevertheless suggest that non-acquired Madelung's deformity is not isolated but syndromic. Early detection of Léri-Weill or Turner syndrome is essential, due to their therapeutic specificities. LEVEL: IV.

Aberrant upregulation of miR-21 in placental tissues of macrosomia.

OBJECTIVE: With China's rapid economic growth in the past 3 decades, an increase in rate of macrosomia has been reported in China. Fetal growth is a result of multiple factors including genetic potential for growth, maternal nutrition, maternal metabolism, endocrine factors and placental perfusion and function. However, the detailed mechanism of how macrosomia happened remains poorly known. Recent studies showed that the expression of a number of microRNAs (miRNAs) in placentas is involved in fetal growth. We hypothesized that aberrant expression of microRNA-21 (miR-21) and microRNA-16 (miR-16) in placenta is associated with macrosomia. STUDY DESIGN: Using quantitative real time PCR, we analyzed the expression level of miR-21 and miR-16 in terminal placentas of macrosomia pregnancies (n=35) and normal controls (n=35). Potential target genes of miRNA were predicted using TargetScan, miRanda and PicTar. Target genes were mapped to KEGG pathways using KEGG Mapper with an in-house Perl script with KEGG Gene IDs. RESULT: MiR-21 showed significant up-regulation in macrosomia (P=0.037). After controlling the potential confounders, multivariable logistic regression analysis suggested the risk of macrosomia increased, multivariable adjusted ORs of macrosomia for those in the highest tertile was 3.931 (95%CI: 1.049-14.736) compared with those in the lowest tertile in terms of miR-21 level. The target genes of miR-21 were involved in eight possible signaling pathways. They were pathways in P53 signaling pathway, MAPK signaling pathway, HIF-1 signaling pathway, TGF-beta signaling pathway and PI3K-Akt signaling pathway (P<0.001), Wnt signaling pathway, Jak-STAT signaling pathway and mTOR signaling pathway (P<0.05). CONCLUSION: Our study is the first to investigate the association between placental miRNA expression and macrosomia. Our results indicate that the expression level of miR-21 in placental tissue may be involved in the development of macrosomia.

Langer mesomelic dysplasia in early fetuses: two cases and a literature review.

In the article, we report the autoptic, histological and radiographic phenotype of two fetuses (22 and 12 weeks) with Langer mesomelic dysplasia, a homozygous deletion of the 3' enhancer of the SHOX gene, and consanguineous parents affected by Léri-Weill dyschondrosteosis, performing a literature review of the primary forms of mesomelic dysplasia. A proper identification of the type of mesomelic dysplasia is important for genetic and reproductive counseling, estimation of child growth and prevention and/or treatment of complications. A competent pathologist could provide important diagnostic information, orienting or confirming the echographic or genetic suspect, sometimes suggesting diagnostic hypothesis concerning parental unidentified congenital syndromes.

Metabolic syndrome and endothelial dysfunction in a population born small for gestational age relationship to growth and Gh therapy.

UNLABELLED: Being born small for gestational age (SGA) and a rapid increase in weight during early childhood and infancy have been strongly linked to metabolic syndrome. A transversal study was conducted on 167 pre-pubertal and 102 pubertal subjects; auxological parameters, systolic and diastolic blood pressure, laboratory data, and carotid-wall thickness (CA-IMT) were measured. RESULTS: Patients born SGA with spontaneous catch-up growth have higher values of BMI, blood pressure, HOMA index, and CA-IMT than those treated with GH and the appropriate-for-gestational age (AGA) group. In conclusion, subjects born SGA are at high risk of developing chronic diseases, including obesity, hypertension, insulin resistant, and endothelial dysfunction, at an early age, mainly those with good catch-up growth compared with the receiving GH because of negative catch-up growth. Our data is compared with published results.

Brothers with germline PTEN mutations and persistent hypoglycemia, macrocephaly, developmental delay, short stature, and coagulopathy.

Phosphatase and tensin homologue deleted in chromosome 10 (PTEN) has dual protein and lipid phosphatase activity, and its tumor suppressor activity is dependent on its lipid phosphatase activity, which negatively regulates the phosphatidylinositol 3-kinase/Akt pathway. Mutations in PTEN have been identified in different clinical disorders such as Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, Proteus syndrome, Proteus-like syndrome, and autism spectrum disorders with macrocephaly (Hobert). The absence of clear genotype-phenotype correlations between these syndromes appears to represent age-related manifestations of the same condition, which shows variable expressivity. Here, we present two siblings whose phenotypes were extremely variable compared with the original descriptions of the syndromes associated with PTEN germline mutations. Our patients present with a unique constellation of features that have not yet been described in humans with PTEN germline mutations, some of which have not been described in the same individual, like severe hypoglycemia, growth hormone deficiency, Von Willebrand disease, and dyslipidemia.

De novo 3q22.1 q24 deletion associated with multiple congenital anomalies, growth retardation and intellectual disability.

We describe a boy with a de novo deletion of 15.67 Mb spanning 3q22.1q24. He has bilateral micropthalmia, ptosis, cleft palate, global developmental delay and brain, skeletal and cardiac abnormalities. In addition, he has bilateral inguinal hernia and his right kidney is absent. We compare his phenotype with seven other patients with overlapping and molecularly defined interstitial 3q deletions. This patient has some phenotypic features that are not shared by the other patients. More cases with smaller deletions defined by high resolution aCGH will enable better genotype-phenotype correlations and prioritizing of candidate genes for the identification of pathways and disease mechanisms.

Imprinted anomalies in fetal and childhood growth disorders: the model of Russell-Silver and Beckwith-Wiedemann syndromes.

Fetal growth is a complex process. Its restriction is associated with morbidity and long term metabolic consequences. Imprinted genes have a critical role in mammalian fetal growth. The human chromosome 11p15 encompasses two imprinted domains regulated by their own differentially methylated region (DMR), also called Imprinted Control Region (ICR1 at the H19/IGF-2 domain, paternally methylated), and ICR2 at the KCNQ1/CDKN1C domain (maternally methylated). Loss of imprinting at these two domains is implicated in two growth disorders clinically opposite. A loss of DNA methylation (LOM) at ICR1 is identified in over 50% of patients with Russell-Silver syndrome (RSS), characterized by intrauterine and postnatal growth retardation, spared cranial growth, frequent body asymmetry and severe feeding difficulties. Inversely, a gain of methylation at ICR1 is found in 10% of patients with Beckwith-Wiedemann syndrome (BWS), an overgrowth syndrome with an enhanced childhood tumor risk. We have identified over 150 RSS patients with 11p15 LOM allowing long-term follow-up studies and proposal of clinical guidelines. We also found that ∼10% of RSS patients and ∼25% of BWS patients have multilocus LOM at imprinted regions other than ICR1 or ICR2 11p15, respectively. Recent studies have identified cis-acting regulatory elements and trans-acting factors involved in the regulation of 11p15 imprinting, establishing new potential mechanisms of RSS and BWS.

Commonest overgrowth syndromes.

Overgrowth syndromes, although rare, are diagnosed more frequently lately. Major progress, such as the identification of genetic causes, has recently enhanced the delineation of the characteristic and noncharacteristic manifestations, phenotype-genotype correlations and knowledge of the underlying pathophysiologic mechanisms. This review provides a summary of the most important overgrowth syndromes aiming to familiarize the treating physician with the cardinal clinical features involved in these syndromes that encompass overgrowth, but also have a variety of other clinical manifestations (neurologic, musculoskeletal, skin, and accompanying tumors).