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A. Kafatos, C. Hatzis, M. Linardakis, D. Athanasopoulos, C. Lionis, E. Balomenaki,A. Kapnisakis, H. Stamataki and Collaborativeresearchers
107 Thyroid volume, prevalence of subclinical
hypothyroidism and autoimmunity in
children and adolescents
I. Kaloumenou, L. Duntas, M. Alevizaki, G. Mastorakos, E. Mantzou, A. Antoniou, C. Ladopoulos, C. Mengreli, D. Chiotis, I. Papassotiriou, C. Dacou-Voutetakis
115 Neurodevelopmental outcome of very low
birth weight neonates at preschool age
H. Bouza, I. Antoniadou, H. Antonopoulou, M. Anagnostakou, F. Anatolitou, M. Morosini, J. Sarafidou, ª. Xanthou
123 Radiofrequency catheter ablation of
accessory pathways in children: immediate
and long-term results
J. Papagiannis, G. Kirvassilis, I. Sofianidou, C. Laskari, M. Kiaffas, S. Apostolopoulou, S. Rammos
135 Use of alternative and complementary
therapy by paediatric oncology patients
in Greece
A. Pourtsidis, D. Doganis, M. Baka, M. Varvoutsi,D. Bouhoutsou, P. Xatzi, H. Kosmidis
141 The epidemiology of chickenpox in school-
age children from the prefecture of Attica
∞. Katsafadou, V. Papaevangelou, G. Ferentinos,A. Constantopoulos
CASE REPORTS
146 Homocystinuria due to cystathionine
‚-synthase deficiency: two sides to the
same coin
P. Augoustides-Savvopoulou, H. Ioannou, N. Kozeis, A. Karagiannidou, M. Athanasiou-Metaxa
152 Neurocysticercosis in childhood:
a case report
M. Theodoridou, V. Vasilopoulou, A. Zisouli, G. Mostrou, V. Syriopoulou
156 PAEDIATRIC NEWS IN BRIEF
∂. Galanakis
158 CLINICAL QUIZ
C. Costalos
159 NEWS FROM THE INTERNET
Adolescent health websites
N. Papadopoulos
163 LETTER TO THE EDITOR
Obituary: R. J. Gorlin
C. S. Bartsokas
PaediatrikiVolume 70 ñ Number 2 ñ March-April 2007
Pediatr Mar-Apr 07 28-03-07 17:22 ™ÂÏ›‰·3
v™À¡∆∞∫∆π∫∏ E¶π∆ƒ√¶∏ EDITORIAL BOARD
ª¤ÏË Ù˘ ¢ÈÂıÓÔ‡˜ ™˘ÓÙ·ÎÙÈ΋˜ ∂ÈÙÚÔ‹˜ ñ Members of the International Editorial Board
Thank you for your kind comments on the improvements of the layout and the content of the journal.We would like to inform you that the new members of the Editorial Board are Dr Stella Andronikou(Neonatology), Dr Manolis Galanakis (Medical Ethics), Dr Sophia Kitsiou (Genetics) and Dr LorettaThomaidou (Developmental Pediatrics). These colleagues have long experience in their respective fields andwe believe that they will contribute to the success of the journal. Dr Christos Kostalos and Dr EleniAntonopoulou stepped down from the Editorial Board. We would like to thank them for their contribution.
The editorial process of the journal is handled electronically since the beginning of this year. All paperscan now be submitted by e-mail. Detailed information about the submission of articles is included in the“Instructions to authors” of this issue. We would like to emphasize the importance of compliance to thesuggested length of publications. We will be able to publish a larger number of papers if the manuscriptsare shorter. In addition shorter papers are more reader friendly. To save space you will find the“Instructions to authors” only in the first issue of each year and at the web page of the journal.
A new section: “Paediatric news in brief” will start from this issue with comments on recent pediatricarticles. We hope that you will find this section interesting. Educational articles will be included in thenext issues with multiple choice answers. Finally we invite you to send us questions that arise from yourevery day practice. These questions will become the topics of the new section: “Ask the expert”.
Warm greetings
Constantinos StefanidisEditor-in-Chief
Pediatr Mar-Apr 07 28-03-07 17:22 ™ÂÏ›‰·11
√¢∏°π∂™ ¶ƒ√™ ∆√À™ ™À°°ƒ∞º∂π™
A. °ÂÓÈΤ˜ ¶ÏËÚÔÊÔڛ˜∆Ô ÂÚÈÔ‰ÈÎfi “¶·È‰È·ÙÚÈ΋” Â›Ó·È Ë ÂÈÛÙËÌÔÓÈ΋ ¤Î-
H Û‡ÓÙ·ÍË ÙˆÓ ‚È‚ÏÈÔÁÚ·ÊÈÎÒÓ ·Ú·ÔÌÒÓ Á›ÓÂÙ·ÈÛ‡Ìʈӷ Ì ÙȘ ÚfiÛÊ·Ù· ÙÚÔÔÔÈË̤Ó˜ ÚԉȷÁڷʤ˜ Ù˘International Committee of Medical Journal Editors/ Uniform Re-quirements for Manuscripts Submitted to Biomedical Journals,(http://www.icmje.org Î·È http:// www.icmje.org/icmje.pdf). OÈÛ˘ÓÙÌ‹ÛÂȘ ÙˆÓ Ù›ÙÏˆÓ ÙˆÓ ÂÚÈÔ‰ÈÎÒÓ Á›ÓÔÓÙ·È Ì ‚¿ÛË ÙÔ Cu-mulated Index Medicus [List of Journals Indexed in Index Medi-cus(http://www.nlm.nih.gov/bsd/uniform_requirements.html)].
Proesmans W. Bartter syndrome and its neonatal variant. EurJ Pediatr 1997;156:669-679.
™˘ÌÏËڈ̷ÙÈÎfi Ù‡¯Ô˜ ÂÚÈÔ‰ÈÎÔ‡:
Flyvbjerg A. Role of growth hormone, insulin-like growth fac-tors (IGFs) and IGF-binding proteins in the renal complicationsof diabetes. Kidney Int 1997;52 (60 Suppl):S12-S19.
Èڛ˜ Û˘ÁÁڷʤ·:
National Institutes of Health Consensus DevelopmentConference. Neurofibromatosis conference statement. ArchNeurol 1988;45:575-578.
¶ÚÔÛ‰ÈÔÚÈÛÌfi˜ Ù‡Ô˘ ¿ÚıÚÔ˘:
Schreiner GF, Lange L. Ethanol modulation of macrophageinflux in glomerulonephritis [Abstract]. J Am Soc Nephrol1991;2:562.
Should antileukotriene therapies be used instead of inhaledcorticosteroids in asthma? [Editorial]. Am J Respir Crit Care Med1998;158:1697-1701.
Laux-End R, Inaebnit D, Gerber HA, Bianchetti MG. Vasculi-tis associated with levamisole and circulating autoantibodies [Let-ter]. Arch Dis Child 1996;75:355-356.
Gorlin RJ, Cohen MM, Levin LS. Syndromes of the head andneck. 3rd ed. New York: Oxford University Press; 1990.
¢ËÌÔÛ›Â˘ÛË Û ÙfiÌÔ Ú·ÎÙÈÎÒÓ:
Bauer AW. The two definitions of bacterial resistance. In:Smith AJ, Rogers CA, eds. Proceedings of the Third InternationalCongress of Chemotherapy; 1962 May 29-31; New York: Interna-tional Society of Chemotherapy; 1963. p. 484-500.
Kaplan SJ. Post hospital home health care: the elderly’s accessand utilization [dissertation]. St. Louis (Mo): Washington Univ.;1995.
πππ. CD-ROM
Anderson SC, Poulsen KB. Anderson’s electronic atlas ofhematology [CD-ROM]. Philadelphia: Lippincott Williams &Wilkins; 2002.
IV. ™∆O ¢π∞¢π∫∆ÀO
ÕÚıÚÔ Û ÂÚÈÔ‰ÈÎfi:
Abood S. Quality improvement initiative in nursing homes:the ANA acts in an advisory role. Am J Nurs [Internet]. 2002 Jun:Webpage:http://www.nursingworld.org/AJN/2002/june/Wawatch.htm
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xiv
ªÔÓÔÁÚ·Ê›·:Foley KM, Gelband H, editors. Improving palliative care for
cancer [Monograph, Internet]. Washington: National AcademyPress; 2001. Webpage: http://www.nap.edu/books/0309074029/html
πÛÙÔÛÂÏ›‰Â˜:Cancer-Pain.org [Webpage, Internet]. New York: Association of
Cancer Online Resources, Inc.; 2002: http://www.cancer-pain.org/
A. General InformationThe Greek Paediatric Society is the owner of “Paedia-
triki”, its official scientific journal, which is distributed to
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The Editorial Board reserves the right to publish articles
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Text
Original articles include: introduction, methods, resultsand discussion. The introduction includes the latest researchdata on the subject and the main references and the objec-tives of the paper. The description of the methods should beprecise and detailed so as to enable reproduction by other re-searchers. In addition, the statistical methods of analysis andevaluation of the results should be described. Results shouldbe presented clearly, together with the appropriate statisticalanalysis. Discussion should cover the results ensuing fromthe research, their significance and possible associations withthe observations of other researchers.
Case reports comprise a short introduction, case de-scription and brief discussion, with emphasis on differentialdiagnosis.
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Units of measures of laboratory analyses
Laboratory analyses should be expressed in the SystèmeInternational (SI) units and in the metric (Conventional)
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·18
xix
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Abbreviations
All issues of the journal contain internationally established ab-
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References
The reference section contains all references numbered in the
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to be indicated by Arabic numerals in parentheses. References
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ñ 70 in review articles;
ñ 40 in original articles;
ñ 20 in current issues and case reports;
ñ 10 in brief reports and letters.
In listing references follow the recently modified standards of
the International Committee of Medical Journal Editors/Uniform
Requirements for Manuscripts Submitted to Biomedical Journals,
(http://www.icmje.org and http:// www.icmje.org/icmje.pdf). Ab-
breviated names of journals should conform to the Cumulated In-
dex Medicus [List of Journals Indexed in Index Medicus
should state that the paper has not been published in part or in
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Delay in submission of the modified paper exceeding 30days entails new submission.
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Before submitting your paper by e-mail, make sure the filecontains:
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phone number;
2. English and Greek abstracts (200-250 words), with the follow-ing structure: background, methods, results and conclusions.
3. Keywords.4. List of abbreviations.5. Text.6. Acknowledgements and reference to funding, sponsorships
or other financial sources.7. References.8. Tables (one per page).9. Figures (one per page).
1. Anttila A, Ronco G, Clifford G, Bray F, Hakama M, Arbyn M, et al. Cervical cancer screening programmes andpolicies in 18 European countries. Br J Cancer 2004;91:935-941.
2. van Ballegooijen M, van den Akker-van Marle E, Patnick J, Lynge E, Arbyn M, Anttila A, et al. Overview ofimportant cervical cancer screening process values in European Union (EU) countries, and tentative predictionsof the corresponding effectiveness and cost-effectiveness. Eur J Cancer 2000;36:2177-2188.
3. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: cancer incidence. Mortality and prevalence worldwide.IARC cancer base no. 5, version 2.0. Lyon (France): IARC Press; 2004.
Homocystinuria due to cystathionine ‚-synthase deficiency
S. H. Mudd
83EDITORIAL COMMENTARY ∞ƒ£ƒ√ ™À¡∆∞•∏™
Laboratory of MolecularBiology, National Institute of Mental Health
Correspondence:
S. Harvey [email protected] 35, Room 1B100635 Convent DriveBethesda, MD 20892, USA
¶·È‰È·ÙÚÈ΋ 2007;70:83-84
In this issue of Paediatriki Persephone Au-goustides-Savvopoulou and coauthors describetwo cases of cystathionine ‚-synthase (C‚S) de-ficiency with emphasis on the clinical and meta-bolic identification of such patients, and the factthat proper treatment can help avoid adverse ef-fects of this genetic abnormality (1). This edito-rial attempts to clarify two nomenclatural issuesthat may make reading about this condition dif-ficult for non-specialists, and to expand uponaspects covered only briefly in the article inquestion (1).
The name of the condition. Homocystinuria(i.e. excessive urinary homocystine) was foundby Nina Carson and coworkers in 1962 amongmentally retarded Northern Irish children andindependently (and virtually simultaneously) byGerritsen and Waisman and by Barber andSpaeth in the United States (2). In 1964 deficientactivity of C‚S, the enzyme that catalyzes thecondensation of homocysteine with serine,forming cystathionine, was shown to be the un-derlying cause of the homocystinuria in Barberand Spaeth’s patient (2). For a few years there-after “homocystinuria” was used as a definitivename of a specific genetic abnormality. Howev-er, in 1969 a patient with excessive urinary ho-mocystine was shown to be unable to convert vi-tamin B12 to its coenzyme forms, methyl-B12 andadenosyl-B12, so that the methyl-B12-dependentmethylation of homocysteine back to methion-ine did not occur normally (3). This defect innow termed cblC (cobalamin C) disorder to dis-tinguish it from other inherited disorders ofcobalamin metabolism. In 1972 a different ho-mocystinuric patient was found to have yet an-other causative metabolic abnormality, severelydeficient activity of 5,10-methylenetetra-hydro-folate reductase (MTHFR), the enzyme thatforms methyltetrahydrofolate, a methyl donorfor methylation of homocysteine (4). [These re-actions are diagrammed in level (2) in Fig. 1 incitation (1)]. It thus became evident that “ho-mocystinuria” is a metabolic abnormality withmultiple causes, and that, to designate a specificdisease with this abnormality, it is important toname the underlying deficiency. In contrast tothe elevated methionine of C‚S deficiency, thetwo additional defects just discussed, as well as
others discovered more recently affecting homo-cysteine remethylation (5), are characterized bylow plasma methionine. A recent report indi-cates the brain damage of MTHFR deficiency isdue to lack of methionine rather than to elevat-ed homocysteine (6). Therefore, establishing theproper cause of a case of homocystinuria be-comes especially important: dietary methioninerestriction is often used beneficially in C‚S defi-ciency, but is contraindicated in a homocysteineremethylation defect.
Homocystine, homocysteine, and total homo-cysteine (tHcy). Homocystine is a disulfide withstructure RS-SR (where R=-CH2CH2CH(NH2)COOH, formed in the body from homocysteine,the metabolically active sulfhydryl form, RSH. Inplasma, homocystine greatly exceeds homocys-teine, and even more homocysteine moieties oc-cur as mixed disulfides bound to cysteine (RS-SR’) or protein cysteine (RS-S-Protein) (7). Ami-no acid chromatography usually measures ho-mocystine, but to measure the sum of the variousforms in which homocysteine moieties occur,modern methods cleave disulfide bonds, assaythe resulting homocysteine and term it “total ho-mocysteine” (tHcy) (7).
The present situation. Based on the experi-ence since 1962, and as described by Au-goustides-Savvopoulou et al (1), C‚S deficiencyis now known to occur in both B6-responsiveand B6-non-responsive forms, ultimately de-pendent upon the specific mutation(s) in the al-leles encoding C‚S (8). Untreated, B6-respon-sive individuals develop less severe clinical ab-normalities or manifest them more slowly. Forexample, in a survey including data for 231 B6-responsive patients and the same number of B6-non-responders, the median IQ among respon-ders was 78 versus 64 for non-responders; thechances of having been found to have dislocatedoptic lenses by age 10 years was 55% and 82%for responders and non-responders; of having athromboembolic event by age 15 years, 12% and27%; of having radiologically detectable spinalosteoporosis by age 15, 36% and 64%; and of notsurviving to age 30, 4% and 23% (9). However,there may have been ascertainment bias for thepatients included in that study, because, to be in-cluded, a patient had either to have some clinical
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·83
manifestation, to be a family member of a diagnosed
patient, or to have been detected by elevated blood
methionine at newborn screening. More recent ge-
netic screening of newborns in Denmark (10) or Nor-
way (11), or of unrelated German control subjects
(12) indicates the prevalence of homozygosity for the
I278T C‚S mutation might be as high as 1:20,500,
1:104,000 and 1:17,800 live births, in those countries,
respectively. Since homozygosity for I278T leads to
B6-responsiveness, and because B6-responders are
usually missed in newborn screening based upon ele-
vated blood methionine concentrations (8), it re-
mains possible that some of these patients may re-
main clinically normal throughout life, or that they
may be diagnosed only later in life if they present with
thromboembolic problems. As illustrated by the re-
port of Augoustides-Savvopoulou et al (1), and sup-
ported now by a variety of further evidence, treat-
ment of responders with pyridoxine and of non-re-
sponders by dietary methionine restriction, often
with betaine in addition, is clearly beneficial (8,9,13).
Much progress has been made also for the homo-
cystinurias due to remethylation defects. Particularly
noteworthy are: The recent identification of the gene,
MMACHC, mutations in which lead to cblC disor-
ders (14). The discovery of further cobalamin disor-
ders producing functional methionine synthase defi-
ciency (cblE and cblG). The cloning of the gene for
MTHFR and identification of several mutations in it
leading to severely deficient activity of that enzyme.
The discovery of the common MTHFR polymor-
phism, C677T, that leads to formation of a thermola-
bile enzyme and, in individuals with serum folate to-
ward the lower end of the reference range, to mild el-
evations of plasma tHcy. The current report that an
Amish baby shown by genetic screening at birth to be
homozygous for a severely inactivating MTHFR mu-
tation and treated early with betaine to maintain me-
thionine levels has been free of the irreversible mental
and developmental problems that affect other indi-
viduals homozygous for the same mutation, but
treated only at older ages (6).
The situation in Greece. It is of interest to the pre-
sent author that, in-so-far as he is aware, the patients
reported by Augoustides-Savvopoulou et al (1) are
the first individuals with homocystinuria due to C‚S
deficiency identified in Greece. On the current Jan
Kraus C‚S website (http://www.uchsc.edu/sm/cbs),
among the 559 alleles responsible for C‚S deficiency
the ancestries of which are shown, none is listed as of
Greek origin. Whether the Greek population is un-
usually free of inactivating C‚S mutations, or
whether individuals with such mutations are present,
awaiting ascertainment and treatment, may pose an
intriguing question for the physicians of Greece.
References
1. Augoustides-Savvopoulou P, Ioannou H, Kozeis N, Kara-
giannidou A, Athanasiou-Metaxa M. Homocystinuria due
to cystathionine b-synthase deficiency: two sides to the
same coin. Paediatriki 2007;70:146-151.
2. Mudd SH, Finkelstein JD, Irreverre F, Laster L. Homo-
cystinuria: an enzymatic defect. Science 1964;143:1443-
1445.
3. Mudd SH, Levy HL, Abeles RH, Jennedy JP Jr. A derange-
ment in B12 metabolism leading to homocystinemia, cys-
tathioninemia and methylmalonic aciduria. Biochem Bio-
Prevention of unintentional injury: relevance to paediatricians
N. Spencer
Public health importance of unintentional
injury
As noted by Nicholson et al in this issue of
the journal, unintentional injuries are the lead-
ing cause of death and disability in European
children. Globally, it is estimated that by 2020
road traffic crashes will have moved from ninth
to third in the world disease burden ranking, as
measured in disability adjusted life years (1).
The costs in premature death and disability and
the burden on health and social care services and
families are huge. Yet injury prevention com-
mands far less attention in most countries than
smoking cessation. The tendency of doctors to
focus on the consequences of injury rather than
prevention contributes to the relatively low pro-
file of this major public health issue.
Contributory factors
European countries that have succeeded in
providing a relatively safe environment for
their children with resulting reduction in
deaths and disability associated with uninten-
tional injury, have done so as a result of a com-
bination of legislation, enforcement and public
education. Legislation, although necessary, is
not sufficient to protect children. For example,
Greece enacted legislation over 20 years ago re-
lated to seat belt wearing by children in cars
and speed limits on urban roads but continues
to have one of the highest road accident death
rates in the EU (see Nicholson et al, Tables 2
and 3). This is likely to be due to limited en-
forcement and relatively poor acceptance of
these measures by the population.
A key factor in relation to child pedestrian
and cyclist injuries is exposure to traffic (2).
Children who are exposed to high volumes of
traffic either as pedestrians or cyclists are at
high risk. Poorer children are more likely to be
exposed in this way as their parents are less
likely to own cars (3).
Effectiveness of preventive interventions
Nicholson et al’s reliance mainly on the re-
sults of individual studies as evidence of effec-
tiveness of preventive interventions to reduce
unintentional injury among children leads
them to slightly overstate the strength of the
available evidence. Good randomised con-
trolled trials in accident prevention are rare
and the evidence base tends to be weak. How-
ever, there are now a series of Cochrane sys-
tematic reviews that report reasonably robust
evidence for some preventive interventions.
For example, speed enforcement devices such
as cameras are associated with a significant re-
duction in crashes (4) and helmets for cyclists
significantly reduce head and facial injuries (5).
The Cochrane reviews highlight the need for
more robust studies of injury prevention inter-
ventions.
Relevance to paediatricians
Due to the heavy burden of death and dis-
ability resulting from unintentional injury,
paediatricians are frequently faced with the
consequences. Paediatricians, in common with
other doctors, tend to focus on curative, clini-
cal interventions at the individual level rather
than preventive approaches at the population
level. Clinical approaches to the consequences
of unintentional injury can relieve suffering but
cannot address the fundamental causes. Thus,
for paediatricians to make a contribution to re-
ducing the burden of unintentional injury, they
need to focus on preventive interventions at the
population level as well as clinical management
of the consequences in individual children.
How might paediatricians contribute?
On matters concerning children, paediatri-
cians have a powerful voice. We need to learn
how to use this power to change public policy
and public perceptions in relation to uninten-
tional injury. The individual paediatrician can
provide developmentally appropriate advice to
parents and can participate in local groups pro-
moting injury prevention strategies. Advocacy is
probably most powerful when undertaken by na-
tional paediatric organisations that can commu-
nicate directly with policy makers and politi-
cians. We, in Europe, can learn from our Ameri-
can colleagues in the American Academy of Pe-
diatrics who have a long tradition of effective
lobbying on a range of child health related issues.
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·85
Paediatricians also have a major potential role inpromoting high quality, robust research to informpreventive strategies. Research of this nature is asimportant as drug trials.
References
1. Murray CJ, Lopez AD. Alternative projections of mortali-ty and disability by cause 1990-2020: Global Burden ofDisease Study. Lancet 1997;349:1498-1504.
2. Sonkin B, Edwards P, Roberts I, Green J. Walking, cyclingand transport safety: an analysis of child road deaths. J RSoc Med 2006;99:402-405.
3. Edwards P, Roberts I, Green J, Lutchmun S. Deaths frominjury in children and employment status in family: analy-sis of trends in class specific death rates. BMJ 2006;333:119.
4. Wilson C, Willis C, Hendrikz JK, Bellamy N. Speed en-forcement detection devices for preventing road traffic in-juries. Cochrane Database Syst Rev 2006;2:CD004607.
5. Thompson DC, Rivara FP, Thompson R. Helmets for pre-venting head and facial injuries in bicyclists. CochraneDatabase Syst Rev 2000;2:CD001855.
86 N. Spencer
Paediatriki 2007;70:85-86
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·86
87REVIEW ARTICLE ∞¡∞™∫√¶∏™∏
¶·È‰È·ÙÚÈ΋ 2007;70:87-92
Background
Injuries are the leading cause of death and
disability for children in the European Union
(EU). In the EU, for every death from injury,
there are 30 hospital admissions and 300
emergency department attendances (1). It has
been estimated that the overall socio-economic
burden of all injuries in Europe is 400 billion
Euros annually (i.e. almost 4 times the entire EU
budget).
The leading causes of injury death for chil-
dren (1-14 years old) in the EU include road-re-
lated (48%), drowning (11%), intentional in-
juries (11%), house fires (5%), high falls (5%),
poisonings (2%) and miscellaneous (18%).
There has been improvement in all EU member
states in the reduction of child injury deaths over
the past 20 years (2-5).
Thus injuries are a neglected problem that
has devastating effects on individuals and
health budgets. Within the expanded EU, most
of the burden of injuries falls on low and mid-
dle-income countries which have undergone
great changes brought about by transition to
market-style economies since the 1990’s. Chil-
dren living in low and middle-income coun-
tries are 3.6 times more likely to die from injury
than those in high income countries (Tables 1
and 2). High income countries have increased
injury rates in socioeconomically deprived
groups and a widening gap between rich and
poor. The increased mortality risk in deprived
groups applies to most injury types including
drowning, falls, poisoning, road-related and
fire-related injuries.
Some countries in the EU, such as the
Netherlands, United Kingdom and Sweden are
among the safest places in the world and if all
countries were to match their figures, two
thirds of the lives lost every year due to injury
could be saved. Countries with low rates of in-
jury have invested in safety as a societal respon-
sibility. Legislation and enforcement to ensure
safer environments (e.g. road and housing de-
sign and the use of safety equipment) and re-
duce risk behaviors (e.g. speeding and driving
under the influence of alcohol) are key changes
at a population level (6-8). These measures
have a synergistic effect when coupled with me-
dia and educational campaigns. There are dif-
ferences that exist in countries throughout
Europe as to how they adopt effective measures
in reducing childhood deaths and serious in-
juries (Table 3).
Road-related injuries
In the area of road safety, the EU has set a
target to halve the number of deaths from road
traffic injuries by 2010.
Without doubt road-related injuries should
Accident PreventionWorking Group of theEuropean Academy ofPaediatrics
Correspondence:
Alf [email protected] Lady of Lourdes Hospital,Drogheda, Co. Louth, Ireland
Creating a safer Europe for children
A.J. Nicholson, D. Van Esso, I. Malcic, A. Biver
Abstract: Unintentional injuries are the leading cause of death and disability in European children withroad-related injuries accounting for just under half of all deaths due to injury. There is a steep socialgradient for all serious childhood injuries and children living in low- and middle-income EuropeanUnion (EU) countries are 3.6 times more likely to die from injury than those in high-income countries.Some EU countries (such as Sweden, the Netherlands and the United Kingdom) are among the safestplaces in the world and, if other EU countries were to match their performance, two thirds of lives lostper year due to injury could be saved. Legislation and enforcement to ensure safer environments (e.g.road and housing design and use of safety equipment) and reduction of risk behavior (e.g. speedingand driving under the influence of alcohol) are effective at a population level. Effective evidence-basedinterventions include reduction of speed limits, traffic calming measures, safer car fronts, correctly-fittedchild passenger restraints, bicycle helmets, swimming pool fencing, personal flotation devices, smokedetectors, child-resistant lighters and child-resistant packaging for medicines and household chemicals.Paediatricians across the EU should be aware of the extent of childhood injury deaths and assume agreater advocacy role to aid their prevention.
Key words: unintentional injury, road-related injuries, drowning, burns and scalds, falls, poisoning, choking
and suffocation.
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·87
88 A.J. Nicholson et al.
be our first priority as these constitute 48% of all in-
jury deaths in the EU. Road-related accidents in-
clude child injury deaths to pedestrians, bicyclists
and motor vehicle passengers (9,10).
A pre-requisite for setting targets is good baseline
data on road-related injuries and this requires either
an injury surveillance system or some other means of
providing complete and accurate information on the
epidemiology of road-related injuries.
A great deal of intervention is being done in
most EU countries but there is evidence that more
lives could be saved on roads if the following strate-
gies were implemented, enforced and taught to the
public.
a. The reduction of speed limits
In the United Kingdom (11), introduction of 20
mph/hour speed limit zones has resulted in local re-
ductions of 48% in child bicycle injuries and a 70%
reduction in fatal road accidents involving pedestri-
ans. Speed cameras or radar can catch drivers who are
exceeding speed limits. Publicizing the presence of
speed cameras or radar, further increases compliance
with speed laws and substantially reduces road-relat-
ed deaths.
b. Traffic calming
Residential access roads should have speed limits
of no more than 30 km/hour and design features that
calm traffic and this has resulted in 60% reductions in
road-related childhood injuries in 30 km/hour zones
(Figure 1).
Pedestrians have twice the risk of injury where they
are not segregated from motor vehicle traffic and
studies in Denmark (12) have shown that segregated
modify car fronts so that they do less harm to cyclists
and pedestrians and yet no EU country requires the
fronts of cars to have a crashworthy design to mini-
mize injury to pedestrians. If vehicles were required
to pass performance tests for vehicle fronts, the annu-
al number of deaths and injuries to pedestrians in the
EU could fall by 20% (13-16,23).
d. Child passenger restraints
To protect occupants, a motor vehicle should be
designed so that the passenger compartment maintains
Table 1. Injury deaths for children (0-14 years) in the EU
Source: WHO 1996-2000 National Sources Average
Malta* 2.19Sweden* 3.79
United Kingdom* 4.21Italy* 4.57
Netherlands* 4.73Finland 5.00
Germany* 5.34Denmark* 5.40
Luxembourg 5.96Austria 6.33
Spain 6.49France* 6.66Ireland* 6.70
Slovenia* 7.36Belgium* 7.44
Greece* 7.87Hungary 8.09
Czech Republic 8.47Portugal 8.95
Poland* 9.16Slovakia 10.53
Lithuania 21.01Estonia 22.60
Latvia 23.51
0.00 5.00 10.00 15.00 20.00 25.00
Rates per 100,000 population
*Some data is missing
Paediatriki 2007;70:87-92
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·88
89
its integrity in a crash and there should be restraintsso that occupants do not eject from the vehicle ortumble about inside it, injuring themselves and otheroccupants.
When used properly, child restraints or car seatshave been shown to have an injury-reducing factorof 90-95% for rear-facing systems and 60% for for-ward-facing systems (17-19,23,24). For children 0-15 months (weight up to 13 kg), rear-facing child re-
straints optimally distribute any force of impact and
thereby reduce sever injuries by 90%. Rear-facing
child restraints should always be placed in the back
seat as many vehicles have front airbags. Child pas-
senger restraints are shown in Figure 2.
e. Bicycle helmets
Correctly fitted, bicycle helmets reduce the risk of
head and brain injury by 63-88% (23).
Drowning
Drowning is the second leading of death for chil-
dren of the EU with more than 70% of the victims be-
ing boys and the most vulnerable being 1 to 4 years of
age (21). Prompt resuscitation following immersion
is critical to survival and the outcome for most chil-
dren with immersion is determined by their status on
arrival to the emergency department - medical and
paediatric intensive care appear to have relatively lit-
tle impact on outcome. Therefore prevention is the
key to decreasing hospitalisations and deaths from
drowning. Effective prevention strategies include
swimming pool fencing (22). Other preventive strate-
gies include personal flotation systems, swimming
lessons, parental supervision and lifeguards.
1
0.8
0.6
0.4
0.2
00 20 40
Impact speed (km/h)60 80 100
Pro
bab
ilit
y o
f d
eath
Figure 1. Pedestrian fatality risk as a function of the impact speedof a car.
Table 2. Road accident deaths for children (0-14 years) in the EU
Source: WHO 1996-2000 National Sources Average
Slovakia 0.09Malta* 0.94
Sweden* 1.56United Kingdom* 1.62
Czech Republic 1.68Finland 1.84
Netherlands* 2.03Germany* 2.19
Austria 2.32Italy* 2.36
Hungary 2.55Denmark* 2.84
France* 3.04Slovenia* 3.12Belgium* 3.20
Luxembourg 3.23Spain 3.32
Ireland* 3.44Poland* 4.07Greece* 4.14
Portugal 5.02Lithuania 5.48
Estonia 5.58Latvia 5.58
0.00 1.00 2.00 3.00 4.00 5.00 6.00
Rates per 100,000 population
*Some data is missing
¶·È‰È·ÙÚÈ΋ 2007;70:87-92
Creating a safer Europe for children
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·89
Burns and scalds
Severe burn injuries require multiple hospitalisa-
tions and lengthy treatment and may result in perma-
nent disability and disfigurement. Scalds and contact
burns occur predominantly to under 2 year-olds. Age
standardized mortality rates for children (1-14 years of
age) dying through fires in the EU show that the low-
est rate is in Italy (0.17 per 100,000) and the highest
rate is in Ireland (0.91 per 100,000). Burn and scald
injuries could be reduced in Europe, if the following
preventive measures were implemented, enforced
and promoted to the general public:
Smoke detectors are an effective, reliable and in-
expensive devices that provide an early warning and
assist in reducing residential fire deaths by 71%
(23,24).
Legislation requiring a safe pre-set temperature
(54oC) for all water heaters has proven to be a more ef-
fective method of reducing scald burns than education
to encourage parents to turn down water heaters.
In the USA, fire deaths associated with cigarette
lighters dropped by 43% with the adoption of child-
resistant designs (14).
A dramatic 75% reduction in burn unit admissions
due to sleepwear occurred following the introduction
of the Flammable Fabrics Act of 1972 in the USA.
Falls
Falls resulting in severe or fatal injuries are usual-
ly due to second storey or higher windows.
Stair gates have been shown to assist in reducing
falls downstairs. Absorbent surface material in play-
grounds and appropriate height of play equipment
for various ages provides an improvement in serious
fall injuries. Window bars have shown a 35% decrease
in deaths and a 31% decrease in reported falls.
Poisoning
Children under 2 years of age are especially vulner-
able and more than 90% of poisonings occur in the
home environment (5). Many common household
products can poison children including cleaning sup-
plies, alcohol, pesticides, medicines and cosmetics (5).
Safe storage is an effective means of preventing
poisoning with both medicinal and non-medicinal
agents (6).
Educational strategies aimed at children and par-
ents have been associated with increased knowledge
Table 3. Effective measures in reducing childhood deaths and serious injuries in Europe (Source: updated from Towner and Towner, 2004)
Bicycle Child safety Seat belt Speed Child resistant Smoke Barrier Children Adoption of No sale ofhelmets seats/ wearing limits - packaging detectors fencing, banned playground fireworks
for children restraints by children roads pharmaceuticals in home domestic from riding/ standards to childrenin cars in urban swimming driving farm
*: New homes only, �: Indicates legislation enacted but year not known , YEAR: Indicates date legislation enacted if known, Blank: Nolegislation measure enacted
90 A.J. Nicholson et al.
Paediatriki 2007;70:87-92
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·90
91Creating a safer Europe for children
¶·È‰È·ÙÚÈ΋ 2007;70:87-92
of poison prevention. The compulsory use of child-
resistant packaging for aspirin and paracetamol led to
a dramatic fall in the number of children admitted to
hospital as a result of these medications in England,
the Netherlands and USA (6).
Choking and suffocation
Choking occurs most commonly on small attrac-
tive products, including balloons, coins, small toy
parts, small food pieces and inedibles in food prod-
ucts. Legislative measures to be implemented include
product bans (inedibles in foodstuffs, drawstrings on
clothing); warning labels on products have reduced
deaths in those countries where this legislation has
been enforced (7).
Socioeconomic deprivation and childhood injury
In England and Wales, the risk of children dying
from fire was 16 times greater in the lowest socioeco-
nomic group (SEG) compared to the highest (10,11),
the risk of pedestrian injuries was 5 times higher in
lower SEG and the overall risk of a childhood injury
death was 3-4 times higher in children of parents in
unskilled manual jobs than children whose parents
were skilled non-manual workers (11). In Germany,
poorer families were twice as likely to be involved in
road traffic accidents (12).
Thus, there is a steep social gradient in relation to
serious childhood injuries and deaths in most EU
countries.
The impact of an expanding EU
The childhood injury death rates for the new EU
countries range from 10.8 per 100,000 in Hungary to
38.4 per 100,000 in Latvia. The only country that has
a higher childhood injury death rate than the new EU
countries is Portugal (17.8 per 100,000). Thus the
childhood injury death rate in Latvia is 8 times that in
Sweden. If the EU is committed to reducing dispari-
ties in living standards between its members, serious
commitments will need to be made to ensure that
childhood injury deaths will be reduced in candidate
countries as a matter of urgent priority.
The role of government and legislation
As of June 2001, only the UK and the Netherlands
have specific targets or specific goals as part of a na-
tional health plan aimed at reducing childhood injury
(12,13,15). It is clear that, before there can be an inte-
grated approach to child safety across the EU, there
needs to be one within each individual member state.
Legislation and its enforcement is one of the most
effective ways to create a safer environment (13).
Whilst no EU member state has adopted all ten pre-
ventive policy measures that were conducted in recent
research by Towner et al (12), Sweden and Spain do
Rearward-facing baby seat(For babies up to 13 kg)
Forward-facing seat (Weight 9-18 kg)
Booster cushion (Weight 22-36 kg)
Figure 2. Car seats at different ages.
Booster seat (Weight 15-25 kg)
Never put arearward-facingseat in the frontseat if there is a
passenger airbag!
Never put arearward-facingseat in the frontseat if there is a
passenger airbag!
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·91
92 A.J. Nicholson et al.
Paediatriki 2007;70:87-92
show commitment to using policy to influence the re-duction of childhood injury by adopting most of themeasures outlined in Table 3. The most common mea-sures are related to motor vehicles and include child re-straints, seat belt wearing and reduced speed limits.The lowest adopted measures include bicycle helmetsand smoke alarms in private residences. Even thoughGermany and the UK introduced mandatory child-re-sistant packaging for medicines 25 years ago, only 4other countries use this proven safety measure. Even insituations where European directives exist, there isgreat variation in how EU member states enact thesedirectives in their bodies of law. Many countries with-in the EU lack even a basic structure for enforcing reg-ulations and standards for consumer products such aschild care articles and toys. Coordination at nationaland European levels is quite deficient.
The role of EU regulations and standards
The Treaty of Maastricht has extended significantlythe authority of the European Commission with re-spect to the protection of the health and safety of Euro-pean citizens. Standards play a key role in regulatingsafety in the EU as they provide technical specificationsfor existing framework legislation. European regula-tions and standards addressing child safety (e.g. child-resistant packaging) are not implemented properly orare not providing the safety measures that are current-ly needed. New directives should be developed at EUlevel for pedestrian and bicycle protection throughsafer car fronts, all under 12 year olds should be pro-tected by child restraint systems in cars, playgroundequipment should meet EU safety standards and Euro-pean regulations should be developed for inedibles infood products, flammability of clothing, cords on chil-dren’s clothes, cigarette lighter that are child-proof andbuilding code requirements for pool fencing, windowad balcony railings and amusement /riding devices.
Legislation of injury strategies and its enforcementis one of the most effective ways to create safer envi-ronments.
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Safer play for children in playgrounds: barriers and prospects
P. Grigoriou, A. Terzidis, E. Petridou
Abstract: Among childhood injuries, those occurring in playgrounds have been recognized as a majorproblem. Each year in the United States, emergency departments treat more than 200,000 childrenaged 14 years and younger for playground-related injuries. Children aged 5 to 9 years have higherrates of emergency department visits for this reason than any other age group. Although common,most playground injuries are not serious enough to cause permanent disability or death. Fatalities areusually the result of asphyxiation secondary to strangulation. Swing accidents have been studiedthrough the European Home and Leisure Accident Surveillance System, and it was concluded that70,000 people are treated every year in emergency departments for swing-related injuries in the Euro-pean Union. While playground-related injuries represent a substantial proportion of childhood injuriesin most developed countries, prevention has always been a sensitive issue, as on the one hand, chil-dren must be allowed to test their skills, while on the other this process should take place in a safe en-vironment. Standards are an essential tool for the prevention of playground injuries. The absence of ap-propriate legislation, inadequate maintenance of facilities, the lack of involvement of medical person-nel, child psychologists, teachers and parents and the huge costs of safety measures complicate the im-plementation and enforcement of standards. Further epidemiological studies focusing on exposure da-ta and the evaluation of prevention strategies will contribute substantially to safer play in playgrounds.
Atherogenic risk factors in preschool children in Crete
A. Kafatos, C. Hatzis, M. Linardakis, D. Athanasopoulos, C. Lionis, E. Balomenaki, A. Kapnisakis,
H. Stamataki and Collaborative researchers
Abstract
Background: The aim of the study was the investigation of atherogenic risk factors in preschool chil-dren of Crete.
Methods: The study population included 1189 children (591 boys), aged 4-7 years. All children wereexamined, for the following: anthropometric and blood pressure measurements. Blood was taken forserum lipoproteins and blood sugar.
Results: According to International Obesity Task Force (IOTF) criteria, 27.4% of the boys were classi-fied as overweight or obese (obese 10.8%). The respective percentage for girls was 28.5% (obese 9%).7.4% of the boys and 7.9% of the girls had blood pressure above the 95th percentile. Total cholesterol>200 mg/dl was found in 14.4% and LDL-C >130 mg/dl in 13.8% of the children. The percentage ofchildren with one, two, and three metabolic syndrome risk factors was 18.3%, 5.9% and 1.4% respec-tively. Children with high serum triglycerides (>100 mg/dl) had significantly higher mean waist cir-cumference (WC) and body mass index (BMI) compared to those with low triglycerides (≤80 mg/dl)(p<0.05). Similarly, children with lower HDL-C (<45 mg/dl) had significantly higher WC and BMI thanchildren with higher HDL-C (≥60 mg/dl) (p<0.05). Moreover, obese children had significantly higherrisk for hypetriglyceridemia as compared to non-obese children (Odds Ratio: 2.87, p=0.041).
Conclusions: These results of high prevalence of overweight and obesity in Cretan preschool children in-dicate the presence of this major public health problem in early ages. Levels of obesity and especially
central obesity were strongly related to other atherogenic risk factors, namely dyslipidemia. Health andnutrition education addressed to parents, teachers and children should become an urgent national pri-ority.
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Thyroid volume, prevalence of subclinical hypothyroidism and
autoimmunity in children and adolescents
I. Kaloumenou1, L. Duntas2, M. Alevizaki2, G. Mastorakos2, E. Mantzou2, A. Antoniou3,
C. Ladopoulos3, C. Mengreli4, D. Chiotis1, I. Papassotiriou5, C. Dacou-Voutetakis1
Abstract
Background: The aim of the study was to determine, in a normal population of children: a) the values ofthyroid volume, the serum concentrations of thyroid hormones, thyroid antibodies (anti-TPOab and anti-TG) and the prevalence of subclinical hypothyroidism, b) the effect of age and puberty on these para-meters, c) the correlation of Body Mass Index (BMI) with TSH, and d) the relationship of thyroid au-toimmunity in children and their mothers.
Methods: The following parameters were assessed in 440 healthy children, aged 5-18 years: height,weight, stage of puberty according to Tanner’s criteria, BMI, BMIsds, Body Surface Area (BSA), urineiodine concentration, thyroid volume by ultrasonography, thyroid hormones, anti-TPOab and anti-TG,using validated techniques. Based on the TSH value of the 97th percentile, subclinical hypothyroidismwas determined.
Results: Thyroid volume increased with age and puberty stage, to a greater degree in boys than in girls.The prevalence of subclinical hypothyroidism was 4.8% in boys and 4.4% in girls. No correlation wasfound between BMIsds and TSH. The prevalence of positive anti-TPOab was 3.2% and 5.8% for boysand girls, respectively and it increased at puberty in girls more than in boys. When children had posi-tive anti-TPOab, 82% of their mothers had positive anti-TPOab, whereas only 18% of the mothers of an-ti-TPOab negative children had positive anti-TPOab.
Conclusions: The definition of normal values of various parameters related to thyroid function in ahealthy paediatric population sample will facilitate early recognition of deviations by the paediatrician.
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37. Zois C, Stavrou I, Kalogera C, Svarna E, Dimoliatis I, Se-feriadis K, et al. High prevalence of autoimmune thyroidi-tis in schoolchildren after elimination of iodine deficiencyin northwestern Greece. Thyroid 2003;13:485-489.
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Neurodevelopmental outcome of very low birth weight neonates at
preschool age
H. Bouza1, I. Antoniadou2, H. Antonopoulou3, M. Anagnostakou1, F. Anatolitou1, M. Morosini3,
J. Sarafidou2, ª. Xanthou1
Abstract
Background: Very Low Birth Weight (VLBW) neonates are at increased risk of neurodevelopmental dis-abilities. Most affected children present mild deficits rather than severe handicap, often appearing at thepreschool or school age. The purpose of this study was to assess VLBW infants at the preschool age in or-der to detect neurodevelopmental disabilities, mainly mild in nature.
Methods: Forty children with a birth weight of <1500 g, participated in the study. Following discharge fromthe Neonatal Intensive Care Unit, the children were monitored longitudinally. At the age of two years theyunderwent detailed neurological assessment. At the age of four years they underwent neurodevelopmen-tal assessment with a combination of structured tests: the Touwen, the Griffiths and the Miller tests. A ques-tionnaire was completed by the parents concerning their opinion of their children’s condition.
Results: At the age of four years, four children had cerebral palsy (10%). The remaining 36 were con-sidered as normal or as having minor functional disabilities. In these children, the combination of neu-rodevelopmental tests showed suboptimal scores in coordination and performance. In the childrenwho had been considered to have a normal outcome at an earlier age, the tests showed a suboptimalperformance in most representative tasks, although 85% of the parents considered that their childrenhad no problems.
Conclusion: Subtle functional disabilities were identified in VLBW neonates at the age of four years.These disabilities had not been detected at earlier ages, and the parents of these children believed thattheir children had no problems. These findings underline the need for a detailed neurodevelopmen-tal assessment of VLBW children at the preschool age in order to intervene, where necessary, beforeschool entry.
1. Wilson-Costello D, Friedman H, Minich N, Fanaroff A∞,
Hack M. Improved survival rates with increased neurode-
velopmental disability for Extremely Low Birth Weight in-
fants in the 1990s. Pediatrics 2005;115: 997-1003.
2. Hack M, Fanaroff A∞. Outcomes of children of extremely
low birthweight and gestational age in the 1990’s. Early
Hum Dev 1999;53:193-218.
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·121
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4. Wood N™, Marlow N, Costeloe K, Gibson A∆, WilkinsonAƒ. EPICure study group. Neurologic and developmentaldisability after extremely preterm birth. N Engl J Med.2000;343:378-384.
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6. Mikkola K, Ritari N, Tommiska V, Salokorpi T, Lehtonen L,Tammela O, et al. Neurodevelopmental outcome at 5 yearsof age of a national cohort of extremely low birth weight in-fants who were born in 1996-1997. Pediatrics 2005;116:1391-1400.
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8. Haataja L, Mercuri E, Regev R, Cowan F, Rutherford M,Dubowitz V, et al. Optimality score for the neurologic ex-amination of the infant at 12 and 18 months of age. J Pe-diatr 1999;135:153-161.
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18. Liebhardt G, Sontheimer D, Linderkamp O. Visual-motorfunction of very low birth weight and full-term children at3ó to 4 years of age. Earl Hum Dev 2000;57:33-47.
19. Pasman JW, Rotteveel JJ, Maassen B. Neurodevelopmen-tal profile in low-risk preterm infants at 5 years of age. EurJ Paediatr Neurol 1998;2:7-17.
20. Goyen TA, Lui K. Longitudinal motor development of“apparently normal” high-risk infants at 18 months, 3 and5 years. Early Hum Dev 2002;70:103-115.
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23. Halsey CL, Collin MF, Anderson CL. Extremely low birthweight children and their peers: a comparison ofpreschool performance. Pediatrics 1993;91:807-811.
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26. Saigal S, Hoult LA, Streiner DL, Stoskopf BL, RosenbaumPL. School difficulties at adolescence in a regional cohortof children who were extremely low birth weight. Pedi-atrics 2000;105:325-331.
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31. Sommerfelt K. Long term outcome for non-handicappedlow birth weight infants - is the fog clearing? Eur J Pediatr1998;157:1-3
Radiofrequency catheter ablation of accessory pathways in children:
immediate and long-term results
J. Papagiannis1, G. Kirvassilis2, I. Sofianidou2, C. Laskari1, M. Kiaffas1, S. Apostolopoulou1, S. Rammos1
Abstract
Background: The most common cause of supraventricular tachycardia in children is an accessory pathway(AP). Because of the chronic course, long-term treatment with antiarrhythmic drugs is not an ideal solu-tion. Radiofrequency ablation (RFA) may offer curative treatment. The purpose of this study was to analyzethe immediate and long-term outcome of radiofrequency ablation of accessory pathways in children.
Methods: The charts were reviewed retrospectively of 94 children aged 4-18 (12.3±3.6) years who had un-dergone complete electrophysiologic study and radiofrequency ablation of AP. The indications for ablationwere: supraventricular tachycardia (78), syncope (9), rapidly occurring atrial fibrillation with cardiogenicshock (2) and asymptomatic patients with a short antegrade accessory pathway refractory period (5).
Results: The final success rate of AP ablation, after possible recurrences, was 96%. Longer fluoroscopytime (p=0.05) and a lower final success rate (p=0.02) were observed in patients with anterior/mid-sep-tal AP. The other categories had comparably favourable results. Patients with right lateral AP had ahigher prevalence of congenital heart disease (p<0.001). Recurrences were more frequent in patientswith multiple AP (p=0.007). There was only one permanent complication, a patient who had aortic in-sufficiency after retrograde transaortic ablation of left lateral AP). Transient complications were ob-served in 3 patients (temporary atrioventricular block in 2 and pericardial effusion in one). The finalsuccess, recurrence rates and complication rates were independent of age.
Conclusions: Radiofrequency catheter ablation of accessory pathways in children may offer a perma-nent cure, with high success and low complication rates and without differences in outcome in patientsabove 4 years of age.
1. Ludomirsky A, Garson A. Supraventricular tachycardia.In: Gillette PC, Garson A Jr, editors. Pediatric Arrhyth-mias, Electrophysiology and Pacing. Philadelphia: WBSaunders; 1990. p. 380-426.
2. Sorbo MD, Buja GF, Miorelli M, Nistri S, Perrone C,Manca S et al. The prevalence of the Wolff-Parkinson-White syndrome in a population of 116,542 young males.G Ital Cardiol 1995;25:681-687.
3. Chung KY, Walsh TJ, Massie E. Wolff-Parkinson-Whitesyndrome. Am Heart J 1965;69:116-133.
32. Vaksmann G, D’Hoinne C, Lucet V, Guillaumont S, Lu-poglazoff JM, Chantepie A et al. Permanent junctionalreciprocating tachycardia in children: a multicentre studyon clinical profile and outcome. Heart 2006;92:101-104.
33. Pappone C, Manguso F, Santinelli R, Vicedomini G, SalaS, Paglino G et al. Radiofrequency ablation in childrenwith asymptomatic Wolff-Parkinson-White syndrome. NEngl J Med 2004;351:1197-1205.
34. Lesh MD, Van Hare GF, Scheinman MM, Ports TA, Ep-stein LA. Comparison of the retrograde and transseptalmethods for ablation of left free wall accessory pathways. JAm Coll Cardiol 1993;22:542-549.
35. Natale A, Wathen M, Yee R, Wolfe K, Klein G. Atrial andventricular approaches for radiofrequency catheter abla-tion of left-sided accessory pathways. Am J Cardiol 1992;70:114-116.
36. Deshpande SS, Bremner S, Sra JS, Dhala AA, Blanck Z, Ba-jwa TK et al. Ablation of left free-wall accessory pathwaysusing radiofrequency energy at the atrial insertion site:transseptal versus transaortic approach. J Cardiovasc Elec-trophysiol 1994;5:219-231.
37. Law IH, Fischbach PS, LeRoy S, Lloyd TR, Rocchini AP,Dick M. Access to the left atrium for delivery of radiofre-quency ablation in young patients: retrograde aortic vstransseptal approach. Pediatr Cardiol 2001;22:204-209.
38. Mandapati R, Berul CI, Triedman JK, Alexander ME,Walsh EP. Radiofrequency catheter ablation of septal ac-cessory pathways in the pediatric age group. Am J Cardiol2003;92:947-950.
39. Benito Bartolome F, Sanchez Fernandez-Bernal C. Ca-theter ablation of accessory pathways in infants and chil-dren weighing less than 10 kg. Rev Esp Cardiol 1999;52:398-402.
40. Paul T, Kakavand B, Blaufox AD, Saul JP. Complete oc-clusion of the left circumflex coronary artery after ra-diofrequency catheter ablation in an infant. J CardiovascElectrophysiol 2003;14:1004-1006.
41. Benito Bartolome F, Sanchez Fernandez-Bernal C,Jimenez Casso S. Coronary ischemia during radiofrequencyablation of left lateral accessory pathway in an infant. RevEsp Cardiol 1998;51:343-345.
42. Schaffer MS, Silka MJ, Ross BA, Kugler JD. Inadvertentatrioventricular block during radiofrequency catheter ab-lation. Results of the Pediatric Radiofrequency AblationRegistry. Pediatric Electrophysiology Society. Circulation1996;94:3214-3220.
43. Drago F, De Santis A, Grutter G, Silvetti MS. Transvenouscryothermal catheter ablation of re-entry circuit locatednear the atrioventricular junction in pediatric patients: ef-ficacy, safety, and midterm follow-up. J Am Coll Cardiol2005;45:1096-1103.
44. Kriebel T, Broistedt C, Kroll M, Sigler M, Paul T. Efficacyand safety of cryoenergy in the ablation of atrioventricularreentrant tachycardia substrates in children and adoles-cents. J Cardiovasc Electrophysiol 2005;16:960-969.
45. Geise RA, Peters NE, Dunnigan A, Milstein S. Radiationdoses during pediatric radiofrequency catheter ablationprocedures. Pacing Clin Electrophysiol 1996;19:1605-1611.
46. Calkins H, Niklason L, Sousa J, el-Atassi R, Langberg J,Morady F. Radiation exposure during radiofrequencycatheter ablation of accessory atrioventricular connec-tions. Circulation 1991;84:2376-2382.
47. Lindsay BD, Eichling JO, Ambos HD, Cain ME. Radiationexposure to patients and medical personnel during ra-diofrequency catheter ablation for supraventricular tachy-cardia. Am J Cardiol 1992;70:218-223.
48. Drago F, Silvetti MS, Di Pino A, Grutter G, Bevilacqua M,Leibovich S. Exclusion of fluoroscopy during ablationtreatment of right accessory pathway in children. J Car-diovasc Electrophysiol 2002;13:778-782.
49. Papagiannis J, Tsoutsinos A, Kirvassilis G, Sofianidou I,Koussi T, Laskari C et al. Nonfluoroscopic catheter navi-gation for radiofrequency catheter ablation of supraven-tricular tachycardia in children. Pacing Clin Electrophysi-ol 2006;29:971-978.
50. Friedman RA, Walsh EP, Silka MJ, Calkins H, StevensonWG, Rhodes LA et al. NASPE Expert Consensus Confer-ence: Radiofrequency catheter ablation in children withand without congenital heart disease. Report of the writingcommittee. North American Society of Pacing and Electro-physiology. Pacing Clin Electrophysiol 2002;25:1000-1017.
Use of alternative and complementary therapy by paediatric
oncology patients in Greece
A. Pourtsidis, D. Doganis, M. Baka, M. Varvoutsi, D. Bouhoutsou, P. Xatzi, H. Kosmidis
Abstract
Background: Complementary and alternative medicine (CAM) therapies are used by increasing num-bers of children with cancer.
Methods: A self-reported questionnaire was given to parents of 184 children with cancer. The preva-lence of the use and non-use of CAM therapies and factors that influence the use were estimated.
Results: Based on the 110 questionnaires which were completed (59.8% of the families), 23 families(21%) had used at least one alternative treatment. The most common forms of CAM therapy were: spir-itual healing/prayer/blessings 18/23 (78%), art therapies 4, dietary supplements 3, massage 3, home-opathy 2, and herbal treatments 2. The reasons given for use of CAM included: making the childstronger 17/23, hope of stopping the cancerous process 11/23, and coping with side effects 6/23.Those parents not using CAM referred to their confidence to the medical team, and the child doing welland therefore their not seeing the need for CAM use (84%), or not being aware of CAM (24%); an-other 7.5 % had considered using it. In bivariate analysis, CAM use was not found to be associated ei-ther with the age, sex, nationality, education or occupation of the respondents at the time of the sur-vey, or with the diagnosis, mode of therapy or the age of the child at diagnosis.
Conclusions: The use of CAM therapies by Greek families for their children with cancer does not ap-pear to be very popular, although the experiences of those who did use them were generally positive.
Key words: Complementary and alternative therapies, child, cancer.
1. Weiger WA, Smith M, Boon H, Richardson MA,Kaptchuk TJ, Eisenberg DM. Advising patients who seekcomplementary and alternative medical therapies for can-cer. Ann Intern Med 2002;137:889-903.
2. Eisenberg DM, Kessler RC, Foster C, Foster C, NorlockFE, Calkins DR, et al. Unconventional medicine in theUnited States. Prevalence, costs, and patterns of use. NEngl J Med 1993;328:246-252.
3. Ernst E. The current position of complementary/alterna-tive medicine in cancer. Eur J Cancer 2003;39:2273-2277.
4. Friedman T, Slayton WB, Allen LS, Pollock BH, Dumont-Driscoll M, Mehta P, et al. Use of alternative therapies forchildren with cancer. Pediatrics 1997;100:E1.
5. Sawyer MG, Gannoni AF, Toogood IR, Antoniou G, RiceM.. The use of alternative therapies by children with can-cer. Med J Aust 1994;160:320-322.
6. Fernandez CV, Stutzer CA, MacWilliam L, Fryer C. Alter-native and complementary therapy use in pediatric oncol-ogy patients in British Columbia: prevalence and reasonsfor use and nonuse. J Clin Oncol 1998;16:1279-1286.
7. Kelly KM. Complementary and alternative medical thera-pies for children with cancer. Eur J Cancer 2004;40:2041-2046.
8. National Center for Complementary and AlternativeMedicine. What is CAM. National Institutes of Health.[Website] http://nccam.nih.gov/health/whatiscam/#1.
9. Fletcher PC, Clarke J. The use of complementary and al-ternative medicine among pediatric patients. Cancer Nurs2004;27:93-99.
10. Kelly KM, Jacobson JS, Kennedy DD, Braudt SM, MallickM, Weiner MA. Use of unconventional therapies by chil-dren with cancer at an urban medical center. J Pediatr He-matol Oncol 2000;22:412-416.
11. Kemper K, Jacobs J. Homeopathy in pediatrics - no harmlikely, but how much good? Contemp Pediatr 2003;20:97.
12. Bold J, Leis A. Unconventional therapy use among chil-dren with cancer in Saskatchewan. J Pediatr Oncol Nurs2001;18:16-25.
13. Neuhouser ML, Patterson RE, Schwartz SM, HeddersonMM, Bowen DJ, Standish LJ. Use of alternative medicine
by children with cancer in Washington state. Prev Med
2001;33:347-354.
14. Yeh CH, Tsai JL, Li W, Chen HM, Lee SC, Lin CF, et al.
Use of alternative therapy among pediatric oncology pa-
tients in Taiwan. Pediatr Hematol Oncol 2000;17:55-65.
15. Myers C, Stuber ML, Bonamer-Rheingans JI, Zeltzer LK.
Complementary therapies and childhood cancer. Cancer
Control 2005;12:172-180.
16. Molassiotis A, Cubbin D. “Thinking outside the box”:
complementary and alternative therapies use in paediatric
oncology patients. Eur J Oncol Nurs 2004;8:50-60.
17. Maskarinec G, Shumay DM, Kakai H, Gotay CC. Ethnic
differences in complementary and alternative medicine
use among cancer patients. J Altern Complement Med
2000;6:531-538.
18. Weyl Ben Arush M, Geva H, Ofir R, Mashiach T, Uziel R,
Dashkovsky Z. Prevalence and characteristics of comple-
mentary medicine used by pediatric cancer patients in a
mixed western and middle-eastern population. J Pediatr
The epidemiology of chickenpox in school-age children from the
prefecture of Attica
∞. Katsafadou, V. Papaevangelou, G. Ferentinos, A. Constantopoulos
Abstract
Background: Epidemiologic data are described regarding varicella in primary school children from theentire prefecture of Attica.
Methods: Parents of children attending the 1st and 6th grades of primary school completed aquestionnaire including questions on demographic data, the history of chickenpox, hospitalizationsecondary to chickenpox complications and herpes zoster, and the age at which the children firstattended day care.
Results: On analysis of 19,381 questionnaires, 48.45% from 1st grade and 51.55% from 6th gradechildren, a history of varicella was reported in 66.65% of 1st grade children and 78.69% of 6th gradechildren, and the mean age of the children at the varicella illness was 3.93 and 5.37 years respectively(p<0.001). A history of herpes zoster was reported in 0.48%, and 1.62% of the children had beenhospitalized because of a varicella-associated complication. Children who had attended day care(72.85%) and children with older siblings were reported to have contracted chickenpox at a youngerage (mean age 4.46 years and 4.36 years, respectively) compared to children who had not attendedday care or who were firstborn (mean age: 5.69 and 5.13 years, respectively, p<0.001). Children ofimmigrants were reported to have had varicella at a comparatively later age but this might besecondary to their low attendance rate at day care (59.3%).
Conclusions: A significant lowering in the mean age at which varicella is contracted by children inAttica was observed, probably due to the increasing rate of children attending day care.
Key words: Varicella, epidemiology, varicella vaccine, day care.
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2. Patel RA, Binns HJ, Shulman ST. Reduction in pediatrichospitalization for varicella-related invasive group Astreptococcal infection in the varicella vaccine era. J Pedi-atr 2004;144:68-74.
3. Weller T. Varicella and herpes zoster: a perspective andoverview. J Infect Dis 1992;166 (1 Suppl):S1-S6.
4. Choo PW, Donahue JG, Manson JE, Platt R. The epi-demiology of varicella and its complications. J Infect Dis1995;172:706-712.
5. Centers for Disease Control and Prevention. Prevention ofvaricella: recommendations of the Advisory Committeeon Immunization Practices (ACIP). MMWR RecommRep 1996;45:1-36
6. Brisson M, Edmunds WJ, Law B, Gay NJ, Walld R,Brownell M, et al. Epidemiology of varicella zoster virusinfection in Canada and the United Kingdom. EpidemiolInfect 2001;127:305-314.
8. Nguyen HQ, Jumaan AO, Seward JF. Decline in mortality
due to varicella after implementation of varicella vaccina-tion in the United States. N Engl J Med 2005;352:450-458.
9. Lieu TA, Cochi SL, Black SB, Halloran ME, Shinefield HR,Holmes SJ, et al. Cost-effectiveness of a routine varicellavaccination program for US children. JAMA 1994;271:375-381.
10. Seward JF, Watson BM, Peterson CL, Mascola L, PelosiJW, Zhang JX, et al. Varicella disease after introduction ofvaricella vaccine in the United States 1995-2000. JAMA2002;287:606-611.
11. Goldman GS. Universal varicella vaccination: efficacytrends and effect on herpes zoster. Int J Toxicol 2005;24:205-213.
12. American Academy of Pediatrics. Committee on Infec-tious Diseases. Varicella vaccine update. Pediatrics2000;105:136-141.
13. Wise RP, Salive ME, Braun MM, Mootrey GT, Seward JF,Rider LG, et al. Postlicensure safety surveillance for vari-cella vaccine. JAMA 2000; 284:1271-1279.
19. Davis MM, Patel MS, Gebremariam A. Decline in varicel-la-related hospitalizations and expenditures for childrenand adults after introduction of varicella vaccine in theUnited States. Pediatrics 2004;114:786-792.
20. Rentier B, Gershon AA. European Working Group onVaricella. Consensus: varicella vaccination of healthy chil-dren - a challenge for Europe. Pediatr Infect Dis J 2004;23:379-389.
22. Kavaliotis J, Petridou S, Karabaxoglou D. How reliable isthe history of chickenpox? Varicella serology among chil-dren up to 14 years of age. Int J Infect Dis 2003;7:274-277.
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¶·È‰È·ÙÚÈ΋ 2007;70:141-145
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·145
146 CASE REPORT ∂¡¢π∞º∂ƒ√À™∞ ¶∂ƒπ¶∆ø™∏
Paediatriki 2007;70:146-151
Introduction
Homocystinuria (HCU) due to cystathionine
‚-synthase deficiency (C‚Sd) (OMIM#+236200)
is a potentially lethal autosomal recessive defect
of methionine (Me) metabolism resulting in the
accumulation of homocysteine (Hcy) and Me in
body fluids (Figure 1) (1). It is considered the
second most common treatable inherited disor-
der of amino acid metabolism (2). The world-
wide incidence of C‚Sd based on data from
newborn screening is ~1: 344.000 live births but
the true incidence is estimated to be much high-
er (3,4). The most frequent clinical manifesta-
tions of C‚Sd affect four organ systems: the eye
(ectopia lentis), the skeleton (dolichostenomelia,
osteoporosis), the central nervous system (psy-
chiatric problems, mental retardation) and the
vascular system, with thromboembolic events
being the commonest cause of death (2,3). The
age of presentation and extent to which affected
patients manifest these abnormalities varies
widely (2). The main target of treatment is the
high Hcy levels. Two clinical forms of the dis-
ease have been delineated on the basis of respon-
siveness to pharmacological doses of vitamin
B6 (pyridoxine), a precursor of pyridoxal phos-
phate, the coenzyme for C‚S. About 50% of pa-
tients respond to B6 therapy, whereas 50% do
not, requiring additional treatment strategies,
including a low Me, cystine-supplemented diet
and/or betaine (5,6). Two patients with C‚Sd
are described: a B6-responsive boy and a B6-non-
responsive girl, in order to highlight the clinical
heterogeneity of this disorder, the crucial impor-
tance of early diagnosis and treatment, and the
difficulties encountered in the treatment of B6-
non-responsive patients.
Case reports
Patient 1
A 9-year-old boy, offspring of unrelated par-
ents, was admitted to the pediatric ICU of our
hospital in a comatose state. On admission, brain
magnetic resonance imaging (MRI) revealed
thrombosis of the superior sagittal sinus (Figure
2) and a regimen of anticoagulants, anticonvul-
sants and antimicrobial agents was immediately
initiated. On day six of hospitalization the pa-
tient was transferred to our pediatric department
for further evaluation and treatment. On day 11
Homocystinuria due to cystathionine ‚-synthase deficiency:
two sides to the same coin
P. Augoustides-Savvopoulou1, H. Ioannou1, N. Kozeis2, A. Karagiannidou3, M. Athanasiou-Metaxa1
Abstract: Cystathionine ‚-synthase (C‚S) deficiency (OMIM#236200) is a rare, autosomal recessivedefect of methionine metabolism, considered to be the most frequent cause of homocystinuria. Clinicalfeatures include severe myopia, ectopia lentis, marfanoid skeletal abnormalities with osteoporosis, mentalretardation and thromboembolism which is the most frequent cause of death. The mainstay of therapy ispyridoxine, the precursor of the coenzyme for C‚S, but only 50% of patients respond. Two patients withC‚S deficiency are described, a B6-responsive boy and a B6-non-responsive girl, with the objective ofhighlighting: 1) the clinical heterogeneity of this disorder, 2) the crucial importance of early diagnosis andtreatment and 3) the difficulties in management of B6 non-responsive patients. Patient 1 was admitted atthe age of 10 because of a cerebrovascular stroke. His history included severe progressive myopia from ayoung age and ectopia lentis. Patient 2, a nine year old girl with pseudophakia and a clinical diagnosis ofMarfan’s syndrome, presented with severe behavioural symptoms. In both patients, a metabolic workuprevealed high plasma levels of total homocysteine and methionine and C‚S deficiency was confirmed byenzyme assay. Pyridoxine administration resulted in a dramatic decrease of homocysteine and methioninelevels in patient 1 but not in patient 2 necessitating alternative therapeutic measures. It is concluded thatC‚S deficiency is a clinically heterogenous disorder which if untreated can lead to life-threateningconsequences. Plasma total homocysteine should be a first-line test in patients with early onset of severemyopia, ectopia lentis, skeletal changes reminiscent of Marfan’s syndrome, thromboembolism, mentalretardation with psychiatric symptoms, bearing in mind that the complete clinical spectrum may notalways be apparent.
Protein C, Protein S, anti-cardiolipin) was unremark-
able but measurement of plasma total homocysteine
[(tHcy) (FPIA IMX, Abbott Labs)] revealed a highly
increased level: 256 Ìmol/L (reference range 3-10).
Quantitative analysis of deproteinized plasma amino
acids (post-column cation-exchange HPLC) showed
increased unbound (free) homocystine (fHcy) (101
Ìmol/l, ref. range 0-5) and methionine (181 Ìmol/l,
ref. range 9-36). Investigation of cobalamin and folate
status of the patient revealed low levels of vitamin B12
(195 pg/ml, ref. range 223-1132) and folic acid (2.2
ng/ml, ref. range 2.8-16.9). He was shown to be ho-
mozygous (677TT) for the 677C→T polymorphism
in the gene that encodes 5, 10-methylenetetrahydro-
folate reductase (MTHFR).
The clinical features of this patient in combination
with the very high plasma tHcy and methionine levels
were conclusive for C‚Sd. Vitamin supplementation
with a B1, B6, B12 complex (Trivimine 125 mg+125 mg
+0.125 mg X 2/d) as well as folic acid (5 mg/d) was
immediately initiated. Trivimine was initially used in
spite of the lack of indication for B1 because it was the
only product commercially available. C‚Sd was fur-
ther confirmed when assay of the activity of CbS in
cultured skin fibroblasts revealed a very low value:
0.05 nmol cystathionine/ h/mg protein (control
range: 2.3-18.2, homozygote range: 0.0-0.19). A mol-
ecular screen for the common B6-responsive C‚S
147
¶·È‰È·ÙÚÈ΋ 2007;70:146-151
(2) Folic acid (3) Diet
Tetrahydrofolate
5,10-Methylene-tetrahydrofolate
Methionine synthase (2) B12
5-Methyl-tetrahydrofolate
MTHFR deficiency
+
+
+
Methionine
S-Adenosyl -methionine
N,N Dimethyl glycine
Betaine homocysteine
methyltransferase
Betaine (4)Homocysteine
S-Adenosyl homocysteine
(1) Pyridoxine(B6)
Cystathionine beta-synthase
Cystathionine
(3) Cysteine
Figure 1. Metabolic pathway of methionine and potential sites oftherapeutic intervention in C‚S deficiency.
The transsulfuration pathway is the chief route of disposal ofMe, converting the sulfur atom of Me into the sulfur atom ofcysteine. Two additional metabolic sequences are thetransmethylation reactions whereby 1) the methyl group of Me isultimately used in the formation of many methylated compoundsand 2) the reformation of Me by methylation of Hcy.Remethylation of Hcy is dependent on B12 (active form,methylcobalamin) and folic acid (active form, MTFHR), and itstransmethylation to cystathionine is dependent on C‚S coenzymeB6 (active form 5 pyridoxyl phosphate).
The level of C‚Sd is shown by X. Potential sites of therapeuticintervention are shown by (1) B6, (2) B12 & folic acid, which increaseremethylation of Hcy to Me; (3) low-protein, low-Me, cystinesupplemented diet; (4 ) betaine, a donor of methyl groups thatincreases remethylation of Hcy to Me.
Figure 2. Brain MRI scan of patient 1 showing thrombosis of thesuperior sagittal sinus.
Figure 3. Photographs showing long digits in hand (3a) and feet(3b) of patient 1.
3a 3b
Homocystinuria due to C‚S deficiency
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·147
mutation T833C (I278T) was negative. After 20 con-
secutive days of treatment with the vitamin supple-
ments, striking decreases of tHcy to 32 Ìmol/l, fHcy to
0 Ìmol/l, and Me to 30 Ìmol/l were found. Family in-
vestigation revealed normal plasma tHcy and Me lev-
els in the patient’s sibling whereas both his father and
mother had increased tHcy (49 Ìmol/l and 21 Ìmol/l
respectively) with normal levels of Me, B12 and folic
acid. Plasma tHcy values of his parents normalized 14
days after initiation of 5 mg/d folic acid therapy.
In view of the diagnosis, he was assessed for osteo-
porosis by a DEXA bone scan, which was normal. In
addition, psychological assessment did not reveal
signs of mental retardation or psychiatric distur-
bances. Re-evaluation of the patient before discharge
showed major improvement in brain MRI imaging
and adequate flow of the popliteal vein. To date (2
years after diagnosis), the patient has not had anoth-
er vascular episode and his plasma tHcy levels are
within the normal range (~10-15 Ìmol/l). Anticoag-
ulant (warfarin) and anticonvulsant (phenytoin)
therapy was discontinued after one year, but supple-
mentation with vitamins B6, B12, and folic acid is be-
ing continued as a life-long regimen with regular
monitoring of tHcy levels. The follow-up protocol for
this patient includes opthalmological examination
every 6 months and yearly monitoring of bone-densi-
ty (DEXA scan) and his vascular system (triplex Dop-
pler scan).
Patient 2
This 9-year-old girl, who had been clinically diag-
nosed as having Marfan’s syndrome at age 8, was re-
ferred for investigation because of learning problems
and severe behavioral symptoms (negative attitude,
frequent outbursts of crying). Physical examination
revealed a body weight and height above the 75th and
97th percentile respectively. Her limbs were dispro-
portionately long in relation to her trunk
(dolichostenomelia). She had pes cavus, genu valgum,
arachnodactyly and a narrow-face with a high-arched
palate (Figures 5, 6, 7) Cardiac ultrasonography was
normal. She had a history of very severe myopia (10
diopters) and astigmatism (1.5 diopters) from age 6.
By age 8, myopia had increased to 18 diopters and
astigmatism had doubled. At age 8 years, 5 months
she had manifested right lens subluxation for which
she was surgically treated with a lens implant. Three
months later, because of the resulting difference in re-
fractive error (anisometropia) the lens of the left eye
was also replaced. Psychological assessment con-
firmed the cognitive deficits and emotional lability
(affective inappropriateness). Her family history was
unremarkable.
In view of the clinical combination of tall stature
with marfanoid skeletal dysmorphy and ectopia lentis,
the initial aim of the diagnostic workup was to ascer-
tain if she had Marfan’s syndrome or C‚Sd. Amino
acid analysis revealed very high plasma levels of tHcy
(268 Ìmol/l), fHcy (93 Ìmol/l) and Me (630 Ìmol/l),
indicating CBS deficiency. This was confirmed by the
fact that CbS activity in cultured skin fibroblasts was
not detected (0.0 nmol cystathionine/ h/mg protein).
Other abnormal laboratory results were the reduced
serum levels of both vitamin B12 (190 pg/ml) and folic
acid. Results of routine haematology and biochem-
istry analyses were unremarkable.
A trial of B6 therapy (250 g/d) was initiated. Ami-
no acid analysis performed 20 days later showed only
slight reduction of the tHcy level to 260 Ìmol/l,
whereas the Me level was essentially unchanged. Con-
sequently, over a period of 2 weeks B6 dosage was
gradually increased to 500 mg/day but, after two
weeks plasma levels of tHcy and Me remained elevat-
ed (535 and 248 Ìmol/l respectively), indicating that
the patient was not responding to pyridoxine. In view
of these findings she was placed on a low protein, Me-
restricted diet with a Me-free amino acid supplement
148 P. Augoustides-Savvopoulou et al.
Paediatriki 2007;70:146-151
Figure 5. Photograph of: a) feet of patient 2 depicting long digitsand pes cavum and b) hands with long digits (arachnodactyly).
5a 5b
Figures 4a, 4b. Photographs of patient 1 showing genu valgum andmild disproportion of limbs to trunk
4a 4b
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·148
rich in cystine and other essential amino acids (Hom-
2 Secunda, SHS). In addition, betaine (Cystadane,
Orphan Europe) was administered in a dosage of 4
g/day. Subsequent monitoring of amino acids re-
vealed a significant reduction in plasma tHcy to 156
Ìmol/l, but also a significant increase in Me to 1238
Ìmol/l. In view of the potential risk of cerebral edema
due to severe hypermethioninemia, the betaine
dosage was reduced, and methionine restriction in-
tensified. With frequent monitoring of this regimen
plasma tHcy levels below 100 Ìmol/l (~90 Ìmol/l)
and Me levels ~600 Ìmol/l were achieved. Assessment
of bone-density (DXA scan) has revealed incipient
osteoporosis of the spinal vertebrae. A vascular screen
was negative (normal Triplex Doppler test), and
brain MRI scans are essentially normal. Monitoring
of these parameters is carried out on a yearly basis.
Discussion
Despite the presence of major clinical features ofC‚Sd in both our patients, they remained undiag-nosed until late childhood, with severe and nearly fa-tal consequences. As shown in Table 1, these two pa-tients had common features, but also significant dif-ferences that illustrate the clinical heterogeneity ofC‚Sd. The striking clinical clues common to bothwere the opthalmological findings of severe myopiafrom a young age and ectopia lentis (Figure 8). Ectopialentis occurs in about 85% of C‚S-deficient patientsbut often a systemic disorder is not suspected, or thepatients are misdiagnosed as having Marfan’s syn-drome (2,7,8). Indeed, such a misdiagnosis was madefor both our patients. Marfan’s syndrome is a rela-tively common (~1:5-10000 live births), but as yetuntreatable, autosomal dominant disorder of connec-tive tissue in which lens dislocation also occurs. How-ever, such patients do not have the increased levels ofplasma tHcy and Me characteristic of C‚Sd (2,3,8).The lenticular origin of myopia in C‚S deficient pa-tients is not always recognized. Clues for lenticularmyopia are abnormally rapid progression of myopia,severe myopia in children and progressive myopia inadults (7). Nevertheless, it should be stressed that anormal ophthalmological examination at any agedoes not exclude the diagnosis of C‚Sd (2,9,10). Fur-ther similarities between patients with Marfan’s syn-drome and those with C‚Sd are that both typicallyhave increased limb length and genu valgum. Patient2 was marfanoid in structure, but she had osteoporo-sis and signs of involvement of the central nervoussystem which are distinguishing features of C‚Sd (2).In accord with the findings in our patients, spinal os-teoporosis and other skeletal abnormalities generallyoccur earlier in pyridoxine non-responsive patientsthan in those responsive to pyridoxine (2).
Thromboembolism, affecting both large and smallarteries and veins, is the most striking cause of mor-bidity and mortality in C‚Sd. Sagittal sinus thrombo-sis was the presenting feature in patient 1. Because the
149Homocystinuria due to C‚S deficiency
¶·È‰È·ÙÚÈ΋ 2007;70:146-151
Table 1. Comparison of clinical features of patient 1 andpatient 2
Patient 1 Patient 2
Severe myopia + +++Ectopia lentis + +Marfanoid habitus + +++Osteoporosis - +Vascular events + -Mental retardation - +B6 response + -Age at diagnosis 10 y 9 y
Figure 6. Photograph depicting high palate of patient 2.
Figures 7a, 7b. Marfanoid habitus of patient 2 (dolichostenomelia,genu valgum, pes cavus) is depicted.
7a 7b
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·149
150 P. Augoustides-Savvopoulou et al.
Paediatriki 2007;70:146-151
laboratory workup for thrombotic events included
measurement of tHcy in plasma, the diagnosis of
C‚Sd was made. This life-threatening complication
in our B6-responsive patient is in agreement with ob-
servations that, although such responsive patients
tend to have less severe clinical manifestations than
do B6-non-responsive patients, the probability of un-
treated patients of both types having vascular events
is about the same (2). Homozygosity (677TT) for the
MTFHR polymorphism in our patient together with
low folic acid and B12 levels may have been an addi-
tional contributory factor (11).
Mental retardation is the most frequent central
nervous system abnormality and, together with psy-
chiatric symptoms, may be the first recognizable sign
of C‚Sd (9). It is of note that the cognitive deficits
and psychiatric problems of patient 2 were the main
reasons for which her parents sought help.
The prognosis for an individual diagnosed with
C‚Sd, if untreated, is one of progressive morbidity and
mortality, as documented by Mudd et al in the largest
to-date survey of C‚S-deficient patients (2). Treatment
of this disorder usually halts progression of skeletal,
neurological and vascular problems, but advanced
opthalmological problems are more difficult to control
(6). In a multicenter study involving 158 patients with
2822 patient-years of treatment, homocysteine-lower-
ing treatment was shown to reduce the vascular risk sig-
nificantly, despite imperfect biochemical control (5).
The main target of treatment in CbSd is to control or
eliminate the severe hyperhomocystinemia characteris-
tic of this disorder, the ultimate goal being to prevent
the life-endangering thromboembolic events and to
prevent further escalation of complications already
present. The basic treatment strategy is: 1) to increase,
where possible, the residual enzyme activity by admin-
istration of the coenzyme precursor, pyridoxine; 2) to
decrease the load on the affected pathway with a low
protein, low Me diet; 3) to supplement deficient prod-
ucts (cystine); 4) and/or to use alternative pathways to
remove toxic substrates or their metabolites (betaine)
(Figure 1) (6). As evidenced by the dramatic response
in patient 1, this is achieved relatively easily in the pyri-
doxine-responsive patient by the administration of
pharmacological doses of B6, together with folic acid 5
mg/d and B12. Patients not given folic acid while on
pyridoxine therapy become folate-depleted, hampering
the biochemical response in a potentially B6-responsive
patient (6,12). All newly diagnosed patients should be
given a pyridoxine trial while remaining on a normal
diet. Biochemically, vitamin responsiveness is indicated
by decreasing Hcy and Me levels. If tHcy and Me levels
remain persistently elevated while on high (500 mg/d)
pyridoxine for several weeks, the patient is deemed bio-
chemically pyridoxine-non-responsive and is com-
menced on a Me restricted diet. Doses of pyridoxine re-
quired for a response vary markedly among pyridoxine
responders and have been associated with different
mutations within the CbS gene (13). Rarely, very high
(2-6 g/d) doses of B6 have caused reversible peripheral
neuropathy but, as yet, this has been seen only in non-
C‚S-deficient patients (12). Treatment of the B6-non-
responsive patient is a challenge because many patients
will not comply with the unpalatable, low protein, Me-
restricted, cystine-supplemented diet which, in addi-
taine may be useful in pyridoxine-non-responsive pa-
tients who will not tolerate Me restriction, or as an ad-
junct to such a diet. This compound acts as a methyl
donor, increasing the rate of remethylation of Hcy to
Me by betaine-homocysteine methyltransferase. Until
recently it was believed that the resultant hyperme-
thioninaemia did not influence the pathophysiology of
the disease. However there has been more than one re-
port of progressive cerebral edema associated with very
high levels of Me (>1000 Ìmol/l) indicating that regu-
lar biochemical monitoring of Me levels should be per-
formed in B6-non-responsive patients on betaine ther-
apy (14,15). The very high levels of Me in patient 2 were
a cause for concern, necessitating intensification of the
low Me diet and regulation of the betaine dose with
concomitant titration of Me.
The biochemical hallmark of C‚Sd is hyperhomo-
cystinaemia in combination with hypermethioni-
naemia. It should be stressed that hypermethionine-
mia is not completely obligatory in C‚Sd (absent in
about 6% of cases) and isolated hyperhomocysti-
naemia does not confirm C‚Sd (2). Pitfalls in the
measurements of Hcy levels can be avoided if blood
samples are from fasting patients and promptly
Figure 8. Photograph of eye of patient with C‚Sd depicting totalsubluxation of the lens (from the Atlas of International Council ofOphthalmology).
Pediatr Mar-Apr 07 28-03-07 17:23 ™ÂÏ›‰·150
151Homocystinuria due to C‚S deficiency
¶·È‰È·ÙÚÈ΋ 2007;70:146-151
processed. Diagnosis is confirmed if C‚S enzyme ac-tivity in cultured skin fibroblasts is non-detectable orup to 15% of mean control levels. In addition to theabove tests, C‚S mutational screening is another op-tion. There are now at least 139 known disease-caus-ing C‚S mutations. (13) The two most common arethe G307S, also known as the “Celtic” mutation, andthe 833 T>C (I278T) mutation. The former is associ-ated with the more severe pyridoxine-non-responsivephenotype whereas the latter is associated with themilder pyridoxine-responsive phenotype. I278T wasnot present in our B6-responsive patient. Althoughmutation analysis is a tool for better understandingthe variability of the clinical phenotype, the existenceof a large number of very rare, often private, muta-tions limits the usefulness of this approach in routinediagnosis. Prenatal diagnosis of C‚Sd is available ei-ther by metabolite or enzyme analysis in amniotic flu-id/cells or mutation analysis in chorionic villi (16).Regarding the detection of C‚Sd by newborn screen-ing by searching for hypermethioninemia, a cause ofconcern is the high number of false-negative results.Pyridoxine-responsive disease is often missed by suchnewborn screening because increased Me levels arenot prominent in these newborns. Newborn screen-ing for common mutations has been suggested bysome workers (4).
In conclusion, C‚Sd is a potentially treatable con-dition, especially if detected and treated early. Un-treated, this disorder can lead to life-threateningcomplications. Its clinical heterogeneity necessitatesincreased awareness of the variety of clinical presen-tations. The recognition of myopia in patients withthromboembolism, skeletal abnormalities or centralnervous system complications, aptly coined by Cruys-berg et al (7) as “myopia plus”, should alert physi-cians to the possibility of C‚Sd. Plasma total homo-cysteine should be a first-line test in patients with ear-ly onset of severe myopia, ectopia lentis, skeletalchanges reminiscent of Marfan’s syndrome, throm-boembolism, mental retardation with psychiatricsymptoms, bearing in mind that these features maybe isolated or in combination.
Accurate diagnosis of a genetic disease has impor-tant consequences for the patient and his family be-cause of the implications for appropriate therapy andgenetic counseling. In the event of diagnosis, high-risk family members should be investigated as well.
Acknowledgements
We express our gratitude to Dr S Harvey Mudd for re-viewing the manuscript and for his advice as regards the man-agement of our patients and to Dr Leo Kluijtmans for his helpwith the enzyme and molecular assays.
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M. Theodoridou, V. Vasilopoulou, A. Zisouli, G. Mostrou, V. Syriopoulou
Abstract: Cysticercosis of the central nervous system (neurocysticercosis) is the commonest parasiticdisease of the human nervous system, affecting mainly populations of developing countries. InEurope, sporadic cases still occur, although the progress in sanitation during the last century hascontributed to the elimination of the disease. Affected children usually present with epilepticseizures. The case reported is the first published case of childhood parenchymal neurocysticercosisin Greece. The child presented with seizures, signs and symptoms of increased intracranial pressureand unilateral peripheral facial palsy. Brain CT and MRI showed multiple hypodense and isodenselesions with peripheral oedema in the cerebral hemispheres and the cerebellum, while the ELISA testfor serum anticysticercal antibodies was positive. Three courses of albendazole were administered,each of 28 days, combined with corticosteroids for one month. One year later the child was healthyand MRI showed only one calcified lesion in the right frontal lobe. Early diagnosis followed byantiepileptic and antiparasitic therapy contributed to a successful outcome. This case report aims topoint out that neurocysticercosis should be included in the differential diagnosis of every childpresenting with seizures and focal neurologic deficits, even in non-endemic countries.
First Department ofPaediatrics, Aghia SofiaChildren’s Hospital,University of Athens, Greece
Correspondence:
Vasiliki [email protected] Department of Paediatrics, University of AthensAghia Sofia Children’sHospital, Thivon and Levadias St., 11527, Athens, Greece
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