Aluminum exposure and toxicity in neonates: a practical guide to halt aluminum overload in the prenatal and perinatal periods

Daniela Fanni, Rossano Ambu, Clara Gerosa, Sonia Nemolato, Nicoletta Iacovidou, Peter Van Eyken, Vassilios Fanos, Marco Zaffanello, Gavino Faa

Cagliari, Italy

Author Affiliations: Department of Pathology, University Hospital San Giovanni di Dio, AOU Cagliari and University of Cagliari, Italy (Fanni D, Ambu R, Gerosa C, Nemolato S, Faa G); National and Kapodistrian University of Athens, Medical School, Athens, Greece (Iacovidou N); Department of Pathology, K.U. Leuven, Leuven, Belgium (Van Eyken P); Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOU Cagliari and University of Cagliari, Italy (Fanos V); Department of Pediatrics, University of Verona, Italy (Zaffanello M)

Corresponding Author: Vassilios Fanos, Neonatal Intensive Care Unit, Puericulture Institute and Neonatal Section, AOU Cagliari and University of Cagliari, Strada Statale 554, Monserrato (CA) 09042, Italy (Tel: +397051093403; Fax: +39706753107; Email: vafanos@tiscali.it)

doi: 10.1007/s12519-014-0477-x

Background: During the last years, human newborns have been overexposed to biologically reactive aluminum, with possible relevant consequences on their future health and on their susceptibility to a variety of diseases. Children, newborns and particularly preterm neonates are at an increased risk of aluminum toxicity because of their relative immaturity.

Data sources: Based on recent original publications and classical data of the literatures, we reviewed the aluminum content in mother's food during the intrauterine life as well as in breast milk and infant formula during lactation. We also determined the possible role of aluminum in parenteral nutrition solutions, in adjuvants of vaccines and in pharmaceutical products. A special focus is placed on the relationship between aluminum overexposure and the insurgence of bone diseases.

Results: Practical points of management and prevention are suggested. Aluminum sources that infants may receive during the first 6 months of life are presented. In the context of prevention of possible adverse effects of aluminum overload in fetal tissues during development, simple suggestions to pregnant women are described.Finally, practical points of management and prevention are suggested.

Conclusions: Pediatricians and neonatologists must be more concerned about aluminum content in all products our newborns are exposed to, starting from monitoring aluminum concentrations in milk- and soy-based formulas in which, on the basis of recent studies, there is still too much aluminum.

Key words: aluminum; fetus; newborn; toxicity

World J Pediatr 2014;10(2):101-107

Epilepsy in Prader-Willi syndrome: clinical, diagnostic and treatment aspects

Alberto Verrotti, Claudia Soldani, Daniela Laino, Renato d'Alonzo, Salvatore Grosso

Perugia, Italy

Author Affiliations: Department of Pediatrics, University of Perugia, Sant' Andrea delle Fratte, Perugia, Italy (Verrotti A, Soldani C, Laino D, d' Alonzo R); Department of Pediatrics, University of Siena, Italy (Grosso S)

Corresponding Author: Alberto Verrotti, Department of Pediatrics, University of Perugia, Sant' Andrea Delle Fratte, Perugia, Italy (Tel: +39-075-5784415; Email: averrott@unich.it)

doi: 10.1007/s12519-014-0478-9

Background: Epilepsy associated with Prader-Willi syndrome (PWS) represents an early and important complication, often not clearly reported and described in the literature. Consequently, there are controversial data about the clinical characteristics of epilepsy and electroencephalographic (EEG) abnormalities found in these patients.

Data sources: Based on recent original publications, we have reviewed the different types of seizures and EEG findings in PWS patients, the response to antiepileptic treatment, and the prognosis of epilepsy.

Results: The frequency of epilepsy in PWS patients ranges from 4% to 26%. The types of seizure include generalized tonic-clonic seizures, complex partial seizures, atypical absence, staring spells, and myoclonic, tonic and hemiclonic seizures, but the most frequent type is focal epilepsy. Status epilepticus has never been reported. EEG abnormalities are not typical but variable in different patients. However, generalized and focal discharges are the most frequently reported findings. There is no evidence of relationship between the course of epilepsy and frequency, morphology and spread of EEG discharges. However, epilepsy in PWS patients is usually responsive to antiepileptic monotherapy with rapid seizure control and a good outcome.

Conclusions: The frequency of epilepsy is higher in PWS patients than in general populations and this complication can be a challenge for the clinicians of these patients. Prospective studies are needed to confirm the good long-term prognosis.

Key words: epilepsy; Prader-Willi syndrome; prognosis

World J Pediatr 2014;10(2):108-113

Comparative effectiveness of intravenous

immunoglobulin from different manufacturing

processes on Kawasaki disease

Ming-Chih Lin

Taiwan, China

Author Affiliations: Division of Pediatric Cardiology, Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan, China (Lin MC); Department of Pediatrics and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, China (Lin MC)

Corresponding Author: Ming-Chih Lin, MD, PhD, 1650 Taiwan Boulevard Sect. 4, Taichung, Taiwan 40705, China (Tel: +886-4-23592525 ext. 8190; Fax: +886-4-23741359; Email: mingclin@gmail.com)

doi: 10.1007/s12519-014-0479-8

Background: The comparative effectiveness of intravenous immunoglobulin (IVIG) for Kawasaki disease was regarded as inconclusive in the international guidelines. However, several new evidences have been published in recent years.

Data sources: A literature search of PubMed was conducted using key words of "Kawasaki disease or mucocutaneous lymph node syndrome" and "immunoglobulin" in combination. Only original articles published after 2004 were selected. A total of 813 papers were found in PubMed. These papers were screened manually by their titles and abstracts.

Results: Patients treated with IVIG prepared by beta-propiolactonation might have worse outcome (a higher non-responsive rate in one report and a higher rate of coronary aneurysm in two reports). Storage of IVIG in acidic solution might be correlated with a higher rate of coronary aneurysm (two reports).

Conclusions: Different processes of preparation and conditions of preservation of IVIG may have profound effects on its clinical effectiveness. Randomized controlled studies are needed to further elucidate this issue.

Key words: coronary aneurysm; immunoglobulin; Kawasaki disease; treatment outcome

World J Pediatr 2014;10(2):114-118

Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency

Rui-Nan Zhang, Yi-Fan Li, Wen-Juan Qiu, Jun Ye, Lian-Shu Han, Hui-Wen Zhang, Na Lin, Xue-Fan Gu

Shanghai, China

Author Affiliations: Department of Pediatric Endocrinology and Genetic Metabolism and Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China (Zhang RN, Li YF, Qiu WJ, Ye J, Han LS, Zhang HW, Lin N, Gu XF)

Corresponding Author: Wen-Juan Qiu, Department of Pediatric Endocrinology and Genetic Metabolism and Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China (Tel: 86-21-25076454; Fax: 86-21-65791316; Email: qiuwenjuanxh@163.com)

doi: 10.1007/s12519-014-0480-2

Background: Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase (VLCAD), and which can present as cardiomyopathy in neonates, as hypoketotic hypoglycemia in infancy, and as myopathy in late-onset patients. Although many ACADVL mutations have been described, no prevalent mutations in the ACADVL gene have been associated with VLCADD. Herein, we report the clinical course of the disease and explore the genetic mutation spectrum in seven Chinese patients with VLCADD.

Methods: Seven Chinese patients, from newborn to 17 years old, were included in this study. Tandem mass spectrometry was performed to screen for VLCAD deficiency. All exons and flanking introns of the ACADVL gene were analyzed using polymerase chain reaction and direct sequencing. Online analysis tools were used to predict the impact of novel mutations.

Results: All cases had elevated serum levels of tetradecanoylcarnitine (C14:1) which is the characteristic biomarker for VLCADD. The phenotype of VLCADD is heterogeneous. Two patients were hospitalized for hypoactivity and hypoglycemia shortly after birth. Three patients showed hepatomegaly and hypoglycemia in infancy. The other two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis. Three of the patients died at the age of 6-8 months. Eleven different mutations in the ACADVL gene in the 7 patients were identified, including seven reported mutations (p.S22X, p.W427X, p.A213T, p.G222R, p.R450H, c.296-297delCA, c.1605+1G>T) and four novel mutations (p.S72F, p.Q100X, p.M437T, p.D466Y). The p.R450H and p.D466Y (14.28%, 2/14 alleles) mutations were identified in two alleles respectively.

Conclusions: The clinical manifestations were heterog- eneous and ACADVL gene mutations were heterozygous in the seven VLCADD Chinese patients. R450H may be a relatively common mutation in Asian populations. The genotype and phenotype had a certain correlation in our patients.

Key words: follow-up; mutation; very long chain acyl-CoA dehydrogenase; VLCAD deficiency; treatment

World J Pediatr 2014;10(2):119-125

Novel collagen VI mutations identified in Chinese patients with Ullrich congenital muscular dystrophy

Yan-Zhi Zhang, Dan-Hua Zhao, Hai-Po Yang, Ai-Jie Liu, Xing-Zhi Chang, Dao-Jun Hong, Carsten Bonnemann, Yun Yuan, Xi-Ru Wu, Hui Xiong

Beijing, China

Author Affiliations: Department of Pediatrics (Zhang YZ, Yang HP, Liu AJ, Chang XZ, Wu XR, Xiong H); Department of Neurology (Zhao DH, Hong DJ, Yuan Y), Peking University First Hospital, Beijing, China; Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke/NIH, USA (Bonnemann C)

Corresponding Author: Hui Xiong, MD, Department of Pediatrics, Peking University First Hospital, Beijing 100034, China (Tel: 0086-10-83573238; Fax: 0086-10-66530532; Email: xh_bjbj@163.com)

doi: 10.1007/s12519-014-0481-1

Background: We determined the clinical and molecular genetic characteristics of 8 Chinese patients with Ullrich congenital muscular dystrophy (UCMD).

Methods: Clinical data of probands were collected and muscle biopsies of patients were analyzed. Exons of COL6A1, COL6A2 and COL6A3 were analyzed by direct sequencing. Mutations in COL6A1, COL6A2 and COL6A3 were identified in 8 patients.

Results: Among these mutations, 5 were novel [three in the triple helical domain (THD) and 2 in the second C-terminal (C2) domain]. We also identified five known missense or in-frame deletion mutations in THD and C domains. Immunohistochemical studies on muscle biopsies from patients showed reduced level of collagen VI at the muscle basement membrane and mis-localization of the protein in interstitial and perivascular regions.

Conclusions: The novel mutations we identified underscore the importance of THD and C2 domains in the assembly and function of collagen VI, thereby providing useful information for the genetic counseling of UCMD patients.

Key words: collagen VI; in-frame; missense; triple helical domain; Ullrich congenital muscular dystrophy

World J Pediatr 2014;10(2):126-132

Decreased concentrating capacity in children with febrile urinary tract infection and normal 99mTc-dimercaptosuccinic acid scan:  does medullonephritis exist?

Víctor García-Nieto, Silvia González-Cerrato, María Isabel Luis-Yanes, Margarita Monge-Zamorano, Beatriz Reyes-Millán

Canary Islands, Spain

Author Affiliations: Pediatric Nephrology Section, "Nuestra Señora de la Candelaria" University Hospital, Santa Cruz de Tenerife, Canary Islands, Spain (García-Nieto V, González-Cerrato S, Luis-Yanes MI, Monge-Zamorano M, Reyes-Millán B)

Corresponding Author: Víctor García-Nieto, MD, Pediatric Nephrology Section, "Nuestra Señora de la Candelaria" University Hospital, Carretera del Rosario, 145 38010-Santa Cruz de Tenerife, Canary Islands, Spain (Email: vgarcianieto@gmail.com)

doi: 10.1007/s12519-014-0482-0

Background: Although 99mTc-dimercaptosuccinic acid (DMSA) scan is considered the gold standard for the diagnosis of acute pyelonephritis (AP), sometimes it produces false results in children with clinical features of AP. There are no studies on the comparison of the sensitivity of DMSA and concentrating capacity test.

Methods: Eighty-five infants with AP of less than one year old were studied to evaluate whether they had real AP or not. Data were compared between infants with an abnormal (group A, n=64) and those with a normal DMSA scan (group B, n=21) respectively. A DDAVP test was performed for each infant.

Results: All the infants in both groups presented a high level of C-reactive protein and fever (≥38ºC). There were no differences in clinical and analytical variables except C-reactive protein level in the two groups. Both groups exhibited a low urinary osmolality (87.5% in the group A vs. 85.7% in the group B). The patients with normal DMSA and decreased concentrating capacity have some renal parenchymal damage and not only a lower urinary infection. Of the infants with an abnormal DMSA scan, 33.9% showed renal scars after 6-12 months. No infant with a normal DMSA scan showed scars. The biochemical variables in both groups of infants were not related to vesicoureteral reflux.

Conclusion: Infants with AP, normal DMSA scan and low concentrating capacity may be characterized by a localized infection in the medulla (medullonephritis) or by a false negative DMSA scan.

Key words: concentrating capacity; infants; pyelonephritis; urinary tract infection

World J Pediatr 2014;10(2):133-137

Expression of Cx43-related microRNAs in patients with tetralogy of Fallot

Yao Wu, Xiao-Jing Ma, Hui-Jun Wang, Wen-Can Li, Long Chen, Duan Ma, Guo-Ying Huang

Shanghai, China

Author Affiliations: Children's Hospital of Fudan University (Wu Y, Ma XJ, Wang HJ, Ma D, Huang GY); Key Laboratory of Molecular Medicine, Ministry of Education (Ma D) and Department of Forensic Medicine (Li WC, Chen L), Fudan University, Shanghai 200032, China

Corresponding Author: Guo-Ying Huang, MD, PhD, Children's Hospital and the Institute of Biomedical Science, Fudan University, Shanghai 200032, China (Tel: +86-21-64931928; Fax: +86-21-64931928; Email: gyhuang@shmu.edu)

doi: 10.1007/s12519-013-0434-0

Background: Abnormal expression of connexin 43 (Cx43) has been reported to play an important role in the development of conotrunccal anomalies. However, less is known about the underlying reason for its abnormal expression. MicroRNAs (miRNAs), as an important part of gene expression regulation, have been implicated in some cardiac diseases. This study aimed to investigate the expression of Cx43 and its related miRNAs in patients with tetralogy of Fallot (TOF), and illustrate the potential role of abnormal miRNAs regulation to Cx43 expression in the pathology of TOF.

Methods: Real-time polymerase chain reaction was used to detect the expression of Cx43 and 10 Cx43-related miRNAs in the myocardium from 30 TOF patients and 10 normal controls. Immunohistochemistry was used to detect Cx43 protein expression. Putative miRNA binding sites in the 3'UTR of Cx43 were examined in 200 TOF patients and 200 healthy individuals, using Sanger sequencing, to exclude sequence variations resulting in binding difficulties of miRNAs.

Results: Cx43 mRNA and protein expression in the myocardium tissue was significantly increased in TOF patients. The expression of MiR-1 and 206 was significantly decreased in the TOF patients as compared with the controls (P<0.05). No obvious difference was observed in the expression of the other 7 miRNAs between the TOF patients and controls (P>0.05). No meaningful sequence variation was detected in the putative miR1/206 binding sites in the 3'UTR of Cx43.

Conclusions: This study indicated that miR-1 and 206 is down-regulated in TOF patients, which may cause an up-regulation of Cx43 protein's synthesis. It provided a clue that miR-1 and 206 might be involved in the pathogenesis of TOF, additional experiments are needed to determine if in fact, miR-1 and 206 contribute substantially to TOF.

Key words: congenital heart disease; Cx43; miRNA; tetralogy of Fallot

World J Pediatr 2014;10(2):138-144

Sibling composition and child immunization in India and Pakistan, 1990-2007

Prashant Kumar Singh, Sulabha Parsuraman

Mumbai, India

Author Affiliations: International Institute for Population Sciences (IIPS), Govandi Station Road, Deonar, Mumbai 400 088, India (Singh PK); Department of Population Policies and Programmes, International Institute for Population Sciences (IIPS), Govandi Station Road, Deonar, Mumbai 400 088, India (Parsuraman S)

Corresponding Author: Prashant Kumar Singh, MA, MPS, International Institute for Population Sciences (IIPS), Govandi Station Road, Deonar, Mumbai 400 088, India (Tel: +91-9969617511; Email: prashant_iips@yahoo.co.in)

doi: 10.1007/s12519-014-0483-z

Background: This study aimed to assess trends in gender differentials in child immunization beyond the conventional male-female dichotomy, by considering gender, surviving siblings, birth order and different compositions of older siblings in tandem, during 1990-2007 in India and Pakistan.

Methods: Using different rounds of Demographic and Health Survey datasets, we adopted the World Health  Organization guidelines for appraising full immunization among children. Sex composition of surviving older siblings was combined. Cochrane-Armitage and the Chi-square tests were used to test linear and nonlinear trends, respectively.

Results: Although child immunization has increased during the period of 1990-2007 in both India and Pakistan, results showed that more than 50% of the eligible children did not receive the recommended immunization. The results also showed that boys and girls with no older surviving siblings and those with only surviving siblings of the opposite sex appeared to have fully immunized proportionally compared with the children with other sibling compositions.

Conclusion: The findings confirmed that girls and boys were not always treated equally, and that there was a clear pattern of selective neglect in child immunization in both countries during the period of 1990-2007.

Key words: gender; immunization; India; Pakistan; sibling composition

World J Pediatr 2014;10(2):145-150

Efficacy of tacrolimus in the treatment of children with focal segmental glomerulosclerosis

Mahmoud Kallash, Diego Aviles

New Orleans, LA, USA

Author Affiliations: Pediatric Nephrology Department, Louisiana State University Health Science Center and Children's Hospital of New Orleans, 200 Henry Clay Ave, New Orleans, LA 70118, USA (Kallash M, Aviles D)

Corresponding Author: Mahmoud Kallash, MD, 200 Henry Clay Ave, New Orleans, LA 70118, USA (Tel: 318 658 5750; Fax: 504 896-9240; Email: mkallash@yahoo.com/mkalla@lsuhsc.edu)

doi: 10.1007/s12519-014-0484-y

Background: Focal segmental glomerulosclerosis (FSGS) is the most common glomerular condition leading to end-stage renal disease (ESRD) and the third most common cause of ESRD in pediatric patients.

Methods: This is a retrospective study consisting of 22 pediatric patients with FSGS and heavy proteinuria. After demonstrating steroids resistance, the patients were treated with tacrolimus, targeting a trough level 5-8 ng/mL. The primary outcome is the induction of remission with tacrolimus.

Results: Thirteen patients (59%) achieved remission (complete in 31.8% and partial in 27.2%) and 12 patients showed stable or improved renal function over an average follow-up of 2.9 years (range: 0.5-7 years). There was no significant difference in response rate between African American and Caucasian patients. None of the patients had significant side-effect to tacrolimus and none of the repeat biopsies showed an increase in interstitial fibrosis compared to baseline. The best renal outcome was for patients who achieved complete remission. Partially responsive patients had improved renal function compared with resistant patients.

Conclusion: Tacrolimus is a viable option in the treatment of children with idiopathic steroid resistant FSGS.

Key words: chronic kidney disease; focal segmental glomerulosclerosis (FSGS); proteinuria; tacrolimus

World J Pediatr 2014;10(2):151-154

Thyroid peroxidase antibody positivity and triiodothyronine levels are associated with pediatric Graves' ophthalmopathy

Jung Hyun Lee, So Hyun Park, Dae Gyun Koh, Byung Kyu Suh

Gyeonggi-do, Korea

Author Affiliations: Department of Pediatrics, the Catholic University of Korea, St. Vincent's Hospital, 93-6, Ji-dong, Paldal-gu, Suwon-si, Gyeonggi-do, Republic of Korea (Lee JH, Park SH, Koh DG); Department of Pediatrics, the Catholic University of Korea, Seoul St. Mary's Hospital, 222 Banpo-daero, Seocho-gu, Seoul, Republic of Korea (Suh BK)

Corresponding Author: So Hyun Park, Department of Pediatrics, The Catholic University of Korea, St. Vincent Hospital, 93-6, Ji-dong, Paldal-gu, Suwon-si, Gyeonggi-do, Republic of Korea (Tel:+82 31 249 8312; Fax: +82 257 9111; Email: nicedoc@catholic.ac.kr)

doi: 10.1007/s12519-014-0476-y

Background: Graves' ophthalmopathy (GO) occurs commonly in children with Graves' disease (GD). However, there are limited studies on the clinical manifestations and thyroid autoantibodies in pediatric GO. The aim of this study was to investigate the prevalence and risk factors of GO in childhood GD.

Methods: Clinical and biochemical data from children and adolescents with GD were retrospectively reviewed. Eighty patients under 19 years of age were included in the present study. We compared the clinical and biochemical differences between patients with and without GO.

Results: Thirty-nine percent of the patients had GO, and 81% of the GO patients were females. Of these, two patients showed unilateral GO. Triiodothyronine (T3) levels were higher in GO patients than in those without GO. Anti-thyroglobulin antibody and thyroid stimulating hormone receptor antibody titers were not significantly different between the two groups. Anti-thyroid peroxidase antibody (TPO Ab) positivity was 68% in the patients with GO and only 47% in the patients without GO. In multivariate regression analysis, high T3 levels and TPO Ab positivity were related to the presence of GO.

Conclusion: In children and adolescents with GD, TPO Ab positivity and high T3 levels could act as predictive factors for the presence of GO.

Key words: Graves' disease; Graves' ophthalmopathy; pediatrics; thyroid peroxidase antibody; triiodothyronine

World J Pediatr 2014;10(2):155-159

Evaluating autism in a Chinese population: the Clinical Autism Diagnostic Scale

Grace Hao, Thomas L Layton, Xiao-Bing Zou, Dong-Yun Li

Durham, NC, USA

Author Affiliations: Department of Allied Professions, North Carolina Central University, 710 Cecil Street, Durham, NC 27707, USA (Hao G); T and T Communication Services, Inc., 100 Meredith Drive, Suite 100, Durham, NC 27713, USA (Layton TL); Children Development and Behavior Center, Third Affiliated Hospital to Sun Yet-sen University, No 600 Tianhe Road, Guangzhou 510630, China (Zou XB, Li DY)

Corresponding Author: Grace Hao, MD, PhD, Department of Allied Professions, North Carolina Central University, 710 Cecil Street, Durham, NC 27707, USA (Tel: 919-530-7836; Fax: 919-484-0081; Email: jhao@nccu.edu)

doi: 10.1007/s12519-014-0466-0

Background: The purpose of this study was to report on the psychometric measures and discriminatory function of a new diagnostic test for autism spectrum disorders, the Clinical Autism Diagnostic Scale (CADS).

Methods: The CADS was used to test 216 children in the study, including 86 with low-functioning autism specturm disorders (ASD), 16 children with high-functioning ASD, 16 with pervasive developmental disorder, not otherwise specified, 7 with Asperger syndrome, 65 with typical development, 11 children with language impairments and 15 with intellectual disabilities. Ages ranged from 38-73 months. Behaviors for the groups were compared across seven domains.

Results: The results indicated the instrument was reliable, valid, and successfully differentiated the different groups of children with and without autism. All ASD groups were found to display difficulties in the domains of sensory behaviors and stereotyped behaviors. The play and social domains were found to measure similar underlying concepts of behaviors, while the receptive language and expressive language domains were also found to measure similar underlying-language concepts. The group of children diagnosed as having low-functioning autism performed less well on all tested domains in the instrument than did the other three groups of children with ASD, and these other three groups each also presented unique patterns of behaviors and differed on individual domains.

Conclusions: CADS is a reliable and valid test. It successfully differentiates the abilities of children with ASD at different levels of functioning.

Key words: autism spectrum disorders; diagnosis; rating scale

World J Pediatr 2014;10(2):160-163

Urinary tract infections in neonates with jaundice in their first two weeks of life

Mehmet Mutlu, Yasemin Çayır, Yakup Aslan

Erzurum, Turkey

Author Affiliations: Department of Neonatology (Mutlu M) and Department of Family Physician (Çayır Y), Erzurum Regional Training and Research Hospital, Neonatal Intensive Care Unit, Erzurum, Turkey; Department of Neonatology, Karadeniz Technical University, Neonatal Intensive Care Unit, Trabzon, Turkey (Aslan Y)

Corresponding Author: Mehmet Mutlu, Department of Neonatology, Erzurum Regional Training and Research Hospital, Neonatal Intensive Care Unit, Erzurum, Turkey (Tel: 0442 2326166; Fax: 0442 2325090; Email: drmehmetmutlu38@hotmail.com)

doi: 10.1007/s12519-013-0433-1

Background: Hyperbilirubinemia is a frequently seen condition in neonates. This study was undertaken to determine the role of urinary tract infections (UTIs) in the etiology of indirect hyperbilirubinemia in neonates with jaundice in their first two weeks of life.

Methods: The study was conducted prospectively. The subjects were neonates aged 4-14 days with hyperbilirubinemia which could not be detected by routine tests and was sufficiently severe to necessitate phototherapy.

Results: The study was performed in 104 neonates, of whom 18% (n=19) had UTI. The most frequently identified micro-organism was Escherichia coli (43%). Phototherapy duration and rebound bilirubin level were higher in neonates with UTI (P<0.05).

Conclusion: UTI should be investigated in neonates with hyperbilirubinemia of unknown etiology in the first two weeks of life.

Key words: hyperbilirubinemia; neonate; urinary tract infection

World J Pediatr 2014;10(2):164-167

Management of children with disorders of sex development: 20-year experience in southern Thailand

Somchit Jaruratanasirikul, Vorapun Engchaun

Songkhla, Thailand

Author Affiliations: Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand (Jaruratanasirikul S, Engchaun V)

Corresponding Author: Somchit Jaruratanasirikul, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand (Tel: 66-074-429618; Fax: 66-074-429618; Email: somchit.j@psu.ac.th)

doi: 10.1007/s12519-013-0418-0

Background: Disorders of sex development (DSD) is a group of sexual differentiation disorders resulting in genital anomalies with defects in gonadal hormone synthesis and/or incomplete genital development. These conditions result in problems concerning the sex assignment of the child. This study aims to describe the clinical features, diagnosis and management of children with DSD in southern Thailand.

Methods: The medical records of 117 pediatric patients diagnosed with DSD during the period of 1991-2011 were retrospectively reviewed.

Results: Disorders of sex development were categorized into 3 groups: sex chromosome abnormalities (53.0%), 46,XX DSD (29.9%) and 46,XY DSD (17.1%). The two most common etiologies of DSD were Turner syndrome (36.8%) and congenital adrenal hyperplasia (29.9%). Ambiguous genitalia/intersex was the main problem in 46,XX DSD (94%) and 46,XY DSD (100%). Sex reassignment was done in 5 children (4.3%) at  age of 3-5 years: from male to female in 4 children (1 patient with congenital adrenal hyperplasia, 1 patient  with 45,X/46,XY DSD, and 2 patients with 46,XX ovotesticular DSD) and from female to male in 1 patient with 46,XX ovotesticular DSD. Of the total 20 children with 46,XY DSD, 16 (80%) were raised as females.

Conclusion: Management of DSD children has many aspects of concern. Sex assignment/reassignment depends on the phenotype (phallus size) of the external genitalia rather than the sex chromosome.

Key words: ambiguous genitalia; disorders of sex development; genital ambiguity; gonadal dysgenesis; intersex; sex assignment

World J Pediatr 2014;10(2):168-174

Effect of maternal lipid profile, C-peptide, insulin, and HBA_1c levels during late pregnancy on large-for-gestational age newborns

Ruo-Lin Hou, Huan-Huan Zhou, Xiao-Yang Chen, Xiu-Min Wang, Jie Shao, Zheng-Yan Zhao

Hangzhou, China

Author Affiliations: Department of Children's Health Care (Hou RL, Zhou HH, Chen XY, Shao J, Zhao ZY), Department of Endocrinology (Wang XM), Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

Corresponding Author: Zheng-Yan Zhao, Department of Children's Health Care, Children's Hospital, Zhejiang University School of Medicine, 57 Zhugan Xiang, Hangzhou 310003, China (Tel: 86-571-87061007 ext 12435; Fax: 86-571-87078641; Email: zhaozy@zju.edu.cn)

doi: 10.1007/s12519-014-0488-7

Background: Large-for-gestational age (LGA) newborns can increase the risk of metabolic syndrome. Previous studies have shown that the levels of maternal blood lipids, connecting peptide (C-peptide), insulin and glycosylated hemoglobin (HbA_1c) were significantly different between LGA and appropriate-for-gestational age (AGA) newborns. This study aimed to determine the effect of the levels of maternal lipids, C-peptide, insulin, and HbA_1c during late pregnancy on LGA newborns.

Methods: This study comprised 2790 non-diabetic women in late pregnancy. Among their newborns, 2236 (80.1%) newborns were AGA, and 554 (19.9%) newborns were LGA. Maternal and neonatal characteristics were obtained from questionnaires and their case records. The levels of maternal fasting serum apolipoprotein A1 (ApoA1), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), C-peptide, insulin and blood HbA_1c were measured. The chi-square and Mann-Whitney U test were used to analyze categorical variables and continuous variables between the AGA and LGA groups, respectively. Binary logistic regression analysis was made to determine the independent risk factors for LGA newborns.

Results: Maternal TG, C-peptide, insulin and HbA_1c levels were significantly higher in the LGA group than in the AGA group (P<0.05). The LGA group had significantly lower levels of maternal TC, HDL-C and LDL-C than the AGA group (P<0.05). After adjustment for confounding variables, including maternal age, pre-pregnancy body mass index, education, smoking, annual household income, amniotic fluid volume, gestational hypertension, newborn gender and gestational age at blood collection, high maternal TG levels remained significantly associated with LGA newborns (P<0.05).

Conclusion: High maternal TG level during late pregnancy is significantly associated with LGA newborns.

Key words: large-for-gestational-age newborns; late pregnancy; maternal lipid profile; triglyceride

World J Pediatr 2014;10(2):175-181

Sixth hour transcutaneous bilirubin predicting significant hyperbilirubinemia in ABO incompatible neonates

Ramesh Y Bhat, Pavan CG Kumar

Manipal, India

Author Affiliations: Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal-576104, Udupi District, Karnataka, India (Bhat RY, Kumar PCG)

Corresponding Author: Ramesh Y Bhat, Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal-576104, Udupi District, Karnataka, India (Tel: 91 9448296564; Fax: 91 820 2571927; Email: docrameshbhat@yahoo.co.in)

doi: 10.1007/s12519-013-0421-5

Background: Neonates with ABO hemolytic disease are at greater risk for developing significant hyperbilirubinemia. We aimed to determine whether sixth hour transcutaneous bilirubin (TcB) could predict such a risk.

Methods: TcB measurements were obtained at the 6th hour of life in blood group A or B neonates born to blood group O, rhesus factor compatible mothers. Subsequent hyperbilirubinemia was monitored and considered significant if a neonate required phototherapy/exchange transfusion. The predictive role of sixth hour TcB was estimated.

Results: Of 144 ABO incompatible neonates, 41(O-A, 24; O-B, 17) had significant hyperbilirubinemia. Mean sixth hour TcB was significantly higher among neonates who developed significant hyperbilirubinemia than those who did not (5.83±1.35 mg/dL vs. 3.65±0.96 mg/dL, P<0.001). Sixth hour TcB value >4 mg/dL had the highest sensitivity of 93.5% and >6 mg/dL had the highest specificity of 99%. Area under receiver operating characteristic curve was 0.898.

Conclusion: Sixth hour TcB predicts subsequent significant hyperbilirubinemia in ABO incompatible neonates.

Key words: ABO incompatibility; neonate; phototherapy; significant hyperbilirubinemia; transcutaneous bilirubin

World J Pediatr 2014;10(2):182-185

Correspondence

Premature and neonate modeling of thimerosal exposure and neurodevelopment: additional comments

Health professionals in pediatrics, especially in neonatology, welcome the timely work of Chen et al.^[1] Despite the widespread use of Thimerosal-containing vaccines (TCVs) in premature newborns, this is the first attempt to model exposure to thimerosal and neurodevelopment; that is why this study is both interesting and important. Given the special circumstances of the immature neurologic and immunologic systems of the premature-newborn, it is worth raising additional relevant issues to this revealing paper.

Metabolic stress is known to exacerbate Hg toxicity in rat model.^[2] Body weight loss in human neonates (10%) occurs at the expense of body water and is more taxing in preterm babies;^[2] neonates lose weight up to 5 days of life, but term-babies regain initial weight at a faster rate than preterm babies (10 days against 10 to 14 days respectively).

So far, all findings of low doses of ethylmercury relevant to vaccines demonstrated that infant animals (mice, rats, and monkeys) manifested neurological delays.^[2] However, it is worth mentioning that another confounder not considered in any experimental study so far is TCV taken during pregnancy and other cumulative sources of environmental Hg exposure. Nowadays, expecting mothers are exposed to environmental Hg (fish-MeHg and dental amalgams) and likely to TCVs. 

What is the vaccine equivalent of the modeled Thimerosal exposure? Actually Chen et al's Thimerosal doses used (32.2 μg/kg b.w. or 16 μgHg/kg b.w.) were close or relatively smaller than that actually reported (21.1 μgHg/kg b.w.) in premature babies;^[3] additionally, the highest dose of Thimerosal (131.2 μg/kg b.w. or 65.6 μgHg/kg b.w.) was less than the cumulative doses received during the first six months, after correcting for weight gain.^[3] In this regard, Chen et al's model is conservative and as a consequence the results are significant to model safety ranges of premature or neonate Hg exposure relevant to pediatric TCVs.

Before 2004, there are hardly any experimental studies addressing small doses of ethylmercury and neurological outcomes; these recent studies confirm well known impairment of nervous system functioning known to be caused by small doses of methylmercury.^[2]It should be noticed that all these results focused on one mercury compound and a specific measured outcome. However, another important topic to consider in relation to experimental neurotoxicity of TCV is the obligatory occurrence of ethylmercury in association with aluminum as an adjuvant of such vaccines. In the specific case of hepatitis B vaccine, the ratio of Al:Hg is 20.^[4] Given the susceptibility of young rats to aluminum toxicity^[5] and translocation of intramuscular injection of alum-containing vaccine from muscle to the brain,^[6] future experiments should explore the combined effect of Al plus Hg at ratios found in pediatric TCVs in order to address the actual range of combined Al and Hg in such vaccines used by the majority of infants in poor countries. Indeed, we are now learning that adjuvant-Al can produce neurological effects on its own,^[7] but we have no clue as to the combined effect of ethylmercury plus adjuvant-Al as they occur in pediatric TCVs used in developing countries. 

José G. Dórea

C.P. 04322

Faculty of Health Sciences, Universidade de Brasilia

70919-970 Brasilia, DF, Brazil

Email: jg.dorea@gmail.com

References

1  Chen YN, Wang J, Zhang J, Li SJ, He L, Shao DD, et al. Effect of thimerosal on the neurodevelopment of premature rats. World J Pediatr 2013;9:356-360.

2  Dórea JG. Low-dose mercury exposure in early life: relevance of thimerosal to fetuses, newborns and infants. Curr Med Chem 2013;20:4060-4069.

3  Dórea JG, Marques RC, Brandão KG. Neonate exposure to thimerosal mercury from hepatitis B vaccines. Am J Perinatol 2009;26:523-527.

4  Dórea JG, Marques RC. Infants' exposure to aluminum from vaccines and breast milk during the first 6 months. J Expo Sci Environ Epidemiol 2010;20:598-601.

5  Veiga M, Bohrer D, Banderó CR, Oliveira SM, do Nascimento PC, Mattiazzi P, et al. Accumulation, elimination, and effects of parenteral exposure to aluminum in newborn and adult rats. J Inorg Biochem 2013;128:215-220.

6  Khan Z, Combadière C, Authier FJ, Itier V, Lux F, Exley C, et al. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain. BMC Med 2013;11:99.

7  Shaw CA, Li Y, Tomljenovic L. Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes. J Inorg Biochem 2013;128:237-244.

doi: 10.1007/s12519-014-0486-9

We are grateful to your comments. The dose of thimerosal used in our study was according to the common mercury content in hepatitis B which was 12.5μg,^[1] and converted into microgram per kilogram for rat by surface conversion formula. Next, according to the 1, 2, 3, 4 times, we designed 4 groups of thimerosal dose. Since thimerosal was dissolved in saline, we used saline group as a control in which main item was excluded for the saline interference.

We agreed that it was worth mentioning that aluminum is not considered in any thimerosal experimental study, which is an adjuvant of thimerosal-containing vaccines (TCVs). Given the reasons you suggested in the letter, we also strongly believed that it is urgent to study the combined effect of ethylmercury plus adjuvant-Al in TCVs. Of course, just as you said that TCV taken during pregnancy and other cumulative sources of environmental Hg exposure are not considered in experimental study now.

Yan-Ni Chen, Jue Wang

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Engineering, School of Life Science and Technology and Affiliated Xi'an Children's Hospital of Medical College, Xi'an Jiaotong University,

Xi'an 710002, China

Email:chenyannichil@163.com

References

1  Stajich GV, Lopez GP, Harry SW, Sexson WR. Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants. J Pediatr 2000;136:679-681.

doi: 10.1007/s12519-014-0487-8