PEDIATRIC CLINICS AMSTERDAM - dds.nlPEDIATRIC CLINICS AMSTERDAM Preface Welcome to the EKZ...

Symposium edition 2010

PEDIATRIC CLINICS AMSTERDAM

Preface

Welcome to the EKZ scientific symposium edition 2010!

We proudly present the abstract book of the 10th edition of the EKZ scientific symposium. For 10 years now this

excellent meeting has been a wonderful opportunity to be informed of the developments that take place in all

fields of basic and clinical science. It enables everyone to be inspired by looking outside one’s own field of inter-

est and to present one’s own research.

Last but not least, it is a great way to meet up with colleagues and start new collaborations in a relaxed atmos-

phere. Traditionally, the authors of the six most excellent abstracts will be invited to present their research in a

Masterclass on January 22. This year’s masters will be Prof.dr. H.S.A Heymans, Prof dr.H.P. Sauerwein, and Prof.

dr. H.M.Caron and Prof.dr. R de Groot. Poster prizes in different categories will be available for the three most

excellent and original posters. I hope the EKZ scientific symposium 2010 will bring you inspiration and new op-

portunities,

Annet M. Bosch

Editor in chief

Pediatric Clinics Amsterdam

is an edition from

Emma Kinderziekenhuis

AMC

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Editorial Board

A.M. Bosch (Editor in Chief)

H.D. Bakker

A.H. van Kaam

J.H.M. Merks

R.R. van Rijn

A.B. Sprikkelman

A.F.W. van der Steeg

J.B.M. van Woensel

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A.M. Bams-Mengerink1, J.H.T.M. Koelman2, M. Duran3,

B.T. Poll-The1

1 Department of Pediatrics and Pediatric Neurology, 2 Department

of Neurology, 3 Laboratory Genetic Metabolic Disorders, Emma

Children’s Hospital, Academic Medical Center Amsterdam, The

Netherlands, Meibergdreef 9 , 1105 AZ, Amsterdam, The Nether-

lands, e-mail:[email protected]

Background:

Rhizomelic chondrodysplasia punctata (RCDP) is a

peroxisomal disorder that is, amongst other important

clinical features, characterized by severe neurological

dysfunction. Milder phenotypes exist and the severity

of the clinical phenotype is reflected in plasmalogen

content of erythrocytes. Since over 80% of patients

with RCDP develop epileptic seizures and neurological

dysfunction is such an important feature of the dis-

ease, we were interested in the diagnostic and evalua-

tive role of EEG and evoked potential (EP) studies.

Methods:

We analysed neurophysiologic assessment in a cohort

of 16 patients with RCDP. The neurophysiology studies

were related to the severity of the phenotype.

Results:

4/16 had a mild phenotype and 12/16 had a severe

phenotype of RCDP. 10/16 patients developed epilep-

tic seizures and 12/16 patients had epileptic activity

on EEG. Epilepsy was seen in both milder and severe

phenotype patients. Visual evoked potential studies

(N=14) showed initial normal latency times in12/14

patients . Deterioration occurred in 3/7 patients in

whom follow up was performed (both mild and severe

phenotype). Brain auditory evoked potential studies

( N=13) showed initial normal latency times in 12/13

patients. Deterioration occurred in 5/8 patients (all

severe phenotype). Somato sensory evoked poten-

tials were performed in 10 patients. Absent cortical

responses were seen in 3/6 patients with the severe

phenotype.

Conclusion:

Epileptic seizures and epileptiform activity on EEG are

important features of both the mild and severe pheno-

types of RCDP and develop over time. EP studies do not

seem to reflect the severity of the clinical and biochemi-

cal phenotype and are thus of no diagnostic value.

P1

Neurophysiologic assessment in patients with rhizomelic chondrodysplasia punctata

Reinout A. Bem1, Job B.M. van Woensel1, Rene Lutter2, Joseph B.

Domachowske3, Jan Paul Medema4, Helene F. Rosenberg5, Albert

P. Bos1

1 Pediatric Intensive Care Unit, Emma Children’s Hospital AMC,

Amsterdam, The Netherlands; 2 Departments of Pulmonology

and Experimental Immunology, Academic Medical Center, Am-

sterdam, The Netherlands; 3 Department of Pediatrics, Upstate

Medical University, Syracuse, NY, USA; 4 Laboratory for Experi-

mental Oncology and Radiobiology, Academic Medical Center,

Amsterdam, The Netherlands; 5 Laboratory of Allergic Diseases,

National Institute of Allergy and Infectious Diseases, National

Institutes of Health, Bethesda, MD, USA.

Gants/funding: supported in part by Ars Donandi, Amsterdam.

H.F. Rosenberg supported by National Institute of Allergy and In-

fectious Diseases Division of Intramural Research (Z01-AI000943).

Correspondence: Reinout A. Bem, Emma Children’s Hospital,

Academic Medical Center, Pediatric Intensive Care Unit, P.O. Box

22660, 1100 DD, Amsterdam, The Netherlands, Tel: +31 20 5665769,

Fax: +31 20 6919338, E-mail: [email protected]

Introduction:

Lower respiratory tract infection by the human pneu-

movirus respiratory syncytial virus is a frequent cause

of acute lung injury in children. Severe pneumovirus

disease in humans is associated with activation of the

granzyme pathway by effector lymphocytes, which may

promote pathology by exaggerating pro-apoptotic cas-

pase activity and pro-inflammatory activity. The main

goal of this study was to determine whether granzymes

contribute to the development of acute lung injury in

pneumovirus-infected mice.

Method:

Granzyme-expressing mice and granzyme A, and

B-cluster single and double-gene deleted mice were

inoculated with the rodent pneumovirus pneumonia

virus of mice strain J3666, and were studied for mark-

ers of lung inflammation and injury.

Results:

Expression of granzyme A and B is detected in effector

lymphocytes in mouse lungs in response to pneumovi-

rus infection. Mice deficient for granzyme A and the

granzyme B-cluster have unchanged virus titers in the

lungs, but show a significantly delayed clinical response

to fatal pneumovirus infection, a feature that is associ-

ated with delayed neutrophil recruitment, diminished

activation of caspase-3 and reduced lung permeability.

Conclusion:

We conclude that granzyme A and B-cluster deficiency

delays the acute progression of pneumovirus disease by

reducing alveolar injury.

P2

Granzyme a and b-cluster deficiency delays acute lung injury in pneumovirus-infected mice

F.J. Berfelo1, T.R. de Haan2, P. Govaert3, G. van Wezel-Meijler4, B.T. Poll-The5, J.R.

Vermeulen6, F. Groenendaal7, L.S. de Vries7, C.H. van Ommen8

1Neurology, AMC, Amsterdam, 2Neonatology, Emma Children's Hospital AMC, Am-

sterdam, 3Neonatology, Sophia Children's Hospital/ Erasmus Medical Center, Rotter-

dam, 4Neonatology, Leiden University Medical Centre, Leiden, 5Paediatric Neurology,

Emma Children's Hospital AMC, Amsterdam, 6Paediatric Neurology, Free University

Medical Centre, Amsterdam, 7Neonatology, Wilhelmina Children's Hospital UMCU,

Utrecht, 8Pediatric Hematology, Emma Children's Hospital AMC, Amsterdam

Neonatal cerebral sinovenous thrombosis (CSVT) is increasingly diag-

nosed due to improved neuroimaging techniques. To evaluate the clini-

cal course, possible risk factors and outcome of neonates with CSVT and

secondly to estimate the incidence in The Netherlands, a multicenter

review of prospectively collected data on neonates with radiographi-

cally confirmed sinovenous thrombosis between 1999 and 2009 was

performed.

Fifty-two neonates [39 males, median gestational age 39 weeks (range

30-42, six preterm infants) from six Dutch tertiary centres were

included. A yearly incidence of 4.2 neonatal SVT cases/100.000 term

newborns was found. Most common presenting symptoms were seizures

(39/52) and apnoea (9/52). In 8/52 CSVT was a chance finding during

cerebral ultrasound in critically ill neonates. Maternal risk factors

like pre-eclampsia and infection were present in 13/52 neonates. The

most frequent perinatal risk factor was assisted or complicated delivery

(31/52). Postnatal risk factors included sepsis/meningitis (8/52) and

asphyxia (3/52). CSVT was suspected by doppler investigation in 19/52

neonates. Diagnosis was confirmed by MRI/MR-venography in all

patients. The superior sagittal sinus was most frequently involved. In

28/52 neonates multiple sinus were affected. Associated laesions were

(haemorrhagic) infarction (35/52), thalamic haemorrhage(24/52) and

intraventricular haemorrhage.

Anticoagulants were given to 23 neonates in whom no haemorrhagic

complications occurred. Eight neonates died due to CSVT. At follow-up

[median age 19 months (range 3 -72 months)] neurological sequelae were

moderate to severe in 20 patients. In conclusion, CSVT is a severe dis-

ease which usually presented with seizures or apnoea in term neonates

after a complicated or assisted delivery.

P3

Neonatal sinovenous thrombosis: clinical presentation, riskfactors, imaging results, outcome

P4

Fas-deficiency is deleterious in a murine model of rsv infectionElske van den Berg1,3, Reinout A. Bem1, Job B.M. van Woensel1, Albert P. Bos1, William

A. Altemeier3, Thomas R. Martin2 and Gustavo Matute-Bello3

1Pediatric ICU, Emma Children’s Hospital, Academic Medical Center, Amsterdam,

The Netherlands; 2VA Puget Sound Health Care System and 3Center for Lung Biology,

Division of Pulmonary and Critical Care Medicine,, University of Washington, Seattle,

Washington

Respiratory syncytial virus (RSV) is an important cause of morbidity in

infants. RSV infections are associated with neutrophilic inflammation

and epithelial cell apoptosis. Activation of the Fas/FasL system in the

lungs can induce neutrophilic inflammation and apoptosis. We hy-

pothesized that Fas-deficient mice (lpr) would be protected in a model

of RSV infection. Lpr and WT mice (C57BL/6) received intratracheal

instillations of the RSV analog, Pneumonia Virus of Mice (PVM). Eight

days later, the mice were subjected to 4 hours of mechanical ventila-

tion with Tv = 10 cc/kg, FiO2 = 0.21 and PEEP = 3 cm H2O. Contrary to

our expectations, the lpr mice had significantly higher mortality than

the WT mice (7/7 vs 3/7, p < 0.05). Because the increased mortality

prevented a direct comparison of lung injury markers, we repeated the

studies on day 7 after PVM instillation. On day 7, all the mice survived

for the duration of the experiments. Compared to WT mice (n = 7), lpr

mice (n = 7) showed decreased BALF neutrophils (15.3 vs 7.0 x 104 cells)

but similar whole lung myeloperoxidase activity (22.5 vs 19.4 mU/ml),

suggesting that neutrophil migration into the airspaces was impaired,

but recruitment into the lungs was preserved. Accordingly, the lpr mice

showed lower BALF concentrations of the chemokine KC (130.0 vs 338.5

pg/mL). The total BAL protein content, lung caspase-3 activity and total

viral load were similar in both groups of mice.

Conclusion:

As compared to WT mice, mechanically ventilated lpr mice have sig-

nificantly increased mortality 8 days after the instillation of PVM, and

this is preceded by an impairment in neutrophil migration into the

airspaces.

O.G. Besancon1, G.A.M Tytgat2, R. Leen1, A.C. Verschuur, H.N. Caron2, A.B.P. van

Kuilenburg1

Academic Medical Centre, University of Amsterdam, 1Laboratory Genetic and Meta-

bolic Diseases, 2Department of Pediatric Oncology, Amsterdam, The Netherlands

Introduction/ Background:

Neuroblastoma is a childhood tumor with a poor prognosis and there-

fore new therapeutical options are needed.

The PI3K/AKT/mTOR pathway is a potent survival-signaling pathway

that is aberrantly activated in a variety of human cancers

We investigated the efficacy of the PI3K/mTOR inhibitor PI-103 and

determined if inhibition of the PI3K/AKT/mTOR pathway sensitized

neuroblastoma cells towards currently applied chemotherapeutic

drugs.

Material and Methods:

Six human neuroblastoma cell lines, three MYCN amplified and three

MYCN single copy, were treated with topotecan, gemcitabine, cisplatin,

etoposide or doxorubicine alone or combined with 4hr preincubation of

PI-103 (80 nM or 400 nM).

The effect of PI-103 was studied in cells growing in monolayers and in

spheroids, a three dimensional tumor model and as such a model for

micrometastases.

Viability was measured using the MTS assay and dose-effect curves

were generated to perform multiple drug effect analysis. A combination

index (CI) < 1.1 indicates a synergistic/additive effect of the combina-

tion.

Results:

In all cell lines we observed a dose- and time-dependent decrease in

viability after treatment with

PI-103 or currently applied chemotherapeutics. PI-103 showed an

inhibiting effect on tumor-spheroids growth. A synergistic effect was

observed for most combinations, with the most pronounced effect for

the combination topotecan – PI-103 (figure 1)

Conclusion:

Our results showed that the combination of PI-103 with five currently

applied chemotherapeutic drugs has a synergistic effect with respect

to viability on most neuroblastoma cell lines and might therefore be a

promising new strategy in treatment of neuroblastoma.

P5

Promising effects of the drug combination pi-103 with currently applied chemotherapeutic drugs on neuroblastoma cell lines

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Schoot R.A.1 / Bleeker G.1, Heij H.A.2, van Eck B.L.F.3, Caron H.N.1,

de Kraker J.1

First two authors contributed equally to this abstract.1Department of Paediatric oncology, 2Department of Paediatric

Surgery, 3Department of Nuclear Medicine, Emma Children's Hos-

pital AMC, F8-239, Academic Medical Centre (AMC), University of

Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands.

Introduction:

In patients with localized non MYCN amplified neu-

roblastoma, observation only is justified. If organ or

life threatening symptoms arise, treatment is required.

Side effects should be minimal, since outcome is good.

Aim of this study was to evaluate response and outcome

of patients under these circumstances, when treated

with ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG).

Patients and Methods:

Between 1989 and 2008 21 patients with a localized

neuroblastoma were treated with ¹³¹I-MIBG (table 1).

Patients were treated if the primary tumour was un-

resectable and organ or life threatening. Fixed dosages

of ¹³¹I-MIBG (6-20 mCi/kg) were infused over two to

four hours, with an interval of four weeks. The median

number of infusions was 2 (range 1-7). Response was

graded according to the International Neuroblastoma

Response Criteria.

Results:

Minimal pretreatment was given to nine patients (sur-

gery or one cycle of chemotherapy), because of organ or

life threatening symptoms. These patients responded

insufficiently or showed return of tumour growth.

After 131I-MIBG treatment 8/21 tumours regressed.

Resection became possible in 13/21 patients. In 10/13

patients resection was macroscopically complete. Three

others had an incomplete resection. They had long-

term progression free survival. At the end of treatment

16/21 patients achieved complete response and 3/21 had

stable disease (2 very good partial response, 1 partial

response) (table 2). Two patients died; one of progres-

sive disease, one due to complications of surgery. One

patient was lost to follow-up. 10 years EFS was 72.4%,

10 year OS was 90.5%. Median follow-up was 7.5 years

(range 1 to 17.4).

Conclusion:131I-MIBG treatment is an effective treatment modal-

ity in unresectable localized neuroblastoma, in case of

organ or life threatening situations.

P6

The role of 131I-metaiodobenzylguanidine (131I-MIbG) therapy in unresectable and compromising localized neuroblastoma

Number (N=21):

Percentage (%):

Sex:

Male 8 38

Female 13 62

Age at diagnosis (years):

mean (range)

<1 year

1.6 (0-5.5)

9

INSS Stage:

1 4 19

2 3 14

3 14 67

Localization:

Neck 1 5

Thoracic 5 24

Abdominal 11 52

Pelvic 4 19

Reasons for ¹³¹I-MIBG:

organ relation 12 57

Intraspinal 7 33

progressive disease 2 10

Genetics:

MNA 2/18 11

1p LOH 1/18 6

Both 1/18 6

Pretreatment:

Chemotherapy 4 19

Surgery 4 19

Both 1 5

Table 1. Patient characteristics.

Table 2.

21 patien ts treated with 131 -I-MIBG

8: 131 -I-MIBG on ly

10: surge ry

3: chemo + surgery

MR PR CR VGPR PD NR

5 2 1

3

9 1

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Bleeker G.1, Caron H.N.1, de Kraker J.1, van Eck-Smit B.L.F.3,

Versteeg R.2, Tytgat G.A.M.1

1 Department of Pediatric Oncology, Emma Children's Hospital/

Academic Medical Centre2 Department of Human Genetics, Academic Medical Centre3 Department of Nuclear Medicine, Academic Medical Centre

Emma Children's Hospital AMC, F8-239, Academic Medical

Centre (AMC), University of Amsterdam, PO Box 22700, 1100 DE

Amsterdam, The Netherlands.

Background:

Neuroblastomas show a variable clinical course rang-

ing from spontaneous regression to high risk disease.

Probably, different patterns of tumour growth and

dissemination in these patients are a reflection of

distinct biological processes. The purpose of this pilot

study was 1. to identify these patterns on MIBG scans;

and 2. to test whether these patterns correlate with

gene expression clusters.

Methods:

All patients diagnosed with a neuroblastoma stage 4

from 1996 up till now were considered for this study.

Both a MIBG scan, as well as an Affymetrix gene

expression analysis of the primary tumour at the time

of diagnosis should be available (n=12). Two inde-

pendent observers evaluated the MIBG scans. Gene

expression data (affymetrix MAS5.0) of the primary

tumours, available in the bioinformatical program R2

of the department of Human Genetics, were used for

unsupervised hierarchical clustering of the 1500 most

diferentially expressed genes. Next we correlated the

gene clusters with the growth and dissemination pat-

terns on MIBG scans.

Results:

Unsupervised hierarchical clustering resulted in

two clusters (I and II) that correlated with different

growth and dissemination patterns on MIBG scans

(table 1). Cluster II showed more extensive dissemina-

tion than cluster I.

Conclusion:

Stage 4 neuroblastoma show different patterns of

tumour growth and dissemination on MIBG scans that

seem to correlate with gene expression clusters. An

extended cohort of all stages is needed to prove the

results of this pilot study. The ultimate goal of this

project is to identify biological processes that play a

role in these patterns.

P7

Patterns of tumour growth and dissemination on MIbG scans seem to correlate with gene expression data of stage 4 neuroblastoma tumours

Table 1. MIBG imaging trat is classified according to gene clusters I and II.1 X2 / Fisher test 2 Extension score per segment: 0: no uptake, 1: one lesion, 2: more than one lesion (<50% of segment),

3: massive involvement (>50% of segment),

BOS: base of skull; FBO: facial bones and orbita; RSCS: ribs, sternum, clavicula and scapula; VC: vertebral column; FAH: fore arms and

hands; MNA: MYCN amplification; 1pLOH: 1p loss of heterozygosity.

MIBG imaging trait: Cluster I (N=5):

Cluster II (N=7):

P1:

Cold node in primary tumour 5 3 0.081

FBO metastases 0 3 0.205

RSCS metastases 0 5 0.028

VC metastases 0 5 0.028

FAH metastases 0 3 0.205

Pelvis extension (>50%) 0 5 0.008

Upper legs extension (>50%) 0 5 0.018

Number of affected body segments 0-5 segments: 4

5-10 segments: 1 0-5 segments: 2

5-10 segments: 5 0.242

Extension of metastases within body segments (total score)2 <10: 4

>10: 1 <10: 2

>10: 5 0.242

MNA 4 1 0.072

1pLOH 5 2 0.028

Machtelt G. Bouwman1; Quirine G.A. Teunissen1; Frits A. Wijburg1; Gabor E.

Linthorst2

1 Division of Metabolic disorders, Emma Children’s Hospital, 2 Division of

Endoc rinology and Metabolism, Internal medicine,Academic Medical Center,

Amsterdam,The Netherlands.

Introduction:

Internet has resulted in widespread availability of medical informa-

tion and much time is spent on the Internet by patients searching for

diagnoses. Especially for rare diseases Internet can be an important tool

in the diagnostic process. We report two cases where parents diagnosed

a lysosomal storage disorder (LSD) in their child by searching the

Internet.

Case 1:

From the age of 5 years this boy had severe pains in hands and feet

during exercise and fever. In addition he had a skin rash. A diagnosis

could not be established by several pediatricians. At the age of 11 years

concerned parents initiated a search on ‘Google’ and rapidly found a

picture of skin rash in a Fabry patient and immediate recognized it as

similar to their child’s. Diagnosis was confirmed by enzymatic studies.

Case 2:

A boy failed his neonatal hearing-tests and had recurrent ENT-infec-

tions. At the age of 3 months a hydrocephalus was diagnosed. From the

age of 12 months parents noticed snoring, a kyphosis, changing facial

features, delayed cognitive development and bowed fingers. Consulted

paediatricians and a geneticist failed to establish a diagnosis. Finally

mother entered ‘bowed finger’ in ‘Google’ and recognized the facial fea-

tures of her child as typical for mucopolysaccharidosis type 1 (MPS-1).

Diagnosis of MPS I was confirmed.

Conclusion:

These cases illustrate the potential of Internet search-engines for

diagnosing rare disorders and illustrate the diagnostic odyssey which

is common in LSD’s. Physicians should consider ’Google’ as part of their

diagnostic strategy in rare disorders.

P8

‘Dr. Google’ ending the diagnostic odyssey in lysosomal storage disorders

Machtelt G. Bouwman1, Myra C.B. van Zwieten2, Gabor E. Linthorst3, Carla E.M.

Hollak3, Frits A. Wijburg1. 1 Division of Metabolic disorders, Emma Children’s Hospital, 2 Department of General

Practice/Medical Ethics, 3 Division of Endocrinology and Metabolism, Internal medi-

cine, Academic Medical Center, Amsterdam, The Netherlands

Background:

In the last decade, rapid technological advancements and new therapeu-

tic options have made newborn screening feasible for many disorders,

including Fabry disease (FD).

FD is an X-linked lysosomal storage disorder, caused by deficiency of

α-galactosidase A (α-Gal A). Accumulation of globotriaosylceramide

(Gb-3) results in renal, cardiac and neurological disease and reduced

life expectancy. Treatment with enzyme replacement therapy reduces

tissue Gb-3 and may stabilize renal disease and other disease features.

Recent studies suggest that early initiation of treatment might be more

efficacious. This observation has led to pilot studies investigating the

feasibility of newborn screening for FD. However, technical and ethical

issues need to be resolved.

Aim of the study:

The aim of this study is to explore experiences of patients with FD that

might be relevant to the current discussions on the pros and cons of in-

cluding FD in the expanded newborn screening programs. Through this

qualitative study approach we aim to enrich the decision making policy

on inclusion of FD in newborn screening programs.

Methods:

This study is a multiple case study, consisting of interviews, docu-

ment analysis and observations of patients with FD. The cases will be

purposively sampled from pre-defined subgroups of FD patients, to yield

an optimum set of relevant data. Semi structured interviews will be

performed, guided by a topic list.

P9

Ethical aspects of newborn screening for fabry disease: a multiple case study

Madeleine Bunders1,2, Chris van der Loos3, Steven Pals3, Taco Kuijpers1

1 Division of Pediatric Hematology, Immunology and Infectious diseases, 2 Dept of

Experimental Immunology, 3 Dept of Pathology, AMC, The Netherlands.

Background:

Every year 600.000 children are infected with HIV due to mother-to-

child-transmission (MTCT). However the route of transmission and resi-

dence of target cells for HIV in neonates remains unknown. The main

target cells for HIV are not present in cord blood. However secondary

lymphoid tissues may harbor a pool of resident memory T cells to offer

protection to imminent microbial exposure after birth and provide a

pool of target celsl for HIV.

Methods:

We performed immuno-histochemistry to identify memory T cells on

post-mortem gut tissues from four 4 neonates and compared these to

splenic tissue. Spectral imaging was used to analyze the images.

Results:

Three children were born prematurely, all died within 24 hrs after

birth and did not receive enteral feeding. In contrast to the blood

compartment, CD4+CCR5+ T cells were abundantly present (26.9%) in

neonatal gut epithelium. Additionally 19.6% of CD4+ T cells carried a

CD45RO phenotype. In the spleen only 3.1% of the CD4+ T cells expressed

CCR5+ and 10.5% of CD4+ T cells had a memory phenotype.

Conclusions:

Target cells for HIV present in the gut are easily accessible for HIV in

infants, which should be taken into account when developing strategies

to prevent MTCT. Furthermore, in contrast to the current paradigm, the

presence of T cells with a memory phenotype suggests that initiation of

memory development commences already during the fetal period.

R. Burgers1,2, O. Liem1,2, S. Canon2; M. Benninga1, H. Mousa2; S. Koff2, C. Di Lorenzo2

1 Emma Children's Hospital, Amsterdam Medical Center, Amsterdam, Netherlands;2 Nationwide Children's Hospital, Columbus, OH, USA

Background:

Although the association between constipation and urinary tract dys-

function in children is well established, the mechanisms underlying

this relationship are yet unknown.


Consecutive children with constipation and/or urology problems who

required urodynamic studies (UDS) for incontinence or infrequent void-

ing (< 4 times per day) were offered participation in the study. Patients

were assigned to a constipation and urology group or a urology-only

group. Definition of constipation was based on the pediatric Rome III

criteria. First, an UDS was performed according to standard protocol.

Secondly, an UDS was repeated simultaneously with pressure control-

led distension of a balloon in the rectum, using the electronic barostat.

Bladder capacity (BC), adjusted for age, and detrusor overactivity (DO)

were evaluated. A BC volume change of 30 ml or more was defined as

clinically relevant.

Results:

The final data set consisted of a total of 26 children (16 female, mean

age 7.8 years range 5-11); 20 in the combination group and 6 in the urol-

ogy-only group. At rest 16 children showed DO. Rectal balloon pressure

ranged between 6 - 39 mmHg. With inflation of the rectal balloon BC in-

creased (n=6), decreased (n=12) or did not change (n=8), three patients

showed new DO. No significant difference was found between children

with or without constipation, either in BC changes or DO appearance.

Conclusion:

This study shows that rectal distention has an unpredictable effect on

bladder capacity and detrusor overactivity in almost all children with

urology symptoms, with and without constipation.

P10

Memory T lymphocytes in the gut of newborns: target cells for neonatal HIV-infection

P11

Effect of rectal distention on bladder function

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P.M. van Brussel1, J. Ottenkamp1,2, C.M. Bilardo3, S.A. Clur1,2

1Department of Pediatric Cardiology Emma Children’s Hospital

Academic Medical Centre, Amsterdam, The Netherlands, 2Center

for Congenital Heart Disease Amsterdam-Leiden, The Nether-

lands, 3Department of Obstetrics and Gynaecology Academic

Medical Centre, Amsterdam, The Netherlands.

Background:

Fetal echocardiography allows for the early prenatal

diagnosis (PreDx) of cardiac defects .

Objectives:

To evaluate the accuracy of prenatal echocardiog-

raphy and counselling in the diagnosis of cardiac

defects.

Methods:

A retrospective study of fetuses referred for fetal

echocardiography between April 1999 and December

2008. The pre- and postnatal congenital heart disease

(CHD) diagnoses were recorded and scored using a

modified Aristotle (modA) score (Lacour-Gayet et al.

2004). The expected surgery (palliation/repair), opera-

tive complexity, repeated operations and co-morbidity

added to the score with a maximum of 25. The pre-

and postnatal scores were compared.

Results:

605 fetuses were examined. A normal heart was found

in 312(51,6%) and 293(48,4%) had cardiac pathology.

The cardiac diagnoses were; CHD in 234(79,95%), pri-

mary arrhythmia in 39(13,3%) and cardiomyopathy/

myocarditis/cardiac tumour in 20(6,8%). The most

frequent major CHD diagnoses were Hypoplastic LV

30(HLHS16, DORV8, AVSD 6), VSD28, AVSD 24, TGV 22,

Heterotaxia 17, Aorta and arch abnormalities 15, DORV

14, TOF 12(5 with PA), Hypoplastic RV 11, Ventricular

disproportion 8, DILV 6, Truncus arteriosus 4.

The average modA score was 8,4±5,4 prenatally and

8,4±5,5 postnatally. The pre- and postnatal scores

correlated well with an average difference of +1,1±4,0

between them.

In 42 fetuses the postnatal course differed from the

prenatal expectation, negatively in only 6. Suspected

aortic coarctation was the preDx in 10 of these 42

fetuses. 15 minor CHDs were missed.

Conclusions:

PreDx of cardiac defects was accurate and the counsel-

ling regarding expected postnatal course appropriate

in most cases except for aortic coarctation.



Academic Medical Centre, Amsterdam, The Netherlands, 2Center for

Congenital Heart Disease Amsterdam-Leiden, The Netherlands, 3De-

partment of Obstetrics and Gynaecology Academic Medical Centre,


Objective:

To evaluate the potential benefit of fetal echocardiogra-

phy in the prenatal diagnosis(PreDx) of cardiac defects.

Methods:


echocar dio graphy (April 1999- December 2008). The fetal

diagnosis was recorded. Congenital heart disease (CHD)

was categorized according to the availability of and

necessity for an intervention to improve outcome (Wald

and Kennard 1998).

Results:

605 fetuses were examined and 546 scored. There were

312(51,6%) normal hearts and 293(48,4%) with cardiac

pathology. The cardiac diagnoses were; CHD-234(79,9%),

primary arrhythmia-39(13,3%) and cardiomyopathy/myo-

carditis/cardiac tumour-20(6,8%).

The classification of CHD was as follows. A: Certain intra-

uterine/neonatal death 2(0,4%), B: Defect palliable but

disabling 39(7,1%), C: Defect not satisfactorily reparable

but in-utero therapy reduces morbidity 0, D: Evidence

lacking for postnatal survival benefit 59(25,1%), E: Defect

not serious enough to warrant preDx 49(22,1%), F: Defects

with proven improved prognosis with preDx 85(35,3%),

G: Normal heart 312.

PreDx was beneficial in:

1) Categories B, C and F, arrhythmias and cardiomyopa-

thies (183).

2) 203 fetuses with a normal heart without extracardiac

abnormalities as the parents were positively reas-

sured.

3) The CHD was diagnosed before 24 weeks’ gestation

(cut-off for legal pregnancy termination (TOP) in

395(65,3%). Karyotyping was performed in 413 and

was abnormal in 97(23,5%).TOP followed in 88(21,3%)

of which 25/88(28,4%) had a normal heart or where in

category A or D.

Conclusions:

PreDx for cardiac defects using echocardiography was

potentially beneficial in 67,9% (183+203+25=411/605) of

the fetuses seen.

Limitations:

The potential benefit/detrimental emotional effect of

preDx in the parents was not evaluated.

P12 Accuracy of prenatal diagnosis of congenital heart defects over a ten year period in a referral center

P13 beneficial effect of prenatal diagnosis of congenital heart defects; ten years in a referral center

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Academic Medical Centre, Amsterdam, The Netherlands, 2Center for

Congenital Heart Disease Amsterdam-Leiden, The Netherlands, 3De-

partment of Obstetrics and Gynaecology Academic Medical Centre,


Objectives:

To document the outcome of fetuses referred for

specialized fetal echocardiography.

Methods:


echocardiography (April 1999-December 2008). Fetal

diagnosis, karyoptye, management and outcome were

recorded. The cardiac diagnosis was scored using a modi-

fied Aristotle (modA) score (Lacour-Gayet et al. 2004)

and correlated with outcome.

Results:

605 fetuses were examined, 312(51,6%) had normal

hearts and 293(48,4%) had cardiac pathology inclu ding;

congenital heart disease (CHD)-234(79,9%), primary ar-

rhythmia-39(13,3%) and cardiomyopathy/myocarditis/

cardiac tumour (CMO)-20(6,1%).

The diagnosis was made before 24 weeks’ gestation

(cut-off for legal TOP) in 395(65,3%). TOP followed in 88

(39(44,2%) CHD and normal karyotype, 27(30,8%) CHD

and abnormal karyotype, 22(25%) no CHD).

413 fetuses were karyotyped. 97(23,5%) had kayrotypic

abnormalities and 58(59,8%) died, (pregnancy termina-

tion (TOP) in 40).

The mortality rates were; arrhythmia-3/39(7,7%), CMO

-7/20(35%) and CHD-114/235 (48,5%) (20,9% in those with

normal karyotype). A TOP was performed in 64(28,1%),

3 miscarried, 16 intrauterine deaths occurred and one

baby was stillborn. Comfort care(10) or a preoperative

death(7) occurred in 17(6,4%). 10/71 died after or during

an interventional heart catheterization or cardiac sur-

gery. 20/61(32,8%) babies surviving an intervention still

require cardiac medication. Three have pacemakers.

The average modA score of babies with CHD and normal

karyotype was 6,5±5,0 in the survivors and 12,1±3,8 in

those that died, (13,5±2,8 in those terminated).

Conclusions:

The referrals were appropriate (48,3% cardiac pathol-

ogy).The mortality was high in these high-risk fetuses.

The fetal outcome and the decision for TOP correlated

with the severity of the CHD.

Marieke van Dijk1, MSc; Marc A. Benninga2, MD PhD; Martha A.

Grootenhuis1, PhD; Bob F. Last1,3, PhD 1Psychosocial Department Emma Children’s Hospital/Academic

Medical Center, University of Amsterdam, Amsterdam, The

Netherlands2Department of Pediatric Gastroenterology and Nutrition Emma

Children’s Hospital/Academic Medical Center, University of

Amsterdam, Amsterdam, The Netherlands3Department of Developmental Psychology, Vrije Universiteit

Amsterdam, Amsterdam, The Netherlands

Introduction:

Behavior problems are common in children with func-

tional constipation. This study assessed the prevalence

of overall, internalizing and externalizing behavior

problems in children with functional constipation

and explored which clinical characteristics of consti-

pation are associated with these behavior problems.

Material and methods:

Children with functional constipation aged 4-18 years

referred to the gastrointestinal outpatient clinic at

the Emma Children’s Hospital were eligible for enrol-

ment. The current study made use from baseline data

of 133 children participating in a randomized control-

led trial evaluating the clinical effectiveness of be-

havioral therapy compared to conventional treatment.

Prevalence of behavior problems was assessed by the

Child Behavior Checklist (CBCL/4–18). Univariate and

multivariate logistic regression model were used to

test the association between clinical characteristics

and behavior problems.

Results:

The prevalence rate of overall, internalizing and

externalizing behavior problems was considerable:

respectively 36.8%, 36.1%, and 27.1% compared to 9%

in the Dutch norm population. A long duration of

treatment was found to have the strongest association

with overall and externalizing behavior problems in

constipated children. Constipated children with night-

time urinary incontinence have an increased risk of

having overall behavior problems. Fecal incontinence

and the production of large stools appeared to be ex-

clusively related to externalizing behavior problems.

Conclusion:

Behavior problems are common in children with

constipation referred to gastrointestinal outpatient

clinics implicating that a behavioral screening should

be incorporated in the diagnostic work-up of children

with constipation.

P14 Outcome of fetuses undergoing fetal echocardiography; ten years in a referral center

P15 The prevalence and associated clinical characteristics of behavior problems in children with functional constipation

C.L. Eckhardt1,2, J.G. van der Bom3, M. van der Naald1, M. Peters1, P.W. Kamphuisen2,

K. Fijnvandraat1

1Department of Pediatric Hematology, Emma Children’s Hospita/AMC, Amsterdam, 2Department of Vascular Medicine, AMC, Amsterdam, 3Department of Clinical Epide-

miology, LUMC, Leiden

Introduction:

The development of inhibiting factor VIII (FVIII) antibodies (inhibi-

tors) is the major complication in the treatment of hemophilia A. In-

hibitors compromise the management of bleeding symptoms, resulting

in a greater rate of complications, mortality and costs.

It has been suggested that surgery, with its attendant exposure to large

amounts of FVIII concentrates, is a risk factor for inhibitor develop-

ment. If the risk of surgical interventions in individual patients could

be predicted, clinicians would be able to adapt their management in

order to reduce the risk by preventive measures.

The purpose of this systematic review was to investigate the association

between surgery and inhibitor development in hemophilia A.

Methods:

A comprehensive search for randomized controlled trials, cohort studies

and case control studies was performed in Medline, Embase and the

Cochrane registry to identify studies in which hemophilia A patients

underwent surgery and inhibitor development was described.

Results:

Eighteen studies involving 2547 patients were included in this review.

Because of heterogeneity between the study populations, individual

data could not be pooled to perform a meta-analysis. Only five studies

were designed to investigate surgery as putative risk factor for inhibitor

development. In 3 studies adjusted relative risks for surgery were cal-

culated, ranging from 1.3 to 2.7 in severe hemophilia A and 186 in mild

patients. In the other two studies more than half of the patients who

underwent surgery developed an inhibitor.

Conclusion:

Available data suggest a potential relation between surgery and inhibi-

tor development, however there is limited good quality evidence that

supports this association.

C.L. Eckhardt1,2, M. Peters1, P.W. Kamphuisen2, K. Fijnvandraat1 1 Dept. of pediatric hematology, Emma Children’s hospital/AMC, Amsterdam, 2 Dept. of vascular medicine, AMC, Amsterdam

Introduction:

The development of inhibiting factor VIII [FVIII] antibodies [inhibitors]

is the most severe complication of the treatment with clothing factor

concentrates for hemophilia A. Inhibitors compromise the ability to

manage hemorrhage in affected individuals, resulting in a greater rate

of complications, costs and disability. Until now, research has focused

on inhibitors in severe hemophilia and neglected inhibitor development

in mild/moderate hemophilia A [MHA]. Since almost one third of the

newly diagnosed inhibitors occur in MHA, the clinical impact of this

problem is substantial.

The purpose of this international cohort study is to evaluate the in-

cidence of inhibitor development in MHA and to establish the source

population for a nested case-control study in which risk factors for

inhibitor development in MHA will be investigated.

Methods:

This retrospective cohort study included the clinical data of all con-

secutive MHA patients from 1-1-1980 to 1-7-2008 in twelve participat-

ing European centers. The outcome was clinically relevant inhibitor

development.

Results:

On October 1st 2009 the cohort yielded 509 MHA patients (median

FVIII:C 11 IU/dL) with a median age of 33 years (IQR, 13-55). Thirty-two

(6%, 95%CI 4.3-8.6) patients developed an inhibitor after a median of

27 (IQR, 20-35) exposures to FVIII. 55% of all non-inhibitor patients

(263/477) had less than 30 exposures and was therefore still at risk of

developing inhibitors. Inhibitor patients did not differ from non-inhibi-

tor patients regarding ethnicity and FVIII level.

Conclusion:

The incidence of inhibitor development in a large European cohort of

MHA patients was 6% during an observation period of 28 years.

P16

Is surgery a risk factor for inhibitor development in hemophilia A?

P17

Inhibitor development in mild/moderate hemophilia a: preliminary results of the insight study

Marc Engelen1, Bjorn van Geel1,4, Inge Dijkstra3, Mercan Akyüz3, Catherine E. van En-

gen3, Nellie Schutte-Lensink3, Ronald Wanders3, Marianne de Vissera, Stephan Kemp3

and Bwee Tien Poll-The2 1Departments of Neurology (a), 2Pediatric Neurology (b), 3Laboratory for Genetic

Metabolic Diseases (c), Academic Medical Center, University of Amsterdam, the

Netherlands. 4Department of Neurology (d), Medical Center Alkmaar, Alkmaar, the

Netherlands.

Introduction:

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder

caused by mutations in the ABCD1 gene. The clinical phenotype is well

described in men, but not in female carriers. It is known that heterozy-

gotes can develop symptoms, but to date, there has been no prospective

study to characterize the phenotype of X-ALD in women. The attention

of the medical community has been focused on boys and men with se-

vere symptoms, the mothers have been largely neglected. This informa-

tion is important to better inform women diagnosed with X-ALD about

the prognosis of their condition. The primary objective of the study is

to describe the phenotype of women with X-ALD. The secondary objec-

tive is to explain the phenotypic heterogeneity.

Methods:

All adult women with confirmed X-ALD were eligible to participate. All

participants visited the hospital once for: history and physical examina-

tion, quality of life assessment (SF-36), disability assessment (ALDS),

blood sampling, skin biopsy, electromyography and evoked potentials.

Results:

A total of 46 women were examined. For analyses women were divided

in age groups: 18 – 39 (I), 40 – 59 (II) and 60 – 79 years (III). History and

neurologic examination was abnormal in 36% (I), 85% (II) and 100% (III).

Biochemical analysis was performed and will be correlated to the clinical

data.

Conclusion:

A large proportion of women with X-ALD have signs and symptoms

attributable to X-ALD and signs of myelopathy are most prominent,

especially urinary and fecal incontinence. There is a strong correlation

between age and symptomatology. Most women also have detectable

abnormalities on biochemical assays and electrophysiological testing. A

correlation between biochemical abnormalities and clinical phenotype

is being investigated.

V. Engelen MSc1, H.M. Koopman PhD2, S.D. Detmar PhD3, M.D. van de Wetering PhD4,

P. Brons PhD5, R. Bredius PhD6, F. Abbink PhD7, M.A. Grootenhuis PhD1.1Academic Medical Centre / Emma Children’s Hospital, Paediatric Psychosocial

Department, Amsterdam; 2Leiden University Medical Center, Medical Psychology,

Leiden; 3TNO Prevention and Health, Leiden; 4Academic Medical Center/ Emma Chil-

dren’s Hospital, Paediatric Oncology Department, Amsterdam; 5Radboud University

Medical Center, Paediatric Oncology Department, Nijmegen; 6Leiden University Medi-

cal Center, Pediatric Oncology Department, Leiden, 7VU University Medical Center,

Amsterdam, Netherlands.

Introduction:

Health related quality of life (HRQOL) in children and adolescents with

cancer immediately after end of treatment, has only been studied to a

limited extend. We aimed to gain more insight in self-reported HRQOL

of children and adolescents that have recently finished cancer treat-

ment.

Methods:

As part of a multicenter intervention study (QLIC-ON), 157 children (8

to 11 years) and adolescents (12 to 18 years) with cancer were requested

to complete the Kidscreen-52 questionnaire, when 0-3 months off treat-

ment. Ninety-nine children and adolescents participated. Differences

in HRQOL between the patient and Dutch norm group were analysed by

one-sample t-tests and effect sizes (e.s.).

Results:

Children (N=26, M=9.4 years of age, 42.3% girls) and adolescents (N=65,

M=15.1 years of age, 52.3% girls) scored significantly lower on physi-

cal well-being compared to the norm population (respectively, M=48.26,

p<.01, e.s.=0.95 and M=43.63, p<.01, e.s.=0.72). In the child group

the mean score on psychological well-being was also significantly lower

(M=50.49, p<.05, e.s.=0.58) than the norm. Adolescents with cancer,

however, obtained significantly higher scores than their healthy peers

on five out of the other nine scales: moods and emotions (M=53.67, p<.05,

e.s.=0.34), parent relation and home life (M=57.46, p<.01, e.s.=0.55), school en-

vironment (M=54.40, p<.01, e.s.=0.43), bullying (M=51.95, p<.01, e.s.=0.31)

and financial resources (M=56.17, p<.01, e.s.=0.37).

Conclusions:

Children and adolescents with cancer immediately after end of treat-

ment experience a decreased physical well-being. Psychological well-being of

children is also affected. Although, overall, children and adolescents

seem resilient, we recommend physicians to monitor HRQOL to make

early detection of psychosocial problems possible.

P18

The clinical phenotype of x-linked adrenoleukodystrophy in women: a prospective cross-sectional clinical & biochemical study

P19

Health related quality of life of children and adolescents with cancer immediately after end of treatment

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F.A. Falix, V.B. Weeda, I.G. Gaemers, D.C. Aronson, W.H. Lamers

Introduction:

Hepatoblastoma (HB) is the most common pediat-

ric liver malignancy, but its pathogenesis remains

unclear. Five-year survival of children with HB is

now 75-80%, often due to unresponsiveness to chemo-

therapy. It is therefore unfortunate that an animal

model for HB to develop new treatment modalities is

not available.

The evolutionarily conserved Delta-Notch signaling

pathway regulates growth in several tissues during de-

velopment and shows altered expression in HB. Recent

data has shown that suppression of Notch receptor

signaling is associated with impaired growth control

of hepatocytes and cholangiocytes. In agreement, the

Notch ligand Delta-like-1 (Dlk1), a negative regulator

of Notch signaling, is highly expressed in HBs. How-

ever, transgenic mice with liver-specific overexpres-

sion of Dlk1, which have been generated in our group,

do not develop liver tumors. A possible explanation

could be that interference with the ligand does not

induce enough dysregulation of Notch signaling for

tumor formation to occur. Therefore, we hypothesize

that early, prenatal inactivation of Notch receptors

in the liver will affect hepatoblast proliferation and

eventually lead to hepatoblastoma.

Materials and methods:

We tested this hypothesis by generating transgenic

mice with liver-specific inactivation of the two rele-

vant Notch pathway receptors (Notch1 and -2) in hepa-

toblasts. (Alfp-Cre mice crossed with Notch1/2-Floxed

mice). The effects of Notch deficiency on hepatocyte

and cholangiocyte differentiation, proliferation and

tumor formation were assessed in postnatal mice.

Results:

Liverspecific knockout of the Notch1 receptor did not

lead to disturbed hepatocyte or cholangiocyte develop-

ment and did not affect liver proliferation. However,

liverspecific knockout of the Notch2 receptor led to

a severe phenotype with jaundice, growth retarda-

tion and complete absence of intrahepatic bile ducts

immediately after birth untill approximately 3 weeks

of age. At 6 weeks of age, knockout livers showed in-

creased hepatocyte proliferation, areas of extensive

necrosis and also early signs of cholangiocyte develop-

ment with a few mature bile ducts. At 6 months of

age knockout livers showed disturbed cholangiocyte

proliferation with a few dilated bile ducts, absence of

necrotic areas and signs of extensive fibrosis.

Conclusion:

Liverspecific knockout of Notch2 in mice leads to

absence of intrahepatic bile ducts prenatally and early

postnatally. These mice survive and show postna-

tal cholangiocyte differentiation with subsequent

bile duct formation in the absence of Notch2. The

responsible compensatory mechanisms are now being

investigated.

E.J. van de Griendt, Pediatrician MD1, O.H. van der Baan-Sloot-

weg, Pediatrician MD2, E.E.M. van Essen-Zandvliet, Pediatric

pulmonologist MD PhD2, J. van der Palen, Clinical Epidemiologist

PhD3, C.L.J. Tamminga-Smeulders, Research Nurse MSc2, M.A.

Benninga, Pediatric Gastroenterologist MD PhD4, W.M.C. van

Aalderen, Pediatric Pulmonologist MD PhD1 1Department of Pediatric Respiratory Medicine and Allergy,

Emma Children's Hospital, Academic Medical Centre, Amster-

dam, The Netherlands 2Department of Pediatrics, Asthma Centre Heideheuvel,

Hilversum, The Netherlands3Department of Epidemiology, Medisch Spectrum Twente, Ensch-

ede, The Netherlands and department of Research Methodology,

Measurement and Data Analysis, University Twente, Enschede4Department of Pediatric Gastroenterology, Emma Children’s

Hospital, Academic Medical Centre, Amsterdam, The Netherlands

Background:

Recent data suggest that obesity has a negative

influence on pulmonary function. However, effect of

weight loss on pulmonary function testing has not

been studied in obese children.

Aim: to evaluate lung function changes in extreme

obese children who significantly lost weight.

Methods:

Obese children participated in a 26 weeks in-hospital

or outpatient multidisciplinary treatment program.

The diagnosis of asthma was appointed after history

and reversible airflow limitation. Pulmonary func-

tion testing was performed at enrollment and after 6

months.

Results:

Data of 133 children were analyzed, mean age 14.4

years (range 8.5 – 18.9 years), 61.7% girls. Asthma was

present in 22 (16.5%) patients (girls 59.0%). Mean

weight at baseline was 109.64 kg (range 52.3 – 192.2 kg)

P21

Changes in lung function after weight reduction in severe obese children: a prospective uncontrolled study

P20

Notch2 regulates biliary development without affecting hepatocyte differentiation

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and after the intervention 96.26 kg (range 43.7 – 200.3

kg). At baseline the mean SDS-BMI score was +3.38

(range 2.50 – 4.62) and after the intervention +2.89

(range 1.67-4.79).

Lung function outcomes: δ FVC (difference between

baseline value and after the intervention) 3.31± 2.0%,

δ FEV1 2.97 ± 1.76%, δ TLC 2.27 ± 1.34% and δ ERV 13.3

± 5.65%. All these changes were statistically signifi-

cant. Only the increase in ERV correlated with the

reduction in SDS-BMI (Pearson correlation coefficient

of -0.220 (p = 0.026) (see table). In the Asthma group

similar results were found, although significance was

less strong, due to the small number of patients.

Conclusion:

Obstructive changes in pulmonary function are most

likely caused by the obstructing abdominal mass. This

study adds evidence for the co-incidence of (obstruc-

tive and non-obstructive) lung function changes in

the severe obesity, but does not add evidence for the

causal relation between obesity and asthma.

DeltaSDSBMI

0,500,00-0,50-1,00-1,50

30,00

20,00

10,00

0,00

-10,00

-20,00

-30,00

R Sq Linear = 1,06E-4

DeltaSDSBMI

0,500,00-0,50-1,00-1,50

75,00

50,00

25,00

0,00

-25,00

-50,00

R Sq Linear = 0,049

Del

taF

EV

1pct

Pre

dD

elta

ER

Vp

ctP

red

1A.

1B.

Figure 1a. Absence of correlation in difference of SDS body mass

index (DeltaSDS-BMI) and difference FEV1 in forced expiratoy

volume in 1 second %predicted (DeltaFEV1pctpred).

Figure 1b. Obvious correlation of difference of SDS body mass

index (DeltaSDS-BMI) and difference in expiratory reserve volume

(DeltaERVpctpred).

Heynric B. Grotenhuis1, Jaap Ottenkamp1, Liesbeth de Bruijn1, Jos

J.M. Westenberg2, Hubert W. Vliegen3, Lucia J.M. Kroft2, Albert

de Roos2.

Afdeling kindercardiologie, AMC/LUMC1, Afdeling radiologie,

LUMC2, Afdeling cardiologie, LUMC3

Introduction/background:

Aortic wall pathology and concomitant aortic dilata-

tion have been described in tetralogy of Fallot (TOF)

patients, which may negatively affect aortic valve and

left ventricular (LV) systolic function. The objectives

of the current study were therefore to assess aortic

dimensions, aortic elasticity, aortic valve competence

and biventricular function in repaired TOF patients

after pulmonary valve replacement (PVR) by using

magnetic resonance imaging (MRI).


MRI was performed in 16 patients with TOF after PVR

(10 male; mean age±standard deviation: 31years±15)

and 16 age- and gender matched healthy subjects.

Results:

TOF patients showed aortic root dilatation (mean dif-

ference 7.8-8.8mm, P<0.01 at all 4 predefined levels)

(Figure 1) and reduced aortic elasticity (pulse wave

velocity in aortic arch: 5.5m/s±1.2 vs. 4.6m/s±0.9,

P=0.04; aortic root distensibility: 1.4*10-3mmHg-1 ±

1.7 vs. 5.7*10-3 mmHg-1±3.6,P<0.01). Minor degrees of

aortic regurgitation (AR) (AR fraction 6%±8 vs. 1%±1,

P<0.01) (Figure 2) and reduced LV ejection fraction

were present (51%±8 vs. 58%±6, P=0.01), whereas right

ventricular (RV) ejection fraction was within normal

limits (47%±8 vs. 52%±7, P=0.06). Degree of AR frac-

tion was associated with dilatation of the aortic root

(r=0.39-0.49, P<0.05) and reduced aortic root disten-

sibility (r=0.44, P=0.02), while reduced LV ejection

fraction was correlated with degree of AR and RV

ejection fraction (r=0.41, P=0.02, and r=0.49, P<0.01,

respectively).

Conclusions:

Aortic root dilatation and reduced aortic elasticity are

frequently present in patients with TOF, in addition to

minor degrees of AR and reduced LV systolic function.

Aortic wall pathology in repaired TOF patients may

therefore represent a separate mechanism leading to

LV dysfunction, in addition to possible adverse right-

to-left ventricular interaction.

P22

Aortic elasticity and size are associated with aortic regurgitation and left ventricular dysfunction in tetralogy of Fallot after pulmonary valve replacement

Kirsten van Ham, medical student1, A.C. Knottnerus1, A.P. Cohen2, E. Kohnhorst2,

M. Strijbos2, H.H.F. Derkx1, Y.Q. Jagt, medical student.1 Emma Kinderziekenhuis AMC Amsterdam; 2 De Bascule, Amsterdam

Introduction/background:

The relationship between Medically Unexplained Symptoms (MUS) and

psychiatric disorders has often been reported in literature. For exam-

ple: there is a broad consensus about the fact that psychiatric disorders

are often present in patients with functional Gastro Intestinal(GI)-tract

syndroms. (Mayer e.a., 2001).

Emotional dysregulation (ED) refers to an emotional response that is

poorly modulated, not falling within the conventionally accepted range

of emotional response. This could result in a DSM-IV classified psychiat-

ric disorder, or might be more delicate such as depressive feelings, mood

fluctuations, or obsessive thoughts.

The question arises whether there is also a more general relation be-

tween emotional dysregulation and MUS in our patient population.

Materials and methods:

The charts of patients with GI-tract problems (nausea, vomiting and

defecation problems) (14 patients) and abdominal pain (ap) (43 patients)

as primary complaints visiting the Psy Med Unit (PMU) (a tertiary re-

ferral centre for invalidating, therapy resistant functional complaints)

were evaluated for the incidence of ED in the patients and their close

relatives (brothers, sisters or parents).

Results:

See table

Conclusion:

There seems to be a correlation between the MUS and ED, as we ex-

pected. This confirms the statement that you cannot divide body and

mind. A considerable amount of the children has a relative with ED as

well. General emotional regulation, genetics and family circumstances

might therefore be of importance in the pathogenesis of MUS.

P23

Is there a high incidence of emotional dysregulation in patients with medically unexplained symptoms?

ED in ap pt group (43 pt) ED in GI-tract problems

pt group (14pt)

Patients 12 (28%) 7 (50%)

Relatives 16 (37%) 5 (36%)

Table. Results.

P24

At risk: health related quality of life in children and adolescents with jIAL. Haverman1, M.A.J. van Rossum2,3, T.W. Kuijpers2, J.M. van den Berg2,3, M. van

Veenendaal2, K.M. Dolman3,4, J. Swart3,5, M.A. Grootenhuis1

1 Academic Medical Centre / Emma Children’s Hospital, Pediatric Psychosocial

Department, Amsterdam, 2 Academic Medical Centre / Emma Children’s Hospital,

Pediatric Rheumatology, Amsterdam, 3 Jan van Breemen Institute, Amsterdam, 4 Sint

Lucas Andreas Hospital, Amsterdam, 5 VU Medical Center, Amsterdam

Introduction:

In the Netherlands the estimated prevalence of children with Juvenile

Idiopathic Arthritis (JIA) is 3000 - 4000 children with yearly 300 new

patients. Research on Quality of Life (QoL) of these children, however,

is lacking behind. The purpose of this study is to investigate QoL of

children with JIA.


This study is part of the KLIK study, which assesses the effect of iden-

tifying and discussing QoL problems using Patient Reported Outcomes

(PROs). The study sample includes all children (8-18 years) visiting the

rheumatologist at four different hospitals in Amsterdam. Patients were

invited to complete questionnaires online, at home, before visiting the

rheumatologist. QoL was measured using the Pediatric Quality of Life

Inventory 4.0 (Pedsql 4.0), which assesses four domains of QoL; physi-

cal, emotional, social and school. The study sample was compared with

healthy sample and a chronic ill condition sample (Engelen, et al. 2009)

using one sample t-tests. In addition, effect sizes were calculated. Data

collection will continue until January 2010.

Results:

Approximately 70% of the patients participated (n=123). Data of 57

children aged 8-12 years (m = 10,8 years) and 66 adolescents aged 13-18

years (m = 15,9 years) were available. Both children with JIA as well as

adolescents differed on almost all domains significantly with healthy

controls and children with a chronic ill condition. Effect sizes were

moderate to large, with the exception of emotional functioning (table

1).

Conclusions:

QoL is severely affected in children and adolescents with JIA. Specific

limitations of this group seem to influence their QoL. These findings

underline the need to systematically pay attention to QoL in clinical

practice and to investigate the effectiveness of QoL feedback to the

pediatric rheumatologist.

Referentie:

Engelen V, Haentjens MM, Detmar SB, Koopman HM, Grootenhuis MA:

Health related quality of life of Dutch children: psychometric proper-

ties of the PedsQL in the Netherlands. BMC Pediatrics. In press.

[see table]

L. Haverman, V. Engelen, M.A.J. van Rossum, H.N. Caron, T.W. Kuijpers, H.S.A.

Heymans, M.A. Grootenhuis

Aims:

Children with a chronic illness can experience quality of life (QoL)

problems. These problems are usually not systematically checked by

the pediatrician. Two multicenter sequential cohort studies (QLIC-ON

& KLIK), measured the effect of the use of Patient Reported Outcomes

(PROs) about QoL in clinical pediatric practice.

Methods:

Participants are children with cancer immediately after end of treat-

ment (QLIC-ON) or with Juvenile Idiopathic Arthritis (KLIK). Before

the consultation with the pediatrician, the child (8-18 years) or parent

(0-8 years) completes a digital QoL questionnaire. The outcome (PROfile)

is presented to the pediatrician, parent and child of the intervention

group, to help identify and discuss possible QoL problems. To optimize

the effect of the PROfile pediatricians receive training using cases on

DVD. Preliminary results in terms of evaluation and satisfaction are

presented.

Results:

Approximately 95% of the parents thought the PROfile correctly repre-

sented the child’s QoL. About 80% of the parents considered the PROfile

as a useful addition to standard health care, also for the future (80%)

(Table 1). Moreover, pediatricians are significantly more satisfied about

the consultations in the intervention group compared to the control

group (p<0.01).

Conclusions:

The results are promising. Parents and pediatricians are positive about

the use of the PROfile in clinical practice. The PROfile can be used for

different patient groups and also by different users (e.g. psychologists,

nurses or social workers). With the use of internet (www.hetklikt.nu)

the PROfile is easy to implement in clinical practice and helpful in

facilitating communication about QoL.

Who wants to profit next?

Interested?

Log in as a pediatrician on www.hetklikt.nu with ‘PRO’ as username

and ‘KLIK’ as password and see a demo.

Subscale N Mean SD N Mean SD N Mean SD

Group 8-12 192 26 15

Total score 82.31 8.83 80.64 9.32 74.86* 12.75

Physical health 85.25 8.85 82.21 12.14 74.58 20.07

Psychosocial health 80.75 10.34 79.81 10.43 75.00 11.25

Emotional functioning 76.85 13.76 78.85 13.21 73.67 14.07

Social functioning 86.51 12.24 83.27 12.80 81.33 11.87

School functioning 78.88 11.90 77.31 13.13 70.00 19.27

Group 13-18 148 25 38

Total score 83.14 8.99 77.09 9.40 67.11**^^ 17.07

Physical health 86.76 9.21 81.00 12.00 63.24**^^ 25.32

Psychosocial health 81.21 10.22 75.00 9.56 69.17**^ 14.92

Emotional functioning 77.53 15.01 71.40 16.62 68.86* 21.82

Social functioning 90.14 11.37 83.40 12.97 79.87** 13.63

School functioning 75.95 12.68 70.20 15.17 58.81**^^ 20.22

Healthy sample Chronic illness JIA sample

Table 1. QoL scores on the Pedsql of a healthy sample, a chronic ill condition sample and a JIA sample.

JIA vs. Healthy sample (ES)

0.85

1.21

0.56

0.2

0.42

0.75

1.78

1.35

*Significant p < .05 compare to healthy sample, **Significant p < .01 compare to healthy sample^Significant p < .05 compare to chronic illness sample, ^^Significant p < .01 compare to chronic illness sample

2.56

1.18

0.58

0.90

P25

Patient reported outcomes (pro’s) in clinical practice: who will profit next?

QLIC-ON KLIK QLIC-ON KLIK

n = 57 n = 49 n = 68 n = 80

Useful 74% 84% 63% 94%

Unnecessary 30% 10% 44% 3%

Clarifying 54% 67% 57% 89%

Practical 63% 78% 59% 91%

Emotional 5% 10% 3% 6%

Unpleasent 7% 0% 3% 5%

Pediatric ianParents

Table 1: Evaluation of the PROfile.

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Maaike van der Heide, Paul Keating, Jacorina van Hoften,

Sebastiaan Mastenbroek, Moniek Twisk, Arend F. Bos, Jan

Maarten Cobben, Joke Kok

Department of neonatology EKZ/AMC, Amsterdam and depart-

ment of Neonatology Beatrix kinderkliniek UMCG Groningen,

Reproductive medicine AMC, Amsterdam

Background:

Pre-implantation genetic screening (PGS) can be used

to detect aneuploidies after embryo biopsy.

In a multicenter trial 408 women 35 through 41 years

of age undergoing IVF / ICSI were randomized for PGS

(n=206) to detect aneuploidies before embryo transfer

or no PGS (n=202). The primary endpoint of the trial

was the number of ungoing pregnancies at 12 weeks

gestation. Significantly more women had an ongoing

pregnancy in the no PGS group (37% vs 25%).

Patients and methods:

In the ongoing pregnancies surviving children were

followed until the age of 2 years. Perinatal data were

obtained from obstetricians or midwives after birth.

At 2 years of age children were examined for morpho-

logical abnormalities using the Amsterdam Morphol-

ogy scale. Other clinical abnormalities were obtained

from history.

Results:

144 children were born alive, 2 died shortly after

birth. 54 children in the PGS+ group (of which 9

twins) and 77 in the PGS – group (14 twins) were

examined at 2 years of age, 3 were lost to follow up in

PGS + and 8 in the PGS – group. Basic characteristics

and the number of morphological abnormalities in

both groups are given in the table. No differences

were found between the groups in morphological

abnormalities.

Conclusion:

The number of morphological abnormalities found in

children following a PGS procedure after ICF or ICSI

as studied by the Amsterdam Morphology Scale is not

significant different from children born after IVF or

ICSI alone. The PGS procedure seems to have no effect

on phenotypic development.

P26

Morphological abnormalities in children born after Pre Implantation Genetic Screening in a multicenter trial of IVF /ICSI with and without PGS

Table.

Children PGS + (N=54) Children PGS - (N=77)

Gestational age (weeks) 38,8 (±2,6) 37,7 (±2,8)

Birth weight (gram) 3264 (±710) 3028 (±736)

Short stature 5,6%(N=3) 3,9%(N=3)

Trigonocephaly - 1,3%(N=1)

Generalized hypopigmentation hair - 1,3%(N=1)

Iris (coloboma/hypopigmentation) 1,9%(N=1) 2,6%(N=2)

Lens (Size/shape abnormality) 1,9%(N=1) -

Hernia inguinalis - 1,3%(N=1)

Syndactyly toes II-III - 3,9%(N=3)

Ear (pits, tags, cupshaped) 5,6% (N=3) 3,9% (N=3)

Clefts (upper jaw, lower lip, palate) 1,9% (N=1) 5,2% (N=4)

Café au lait (multiple) 1,9% (N=1) 1,3% (N=1)

Hemangioma 7,5% (N=4) 9,1%(N=7)

Hypermobility joints 5,6% (N=3) 1,3% (N=1)

Extra nipples 1,9% (N=1) -

Syndrome 1,9% (N=1) -

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Channa T. Hijmans1,2, Karin Fijnvandraat2, Martha A. Grooten-

huis1, Nan van Geloven3, Harriët Heijboer2, Marjolein Peters2,

and Jaap Oosterlaan4

1Psychosocial Department, Emma Children’s Hospital, Academic

Medical Center, Amsterdam, The Netherlands; 2Department

of Pediatric Hematology, Emma Children’s Hospital, Academic

Medical Center, Amsterdam, The Netherlands; 3Department of

Clinical Epidemiology, Biostatistics and Bioinformatics, Academic


Clinical Neuropsychology, VU University Amsterdam, Amster-

dam, The Netherlands

Background:

Although sickle cell disease (SCD) is increasingly

prevalent in children living in Western Europe and

can lead to profound cerebral damage, European stud-

ies on the neurocognitive consequences are scarce. The

aim of this study was to investigate neurocognitive

functioning of children with SCD living in the Nether-

lands, compared to healthy siblings.


Forty-one children with homozygous SCD (HbSS or

HbS-β0-thalassemia) and 36 healthy siblings were

assessed on a comprehensive set of well-defined and

validated measures of neurocognitive functions. These

included general intelligence, response inhibition,

sustained attention, planning, visuo-spatial and ver-

bal working memory, and visuo-motor functioning.

Results:

SCD was associated with lower intelligence and poor

performance on measures of visuo-spatial working

memory and visuo-motor functioning. Some evidence

was found for lower levels of sustained attention

and planning. No significant differences were found

between children with SCD and healthy siblings in

terms of response inhibition and verbal working

memory.

Conclusions:

Children with SCD are at increased risk of specific

neurocognitive deficits. Such deficits may underlie

high rates of scholastic impairments and both behav-

ioral and emotional problems in these children. These

findings further illuminate the importance of regular

neurocognitive evaluations in children with SCD in

daily clinical practice.

Channa T. Hijmans1,2, Karin Fijnvandraat2, Jaap Oosterlaan3,

Harriët Heijboer2, Marjolein Peters2 and Martha A. Grootenhuis1

1Psychosocial Department, Emma Children’s Hospital, Academic


Pediatric Hematology, Emma Children’s Hospital, Academic Medi-

cal Center, Amsterdam, The Netherlands; 3Department of Clinical

Neuropsychology, VU University Amsterdam, Amsterdam, The

Netherlands

Background:

Low health-related quality of life (HRQoL) of children

with sickle cell disease (SCD) may be associated with

disease factors, or socio-demographic factors. The aim

of this study was to investigate the HRQoL of children

with SCD compared to healthy siblings (matched on

age, gender, ethnicity and socio-economic status), and

to a Dutch norm population.


The HRQoL of 40 children with homozygous SCD and 36

healthy siblings was evaluated by the KIDSCREEN-52.

This self-report questionnaire assesses ten domains of

HRQoL: Physical well-being, Psychological well-being,

Moods and emotions, Self perception, Autonomy, Parent

relations, Financial resources, Peers, School environ-

ment, and Bullying. Differences between children with

SCD and healthy siblings were analyzed using linear

mixed models. One-sample t-tests were used to analyze

differences with the Dutch norm population.

Results:

Young children with SCD and healthy siblings (aged

6-11) had comparable HRQoL, apart from somewhat

lower scores on Physical well being. Compared to the

Dutch norm population, young children with SCD had

significantly lower HRQoL on 7 domains. Adolescents

with SCD had a significantly lower HRQoL on Autono-

my compared to both healthy siblings and the Dutch

norm population. Trends were found for a lower HRQoL

of adolescents with SCD on 5 domains, compared to the

Dutch norm population.

Conclusions:

Children with SCD generally experience lower HRQoL

than the Dutch norm population, which mainly seems

to be associated with socio-demographic factors.

However, the low HRQoL on Autonomy, as reported

by adolescents with SCD, seems to be associated with

disease factors.

P27

Neurocognitive deficits in children with sickle cell disease: a comparison with healthy siblings

P28

Health-related quality of life of children with sickle cell disease and healthy siblings

A.E. ten Hoedt1, L.M. de Sonneville2, B. Francois3, N.M. ter Horst4, M.C.H. Janssen5,

M.E. Rubio-Gozalbo6, N.G. Abeling7, F.A. Wijburg1, C.E. Hollak8, A.M. Bosch1

1department of pediatrics, Academic Medical Center, university of Amsterdam, Am-

sterdam; the Netherlands, 2department of clinical neuropsychology, Leiden University

Medical Center, Leiden; the Netherlands, 3department of metabolic diseases, Centrum

Pinocchio, Diepenbeek; Belgium, 4department of dietetics, Academic Medical Center,

university of Amsterdam, Amsterdam; the Netherlands, 5department of internal

medicine, Radboud University Medical Centre, 6department of pediatrics, Maastricht

University Medical Center, Maastricht, the Netherlands, 7laboratory of genetic meta-

bolic disease, Academic Medical Center, university of Amsterdam, Amsterdam; the

Netherlands, 8department of internal medicine, Academic Medical Center, university

of Amsterdam, Amsterdam; the Netherlands

Introduction:

Phenylketonuria (PKU) is an autosomal recessive disorder of pheny-

lalanine (Phe) metabolism. Intellectual disability and neurological

sequelae are prevented with early initiation of a Phe-restricted diet and

amino acid supplementation. Currently, there is much debate whether

this strict and socially invalidating diet is necessary for adults. Aim of

our study is to evaluate the effects of short term elevation of Phe levels

on neuropsychological functions and wellbeing of adults with PKU.

Methods:

9 continuously treated adults with PKU participated in a double blind

randomized crossover trial. During two 4 week periods, patients used

either placebo or Phe as a supplement to their diet. The amount of sup-

plemented Phe was individually calculated to reach a normal intake

for a healthy adult. Each study period patients underwent neuropsy-

chological tests, and both patients and one significant other completed

a weekly questionnaire evaluating the patients’ mood and wellbeing

(Profile of mood states: POMS). Phe levels were measured twice every

week during both study periods.

Results:

Phe levels were significantly higher during Phe supplementation than

during the placebo phase. Neuropsychological tests demonstrated a

significant impairment in sustained attention at the time of high Phe

levels. Furthermore, both patients and their significant other reported

a significant lower score on the POMS questionnaire at the time of high

Phe levels.

Conclusion:

High Phe levels have a direct and negative effect on both neuropsy-

chological performance as well as mood of adult patients with PKU.

Therefore, a Phe restricted “diet for life” should be advised for adults

with phenylketonuria.

Sander M. Houten1,2, Cory Wagg3, Heleen te Brinke1, Ronald J.A. Wanders1,2, Gary D.

Lopaschuk3

Department of 1Clinical Chemistry, Laboratory Genetic Metabolic Diseases and 2Department of Pediatrics, Emma Children's Hospital, AMC; 3Departments of Pedi-

atrics and Pharmacology, Heritage Medical Research Center, University of Alberta,

Edmonton, Canada

Introduction:

Inherited defects of mitochondrial long chain fatty acid oxidation (FAO)

such as very long chain acyl-CoA dehydrogenase (VLCAD) deficiency

may present with cardiomyopathy and arrhythmias. The pathophysi-

ology of these cardiac symptoms is poorly understood and rational

therapeutic strategies are lacking. The LCAD KO mouse reproduces

many aspects of human long chain FAO defects. In mice, LCAD plays

an important role in the oxidation of unsaturated fatty acids. LCAD

KO mice display fasting-induced fatty liver with a marked hypoketotic

hypoglycemia. Moreover, LCAD KO mice have a non-progressive heart

hypertrophy (26% at 2 months and 23% at 6 months of age), but expres-

sion of molecular markers for cardiomyopathy such ANF and β-MHC is

not increased.

Methods:

We determined whether LCAD KO mice have alterations in cardiac en-

ergy metabolism using isolated working heart perfusions.

Results:

Hearts from LCAD KO mice functioned normally during 30 minutes of

low workload, but also during a 30 minute period of increased workload

and pacing. Remarkably, palmitate as well as oleate oxidation was in-

creased in LCAD KO hearts, with a parallel decrease in glucose oxidation

rates. Expression analysis of LCAD KO hearts revealed elevated PDK4,

PGC-1α and UCP3 levels and normal VLCAD, ACC and MCD levels.

Conclusion:

Our results suggest that a defect in LCAD does not lead to a decrease in

FAO, but rather leads to decreased glucose oxidation as a consequence of

changes at the level of pyruvate dehydrogenase activity.

P29

High phenylalanine levels directly affect mood and performance in adults with Phenylketonuria

P30

Increased fatty acid oxidation in long chain acyl-coa dehydrogenase-deficient hearts

G.J. Hutten1,2, L.A van Eykern1, P. Latzin2, U. Frey2, W.M.C van Aalderen1

1Department of Paediatrics Pulmonology, Emma Children’s Hospital, University of

Amsterdam, Netherlands, 2Department of Respiratory Medicine, University Children’s Hospital of Bern, Switzer-

land

Rationale:

Wheeze is a common symptom during infancy and the treatment of

wheezy infants with bronchodilators remains controversial. We hypoth-

esise that administration of β2-agonist may lead to differences in the

relationship between respiratory muscle activity (rEMG), flow pattern

and lung volume.

Methods:

Simultaneous measurements of lung function and transcutaneous rEMG

were performed in 25 sedated infants with recurrent wheeze before and

after inhalation of β2-agonist. We compared the coefficient of variation

(CV) of rEMG and its temporal relationship to flow and lung volume (FRC

before and after inhalation of β2-agonist).

Results:

The time delay between start of inspiratory muscle activity and resulting

flow (tria) in relation to respiratory cycle time was significantly shorter

after administration of the inhaled β2-agonist. The breath to breath vari-

ability (CV) of the diaphragm was significantly increased after inhala-

tion of the β2-agonist. Although FRC remained unchanged, tidal volume

increased significantly after administration of the β2-agonist.

Conclusion:

The temporal relationship of rEMG to flow and the profit of adaptive

breath to breath variability provide additional information on the

response of wheezy infants to inhaled β2-agonist, which becomes not

obvious from lung function measurements alone. Thus, non-invasive

combined rEMG and tidal flow measurements could be a potential new

technique to assess bronchodilator response in a bedside manner.

P31

Response to 2-agonist of respiratory muscle activity, flow and lung volume in wheezy infants

P32

Are there major differences in the severity of invalidation between the patient groups with headaches and abdominal pain as primary complaint?Y.Q. Jagt medical student1, A.C. Knottnerus1, A.P. Cohen2, E. Kohnhorst2,

M. Strijbos2, H.H.F. Derkx1

1Emma Kinderziekenhuis AMC; 2De Bascule, Amsterdam

Introduction:

Psy Med Unit (PMU), Emma Children’s hospital, Amsterdam, is a

tertiary referral centre for children with severe long-lasting therapy

resistant functional complaints. The question arose if there were major

differences in the severity of invalidation between patients with ab-

dominal pain (ap) and headache as primary complaint before and after

treatment.

Methods:

retrospective observational study of consecutive patients with ap and

headache as primary complaint. Charts of patients were evaluated

for severity of invalidation; school absenteeism, given up hobbies and

state of social lives before and after treatment at PMU. Duration of

complaints before treatment, duration of treatment and amount of

complaints after treatment were included.

Results:

Conclusions:

Before treatment; patients with headache as primary complaint had

complaints for longer than 2 years in 63% comparing to 37% in patients

with ap. Patients with ap seemed more invalidated concerning school

absenteeism and their hobbies. The suggestion could be made that the

duration of the complaints had no leading influence on the degree of

invalidation.

After treatment; patients with headache more often seemed to have no

or less complaints after treatment. This suggests that for the treatment

to be effective, the duration of the complaints does not play a leading

role.

It looked like more patients with ap still had >80% school absenteeism,

no hobbies and no social life and less often no or less complaints. The

hypothesis could be made that the patients with ap were more invali-

dated before and therefore more difficult to treat.

Before treatment Abdominal pain Headache

Number of patients 43 32

Duration of complaints longer than 2 years

37% 63%

>80% school absenteeism 40% 19%

Hobbies given up 77% 59%

No social life 30% 28%

Table 1.

Table 2.

After treatment Abdominal pain Headache

Number of patients

(finished treatment) 22 14

Duration of treatment longer than 1 year 36% 36%

No or less complaints after treatment 63% 86%

>80% school absenteeism 14% 0%

Hobbies given up 27% 14%

No social life 18% 7%

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F. Jonker, J. Calis ,M. Boele van Hensbroek, T. Leenstra

Background:

Anaemia is a major global (child) health problem. Iron

deficiency is considered as an important cause and

uniform iron supplementation in all children forms

part of national and international health policies to

prevent and treat anaemia. Recent studies have shown

increased morbidity and mortality in children receiv-

ing iron supplementation.. We hypothesize that this

may be due to an increased incidence of malaria and

other infections in children with an excess of (free)

iron. We are studying the effect of iron status and

iron supplementation on the risk of malaria and other

infections in children in areas with high infection

pressure.

Methods:

A cohort of 532 preschool children (6-60 months) in a

rural and urban setting in Malawi has been followed

over a 6 months period after receiving iron supple-

mentation ( for one month). Incidence of malaria, gas-

tro-intestinal and respiratory tract infectious episodes

were observed in iron deplete (ferritin < 30 ug/l) and

iron replete children and compared using multivari-

ate Poisson regression analyses.

Results:

Iron deplete children (n=146, 27.8%) had less malaria

infections than iron replete children (adjusted rate

ratio 0.56; 95% CI 0.42 to 0.74 p <0.001). There was no

significant difference in incidence of gastro intesti-

nal and respiratory infections (p-values respectively

0.6 and 0.2). There was no significant difference in

mortality. Iron deficient children and iron replete

children had a mortality of respectively 0.53% and

0.68% (p = 0.8).

Conclusion:

Giving iron supplementing to iron repleded children

in Africa may be harmfull by increasing their suscep-

tibilty to clinical malaria infections.

Rob Ofman, Inge M.E. Dijkstra, Ronald J.A. Wanders and

Stephan Kemp

Laboratory for Genetic Metabolic Diseases, Academic Medical

Center, University of Amsterdam, the Netherlands.

Introduction:

X-linked adrenoleukodystrophy (X-ALD) is the most

common peroxisomal disorder. Mutations in the ABCD1

gene that encodes ALDP result in impaired peroxiso-

mal beta-oxidation and subsequent accumulation of

very long-chain fatty acids (VLCFA; >C22) in plasma

and tissues. Recently, patients have been described

with large genomic deletions spanning the ABCD1 gene

and its neighboring gene DXS1357E that codes for the

B-cell associated protein 31 (BCAP31). This disorder

is referred to as CADDS and patients have a clinical

presentation that is more severe than X-ALD and more

consistent with a peroxisomal biogenesis disorder.

Isolated BCAP31 deficiency has never been reported

before. Hence, it is unclear what the contribution of

BCAP31 to this phenotype is. We set up a method to

get more insight in the relation between BCAP31 and

VLCFA metabolism.


Cultured skin fibroblasts derived from patients with

X-ALD or CADDS were cultured in the presence of VL-

CFA and the effect on cell viability was studied.

Results/Conclusion:

Initial results revealed a poor survival of fibroblasts

from CADDS patients when cultured in the presence

of docosanoic acid (C22:0). We demonstrate that the

increased sensitivity of CADDS fibroblasts towards

VLCFA is caused by the combined defect of both ALDP

and BCAP31.

P33

Iron and the susceptibility to infection

P34

Toxicity of very long-chain fatty acid in relation with a combined deficiency of ALDP and bCAP31

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Rob Ofman, Inge M.E. Dijkstra, Ronald J.A. Wanders and

Stephan Kemp



Introduction:

X-linked adrenoleukodystrophy (X-ALD) is the most

common peroxisomal disorder characterized by rap-

idly progressive cerebral demyelination or gradually

progressive myelopathy with or without adrenocorti-

cal insufficiency. The disease is caused by mutations

in the ABCD1 gene that encodes ALDP an ATP-binding-

cassette (ABC) transporter located in the peroxisomal

membrane. A defect in ALDP results in impaired

peroxisomal beta-oxidation and the subsequent accu-

mulation of very long-chain fatty acids (VLCFA; >C22)

in plasma and tissues. There is no curative therapy for

X-ALD. Recently, we identified ELOVL1 as the key en-

zyme involved in the synthesis of VLCFA. We hypoth-

esized that inhibition of ELOVL1 would result in the

prevention or reduction of the formation of VLCFA.


Human primary fibroblasts from X-ALD patients were

transfected with Accell SMARTpool siRNA to ELOVL1.

The effect on ELOVL1 expression, de novo VLCFA syn-

thesis and VLCFA levels was determined.

Results and Conclusions:

We demonstrate that knockdown of ELOVL1 results

in lowering in de novo C26:0 synthesis and a reduction

of C26:0 levels. Our findings pave the way to gener-

ate new therapeutic options for X-ALD aimed at the

inhibition of ELOVL1 activity.

Inge M.E. Dijkstra, Rob Ofman, Catherine E. van Engen, Marc

Engelen, Ronald J.A. Wanders and Stephan Kemp.



Introduction:

The two most common phenotypes of X-linked adreno-

leukodystrophy are childhood cerebral ALD (CCALD)

and adrenomyeloneuropathy (AMN). While all X-ALD

patients have elevated levels of very long-chain fatty

acids (VLCFA), it remains unknown how elevated

levels of VLCFA result in cerebral ALD. A mouse

model for X-ALD is available, but knockout mice do

not develop cerebral ALD. Feeding experiments with

high-fat diets resulted in mild myelin abnormalities.

VLCFA are derived from endogenous synthesis through

elongation of long-chain fatty acids. ELOVL1 is the

most important enzyme in the synthesis of VLCFA and

over-expression of ELOVL1 in fibroblasts results in a

strong increase in VLCFA. We developed a new mouse

model for X-ALD in which ELOVL1 expression can be

activated in a tissue-specific or time-specific manner.

Materials and Methods:

The human ELOVL1 transgene under the control of the

pCAG promoter was introduced into the Rosa26 locus

by homologous recombination in embryonic stem

cells. Expression of the transgene will be dependent

upon the Cre recombinase mediated excision of a tran-

scriptional STOP cassette placed between the promoter

and the ELOVL1 cDNA.

Results and Conclusion:

The conditional ELOVL1 mice are ready and are

currently crossed with X-ALD mice. The resulting

mouse line will then be crossed with various Cre

recombinase lines to activate ELOVL1 expression.

Based on the high-fat diet study results, we expect

that this will induce myelin instability and cause the

onset of cerebral ALD. This improved mouse model

will allow us to resolve the role of VLCFA in the patho-

genesis of X-ALD.

P35

ELOVL1 is a potential target for therapeutic intervention in x-linked adrenoleukodystrophy

P36

Development of a mouse model to investigate the role of VLCFA in the onset of cerebral adrenoleukodystrophy

Rutger R.G. Knops1, Charles B. Majoie2, Huib N. Caron1 and Antoinette Y.N. Schouten-

van Meeteren1

1 Department of Pediatric Oncology, Emma Children’s Hospital/Academic Medical

Centre, Amsterdam.2 Department of Radiology, Academic Medical Centre, Amsterdam.

Introduction/Background:

Medulloblastoma is the most common malignant brain tumor in

childhood. Several molecular genetic pathways are involved in the

development of medulloblastoma which are also crucial in early CNS

development. This suggests a relationship between neurogenesis and

oncogenesis in medulloblastoma patients. The purpose of this study is

to detect developmental CNS variations in medulloblastoma patients by

means of MRI.


We measured MRI-based volumes of 14 brain structures in medullob-

lastoma patients. From our retrospective cohort of 66 medulloblastoma

patients only 8 met the technical criteria for precise MRI 3D volume

measurement. To establish normal CNS morphometry we performed a

literature search to identify age and gender specific volumes of these

brain structures in healthy children as measured by MR imaging. The

literature derived MRI-based brain volumetric data of healthy children

were compared with the volumes of brain structures in the medulloblas-

toma patients.

Results:

The measured brain volumes of medulloblastoma patients were all with-

in the range of those of the normal population. Only the corpus cal-

losum showed a slightly increased volume compared to normal values,

maybe due to early radiation effects. Also revision of the MRI’s of the

medulloblastoma patients showed no remarkable structural anomalies.

Conclusion:

We found no significant variations in CNS-development of medulloblas-

toma patients.

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Developmental CNS variations in medulloblastoma patients: a MRI-based volumetric study

Case 1 2 3 4 5 6 7 8 Mean difference

measurements

regarding normal

values

Range

Age 9y 9y 13y 7y 10y 4y 10y 12y

Gender Male Male Male Female Male Female Male Male

Location tumor Midline Left cerebellum Midline Midline Midline Midline Midline Midline

Histology tumor Classical/

desmoplastic

Classical Desmoplastic Classical Classical Classical/

desmoplastic

Desmoplastic Classical

Cerebrum (ml) 1419 (1397) 1387 (1397) 1363 (1397) 1077 (1397) 1424 (1397) 1028 1376 (1397) 1312 (1397) -60 -320 to +27

Nucl caud R (ml) 5.0 4.3 4.8 3.9 5.0 4.2 4.3 4.2

Nucl caud L (ml) 4.7 4.2 4.2 3.8 4.8 3.9 4.2 4.0

Nucl caud tot (ml) 9.7 (7.6) 8.5 (7.6) 9.0 (7.6) 7.7 (7.6) 9.8 (7.6) 8.1 8.5 (7.6) 8.2 (7.6) +1.2 +0.1 to +2.2

Corp call opp (mm2) 831 (530) 671 (530) 694 (540) 634 (520) 697 (530) 335 649 (530) 595 (540) +149 +45 to +301

Cerebellum (ml) 159 (158) 117 (158) 152 (158) 124 (158) 151 (158) 132 124 (158) 140 (158) -20 -41 to +1

Putamen R (ml) 4.7 4.1 5.6 4.7 5.3 3.7 4.6 4.3

Putamen L (ml) 4.5 4.3 5.8 4.7 5.2 3.3 4.4 4.7

Putamen tot (ml) 9.2 (9.5) 8.4 (9.5) 11.4 (9.5) 9.4 (9.5) 10.5 (9.5) 7.0 9.1 (9.5) 9.0 (9.5) -0.3 -2.5 to +1.9

Glob pal R (ml) 1.6 1.4 XXXX 1.1 1.3 1.5 1.3 1.3

Glob pal L (ml) 1.5 1.8 XXXX 1.1 1.3 1.7 0.9 1.2

Glob pal tot (ml) 3.1 (2.6) 3.2 (2.6) XXXX 2.2 (2.5) 2.6 (2.6) 3.2 (2.6) 2.2 (2.6) 2.5 (2.6) +0.1 -0.4 to +0.6

Thalamus area (mm2 ) 23 (160) 210 (160) 178 (150) 40 (140) 329 (160) 215 (120) 284 (160) 56 (160) +16 -137 to +169

Hippocampus R (ml) 3.4 (2.7) 3.1 (2.7) 2.7 (3.4) 2.4 (2.4) 3.5 (2.8) 3.1 (2.1) 3.7 (2.8) 3.1 (3.3) +0.4 -0.7 to +1.0

Hippocampus L (ml) 3.1 (2.4) 2.8 (2.2) 3.3 (2.9) 2.2 (2.1) 3.4 (2.4) 2.9 (1.9) 3.0 (2.4) 2.7 (2.8) +0.5 -0.1 to +1.0

Hippocampus tot (ml) 6.5 5.9 6.0 4.6 6.9 6.0 6.7 5.8

Pituitary gland (ml) 0.25 (0.30) 0.11 (0.30) 0.47 0.16 (0.26) 0.09 (0.30) 0.16 (0.21) 0.41 (0.30) 0.21 -0.08 -0.21 to +0.11

Pinealis (ml) 0.109 (0.058) 0.096 (0.058) 0.073 (0.064) XXXX 0.123 (0.048) 0.087 (0.052) 0.047 (0.048) 0.058 (0.050) +0.031 -0.001 to +0.075

Septum pellucidum

length (mm)

45 (28) 40 (28) 38 (28) 36 (28) 38 (28) 29 (28) 43 (28) 40 (28) +11 +1 to +17

Brain abnormalities Hygroma

after surgery, VPD

removed

Cavum septum

pellucidum

Globus pallidum

unclear, cavum

septum pellucidum

Pinalis unclear.

Omaya drain, Cavum

septum pellucidum

VPD left, hygroma

after surgery, cavum

septum pellucidum

Hygroma after

surgery, Omaya

drain, 2x VPD,

cavum septum

pellucidum, asym-

metric ventricles

Hygroma after

surgery,

cavum septum

pellucidum

VPD right, cyst right

cerebellum after

surgery

Table 1. MRI based volumes of brain structures in 8 medulloblastoma patients and the mean differences between the measurements and the normal values from literature with

their range

(); mean age dependent values derived from literature

VPD: ventriculo peritoneal drain

XXXX: No measurements could be performed due to poor contrast.

Astrid König, ent-department, AMC

Introduction/Background:

Tracheotomy in children is still often perceived as last choice treat-

ment. There are fears about its risks as blockage and dislocation of the

cannula, especially in the homecare setting. On the other hand the in-

dications have changed during the years from temporarily tracheotomy

during acute infections to long term tracheotomy required by long term

diseases of the children.


A retrospective evaluation were performed of 66 patients who under-

went a tracheotomy between 1996 and 2008. We compared our indica-

tions with the literature as well as the ratio of complications.

Results:

On average 5 to 6 tracheotomies were performed per year, with 37 boys

and 29 girls, aged between 28 days until 18 years, with 53% younger

than 4 years. Airway obstruction (AO) was the most common indication,

with ventilation dependency (VD) as the second most common group

and thirdly high energetic trauma (HET). The average age of patients

differed per indication group, as did the ratio of decannulation and the

duration of the tracheotomy. No cannula related mortality occurred,

although 15 patients died of their primary diseases. The most common

complication were development of granulations (n=25), suprastomal

collaps (n=11), accidential decannulation (n=11), pneumonia (n=7), irria-

tion of the stoma (n=4) and tracheal ulceration (n=1). The parents were

after the training capable to handle especially the accidental decannu-

lation themselves. Conclusion: Even longterm tracheotomy of children

is safe after optimal training of parents.

André B.P. van Kuilenburg1, Judith Meijer1, Adri N.P.M. Mul1, Raoul C. M.

Hennekam1, Christine E.M. de Die-Smulders2, Peter Weber3, Andrea Capone Mori4,

Jörgen Bierau2, Brian Fowler3, Klaus Macke5, Jörn O. Sass6, Rutger Meinsma1, Julia

B. Hennermann7, Peter Miny3, Lida Zoetekouw1, Raymon Vijzelaar8, Joosr Nicolai2,

Bauke Ylstra9 and M. Estela Rubio-Gozalbo2

1Academic Medical Center, Amsterdam, The Netherlands. 2University Hospital

Maastricht, Maastricht, The Netherlands. 3University Children’s Hospital Basel,

Basel, Switzerland. 4Children’s Hospital Aarau, Aarau, Switzerland. 5Rheinhessen-

Fachklinik, Alzey, Germany. 6Universitätsklikum Freiburg, Zentrum für Kinder- und

Jugendmedizin, Freiburg, Germany. 7Charité Universitätsmedizin Berlin, Berlin,

Germany. 8MRC-Holland bv, Amsterdam, The Netherlands. 9VU University Medical

Center, Department of Pathology, Amsterdam, The Netherlands

Background:

Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently

described autosomal recessive disorder of the pyrimidine degradation

pathway. Various mutations and polymorphisms have been identified in

the DPD gene (DPYD) leading to a phenotype that is mainly characterized

by mental and motor retardation and convulsions.

Methods:

In an ongoing study of 72 DPD deficient patients, we analysed the mo-

lecular background of 5 patients in more detail, using sequencing of all

coding exons and flanking intronic regions, cDNA analysis, multiplex

ligation-dependent probe amplification (MLPA), FISH analysis and

array-based comparative genomic hydridization.

Results:

Clinical features in the patients include psychomotor retardation,

convulsions, respiratory distress syndrome, skeletal abnormalities and

marked craniofacial dysmorphia. In three patients, including two sib-

lings, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb

deletion of exon 14-16 of DPYD. In the fifth patient, a c.299_302delTCAT

mutation in exon 4 was found and also loss of heterozygosity of the

entire DPD gene. Further analysis demonstrated a de novo deletion of ap-

proximately 14 Mb of chromosome 1p13.3-1p21.3, which included DPYD.

Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have

contributed to the severe psychomotor retardation and unusual cranio-

facial features in this patient.

Conclusion:

Our study showed for the first time the presence of large genomic dele-

tions affecting DPYD in 7% (5/72) of all DPD deficient patients. Screen-

ing of DPD deficient patients for genomic deletions should be consid-

ered, especially those patients with an unusual clinical presentation.

P38

Tracheotomy in children: indications, complications and impact on the family

P39

Dihydropyrimidine dehydrogenase deficiency caused by intragenic rearrangements of DPyD and a de novo interstitial deletion del(1)(p13.3p21.3)

Table of patients

Number of patients

Average age Ratio of decannu-lation

Duration of tracheotomy

AO 35 (53%) 48 months 48,6% 32 months 18 days

VD 21 (31,8%) 73 months 52,4% 15 months 27 days

HET 10 (15,2%) 12 years 7 months

70% 2 months 22 days

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F. Lamers, J.J. Molenaar, I. van der Ploeg, M.E. Ebus, J. Koster,

R. Versteeg, H.N. Caron

Department of Human Genetics, Academic Medical Center,

University of Amsterdam.

Neuroblastoma are pediatric tumors with a bad

prognosis, despite extensive treatment. Therefore new

therapeutic targets should be identified. The inhibi-

tor of apoptosis protein BIRC5 (Survivin) is one of the

genes located on 17q in the region that is often gained

in neuroblastoma.

Using Affymetrix mRNA expression data, we could

show that BIRC5 expression is strongly upregulated in

neuroblastoma compared to normal tissue, other adult

malignancies and also compared to non malignant

fetal adrenal neuroblasts. The high BIRC5 expression

is correlated to 17q gain indicating that the genetic ab-

erration on 17q is contributing to the overexpression.

Finally the overexpression of BIRC5 strongly corre-

lates to a bad prognosis independent of the presence of

17q gain. To further validate BIRC5 as a potential drug

target we used both LNA and siRNA to inhibit BIRC5

in neuroblastoma cell lines. Both BIRC5 siRNAs caused

a specific knock down on mRNA and protein level.

This resulted in massive apoptosis as indicated by

PARP cleavage and an increase of the sub-G1 fraction

on FACS analysis. We were not able to show interac-

tion of BIRC5 with DIABLO or XIAP. On the contrary,

we could show P53 activation after BIRC5 inhibition

and we could rescue apoptosis after BIRC5 silencing by

CASP2 (caspase-2) inhibition.

We conclude that both the BIRC5 LNA and the siRNA

cause a specific inhibition of BIRC5 which results in a

pro-apoptotic effect on neuroblastoma cells via mitotic

catastrophe in vitro.

C.M. Loots1, M.A. Benninga1, G.P. Davidson2, T.I. Omari2

1Dept of Pediatric Gastroenterology and Nutrition, Emma Chil-

dren Hospital, AMC, Amsterdam, the Netherlands2Dept. of Pediatric Gastroenterology, Women’s and Children’s Hos-

pital, Adelaide, Australia

Introduction:

Since the introduction of pH-impedance (pH-MII)

monitoring, more accurate assessment of gastroesopha-

geal reflux (GER)-symptom associations has been pos-

sible. The aim of this study was to assess the ability of

pH-MII to predict therapeutic response to PPI therapy.

Methods:

Fifty-one pediatric GER patients who underwent 24

pH-impedance monitoring received clinical follow-up

via retrospective parental telephone questionnaire

(surveying patient management and clinical out-

comes). Three diagnostic outcomes were assessed: (1)

pathological 24h esophageal acid exposure (defined by

positive reflux index (RI)); the association between

bolus GER and symptoms, defined by (2) positive

symptom association probability (SAP≥95%) or (3) posi-

tive symptom index (SI>50%). Parents were informed

about the RI only.

Results:

Twenty-eight infants (14 female, median age [IQR]

130 days [53-160]) and 23 children (10 female, median

age [IQR] 5.8 year [2.2-13.0]) were included. Follow-up

occurred 35-53 weeks after study. Fourteen patients

had a positive RI, 14 patients had a positive SI and 32

patients had a positive SAP. Forty-four patients were

prescribed PPI, at the time of follow up, 15 were still

on PPI. For patients treated with PPI therapy (N=44),

a response was requested to the proposition; ‘I think the

medication has improved the wellbeing of my child’. In Table 1,

the correlation between parental response and diag-

nostic outcome is presented.

Conclusion:

In pediatric patients undergoing pH-impedance moni-

toring, a positive SAP was shown to be predictive for

symptomatic improvement on PPI therapy as judged

by the parents whereas a positive SI and RI have no

predictive value.

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Survivin (bIRC5) inhibition in neuroblastoma causes cell death via mitotic catastrophe

P41

Positive symptom association probability predicts symptomatic improvement in children with gastroesophageal reflux

Pos. test and im-proved on PPI

Neg. test and not improved on PPI

Sensitivity Specificity p-value*

RI 8 8 25% 67% 0.7

SI 9 9 75% 28% 1

SAP 23 9 72% 75% 0.007

Table 1. Diagnostic test outcome compared to symptomatic improvement on PPI therapy as judged by parents (n=44).

* P-values are calculated with a 2-tailed Fisher’s-exact test.

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Iris M. Markusse, Andrieke C. Knottnerus, A.P. Cohen, E. Kohn-

horst, Bert H. Derkx

Emma Children’s Hospital, Amsterdam

Introduction:

Childhood experience of illness in parents is an inde-

pendent risk factor for later unexplained symptoms

(Hotopf 2002). Gilleland (2009) suggests parent somati-

zation as an important factor in developing medically

unexplained symptoms (MUS) in children.

Methods:

At Psy Med Unit of the Emma Children’s Hospital,

tertiary referral centre for children with invalidating

therapy resistant MUS, an observational retrospective

study of patients presenting with fatigue or pain as

primary complaint was completed. Patients’ charts were

evaluated for somatic/psychiatric disease or MUS in

their parents.

Results:

Healthiness is defined as absence of somatic/psychiatric

disease and MUS. Somatic is defined as a common admit-

ted physical disease; psychiatric as DSM IV diagnosis.

This table shows 22% / 23% of the children having two

healthy parents. When a child has one parent with a

somatic disease and one with a psychiatric disease both

are counted. This declares the total percentage over a

100%.

Parents Patients with fatigue

Patients with pain

Healthiness 22% 23%

Somatic disease 48% 62%

Psychiatric disease

13% 15%

MUS 17% 23%

Unknown 4% -

Table 1.

Conclusions:

Almost 80% of our patients has an unhealthy parent.

This could mean a correlation between somatic/psy-

chiatric disease or MUS in parents and the presence of

MUS in their children . Hotopf suggests this relation-

ship, in grown-up children.

About 20% of the parents has MUS, which supports

the statement of Gilleland. It is important to note that

information is provided by the family. Thus, underesti-

mation is likely.

P42

Do patients with unexplained chronic fatigue/pain have healthy parents?

P43

benefit and burden scale for children (bbSC): validation in a sample of young dutch cancer survivorsH. Maurice-Stam1, A. Broek1, C.J.M. Vrijmoet-Wiersma2, E. Meijer-

van den Bergh3, E.M. van Dijk4, M.A. Grootenhuis1

1Emma Children’s Hospital AMC, Paediatric Psychosocial Depart-

ment, Amsterdam; 2Leiden University Medical Centre, Paediatric

Department, Leiden; 3Radboud University Medical Centre, Medical

Psychology, Nijmegen; 4VU University Medical Centre, Medical

Psychology, Amsterdam

Introduction:

Understanding of survivor-specific quality of life is-

sues such as disease-related burden and benefit could

yield a more complete picture of the impact of cancer

on (daily) life of survivors. To date, a survivor-specific

Dutch questionnaire is not available.

The aim of the study is to validate the Benefit and

Burden Scale for Children (BBSC; Phipps, 2008) and

to assess the psychometric characteristics in a Dutch

population.

Method:

Children aged 8 to 18, who had successfully finished

cancer treatment six months to three years before,

completed eight questionnaires measuring psychologi-

cal outcomes (benefit and burden of the disease, quality

of life, self-esteem, cognitions about the disease, PTSS,

anxiety, behavioural functioning and coping). For

measuring test-retest reliability, the BBSC was adminis-

tered again after two weeks.

Principal component analyses and reliability analyses

were conducted to assess psychometric characteristics;

Pearson correlations and ANOVAs to test validity.

Results:

A total of 78 (61%) children completed the question-

naires. Response rate for the retest was 89%. The BBSC

demonstrated good internal consistency (0.72<α< 0.84)

and high test-retest reliability (0.74<r<0.78). Children’s

benefit and burden scores did not differ as a function of

gender, ethnicity, socioeconomic status and treatment.

Brain tumour (versus other diagnosis) and shorter time

elapsed since treatment were related to higher levels of

burden. Especially disease-related burden was related

to negative psychological outcomes.

Conclusion:

The Dutch BBSC appears to be a valid instrument

with good psychometric characteristics, similar to the

original version. The instrument has the potential to

be used as a screener in Dutch paediatric survivors of

childhood cancer.

A. Klassen1, S. Strohm1, H. Maurice-Stam2, M.A. Grootenhuis2

1McMaster University, Department of Paediatrics, Hamilton, Canada; 2Emma Chil-

dren’s Hospital AMC, Paediatric Psychosocial Department, Amsterdam.

Introduction:

A systematic review was completed to identify and appraise all pub-

lished QoL questionnaires developed for use with children with cancer

and childhood cancer survivors. Aim was to discuss the nature of

the different measures available along with considerations on how to

choose an appropriate QoL questionnaire.

Methods:

MEDLINE, CINAHL, EMBASE, PsycINFO, CancerLit, and Sociological

Abstracts were searched from the inception of each database to June

2009. Included articles were ones that described the development and/

or psychometric evaluation of a QOL measure developed for use with

children with cancer or childhood cancer survivors. Articles were ap-

praised for adherence to internationally recommended guidelines for

item generation, item reduction, and psychometric evaluation.

Results:

Thirteen QOL questionnaires were identified. Eleven measures are ap-

plicable to measuring QOL in children with any type of cancer, and two

are specific to children with brain cancer. Four measures can be used to

measure QOL in children undergoing cancer treatment, six can be used

with children on or off treatment, and three are specific to childhood

cancer survivors.

While all measures underwent some degree of formal development and

validation, item generation often did not involve children with cancer

or their parents, and a number of measures did not describe or utilize

recommended methods for item reduction and psychometric evaluation.

Conclusion:

Most of the measures identified in this review were designed to meas-

ure QOL concerns of children with any type of cancer and at any time,

during treatment or survivorship. The review can help researchers and

clinicians identify scientifically sound measures.

P44

Systematic review of paediatric oncology-specific quality of life questionnaires

J.J. Molenaar, E.M. Westerhout, M.L. den Boer, S.C. Clifford, O. Delattre, B. Geoerger,

C. Lanvers, T. Pietsch, M. Serra, J. Shipley, G. Vassal, R. Versteeg, A.C. Verschuur,

H.N. Caron

Dept of human genetics and dept of pediatric oncology of the university of Amsterdam

The KCK consortium has validated CDK2 as potential drug target in six

highly malignant pediatric tumor types (i.e Ewing sarcoma, osteosar-

coma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and ALL).

The stepwise procedure started with the selection of genes that can be

targeted using small molecule inhibitors. Drug target genes and signal

transduction routes were studied using Affymetrix mRNA profiles of

over 500 tumors and cell lines. CDK2 and cell cycle signal transduction

genes showed expression patterns that were significantly different

from reference tissues and expression was related to poor prognosis.

The next step to evaluate the potential drug targets consisted of tar-

geted knock down using RNA interference. Inhibition of CDK2 resulted

in significant phenotypes in several pediatric tumor models. Cell lines

from most tumor types showed growth inhibition and differentiation.

Neuroblastoma cell lines showed extensive apoptosis. Highly interest-

ing was the synthetic lethal relation between CDK2 and the driving

oncogene MYCN. These findings warranted further evaluation using the

CDK2 inhibiting small molecule Roscovitine. This compound was tested

in the core panel of pediatric tumor cell lines and more extensive in

tumor types that showed high sensitivity for the compound. Neurob-

lastoma cell lines were most sensitive with IC50 in the low uM range.

Neuroblastoma, which showed high sensitivity for Roscovitine, are now

being evaluated in in vivo mouse xenograft models.

P45

Validation of CDk2 as potential drug target in pediatric tumors

Renée L. Mulder, MSc1, Elvira C. van Dalen, MD, PhD1,2, Dorine Bresters, MD, PhD3,

Yoon K. Loke, MD, PhD4, Edith Leclercq, PhD1,2, Aleida Postma, MD, PhD5, Piet N.

Post, MD, PhD6, Bart G.P. Koot, MD7, Huib N. Caron, MD, PhD1, Leontien C.M.

Kremer, MD, PhD1,2

1Department of Paediatric Oncology, Emma Children’s Hospital/Academic Medical

Center, Amsterdam, The Netherlands, 2Cochrane Childhood Cancer Group, 3Depart-

ment of Paediatric Immunology, Haemato-Oncology, Bone Marrow Transplantation

and Auto-Immune Diseases, Willem-Alexander Kinder- en Jeugdcentrum/Leiden

University Medical Center, Leiden, The Netherlands, 4School of Medicine, University

of East Anglia, Norwich, United Kingdom, 5Department of Paediatric Oncology,

University Medical Center Groningen and University of Groningen, Beatrix Children's

Hospital, Groningen, The Netherlands, 6Dutch Institute for Healthcare Improvement

CBO, Utrecht, The Netherlands, 7Department of Paediatric Gastroenterology and

Nutrition, Emma Children’s Hospital/Academic Medical Center, Amsterdam, The

Netherlands

Background:

Until now, no Cochrane systematic reviews about late adverse effects

after treatment for childhood cancer have been performed. Because

of a growing number of studies in the field of late adverse effects in

survivors of childhood cancer, there is a need for overviews of the best

evidence. In this way, clinicians are enabled to make well-informed deci-

sions about treatment and follow-up policies. The aim of this Cochrane

systematic review is to evaluate the existing evidence involving the ef-

fect of treatment for childhood cancer on hepatic late adverse effects.


MEDLINE, EMBASE and CENTRAL will be searched to identify all studies

reporting on hepatic late adverse effects after treatment for childhood

cancer. Information about study characteristics, hepatic late adverse

effects and risk factors will be abstracted and a risk of bias assessment

will be performed.

Results:

Not applicable.

Conclusions:

This will be the first Cochrane systematic review on late adverse effects

after treatment for childhood cancer. We now provide a framework for

the performance of Cochrane systematic reviews on late adverse effects.

For the development of future treatment policies for childhood cancer

more insight into the effect of the cancer treatment on late adverse

effects is essential. Furthermore, for the follow-up of childhood cancer

survivors it is crucial to know the risk and associated risk factors so that

patients at greatest risk can be identified and adequate follow-up proto-

cols can be established. Therefore, more Cochrane systematic reviews on

late adverse effects in survivors of childhood cancer are essential.

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Protocol of the first cochrane systematic review on late adverse effects in childhood cancer survivors

P47

Reproductive choices after genetic counselling for sickle cell diseaseH.E. Peters, Medical student AMC/UvA, M.A. Legdeur, Department of Clinical Genet-

ics, AMC, Dr. E.M.A. Smets, Department of Medical Psychology and Clinical Genetics,

AMC, Dr. C.A.J.M. de Borgie, Department of Clinical Epidemiology and Biostatistics,

AMC, Drs. I.B. Mathijssen, Department of Clinical Genetics, AMC, Dr. M. Peters,

Department of Paediatric-Haematology, Emma Children’s Hospital AMC

Introduction:

Sickle cell disease (SCD) is an autosomal recessive disorder with its

highest incidence in people of African ancestry. When both parents in

a couple are carriers of SCD, in each pregnancy there is a 25% risk of

having a child with SCD. Couples at risk can receive genetic counseling

to support them in making reproductive choices. The aim of this study

was to evaluate the impact and uptake of information after such coun-

seling and the subsequent reproductive decisions of risk couples.


Risk couples, counseled after the birth of a child with SCD, were invited

to participate in a qualitative interview study. In total 45 couples who

received counseling in the Academic Medical Centre in the period 2001-

2008 were selected and 21 of them participated (19 interviews with only

the mother, 2 with both parents). The semi-structured interviews con-

tained knowledge questions about SCD and inheritance and questions

about reproductive choices.

Results:

48% of the participants were of Surinam origin and 39% of African

origin. Sixteen parents were Christian, 5 Muslim and 2 had no religion.

All interviewees were aware of the different reproductive options, such

as prenatal diagnosis (PND) in a subsequent pregnancy. After the birth

of their child with SCD, 14 couples refrained from further pregnancy

for different reasons. Seven mothers gave birth to 8 children of whom 3

had SCD. PND was performed in 2 cases. Religion was an important bar-

rier for PND because it rules out the option of abortion.

Conclusion:

The reproductive choice of risk couples for SCD is mainly influenced by

cultural and religious background not by lack of knowledge.

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Evelyn M. van der Plas1, Xandra W. van den Tweel2, Harriët

Heijboer3, Ronald B. Geskus4, B.J. Biemond5, Marjolein Peters,

MD, PhD6 and Karin Fijnvandraat2

1Department of Pediatric Hematology, Emma Children's Hospital,

Academic Medical Center Amsterdam, Amsterdam, Netherlands; 2Pediatric Hematology, Emma Children's Hospital/Academic

Medical Center, Amsterdam, Netherlands; 3Department of Pedi-

atric Hematology, Emma Children's Hospital, AMC, Amsterdam; 4Department of Clinical Epidemiology, Biostatistics and Bioin-

formatics, Academic Medical Center, Asmterdam, Netherlands; 5Academic Medical Center, Amsterdam, Netherlands; 6Pediatric

hematology, Academic Medical center, Amsterdam, Netherlands

Introduction:

Despite the increasing incidence of sickle cell disease

(SCD) in the Netherlands, mortality among this pa-

tient group has never been investigated. This informa-

tion is essential to provide a baseline for monitoring

the effect of health care interventions, such as the

introduction of nationwide neonatal screening (2007).

Patients and Methods:

All patients that were diagnosed with sickle cell

disease (HbSS, HBSC, HbS-beta0, HbS-beta+) before

the age of 18 years at the laboratory of the Academic

Medical Center (AMC) in Amsterdam in 1985-2006

were included in the study. Vital status at the end of

study was determined by the last hospital visit or per-

sonal contact between January 2007 and March 2008.

Survival estimates were obtained using the Kaplan-

Meier estimator

Results:

In this time period we identified 298 pediatric pa-

tients with SCD. Homozygous sickle cell disease (HbSS)

was present in 189 (63%) patients. The total time of

follow-up was 2621 patient years. Twelve patients

had died and all deaths were SCD related. Stroke (3

patients; 25%) and sepsis/meningitis (3 patients; 25%)

were the most common causes of death. A similar pro-

portion of patients with the HbSS and HbSC genotype

died (respectively 4.2% (95% CI: 1.9-7.9%) and 4.2%

(95% CI: 1.0-10.8%). The estimated survival rate of

children with SCD at the age of three years was 93%

(95% CI: 87-100%). At the age of 18 the survival was

91% (95% CI: 84 -99%).

Conclusions:

In children with SCD living in the Netherlands, born

before nationwide neonatal screening was implement-

ed in 2007, 91% survives until the age of 18. Infection

and stroke are the most common causes of death.

Further study of children with SCD born after 2007,

will elucidate whether neonatal screening for SCD has

improved survival in these patients.

P48

Mortality and Causes of Death in Children with Sickle Cell Disease in the Netherlands

P49

Less than 30 percent of very preterm children is without disability at age fiveEva S. Potharst, MSc1, Aleid G. Van Wassenaer, MD, PhD1, Bregje

A. Houtzager, PhD1, Janeline W.P. van Hus, MSc1, Bob F. Last,

PhD2 and Joke H. Kok, MD, PhD1.1Emma Children's Hospital Academic Medical center, Amsterdam,

Netherlands and 2Psychology, Free University, Amsterdam,

Netherlands.

Background:

Children born preterm are at risk of disabilities on

multiple domains. It is unclear how many of them, in

comparison with term born peers, are without disabil-

ities if assessed on multiple domains with inclusion of

components of IQ and behaviour.

Objective:

To study how many preterm born, 5 year old children

are without disability in comparison with term born

comparison children.

Design/Methods:

Children (n = 127) born at <30 weeks GA or BW <1000

g, born in our hospital, participating in our follow-

up program, reaching the corrected age of 5 between

December 2007 and August 2009, were eligible. Term

born class mates in main stream school, were re-

cruited via the preterm child. Children were assessed

using the Movement Assessment Battery for Children

(M-ABC II) and the Touwen neurological examination,

while the Wechsler Preschool and Primary Scale of

Intelligence was used to assess verbal and performal

intelligence and processing speed quotient. Parents

and teachers filled out the Strengths and Difficulties

Questionnaire. A disability was defined as a (mildly)

abnormal result on the different tests (most often

>1SD below the test mean), based on the age corrected

for prematurity.

Results:

105 preterms (mean GA 28.8 weeks (SD 1.6), mean BW

1043 grams (SD 253)) and 92 controls (mean gestational

age 39.9 weeks (SD 1.8), mean birth weight 3441 (SD

519)) participated. Non-participant preterms were ei-

ther too handicapped (n = 5), had a genetic syndrome

(n = 2), moved abroad (n = 5), were lost to follow up (n

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= 4) or refused (n=7). In the preterm group more often

fathers (p = .01) and mothers (p = .02) were not born

in the Netherlands, and mothers (not fathers) more of-

ten had a low education (p = .00) compared to terms.

Significantly less preterms were without disabilities

(28%) compared to terms (77%) ( OR 7.02, p = .00, after

correction for SES) (see table).

Conclusions:

Three times as many preterm as term born five yr old

children has one or more disability on the neurologi-

cal, motor, cognitive and/or behavioural domain. Al-

though evaluation of children with major disabilities

is important for medical decision making, survival

with a minimum of mild and major disabilities must

be the ultimate goal of neonatal medicine.

Disabilities in preterm and term born children at age 5 yr

Number of disabilities

preterm group

term group p-value

n=105 n=92

0 28% 77%

1 22% 13%

2 30% 8%

3 13% 2%

4 7% 0% 0.00

P50

job-aid: ‘nursing report on ethical discussion in the nicu’G. Royé, RN1, M.J. Hemmink, RN1, A.T.A.M Claassen, RN1,

J.M. Wielenga, RN PhD1

1IC neonatology, Emma Children’s Hospital/Academic Medical

Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Objectives:

As neonatal medicine and technical capabilities in

the NICU have developed, clinical ethics and ethical

decision-making have increased. A (moral) dilemma

requires an effective, efficient and structured ap-

proach and data should be current, complete and

comprehensive.

Complicated ethical issues can become (more) compre-

hensible, manageable, (more) transparent and easier

to assess.

In 2006 the nursing staff of the Emma Children's

Hospital / AMC NICU assigned us to develop an instru-

ment to facilitate nurses in writing an univocal and

efficient report with all aspects of the dilemma taken

into consideration and help to act only based on agree-

ments and facts.

Methods:

By systematic evaluation of literature on ethical

and moral dilemma’s, decision-making processes and

requirements on reporting such an instrument is

developed.

Results:

The instrument called a “Job-Aid” can be used before,

during and after a meeting as a questionnaire, step-

by-step plan as well as a checklist.The job-aid contains

nine questions (medical and nursing) to gather

information on a patient from different perspective,

providing a more integrated and holistic view. The

job-aid consists of five steps; collection and analysis of

objective data (facts); clarifying standards and values

(principles); clarifying the perception of the people

concerned (interests); substantiate the decision, tak-

ing the standards and values into consideration; and

evaluation and reflection.

Conclusions:

The Job-Aid reflects the thoughtful consideration by

professionals. It does not provide an absolute answer

but provides possible answers, stimulates self reflect-

ed behaviour, increases nurses input in ethical discus-

sions and improves the quality of written reports.

M.A. de Ruiter¹, A.Y.N. Schouten-van Meeteren², J. Oosterlaan³ and M.A. Grootenhuis¹1 Paediatric Psychosocial department, Emma Children’s Hospital AMC2 Department of Pediatric Oncology, Emma Children’s Hospital AMC 3 Department of Clinical Neuropsychology, VU University Amsterdam

Introduction:

The aim of this study is to investigate the efficacy of neurofeedback

(NFB) to improve attention, memory and processing speed in children

treated for a Brain Tumour (BT). In the Netherlands every year approxi-

mately 100 children are diagnosed with a BT. Nowadays over 65% of

these children have a 5-year survival. Neurotoxicity caused by treat-

ment for a BT is a major cause of neurocognitive decline in Childhood

Brain Tumour Survivors (CBTS).

Approach:

Several studies have shown that NFB has the capacity to improve the

brain systems mediating selective attention and response inhibition in

children with Attention Deficit/Hyperactive Disorder (AD/HD). CBTS

exhibit symptoms comparable to those of children with AD/HD and

positive response to methylphenidate has been found in CBTS. However,

NFB has not been used as an intervention in CBTS yet. The effectiveness

of NFB in CBTS will be investigated in a randomized controlled trial.

The intervention group of 35 patients will receive 30 sessions of NFB;

the control group, also consisting of 35 patients, will receive 30 session

of placebo neurofeedback. Neuropsychological tests and psychosocial

questionnaires will be used to evaluate pre- and post-NFB intervention

functioning, as well as a 6-month follow-up. To control for test-retest

effect, a group of 35 healthy siblings will be included in the study. They

will not receive any intervention.

Relevance:

If NFB proofs to be effective for CBTS this will be a great improvement

for their (neuro-) psychological functioning and quality of life, without

the disadvantage of the side effects of medication.

P51

PRISMA: Pediatric oncologic Research on Improving Speed, Memory and AttentionThe efficacy of neurofeedback to improve speed, memory and attention in childhood brain tumour survivors: a randomized controlled trial

P52

Intra and inter rater reproducibility of ultrasound cardiography in children with end stage renal diseaseN.J. Schoenmaker1, I.M. Kuipers2, J.H. van der Lee3; J.W. Groothoff1 on behalf of the

RICH-Q working group1Department of Pediatric Nephrology, 2Department of Pediatric Cardiology, 3Depart-

ment of Pediatric Clinical Epidemiology, Emma Children’s Hospital AMC, Amsterdam,

The Netherlands

Introduction:

Cardiovascular disease is the main cause of death in young adults with

end stage renal disease (ESRD) since childhood. Therefore, early detec-

tion and therapeutic intervention is essential in children with ESRD.

The prevalence of left ventricle hypertrophy appears to vary consider-

ably between various dialysis centers. This might be due to differences

in measurement and interpretation of the heart ultrasounds.

The aim of this study is to assess the intra and inter rater reproducibil-

ity of ultra sound cardiography with respect to the assessment of LVH

and diastolic dysfunction. This study will help to improve standardiza-

tion of measurement of cardiological parameters in children.


All patients on chronic dialysis aged <19 years in the Netherlands for

whom informed consent is obtained were included. The number of eligi-

ble patients is 101. Heart ultrasounds were performed by cardiologists in

the local medical centers and the digital files were sent to one expertise

center for assessment. The ultrasound recordings will be assessed twice

by two blinded observers independently according to a measurement

protocol. The intra and inter rater reproducibility of the measurements

underlying cardiological diagnoses such as left ventricle hypertrophy

will be estimated using Bland-Altman plots and coefficients of varia-

tion.

Results:

The results will become available from January 2010.

L. Scholten¹, A.M. Willemen², M.A. Grootenhuis¹, H. Maurice-Stam¹, C. Schuengel²,

B.F. Last1,2

¹ Emma Kinderziekenhuis AMC, Psychosociale Afdeling

² Vrije Universiteit, Faculteit Psychologie & Pedagogiek

Background:

Children with a chronic illness (CI), like asthma, diabetes, sickle cell

anemia and inflammatory bowel diseases, are twice as likely to develop

psychosocial problems as healthy children. To adequately prevent chil-

dren with CI from developing psychosocial problems, evidenced based

intervention programs are needed. A standardized group-based inter-

vention program was developed in the Emma Kinderziekenhuis AMC,

called Op Koers. Based on cognitive-behavioural principles, children

learn to use skills to help them to cope with the consequences of their

disease. Children that participated in Op Koers reported significant

improvement of social-emotional functioning than before the interven-

tion. Parents were, however, not involved in this program, while they

may be the best support of their ill child. To enhance the effect of in-

tervention, a complementary program for parents was developed (called

Samen op Koers). This program is expected to strengthen the interven-

tion effects of Op Koers.

Methods:

Effects will be evaluated in a randomized controlled design. First, the

effects of Op Koers on social-emotional outcomes will be compared with

a control group. Secondly, the additional value of the intervention for

parents will be investigated in relation to both conditions. Effects of

the different conditions will be investigated in a moderate (6 months)

to long term (12 months) schedule. Five hospitals will cooperate in

this study. If proven effective, Op Koers will be made available to all

medical centres. The ultimate goal of this study is that children with a

chronic illness and their parents will have access to an evidence based

program that limits the mental health consequences of their physical

health.

P53

Samen op koers: effectiveness of a cognitive behavioral based group intervention for children with a chronic illness: a randomized controlled trail

E. Sieswerda, L.C.M. Kremer, H.N. Caron, E.C. van Dalen

Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical

Center Amsterdam, The Netherlands

Category:

Oncology

Background:

Currently, nearly 60% of children diagnosed with a malignancy receive

conventional anthracyclines as part of their treatment and are there-

fore at risk to develop anthracycline-induced cardiotoxicity.

Liposomal anthracyclines have been shown to decrease the risk of

cardiotoxicity in adults with solid tumors while attaining similar anti-

tumour efficacy compared to conventional anthracyclines.

We aimed to evaluate the available evidence of the benefits and harms

of liposomal anthracyclines in childhood cancer patients.

Methods

We searched the databases of MEDLINE, EMBASE and CENTRAL as

well as relevant reference lists and ongoing trial databases for studies

reporting on the use of liposomal anthracyclines in childhood cancer

patients. Two reviewers independently selected studies, extracted data

on study characteristics and outcomes and performed quality-assess-

ments.

Results:

A total of 15 studies met our inclusion criteria. No randomized control-

led trials were reported. Incidence of cardiotoxicity was evaluated in

ten studies and ranged from 0% to 67%. The studies were heterogene-

ous and had methodological limitations. Almost all patients had a poor

prognosis and had been treated extensively previously. Therefore, no

conclusions could be made about risks of cardiotoxicity of liposomal

anthracyclines alone. Similarly, no conclusions could be made about

anti-tumor efficacy and risks of other toxicities.

Conclusions:

There is currently no evidence to support or discourage the use of lipo-

somal anthracyclines in childhood cancer patients. There is an urgent

need for well-designed (randomized controlled) studies that accurately

evaluate if the benefits of liposomal anthracyclines found in adults

apply to children with cancer.

P54

The use of liposomal anthracycline analogues for childhood malignancies: a systematic review

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J. Stutterheim1,2, L. Zappeij-Kannegieter2, H.N. Caron1, C.E. van

der Schoot2, G.A.M. Tytgat1

1Department of pediatric oncology, Emma Children’s Hospital,

Academic Medical Center, Amsterdam, the Netherlands2Department of Immunohematology, Sanquin-AMC Landsteiner

Laboratory, Amsterdam, the Netherlands

Aims (264):

Real-time quantitative (RQ)-PCR for detection of mini-

mal residual disease (MRD) in children with neurob-

lastoma (NBL) is studied for evaluation of molecular

bone marrow (BM) response, however its prognostic

value has still to be established. We previously devel-

oped a new panel of specific neuroblastoma RQ-PCR

markers for MRD testing. The goal of this study was to

determine whether molecular sequential assessment

of bone marrow using this new panel of markers was

prognostic for ultimate overall survival (OS).

Methods:

RQ–PCR was performed with five NBL-specific mark-

ers: homeobox2b (PHOX2B), tyrosine hydroxylase (TH),

dopamine decarbohydroxylase (DDC), growth associ-

ated protein 43 (GAP43) and cholinergic receptor3

(CHRNA3), on 67 retrospectively collected samples of

48 patients with metastatic disease > 1 year. The prog-

nostic impact of MRD at 2-4 months after diagnosis

(n=38) and after induction chemotherapy (n=29) for

predicting outcome was assessed using univariate log-

rank test and multivariate Cox regression analysis.

Results:

All patients had BM positive disease at initial diagno-

sis. At the early time point, 29% (11/38) of the patients

had no molecular BM disease anymore and this was

associated with good outcome (5-y-OS 62,3±15,0%

versus 18,5±7,5%;p=0,004). After induction chemo-

therapy, BM of 41% (12/29) of the patients was still

MRD positive which was associated with poor outcome

(5-y-OS 0% versus 52,3±12,3;p<0,001). For both time

points, the prognostic value of molecular response was

independent of other response parameters (p=0.05,

p=0.004, respectively).

Conclusion:

MRD detection as reliably measured by a panel of NBL

specific-PCR targets could identify fast responders,

who clear their BM early during treatment. Fast mo-

lecular response was associated with better outcome.

P55

Fast molecular response of bone marrow disease is highly prognostic for survival in metastatic neuroblastoma > 1 year

P56

The FOCUS study (FOllow Up of Children with Sickle cell disease)First follow-up resultsM. Suijker, N. Dors, F. van Herrewegen, H. Heijboer, M. Peters,

K. Fijnvandraat

Department of Pediatric Hematology, Emma Children’s Hospital/

AMC Amsterdam

Introduction:

Sickle cell disease (SCD) is an inherited disorder of

haemoglobin. Patients with SCD may die early in life

from complications as sepsis and splenic sequestra-

tion. Neonatal screening enables early diagnosis and

installation of antibiotic prophylaxis and vaccina-

tion to prevent severe infections. National neonatal

screening for SCD was introduced in the Netherlands

in 2007. At the same moment the FOCUS study was

started with the objectives to assess the effects of

neonatal screening on mortality and morbidity.

Methods:

Longitudinal data are collected from all children

diagnosed with SCD in the Netherlands by neonatal

screening from January 2007 till July 2009.

Results:

Fifty-eight children with SCD were included in our

study. Data from 25 (43%) of these children, under the

care of the EKZ/AMC, are presented.

The median follow up is 17.4 months (6-24 months).

No SCD related mortality nor pneumococcal sepsis

occurred. Seven children (28%) were admitted to

the hospital at least once (1-5 admissions). The most

frequent reason for hospitalization was vaso-occlusive

crises (45% of hospitalizations). The risk of hospital

admission for children with SS/SBeta0 genotype was

increased in comparison to children with the SC/

SBeta+ genotype (0.49 versus 0.09; Relative Risk: 5.5,

95% CI 0.8-39).

Conclusions:

No SCD related mortality nor pneumococcal sepsis was

found. Morbidity is more severe in the HbSS group.

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C.E.A. Tacke¹, I.M. Kuipers², M. Groenink³, T.W. Kuijpers¹

¹Department of Pediatric Hematology, Immunology & Infectious

Disease ²Department of Pediatric Cardiology ³Department of Radi-

ology, Academic Medical Center, Amsterdam, the Netherlands

Background: Kawasaki disease (KD) contributes to

coronary artery aneurysm (CAA) in 15-25% of patients.

Transthoracic echocardiography is accepted as first

choice for coronary surveillance. Cardiac magnetic

resonance imaging (CMRI) is increasingly used as a

non-invasive and radiation-free imaging method. This

study evaluates the feasibility of CMRI during follow-up

of KD patients.

Methods: In this single-center study KD patients were

recruited over a 2-year period for contrast-enhanced

CMRI with adenosine-stress testing. Until CMRI assess-

ment, patients had been followed by serial echocar-

diography. CMRI findings were compared with these

longitudinal data.

Results: Thirty-nine patients (74% male, median age

14.6 years) underwent CMRI. CAAs were identified in

12 patients (30.8%) and were unexpected in 7 (17.9%)

because of the normal echocardiography findings. Only

in 2 patients the CAAs were discarded as false-positive

findings, following further imaging. Coronary artery

evaluation was incomplete in 6 patients (15.4%) due to

motion artifacts. Reversible ischemia was observed in

4 (10.3%) and an area of infarction in 3 patients (7.7%).

Only in 2 patients reversible ischemia evaluation was

not possible due to side-effects of adenosine. CMRI

led to conventional or CT-scanning angiography in 6

patients, and resulted to a change in treatment in 7

(17.9%), including coronary artery bypass grafting in 2

(5.2%).

Conclusion: CMRI is a reliable imaging tool for CAA and

cardiac function during follow-up of KD when compared

to echocardiography. In the near future functional CMRI

may replace the recommended conventional angiography

and nuclear left-ventricle scanning for follow-up after

KD, as being sensitive, non-invasive and radiation-free.

P57 Functional cardiac magnetic resonance imaging for non-invasive assessment of cardiovascular disease folluwing kawasaki Disease

Bastiaan Schouten1, Anders O.J. van Thuijl2, Betty C.A.M. van

Esch1,3, Bart R.J. Blokhuis1, Tom Groot Kormelink1, Gerard A. Hof-

man1, Guido E. Moro4,, Günther Boehm5,6, Sertac Arslanoglu4, Linette

E.M. Willemsen1, Léon M.J. Knippels3, Aline B. Sprikkelman2, Wim

M.C. van Aalderen2, Frank A. Redegeld1 and Johan Garssen1,3

1Department of Pharmacology and Pathophysiology, Utrecht Insti-

tute for Pharmaceutical Sciences, Faculty of Science, Utrecht Univer-

sity, Utrecht, The Netherlands; 2Department of Pediatric Respiratory

Medicine and Allergy, Emma Children’s Hospital, Amsterdam, The

Netherlands; 3Danone Research - Centre for Specialised Nutrition,

Wageningen, The Netherlands; 4Center for infant Nutrition, Mac-

edonio Melloni Maternity Hospital, Milan, Italy; 5Danone Research

- Centre for Specialised Nutrition, Friedrichsdorf, Germany; 6Sophia

Children’s Hospital, Erasmus University, Rotterdam,The Netherlands

Background: Cow’s milk allergy (CMA) is affecting 2.5%

of young infants. A substantial number of patients has

no detectable cow’s milk specific serum immunoglobulin

(Ig)E. In previous studies it was observed that allergic

sensitization of mice to the major cow’s milk allergens,

casein and whey, led respectively to non-IgE and IgE im-

munoglobulin profiles.

Objective: To investigate the mechanism of the IgE-

independent hypersensitivity response to casein with

respect to immunoglobulin free light chains (Ig-fLC) in

mice and children with and without CMA.

Methods: Animal study: Mice were orally sham- ca-

sein- or whey-sensitized. Acute allergen specific skin

responses were determined, serum IgE and Ig-fLC were

measured. Ig-fLC dependency was investigated using a

specific blocker and passive transfer studies of spleen

supernatants. Human study: Ig-fLC concentrations were

determined in plasma of children with CMA and non-

allergic controls.

Results: Animal study: After sensitization, no specific

IgE was detectable in serum of casein-sensitized mice,

while in whey-sensitized mice specific IgE was enhanced.

Instead, Ig-fLC levels were increased in serum from

casein-sensitized mice. Furthermore, blocking Ig-fLC

strongly diminished allergic skin responses in casein-

sensitized mice. Also allergic sensitization could be trans-

ferred using spleen cell culture supernatant from casein-

sensitized mice and was found to be Ig-fLC dependent.

Human study: Significant higher Ig-fLC concentrations

were measured in children with CMA as compared to

non-allergic controls.

Conclusions: The results of the mice study indicate

that sensitization with cow’s milk proteins can lead to

both IgE-dependent and Ig free light chain-dependent

allergic hypersensitivity responses. As free light chains

were significantly increased in children with CMA in

comparison with non-allergic controls, the possible

clinical relevance of Ig-fLC was further substantiated.

These findings suggest an important role of Ig-fLC in the

diagnosis and pathophysiology of CMA.

P58 Contribution of IgE and Immunoglobulin free light chain in the allergic reaction to cow's milk proteins

Joost A. Aalberse1,2, Anders O. van Thuijl3, Maarten O. Hoekstra1, Wilco de Jager2,

Tjitske van der Palen-Merkus4, Aline B. Sprikkelman3, Berent J. Prakken2 and Femke

van Wijk2

1Department of General Paediatrics, 2Centre for Molecular and Cellular Intervention;

Department of Paediatric Immunology, Wilhelmina Children's Hospital, Utrecht,

Netherlands, 3Department of Pediatric Respiratory Medicine and Allergy, Emma

Children’s Hospital, Amsterdam, Netherlands, 4Department of Immunopathology,

Sanquin, Amsterdam, Netherlands.

Background:

Different patterns of cytokines can initiate, maintain or suppress the

occurence of an allergic immune response. In the current study we

addressed the question whether there is a different cytokine profile in

plasma of children previously sensitized and/ or allergic to peanut that

either remained allergic or became tolerant to peanut later in childhood.

Objective:

The purpose of this study was to compare plasma cytokine levels in

peanut allergic and peanut tolerant children.

Methods:

A panel of 18 cytokines was measured in thirty children (age 3-17 years)

suspected of peanut allergy, who performed a double-blind placebo-

controlled food challenge. Next, to understand the potential role of two

outstanding cytokines more clearly, IL-17 and IL-25, were also tested in

three control groups, namely a younger group of food allergic children

(age <12 months) suspected of cow milk allergy (n=32), secondly an age

matched healthy control group (n=20), and finally an age matched group

of children with juvenile idiopathic arthritis, a Th1-disease (n=20).

Results:

IL-25 was highly elevated only in children with a proven peanut allergy

(figure 1). These high levels of IL-25 were not measured in non-peanut

allergic children, nor in young food allergic infants, in healthy controls

or in children with juvenile arthritis. Interestingly IL-17 was lower in

peanut responsive- than in the peanut tolerant children. We did not

find differences in the conventional Th2 cytokines, IL-4, IL-5 and IL-13.

Conclusion:

Our data indicate that IL-25 is a prominent secreted cytokine only in

children with a clinical allergic response to peanut. In combination

with the finding that IL-17 is more secreted in peanut tolerant children,

this study suggests that the IL-17 cytokine family plays an important

role in peanut allergy.

P59

Plasma IL-25 contributes to a peanut allergic response in children

Figure 1. Plasma IL-25 cytokine levels in children suspected of peanut and cow’s milk allergy who performed a double blind placebo controlled food challenge

(with positive or negative result), children with juvenile idiopathic arthritis (JIA) and healthy non-allergic controls.

W.F. Tromp1, J.H. van der Lee2, M. Offringa2 and J.W. Groothoff1

1Department of Pediatric Nephrology Emma Children’s Hospital AMC Amsterdam 2Department of Pediatric Clinical Epidemiology Emma Children’s Hospital AMC

Amsterdam

Introduction:

Applanation tonometry by SphygmoCor is frequently used to measure

Pulse Wave Velocity in adults and children. However, its validity in

children is uncertain since most reports lack data on reproducibility.

We studied the intra-observer variability of the carotid-femoral Pulse

Wave Velocity (PWVcf) in children with End Stage Renal Disease.


PWVcf was measured twice in 48 children with End Stage Renal Disease

using applanation tonometry (SphygmoCor) by a single well trained

investigator during one visit. Intra-observer reproducibility was as-

sessed by the Bland-Altman method. Coefficient of variation (CV) was

calculated and compared to reported CVs in studies in adults.

Results:

he mean difference [95% Confidence Interval] between the repeated

measurements was 0.16 [-0.01 - 0.32] m/s. The Limits of Agreement

were -0.91 - 1.23 m/s (Fig. 1). Splitting up the group by age (6-10 years,

n=16, and 11-18 years, n=32) made almost no difference (Mean Diff.

[95% Confidence Interval] 6-10 years: 0.12 [-0.17 - 0.40] m/s LoA: -0.95 -

1.19 m/s (Fig. 2a) and Mean Diff. [95% Confidence Interval] 11-18 years:

0.18 [-0.01 - 0.38] m/s and LoA -0.89 – 1.26 m/s (Fig. 2b). CV was 6 %,

relatively low compared to reported CVs in studies in adults.

Conclusion:

In children PWVcf changes, measured with the SphygmoCor by a single,

well-trained observer, smaller than 1.23 m/s cannot be distinguished

from measurement error, despite the fact that the CV is lower than

those presented in adult studies, where the feasibility might be better.

This device is not suitable for pediatric studies.

Figure 2b. Intra-observer variability SphygmoCor in children aged 11-18 years

Figure 1. Intra-observer variability SphygmoCor in a pediatric population with End

Stage Renal Disease

Figure 2a. Intra-observer variability SphygmoCor in children aged 6-10 years

P60

Intra-observer variability of pulse wave velocity measurement in children

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M. van Veenendaal1, M. Maas2, J.M. van den Berg1,3, K.M.

Dolman1,3, J. Swart3, J. Anink1, R. Hemke2, E. Deurloo2, R.R. van

Rijn2, T.W. Kuijpers1, M.A.J. van Rossum1,3

1 Emma Children’s Hospital, Academic Medical Center (AMC),

Dept of Pediatric Rheumatology, 2AMC, Dept of Radiology, 3Jan

van Breemen Institute (JBI), Dept of Rheumatology, Amsterdam,

the Netherlands

Background:

MRI has shown to be superior in detecting inflamma-

tory changes and early damage in the joint. The objec-

tive of our study was to investigate the use of an open

MRI in evaluating children with juvenile idiopathic

arthritis (JIA) compared to clinical and conventional

radiographic assessment.


We analyzed data of 77 patients (> 5 years) who

underwent an open non-enhanced MRI. The target

joints were selected by the treating physician and all

patients had a rheumatologic work-up including X-rays

of the selected joints. Clinical and radiological data

were related with the MRI results.

Results:

The mean age was 12 years (range 6-18) and 65% was

female. The study group consisted of 30 new patients

suspected for JIA (group I), 19 JIA patients with clini-

cal exacerbation of arthritis (group II) and 28 patients

with clinical remission (group III). Target joints

comprised 65% knees, 22% wrists and 13 % ankles.

MRI findings in group I showed in 20% findings not

recognized by clinical examination or X-ray, such

as joint erosions and orthopedic pathology. Group

II, with recurrence of arthritis, 10% did not show

synovitis on MRI however clinically suspect. Although

clinically considered in remission 61% in group III

had synovitis on MRI. Damage (erosions or joint space

narrowing) was observed in 23% as compared to 9% by

conventional X-rays.

Conclusion:

MRI is a valuable tool for detection of joint inflam-

mation and is often superior to clinical examination.

Furthermore it is more sensitive than conventional

joint radiographs in detecting early damage.

P61

Value of non-enhanced open-MRI in the evaluation of juvenile arthritis

E.J. Verhoof, H. Maurice-Stam, H.S.A. Heymans,

M.A. Grootenhuis

Psychosociale Afdeling, Emma Kinderziekenhuis AMC

Background:

A growing number of young adults with a somatic

disorder since childhood is claiming a Wajong-benefit,

a Dutch benefit for partially disabled who have not

yet joined the work force (Wajongers). Despite care-

ful guidance and support, many Wajongers are not

successfully integrating into workforce. We assume

that the achievement of milestones while growing

up (course of life) is related to job participation. The

aim of this study was to assess the course of life of

Wajongers with a somatic disorder since childhood

compared to peers from the general population.

Methods:

Young adults aged 22 to 30, who have claimed a

Wajong-benefit in 2003 or 2004 at the UWV because of

a somatic disorder, completed among others the Course

of Life Questionnaire. This instrument assesses the

achievement of developmental milestones (Autonomy,

range 6-12; Psycho-sexual, range 4-8; Social develop-

ment, range 12-24), and risk behaviour (Anti-social

behaviour, range 4-8; Substance use and gambling,

range 12-24). Differences between Wajongers and peers

from the general Dutch population were tested using

analysis of variance by group, age and gender.

Results:

Wajongers (N=416; response rate approximately 31%)

scored significantly lower (p<0.001) than their peers

(N=500) on all course of life domains: autonomy (8,7

versus 9,5), psychosexual (6,3 versus 7,1), social (19,1

versus 21,0), antisocial behaviour (4,3 versus 4,7) and

substance use and gambling (13,5 versus 15,0).

Conclusions:

Young adults with a Wajong-benefit because of a

somatic disorder since childhood are at risk of a

delayed course of life. Further research is directed at

correlations of course of life with job participation.

More insight into determinants of integration into

workforce will enable us to intervene during treat-

ment in childhood.

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Course of life of young adults with a Wajong-benefit as a result of a somatic disorder since childhood

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J.L. Vogelzang¹; dr. J.W. Groothoff¹; dr. K.J. Jager²; prof. dr.

H.S.A. Heymans³

1Emma Children’s Hospital AMC Amsterdam, Department of

Pediatric Nephrology

²AMC Amsterdam, Department of Clinical Epidemiology

³Emma Children’s Hospital AMC Amsterdam

Background:

The LERIC study (Late Effects of Renal Insufficiency

in Children), 1998-2000, is a long-term follow up study

which describes the late somatic, social and psycholog-

ical consequences in renal insufficiency in children.

The cohort consisted of all 249 patients who started

chronic renal replacement therapy at age <15 years

between 1972 and 1992 and who were born before 1979.

Mean age of living patients was 30 years (range 20-42).

In this study, we found a 40 times increased mortal-

ity risk, cardiovascular disease accounting for most

deaths. Mean arterial wall stiffness of all patients

was increased as compared to the normal population.

39% of all female and 47% of all male patients had

apparent left ventricular hypertrophy. 40% of all liv-

ing patients had apparent co-morbidity. The risk for

malignancies was 10 times increased. The mean IQ was

-10 points as compared to the Dutch population. This

study is designed as a 10 years follow up study.

Methods:

All eligible 187 patients of the LERIC cohort who

were alive in 2000 are included. Data on therapeutic

characteristics and outcome covering the period 1999-

2009 will be derived from all available medical charts.

Outcome measures include mortality, causes of death

and co-morbidity with special focus on malignancies

and cardiovascular disease and its determinants. Also,

we will evaluate the prospective value of arterial

wall and cardiac ultrasound measurements in 1999.

Patients who participated in the former cross-section-

al part of the study will be contacted to in order to

establish their current psychosocial status. Data on

mortality and causes of death will be compared with

data from the ESPN and ERA-EDTA database. The

study will take place between November 2009 and

November 2012.

Results and discussion:

Results will be reported from 2010.

P63

Leric-2: late effects of renal insufficiency in children – a 10 years follow up study

Michel van Weeghel1, Heleen te Brinke1, Ronald J.A. Wanders1,2,

Sander M. Houten1,2

1Department of Clinical Chemistry, Laboratory Genetic Metabolic

Diseases, 2Department of Pediatrics, Emma Children’s Hospital,

Academic Medical Center, University of Amsterdam, Meib-

ergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Introduction:

Mitochondrial β-oxidation of saturated and unsatu-

rated fatty acids plays a pivotal role in metabolism

and energy homeostasis in organs such as the liver,

heart and muscle. Mitochondrial 3,2-trans-enoyl-

CoA isomerase (mECI) is an auxiliary enzyme of the

mitochondrial β-oxidation of unsaturated fatty acids,

which catalyzes the isomerisation of the double bond

in cis-3-enoyl-CoA or trans-3-enoyl-CoA to trans-2-

enoyl-CoA. After isomerisation, trans-2-enoyl-CoA

re-enters the β-oxidation cycle. Interestingly, a

deficiency of mECI has not yet been found in humans.

However, a mECI KO mouse (dci -/- mouse) was recently

described. Upon fasting, dci -/- mice had a fatty liver

with increased unsaturated fatty acyl chains. In addi-

tion, the dci -/- mouse showed dicarboxylic aciduria. The

dci -/- mouse could therefore be a good model to identify

the potential presentation of human mECI deficiency.

In this study, we characterised the dci -/- mouse.


Wild type and dci -/- mice were placed in a metabolic

cage and urine was collected for three days. On the

last day the mice were fasted for 24h, sacrificed and

dissected. Biochemical studies were performed in

plasma, urine, tissues and fibroblasts.

Results/conclusion:

Upon fasting, the dci -/- mouse showed hypoglycaemia

and slightly elevated levels of unsaturated acylcar-

nitines in plasma and blood. Surprisingly, there was

no accumulation of unsaturated acylcarnitines in

tissues. Moreover oleate oxidation in dci -/- fibroblasts

was normal, providing challenging questions for our

future studies.

P64

Characterisation 3,2-trans-enoyl-coa isomerase deficient mice

C.S. van Woerden1, M. Zwols2, F.C.B. Abbad2, F.D. Muskiet2

1,2Academic Medical Center, Department of Pediatrics, University of Amsterdam,

Amsterdam, The Netherlands and 2St Elizabeth Hospital, Department of Pediatrics,

Curaçao, Netherlands Antilles. E-mail: [email protected]

Background:

Bacterial infections frequently occur in febrile infants. No information

is available about the incidence of serious bacterial infections in infants

in our hospital. Our aim is to investigate the incidence of infections in

young infants less than 12 months of age, in relation to age and labora-

tory parameters.


Retrospective cohort study in a pediatric referral hospital; review of

clinical and laboratory data of patients below 12 months of age, admit-

ted with fever or history of persistent fever. Review period: between

January 2007 and December 2007.

Results:

Sixty-three patients were selected for the study. Bacterial infections

were found in 11 of them (17%) mostly occurring as urinary tract infec-

tions (eight out of 11, 73%), with E. coli as the predominant pathogen in

four. Of all children with bacterial infections, 64% was less than three

months of age. Viral cultures were occasionally performed and showed

positive results in three patients. Median level of CRP (range) was 69

(0-230) mg/l in patients with positive cultures and median level of CRP

(range) was 5 (0-240) mg/l in patients without positive cultures.

Conclusions:

Serious bacterial infections occur predominantly in infants below three

months of age, mostly as urinary tract infections. Levels of infection

parameters may vary widely in patients even in the absence of a proven

bacterial pathogen. Complete sepsis work-up including urine culture is

warranted in febrile infants.

P65

Epidemiology of infections in infants less than 12 months of age – the curaçao experience

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0Aalberse, J.A. 35

Aalderen, W.M.C van 13, 20, 34

Abbad, F.C.B. 39

Abbink, F. 12

Abeling, N.G. 19

Akyüz, M. 12

Altemeier, W.A. 3

Anink, J. 37

Aronson, D.C. 13

Arslanoglu, S. 34

Baan-Slootweg, O.H. van der 13

Bams-Mengerink, A.M. 2

Bem, R.A. 2, 3

Benninga, M.A. 8, 10, 13, 25

Berfelo, F.J. 3

Berg, E. van den 3

Berg, J.M. van den 15, 37

Besancon, O.G. 4

Biemond, B.J. 29

Bierau, J. 24

Bilardo, C.M. 9, 10

Bleeker G. 5, 6

Blokhuis, B.R.J. 34

Boehm, G. 34

Boer, M.L. den 27

Bom, J.G. van der 11

Borgie, C.A.J.M. de 28

Bos, A.F. 17

Bos, A.P. 2, 3

Bosch, A.M. 19

Bouwman, M.G. 7

Bredius, R. 12

Bresters, D. 28

Brinke, H. te 19, 38

Broek, A. 26

Brons, P. 12

Bruijn, L. de 14

Brussel, P.M. van 9, 10

Bunders, M. 8

Burgers, R. 8

Calis, J. 21

Canon, S. 8

Caron, H.N. 4, 5, 6, 16, 23, 25, 27, 28, 32, 33

Claassen, A.T.A.M 30

Clifford, S.C. 27

Clur, S.A. 9, 10

Cobben, J.M. 17

Cohen, A.P. 15, 20, 26

Dalen, E.C. van 28, 32

Davidson, G.P. 25

Delattre, O. 27

Derkx, B.H. 26

Derkx, H.H.F. 15, 20

Detmar, S.D. 12

Deurloo, E. 37

Die-Smulders, C.E.M. de 24

Dijk, E.M. van 26

Dijk, M. van 10

Dijkstra, I.M.E. 12, 21, 22

Dolman, K.M. 15, 37

Domachowske, J.B. 2

Dors, N. 33

Duran, M. 2

Ebus, M.E. 25

Eck, B.L.F. van 5

Eckhardt, C.L. 11

Eck-Smit, B.L.F. van 6

Engelen, M. 12, 22

Engelen, V. 12, 16

Engen, C.E. van 12, 22

Esch, B.C.A.M. van 34

Essen-Zandvliet, E.E.M. van 13

Eykern, L.A van 20

Falix, F.A. 13

Fijnvandraat, K. 11, 18, 29, 33

Fowler, B. 24

Francois, B. 19

Frey, U. 20

Gaemers, I.G. 13

Garssen, J. 34

Geel, B. van 12

Geloven, N. van 18

Geoerger, B. 27

Geskus, R.B. 29

Govaert, P. 3

Griendt, E.J. van de 13

Groenendaal, F. 3

Groenink, M. 34

Grootenhuis, M.A. 10, 12, 15, 16, 18, 26, 27, 31, 32, 37

Groothoff, J.W. 31, 36, 38

Grotenhuis, H.B. 14

Haan, T.R. de 3

Ham, K. van 15

Haverman, L. 15, 16

Heide, M. van der 17

Heijboer, H. 18, 29, 33

Heij, H.A. 5

Hemke, R. 37

Hemmink, M.J. 30

Hennekam, R.C.M. 24

Hennermann, J.B. 24

Hensbroek, M.B. van 21

Herrewegen, F. van 33

Heymans, H.S.A. 16, 37, 38

Hijmans, C.T. 18

Hoedt, A.E. ten 19

Hoekstra, M.O. 35

Hofman, G.A. 34

Hoften, J. van 17

Hollak, C.E.M. 7, 19

Horst, N.M. ter 19

Houten, S.M. 19, 38

Houtzager, B.A. 29

Hus, J.W.P. van 29

Hutten, G.J. 20

Jager, K.J. 38

Jager, W. de 35

Jagt, Y.Q. 15, 20

Janssen, M.C.H. 19

Jonker, F. 21

Index

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Kamphuisen, P.W. 11

Keating, P. 17

Kemp, S. 12, 21, 22

Klassen, A. 27

Knippels, L.M.J. 34

Knops, R.R.G. 23

Knottnerus, A.C. 15, 20, 26

Koelman, J.H.T.M. 2

Koff, S. 8

Kohnhorst, E. 15, 20, 26

Kok, J.H. 17, 29

König, A. 24

Koopman, H.M. 12

Koot, B.G.P. 28

Kormelink, T.G. 34

Koster, J. 25

Kraker, J. de 5, 6

Kremer, L.C.M. 28, 32

Kroft, L.J.M. 14

Kuijpers, T. 8

Kuijpers, T.W. 15, 16, 34, 37

Kuilenburg, A.B.P. van 4, 24

Kuipers, I.M. 31, 34

Lamers, F. 25

Lamers, W.H. 13

Lanvers, C. 27

Last, B.F. 10, 29, 32

Latzin, P. 20

Leclercq, E. 28

Lee, J.H. van der 31, 36

Leen, R. 4

Leenstra, T. 21

Legdeur, M.A. 28

Liem, O. 8

Linthorst, G.E. 7

Loke, Y.K. 28

Loos, C. van der 8

Loots, C.M. 25

Lopaschuk, G.D. 19

Lorenzo, C. Di 8

Lutter, R. 2

Maas, M. 37

Macke, K. 24

Majoie, C.B. 23

Markusse, I.M. 26

Martin, T.R. 3

Mastenbroek, S. 17

Mathijssen, I.B. 28

Matute-Bello, G. 3

Maurice-Stam, H. 26, 27, 32, 37

Medema, J.P. 2

Meijer, J. 24

Meijer-van den Bergh, E. 26

Meinsma, R. 24

Miny, P. 24

Molenaar, J.J. 25, 27

Mori, A.C. 24

Moro, G.E. 34

Mousa, H. 8

Mul, A.N.P.M. 24

Mulder, R.L. 28

Muskiet, F.D. 39

Naald, M. van der 11

Nicolai, J. 24

Offringa, M. 36

Ofman, R. 21, 22

Omari, T.I. 25

Ommen, C.H. van 3

Oosterlaan, J. 18, 31

Ottenkamp, J. 9, 10, 14

Palen, J. van der 13

Palen-Merkus, T. van der 35

Pals, S. 8

Peters, H.E. 28

Peters, M. 11, 18, 28, 29, 33

Pietsch, T. 27

Plas, E.M. van der 29

Ploeg, I. van der 25

Poll-The, B.T. 2, 3, 12

Postma, A. 28

Post, P.N. 28

Potharst, E.S. 29

Prakken, B.J. 35

Redegeld, F.A. 34

Rijn, R.R. van 37

Roos, A. de 14

Rosenberg, H.F. 2

Rossum, M.A.J. van 15, 16, 37

Royé, G. 30

Rubio-Gozalbo, M.E. 19, 24

Ruiter, M.A. de 31

Sass, J.O. 24

Schoenmaker, N.J. 31

Scholten, L. 32

Schoot, C.E. van der 33

Schoot R.A. 5

Schouten, B. 34

Schouten-van Meeteren, A.Y.N. 23, 31

Schuengel, C. 32

Schutte-Lensink, N. 12

Serra, M. 27

Shipley, J. 27

Sieswerda, E. 32

Smets, E.M.A. 28

Sonneville, L.M. de 19

Sprikkelman, A.B. 34, 35

Strijbos, M. 15, 20

Strohm, S. 27

Stutterheim, J. 33

Suijker, M. 33

Swart, J. 15, 37

Tacke, C.E.A. 34

Tamminga-Smeulders, C.L.J. 13

Teunissen, Q.G.A. 7

Thuijl, A.O.J. van 34, 35

Tromp, W.F. 36

Tweel, X.W. van den 29

Twisk, M. 17

Tytgat, G.A.M 4, 6, 33

Vassal, G. 27

Veenendaal, M. van 15, 37

Verhoof, E.J. 37

Vermeulen, J.R. 3

Verschuur, A.C. 4, 27

Versteeg, R. 6, 25, 27

Vijzelaar, R. 24

Visser, M. de 12

Vliegen, H.W. 14

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Vogelzang, J.L. 38

Vries, L.S. de 3

Vrijmoet-Wiersma, C.J.M. 26

Wagg, C. 19

Wanders, R.J.A. 12, 19, 21, 22, 38

Wassenaer, A.G. Van 29

Weber, P. 24

Weeda, V.B. 13

Weeghel, M. van 38

Westenberg, J.J.M. 14

Westerhout, E.M. 27

Wetering, M.D. van de 12

Wezel-Meijler, G. van 3

Wielenga, J.M. 30

Wijburg, F.A. 7, 19

Wijk, F. van 35

Willemen, A.M. 32

Willemsen, L.E.M. 34

Woensel, J.B.M. van 2, 3

Woerden, C.S. van 39

Ylstra, B. 24

Zappeij-Kannegieter, L. 33

Zoetekouw, L. 24

Zwieten, M.C.B. van 7

Zwols, M. 39

PCA_symposium 06-01-2006 09:36 Pagina 31

Verkort IB-tekst:

Samenstelling: CARNITENE bevat L-carnitine en is verkrijgbaar als: CARNITENE tabletten, 330 mg, CARNITENE drank 1 gram/ 10 ml (100 mg/ml) CARNITENE injectievloeistof, 1 gram / 5 ml(200 mg/ml). Indicaties: Primaire (systemische) carnitine deficiënties, Eigenschappen: CARNITENE, L-carnitine (y-trimethylamino-B-hydroxybutyraat) is een lichaamseigen stof. L-carnitine wordtbij de mens hoofdzakelijk gevormd door endogene synthese uit lysine en methionine in de lever en de nier, maar kan ook verkregen worden uit de voeding. De L-isomeer, is biologisch actief enspeelt een essentiële rol zowel in het lipide metabolisme als in het metabolisme van ketonlichamen en vertakte-keten aminozuren. L-carnitine is noodzakelijk voor het transport van lang-keten vet-zuren over het binnenmembraan van de mitochondria naar de mitochondriale matrix, waar de B-oxidatie plaatsvindt met als resultaat productie van ATP. Bij een systemische carnitinedeficiëntie iser een tekort aan L-carnitine in het serum en in een of meerdere weefsels. De meest voorkomende symptomen van een systemische carnitine-deficiëntie zijn: 1. manifestatie begint in de eerstelevensjaren, 2. acute episoden van encefalopathie (braken gevolgd door een progressief verlopende stupor, verwarring en coma) die geassocieerd wordt met leverfunctie stoornissen, zeer vaakgeïnduceerd door een verminderde opname en/of fysieke inspanningen, 3. progressieve spierfunctie achteruitgang, 4. vetopstapeling in de spier- en andere weefsels (lever, nier enz.), 5. sterk ver-laagde carnitinespiegels zowel in het bloed als in weefsel. Laboratorium onderzoek toont aan een hypoglykemie, een verhoging van CPK en leverenzymen in het serum, verhoogde ketose tijdensvasten, EMG (electromyogram) veranderingen. De rationale om patiënten met een carnitinedeficiëntie te behandelen met L-carnitine ligt in het normaliseren van de weefselspiegels en/of deze in overeenstemming te brengen met de behoefte vanhet organisme op dat moment en de spierfunctie te herstellen. Waarschuwingen voorzorgsmaatregelen: Daar L-carnitine slechts in geringe mate gemetaboliseerd wordt, en als L-carnitine doorde nier wordt uitgescheiden, wordt bij patiënten met een verminderde nierfunctie (GFR < 10 ml/min) aangeraden de medicatie te doen plaatsvinden op geleide van plasmaspiegels. Toediening vaneen hoge orale doses Levocarnitine gedurende lange perioden wordt niet aanbevolen in patiënten met een chronische nierinsufficiëntie, die gedialyseerd worden. Er vindt dan een cumulatie plaatsvan belangrijke metabolieten zoals trimethylamine (TMA) en trimethylamine-N-oxide (TMAO) omdat deze niet in voldoende mate door de nier geëlimineerd kunnen worden. Dit verschijnsel treedt nietin dezelfde mate op na intraveneuze toediening. Een cumulatie van TMA is nadelig omdat hiermee de stikstofhoudende afval producten die door dialyse verwijderd worden, verhoogd wordt. Boven-dien worden de verhoogde TMA spiegels geassocieerd met neurofysiolosche effecten. De onvolledige eliminatie van TMA kan resulteren in de ontwikkeling van een vislucht geur. Indien overwogenwordt om deze patiënten levocarnitine toe te dienen wordt aangeraden dit intraveneus te doen. Gebruik in de zwangerschap: Over het gebruik van deze stof in de zwangerschap bij de mensbestaan onvoldoende gegevens om de mogelijke schadelijkheid te beoordelen. Er zijn tot dusver geen aanwijzingen verkregen voor schadelijkheid bij dierproeven. Bijwerkingen: Een lichte vormvan diarree bij sommige patiënten is na hoge orale toediening gerapporteerd. Dosering: De dosering wordt bepaald door de mate van carnitine deficiëntie. Indien mogelijk moet op geleide van car-nitine bloed-/weefselspiegels behandeld worden.

Primaire (systemische) carnitine deficiëntie. Aanbevolen wordt de volgende dosering per os per dag:Zuigelingen 100-150 mg/kg lichaamsgewicht Kinderen tot 12 jaar 50-100 mg/kg lichaamsgewicht Volwassen en kinderen boven de 12 jaar 20-40 mg/kg lichaamsgewicht

In de praktijk betekent dit dat de gemiddelde dosering per os per dag ligt voor: Zuigelingen 1 gram Kinderen tot 12 jaar 2 gram Volwassen en kinderen boven de 12 jaar 2-4 gram (in twee a drie giften)

Indien er geen verbetering optreedt in de klinische en biochemische symptomen/spierzwakte, kan de dosering verhoogd worden tot 15 gram per dag, gedurende korte tijd. De CARNITENE injectie-vloeistof is bedoeld voor acute gevallen en wanneer toediening per os niet mogelijk is. De injectievloeistof dient langzaam (3 minuten) intraveneus toegediend te worden. Met de intraveneuze vormkan met lagere doseringen (maximaal 30 mg/kg lichaamsgewicht per dag) worden volstaan, gezien de volledige beschikbaarheid van de stof na i.v. toediening ten opzichte van < 10% na orale toe-diening.

Onderverdeeld naar leeftijd betekent dit per dag: Zuigelingen maximaal 30 mg/kg lichaamsgewichtKinderen tot 12 jaar maximaal 20 mg/kg lichaamsgewichtVolwassen en kinderen boven de 12 jaar maximaal 10 mg/kg lichaamsgewicht

Registratie: Ingeschreven in het register onder: RVG 11192 CARNITENE sigma tau injectievloeistof 1 gram RVG 11193 CARNITENE sigma tau drank 1 gram RVG 11194 CARNITENE sigma tau tabletten 330 mg Registratiehouder: Sigma Tau Ethifarma B.V., Postbus 10072, 9400 CB Assen. Voor inlichtingen: Sigma Tau Ethifarma B.V.,Postbus 10072, 9400 CB Assen, telnr. 0592 333000.

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Dos Medical BV Tel 073 64 44 831 Fax 084 22 88 954 www.dermel.nl

verbetert de huidbarrière

verlaagt de kolonisatie van S. aureus op de huid

wondhelend, ontstekingsremmend

geschikt voor baby’s, kinderen en volwassenen

bevat geen corticosteroïden

wordt volledig vergoed

de basisbehandeling bij constitutioneel eczeem

gratis proefverpakking aanvragen via www.dermel.nl

1627-Pag-12 13-04-2004 11:39 Pagina 1

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