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1.  Berardinelli-Seip syndrome and achalasia: a shared pathomechanism? 
European Journal of Pediatrics  2015;174(7):975-980.
Berardinelli-Seip congenital lipodystrophy (BSCL) is an uncommon autosomal recessive disorder. Patients with BSCL present with a distinct phenotype since subcutaneous fat is largely lacking and musculature has become more prominent. During childhood, diabetes and acanthosis nigricans evolve and female patients may develop hirsutism. Different genes encoding this entity have been described. Achalasia is a rare esophageal motility disorder, characterized by its distinct motility pattern with absent or incomplete lower esophageal sphincter (LES) relaxations. The exact cause of achalasia is yet unknown. Here, we describe a patient with achalasia in the context of BSCL, which might be linked by a shared pathophysiologic background, as evaluated in this case report.
Conclusion: In a BSCL patient presenting with gastrointestinal symptoms, a motility disorder of the gastrointestinal tract should be considered. What is Known: • Berardinelli-Seip congenital lipodystrophy (BSCL) and achalasia are both disorders characterized by low prevalence. What is New: • Co-existence of both diseases is described in this report. Linkage by a potential common pathophysiologic background is discussed in this paper.
doi:10.1007/s00431-015-2556-y
PMCID: PMC4475245  PMID: 25994244
Berardinelli-Seip congenital lipodystrophy; Achalasia; Manometry
2.  Cancer susceptibility syndromes in children in the area of broad clinical use of massive parallel sequencing 
European Journal of Pediatrics  2015;174(8):987-997.
Children diagnosed with cancer are considered for inherited cancer susceptibility testing according to well-established clinical criteria. With increasing efforts to personalize cancer medicine, comprehensive genome analyses will find its way into daily clinical routine in pediatric oncology. Whole genome and exome sequencing unavoidably generates incidental findings. The somatic “molecular make-up” of a tumor genome may suggest a germline mutation in a cancer susceptibility syndrome. At least two mechanisms are well-known, (a) chromothripsis (Li-Fraumeni syndrome) and (b) a high total number of mutational events which exceeds that of other samples of the same tumor type (defective DNA mismatch repair). Hence, pediatricians are faced with the fact that genetic events within the tumor genome itself can point toward underlying germline cancer susceptibility. Whenever genetic testing including next-generation sequencing (NGS) is initiated, the pediatrician has to inform about the benefits, risks, and alternatives, discuss the possibility of incidental findings and its disclosure, and to obtain informed consent prior to testing.
Conclusions: Genetic testing and translational research in pediatric oncology can incidentally uncover an underlying cancer susceptibility syndrome with implications for the entire family. Pediatricians should therefore increase their awareness of chances and risks that accompany the increasingly wide clinical implementation of NGS platforms. What is Known:• The proportion of cancers in children attributable to an underlying genetic syndrome or inherited susceptibility is unclear.• Pediatricians consider children diagnosed with cancer for inherited cancer susceptibility according to well-established clinical criteria. What is New:• Genetic testing of tumor samples can incidentally uncover an underlying cancer susceptibility syndrome.• Findings in tumor genetics can be indicative that the tumor arose on the basis of the child’s germline alteration, (a) chromothripsis and (b) a high total number of mutational events which exceeds that of other samples of the same tumor type.
doi:10.1007/s00431-015-2565-x
PMCID: PMC4516864  PMID: 25982339
Cancer susceptibility syndrome; Hereditary; Childhood; Next-generation sequencing; Chromothripsis; Mutation rate
3.  Identification of SLC26A4 gene mutations in Iranian families with hereditary hearing impairment 
European journal of pediatrics  2008;168(6):651-653.
Mutations in the SLC26A4 gene at the DFNB4 locus are responsible for Pendred syndrome and non-syndromic hereditary hearing loss (DFNB4). This study included 80 nuclear families with two or more siblings segregating presumed autosomal recessive hearing loss. All deaf persons tested negative for mutations in GJB2 at the DFNB1 locus and were therefore screened for autozygosity by descent (ABD) using short tandem repeat polymorphisms (STRPs) that flanked SLC26A4. In 12 families, homozygosity for STRPs suggested possible ABD in this genomic region. Affected individuals in 5 families had a positive perchlorate discharge test. Sequence analysis of SLC26A4 identified 10 mutations in 8 families (T420I, 1197delT, G334V, R409H, T721M, R79X, S448L, L597S, 965insA and L445W) of which 4 are novel (T420I, G334V, 965insA and R79X). These results imply that Pendred syndrome is the most prevalent form of syndromic hereditary hearing loss in Iran.
doi:10.1007/s00431-008-0809-8
PMCID: PMC4428656  PMID: 18813951
DFNB4; SLC26A4 gene; Pendred; PDS gene
4.  Failure of introduction of food allergens after negative oral food challenge tests in children 
European Journal of Pediatrics  2015;174(8):1093-1099.
One of the purposes to perform an oral food challenge (FC) test is to avoid unnecessary elimination of food allergens. In case of a negative FC test result, the food can be introduced. It is, however, unknown if patients act according to the outcome of the test. This study evaluates the rate of introduction of peanut, hazelnut, cow’s milk or hen’s egg allergens after a negative FC test. We investigated the introduction rate of children (0–18 years) with a negative FC test visiting the Department of Allergology, Erasmus Medical Centre Rotterdam from 2008 till 2013 and the factors that influence the rate of introduction. Patients were asked to complete a comprehensive questionnaire about their FC test. In total, 157 (38 % girls, mean age during challenge 6.9 years) participated in the study. Of these FC tests, 104 (56 %) were followed by a successful introduction, 30 (16 %) by a partly introduction (traces or processed foods) and 52 (28 %) by a failed introduction. Peanut and hazelnut showed a statistically significant lower successful introduction rate. Age, gender, symptoms during FC test, dietary advice and time period to introduction significantly influenced the rate of introduction. One fourth of the children with failure of introducing foods experienced symptoms during the introduction.
Conclusion: More than one quarter of all children with a negative FC test result did not introduce the food. The FC test in its current form does not achieve its objective for this group of children. What is Known: • When the outcome of a food challenge test is negative, the food should be introduced in the diet of the child. • Failure of this introduction has negative consequences for the health of the child. What is New: • Failure of introduction of foods after a negative challenge test is reported in almost 25 % of the challenged children. • Failure of introduction after a negative challenge test is significant associated with gender, age, allergens, symptoms during OFC (according to the parents), advice, time start eating the food, and symptoms during introduction.
doi:10.1007/s00431-015-2504-x
PMCID: PMC4516899  PMID: 25762026
Children; Failed introduction; Food allergy; Oral food challenge test
6.  Relationship between clinical sinusitis symptoms and sinus CT severity in pediatric post bone marrow transplant and immunocompetent patients 
European journal of pediatrics  2011;171(2):375-381.
Since typical inflammatory responses may be diminished in children following bone marrow transplant (BMT), computed tomography (CT) imaging of the sinuses has been increasingly ordered to diagnose sinusitis in this group. The objective of this study was to determine the association between clinical sinusitis symptoms and sinus opacification on CT scans in post BMT versus immunocompetent children. Our sample was comprised of 64 post BMT and 86 immunocompetent children with sinus CT scans. CT sinus opacification was scored using the modified Lund–Mackay staging system. The relationship between clinical sinusitis symptoms (rhinorrhea, nasal congestion, cough, headache, and facial pain) and opacification was compared for the two groups. The severity of sinus opacification in the BMT group was significantly higher compared to the immunocompetent group. In combined patient groups the odds ratio (OR) for moderate/severe sinusitis was significantly elevated for rhinorrhea (OR=3.00; 95% confidence interval [CI], 1.27–7.12), cough (OR=2.80; 95% CI, 1.22–6.42), and having either rhinorrhea, nasal congestion, or cough (OR= 4.76; 95% CI, 1.71–13.24). While the immunocompetent group had a greater number of sinusitis symptoms compared to the post BMT group, both groups had a significant increase in the severity on CT with increasing number of symptoms.
Conclusion
In post BMT patients, our data demonstrated higher odds of moderate/severe sinusitis on CT scans associated with rhinorrhea, cough or nasal congestion. These finding suggest that in post BMT children, detailed sinus history may still play a vital role in the diagnosis of sinusitis.
doi:10.1007/s00431-011-1560-0
PMCID: PMC4234098  PMID: 21904829
Sinusitis; Children; Bone marrow transplant; Computed tomography; Paranasal sinuses; Symptoms
7.  Examining a possible association between human papilloma virus (HPV) vaccination and migraine: results of a cohort study in the Netherlands 
European Journal of Pediatrics  2014;174(5):641-649.
Since the introduction of the bivalent human papilloma virus (HPV) vaccine in the Netherlands, migraine has been reported as a notable event in the passive safety surveillance system. Research on the association between HPV vaccination and migraine is needed. Therefore, potential migraine cases in 2008–2010 were selected from a group of general practitioners and linked to the vaccination registry. Data were analysed in three ways: (i) incidences of migraine postvaccination (2009/2010) were compared to pre-vaccination incidences (2008); (ii) in a cohort, incidence rates of migraine in vaccinated and unvaccinated girls were compared and (iii) in a self-controlled case series analysis, the relative incidence of migraine in potentially high-risk periods was compared to non-high-risk periods. Incidence rates of migraine for 12- to 16-year-old girls and boys postvaccination were slightly higher than pre-vaccination incidence rates. Incidence rate ratios (IRRs) for vaccinated compared to unvaccinated girls were not statistically significantly higher. Furthermore, the RR for migraine in the high-risk period of 6 weeks following each dose versus non-high-risk period was 4.3 (95% confidence interval (CI) 0.69–26.6) for certain migraine.
Conclusion: Using different methods, no statistically significant association between HPV vaccination and incident migraine was found. However, the number of cases was low; to definitively exclude the risk, an increased sample size is needed.
doi:10.1007/s00431-014-2444-x
PMCID: PMC4412283  PMID: 25367054
HPV; Human papilloma virus; Bivalent vaccine; Safety; Migraine
8.  Cow’s milk allergy: evidence-based diagnosis and management for the practitioner 
European Journal of Pediatrics  2014;174:141-150.
This review summarizes current evidence and recommendations regarding cow’s milk allergy (CMA), the most common food allergy in young children, for the primary and secondary care providers. The diagnostic approach includes performing a medical history, physical examination, diagnostic elimination diets, skin prick tests, specific IgE measurements, and oral food challenges. Strict avoidance of the offending allergen is the only therapeutic option. Oral immunotherapy is being studied, but it is not yet recommended for routine clinical practice. For primary prevention of allergy, exclusive breastfeeding for at least 4 months and up to 6 months is desirable. Infants with a documented hereditary risk of allergy (i.e., an affected parent and/or sibling) who cannot be breastfed exclusively should receive a formula with confirmed reduced allergenicity, i.e., a partially or extensively hydrolyzed formula, as a means of preventing allergic reactions, primarily atopic dermatitis. Avoidance or delayed introduction of solid foods beyond 4–6 months for allergy prevention is not recommended.
Conclusion: For all of those involved in taking care of children’s health, it is important to understand the multifaceted aspects of CMA, such as its epidemiology, presentation, diagnosis, and dietary management, as well as its primary prevention.
doi:10.1007/s00431-014-2422-3
PMCID: PMC4298661  PMID: 25257836
Allergy; Children; Infants; Pediatrics
9.  Successful private–public funding of paediatric medicines research: lessons from the EU programme to fund research into off-patent medicines 
European Journal of Pediatrics  2014;174(4):481-491.
The European Paediatric Regulation mandated the European Commission to fund research on off-patent medicines with demonstrated therapeutic interest for children. Responding to this mandate, five FP7 project calls were launched and 20 projects were granted. This paper aims to detail the funded projects and their preliminary results. Publicly available sources have been consulted and a descriptive analysis has been performed. Twenty Research Consortia including 246 partners in 29 European and non-European countries were created (involving 129 universities or public-funded research organisations, 51 private companies with 40 SMEs, 7 patient associations). The funded projects investigate 24 medicines, covering 10 therapeutic areas in all paediatric age groups. In response to the Paediatric Regulation and to apply for a Paediatric Use Marketing Authorisation, 15 Paediatric Investigation Plans have been granted by the EMA-Paediatric Committee, including 71 studies of whom 29 paediatric clinical trials, leading to a total of 7,300 children to be recruited in more than 380 investigational centres.
Conclusion: Notwithstanding the EU contribution for each study is lower than similar publicly funded projects, and also considering the complexity of paediatric research, these projects are performing high-quality research and are progressing towards the increase of new paediatric medicines on the market. Private–public partnerships have been effectively implemented, providing a good example for future collaborative actions. Since these projects cover a limited number of off-patent drugs and many unmet therapeutic needs in paediatrics remain, it is crucial foreseeing new similar initiatives in forthcoming European funding programmes.
doi:10.1007/s00431-014-2398-z
PMCID: PMC4369287  PMID: 25241827
Paediatric clinical trials; Seventh Framework Programme; Drug development; PUMA
10.  Early exposure to thimerosal-containing vaccines and children’s cognitive development. A 9-year prospective birth cohort study in Poland 
European Journal of Pediatrics  2014;174(3):383-391.
The controversial topic of the early exposure to mercury is regarding ethylmercury, which is present in the thimerosal-containing vaccines (TCVs). The objective of this study was to determine the relationship between the early exposure to TCVs and cognitive development in children during the first 9 years of life. The cohort included 318 children vaccinated in an early period (neonatal and up to 6 months) against hepatitis B and diphtheria-tetanus-pertussis (DTP) using formulation with or without thimerosal. The children’s development was assessed using the Fagan test (6th month of life), the Bayley Scales of Infant Development (BSID)-II (12th–36th month), the Raven test (5th, 8th year), and the Wechsler Intelligence Scale for Children (WISC-R) (6th, 7th, 9th year). Results were determined by multivariable linear and logistic regression, adjusted to potential confounders. Children exposed and not exposed to TCVs in the neonatal period had similar outcomes of cognitive-developmental tests; only the results of BSID-II at the 36th month and WISC-R at the 9th year were significantly higher for those exposed to TCVs. Developmental test results in children exposed to TCVs up to the 6th month of life also did not depend on thimerosal dose.
Conclusion: TCV administration in early infancy did not affect children’s cognitive development.
doi:10.1007/s00431-014-2412-5
PMCID: PMC4334107  PMID: 25185528
Ethylmercury; Vaccines; Children; Developmental outcomes
11.  The influence of hepatitis B and C virus coinfection on liver histopathology in children 
European Journal of Pediatrics  2014;174(3):345-353.
The influence of hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection on liver histology in children remains unknown. We analyzed histopathological features in 70 treatment-naïve children: 10 with HBV/HCV coinfection (case group A), 30 with HBV (control group B), and 30 with HCV (control group C). Liver biopsies were scored for grading and staging according to Knodell’s modified system and were tested for an association with demographic and laboratory data. The mean grade was higher in coinfected children compared to control group C (6.2 ± 3.0 vs. 4.2 ± 2.5, p = 0.04), but not control group B (p = 0.47). A higher proportion of patients with moderate to severe necroinflammation were observed in case group A compared to isolated HCV (p = 0.05). Mean staging did not differ between the case and control groups. Multivariate analysis revealed that HBV/HCV coinfection and aminotransferase activity were independently associated with moderate to severe necroinflammatory activity
Conclusion: HBV/HCV coinfection was associated with moderate to severe necroinflammation irrespective of age at biopsy or duration of infection and led to significantly higher necroinflammatory activity than HCV monoinfection. HBV/HCV coinfection did not enhance fibrosis. High aminotransferase levels were positively associated with moderate to severe necroinflammation.
doi:10.1007/s00431-014-2402-7
PMCID: PMC4334106  PMID: 25172445
Chronic hepatitis; Grading and staging; Hepatitis B virus; Hepatitis C virus; Liver biopsy
12.  Three novel mutations of the G6PC gene identified in Chinese patients with glycogen storage disease type Ia 
Glycogen storage disease type Ia (GSDIa) is an autosomal recessively inherited disease characterized by poor tolerance to fasting, growth retardation, and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Germline mutations of glucose-6-phosphatase (G6PC) gene have been identified as a cause of GSDIa. In this study, we performed mutation analysis in five Chinese GSDIa patients belonging to five unrelated families by direct DNA sequencing. All patients were clinically classified as GSDIa. Mutation analysis of the G6PC gene revealed that all patients carried biallelic G6PC mutations (p.Ile341Asn, p.Ala274Val, p.Phe80Ile, p.Gly118Asp, p.Arg83His, c.262delG, and c.648G>T). Of the seven different mutations identified, three were found to be novel. All of the novel mutations were missense (p.Ala274Val, p.Phe80Ile, and p.Gly118Asp). The c.262delG mutation which leads to a frame-shift and truncated forms of glucose-6-phosphatase was present in three unrelated patients (one homozygote and two heterozygotes). Conclusion: By direct DNA sequencing, three novel G6PC variations were identified which expanded the G6PC mutation spectrum, and provided conclusive genetic evidences for the definitive diagnosis of the Chinese patients.
doi:10.1007/s00431-014-2354-y
PMCID: PMC4289013  PMID: 24980439
GSDIa; Glucose-6-phosphatase; Germline mutation
13.  Prediction of the risk of coronary arterial lesions in Kawasaki disease by serum 25-hydroxyvitamin D3 
European Journal of Pediatrics  2014;173(11):1467-1471.
Kawasaki disease (KD) is associated with the development of coronary arterial lesions (CALs) in children. We aimed to test the hypothesis that circulating 25-hydroxyvitamin D3 [25-(OH)D3] could be identified as a clinical parameter for predicting CALs secondary to KD in children. We enrolled 35 children with KD in the acute phase and measured serum 25-(OH)D3 levels in all of them, then followed up by echocardiography for CALs. Additionally, serum 25-(OH)D3 levels were obtained in 23 febrile children with respiratory tract infections and 30 healthy children. Of the 35 KD children, nine had CALs according to echocardiography and 26 did not (NCALs). Serum 25-(OH)D3 levels were not significantly different between NCALs and healthy children (49.2 ± 23.8 versus 44.1 ± 30.2 ng/ml; P = 0.49). Serum 25-(OH)D3 levels were significantly higher in children with CALs than those without CALs (83.9 ± 26.3 versus 49.2 ± 23.8 ng/ml; P = 0.001). The cutoff value of 65 ng/ml to predict subsequent CALs had a specificity of 0.73, sensitivity of 0.78, and diagnostic accuracy of 0.74. Conclusion: Serum 25-(OH)D3 levels were elevated dur-ing the acute phase in KD children who had subsequent CALs. Serum 25-(OH)D3 levels in the acute phase of KD may be used to predict subsequent CALs.
doi:10.1007/s00431-014-2346-y
PMCID: PMC4194745  PMID: 24889335
Kawasaki disease; 25-Hydroxyvitamin D3; Coronary artery lesions
14.  Infantile Hemangiomas and Retinopathy of Prematurity: Clues to the Regulation of Vasculogenesis 
European journal of pediatrics  2013;172(6):803-809.
Retinopathy of prematurity (ROP) and infantile hemangiomas are vascular disorders that may share common mechanisms. This study examined a potential clinical association between these disorders in populations of preterm infants at two hospitals in the U.S. and Hungary. Clinically collected data from infants with gestational ages less than 32 weeks born between May 1, 2007 and December 31, 2010 seen in the University of Iowa Children’s Hospital or the Department of Obstetrics and Gynecology, University of Pécs, were abstracted from electronic medical records and entered into a study database. Demographic and clinical variables were examined as potential covariates to the disorders of interest. Data were initially analyzed by center and then combined through meta-analysis. Six hundred eighty-four subjects were studied, 236 from Pécs and 448 from Iowa. There were no significant demographic differences between populations. Univariate analysis on each study population yielded covariates to ROP in each population, including infantile hemangioma, which were entered into a logistic regression model. These models were combined through random effects meta-analysis and demonstrated a significant relationship between infantile hemangioma and ROP (odds ratio=1.84, 95% confidence interval 1.08–3.12).
Conclusion
Infantile hemangioma and ROP co-occur in premature infant populations. Further studies are needed to investigate the pathogenesis of both disorders.
doi:10.1007/s00431-013-1966-y
PMCID: PMC3664111  PMID: 23408311
Angiogenesis; Hemangioma; Preterm infants; Retinopathy of prematurity; Vascular endothelial growth factor; Vasculogenesis
16.  The efficacy of Lactobacillus reuteri DSM 17938 in infants and children: a review of the current evidence 
European Journal of Pediatrics  2014;173(10):1327-1337.
We aimed to systematically evaluate evidence on the effectiveness of Lactobacillus reuteri DSM 17938 (L. reuteri) for treating and preventing diseases in infants and children. MEDLINE and the Cochrane Library were searched in December 2013, with no language restrictions, for relevant randomized controlled trials (RCTs) and meta-analyses. The search was updated in April 2014. One systematic review and 14 RCTs met the inclusion criteria. The use of L. reuteri may be considered in the management of acute gastroenteritis as an adjunct to rehydration. There is some evidence that L. reuteri is effective in reducing the incidence of diarrhea in children attending day care centers. There is no evidence of effectiveness of L. reuteri in preventing nosocomial diarrhea in children. The administration of L. reuteri is likely to reduce crying time in infants with infantile colic in exclusively or predominantly exclusively breast-fed infants, but not in formula-fed infants. More studies are needed. Preliminary data suggest that L. reuteri may be effective in the prevention of some functional gastrointestinal disorders, such as colic and regurgitation. This innovative approach needs further evaluation by an independent research team. Preliminary evidence provides a rationale for further assessing the efficacy of L. reuteri for treating functional constipation or functional abdominal pain. However, it is too soon to recommend the routine use of L. reuteri for these conditions. There are no safety concerns with regard to the use of L. reuteri in nonimmunocompromised subjects. There are also data to support the safety of using L. reuteri in preterm infants. Conclusion: Our results precisely define current evidence on the effects of the administration of L. reuteri DSM 17938 to the pediatric population.
doi:10.1007/s00431-014-2328-0
PMCID: PMC4165878  PMID: 24819885
Probiotics; Randomized controlled trial; Systematic review
17.  Clinical practice 
European journal of pediatrics  2010;170(6):681-688.
The incidence of urolithiasis in children is increasing. Adequate knowledge of treatment modalities and surgical options is therefore essential for every pediatrician. Surgical approaches to urolithiasis in children continue to evolve with advancements in technology and sophistication of current equipment and techniques. Perhaps the most significant development in new techniques is the advent of robotic-assisted laparoscopy. This review, for the general pediatrician, summarizes the most recent pediatric data and guidelines for surgical approaches to treatment of urolithiasis.
doi:10.1007/s00431-010-1373-6
PMCID: PMC4011548  PMID: 21190040
Urolithiasis; Pediatrics; Surgery; Endoscopy
18.  Serious Aortic Complications in a Patient with Turner Syndrome 
European journal of pediatrics  2012;172(5):703-705.
An asymptomatic young woman was discovered to have life-threatening aneurysms and dissection of the thoracic aorta during routine evaluation in a Turner syndrome (TS) study. The presence of a heart murmur and hypertension had led to diagnosis and surgical repair of an atrial septal defect at age 5 and of aortic coarctation at age 12 years. The diagnosis of TS was made at age 16 year due to short stature and delayed pubertal development. She was treated with growth hormone from age 16–18 year, and with atenolol, thyroid hormone and estrogen. She discontinued her medications and was lost to medical follow-up at age 20 year. On presenting here at age 26 year, she reported a very active lifestyle, including vigorous exercise and an acting career, with no symptoms of chest or back pain or shortness of breath. Cardiovascular imaging revealed aortic regurgitation, an unsuspected dissection of a severely dilated ascending aorta, and a large descending aortic aneurysm. She required surgical replacement of her aortic valve and ascending aorta, followed by endovascular repair of the descending aortic aneurysm. Conclusion: This patient illustrates the importance of considering the diagnosis of TS in girls with congenital aortic defects and the absolute necessity for close, expert follow-up of these patients who are at high risk for complications after surgical repair due to an underlying aortopathy, hypertension and metabolic disorders. This patient also emphasizes the need to publicize and follow screening guidelines as an increasing number of patients with congenital defects transition to adult care.
doi:10.1007/s00431-012-1808-3
PMCID: PMC3538087  PMID: 22923005
aortic dissection; X chromosome; hypoplastic aorta; congenital heart defect
19.  Hypermethylation of the enolase gene (ENO2) in autism 
European Journal of Pediatrics  2014;173(9):1233-1244.
It has been hypothesized that dysregulation of brain-expressed genes is the major predisposing underlying mechanism for autism. This dysregulation may be mediated by differential methylation of CpG sites within gene promoters, which could be candidate biomarkers and used for early clinical screening of autism. A total of 131 pairs of age- and sex-matched autistic and control subjects were recruited in this study. Peripheral blood cells were analyzed. The first five pairs were randomly applied to array-based genome-wide methylation studies. A neuron-specific gene, ENO2, was found to be hypermethylated in the autistic samples. This difference was validated by bisulfite sequencing PCR (BSP). The differential expression of ENO2 gene was further analyzed with RT-qPCR and ELISA. The hypermethylation of ENO2 within the promoter region was confirmed by BSP to be present in 14.5 % (19/131) of the total of the autistic samples. The mean ENO2 RNA level in these 19 autistic samples was reduced by about 70 % relative to that in controls. The average level of ENO2 protein expression in the 19 autistic samples (15.18 ± 3.51 μg/l) was about half of that in the controls (33.86 ± 8.16 μg/l). Conclusion: These findings suggest that reduced ENO2 expression may be a biomarker for a subset of autistic children.
Electronic supplementary material
The online version of this article (doi:10.1007/s00431-014-2311-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00431-014-2311-9
PMCID: PMC4134484  PMID: 24737292
Autism; Neurodevelopment; Gene ENO2; Methylation; Epigenetics
20.  Safety and tolerance of a new extensively hydrolyzed rice protein-based formula in the management of infants with cow’s milk protein allergy 
European Journal of Pediatrics  2014;173(9):1209-1216.
Guidelines recommend the use of extensively hydrolyzed cow’s milk protein-based formulas (eHF) in the treatment of infants with cow’s milk protein allergy (CMPA). Extensively hydrolyzed rice protein infant formula (eRHF) has recently become available and could offer a valid alternative. A prospective trial was performed to evaluate the hypo-allergenicity and safety of a new eRHF in infants with a confirmed CMPA. Patients were fed the study formula for 6 months. Clinical tolerance of the eRHF was evaluated with a symptom-based score (SBS) and growth (weight and length) was monitored. Forty infants (mean age, 3.4 months; range, 1–6 months) with CMPA confirmed by a food challenge were enrolled. All infants tolerated the eRHF and the SBS significantly decreased as of the first month of intervention. Moreover, the eRHF allowed a catch-up to normal weight gain as of the first month as well as a normalization of the weight-for-age, weight-for length, and BMI z-scores within the 6-month study period. Conclusion: In accordance with current guidelines, this eRHF was tolerated by more than 90 % of children with proven CMPA with a 95 % confidence interval. This eRHF is an adequate and safe alternative to cow milk-based eHF.
doi:10.1007/s00431-014-2308-4
PMCID: PMC4134482  PMID: 24723091
Cow’s milk protein allergy; Extensive hydrolysate; Extensively hydrolyzed rice protein formula
21.  Clinical and molecular characteristics of two transaldolase-deficient patients 
European Journal of Pediatrics  2014;173(12):1679-1682.
Transaldolase (TALDO) deficiency is a rare metabolic disease in the pentose phosphate pathway, which manifests as a severe, early-onset multisystem disease. The body fluids of affected patients contain increased polyol concentrations and seven-carbon chain carbohydrates. We report the molecular and clinical findings in two recently diagnosed transaldolase-deficient children, both presented at birth. During infancy, they presented thin skin with a network of visible vessels, spider telangiectasias and multiple haemangiomas. Such unusual skin changes are characteristic of liver damage. Later, the patients developed rapidly progressive nodular liver fibrosis, tubulopathy and severe clotting disturbances. The clinical features of these patients were in line with previously studied patients with transaldolase deficiency. The diagnosis was established by detecting high concentrations of erythritol, ribitol, arabitol, sedoheptitol, perseitol, sedoheptulose and sedoheptulose-7-phosphate in the urine. Detection was made by gas chromatography and liquid chromatography-tandem mass spectrometry and then confirmed by molecular analysis of the TALDO gene. Conclusion: Transaldolase deficiency, a rare early-onset multisystem disease, should be considered by neonatologists, paediatricians, hepatologists and nephrologists in the differential diagnosis of patients presenting hepatosplenomegaly, thrombocytopenia, anaemia, bleeding diathesis, liver failure and tubulopathy.
doi:10.1007/s00431-014-2261-2
PMCID: PMC4245499  PMID: 24497183
Transaldolase deficiency; Polyol concentration; Seven-carbon chain carbohydrates; Pentose phosphate pathway
22.  International survey on diagnosis and management of hypotension in extremely preterm babies 
European Journal of Pediatrics  2014;173(6):793-798.
Hypotension is a commonly diagnosed and treated complication of extremely low gestational age newborns (ELGAN), but enormous variation in diagnosis, management and clinical practice has been documented. We sought to evaluate practice regarding the management of hypotension in ELGANs and developed a web-based questionnaire addressing diagnosis, intervention thresholds and modes of treatment of hypotension in ELGANs. We received 216 completed questionnaires from respondents in 38 countries. Most responses (83 %) were from specialist units where, together, over 26,000 very low birth weight (VLBW) infants are cared for annually. The majority (73 %) defined hypotension as a mean blood pressure (BP) in mmHg less than the gestational age in weeks. Sixty percent assessed the circulation with additional methods; echocardiography was the most commonly used (74 %), with left ventricular output and fractional shortening the two most common measurements made. The majority (85 %) used volume administration as the initial intervention. Dopamine was the inotrope most commonly used initially (80 %). If the initial inotrope therapy failed, dobutamine was the most popular second-line treatment (28 %). Delayed cord clamping was used at 51 % of the centres. Conclusion: The definition of hypotension in ELGANs continues to follow traditional standards. Functional echocardiography is now used to assess the circulation at many centres. Volume expansion and dopamine remain the most frequently used therapies.
Electronic supplementary material
The online version of this article (doi:10.1007/s00431-013-2251-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00431-013-2251-9
PMCID: PMC4032643  PMID: 24390060
Diagnosis; Extremely low gestational age; Hypotension; Survey; Treatment
23.  Towards a safety net for management of 22q11.2 deletion syndrome: guidelines for our times 
European Journal of Pediatrics  2014;173(6):757-765.
The commonest autosomal deletion, 22q11.2 deletion syndrome (22q11DS) is a multisystem disorder varying greatly in severity and age of identification between affected individuals. Holistic care is best served by a multidisciplinary team, with an anticipatory approach. Priorities tend to change with age, from feeding difficulties, infections and surgery of congenital abnormalities particularly of the heart and velopharynx in infancy and early childhood to longer-term communication, learning, behavioural and mental health difficulties best served by evaluation at intervals to consider and initiate management. Regular monitoring of growth, endocrine status, haematological and immune function to enable early intervention helps in maintaining health. Conclusion: Guidelines to best practice management of 22q11DS based on a literature review and consensus have been developed by a national group of professionals with consideration of the limitations of available medical and educational resources.
doi:10.1007/s00431-013-2240-z
PMCID: PMC4032642  PMID: 24384789
22q11 deletion syndrome; Guidelines; Di George; Velocardiofacial; Congenital abnormalities; Resource management
24.  Neuroleptic malignant syndrome in an adolescent with CYP2D6 deficiency 
European Journal of Pediatrics  2013;173(12):1639-1642.
We describe a patient with dystonia and psychotic symptoms treated with standard doses of antipsychotics, who developed neuroleptic malignant syndrome (NMS). A 16-year-old male with a history of misuse of dextromethorphan and pseudoephedrine for recreational purpose presented with dystonia and a psychotic episode. Following continuous treatment with olanzapine (10 mg/day), repeated injections of levomepromazine (37.5 mg/day), and a single injection of haloperidol (2.5 mg), the patient developed NMS. Muscular rigidity, fever (up to 41 °C), hypotension (100/70 mmHg), tachycardia (120 beats per minute), tachypnea (26 breaths per minute), elevated leukocyte count (up to 16.6 × 103/μL), and elevated serum creatinine phosphokinase (CPK) (up to 15,255 U/L) were observed. A diagnosis of NMS was made according to the DSM-IV TR criteria. Genotyping revealed that he was homozygous for a non-functional CYP2D6*4 allele. The case highlights the importance of therapeutic drug monitoring in identification and differentiation of drug-induced effects in psychiatric disorder to prevent NMS and its complications. In addition, genotyping of CYP2D6 might be considered in patients with symptoms suggestive of drug toxicity who are treated with neuroleptics metabolized via the CYP2D6 pathway, as carriage of one or more non-functional alleles may increase the risk for adverse reactions, such as NMS.
doi:10.1007/s00431-013-2208-z
PMCID: PMC4245487  PMID: 24253372
Adverse drug reactions; Pharmacogenetics; CYP2D6; Poor metabolizer; Neuroleptic malignant syndrome
25.  Clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with febrile urinary tract infection 
European Journal of Pediatrics  2013;173(4):533-536.
Common pathogens of clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) are viruses, such as influenza virus. However, bacteria are rare pathogens for MERS. We report the first patient with MERS associated with febrile urinary tract infection. A 16-year-old lupus patient was admitted to our hospital. She had fever, headache, vomiting, and right back pain. Urinary analysis showed leukocyturia, and urinary culture identified Klebsiella pneumoniae. Cerebrospinal fluid examination and brain single-photon emission computed tomography showed no abnormalities. Therefore, she was diagnosed with febrile urinary tract infection. For further examinations, 99mTc-dimercaptosuccinic acid renal scintigraphy showed right cortical defects, and a voiding cystourethrogram demonstrated right vesicoureteral reflux (grade II). Therefore, she was diagnosed with right pyelonephritis. Although treatment with antibiotics administered intravenously improved the fever, laboratory findings, and right back pain, she had prolonged headaches, nausea, and vomiting. T2-weighted, diffusion-weighted, and fluid attenuated inversion recovery images in brain magnetic resonance imaging showed high intensity lesions in the splenium of the corpus callosum, which completely disappeared 1 week later. These results were compatible with MERS. To the best of our knowledge, our patient is the first patient who showed clinical features of MERS associated with febrile urinary tract infection. Conclusion: In patients with pyelonephritis and an atypical clinical course, such as prolonged headache, nausea, vomiting, and neurological disorders, the possibility of MERS should be considered.
doi:10.1007/s00431-013-2199-9
PMCID: PMC3951960  PMID: 24221606
Bacteria; Febrile urinary tract infection; MERS; Pyelonephritis; Systemic lupus erythematosus

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