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One Belt, One Road Reference Source Year XVII • No. 64 (4) 2021 • DOI: 10.26416/Pedi.64.4.2021

ISSUE
THEME
UP-TO-DATE
IN PEDIATRICS

REVIEW
Update on the diagnosis
of pediatric autoimmune
hepatitis
page 8

CLINICAL STUDIES
Clinical and
hematological aspects
in pediatric patients
diagnosed with Fanconi
anemia – a single-center
experience
page 22

CASE REPORT
Rectal bleeding
in children – case report
page 46
PHOTO: SHUTTERSTOCK
 Revistă de educaţie medicală continuă
Elemente care definesc infecţia
cu SARS-CoV-2 la copii
Denumit inițial noul coronavirus,
SARS-CoV-2 s-a răspândit rapid, fiind
dificil de gestionat la nivel mondial și
devenind o problemă globală de să­nă­ta­te
publică, ducând la o mobilizare in­ter­na­
țională probabil fără precedent în istoria
umanitară recentă(1,2,3).
Cunoștințele actuale despre infecția cu
SARS-CoV-2 sunt încă la început și multe
întrebări așteaptă un răspuns, dar apar-
ent evident, cel puțin până acum, în rân-
dul populației pediatrice incidența bolii
este scăzută.
Analizând datele epidemiologice in­
ter­na­ționale și naționale, se constată un
im­pact redus asupra populației pe­dia­tri­ce
comparativ cu adulții. La nivel global, in­­ci­
den­ța noului tip de coronavirus în rândul
copii­lor a crescut de la mai puțin de 1-2%
la începutul anului 2020 la peste 26% în
pre­zent(1,2,3). Cu toate acestea, decesele la
vârs­ta pediatrică sunt extrem de scăzute în
comparație cu ceea ce se întâmplă la adulți.
Incidența scăzută a bolii în rândul po­
pu­lației pediatrice este un subiect de ma­re
interes pentru cercetările actua­le și vii­toa­
re. Literatura de specialitate men­țio­nea­ză
până acum mai multe teo­rii, dar cele mai
importante sunt trei ipo­te­ze privind in­ci­
den­ța scăzută a in­fec­ției cu noul coronavi-
rus în po­pu­la­ția pe­dia­tri­că(3,4,5).
S-a demonstrat că receptorii enzimei
de conversie a angiotensinei 2 (ACE 2)
ar fi poarta de intrare în celulele umane
pentru unele coronavirusuri, inclusiv
pentru SARS-CoV-2; de asemenea, ex-
presia scăzută a acestor receptori în
tractul respirator al copiilor ar putea fi
explicația pentru care ei sunt mai puțin
vulnerabili la SARS-CoV-2(4,5). Studiile
Reclamă PED(64)0101
mai recente însă pun la îndoială această
teorie, deoarece categoria de pacienți cu
vârsta sub 1 an la care expresia ACE 2
este cea mai scăzută este încă un grup
extrem de vulnerabil pentru noul tip
de coronavirus. O altă ipoteză care a
atras atenția cercetătorilor este afec-
tarea endotelială, care a avut loc înainte
de agresiunea infecțioasă ce facilitează
răspândirea infecției și implicit a proce-
sului inflamator.
Deoarece în populația pediatrică exis­ Prof. dr. Doina Anca
tă o incidență redusă a bolilor recunoscu­ Pleșca
te ca provocând distrugeri endoteliale Redactor-şef
(ex.: boli cardiovasculare, diabet), se
apre­­cia­ză că răspândirea procesului in­
fla­mator este limitată în condițiile unui
en­do­te­liu indemn.
Numeroasele infecții virale pe care
copiii le prezintă în primii ani de viață,
precum și administrarea de vaccinuri
stimulează răspunsul imunitar al aces-
tora. Sistemul imunitar înnăscut joacă
un rol important în protecția împotriva
SARS-CoV-2.
Această ipoteză pare să fie din ce în
ce mai exploatată și necesită o atenție
spe­cia­lă în viitor, mai ales că cercetătorii
men­țion­ea­ză unele posibile corelații între
imu­ni­za­rea antigripală și protecția împo­
tri­va coronavirusului.
România s-a confruntat cu primul
caz pozitiv confirmat de infecție cu
SARS-CoV-2 la 26 februarie 2020, iar la
aproximativ o lună au apărut primele de-
cese secundare acestei infecții. Situația
epidemiologică a impus, începând cu data
de 16 martie 2020, instituirea stării de
ur­gen­ță pe teritoriul României, implicând
mă­suri speciale atât din punct de vedere
sa­ni­tar, cât și socioeconomic. Ulterior, din
14 mai 2020, starea de urgență a fost în­
lo­cui­tă cu o serie de alte măsuri, iar la 19
luni de la primul caz confirmat în țară
încă se luptă pentru a se încerca limita­
rea răspândirii și mai ales a impactu­
lui pande­m iei de COVID-19 în cadrul
po­­pu­la­ției.
Din analiza datelor epidemiolo­g i­
ce internaționale și naționale, încă din
primele luni de pandemie, exis­t ă o di­
fe­ren­ț ă semnificativă în­t re populația
editorial

pedia­trică față de po­pu ­la­ț ia adultă
în ceea ce privește ra­ta de infecție,
modalitățile de trans­mi­tere și ma­
ni­fes­t ă­r i­le clinice. În primele luni
de pan­de­mie, in­ci­den­ța raportată la
ni­vel național a nou­lui tip de coro-
navirus în rândul copii­lor a fost de
aproximativ 1-2%, dar în prezent
a ajuns la 6,52%, dintr-un număr
total de 74474 de copii in­fec­tați
(19 septembrie 2021)(2). Ra­poar ­te­
le de la Centers for Disease Con­trol
(CDC) din SUA privind rata in­fec­ției
cu SARS-CoV-2 la copii au ară­tat o
tendință ascendentă mai ales în a
doua jumătate a acestui an. Astfel,
dacă la începutul lunii apri­lie 2020
incidența infecției cu noul coronavi-
rus la copii era de doar 2,6%, 18 luni
mai târziu (11.11.2021) proporția a
crescut la 27%, în condițiile în care au
fost raportați aproximativ 6.625.857
de copii in­fec­tați(1).
Creșterea ratei de infecție cu
SARS-CoV-2 în rândul copii­lor a ridi­
cat mai multe semne de în­tre­bare:
Au fost extinse testările în masă la
copii? Există o legătură cu re­des­chi­
de­rea școlilor? Este vorba despre alte
variante de virus?(6)
O metaanaliză amplă în care au
fost incluse peste 90 de studii între-
prinse la adulți și copii și care a anali-
zat modul de transmitere a infecției
cu SARS-CoV-2 în rândul copiilor și
adolescenților (în mediul familial, în
comunitate și la școală/grădiniță) a
subliniat că pentru copiii sub 10 ani
există o susceptibilitate redusă la
infecție comparativ cu adolescenții
și adulții. În plus, riscul de infectare
a copiilor sub 10 ani la școală a fost
mai redus comparativ cu riscul de
infectare a acestora în comunitate(7).
Manifestările clinice ale infecției
cu SARS-CoV-2 în populația pe­dia­tri­
că sunt mai puțin severe compara­tiv
cu cele de la adulți(8). La co­pii, ma­ni­
fes­tă­ri­le cli­ni­ce sunt în ge­ne­ral ușoa­
re, de cele mai multe ori îm­bră­când
un aspect pseu­dogripal, iar ca­zu­ri­le
se­ve­re sunt rare (5,2% cazuri severe
și 0,6% ca­zuri critice)(9) și de cele mai
mul­te ori acestea s-au re­cu­pe­rat.
La câteva săptămâni de la confir­
ma­rea infecției cu SARS-CoV-2 (2-6
săp­tă­mâni) s-a descris apariția foarte
rară (un caz la 3200 de infecții) a unui
ta­blou clinic definit drept sindrom
in­f la­m a­tor multisistemic la copii
(MIS-C). Acest sindrom inflamator
interesează mai multe sisteme și or-
gane, precum inima, plămânii, cre­ie­
rul, rinichii, tegumentele, apa­ra­tul
di­ges­tiv sau ochii, determinând un
ta­blou cli­nic complex(10).
În concluzie, trebuie să subliniez
următoarele:
n Copiii de toate vârstele sunt sus­cep­
tibili să se infecteze, dar în cazul ex-
punerii aceștia sunt cu aproximativ
50% mai puțin in­fec­tați comparativ
cu adulții.
n Copiii de toate vârstele pot să fie
in­fec­tați; parametrii virusologici
pen­tru virusul identificat sunt
iden­tici la copii și la adulți, dar în­
căr­cătura virală pare mai mică la
copii față de adulți; oare copiii sunt
mai puțin contagioși și pentru o
pe­rioa­dă mai scurtă?
n Când sunt infectați, copiii prezin-
tă o simptomatologie mai puțin
severă (este surprinzător și încă
de neînțeles).
n Au fost lansate mai multe ipoteze
care să explice de ce copiii sunt
mai puțin afectați de infecția cu
SARS-CoV-2 (exceptând modifi-
cările legate de vârstă, ale funcției
imune, endoteliale/de coagulare).
n Descoperirea mecanismelor care
stau la baza diferențelor legate de
vârstă în ceea ce privește severita-
tea COVID-19 va oferi oportunități
importante pentru prevenirea și
tratamentul acestei noi infecții.
În urma evoluției pandemiei, con­
sta­tăm că are loc o modificare a mo­
de­lu­lui de implicare a populației pe­
dia­trice, care, deși rămâne mai puțin
afec­ta­tă în comparație cu adulții, se
con­frun­tă cu noi fațete ale infecției
cu SARS-CoV-2 odată cu evoluția
celui de-al doilea, de-al treilea, dar
mai ales al celui de-al patrulea val
pandemic.

Bibliografie
1. World Health Organisation https://www.who.int/ith/diseases/sars/en - SARS; Severe Acute Respiratory Syndrome.
2. Institutul Național de Sănătate Publică - http://www.cnscbt.ro/ - Infectia cu noul coronavirus SARS-CoV-2- situatia-la-nivel-global-actualizata-zilnic
3. https://data.unicef.org/topic/covid-19-and-children
4. Zimmermann P, Curtis N. Coronavirus infections in children including COVID-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options
in children. Pediatr Infect Dis J. 2020;May;39(5):355-368.
5. García-Salido A. Three Hypotheses About Children COVID19. Pediatr Infect Dis J. 2020 Jul;39(7):e157. doi: 10.1097/INF.000000000000270.
6. AAP: State level data, 2021.
7. Irfan O, Li J, Tang K, Wang Z, Bhutta ZA. Risk of infection and transmission of SARS-CoV-2 among children and adolescents in households, communities and educational settings:
A systematic review and meta-analysis. J Glob Health. 2021 Jul 17;11:05013. doi: 10.7189/jogh.11.05013.
8. Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020 Jun;109(6):1088-1095. doi: 10.1111/apa.15270.
9. Lu X, Zhang L, et al. The Chinese Pediatric Novel Coronavirus Study Team. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;2020:NEJM c2005073.
10. CDC: Raported cases of Multisystemic Inflammatory Syndrome in children (MIS-C) in the United States, 11.11.2021.
Reclamă PED(64)0102
 NOU
NUMAI DE LA

Susține
dezvoltarea
naturală
a copilului

Susține Inspirat
microbiota din natură
intestinală

Bewiesene
Bewiesene
Siguranță
Sicherheit
Sicherheit dank
dank
dovedită
bewährtem Konzept
bewährtem Konzept

Știința și Natura
Mână în Mână
 content Year XVII • No. 64 (4) December 2021

REVIEW
8 Update on the diagnosis of pediatric autoimmune hepatitis
Claudia Sîrbe, Alina Grama, Tudor Lucian Pop HONORARY EDITOR-IN-CHIEF
Prof. Mircea NANULESCU, MD, PhD (Cluj-Napoca, Romania)

UP-TO-DATE EDITOR-IN-CHIEF
Prof. Doina Anca PLEȘCA, MD, PhD (Bucharest, Romania)
DEPUTY EDITOR-IN-CHIEF
14 The role of breastfeeding in preventing a global health problem: Assoc. Prof. Tudor Lucian POP, MD, PhD (Cluj-Napoca, Romania)

pediatric obesity EDITORIAL GENERAL SECRETARY

Assoc. Prof. Tatiana CIOMÂRTAN, MD, PhD (Bucharest, Romania)
Heidrun Adumitrăchioaiei, Bogdan Stana, Alina Costina Luca EDITORIAL SECRETARY
Lecturer Laura BOZOMITU, MD, PhD (Iaşi, Romania)
18 Expression of interleukin-31 and interleukin-33 in atopic dermatitis Lecturer Bogdan STANA (Iași, Romania)
Lecturer Iulia ŢINCU, MD, PhD (Bucharest, Romania)
and correlation with clinical features INTERNATIONAL EDITORIAL BOARD
Emanuela Duca, Tudor Lucian Pop Prof. Vassilios FANOS (Cagliari, Italy)
Prof. Salvatore VENDEMMIA (Aversa, Italy)
EDITORIAL BOARD

CLINICAL STUDIES Prof. Evelina MORARU MD, PhD (Iaşi, Romania)

22 Clinical and hematological aspects in pediatric patients diagnosed
with Fanconi anemia – a single-center experience
Cristina Jercan, Ana Maria Bică, Andra Daniela Marcu, Letiţia Elena Radu,
Andreea Șerbănică, Mirela Asan, Camelia Dobrea, Cerasela Jardan,
Alexandra Ionete, Carmen Călugăroiu, Ileana Constantinescu,
Aurora Dragomirișteanu, Constantin Arion, Anca Coliţă
30 Vitamin D intake and weight status in preschool children
Diana Voican, Anca Angela Simionescu, Ana Maria Alexandra Stănescu,
Marina Ruxandra Oţelea
34 Abdominal trauma in children – one-year single-center experience
O. Bîcă, Diana Benchia, Klara Sârbu, Carmen Iulia Ciongradi, I. Sârbu, Ș. Popa
Prof. Cristina BORZAN, MD, PhD (Cluj-Napoca, Romania)
Assoc. Prof. Anca COLIŢĂ, MD, PhD (Bucharest, Romania)
Prof. Cristian GHEONEA, MD, PhD (Craiova, Romania)
Prof. Mihai GAFENCU, MD, PhD (Timişoara, Romania)
Prof. Sorin MAN, MD, PhD (Cluj-Napoca, Romania)
Prof. Otilia MĂRGINEAN (Timișoara, Romania)
Prof. Oana MĂRGINEAN (Târgu-Mureş, Romania)
Prof. Dan MORARU (Iaşi, Romania)
Prof. Aurel NECHITA, MD, PhD (Galaţi, Romania)
Prof. Liviu POP, MD, PhD (Timişoara, Romania)
Assoc. Prof. Victoria HURDUC (Bucharest, Romania)
Assoc. Prof. Daniela ȘERBAN, MD, PhD (Cluj-Napoca, Romania)
Lecturer Simona CĂINAP, MD, PhD (Cluj-Napoca, Romania)
Lecturer Daniela PĂCURAR, MD, PhD (Bucharest, Romania)
SL Alexandru PÂRVAN, MD (Cluj-Napoca, Romania)
Assistant Prof. Bianca SIMIONESCU, MD, PhD (Cluj-Napoca, Romania)
DTP
Ioana BACALU
PROOFREADING
Florentin CRISTIAN
PHOTOPROCESSING
Radu LEONTE

CASE REPORT
41 Adrenocortical carcinoma – fatal evolution of a rare cancer
in children
Georgiana Scurtu, Magdalena Starcea, Mirabela Alecsa, Silvia Dumitraş,
Antonela Ciobanu, Anca Ivanov, Adriana Mocanu, Ingrith Miron,
CEO
Roxana Bogos Simona MELNIC

46 Rectal bleeding in children – case report DEPUTY CEO MULTICHANNEL & EVENTS MANAGER
Lavinia SIMION
Iulia Florentina Ţincu, Andrei Zamfirescu, Cristian Ioan Nedelcu, EDITORIAL MANAGER
Anca Ioana Avram, Doina Anca Pleşca Oana NEACȘU
SALES MANAGER
Mircea TOMESCU
ADMINISTRATIVE MANAGER
Dana STUPARIU
SUBSCRIPTIONS MANAGER
Cristina GRECU, Amelia SAVU
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 review

Update on the diagnosis

Claudia Sîrbe,
Alina Grama,
Tudor Lucian
Pop
Second Pediatric Discipline,
Department
of Mother and Child,
“Iuliu Haţieganu” University
of Medicine and Pharmacy,
Cluj-Napoca, Romania
Second Pediatric Clinic,
Center of Expertise
in Pediatric Liver
Rare Disorders,
Emergency Clinical Hospital
for Children,
Cluj-Napoca, Romania
Corresponding author:
Alina Grama
E-mail: gramaalina16@yahoo.com
of pediatric autoimmune
hepatitis
Abstract
The types of autoimmune liver disorders recognized in the
pediatric population are: autoimmune hepatitis (AIH), auto­
immune sclerosing cholangitis (ASC), and de novo AIH after
liver transplant. AIH can present with a broad clinical spec­
trum, specifically acute or severe acute hepatitis and chro­nic
hepatitis. The diagnosis of AIH is based on clinical as­pects,
the laboratory investigations comprising liver and im­mu­no­
lo­gy analysis, and in some cases liver biopsy. AIH should be
sus­pec­ted after excluding other similar causes of liver disor­
ders, such as viral hepatitis and metabolic disorders.
Keywords: pediatric autoimmune hepatitis, diagnosis,
autoimmune sclerosing cholangitis, autoantibodies,
magnetic resonance cholangiopancreatography
Submission date:
25.11.2021 Actualităţi în diagnosticul hepatitei autoimune la copil
Acceptance date: Suggested citation for this article: Sîrbe C, Grama A, Pop TL. Update on the diagnosis of pediatric autoimmune hepatitis. Pediatru.ro. 2021;64(4):8-13.
6.12.2021
Rezumat
Tipurile de boli hepatice autoimune recunoscute la po­­pu­
la­ția pediatrică sunt: hepatita autoimună (AIH), co­lan­
gi­ta scle­ro­zan­tă autoimună (ASC) și AIH de novo după
trans­plant he­pa­tic. AIH prezintă un spectru clinic larg, ca
hepatită acută, for­mă acută severă sau hepatită cro­ni­că.
Diag­nos­ti­cul AIH se bazează pe aspecte clinice, in­ves­ti­ga­ții­
le de laborator cu­prin­zând analize hepatice și imunologice,
iar în unele cazuri biop­sie hepatică. AIH tre­bu­ie suspectată
după excluderea altor cauze similare, cum ar fi hepatitele
vi­ra­le și bolile metabolice.
Cuvinte-cheie: hepatită autoimună, copil, diagnostic,
colangită sclerozantă autoimună, autoanticorpi,
colangiopancreatografie prin rezonanţă magnetică

Introduction 1 antibody (anti-LC-1). AIH should be suspected after

The types of autoimmune liver disorders recognized
in the pediatric population are autoimmune hepatitis
(AIH), autoimmune sclerosing cholangitis (ASC), and
de novo AIH after liver transplant(1). AIH is a complex
liver disease characterized by immune-mediated hepato-
cyte injury associated with the destruction of liver cells,
causing inflammation, liver failure and fibrosis. AIH
is an uncommon condition that affects all ages and all
ethnicities. Some studies suggest that the incidence of
pediatric AIH has been rising in the last two decades(2),
while others consider that these cases are more often
diagnosed compared to the past due to the increased
awareness and the decrease in the number of cases of
viral hepatitis after hepatitis B vaccination and hepatitis
C effective treatment(1). AIH can present with a broad
clinical spectrum, specifically acute(3) or severe acute
hepatitis(4) and chronic hepatitis(5). The diagnosis of
AIH is based on clinical aspects, the laboratory inves-
tigations comprising liver and immunology analysis,
and in some cases liver biopsy. There are described two
types of AIH that can be distinguished based on the
serological profile: type 1 AIH (AIH-1) is positive for
antinuclear antibody (ANA) and/or anti-smooth muscle
antibody (SMA), and type 2 AIH (AIH-2) is defined by
positivity for anti-liver kidney microsomal type 1 an-
tibody (anti-LKM-1) and/or for anti-liver cytosol type
excluding other similar causes of liver disorders, such as
viral hepatitis and metabolic disorders(6). In the presence
of a progressive inflammatory process, the continuous
loss of hepatocytes can cause liver dysfunction and liver
fibrosis in the long term(7).
Genetic trait
The mechanisms involved in autoimmune diseases
represent a complex pathway between human leuko-
cyte antigen (HLA) predisposing genes and non-HLA
systems(8). The importance of HLA variants implicated
in AIH-1 was demonstrated by a genome-wide associa-
tion study (GWAS)(9). HLA genes responsible for AIH-1
susceptibility in adults are associated with the HLA-
DRB1 variant on chromosome 6, representing a class
II human major histocompatibility complex (MHC).
The HLA-DR3 (DRB1*0301) and DR4 (DRB1*0401)
molecules are described in North American and Euro-
pean populations(10,11), and the latest allele in Oriental
populations(12). HLA genes responsible for AIH-1 sus-
ceptibility in children are associated with HLA-DR3 in
northern Europe, but the DR4 encoding allele is not de-
scribed as a genetic predisposition in pediatric AIH-1(13).
The predisposition for AIH-2 is associated with HLA
DRB1*0701(14) and DRB1*0301(15). There are multiple al-
lele variants reported in AIH-1 susceptibility in different

8 Year XVII • No. 64 (4/2021)


world areas, such as DRB1*1301 and DRB1*0301 in
Brazil and Egypt(16), and also HLA-DRB1*1301 in South
America(17). The susceptibility for AIH-2 in Egypt is
described in the genetic variant HLA DRB1*15(16). In
children with AIH-1 and AIH-2, a partial deficiency of
the class III MHC complement component C4 was re-
ported(18). In one-quarter of the cases, the autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED) syndrome can be associated with AIH-2(19). A
Danish nationwide registry analysis demonstrated the
intricate relation between genetic and environmental
factors, showing that in families with cases of AIH,
first-degree relatives present a five-fold increased risk
of developing AIH(20).
Clinical features and diagnosis
Specific features that can help establish the diagnosis
of AIH are described: female preponderance(21), elevated
immunoglobulin G (IgG), the presence of autoantibodies
and histological findings that suggest interface hepati-
tis(22). The presence of ANA and/or SMA indicates AIH-1.
In contrast, the presence of anti-LKM-1 and/or anti-LC-1
is attributed to AIH-2(23) (Table 1).
AIH-1 is described in both children and adults, while
AIH-2 mainly affects children. There are little data based
on the incidence of childhood AIH, but it is known that
AIH type 1 accounts for approximately 60% of cases
and appears most commonly in adolescents. In con-
trast, AIH-2 appears more frequently in younger chil-
dren and infants(29). Presentation as fulminant hepatic
failure, with elevated transaminase and bilirubin levels,
is more often encountered in AIH-2 than in AIH-1(30).
However, AIH-2 is more often refractory to treatment
withdrawal(13).
Adult patients with AIH type 1 present a chronic
course of the disease with symptoms such as abdominal
and joint pain, nausea and fatigue(31), in comparison
with juvenile AIH where children present with more
severe wide-ranging symptoms, making the timing of
diagnosis important, especially in prolonged severe
liver disease. The diagnosis is often delayed in relaps-
ing forms where awareness should be raised, and AIH
should be excluded in the presence of sustained symp-
toms(1). The broad clinical spectrum can range from
an acute presentation with nonspecific symptoms fol-
lowed by jaundice, dark urine and pale stools (in almost
half of the patients with both types)(27) to severe acute
hepatitis with liver failure, developing encephalopathy
in a period between two weeks and two months after
presentation (3% of cases with AIH-1 and 25% of cases
with AIH-2)(30). There is also described a slowly progres-
sive course of disease in 40% of cases with AIH-1 and
in 25% of cases with AIH-2, which can last for a period
of a few months to a few years before diagnosis, char-
acterized by malaise, headache, anorexia, weight loss,
arthralgia, abdominal pain and relapsing jaundice(1).
Only in rare asymptomatic cases, the diagnosis is based
on an incidental finding of modified laboratory inves-
tigations(32). Approximately 10% of patients with both
Year XVII • No. 64 (4/2021)
pediatru
AIH types may present with end-stage liver disease
and with symptoms of portal hypertension such as
digestive bleeding and splenomegaly(28).
The presence of autoimmunity in the family is found in
40% of the cases. One-fifth of the patients present other
overlapped autoimmune diseases such as inflamma­tory
bowel disease (IBD), nephrotic syndrome, thy­ro­id­itis,
viti­ligo, insulin-dependent diabetes(13), hemo­lytic ane-
mia, idiopathic thrombocytopenia, celiac disease and
urticaria pigmentosa(33). These disorders should be inves-
tigated in the presence of AIH, and immediate treatment
should be conducted(34).
Among these, the most common disorders associated
with AIH are autoimmune thyroiditis(33), celiac disease(35)
and IBD(28). Recently, a study suggested that a gluten-free
diet may have a positive long-term effect in patients
with AIH and celiac disease. This statement was based
on the differences between patients with AIH and celiac
disease and those without celiac disease. These findings
suggested that gluten withdrawal may strengthen the
immunosuppressive treatment, resulting in sustained
remission in the treatment-free period, reshaping the
progression of AIH with overlapped celiac disease(36).
This effect is compared with that seen in patients with
type 1 diabetes mellitus and celiac disease with a gluten-
free diet which displays an improved glycemic control
due to enhanced gut permeability(37).
Addison disease and hypoparathyroidism are de-
scribed most frequently in AIH-2 or autoimmune pol-
yendocrinopathy-candidiasis-ectodermal-dystrophy
(APECED). APECED is an autosomal recessive genetic
disease characterized by Addison disease, hypoparathy­
roidism and chronic mucocutaneous candidiasis(38).
Some studies described multiple single-gene mutations
that result in the association between immunodeficiency
and autoimmunity, as well as AIH, based on an impaired
immune system(39).
The diagnosis of AIH is based on clinical aspects,
laboratory investigations comprising liver and immu-
nology analysis, and in some cases liver biopsy. AIH
should be suspected after excluding other similar causes
of liver disorders such as drug-induced liver disease,
nonalcoholic steatohepatitis, viral hepatitis B, C and E,
and Wilson disease(40). The International Autoimmune
Hepatitis Group (IAIHG) proposed a diagnostic system
that provides the probability of AIH using several posi-
tive and negative scores(41). Recently, simplified IAIHG
criteria were suggested for being much easier to use in
a clinical setting. The simplified score is based on IgG,
autoantibodies, the histological examination, which
forms the positive criteria, and the exclusion of other
causes of hepatitis, such as hepatitis B, C or E viruses,
Wilson disease or alcohol use, which form the negative
criteria from the IAIHG score(22). Neither the original,
nor the simplified scoring system is recommended in
juvenile AIH, especially in the presence of severe acute
hepatitis(42).
IAIHG cannot state the distinction between AIH and
ASC. The difference between AIH and ASC can only be
9
review

made by performing a cholangiogram that describes the juvenile AIH, proposing a diagnostic score to help dif-
bile duct disorder from disease onset(28). More recently, ferentiate between AIH and ASC(1) (Table 2).
ESPGHAN Hepatology Committee published a Position ASC is a chronic disease characterized by intrahepatic
Statement based on the diagnosis and management of and/or extrahepatic biliary tree inflammation, resulting

Table 1 Comparison between AIH-1, AIH-2 and ASC

AIH-1 AIH-2 ASC
Proportion of cases 90%(24) 10%(24) 20-50%(25)
More frequent More frequent in northern
Geography Worldwide(24)
in northern Europe(24) Europe and North America(26)
Sex 80% female, 20% male(1) 80% female, 20% male(1) 50% female, 50% male(1)
Age at diagnosis (years), median (range) 12 (range: 11-14)(27) 10 (range: 4.5-13)(27) 11.8 (range: 2.3-16)(28)
Acute hepatitis in 37% of cases
Chronic hepatitis in 26%
Insidious onset in ∼38%
Clinical presentation Acute liver failure in ∼25%(27) of cases
with cirrhosis in ∼20%(27)
No history of jaundice in 37%
of cases(28)
Concomitant autoimmune disease ∼20%(27) ∼20%(27) 48%(28)
Family history of autoimmune disease ∼40%(27) ∼40%(27) ∼40%(28)
ANA or SMA ≥1:20 ++(1) +/-(1) ++(1)
Anti-LKM-1 ≥1:10 -(1) ++(1) +/-(1)
Anti-LC-1 (Positive) -(1) ++(1) -(1)
Anti-SLA (Positive) -(1) ++(1) -(1)
pANCA (Positive) +(1) -(1) ++(1)
IgG
>Upper limit of normal ++(1) +(1) ++(1)
>1.20 times upper limit of normal ++(1) +(1) ++(1)
Liver histology
Compatible with AIH +(1) +(1) +(1)
Typical of AIH +(1) +(1) +(1)
Viral hepatitis (A, B, C, E, EBV), NASH,
-(1) -(1) -(1)
Wilson disease, and drug exposure
Cholangiography Normal(1) Normal(1) Abnormal(1)
DRB1*0301 (Europe,
North America, Egypt, Brazil) DRB1*0701, DRB1*0301, DQB1*0201
HLA predisposition
DRB1*1301 (Egypt, Brazil, DRB1*15 (Egypt)(27) DQB1*0302 (England)(28)
South America)(27)
Biochemical and immunological response
Yes(1) Yes(1) Yes(1)
to steroid treatment
AIH-1 – autoimmune hepatitis type 1; AIH-2 – autoimmune hepatitis type 2; ANA – anti-nuclear antibody; anti-LC-1 – anti-liver cytosol type 1; anti LKM-1 – anti-liver
kidney microsomal antibody type 1; anti-SLA – anti-soluble liver antigen; ASC – autoimmune sclerosing cholangitis; EBV – Epstein-Barr virus; IgG – immunoglobulin
G; NASH – nonalcoholic steatohepatitis; pANNA – peripheral anti-nuclear neutrophil antibodies; SMA – anti-smooth muscle antibody. Antibodies measured by indirect
immunofluorescence on rodent model (kidney, liver, stomach).

10 Year XVII • No. 64 (4/2021)

 pediatru

Table 2 Proposed scoring criteria for the diagnosis of juvenile autoimmune liver disease(1)
Cut-off AIH ASC
≥1/20 1 1
ANA and/or SMA
≥1/80 2 2
≥1/10 1 1
Anti-LKM-1
≥1/80 2 1
Anti-LC-1 Positive 2 1
Anti-SLA Positive 2 2
pANNA Positive 1 2
>ULN 1 1
IgG
>1.2 x ULN 2 2
Compatible with AIH 1 1
Liver histology
Typical of AIH 2 2
Absence of viral hepatitis (A, B, E, EBV), NASH,
Yes 2 2
Wilson disease and drug exposure
Presence of extrahepatic autoimmunity Yes 1 1
Family history of autoimmune disease Yes 1 1
Normal 2 2
Cholangiography
Abnormal 2 2
Score ≥7: probable AIH; ≥8: definite AIH. Score ≥7: probable ASC; ≥8: definite ASC.
AIH – autoimmune hepatitis; ANA – anti-nuclear antibody; anti LC-1 – anti-liver cytosol type 1; anti-LKM-1 – anti-liver kidney microsomal antibody type 1;
anti-SLA – anti-soluble liver antigen; ASC – autoimmune sclerosing cholangitis; EBV – Epstein-Barr virus; IgG – immunoglobulin G; NASH – nonalcoholic
steatohepatitis; pANNA – peripheral anti-nuclear neutrophil antibodies; SMA – anti-smooth muscle antibody; ULN – upper limit of normal

in bile duct injury and liver fibrosis, with significant
morbidity and mortality. Even though ASC was consid-
ered rare in children, the usage of noninvasive biliary
imaging showed an increased frequency of ASC in the
pediatric population, being as prevalent as AIH-1(28).
Overlapping syndrome between AIH and ASC is more
frequently described in children than in adults(1).
The clinical features of ASC, when compared to AIH,
include: half of the patients with ASC are male; the com-
mon presenting symptoms in both ASC and AIH-1 are
abdominal pain, jaundice and weight loss; IBD is en-
countered in almost half of children with ASC and in
only 20% of those with AIH; all ASC patients have posi-
tive ANA and/or SMA and almost all have a significant
increase in serum IgG levels; the presence of pANCA is
described in two-thirds of children with ASC compared
to half of the patients with AIH-1 and only 10% of those
with AIH-2; standard liver function tests at presentation
cannot differentiate between AIH and ASC.
In the early disease stages of ASC, alkaline phos-
phatase and gamma-glutamyl transpeptidase levels are
usually normal or only slightly increased. This under-
lines the importance of performing a cholangiogram or
a magnetic resonance cholangiopancreatography from
the presentation. Despite abnormal images on cholan-
giograms, 25% of the patients with ASC have no bile duct
involvement on histology, while 27% of the children with
AIH have biliary disease on histology(1). Often, ASC is
initially diagnosed and treated as AIH-1 and is discov-
ered during follow-up only after the appearance of the
cholestatic disease(28).
Laboratory investigations
The laboratory investigations reveal a wide range
of abnormalities; among these, there are elevated
transaminase values and impaired synthetic function
in almost half of the patients, with low albumin levels
and modified coagulation tests(28). Most of the patients
have high IgG levels, but normal values of IgG do not
exclude the diagnosis of AIH(13). The cut-off value of
autoantibodies is lower in pediatric patients than in
adults(43). One-quarter of the cases with AIH-2 and ap-
proximately 15% of those with AIH-1 have a normal
level of IgG levels, especially in an acute clinical set-
ting(1). There is described a reduction in the levels of
IgG among these children after beginning the immu-
nosuppressive treatment. Also, AIH-2 can have partial
IgA deficiency more often than AIH-1(29).

Year XVII • No. 64 (4/2021)

11
review
The presence of antinuclear antibody (ANA) and/or
anti-smooth muscle antibodies (SMA) indicates AIH
type 1 (AIH-1), while the presence of anti-liver kidney
microsomal antibody type 1 (LKM-1) and/or anti-liver
cytosol type one antibody (LC-1) is attributed to AIH type
2 (AIH-2)(23). Some patients with hepatitis C can also have
positive anti-LKM-1. Therefore, the exclusion of hepa-
titis C is mandatory before diagnosing AIH-2(44). Other
autoantibodies that can be used include anti-solu­ble liver
antigen (anti-SLA) and peripheral antinuclear neu­tro­phil
antibody (atypical pANCA or pANNA). pANCA is often
observed in AIH-1 or ASC and IBD, whereas in AIH-2 it
is absent(45). SMA can be used for monitoring treatment
efficiency in children(46) and adults with AIH-1(47), while
anti-LKM1 and anti-LC1 can be used in monitoring res­
ponse to therapy in juvenile AIH-2(48).
Anti-SLA (autoantibodies to soluble liver antigen)
were first characterized as specific for AIH type 3(49).
Still, recently the development of these autoantibodies
has been described in both types of AIH. Even though
they were only found in a few cases of AIH, they are an
indicator of disease severity with a higher number of
relapses(50).
Histology
Almost one-third of the cases have cirrhosis on liver
biopsy at the diagnostic moment, even those presenting
with acute symptoms, therefore AIH should be suspected
regardless of the mode of presentation(13). Liver biopsy in
both types demonstrates a similar aspect regarding the
severity of interface hepatitis, but in AIH-1 the initial
biopsy describes more often cirrhosis than in type 2(28).
Liver biopsy in AIH shows: portal inflammatory in-
filtrate with dense mononuclear cells and plasma cells
1. Mieli-Vergani G, Vergani D, Baumann U, et al. Diagnosis and Management
References
of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee
Position Statement. J Pediatr Gastroenterol Nutr. 2018;66(2):345-360.
2. Sebode M, Kloppenburg A, Aigner A, et al. Population-based study of
autoimmune hepatitis and primary biliary cholangitis in Germany: rising
prevalences based on ICD codes, yet deficits in medical treatment.
Z Gastroenterol. 2020;58(5):431-438.
3. Czaja AJ. Acute and acute severe (fulminant) autoimmune hepatitis. Dig Dis
Sci. 2013;58(4):897-914.
4. Yasui S, Fujiwara K, Yonemitsu Y, et al. Clinicopathological features of
severe and fulminant forms of autoimmune hepatitis. J Gastroenterol.
2011;46(3):378-390.
5. Heneghan MA, Yeoman AD, Verma S, et al. Autoimmune hepatitis. Lancet
(London, England). 2013;382(9902):1433-1444.
6. Corrigan M, Hirschfield GM, Oo YH, et al. Autoimmune hepatitis: an approach
to disease understanding and management. Br Med Bull. 2015;114(1):181-191.
7. Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver
disease. World J Gastroenterol. 2014;20(10):2515.
8. Seldin MF. The genetics of human autoimmune disease: A perspective on
progress in the field and future directions. J Autoimmun. 2015;64:1-12.
9. de Boer YS, van Gerven NM, Zwiers A, et al. Genome-wide association
study identifies variants associated with autoimmune hepatitis type 1.
Gastroenterology. 2014 Aug;147(2):443-52.e5.
10. Donaldson PT. Genetics in autoimmune hepatitis. Semin Liver Dis.
2002;22(4):353-363.
11. van Gerven NMF, de Boer YS, Zwiers A, et al. HLA-DRB1*03:01 and HLA-
DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis
type-1. Genes Immun. 2015;16(4):247-252.
12. Furumoto Y, Asano T, Sugita T, et al. Evaluation of the role of HLA-DR
antigens in Japanese type 1 autoimmune hepatitis. BMC Gastroenterol.
2015;15(1):1-9.
13. Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in childhood: a
20-year experience. Hepatology. 1997;25(3):541-547.
14. Bittencourt PL, Goldberg AC, Cançado EL, et al. Different HLA profiles confer
12
which extends into lobule; interface hepatitis displayed
by damage in the outer layer of periportal hepatocytes;
enhanced collagen synthesis resulting from hepato-
cyte destruction which extends from periportal space
into the lobule; liver cells regeneration with “rosette”
formation(51).
The severity of inflammation, hepatocyte destruction
and the presence and extension of fibrosis are variable
among cases. Liver biopsy can also demonstrate the pres-
ence of an overlapped nonalcoholic fatty liver disease or
ASC. Interface hepatitis is not pathognomonic for AIH;
it can also be encountered in other disorders and can be
absent in cases with AIH which were previously treated
with immunosuppressive medication(28). The relapse of
AIH can include panlobular inflammatory infiltrate with
periportal necrosis expanding to the centrilobular area,
forming bridging necrosis(52).
Conclusions
The early diagnosis is important, but the currently
used AIH scoring systems do not display sufficient sensi-
tivity, and further firm diagnostic tools are still needed.
There are guidelines that provide a fundamental over-
view about diagnostic and therapeutic approaches. This
underlines the importance of distinguishing between
AIH and other similar causes of liver disorders such as vi-
ral hepatitis, metabolic disorders, ASC and drug-induced
liver disease. The prognosis of pediatric cases with AIH
who are treated with immediate immunosuppressive
treatment is favorable, with good long-term survival
rates and a reduced effect on the quality of life. n
Conflict of interests: The authors declare no con­
flict of interests.
susceptibility to autoimmune hepatitis type 1 and 2. Am J Gastroenterol.
1998;93(8):1394-1395.
15. Ma Y, Bogdanos DP, Hussain MJ, et al. Polyclonal T-cell responses to cyto­
chrome P450IID6 are associated with disease activity in autoimmune hepa­
titis type 2. Gastroenterology. 2006;130(3):868-882.
16. Elfaramawy AA, Elhossiny RM, Abbas AA, et al. HLA-DRB1 as a risk factor in
children with autoimmune hepatitis and its relation to hepatitis A infection.
Ital J Pediatr. 2010 Nov 10;36:73.
17. Pando M, Larriba J, Fernandez GC, et al. Pediatric and adult forms of type
I autoimmune hepatitis in Argentina: evidence for differential genetic
predisposition. Hepatology. 1999;30(6):1374-1380.
18. Vergani D, Wells L, Larcher VF, et al. Genetically determined low C4: a pre­
dis­p osing factor to autoimmune chronic active hepatitis. Lancet (London,
England). 1985;2(8450):294-298.
19. Meloni A, Willcox N, Meager A, et al. Autoimmune Polyendocrine Syndrome
Type 1: An Extensive Longitudinal Study in Sardinian Patients. J Clin
Endocrinol Metab. 2012;97(4):1114-1124.
20. Grønbæk L, Vilstrup H, Pedersen L, et al. Family occurrence of autoimmune
hepatitis: A Danish nationwide registry-based cohort study. J Hepatol.
2018;69(4):873-877.
21. Tenca A, Farkkila M, Jalanko H, et al. Environmental risk factors of pediatric-
onset primary sclerosing cholangitis and autoimmune hepatitis. J Pediatr
Gastroenterol Nutr. 2016;62(3):437-442.
22. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of
autoimmune hepatitis. Hepatology. 2008;48(1):169-176.
23. Muratori P, Granito A, Quarneti C, et al. Autoimmune hepatitis in Italy: the
Bologna experience. J Hepatol. 2009;50(6):1210-1218.
24. Webb GJ, Hirschfield GM, Krawitt EL, et al. Cellular and Molecular
Mechanisms of Autoimmune Hepatitis. Annu Rev Pathol Mech Dis.
2018;13:247-292.
25. Rodrigues AT, Liu PMF, Fagundes EDT, et al. Clinical Characteristics and
Prognosis in Children and Adolescents with Autoimmune Hepatitis and
Overlap Syndrome. J Pediatr Gastroenterol Nutr. 2016;63(1):76-81.
26. Tanaka A, Takikawa H. Geoepidemiology of primary sclerosing cholangitis: a
Year XVII • No. 64 (4/2021)

critical review. J Autoimmun. 2013;46:35-40.
References
27. Jiménez-Rivera C, Ling SC, Ahmed N, et al. Incidence and Characteristics of
Autoimmune Hepatitis. Pediatrics. 2015;136(5):e1237-e1248.
28. Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis/sclerosing
cholangitis overlap syndrome in childhood: a 16-year prospective study.
Hepatology. 2001;33(3):544-553.
29. Oettinger R, Brunnberg A, Gerner P, et al. Clinical features and biochemical
data of Caucasian children at diagnosis of autoimmune hepatitis.
J Autoimmun. 2005;24(1):79-84.
30. Di Giorgio A, Bravi M, Bonanomi E, et al. Fulminant hepatic failure of auto­
immune aetiology in children. J Pediatr Gastroenterol Nutr. 2015;60(2):159-
164.
31. Al-Chalabi T, Underhill JA, Portmann BC, et al. Impact of gender on the long-
term outcome and survival of patients with autoimmune hepatitis. J Hepatol.
2008;48(1):140-147.
32. Brissos J, Carrusca C, Correia M, et al. Autoimmune hepatitis: trust in
transaminases. BMJ Case Rep. 2014; 2014: bcr2014203869.
33. Wong GW, Heneghan MA. Association of Extrahepatic Manifestations with
Autoimmune Hepatitis. Dig Dis. 2015;33 Suppl 2:25-35.
34. Guo L, Zhou L, Zhang N, Deng B, et al. Extrahepatic Autoimmune Diseases
in Patients with Autoimmune Liver Diseases: A Phenomenon Neglected by
Gastroenterologists. Gastroenterol Res Pract. 2017; 2017:2376231.
35. Najafi M, Sadjadei N, Eftekhari K, et al. Prevalence of Celiac Disease
in Children with Autoimmune Hepatitis and vice versa. Iran J Pediatr.
2014;24(6):723.
36. Nastasio S, Sciveres M, Riva S, et al. Celiac disease-associated autoimmune
hepatitis in childhood: long-term response to treatment. J Pediatr
Gastroenterol Nutr. 2013;56(6):671-674.
37. Uibo R, Panarina M, Teesalu K, et al. Celiac disease in patients with type 1
diabetes: a condition with distinct changes in intestinal immunity? Cell Mol
Immunol. 2011;8(2):150.
38. Ahonen P, Myllärniemi S, Sipilä I, et al. Clinical variation of autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series
of 68 patients. N Engl J Med. 1990;322(26):1829-1836.
39. Grimbacher B, Warnatz K, Yong PFK, et al. The crossroads of autoimmunity
and immunodeficiency: Lessons from polygenic traits and monogenic
defects. J Allergy Clin Immunol. 2016;137(1):3-17.
pediatru
40. Association for the Study of the Liver E. Corrigendum to “EASL Clinical
Practice Guidelines: Autoimmune hepatitis”. J Hepatol. 2015;63(6):1543-1544.
41. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis
Group Report: review of criteria for diagnosis of autoimmune hepatitis.
J Hepatol. 1999;31(5):929-938.
42. Ferri PM, Ferreira AR, Miranda DM, et al. Diagnostic criteria for autoimmune
hepatitis in children: A challenge for pediatric hepatologists. World J
Gastroenterol. 2012;18(33):4470.
43. Vergani D, Alvarez F, Bianchi FB, et al. Liver autoimmune serology: a con­
sen­s us statement from the committee for autoimmune serology of the
International Autoimmune Hepatitis Group. J Hepatol. 2004;41(4):677-683.
44. Lamireau T, McLin V, Nobili V, et al. A practical approach to the child with
abnormal liver tests. Clin Res Hepatol Gastroenterol. 2014;38(3):259-262.
45. Terziroli Beretta-Piccoli B, Mieli-Vergani G, et al. Serology in autoimmune
hepatitis: A clinical-practice approach. Eur J Intern Med. 2018;48:35-43.
46. Gregorio GV, McFarlane B, Bracken P, et al. Organ and non-organ specific
autoantibody titres and IgG levels as markers of disease activity: a longi­
tu­d inal study in childhood autoimmune liver disease. Autoimmunity.
2002;35(8):515-519.
47. Couto CA, Bittencourt PL, Porta G, et al. Antismooth muscle and antiactin
antibodies are indirect markers of histological and biochemical activity of
autoimmune hepatitis. Hepatology. 2014;59(2):592-600.
48. Muratori L, Cataleta M, Muratori P, et al. Liver/kidney microsomal antibody
type 1 and liver cytosol antibody type 1 concentrations in type 2 autoim­
mune hepatitis. Gut. 1998;42(5):721.
49. Manns M, Kyriatsoulis A, Gerken G, et al. Characterisation of a new subgroup
of autoimmune chronic active hepatitis by autoantibodies against a soluble
liver antigen. Lancet (London, England). 1987;1(8528):292-294.
50. Ma Y, Okamoto M, Thomas MG, et al. Antibodies to conformational epitopes
of soluble liver antigen define a severe form of autoimmune liver disease.
Hepatology. 2002;35(3):658-664.
51. de Boer YS, van Nieuwkerk CMJ, Witte BI, et al. Assessment of the histo­
patho­l o­g ical key features in autoimmune hepatitis. Histopathology.
2015;66(3):351-362.
52. Hegarty JE, Nouri Aria KT, Portmann B, et al. Relapse following treatment
withdrawal in patients with autoimmune chronic active hepatitis.
Hepatology. 1983;3(5):685-689.
Reclamă PED(64)0204
 up-to-date

The role of breastfeeding

in preventing a global health
problem: pediatric obesity
Heidrun Abstract Rezumat
Adumitrăchioaiei,
Bogdan Stana, Obesity among children and adolescents has become a Obezitatea în rândul copiilor și adolescenților a devenit o pro­ble­
global health problem, with a significant increase in pre­va­ mă globală de sănătate, cu o creștere semnificativă a prevalenței
Alina Costina lence in recent years. Preventing the increase of the number în ultimii ani. Scăderea numărului de copii afectați de obezitate
Luca of people affected by this malnutrition is seen as an early se realizează prin măsuri nutriționale precoce la vârsta pediatrică,
“Grigore T. Popa” University mea­sure to reduce chronic noncommunicable diseases in pentru a reduce incidența bolilor cronice netransmisibile în
of Medicine and Pharmacy, adult­hood. The natural diet of the newborn and the small pe­­rioa­­da de adult. Alimentația naturală a nou-născutului și a
Iaşi;
“Sf. Maria” Emergency child in the prevention of obesity is an intensely researched co­­pi­­lu­­lui mic reprezintă un subiect intens cercetat, cu diverse noi
Clinical Hospital for Children, topic. We propose a review of the evidence linking exclusive fa­­țe­­te. Propunem o revizuire a dovezilor din literatură care leagă
Iaşi, Romania
breast­feeding to the prevention of obesity in the literature. alăp­­ta­­rea de prevenirea obezității ulterioare.
Keywords: breastfeeding, obesity, children Cuvinte-cheie: alimentație naturală, obezitate, copii

Submission date:
30.10.2021 Rolul alimentației naturale în prevenția unei probleme mondiale de sănătate
Acceptance date:
17.11.2021 publică: obezitatea la vârsta pediatrică
Suggested citation for this article: Adumitrăchioaiei H, Stana B, Luca AC. The role of breastfeeding in preventing a global health problem: pediatric obesity.
Pediatru.ro. 2021;64(4):14-16.

Introduction The benefits of breastfeeding

Numerous studies have shown the importance of
breastfeeding in the prevention of childhood obesity.
The importance of the first 1000 days of life – starting
from the first day of conception – for the child’s health
is widely discussed, the processes of development and
growth are intense for such a short period, which is why a
balanced maternal diet during pregnancy together with
exclusively natural feeding from the first moments of
the newborn’s extrauterine life are essential criteria for
a harmonious development(1).
According to the World Health Organization (WHO),
exclusive breastfeeding in the first six months of life
with a continuation until the age of 2 years old and after
this age, if the mother and child wish, is associated with
a low risk of childhood obesity(2).
Breastfeeding defines the feeding of the newborn
with exclusively breast milk in the first six months of
life, being the safest, most efficient, easiest and cheapest
way to feed an infant.
The secretory immunoglobulin A contains specific
antibodies against bacteria, viruses, fungi and proto-
zoa, the exclusively natural diet giving the newborn an
intake of 0.5-1 g of IgAs. Lactoferrin have a role in iron
transport, being also an anti-infective agent. Lipids have
antiviral, antimicrobial and antiprotozoal properties.
Oligosaccharides, with protection against thermostable
enterotoxins, favor the development of bifidobacteria(16).
Immunomodulatory factors play a role in decreasing
the risk of terminal ileitis, increasing tone and decreas-
ing the pain response(17).

Epidemiology The composition of breast milk

According to the WHO and International Obesity
Taskforce (IOTF), in 2010 there were over 200 million
overweight or obese children worldwide, and 42 million
were children under 5 years old(2).
If each child were exclusively breastfed for the first
6 months, with a continuation of up to 2 years old,
800,000 children would be saved from death each year(3).
In 2012, only 38% of infants under 6 months of age
were exclusively breastfed worldwide(4).
The aim of the World Health Organization is to increase
the rate of exclusive breastfeeding to 50% until 2025.
Human milk is a biological liquid with a unique com-
plexity, consisting of 87% water, 7% carbohydrates, 4%
lipids and 1% protein. The energy of human milk is 70
kcal/dL, being significantly associated with the amount
of fat in milk. Lipids are the group of macronutrients
with the highest variability in the composition of breast
milk (50-55%). The amount of lipids is inversely propor-
tional to the amount of milk in the breast, at the begin-
ning of sucking, when the breast is full; the quantity of
lipids is small, they increase with the decrease in the
amount of milk, towards the end of sucking, 98% of

14 Year XVII • No. 64 (4/2021)

 pediatru

Table 1 The benefits of breastfeeding

Low mortality and morbidity
Anti-infective protection
Reducing the frequency of otitis and food allergies
Newborn benefits
Decreased incidence of type 1 and type 2 diabetes, asthma and obesity
Optimal vitamin content
Optimal iron absorption

Mother-child attachment
Protection for a new task
Mother benefits Reducing the incidence of ovarian and breast cancers
Reducing the incidence of osteoporosis
Rapid return of the uterus to its original size

Financial: saving money for milk powder

Family benefits More time together: saving time for preparing powdered milk/sterilizing instruments
More time spent in the family

Less pollution by reducing milk powder production and packaging

Society benefits Low costs for the health system, breastfed children have fewer diseases
Reduced costs for the maternal employer, fewer days of maternity leave due to the child’s illness

lipids being represented by triglycerides, the rest being
represented by cholesterol, free fatty acids, phospho­
lipids and sphingolipids(8-10). Cholesterol is found in
higher amounts in breast milk than in cow’s milk. The
amount of fatty acids in human milk is influenced by
diet and maternal nutritional status, exclusively in the
natural diet, the newborn benefiting from the presence
of omega 3 and 6 acids(14,15).
Casein is a protein present in about 40% in breast
milk. It contains less phosphorus compared to cow’s milk
and is easier to digest. The rest are whey proteins (60%);
alpha-lactoglobulin predominates in breast milk and
whey proteins are easy to digest, which leads to a rapid
gastric emptying; for this reason, naturally breastfed
babies need, physiologically, more meals than those who
receive artificial feeding(8,9,11,13-15).
Carbohydrates from natural food provide 35-40% of
the total energy provided by breast milk. Lactulose is
the main carbohydrate of human milk, being associated
with the growth of the infant.
The amount of lactulose in breast milk is not influ-
enced by the maternal diet and is the only source of ga-
lactose, with a major role in myelination and cerebroside
synthesis, stimulating lactase synthesis, accelerating in-
testinal transit, having an antirotting and fermentative
role, and promoting phosphor-calcic metabolism(11,13).
Proteins and carbohydrates are increased in the begin-
ning of sucking.
Breast milk has a role in the formation of colic flora
specific to the breastfed child, oligosaccharides being
sources of probiotics.
Breast milk is the most hypomineralized milk. Phos-
phorus and calcium are found in lower amounts than in
cow’s milk, but the Ca/P ratio of 2.12 leads to a higher
absorption than the absorption of calcium from cow’s
milk. Due to the load of 80-98 mOsm/L, breast milk
loads the kidney much less osmotically(16).
The average energy value of breast milk is 670 kcal/L,
with variations between 640 and 723 kcal/L, with 5-7%
proteins, 35-40% carbohydrates and 50-55% lipids(13).
Studies
The studies have shown a healthier eating behavior
among those who were breastfed compared to those who
were fed on formula(1).
The duration of breastfeeding was associated with a
decrease in the risk of childhood obesity. Thus, a meta-
analysis showed a significant reduction in those who
were breastfed for more than seven months (AOR=0.79;
95% CI; 0.7-0.88), observing the decrease of obesity risk
in relation to the increase of the number of months in
which the child was breastfed(4).
McCrory et al. showed that being breastfed for be-
tween 13 and 25 weeks was associated with a 38% re-
duction in the risk of obesity at 9 years of age, while
being breastfed for 26 weeks or more was associated
with a 51% reduction in the risk of obesity at 9 years
old(5). Harder et al. found that each additional month of
breastfeeding reduced the risk of obesity by 4%(6).
A higher prevalence of obesity was demonstrated
in those who have never been breastfed or have been
breastfed for less than six months compared to those
who have been exclusively breastfed for six months or
more than six months. A study also showed that the
Mediterranean countries have the highest prevalence
rates of obesity (more than 16%)(7).
In a study conducted in Oregon, the authors followed
for two years all children born in 2009 and showed that,

Year XVII • No. 64 (4/2021)

15
up-to-date
for each additional week of breastfeeding, the probabil-
ity of the child being obese at the age of 2 years old de-
creased by 0.82%(18).
Conclusions
The concern of health experts is closely linked to the
fact that most of those affected by this malnutrition
are prone to obesity in adulthood, where the occurrence
of noncommunicable chronic diseases and psychiatric
disorders caused by obesity lead to huge costs to the
health system.
1. Ventura AK. Does Breastfeeding Shape Food Preferences? Links to Obesity. Ann
References
Nutr Metab. 2017;70 Suppl 3:8-15.
2. WHO. http://www.who.int/topics/breastfeeding/en/
3. Chivers P, Hands B, Parker H, Bulsara M, Beilin LJ, Kendall GE, Oddy WH. Body
mass index, adiposity rebound and early feeding in a longitudinal cohort (Raine
Study). Int J Obes (Lond). 2010 Jul;34(7):1169-76
4. Yan J, Liu L, Zhu Y, Huang G, Wang PP. The association between breastfeeding
and childhood obesity: a meta-analysis. BMC Public Health. 2014;14(1):1267.
5. McCrory C, Layte R. Breastfeeding and risk of overweight and obesity at nine-
years of age. Soc Sci Med. 2012 Jul;75(2):323-30.
6. Harder T, Bergmann R, Kallischnigg G, Plagemann A. Duration of breastfeeding
and risk of overweight: a meta-analysis. Am J Epidemiol. 2005 Sep 1;162(5):397-
403.
7. Rito AI, Buoncristiano M, Spinelli A, Salanave B, Kunešová M, Hejgaard T, García
Solano M, Fijałkowska A, Sturua L, Hyska J, Kelleher C, Duleva V, Musić Milanović
S, Farrugia Sant’Angelo V, Abdrakhmanova S, Kujundzic E, Peterkova V, Gualtieri
A, Pudule I, Petrauskienė A, Tanrygulyyeva M, Sherali R, Huidumac-Petrescu
C, Williams J, Ahrens W, Breda J. Association between Characteristics at Birth,
Breastfeeding and Obesity in 22 Countries: The WHO European Childhood
Obesity Surveillance Initiative - COSI 2015/2017. Obes Facts. 2019;12(2):226-243.
8. Kent JC, Mitoulas LR, Cregan MD, Ramsay DT, Doherty DA, Hartmann PE. Volume
and frequency of breastfeedings and fat content of breast milk throughout the
day. Pediatrics. 2006 Mar;117(3):e387-95.
9. Breastmilk composition, Australian Breastfeeding Association.
16
Breast milk is the best food for the human species,
perfectly adapted to the needs, always at hand, present
at the ideal temperature, having antimicrobial, antitu-
mor and antiobesity protection, being a growth factor
and an emotional stabilizer, with nutritional balance.
Therefore, breast milk is the gold standard of the new-
born diet and for the infant, subsequently representing
the completion of the small child. n
Conflict of interests: The authors declare no con­
flict of interests.
10. Lönnerdal B. Human milk proteins: key components for the biological activity of
human milk. Adv Exp Med Biol. 2004;554:11-25.
11. Gay MCL, Koleva PT, Slupsky CM, Toit ED, Eggesbo M, Johnson CC, Wegienka
G, Shimojo N, Campbell DE, Prescott SL, Munblit D, Geddes DT, Kozyrskyj AL;
InVIVO LactoActive Study Investigators. Worldwide Variation in Human Milk
Metabolome: Indicators of Breast Physiology and Maternal Lifestyle? Nutrients.
2018 Aug 23;10(9):1151.
12. Azad MB, Robertson B, Atakora F, Becker AB, Subbarao P, Moraes TJ, Mandhane
PJ, Turvey SE, Lefebvre DL, Sears MR, Bode L. Human Milk Oligosaccharide
Concentrations Are Associated with Multiple Fixed and Modifiable Maternal
Characteristics, Environmental Factors, and Feeding Practices. J Nutr. 2018 Nov
1;148(11):1733-1742.
13. Florea Iordăchescu. Pediatrics Treaty, Ed. ALL, 2019.
14. Breastfeeding and the use of human milk. American Academy of Pediatrics.
Work Group on Breastfeeding. Pediatrics. 1997 Dec;100(6):1035-9.
15. Fernández L, Langa S, Martín V, Maldonado A, Jiménez E, Martín R, Rodríguez
JM. The human milk microbiota: origin and potential roles in health and disease.
Pharmacol Res. 2013 Mar;69(1):1-10.
16. Hamosh M. Bioactive factors in human milk. Pediatr Clin North Am. 2001
Feb;48(1):69-86.
17. Labbok MH. Effects of breastfeeding on the mother. Pediatr Clin North Am. 2001
Feb;48(1):143-58.
18. Modrek S, Basu S, Harding M, White JS, Bartick MC, Rodriguez E, Rosenberg KD. Does
breastfeeding duration decrease child obesity? An instrumental variables analysis.
Pediatr Obes. 2017 Aug;12(4):304-311.
Year XVII • No. 64 (4/2021)
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 up-to-date

Emanuela Duca1,
Tudor Lucian Pop2
1. Pediatric Pneumology,
Emergency Clinical Hospital
for Children, Cluj-Napoca;
Second Pediatric Discipline,
“Iuliu Haţieganu”University
of Medicine and Pharmacy,
Cluj-Napoca, Romania
2. Second Pediatric Clinic,
Emergency Clinical Hospital
for Children, Cluj-Napoca;
Second Pediatric Discipline,
“Iuliu Haţieganu”University
of Medicine and Pharmacy,
Cluj-Napoca, Romania
Corresponding author:
Emanuela Duca
E-mail: emma_floca@yahoo.com
Expression of interleukin-31
and interleukin-33
in atopic dermatitis
and correlation with clinical
features
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin
di­sease with different degrees of severity that can sig­ni­fi­
can­tly affect patients’ quality of life. The patho­ge­ne­sis of
this disorder results from the interplay between defects in
skin barrier function, immune response dys­re­gu­la­tions,
and allergic and infectious agents. There are no diag­
nos­­tic laboratory tests. The diagnosis is based on cli­ni­cal
cri­te­ria, including clinical manifestations and al­lergic
his­to­ry. Cytokines play a decisive role in the re­gu­la­tion
of the immune system. IL-31 is a potentially pru­ri­to­ge­
ne­tic cytokine and IL-33 contributes to inflammation
from allergic diseases, including AD. There is a link
be­tween the two cytokines’ actions, and their serum
le­vel correlates with the severity of the disease. The
eva­lua­tion of IL-31 and IL-33 expression in patients
with AD is essential in identifying biomarkers of disease
se­ve­rity and for establishing new therapeutic targets.
This article summarizes the current literature related
to the role of IL-31 and IL-33 in atopic dermatitis.
Keywords: atopic dermatitis, cytokines, IL-31, IL-33
Rezumat
Dermatita atopică (DA) este o boală inflamatorie cronică a
tegumentului, cu grade variate de severitate, care poate afec­ta
semnificativ calitatea vieții pacientului. Mecanismul pa­to­
ge­ne­tic al acestei afecțiuni este rezultatul interacțiunii din­tre
de­fec­te­le funcției de barieră a tegumentului, tulburările răs­
pun­­su­­lui imunitar și factorii alergici și infecțioși. Nu exis­tă tes­te
de laborator disponibile pentru diagnosticul DA. Diag­nos­­ti­­cul
se bazează pe criterii clinice, acestea cuprinzând ma­ni­fes­
tă­rile clinice și istoricul de boli alergice. Citokinele au un rol
de­ci­siv în reglarea sistemului imunitar. IL-31 este o citokină
cu potențial pruritogenetic, iar IL-33 contribuie la inflamația
din cadrul bolilor alergice, inclusiv DA. S-a constatat existența
unei legături între modul de acțiune al celor două citokine,
iar nivelul seric al fiecăreia se corelează cu severitatea bolii.
Eva­lua­rea expresiei citokinelor IL-31 și IL-33 la pacienții cu DA
este importantă pentru identificarea unor markeri de severitate
ai bolii și pentru stabilirea unor noi ținte terapeutice. Scopul
aces­tui articol este de a prezenta rolul citokinelor IL-31 și IL-33 în
der­ma­tita atopică.
Cuvinte-cheie: dermatită atopică, citokine, IL-31, IL-33

Submission date:
30.11.2021 Expresia interleukinelor IL-31 și IL-33 în dermatita atopică și corelația
Acceptance date:
11.12.2021 cu manifestările clinice
Suggested citation for this article: Duca E, Pop TL. Expression of interleukin-31 and interleukin-33 in atopic dermatitis and correlation with clinical features.
Pediatru.ro. 2021;64(4):18-21.

Introduction There are cases of severe diseases that do not improve

Atopic dermatitis (AD) is a chronic inflammatory skin
disorder characterized by an impaired skin barrier function
associated with immune response abnormalities. It is a di­
sease with increasing incidence and manifestations that can
significantly affect the patient’s quality of life(1). Recent data
show that AD affects worldwide 15-30% of children and
2-10% of adults. Being a component of the allergic march,
patients with atopic dermatitis can develop asthma and
allergic rhinitis in evolution, thus substantially impacting
weight and psychomotor development and, subsequently,
reflecting on the child’s social relationships. However, the
therapeutic possibilities are limited, especially for the mode­
rate and severe forms of the disease(2).
with conventional therapy. For that reason, some cases
of AD need targeted therapies(3-5).
It is known that the immune system is involved in
the pathogenesis of atopic dermatitis. Interleukins are
thought to play an essential role in triggering immune
reactions and clinical manifestations. Several interleu-
kins and their role in the pathogenesis of AD have been
studied, but the mechanism is complex and incompletely
elucidated(6,7).
It is believed that the immune response by the activa-
tion of T lymphocytes is involved in the lesion mecha-
nism. Th1 and Th2 lymphocytes contribute to the initia-
tion and maintenance of skin lesions. There are studies

18 Year XVII • No. 64 (4/2021)


in which it has been observed that patients with atopic
dermatitis have a Th1/Th2 imbalance in favor of Th2.
Th2 lymphocytes, by synthesized cytokines, regulate
immunoglobulin E production, reduce the expression of
antimicrobial peptides from keratinocytes and stimulate
epidermal hyperplasia(8,9).
Cytokines play an essential role in the pathogenesis
of AD. There are many cytokines involved in the pro-
inflammatory process of atopic dermatitis. Of these,
interleukin-31 (IL-31) and interleukin-33 (IL-33) are
considered novel cytokines. Data showed that, in many
cases diagnosed with AD, the expression of IL-31 and
IL-33 correlate with disease severity.
Interleukin-31
IL-31 represents a cytokine produced by CD4+ T helper
cells and mast cells, and its secretion depends on IL-4. It
is proven that IL-31 exerts its action on fibroblasts and
eosinophils. The most acute effects of IL-31 action include
proinflammatory cytokines production, cellular differen-
tiation and proliferation, and tissue remodeling(10).
IL-31 signals through a complex receptor consist-
ing of IL-31 receptor alpha (IL-31RA) and oncostatin
M receptor beta (OSMR). The components of the IL-31
receptor are expressed on keratinocytes and activated
monocytes(11).
It has been shown that staphylococcal enterotoxin
B increases IL-31 in peripheral mononuclear cells. The
stimulation of histamine receptor 4 associated with
staphylococcal enterotoxin B may occur due to IL-31
mRNA expression(12).
Interleukin IL-31 in atopic dermatitis
The role of IL-31 in the pathogenesis of atopic dermati-
tis is still being studied. The literature data indicated that
IL-31 activation might be triggered directly by allergen
stimulation. This fact has not yet been clarified. There is
also the hypothesis that secondary factors could deter-
mine the expression of this cytokine. Although Th2 cells
are one of the primary producers of IL-31, both Th1 and
Th2 cytokines could take part in the IL-31 pathway(13).
Itch is the most distressing manifestation of AD.
Chemical mediators of pruritus include endogenous and
exogenous substances, such as histamine, 5-hydroxy-
tryptamine, substance P, and proteases. The role of IL-31
and its receptor in itching was a carefully studied topic. In
2004, the pruritogenic action of IL-31 in mice was disco­
vered. Recent studies show the involvement of IL-31 in the
pathogenesis of pruritus in inflammatory skin diseases,
including atopic dermatitis(14,15).
The serum level of IL-31 in patients with AD is higher
than the serum level of healthy individuals. A few stud-
ies have identified a correlation between the IL-31 se-
rum level and the severity of AD or itchy intensity. The
serum level of IL-31 correlates with the disease activity
of atopic dermatitis(16).
Byeon et al. showed that the serum levels of IL-31 were
significantly higher in children with AD than in healthy
children. The serum IL-31 is correlated with AD severity
Year XVII • No. 64 (4/2021)
pediatru
evaluated through the SCORAD index. The researchers
obtained a correlation between IL-31 serum levels and
blood eosinophilic inflammatory markers in this study(17).
Other authors have studied IL-31 levels in biopsy speci-
mens of patients with atopic dermatitis. Nobbe et al. and
Neiss et al. found increased mRNA levels of IL-31 in skin
biopsy of AD patients, without a significant correlation
with the atopic dermatitis severity(18,19).
Interleukin-33
IL-33 is a new cytokine, a member of the IL-1 cytokine
family. Numerous cells, including the following, secrete
this cytokine: dendritic cells, fibroblasts, osteoblasts,
macrophages, adipocytes, endothelial cells, bronchial
epithelium, and smooth muscle cells. Its secretion begins
after the cell damage signal. There is a specific receptor
for IL-33, namely the ST receptor. The immune cascade
initiates after attaching IL-33 to this receptor(20).
IL-33 activates mast cells and basophils, and this
leads to the overproduction of proinflammatory cy-
tokines. At the same time, it is implicated in mast cell
maturation and activation(21).
IL-31 induces a T helper type-2 inflammation. IL-31
has an essential role in the inflammation of allergic dis-
eases mediated by eosinophils and basophils’ activation.
The role of genetic variants of IL-33 and its receptor on
allergic disease risk is a studied topic. Studies carried out
in the Brazilian and Chinese populations demonstrate a
relationship between the genetic variants of IL-33 and
the development of asthma(22-24). We do not have enough
data about the association of IL-33 polymorphism with
the risk and severity of AD. More studies are necessary
on this topic.
Interleukin-33 in atopic dermatitis
The role of IL-33 in AD pathogenesis was not clarified.
This cytokine is secreted by damaged tissue or the site of
inflammation. ST2, the IL-33 receptor, is expressed on
Th2 cells, eosinophils and mast cells. By activating these
cells, IL-33 promotes a Th2-type immune response. This
receptor contributes to the secretion of some proinflam-
matory factors, including TNF alpha, IL-6 and leuko­
trienes. In the skin of patients with AD, the expression
of IL-33 increases in keratinocytes, endothelial cells and
fibroblasts(25).
The serum level of IL-33 in a patient with atopic der-
matitis is higher than those without atopy. Some studies
confirm the correlation between serum level of IL-33
and skin lesion severity(26-28).
In studies performed on patients with AD, the corre-
lations between the serum level of IL-33 and other bio-
markers were also evaluated. No significant correlation
between the serum level of IL-33 and the serum level of
IgE or peripheral eosinophils count was identified(25,26,28).
Studies on mouse models revealed an increased ex-
pression of IL-33 and ST2 in the skin of mice with filag-
grin deficiency. This may indicate a relationship between
IL-33 and epidermal barrier defects in patients with
atopic dermatitis(28).
19
up-to-date
Il-33/IL-31 axis
Most recent data showed that IL-33 and IL-31 link to
each other in many patients with AD, and their expres-
sion correlates with skin lesion severity. In a patient with
atopic dermatitis, the serum level of IL-33 increases due
to skin damage. After its secretion, the immune cascade
is initiated, inducing the augmentation of inflammatory
cytokines. The IL-33 promotes the IL-4-dependent pro-
duction of IL-31 by CD4+ Th cells(29,30).
In their study on mice (2016), Rizzo et al. showed that
DNp63 regulates IL-33 and IL-31 signaling in atopic
dermatitis(31). The results of this study indicate that the
isoform DNp63, a family member p63, plays an essential
role in keratinocyte activation in AD. The overexpression
of DNp63 in the basal keratinocyte of mouse models’ epi-
dermis gave rise to epidermal hyperplasia, low terminal
differentiation, Th2 inflammation and elevated expres-
sion of inflammatory molecules. The study on the mouse
model highlighted that DNp63 has a direct effect on IL-31
and IL-33 expression. Shortly after Np63 expression, an
elevated level of Th2 cytokines was observed in the skin.
IL-31, IL-33 and new therapeutic targets
Topically applied emollients, corticosteroids and
calcineurin inhibitors for skin inflammation are the
first-line treatment for atopic dermatitis. Second-line
therapies include phototherapy, systemic cyclosporine,
and oral steroids. Target treatment is an essential goal
of research on AD(32).
Many studies have shown that IL-31 is a cardinal pru-
ritogenetic cytokine. We know that itching significantly
affects the quality of life of the patient with AD(33). IL-31
and antibodies against IL-31 were extensively studied to
identify targeted therapies for atopic dermatitis.
Nemolizumab is a humanized anti-human IL-31 anti-
body(34). A randomized, double-blind, phase II, long-term
extension study was conducted in more countries by Kenji
et al. to evaluate the effect of nemolizumab in adults with
moderate-severe atopic dermatitis(35). The study showed
that the subcutaneous administration of anti-IL-31-an-
tibody improved pruritus, lesions and sleep disturbances
in patients with AD versus placebo in the 12 weeks of the
study. Being a pathology that can be severe in childhood,
studies to evaluate the efficacy and effects of anti-IL-31
antibodies are required for different age groups.
Chen et al. investigated the role of IL-33 inhibition
in adult patients with moderate to severe AD(36). Their
results showed that, in patients with atopic dermatitis
1. Peters N, Peters AT. Atopic dermatitis. Allergy and Asthma Proceedings.
References
2019;40(6):433-436.
2. Waldman AR, Ahluwalia J, Udkoff J, Borok JF, Eichenfield LF. Atopic dermatitis.
Pediatrics in Review. 2018;39(4):180-193.
3. Cabanillas B, Brehler AC, Novak N. Atopic dermatitis phenotypes and the need
for personalized medicine. Curr Opin Allergy Clin Immunol. 2017;17(4):309-315.
4. Saini S, Pansare M. New insights and treatments in atopic dermatitis. Pediatr Clin
North Am. 2019;66(5):1021-1033.
5. Huang E, Ong PY. Severe atopic dermatitis in children. Curr Allergy Asthma Rep.
2018;18(6):35.
6. Kim JE, Kim JS, Cho DH, Park HJ. Molecular mechanism of cutaneous
inflammatory disorder: atopic dermatitis. Int J Mol Sci. 2016;17(8):1234.
20
who received IL-33 antibody, the skin inflammation was
reduced. More studies are needed to evaluate the effects
of anti-IL-33 antibodies in patients with AD.
Role of IL-31 and IL-33
in extrinsic AD versus intrinsic AD
Depending on the total serum level of IgE, atopic der-
matitis can be classified into two forms: intrinsic AD
and extrinsic AD. Extrinsic atopic dermatitis is defined
by an increased level of total IgE and specific IgE in en-
vironmental and food allergens. The intrinsic form is
non-allergic(37). The two forms of atopic dermatitis have
the same clinical phenotypes. Regarding the expression
of cytokines, there may be differences between the two
forms. Some studies have shown that patients with ex-
trinsic atopic dermatitis have elevated serum levels of Th2
cytokines (IL-4, IL-5, IL-13, IL-31), while in the case of in-
trinsic forms, the expression of IL-4 and IL-13 is lower(38).
Suárez-Fariñas et al. showed a significant correlation
between Th2 cytokine levels and disease severity in both
intrinsic and extrinsic forms of AD in adults(39).
Regarding IL-33, the studies did not show a signifi-
cant correlation with the serum level of IgE, but only
with the severity of the lesions(25).
We have to apply targeted therapy in both forms,
therefore establishing differences in cytokine expres-
sion is imperative.
Conclusions
Atopic dermatitis is not a life-threatening disease, but
the pruritogenic character can significantly influence
the quality of life. Evaluating cytokine expression in AD
is essential for establishing disease severity markers and
for identifying new therapies.
Each of the two cytokines presented, IL-31 and IL-33,
has an essential role in atopic dermatitis’s pathophysi-
ological mechanism, being involved in skin inflamma-
tion and pruritus.
The evaluation of the IL-31/IL-33 axis and a better
understanding of the relationship between the two in-
terleukins could provide essential data for establishing
a combined therapeutic target.
It is essential to establish the differences in immune
mechanisms of the two forms of atopic dermatitis in
order to select the appropriate targeted therapy. n
Conflict of interests: The authors declare no con­
flict of interests.
7. Furue M, Ulzii D, Vu YH, Tsuji G, Kido-Nakahara M, Nakahara T. Pathogenesis
of atopic dermatitis: Current Paradigm. Iranian Journal of Immunology.
2019;16(2):97-107.
8. Malajian D, Guttman-Yassky E. New pathogenetic and therapeutic paradigms in
atopic dermatitis. Cytokine. 2015;73(2):311-318.
9. El Hachem M, Di Mauro G, Rotunno R, et al. Pruritus in pediatric patients with
atopic dermatitis: a multidisciplinary approach – summary document from an
Italian expert group. Ital J Pediatr. 2020;46(1):11.
10. Lu J, Wu K, Zeng Q, Xiang Y, Gao L, Huang J. Serum interleukin-31 level and
pruritus in atopic dermatitis: A Meta-analysis. Zhong Nan Da Xue Xue Bao Yi Xue
Ban. 2018;43(2):124-130.
11. Meng J, Moriyama M, Feld M, et al. New mechanism underlying Il-31-induced
Year XVII • No. 64 (4/2021)

atopic dermatitis. J Allergy Clin Immunol. 2018;141(5):1677-1689.
References
12. Nakashima C, Otsuka A, Kabashima K. Interleukin-31 and interleukin-31
receptor: new therapeutic targets for atopic dermatitis. Exp Dermatol. 2018;
27(4):327-331.
13. Miake S, Tsuji G, Takemura M, et al. IL-4 augments IL-31/IL-31 receptor alpha
interaction leading to enhanced Ccl 17 and Ccl 22 production in dendritic cells:
implications for atopic dermatitis. Int J Mol Sci. 2019; 20(16):4053
14. Nakashima C, Ishida Y, Kitoh A, Otsuka A, Kabashima K. Interaction of peripheral
nerves and mast cells, eosinophils, and basophils in the development of
pruritus. Exp Dermatol. 2019;28(12):1405-1411.
15. Ma H, Gao T, Jakobsson JET, et al. The neuropeptide Y Y2 receptor is coexpressed
with Nppb in primary afferent neurons and Y2 activation reduces histaminergic
and Il-31-induced itch. J Pharmacol Exp Ther. 2020;372(1):73-82.
16. Furue M, Yamamura K, Kido-Nakahara M, Nakahara T, Fukui Y. Emerging role
of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis.
Allergy. 2018;73(1):29-36.
17. Byeon JH, Yoon W, Ahn SH, Lee HS, Kim S, Yoo Y. Correlation of serum
interleukin-31 with pruritus and blood eosinophil markers in children with
atopic dermatitis. Allergy Asthma Proc. 2020;41(1):59-65.
18. Nobbe S, Dziunycz P, Muhleisen B, et al. IL-31 expression by inflammatory cells is
preferentially elevated in atopic dermatitis. Acta Derm Venereol. 2012;92(1):24-28.
19. Neis MM, Peters B, Dreuw A, et al. Enhanced expression levels of IL-31 correlate
with IL-4 and IL-31 in atopic and allergic contact dermatitis. J Allergy Clin
Immunol. 2006;118(4):930-937.
20. Ryu WI, Lee H, Bae HC, et al. IL-33 down-regulates CLDN1 expression through
the ERK/STAT3 pathway in keratinocytes. J Dermatol Sci. 2018;90(3):313-322.
21. Ryffel B, Alves-Filho JC. ILC2s and basophils team up to orchestrate IL-33-
induced atopic dermatitis. J Invest Dermatol. 2019; 139(10):2077-2079.
22. Queiroz G, Costa RS, Alcantara-Neves NM, et al. IL33 and IL1RL1 variants are
associated with asthma and atopy in a Brazilian population. Int J Immunogenet.
2017;44(2):51-61.
23. Chan BCL, Lam CWK, Tam LS, Wong CK. IL33: Roles in Allergic Inflammation and
Therapeutic Perspectives. Front Immunol. 2019;10:364.
24. Yi L, Cheng D, Zhang K, et al. Intelectin contributes to allergen-induced IL-25,
IL-33 and TSLP expression and type 2 response in asthma and atopic dermatitis.
Mucosal Immunol. 2017;10(6):1491-1503.
25. Li C, Maillet I, Mackowiak C, et al. Experimental atopic dermatitis depends on
pediatru
IL-33R signaling via MyD88 in dendritic cells. Cell Death Dis. 2017;8(4):e2735.
26. Imai Y. Interleukin-33 in atopic dermatitis. J Dermatol Sci. 2019;96(1):2-7.
27. Gupta RK, Gupta K, Dwivedi PD. Pathophysiology of IL-33 and IL-17 in allergic
disorders. Cytokine Growth Factor Rev. 2017;38:22-36.
28. Nygaard U, Hvid M, Johansen C, et al. TSLP, IL-31, IL-33 and sST2 are new
biomarkers in endophenotypic profiling of adult and childhood atopic
dermatitis. J Eur Acad Dermatol Venereol. 2016;30(11):1930-1938.
29. Murdaca G, Greco M, Tonacci A, et al. IL-33/IL-31 axis in immune-mediated and
allergic diseases. Int J Mol Sci. 2019;20(23):5856
30. Petra AI, Tsilioni I, Taracanova A, Katsarou-Katsari A, Theoharides TC. Interleukin
33 and interleukin 4 regulate interleukin 31 gene expression and secretion from
human laboratory of allergic diseases 2 mast cells stimulated by substance P
and/or immunoglobulin E. Allergy Asthma Proc. 2018;39(2):153-160.
31. Rizzo JM, Oyelakin A, Min S, et al. ΔNp63 regulates IL-33 and IL-31 signaling in
atopic dermatitis. Cell Death Differ. 2016;23(6):1073-85.
32. Fabbrocini G, Napolitano M, Megna M, Balato N, Patruno C. Treatment of Atopic
Dermatitis with Biologic Drugs. Dermatol Ther (Heidelb). 2018;8(4):527-538.
33. Mollanazar NK, Smith PK, Yosipovitch G. Mediators of Chronic Pruritus in Atopic
Dermatitis: Getting the Itch Out? Clin Rev Allergy Immunol. 2016;51(3):263-292.
34. Silverberg JI, Pinter A, Pulka G, et al. Phase 2B randomized study of
nemolizumab in adults with moderate-to-severe atopic dermatitis and severe
pruritus. J Allergy Clin Immunol. 2020;145(1):173-182.
35. Kabashima K, Furue M, Hanifin JM, et al. Nemolizumab in patients with
moderate-to-severe atopic dermatitis: Randomized, phase II, long-term
extension study. J Allergy Clin Immunol. 2018 Oct;142(4):1121-1130.e7.
36. Chen YL, Gutowska-Owsiak D, Hardman CS, et al. Proof-of-concept clinical trial
of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis. Sci
Transl Med. 2019;11(515):eaax2945.
37. Hon KL, Lam MC, Leung TF, et al. Are age-specific high serum IgE levels
associated with worse symptomatology in children with atopic dermatitis? Int J
Dermatol. 2007;46(12):1258-62.
38. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci.
2010;58(1):1-7.
39. Miraglia del Giudice M, Decimo F, Leonardi S, et al. Immune dysregulation in
atopic dermatitis. Allergy Asthma Proc. 2006;27(6):451-5.
Reclamă PED(64)0205
 clinical studies

Clinical and hematological

aspects in pediatric patients
diagnosed with Fanconi
anemia – a single-center
experience
Cristina Jercan1,2, Abstract Rezumat
Ana Maria Bică2,
Inherited bone marrow failure syndromes (IBMFS) are rare Sindroamele de insuficiență medulară congenitală reprezintă
Andra Daniela un grup de afecțiuni hematologice rare care se caracterizează
hematological disorders that characteristically associate
Marcu2, physical abnormalities, ineffective hematopoiesis and pre­ prin insuficiență medulară, având o predispoziție pentru
Letiția Elena dis­position to cancer, accompanied by a range of congenital ma­­lig­ni­tăți. Cel mai des întâlnite sunt anemia Fanconi, dis­ke­
Radu1,2, abnormalities. The most common are Fanconi anemia (FA), ra­to­za con­ge­ni­tală, anemia Diamond-Blackfan şi sindromul
Andreea dyskeratosis congenita (DC), Diamond-Blackfan anemia Schwachman-Diamond. Majoritatea pacienților asociază
(DBA) and Schwachman-Diamond syndrome (SDS). Most și malformații/anomalii scheletale, importante în stabilirea
Șerbănică ,1,2
di­ag­nos­ti­cu­lui.
pa­tients have specific clinical features, making them very
Mirela Asan2, im­ p or­t ant for establishing the correct diagnosis. Cuvinte-cheie: Fanconi, insuficiență medulară,
Camelia Dobrea2, Keywords: Fanconi, bone marrow failure, thumb malformații police, transplant de celule stem
Cerasela Jardan1,2, anomalies, hematopoietic stem cell transplantation
Alexandra
Ionete2,
Carmen
Submission date:
25.11.2021 Aspecte clinice şi hematologice la pacienţii pediatrici diagnosticaţi
Călugăroiu , 2
Acceptance date:
8.12.2021 cu anemie Fanconi – experienţa unui centru
Suggested citation for this article: Jercan C, Bică AM, Marcu AD, Radu LE, Șerbănică A, Asan M, Dobrea C, Jardan C, Ionete A, Călugăroiu C, Constantinescu I,
Ileana Dragomirișteanu A, Arion C, Coliță A. Clinical and hematological aspects in pediatric patients diagnosed with Fanconi anemia – a single-center experience.
Constantinescu1,2, Pediatru.ro. 2021;64(4):22-28.
Aurora
Dragomirișteanu3,
Constantin Arion1,
Anca Coliță1,2
Introduction is the predisposition to bone marrow failure and malig-
Inherited bone marrow failure syndromes (IBMFS) are nancies. The patients can have skeletal abnormalities,
1. “Carol Davila” University considered pediatric diseases, though many patients are skin lesions, urinary tract malformations, intestinal or
of Medicine and Pharmacy,
Bucharest, Romania still diagnosed as adults. The most frequent are Fanconi neurological symptoms, but approximately one-third of
2. Fundeni Clinical Institute, anemia (FA), dyskeratosis congenita (DC), Schwachman- patients do not have somatic abnormalities. Bone mar-
Bucharest, Romania Diamond syndrome (SDS) and amegakaryocytic thrombo- row failure is most frequently diagnosed around the age
3. RNDVCSH, cytopenia (which can often evolve to myelodysplastic syn- of 7 years old, the patients presenting with cytopenia
Bucharest, Romania
drome or leukemia). Blackfan-Diamond anemia (DBA), affecting one line or pancytopenia (anemia, thrombo-
severe congenital neutropenia (SCN) and thrombocyto- cytopenia, neutropenia). The clinical findings include
penia with absent radii (TAR) are cytopenias involving café-au-lait spots on skin, skeletal abnormalities (short
only one line, rarely evolving to severe aplastic anemia, stature, microcephaly, hypoplastic thumbs, absence of
but with a high risk of developing acute leukemia(3,4). thumbs/radius, polydactyly, syndactyly), other abnor-
The diagnosis of these diseases requires knowing the malities (hypogenitalia, renal hypoplasia, micro­phtalmy,
clinical signs, with specific laboratory evaluations and mental retardation) and chromosomal instability with
genetic testing. Patients with IBMFS have an increased ruptures, increasing the risk for acute leukemia or solid
risk of developing malignancies during their second life- tumours(3,5,7).
time period. The only treatment option for patients who The frequency of upper limbs abnormalities in FA pa-
have developed pancytopenia is hematopoietic stem cell tients is high, 50% of children having skeletal anomalies
transplantation(5,6). and 70% having upper limbs anomalies: thumbs deformi-
Fanconi anemia is a congenital disease with autosomal ties, radius malformation. Thumb malformation is graded
recessive inheritance. The most important characteristic in Table 2(1,2).

22 Year XVII • No. 64 (4/2021)

 pediatru

Table 1 Anomalies/abnormalities associated with FA

Organ/system Abnormality/anomaly

Skin hyperpigmentation, café-au-lait spots, hypopigmentation spots

Stature dwarfism

fingers: absent or hypoplastic, bifidity, rudimentary, triphalangeal

radius: absent or hypoplastic, weak or absent pulse in the radial artery

Upper limbs hand: hypoplastic tenar eminence, absence of metacarpal I

ulna: dysplastic features

nails: nail dysplasia

Lower limbs congenital dysplasia of the hip, syndactyly, abnormal fingers

boys: insufficient development of the genitals, lowered testicles, hypospadias, micropenis

Gonads
girls: insufficient development of the genitals, bicorn uterus, abnormal menstruation

head and face: microcephaly, micronathism, triangular facies

Other skeletal cervical: Sprengel’s anomaly, Klippel-Fiel syndrome
abnormalities spine: spina bifida, scoliosis
thorax: rib abnormalities

Eye microphtalmia, hyperthelorism, strabismus, epicanthus folds, cataracts, astigmatism

Ear hearing loss, abnormal shape, atresia, middle ear abnormalities

Urogenital tract ectopic kidney, horseshoe shaped kidney, hypoplastic/dysplastic/absent kidney, hydronephrosis or megaureterus

Digestive tract esophageal/duodenal/jejunal atresia, imperforate anus, esotracheal fistula, leukoplakia, exocrine pancreatic insufficiency

Cardiopulmonary various structural heart defects: ductus arteriosus, VSD, pulmonary stenosis, aortic stenosis, aortic coarctation, duble aortic
system arch, cardiomiopathy, Fallot tetralogy

Objective and procedure. Post-HSCT monitoring was perfomed

To evaluate the pediatric patients diagnosed with
FA between 2002 and 2021 in the Pediatric Depart-
ment of the Fundeni Clinical Institute, Bucharest,
Romania.
Materials and method
We performed a retrospective study to analyze the
clinical data, laboratory values, treatment options and
the evolution of pediatric patients diagnosed with FA.
The diagnosis was established on clinical findings
and investigations: complete blood count, bone mar-
row biopsy, cytogenetic examination, α-feto-protein
levels, imaging and genetic tests in complex cases. The
conditioning regimens used in patients who received
hematopoietic stem cell transplantation (HSCT) was
adapted to each patient, according to the type of donor
using STR (short tandem repeats) technique to ana-
lyze chimerism. All parents signed the informed con-
sent forms.
Results
Between January 2002 and January 2021, 16 pa-
tients with AF (seven girls and nine boys), with a mean
age at diagnosis of 7 years old (range: 1-15 years old)
were diagnosed and treated in our department. Twelve
out of 16 (75%) had bone malformations, nine out of
16 (56%) were short of stature, nine out of 16 (56%)
had dysmorphic facies, six out of 16 (38%) had mental
retardation, five out of 16 (31%) presented skin le-
sions, five out of 16 (31%) had renal malformations,
three out of 16 (19%) had heart malformations and
three out of 16 (19%) had genital tract abnormalities.

Year XVII • No. 64 (4/2021)

23
clinical studies

Table 2 Thumb malformation (adapted from Fanconi Anemia: Standards for Clinical Care)
Type Characteristics Treatment

I Minor hypoplasia Surgical

Absence of intrinsec tender muscles Plastia

II Narrowing of the first interdigital space Reconstruction
Insufficient development of the collateral ulnar ligament Reconstruction

Type II +
Extrinsic muscle abnormalities and tendons skeletal deficiencies
III
A: stable carpo-metacarpal joint A: Reconstruction
B: unstable carpo-metacarpal joint B: Surgery

IV Floating thumb Surgery

V Absence of thumb Surgery

Initially, we performed pulmonary evaluations only
for patients who developed symptoms after HSCT,
to exclude GvHD (graft versus host disease). Conse-
quently, we extended the pulmonary screening to all
IBMFS patients, several studies showing pulmonary
changes as being characteristic in FA. In our study,
six out of 16 patients had severely decreased DLCO
(diffusing capacity for carbon monoxide), one of the
patients having restrictive chronic respiratory failure
due to thorax conformation.
The clinical findings are presented in Figures 1-6.
The patients’ data are presented in Table 3.
At onset, all patients had macrocytic anemia (medi-
an 10.8 g/dl, with median MCV of 95.65 fL), thrombo-
cytopenia (median 41.5x10 9/L), neutropenia (median
1.4x10 9/L). The hematological findings are presented
in Table 4. Bone marrow biopsy showed hipocellularity
in all patients.
We performed HSCT procedure in 11 out of 16 pa-
tients, in four cases from a related donor and in seven

Figure 1. Head abnormalities in a patient with FA: Figure 2. Café-au-lait spots and hypopigmentation
accessory tragus, triangular face lesions

24 Year XVII • No. 64 (4/2021)


Figure 3. Hypoplastic thumbs – variant of thumb
malformation
Figure 5. Hypoplastic thumbs with muscle abnormality –
variant of thumb malformation
Figure 6. Floating thumb and absence of thumb –
variants of thumb malformation
Year XVII • No. 64 (4/2021)
pediatru
Figure 4. Floating thumb and hypoplastic thumb –
variants of thumb malformation
cases from an unrelated donor. Four out of 16 patients
did not present to further monitoring visits, one patient
being currently monitored. Overall survival was 66.66%,
with seven out 11 (63.6%) transplant recipients alive,
with 100% donor chimerism at the last follow-up.
Discussion
Bone marrow failure syndromes – AF in this case –
are complex conditions that require a multidisciplinary
therapeutic approach.
Monitoring and correcting some of the physical ab-
normalities are necessary for improving the quality of
life: orthopedic interventions for hand, finger, spine,
lower limb abnormalities, plastic surgery interven-
tions for certain facial abnormalities; monitoring and
hearing aid in case of hearing abnormalities; moni-
toring and correction of cardiac, pulmonary, renal or
gastrointestinal abnormalities.
Regularly asessments for establishing the indica-
tion for bone marrow transplantation are required.
Also, monitoring and hormone replacement therapy
for patients with various types of associated endo-
crine impairment are to be performed.
The long-term monitoring for the risk of cancer by
including the patients in screening programs appro-
priate to individual risk should be performed.
It should be noted that bone marrow transplanta-
tion does not cure the disease, it only improves the
qua­l ity of hematopoiesis, without reducing the risk
of cancer; on the contrary, some studies suggest an
in­c reased risk of malignancy in these patients, se­
con­d ­­­ary to chemotherapy used for the conditioning
regimen.
Patients and their families require psychological
counseling for adapting to the chronic condition, with
evolutionary potential and involving many medical
procedures.
Genetic counseling is needed to identify other family
members affected by the same disease and the possibil-
ity of transmission to future generations(1,2). n
Conflict of interests: The authors declare no con­
flict of interests.
25
 Table 3 Patients clinical findings

26
Renal
Age at Skeletal Neurological Developmental malformations Digestive Heart Pulmonary
Patient Gender Skin lesions
diagnosis malformations features delay/malnutrition Genital malformation malformation changes
malformations
one kidney with
microretrognatia, no tests
FA1 12 years M hearing loss short of stature café-au-lait spots duplex collecting none none
hypoplastic thumb performed
system
5 years and microcephaly mild mental no tests
FA2 M short of stature café-au-lait spots none none none
11 months hypoplastic thumb retardation performed
clinical studies

floating thumb,
7 years and bilaterally mild mental no tests
FA3 M short of stature café-au-lait spots right ectopic kidney none none
10 months hypertelorism, low retardation performed
implanted ears
hypoplastic thumb,
9 years and mild mental no tests
FA4 F microcephaly, short of stature café-au-lait spots none none none
10 months retardation performed
accessory tragus*

hypoplastic thumb,
1 year and 6 mild mental DLCO severely
FA5 M microcephaly, short of stature café-au-lait spots third ectopic kidney none none
months retardation decreased
accessory tragus*

no tests
FA6 14 years F none none short of stature none horseshoe kidney none none
performed
3 years and low implanted ears, mild mental no tests
FA7 M short of stature café-au-lait spots none none none
10 months hypertelorism retardation performed
syndactyly lower
limbs, hypoplasia mild mental patent ductus no tests
FA8 11 years F short of stature none none none
of the thenar retardation arteriosus performed
eminence
2 years and palatoschizis, mild mental atrial septal no tests
FA9 F severe malnutrition none renal malformation none
11 months micrognathia retardation defect performed
microcephaly,
microphthalmia,
hypoplasia with
vicious-sessile bicuspid aortic
mild mental
8 years and implantation skin hypospadias, valve DLCO severely
FA10 M retardation, short of stature none
10 months of both thumbs hyperpigmentation hypoplastic kidneys minimal decreased
behavior issues
bilaterally, regurgitation

Year XVII • No. 64 (4/2021)

metacarpo-
phalangeal
hypoplasia
 Table 3 Patients clinical findings (cont.)
Renal
Age at Skeletal Neurological Developmental malformations Digestive Heart Pulmonary
Patient Gender Skin lesions
diagnosis malformations features delay/malnutrition Genital malformation malformation changes
malformations
dysmorphic facies,
microcephaly, short
neck, asymmetry of
the scapular girdle,

Year XVII • No. 64 (4/2021)

4 years and agenesis of the left mild mental short of stature, DLCO severely
FA11 F café-au-lait spots none none none
1 month thumb, floating retardation underweight decreased
right thumb,
absence of the first
metacarpal in the
left hand
microcephaly,
micrognathia
8 years and mild mental short of stature café-au-lait spots, no tests
FA12 F hypoplastic thumb, none none none
10 months retardation underweight hypochromic spots performed
hypoplasia of the
thenar eminence
dysmorphic facies,
microcephaly, low
restrictive
implanted ears, mild mental
dystrophic nails chronic
FA13 15 years M chest malformation retardation, underweight none none none
clubbing respiratory
(dull), hypotonic, behavior issues
failure
hypokinetic muscle
system

no tests
FA14 4 years F short neck none none none none none none
performed

dysmorphic facies,
short neck, right
hypoplastic thumb, 4 café-au-lait spots,
malformation of mild mental >1 cm, DLCO severely
FA15 9 years M short of stature micropenis, fimosis none none
the left thumb, retardation 7 hypochromic decreased
syndactyly in lower spots, >1 cm
limbs, fingers II-III
bilaterally
hypoplastic thumb,
7 years and microcephaly, low hyperpigmentation DLCO severely
FA16 M none short of stature none none none
5 months implanted ears, spots decreased
short neck

27
pediatru

*brother and sister; DLCO – diffusing capacity for carbon monoxide

clinical studies

Table 4 Hematological findings

Hematological findings Patients
Macrocytosis 16/16
Hb <7 g/dl 2 (12.5%)
Hb 7-10 g/dl 6 (37.5%)
Hb >10 g/dl 8 (50%)
Reticulocyte count 16/16
<50 x 109/L 7 (44%)
50-100 x 109/L 8 (50%)
>100 x 109/L 1 (6%)
Thrombocytopenia 15/16
PLT <20 x 109/L –
PLT 20-50 x 109/L 9 (60%)
PLT >50 x 109/L 3 (20%)
PLT >100 x 109/L 3 (20%)
ANC 15/16
>1 x 109/L 9 (60%)
1 x 109/L – 0.5 x 109/L 6 (40%)
<0.2 X 109/L –
BM hypocellularity 8/16
<10% 2 (25%)
10-25% 4 (50%)
>25% 2 (25%)

References
1. Tratat de Pediatrie (coord.: Prof. Dr. Doina Pleșca), Ed. 1, 2021.
2. Fanconi Anemia Guidelines for diagnosis and management, 4th Edition.
3. Dokal I, Vulliamy T. Inherited bone marrow failure syndromes. Haematologica.
2010;95(8):1236–1240. doi: 10.3324/haematol.2010.025619
4. Shimamura A, Alter BP. Pathophysiology and management of inherited bone
marrow failure syndromes. Blood Rev. 2010;24(3):101-122.
5. Bogliolo M, Surralles J. Fanconi anemia: a model disease for studies on human
genetics and advanced therapeutics. Curr Opin Genet Dev. 2015;33:32-40.
6. Online Mendelian Inheritance in Man, OMIM (TM) [homepage on the Internet].
Baltimore e Bethesda: BeMcKusick-Nathans Institute for Genetic Medicine, Johns
Hopkins University and National Center for Biotechnology Information, National
Library of Medicine. Available at: http://www.ncbi.nlm.nih.gov/omim/
7. Dufour C. How I manage patients with Fanconi anaemia. Br J Haematol.
2017;178:3247. https://doi.org/10.1111/bjh.14615

28 Year XVII • No. 64 (4/2021)

 clinical studies
Vitamin D intake and weight
status in preschool children
Diana Voican1, Abstract
Anca Angela
Simionescu2, The Romanian guide for the assessment of vitamin D during
pregnancy, in infants or preschool children, underlines the
Ana Maria per­so­nalization of vitamin D therapy in obese children, after
Alexandra mea­suring the plasma level. Materials and method. It was
Stănescu2, con­ducted a study to identify if there were any differences
Marina Ruxandra in nutrition, supplemental vitamin D administration and
Oțelea2 ex­po­sure to sunlight of children aged between 3 and 6
years old, from three kindergartens. Results. One hundred
1. SAMAS Association,
Bucharest, Romania sixty children were analyzed. The optimal serum level of
vi­ta­min D (25(OH)D) is 40-70 ng/mL, and a level above 30
2. “Carol Davila” University
of Medicine and Pharmacy, ng/mL is considered sufficient. This study revealed a low
Bucharest, Romania aware­ness among parents on the necessity of achieving a
Corresponding author: physio­logical level of vitamin D. Most children improved
Anca Angela Simionescu their endogenous production during the summer holidays,
E-mail: anca.simionescu@
umfcd.ro
be­cause in the wintertime they spent an average of 1.66
hour per day outdoor. Fish intake was low, with only three
chil­dren reaching the recommended level. In 42.9% of the
chil­dren, the supplementation with vitamin D was missing.
No differences were noted regarding any of these lifestyle
fac­tors or in vitamin D therapy according to the weight
ca­te­go­ries. Discussion and conclusions. This study shows
a rather good sunlight exposure during summer, however
not sufficient to assure the necessary level of vitamin D
du­ring the whole year. The personalization of vitamin D
the­ra­py in obese children should be better communicated
by healthcare providers in order to correspond to the current
guide­lines recommendations.
Keywords: vitamin D, preschool children, Body Mass
Index, sunshine exposure, dietary intake, therapy with
vitamin D, obesity
Submission date:
28.11.2021 Aportul de vitamină D și starea greutății la copiii preșcolari
Acceptance date: Suggested citation for this article: Voican D, Simionescu AA, Stănescu AMA, Oțelea MR. Vitamin D intake and weight status in preschool children.
7.12.2021 Pediatru.ro. 2021;64(4):30-33.
Introduction
Vitamin D is important for the children’s develop-
ment and the parents’ awareness regarding the vitamin
D sources is important to assure the necessary level for
a harmonious growth. The level of vitamin D in the Ro-
manian population is too low and young mothers are the
risk category groups(1). This makes infants and children
start their life trajectory with an insufficient reserve.
The lack of awareness leads not only to a personal intake
below the one recommended during pregnancy(2), but
prolonged during the postnatal developmental period
of their children.
Vitamin D is important for bone metabolism and for
a myriad of other immunological and nonimmunological
effects. The rapid periods of growth that characterize
30
Rezumat
Ghidul privind evaluarea și terapia deficitului de vitamină
D la gravide, nou-născuţi și la copiii preşcolari subliniază
im­por­tanța abordării personalizate a copilului obez, prin
do­za­rea vitaminei D. Materiale şi metodă. S-a efectuat un
stu­diu pentru a identifica diferențele în dietă, suplimentarea
cu vitamină D și expunerea la soare a copiilor în vârstă de
3-6 ani din trei grădinițe. Rezultate. Au fost analizaţi 160 de
co­pii. Nivelul optim seric ideal al vitaminei D (25(OH)D) este
de 40-70 ng/mL, peste 30 ng/mL fiind considerat suficient.
Da­te­le obţinute arată un nivel scăzut de conștientizare pri­
vind necesitatea de a avea un nivel fiziologic de vitamină D.
Ma­jo­­ri­tatea copiilor îşi îmbunătățesc sinteza endogenă în
tim­pul vacanței de vară, în timp ce iarna petrec, în medie,
1,66 ore pe zi afară. Consumul de pește a fost scăzut în rân­dul
copiilor incluşi în studiu, doar trei dintre ei atingând ni­ve­lul
recomandat. Suplimentarea cu vitamină D a lipsit la 42,9%
dintre copii. Nu s-au constatat diferențe semnificative sta­tis­tic
pentru niciun element legat de stilul de viață și nici pen­tru
terapia cu vitamina D în funcție de statusul ponderal. Dis­cu­
ţie şi concluzii. Acest studiu arată o expunere destul de bună
la lumina soarelui în timpul verii, însă insuficientă pen­tru a
asi­gu­ra nivelul necesar de vitamină D pe tot par­cur­sul anu­lui.
Per­so­na­li­za­rea tratamentului cu vitamină D la copiii obezi
tre­buie comunicată mai bine de către cadrele me­di­ca­le apar­ți­
nă­to­rilor, pentru a implementa corect ghidul ac­tual.
Cuvinte-cheie: vitamina D, preşcolari, indicele de masă
corporală, expunere la soare, aport alimentar, terapie cu
vitamina D, obezitate
the pediatric age and the insufficient intake and internal
production of vitamin D metabolites can have a signifi-
cant impact. Vitamin D participates in the defense mech-
anisms against pathogens, mitigates the inflammatory,
allergic and/or autoimmune response, and has a certain
role in the reduction of the cancer risk(3). Children with
vitamin D insufficiency have a higher risk of allergy(4)
and have more severe infections(5), besides the classical
skeletal effects on bone health.
Several studies have shown that 25-OH vitamin D
(25(OH)D) plasma level (the currently accepted method
to evaluate the vitamin D status)(6) reflects the balance
between production, absorption, transport, distribu­tion,
utilization and catabolism. The ideal level of 25(OH)D is
40-70 ng/mL; however, more than 30 ng/mL is considered
Year XVII • No. 64 (4/2021)

a sufficient level(7,8). The prevalence of optimal value
reaches only 33.7% of children under 6 years old, even
in developed countries(9). In a study performed by Voort-
man et al.(9), which inluded 4167 children, vitamin D
was significantly lower in under-weight compared to
normal-weight children, even after the adjustment for
sociodemographic (e.g., ethnicity, economical status) and
lifestyle determinants (e.g., exposure to sunlight, indoor
activities). Other studies have found low vitamin D levels
in obese children(10), these finding being explained as the
result of a poor diet which does not fulfill the micronutri-
ent requirements despite a high caloric intake. Therefore,
an adaptation of vitamin D to the weight status is recom-
mended in some countries(11), including in the Romanian
legislation(12).
As deficiency was reported in both wasted and obese
children, we have conducted an observational cross-
sectional study to identify if there are lifestyle factors
that influence the vitamin D status which might be dif-
ferent according to the weight categories in preschooler
children.
Materials and method
A survey was conducted in three kindergartens from
Bucharest and distributed to the parents. The question-
naire was intended to assess the sun exposure and the
awareness on vitamin D sources. It included items such
as time spent outdoor during different seasons, the
Year XVII • No. 64 (4/2021)
pediatru
intake of vitamin D supplements, or food fortified in
vitamin D. There were also some items related to the
awareness on the food content of vitamin D.
A section of the questionnaire was dedicated to height
and weight data. The Body Mass Index (BMI) was calcu-
lated according to the following formula: BMI = weight
(kg) ÷ height2 (m). The classification in BMI categories
(obese/overweight/normal/wasted/severely wasted) was
based on the WHO charts(13). Based on these data, we
have estimated if the child was at risk of vitamin D de-
ficiency. Secondly, we checked if there were differences
in sun exposure and diet intake according to BMI status.
Data were processed with SPSS software. The numeri-
cal data were compared with the Kruskal-Wallis test and
the categorical ones were compared using the chi-square
test. The statistically significant level was set for a 95%
probability.
Results
We received questionnaires from 160 parents out of
500, which represented a 32% rate of responses.
The average child’s age was 4.62 years old. The ma-
jority of the children had normal BMI (73%), 5% were
severely wasted, 14% were wasted, 6% were overweight,
and 2% were obese. On average, children spent outside
4.33 hours per day during the summer and 1.9 hours
per day during winter (Figure 1 and Figure 2). There was
no statistically significant difference noted among BMI
Figure 1. Number of hours
spent outdoor during
summer
Figure 2. Number of hours
spent outdoor during winter
31
clinical studies
Estimated content of vitamin D from
Table 1
fish intake
Estimated vitamin D Number of children
from fish intake (IU) (%)
0 38 (24.1%)
6.67-21.33 28 (17.7%)
26.67-50 29 (18.4%)
53.33-73.33 28 (17.7%)
80-100 17 (10.8%)
106.67 -120 6 (3.8%)
133.33 4 (2.5%)
160 5 (3.2%)
≥ 200 3 (1.9%)
categories, neither in summer (H=0.17, p=0.92), nor dur-
ing wintertime (H=0.98, p=0.61), although overweight
and obese children spent, on average, less time outside
(4.16 hours per day during summer and 1.66 hours per
day during winter).
The lack of exposure to sunlight in winter was par-
tially compensated in most of the children (90.1%) with
an average of 8.9 days per year of holidays at the seaside.
The majority (63%) of the children spent between 7 and
13 days per year. Twenty-eight percentage spent less
than seven days, and 9% had holidays longer than 14
days per year at the seaside.
Only 135 children ate fat fish at least once a month (ave­
rage intake = 360 g/month). Apparently, the underweight
children ate more fish (average intake = 467 g/month) than
normal weight (average intake = 323 g/month) and over-
weight children (average intake = 368 g/month).
However, the difference was not statistically sig­ni­fi­
cant (H=2.17, p=0.34). The distribution and the es­ti­ma­
ted vitamin D intake are presented in Table 3. The to­tal
recommended dietary intake of vitamin D for children
aged 1-17 years old is 600 UI/day(14). Unfortunately, na­tu­
ral foods are not very rich in these micronutrients. Fatty
fish has the highest natural content of vitamin D(15). If
we estimate that one-third of the total intake of vitamin
D comes from fish, only three children have a sufficient
level in their diet.
The distribution and the estimated vitamin D intake
are presented in Table 1. As noticed, only three children
had fish intake as recommended; one child had normal
weight and the other two were overweight. Only 12 par-
ents correctly identified a food that contains vitamin D
and five others mentioned cereals as food with a high
content of vitamin D, most probably referring to break-
fast cereals that are supplemented with vitamin D.
In total, 73 children received vitamin D as a supple-
ment. There was a high heterogeneity in the administra-
tion of the vitamin D, ranging from daily (15 children)
to 10 days per month (one child), 6-8 months per year
(28 children), four months per year (two children), three
32
months per year (seven children), and two months/year
(two children). Eleven parents did not specify the length
of the administration. This might reflect a lack of com-
munication with the healthcare professionals, but also
some ambiguity and no consensus inside the medical
community.
Even though the dosage were correct, 42.9% of the
children would be at risk of not achieving the target for
vitamin D and for becoming deficient in this essential el-
ement for growth and development. Worth mentioning,
the three children who had a recommended intake of fish
also received vitamin D as a supplement during winter.
Comparing according to BMI the children who re-
ceived vitamin D as a supplement, 38.09% were under-
weight, 45.6% had a normal weight, and 33.33% were
overweight. This distribution was also statistically in-
significant (chi2=0.96, p=0.62).
Discussion
The prevalence of vitamin D insufficiency or even
deficiency in the first decade of life is around 35% in
Romania(16). Our figures show a rather good sunlight
exposure during summer, however not sufficient to as-
sure the necessary level of vitamin D during the whole
year. In winter, the levels of vitamin D decrease signifi-
cantly(17) and less than 2 hours per day (as found by us) of
exposure of the face to sunlight would definitely not be
enough for endogenous production. The direct relation
between playing outdoor and the vitamin D levels, and
the inverse relationship between the number of hours of
watching television and the vitamin D levels were found
in other studies(9) and should be subject to appropriate
messages to parents, in order to improve as much as
possible the sunlight exposure from June to September.
Diet and supplements were also insufficient to meet
the requirements of vitamin D intake. The therapy was
administered in very different schemes by the parents and
most of them did not follow a clear medical recommen-
dation. The awareness about foods with high content of
vitamin D was very low and so was the fish consumption.
The most important finding of this study is that obese
and overweight children do not benefit from a special
approach, as recommended by the Romanian guide-
line. No statistical differences were recorded regarding
sunlight exposure, fish intake and vitamin D therapy
which makes the guideline recommendation inefficient
in terms of implementation. Of course, this is not a study
representative for the whole Romanian population and
in other communities the personalized approach might
be better. It is, however, a signal that not all children
receive the proper treatment and this treatment does
not follow a plasma measurement of 25(OH) vitamin D.
In terms of clinical attitude, it is to underline that the
lower level of vitamin D in obese children is also a conse-
quence of a volumetric dilution and of its liposolubility
which produces adipose tissue sequestration(18), and the
plasma level would not reflect as accurately the body
content of vitamin D as it does for the normoponderal
subjects. On the other hand, bone metabolism seems to
Year XVII • No. 64 (4/2021)

be more impaired in obese girls than in obese boys(19).
Therefore, the optimal solution would be to first restore
the normal body weight, and only if there is no improve-
ment in the vitamin D level, to correct it therapeutically.
In conclusion, there is no differentiation regarding
the vitamin D intake (either from diet, or from therapy)
and the exposure to sunlight according to the BMI sta-
tus. A personalized recommendation of vitamin D for
1. Zugravu C, Tarcea M, Soptica F, Cucu A. Pertinence of Vitamin D supplementation
References
in the adult Romanian population. Farmacia. 2016;64:467-720
2. Zugravu C, Rașcu A, Oțelea MR, Macri A. Vitamin D from food and supplement
intake in pregnancy. A pilot study. Farmacia. 2020;68:150-154.
3. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B.
Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple
health outcomes. Am J Clin Nutr. 2006;84(1):18-28.
4. Neeland MR, Tursi AR, Perrett KP, Saffery R, Koplin JJ, Nadeau KC, Andorf S. Vitamin
D insufficiency is associated with reduced regulatory T cell frequency in food-
allergic infants. Pediatr Allergy Immunol. 2021;32(4):771-775.
5. Shah K, Varna VP, Pandya A, Saxena D. Low vitamin D levels and prognosis in a
COVID-19 pediatric population: a systematic review. QJM. 2021;114(7):447-453.
6. Holick MF. Vitamin D status: measurement, interpretation, and clinical application.
Ann Epidemiol. 2009;19(2):73-78.
7. Vasquez A, Manso G, Cannell J. The clinical importance of vitamin D
(cholecalciferol): a paradigm shift with implications for all healthcare providers.
Altern Ther Health Med. 2004 Sep-Oct;10(5):28-36; quiz 37, 94.
8. Weydert JA. Vitamin D in Children’s Health. Children (Basel). 2014 Sep 12;1(2):208-
26.
9. Voortman T, van den Hooven EH, Heijboer AC, Hofman A, Jaddoe VW, Franco OH.
Vitamin D deficiency in school-age children is associated with sociodemographic
and lifestyle factors. J Nutr. 2015;145(4):791-798.
10. Bindayel IA. Effect of age and body mass index on vitamin D level in children with
pediatru
different BMI categories provides benefits for children’s
growth and development. The implementation of the
national guideline needs a better partnership between
healthcare providers and parents in order to achieve the
recommendations for obese children. n
Conflict of interests: The authors declare no con­
flict of interests.
asthma in Riyadh. Sci Rep. 2021;11(1):11522.
11. Zakharova I, Klimov L, Kuryaninova V, et al. Vitamin D Insufficiency in Over­weight
and Obese Children and Adolescents. Front Endocrinol (Lausanne). 2019 Mar
1;10:103.
12. Ministerul Sănătății. Ghid privind evaluarea și terapia deficitului de vitamină D la
gravidă, nou-născut și copil. Monitorul Oficial, nr. 773 din 24 septembrie 2019.
13. de Onis M (coord.). WHO child growth standards. Available at: https://www.who.
int/publications/i/item/924154693X).
14. EFSA Panel on Dietetic Products, Nutrition and Allergies), 2016. Scientific opinion
on dietary reference values for vitamin D. EFSA Journal. 2016;14(10):4547.
15. Schmid A, Walther B. Natural vitamin D content in animal products. Adv Nutr. 2013
Jul 1;4(4):453-62.
16. Chiriţă-Emandi A, Socolov D, Haivas C, Calapiș A, Gheorghiu C, Puiu M. Vitamin D
Status: A Different Story in the Very Young versus the Very Old Romanian Patients.
PLoS One. 2015;10:e0128010.
17. Ene MC, Tertiu O, Vrâncianu O, Chifiriu MC. Vitamin D status in adult and pediatric
romanian population. Roum Arch Microbiol Immunol. 2018;77:198-212.
18. Vranić L, Mikolašević I, Milić S. Vitamin D Deficiency: Consequence or Cause of
Obesity?. Medicina (Kaunas). 2019;55(9):541.
19. Pimentel D, Suttkus A, Vogel M, Lacher M, Jurkutat A, Poulain T, Ceglarek U,
Kratzsch J, Kiess W, Körner A, Mayer S. Effect of physical activity and BMI SDS on
bone metabolism in children and adolescents. Bone. 2021;153:116131.
Reclamă PED(64)0206
 clinical studies
Abdominal trauma in children –
one-year single-center
experience
O. Bîcă1, Abstract
Diana Benchia1,
Klara Sârbu2, Trauma is the leading cause of childhood morbidity and
mor­ta­li­ty. With newer technologies, clinical guidelines and
Carmen Iulia mi­ni­mally invasive interventions, the management of trau­ma
Ciongradi1, is different today than just a few years ago. There are multiple
I. Sârbu1, imaging and treatment protocols for clinicians to follow, but
Ș. Popa1 we need to highlight that every pediatric pa­tient is unique,
1. “Grigore T. Popa”
owing to the mechanism of injury or their cha­rac­te­ris­tics. The
University of Medicine objective of this study was to investigate pa­tients presented
and Pharmacy, to our emergency department during one calendar year, with
Iași, Romania
blunt abdominal traumas, by reviewing their cha­rac­te­ris­tics,
2. Klara Sârbu Family the degree of intraabdominal solid organs in­ju­ries (ac­cording
Practitioner Office,
Târgu-Neamț, Romania to biological and imaging find­ings), and the as­so­cia­tion
with the nonoperative or ope­ra­tive ma­nage­ment. The total
number of patients included in the study groups was 102,
with an average age of 8.3 ± 3.2 years old (6 months to 17
years old). The most common cause of trauma was physical
assault (24.5%) followed by falling from height (23.5%).
Regarding the treatment, 90 of the patients received con­
ser­va­tive methods and 12 of them required surgery due to
hemodynamic instability. The mean hospital length of stay
was 9.3 days; 17 patients were hospitalized in the intensive
care unit, and the remaining patients were hospitalized in
the sur­ge­ry department. The evaluation and management
of pediatric abdominal trau­ma have changed significantly
in the last decades, con­ser­va­tive treatment becoming a
universal standard ma­nage­ment implemented worldwide in
stable children with fa­vo­rable clinical outcomes.
Keywords: abdominal trauma, children
Submission date:
24.10.2021 Traumatismele abdominale la copii – experiența unui singur centru
Acceptance date:
5.11.2021 pe o perioadă de un an
Suggested citation for this article: Bîcă O, Benchia D, Sârbu K, Ciongradi CI, Sârbu I, Popa Ș. Abdominal trauma in children – one-year single-center experience.
Pediatru.ro. 2021;64(4):34-40.
Introduction
Trauma is the leading cause of childhood morbidity
and mortality. Abdominal injuries represent the third
most common type of trauma in children, after head
and chest injuries, and the most common cause of death
due to unrecognized lesions. Blunt trauma accounts for
more than 80% of abdominal trauma at a young age and
represents about 11-26% of total laparotomies. There are
certain mechanisms of injury in the pediatric popula-
tion, the main causes being traffic accidents, trauma
caused by falling from a height altitude and physical
attacks(1-4).
34
Rezumat
Trauma este principala cauză a morbidității și mortalității la copii.
Datorită tehnologiei moderne, ghidurilor clinice și intervențiilor
minim invazive, managementul traumei este diferit actualmente
față de acum câțiva ani. Există mai multe protocoale imagistice
și de tratament pe care medicii trebuie să le urmeze, dar trebuie
să subliniem că fiecare pacient pediatric este unic, din cauza
mecanismului leziunii sau a caracteristicilor acestora. Obiectivul
acestui studiu a fost acela de a analiza pacienții care s-au pre­
zentat în cadrul unității de primiri urgențe pe parcursul unui an
calendaristic cu traumatisme abdominale contondente și am
analizat caracteristicile acestora, gradul leziunii organelor solide
intraabdominale (conform rezultatelor biologice și imagistice)
și asocierea cu managementul conservator (nonoperatoriu) sau
chirurgical. Numărul total de pacienți incluși în lotul de studiu a
fost de 102, cu o vârstă medie de 8,3 ± 3,2 ani (6 luni până la 17
ani). Cea mai frecventă cauză a traumei a fost agresiunea fizică
(24,5%), urmată de căderea de la înălțime (23,5%). Referitor la
tratamentul pacienților incluși, 90 dintre aceștia au fost tratați
con­ser­va­tor, nonoperatoriu, și doar 12 au necesitat intervenții
chi­­rur­­gi­­ca­le din diferite cauze care au dus la instabilitate he­mo­­di­
na­mi­că. Durata medie de spitalizare a fost de 9,3 zile. 17 pa­cienți
au fost internați în secția de terapie intensivă, restul ne­­ce­si­tând
supraveghere pe secția de chirurgie. Evaluarea și ma­nage­men­tul
traumatismelor abdominale pediatrice s-au schim­bat sem­ni­fi­ca­tiv
în ultimele decenii, tratamentul con­ser­va­tor devenind ma­nage­
mentul standard universal implementat la nivel mondial, cu
re­zul­tate clinice favorabile în cazul copiilor sta­bili.
Cuvinte-cheie: traumatism abdominal, copii
Children have an increased risk of suffering injuries of
intraabdominal organs after a blunt abdominal trauma
due to their anatomical and physiological characteristics.
Compared to the adult population, children have a higher
elasticity of the body, the intraabdominal organs are pro-
portionally larger and relatively close to each other, they
have a smaller adipose panniculus, an abdominal wall
with less muscle layer, and an incompletely ossified chest
cage that provides limited protection of the liver, spleen
and kidneys (most commonly injured organs)(5-8).
The field of trauma is expanding and pediatric trau-
ma is no exception. With newer technologies, clinical
Year XVII • No. 64 (4/2021)

guidelines, minimally invasive and percutaneous inter-
ventions, the world of trauma care is dramatically differ-
ent today than just a few years ago. There are multiple
imaging and treatment protocols for clinicians to follow,
but we need to highlight that every pediatric patient is
unique, owing to the mechanism of injury or their char-
acteristics. The ability to manage injuries relies on the
surgeon’s comfort with pediatric protocols and experi-
ence with nonoperative management (NOM)(9).
In the emergency department (ED), after the evalu-
ation of trauma patients, one should make a detailed
physical exam that sometimes remains a challenge
due to a poor description of symptoms and mostly the
absence of physical examination findings that cannot
exclude any kind of intraabdominal injury. The most
commonly used imaging tools in children with blunt ab-
dominal injuries are ultrasonography (US) and computed
tomography (CT) – the gold standard in the diagnosis
and therapeutical planning and also in the follow-up for
cases with NOM(10).
Mostly, in pediatric surgery practice, blunt abdominal
traumas are managed nonoperatively and defined as the
choice, made after a primary and secondary revision, of
not performing surgery immediately after imagistic and
blood tests results. A surgeon must be available in case
of a patient who becomes unstable, despite maximal
resuscitation efforts, and requires surgical intervention.
Surgery is traditionally preformed via laparotomy, but
more common nowadays via laparoscopy(11-13).
The objective of this study was to investigate patients
presented to our emergency department during one cal-
endar year, with blunt abdominal traumas, by reviewing
their characteristics, the degree of intraabdominal solid
organs injuries (according to biological and imaging find-
ings), and the association with the NOM or the operative
management (OM).
Materials and method
A retrospective, observational study was performed to
investigate the management of pediatric blunt abdomi-
nal trauma in the “Sf. Maria” Emergency Clinical Hos-
pital for Children, Iaşi, Romania, in patients registered
13-18 years old
7-12 years old
2-6 years old 18
0-1 year old 5
0 13 25
Year XVII • No. 64 (4/2021)
pediatru
in our emergency service in 2014. Children under 18
years of age were considered cases of pediatric trauma.
The medical records of the patients admitted to the
pediatric surgery service with potential abdominal inju-
ries were analyzed. We included in this study patients and
trauma characteristics such as age, gender, demographics,
localization of trauma, type of trauma (i.e., blunt or pen-
etrating), mechanism, and period of trauma. The physical
examination was rigorously performed. The imagistic
results were obtained by performing US and/or CT of the
abdomen. Abdominal CT was performed on multiple trau-
ma patients with pathologic findings on physical and US.
Diagnostic workup, treatment (number and percentage
of conservative treatment and need or indication of im-
mediate surgery, intraoperative findings), and outcomes
were retrieved from the database.
The patients were separated into two groups and
categorized by the type of treatment they initially re-
ceived. The first group of patients was treated by NOM
and those who received OM were included in the second
group. The operative reports were reviewed for details
regarding the type and extension of the trauma, addi-
tional to the information previously obtained from clini-
cal and imaging exams and from lab findings. The out-
come measurements of this study included postoperative
abdominal complications, length of hospital stay (LOS),
length of intensive care unit (ICU) stay, reintervention
for abdominal complications, and mortality.
In the quantitative variables, measures of central ten-
dency and dispersion were calculated – (n) and relative
frequencies (%) were calculated for qualitative variables,
along with percentage for all data. The process and stor-
age of data are following privacy and ethics regulations
under the institutional medical ethics committee.
Results
Demographics. The total number of patients included
in the study groups was 102. There were 42 females (41%)
and 60 males (59%), with an average age of 8.3±3.2 years
old (from 6 months old to 17 years old). The distribution
of cases by group age was analyzed according to the age
range: 50 abdominal traumas were encountered in the
Figure 1. Age distribution
41 of the patients
38
38 50
35
clinical studies
crush injuries 3 Figure 2. The distribution
bicycle handlebar injuries 5 the cause of abdominal
accidental hitting 6
horse kick injury 8
road accidents
fall from height
physical assaults
0 5 10
range 0-10 years old, and 52 cases in the age range 11-18
years old. Thus, the predominance of abdominal trau-
mas is observed in the age range 11-18 years old, with a
percentage of 51%, and in the case of the age range 0-10
years old, a percentage of 49% was recorded. Considering
the distribution of patients according to the develop-
ment groups, it can be observed that: five cases were
registered in the interval 0-1 year old (infants), 18 cases
were registered in preschool children (2-6 years old); in
the case of school-age children (7-12 years old) there
were 38 cases, and 41 children (13-18 years old) were
registered in adolescents (Figure 1). We found a higher
preponderance of abdominal injuries among people from
rural areas (n=73; 72%) compared to those from urban
areas (n=29; 28%).
Trauma characteristics. The distribution of inju-
ries according to the cause of abdominal traumas was
registered as follows: 25 physical assaults; 24 children
who fell from height altitude; 13 road accidents as pe-
destrians, six as passengers and four bicycle accidents;
eight injuries from horse kick injury; six due to accidental
hitting; five caused by hitting the handlebars of the bi-
cycle; three children presented crush injuries. The most
common cause of trauma was physical assault (24.5%), the
second was falling from a height (23.5%), and the third
trauma mechanisms in this series were accidents (22.5%)
as car accidents, vehicle occupants or bicycle. Some of
the patients had more than one lesion, 8% of patients
had fractures in addition to abdominal trauma, 56% had
chest trauma and 36% of patients had a head injury. In our
series, there was no penetrating trauma reported. Analyz-
ing the distribution of cases and taking into account the
seasons, we can see the increased incidence of abdominal
trauma in summer (36 cases; 35%), in autumn 33 cases
were reported (32%), in the spring there were 21 cases
(21%), and in winter there were 12 abdominal injuries
(12%). Regarding the distribution of the cases according
to the months of the year, it was found that most injuries
were in June (n=16), followed by July (n=14), and the lower
frequency was identified in December, with only one case
registered. According to the days of the week, it can be
36
of injuries according to
traumas
23
24
25
15 20 25 30
noticed that most abdominal traumas were registered
on Friday (n=20; 19%), followed by Wednesday (n=19;
18%) and Tuesday (n=12; 12%); on Thursday, there were
nine abdominal injuries (9%). Analyzing the data related
to the time when trauma occurred, we can notice the net
predominance of trauma during the week, with a percent-
age of 73%, while during the weekends there were 28
abdominal traumas (27%).
Imaging results. The radiological examination was
the most frequently used in the diagnosis of abdominal
trauma. The radiological investigation methods were
based on clinical criteria, the risks of the chosen method
being irradiation. Referring to the imaging investiga-
tions that were performed, 94 of the patients benefited
from US (fluid being identified in 80% of cases), repre-
senting 92%. Twenty-seven of those patients needed
CT, representing 26.5%, and 64 of the patients had an
X-ray, representing 62.7%. There were 29% of patients
diagnosed with a liver trauma, 37% had a renal one, 11%
had a splenic trauma, and 11% had a pancreatic trauma.
Small bowel injury was diagnosed in 4% of patients, gall-
bladder in 4% of patients, and stomach injury in 4%.
Lab results. Pathological values in biochemical tests
were observed in a certain percentage of patients, as
follows: Hb determined in all patients, with pathologi-
cal values recorded in only 26% of patients; in 23% of
patients there were changes in Hct values. Abnormal
amylase values were recorded in 11% of patients, and
abnormal urine amylase values were observed in 4% of
patients; abnormal AST values were identified in only
16% of patients and abnormal ALT values were identi-
fied in 14% of patients; ESR and fibrinogen values were
abnormal in 2% of patients; hematuria was observed in
2% of patients and urea showed pathological values in
1% of patients.
Diagnostic workup and management. Regarding
the treatment, it can be seen that 90 of the patients
received conservative treatment, with a percentage of
88%, and 12 patients required surgery (12%). Other
treatments, such as plaster, splints, suture and dress-
ing, were applied to the NOM group. Ninety-four of the
Year XVII • No. 64 (4/2021)
 pediatru

patients did not need a transfusion (92%), and eight

patients benefited from blood transfusions, with a per-
centage of 8%. Among the eight patients, there were:
four patients who required surgery for associated frac-
tures; one patient diagnosed with splenic rupture, who
required transfusion of 200 ml of blood and 200 ml of
frozen plasma; one patient diagnosed with pancreatic
rupture (caudal fragment) who required transfusion of
250 ml of blood; one patient diagnosed with hemopneu-
mothorax, abdominal trauma, following a horse’s kick,
who required transfusion of 250 ml of blood and 200 ml
of frozen plasma, and another patient diagnosed with
hemoperitoneum, traumatic pneumothorax, secondary
to a fall from a height of about 8 m, who required the
transfusion of 150 ml of blood.
Analyzing the data according to the number of hos-
pitalization days, 51 patients had a hospitalization un-
der five days (50%), 40 children had a hospitalization
between 5 and 10 days (39%), and 11 of the patients
had a hospitalization that exceeded 10 days, with a per-
centage of 11%. The mean hospital length of stay was
9.3 days. Examining the data according to the need for
hospitalizations in the intensive care unit, we observed
that 17 patients were hospitalized in ICU (17%), and the
remaining 85 patients were hospitalized in the surgery
department, with a percentage of 83%. Regarding the
need for days of hospitalization in the ICU per patient, it
can be noticed that eight patients (47%) had hospitaliza-
tions under four days, four patients (24%) needed hospi-
talizations between four and six days, and five patients
(29%), over seven days.
Surgical treatment (OM). The operative manage-
ment was needed in 12 patients. We mention:
n Patient number 1, diagnosed with splenic rup-
ture, following a physical assault. CT scan results: splenic
fracture grade III and hemoperitoneum (Figure 3). Be-
cause there were signs of hemodynamic instability, he
required laparotomy, splenorrhaphy, hemostasis, ab-
dominal lavage, and drainage with one tube.
n Patient number 2, diagnosed with pancreatic
rupture (caudal segment), following a bicycle handle-
bar impact. Initially treated conservatively, the patient
developed five weeks later a pseudocyst (8.16/11.6/14
cm). For the treatment of the pseudocyst, surgery was
performed: a laparotomy was done, cystogastrostomy,
abdominal lavage and drainage with one tube (Figure 4).
n Patient number 3, diagnosed with an abdominal
trauma, following a horse’s hoof kick in which the CT
examination revealed the presence of a right hydropneu-
mothorax, associating signs of hemodynamic instability.
An emergency procedure was needed: pleural drainage
in VIII intercostal right space.
n Patient number 4, diagnosed with an abdominal
trauma, following a horse’s hoof kick, initially treated
conservatively, with dynamic ultrasound monitoring
showing an increase peritoneal fluid and exacerbation
of abdominal pain syndrome. An exploratory laparo­ Figure 3. Patient number 1. Computed tomography
scopy was performed and the presence of blood in the section: a) coronal section; b) sagittal section; c) axial
peritoneal cavity was confirmed (300 ml of old blood (transverse) section

Year XVII • No. 64 (4/2021)

37
clinical studies
Figure 4. Patient number 2: a) traumatic sign – clinical
examination; b) evolution of Hb and of amylase values
during hospitalization; c) pancreas pseudocyst
38
was evacuated), without any other lesions of the paren-
chymal organs. Peritoneal lavage was performed and a
continuity solution was identified, involving the parietal
peritoneum, the transverse aponeurosis and partially
the parietal muscular body, at the level of the right flank.
A postoperative abdominal drainage tube was placed.
n Patient number 5, diagnosed with hemopneumo-
thorax following a fall from a height of approximately
8 m, for which surgery was performed in emergency
because he showed signs of hemodynamic instability.
A drainage tube was placed in VII intercostal left space,
with blood removal.
n Patient number 6, diagnosed with an abdominal
trauma, following a direct impact to the handlebars of
the bicycle. He required surgery because he showed signs
of peritonitis and free gas was revealed by X-ray. A lapa-
rotomy was performed and an intestinal perforation was
identified. Resection of the perforation edge, suture of
jejunal loop perforation, peritoneal lavage and drainage
with two tubes were performed.
n Patients number 7-12 required surgeries for the
treatment of associated injuries – wounds, fractures.
Discussion
The evaluation and management of pediatric abdomi-
nal trauma have changed significantly in the last dec-
ades. In our study, 88% of patients with intraabdominal
injuries were treated with conservative methods and
12% of them required surgery. It was reported that the
liver is the second most commonly injured organ, follow-
ing the spleen in blunt traumas. Wisner et al. investi-
gated a total of 605 children with solid organ injuries and
found spleen injury in 49% of these children, liver injury
in 47%, and renal injury in 24% of these patients(5). Our
study found that the most commonly injured organ was
the kidney, in 37% of patients, followed by the liver in
29% of cases, and pancreatic or spleen trauma in 11%
of patients. When compared with other studies, the re-
sults are different, as in our series renal trauma was
the most common. In our study, 88% of patients with
intraabdominal solid organ injuries were treated with
conservative methods and 12% of them needed surgery.
These rates are compatible with those from literature(14).
Basaran et al. investigated the characteristics and the
degree of intraabdominal solid organ injuries in a study
where 1066 pediatric patients were included, with 92.8%
blunt injuries, from which liver injury was detected in
47% of patients, spleen injury in 36% and renal injury
in 17% of patients. Grade II injury was the most com-
mon and 96.5% of patients were provided conservative
treatment, while only 3.5% of patients were treated
surgically(15).
In our study, posttraumatic pancreatic rupture was
treated conservatively, because at the initial examina-
tion the patient was stable, the dynamic evolution of
amylase values was favorable, the initial increase being
followed by a decrease (indicating a minor pancreatic
lesion), and the imaging examinations did not detect
the presence of free fluid in the peritoneal cavity. The
Year XVII • No. 64 (4/2021)

evolution under conservative treatment was favorable.
After five weeks of conservative supportive treatment
and protective therapy with antibiotics in the ICU de-
partment, a CT revealed a pseudocyst. For the treat-
ment of the pancreatic pseudocyst (with dimensions
exceeding 6 cm) surgery was performed, consisting in a
transgastric drainage of the cyst, with a favorable out-
come. The incidence of pancreatic lesions in children
with nonpenetrating abdominal trauma varies between
3% and 12%. A report from San Diego revealed 18 cases
of major pancreatic injury over a 14-year period. Of these
18 patients, seven were diagnosed with pancreatic pseu-
docyst, and in 11 patients a distal pancreatectomy was
performed. Two of the seven pseudocysts were treated
conservatively and five were treated by cystogastros-
tomy. Thus, distal pancreatic lesions must be treated
by distal pancreatectomy, proximal lesions require con-
servative treatment, and pseudocysts may be treated
conservatively or require cystogastrostomy. Endosco­
pic retrograde cholangiopancreatography (ERCP) with
a stent placement management has been shown to be
also effective. It has been found that CT examination
is suggestive, but the diagnosis cannot always be made
based on this examination(16). The mortality associated
with pancreatic trauma varies between 8% and 10% in
pediatru
children and is usually due to associated lesions, espe-
cially vascular ones with hemorrhages or neurological
lesions and multiple organ failure(17).
In our study, we had a 15-year-old male patient who
was hospitalized in our surgery department for supervi-
sion, following a bicycle accident. At admission, the pa-
tient had a good general condition, stable and at local
exam he presented multiple superficial wounds in the
left lumbar and hypochondrium, spontaneous pain and
at palpation in the left hemiabdomen, and also micro-
scopic hematuria. The imaging test in ER (chest X-ray and
ultrasonography) showed no changes. At approximately
48 hours after the admission, his general status showed
signs of impairment, with a progressive increase in pain
in the left hypochondrium and the suspicion of splenic
rupture was raised, a reason for which abdominal CT was
performed. The study revealed posttraumatic splenic lac-
erations, grade III AAST, posterior arch fracture – left C9
rib, left pleural fluid in small amounts, bilateral poster-
obasal lung lesion. The patient’s general good condition
and the laboratory results permitted the management
by conservative treatment. The outcome was favorable.
The conservative treatment in isolated spleen and liver
ruptures in stable children is a universal standard manage­
ment implemented for about three decades worldwide, with
Reclamă PED(64)0207
clinical studies
favorable outcomes. It involves bed rest, supportive treat-
ment and blood transfusion, if needed.
The course of a spleen rupture can be variable. Apart
from the obvious cases with operative indication, there
are smaller spleen ruptures which may evolve over time
with small signs of internal bleeding or which, after sur-
veillance for several days, are suddenly manifested with
signs of a delayed severe hemorrhage. This possibility of
evolution must be taken into account and it is necessary to
recommend a minimum safety interval of time until the
resumption of daily activities. If the supportive treatment
fails and surgery is performed, the purpose of the interven-
tion is to control bleeding and preserve the splenic tissue.
Laparotomy is performed and, depending on the degree
of the lesions, splenic suturing can be applied, using he-
mostatic agents, partial splenectomy or total splenectomy.
In case of splenic lesions, conservative treatment is
preferred more frequently recently compared to surgery.
The conservative treatment will apply to cases where the
estimated blood loss is less than 500 ml or one-third
of the child’s blood volume, the lesions associated are
minimal, without interesting the hilum, and with nor-
mal hemostasis(18).
In research performed by Bairdain et al., on patients
diagnosed with splenic lesions, admitted to the Boston
1. Gaines BA. Intra-abdominal Solid Organ Injury in Children: Diagnosis and
References
Treatment. The Journal of Trauma. 2009;67:S135-S139.
2. Holmes JF, Mao A, Awasthi S, McGahan JP, Wisner DH, Kuppermann N. Validation
of a prediction rule for the identification of children with intra-abdominal
injuries after blunt torso trauma. Ann Emer Med. 2009 Oct;54(4):528e533.
3. Gaines BA, Rutkoski JD. The role of laparoscopy in pediatric trauma. Semin
Pediatr Surg. 2010;19:300e303.
4. NationalVital Statistics System, NationalCenter forHealth Statistics (CDC).
10 Leading causes of death by age group, Unites States – 2014. Available at:
http://www.cdc.gov/injury/wisqars/pdf/leading_causes_of_death_by_age_
group_2014-a.pdf.
5. Notrica DM. Pediatric blunt solid organ injury: beyond the APSA guidelines. Curr
Surg Rep. 2015;3:1-6.
6. Wegner S, Colletti JE, Van Wie D. Pediatric Blunt Abdominal Trauma. Pediatr Clin
N Am. 2006;243-56.
7. Wisner DH, Kuppermann N, Cooper A, Menaker J, Ehrlich P, Kooistra J, et al.
Management of children with solid organ injuries after blunt torso trauma.
J Trauma Acute Care Surg. 2015;79(2):206-14.
8. Pariset J, Feldman, K, Pari C. The Pace of Signs and Symptoms of Blunt
Abdominal Trauma to Children. Clinical Pediatrics. 2010;49(1):24-8.
9. Drexel S, Azarow K, Jafri MA. Abdominal Trauma Evaluation for the Pediatric
Surgeon. Surg Clin N Am. 2017;97(1):59-74.
10. Houda II WE. Pediatric Trauma. In: Tintinalli JE, Stapczynski JS, Cline DM, Ma OJ,
Cydulka RK, Meckler GD (eds): Emergency Medicine A Comprehensive Study
Guide. 7th ed. New York: The Mac Graw Hill Companies, 2010.
11. Morales C, Correa J, Villegas M. Efficacy and safety of non-operative
40
Hospital between 1994 and 2014, it was concluded that
no patient diagnosed with splenic lesions had died or
had a splenectomy in the last 20 years. The length of
hospitalization decreased over time, despite the increase
in the severity of splenic lesions(19).
In the literature, the surgical treatment percentages
are reported at 8-31% and the conservative treatment
percentages are reported at 70-92%(14,20,21). More com-
monly in recent studies, the surgery ratio is low. In the
study of Henderson et al., the prevalence of surgery was
reported at 8.7%(14). In the study of Rogers et al., 10% of
patients with a high-grade injury (grade IV) were surgi-
cally treated and 80% of them were conservatively man-
aged(22). In our study, 90 children with different traumas
(88%) were observed and the conservative treatment
was applied, and only in 12 children (12%) a surgical
approach was applied.
In conclusion, solid organ injuries due to pediatric
abdominal blunt trauma are generally severe injuries,
with high morbidity and mortality. Nowadays, more
than 90% of pediatric solid organ injuries are success-
fully treated with conservative methods. n
Conflict of interests: The authors declare no con­
flict of interests.
management of blunt liver trauma. Eur J Trauma Emerg Surg. 2011;37(6):591-6.
12. Cherkasov M, Sitnikov V, Sarkisyan B, Degtirev O, Turbin M, Yakuba A.
Laparoscopy versus laparotomy in management of abdominal trauma. Surg
Endosc. 2008;22:228e231.
13. Mandrioli M, Inaba K, Piccinini A, et al. Advances in laparoscopy for acute care
surgery and trauma. World J Gastroenterol. 2016;22:668e680.
14. Sanchez JI, Chaidas CN. Childhood trauma: now and in the new millennium. The
Surg Clin North Am. 1999 Dec;79(6):1503-35.
15. Basaran A, Ozkan S. Evaluation of intra-abdominal solid organ injuries in
children. Acta Biomed. 2019 Jan 15;89(4):505-512.
16. Wesson DE, Cooper A. Pediatric Trauma Pathophysiology, Diagnosis and
Treatment, Taylor and Francis Group, 2006.
17. George W. Holcomb, Aschcraft’s pediatric surgery fifth edition, Saunders
Elsevier, 2010.
18. Lippert SJ, Hartin CW, Ozgediz DE, et al. Splenic conservation: variation between
pediatric and adult trauma centers. J Surg Res. 2013;182(1):17-20.
19. Bardain S. Twenty-years of splenic preservation at a level 1 pediatric trauma
center. J Pediatr Surg. 2015 May;50(5):864-8.
20. Balcioglu ME, Boleken ME, Cevik M, Savas M, Boyacı FN. Blunt renal trauma
in children: a retrospective analysis of 41 cases. Ulus Travma Acil Cerrahi Derg.
2014;20(2):132-5.
21. Sahin H, Akay AF, Yılmaz G, Tacyıldız IH, Bircan MK. Retrospective analysis of 135
renal trauma cases. Int J Urol. 2004 May;11(5):332-6.
22. Rogers CG, Knight V, MacUra KJ, Ziegfeld S, Paidas CN, Mathews RI. High-grade
renal injuries in children is conservative management possible? Urology. 2004
Sep;64(3):574-9.
Year XVII • No. 64 (4/2021)
case report
Adrenocortical carcinoma –
fatal evolution of a rare cancer
in children
Abstract
Adrenocortical carcinoma in children is a rare tumor de­
veloped from the adrenal cortical cells. A very important
step in the diagnosis process is represented by the tumor
biopsy and the immunohistochemical exam of the resection
piece, adding the molecular analysis. The suggestive fin­
dings for the diagnosis are: abdominal or suprarenal gland
mass, virilization syndrome, Cushing or adrenogenital
syn­drome and primary hyperaldosteronism with secondary
hy­per­tension. We present the case of a 13-year-old boy who
was diagnosed in our clinic with adrenocortical carcinoma
and who had a fatal evolution in only 18 days, in the con­text
of metastatic tumor complicated with malignant hy­per­
tension.
Keywords: adrenocortical carcinoma, children
Submission date:
26.10.2021 Carcinomul corticosuprarenal – evoluția fatală a unui tip rar de cancer la copil
Acceptance date: Suggested citation for this article: Scurtu G, Starcea M, Alecsa M, Dumitraş S, Ciobanu A, Ivanov A, Mocanu A, Miron I, Bogos R. Adrenocortical carcinoma –
10.11.2021 fatal evolution of a rare cancer in children. Pediatru.ro. 2021;64(4):41-45.
Introduction
Adrenocortical carcinoma in children (ACC) is a
rare tumor developed from the adrenal cortical cells. It
represents 0.05-0.2% of all type of tumors, its peak of
incidence being in the fourth decade of life and being
responsible for 0.2% of all deaths from cancer(1). The
incidence is 0.2–0.3 new cases per 1 million people/year
worldwide(2). The clinical diagnosis is very difficult to
make without key investigations such as CT scan, MRI,
PET-CT scan and laboratory findings (blood glucose,
cortisol, aldosterone, DHE-S, urinary and blood me-
tanephrine, urinary measurement of homovanillic acid
and vanilmandellic acid).
Case presentation
We present the case of a 13-year-old boy who was
admitted in the oncology department for alteration of
the general condition, large abdomen, dyspnea at small
and medium efforts, nervousness and fatigue, symptoms
that lasted for four weeks. The family took the child at
the regional hospital where the ultrasound described a
scratchy mass of about 105/100 mm, localized in the
left upper side of the abdomen that may develop from
the left kidney. They also took a CT scan that described:
bilateral pulmonary nodules, around 1 cm, localized at
the base of the lungs, that suggested secondary lesions,
Year XVII • No. 64 (4/2021)
pediatru
Rezumat Georgiana
Scurtu1,2,
Carcinomul corticosuprarenal la copii este o tumoră rară, dez­vol­ Magdalena
tată din celulele corticale suprarenale. Un pas foarte important
în procesul de diagnostic este reprezentat de biopsia tumorală și Starcea2,
de examenul imunohistochimic al piesei de rezecție, completate Mirabela
de analiza moleculară. Elementele sugestive pentru diagnostic Alecsa1,2,
sunt: masă abdominală sau suprarenală, sindromul de virilizare, Silvia Dumitraş2,
sindromul Cushing sau adrenogenital, hiperaldosteronismul Antonela
primar cu hipertensiune arterială secundară. Prezentăm cazul
unui băiat de 13 ani care a fost diagnosticat în clinica noastră cu Ciobanu2,
adenocarcinom corticosuprarenal și care a avut o evoluție fatală Anca Ivanov1,2,
în numai 18 zile, în context de tumoră metastazată pulmonar Adriana Mocanu1,
şi hepatic încă de la diagnostic, complicată cu hipertensiune Ingrith Miron1,2,
arterială malignă. Roxana Bogos1
Cuvinte-cheie: carcinom suprarenalian, copii
1. Department of Pediatrics,
“Grigore T. Popa” University
of Medicine and Pharmacy,
Iaşi, Romania
2. Department
of Pediatric Oncology,
“Sf. Maria” Emergency
Clinical Hospital for Children,
Iaşi, Romania
Corresponding author:
without any fluids in the pulmonary cavities. An ex- Magdalena Starcea
E-mail: magdabirm@yahoo.com
tremely large tumor with heterogeneous appearance,
with internal necrosis, compressed the proximity or-
gans, of about 15/12 cm. The left renal vein could not
be seen. There were many secondary lesions seen in the
liver’s VII segment of about 6 cm diameter. The left cor-
ticosuprarenal gland could not be seen. The right kidney
was normal. There was no fluid in the abdominal cavity.
The right iliac crest had a heterogeneous aspect. For
these reasons, the child was transferred to our depart-
ment for further investigations and treatment.
The medical history of the patient mentions mental
retardation since 2014. In the same time, he was di-
agnosed with precocious puberty. From some religious
reasons, the family didn’t investigate further in this
direction. No other chronical diseases were known by
the patient’s mother. In the patient’s family, there were
no genetical syndromes.
The clinical data at the moment of the admission:
the general condition of our patient was severely altered,
with plethoric face, cortisone-related acne (Figure 1),
signs of early virilization (mustache, thoracic and ax-
illary pilosity), stretch marks on his abdomen, supe-
rior limbs and on the thorax (Figure 2). The adiposity
was asymmetrically distributed, especially in the ab-
dominal area. No hepatosplenomegaly or lymph nodes
41
case report

Figure 1. Plethoric face and cortisone-related acne Figure 2. Stretch marks and the abdominal adiposity

were palpable. He had also high blood pressure (HBP),
150/100 mmHg, over the 97.5th percentile for height.
Biological data at the admission
At that point, we had five possible diagnostics:
n Pheochromocytoma – based on HBP and the plethoric
aspect of the patient.
n Medullo or adrenocortical carcinoma – CT scan and
the clinical aspect.
n Adrenogenital syndrome – HBP and the precocious
puberty.
n Left kidney tumor with lung metastases – CT scan
aspect.
n Renal vein and superior vena cava thrombosis – CT
scan aspect.
For the evaluation of heart impact of the HBP, we per-
formed cardiac ultrasound that showed ascended heart,
pushed by the tumor, with a normal structure, slightly
concentric left ventricular hypertrophy (LVH), without
pericardial fluid, with ejection fraction (EF) of 86%.
In the context of the existence of lung and liver me-
tastases, we considered useful to make bone marrow

Table 1 Hematological data

HLG 05.02 09.02 11.02
GA/mmc 9520 9620 9220
PMN (%) 84.7 78.7 74.5
Lymph (%) 9.6 14.1 18.7
Hb (g/dl) 12.6 12.5 12.1
PLT/mL 167,000 213,000 248,000

Table 2 Biochemistry data

Biochemistry 05.02 09.02 17.02
ALT/TGP 129 127 182
AST/TGO 95 123 165
ALKALINE RESERVE 29 32 28
LDH 2093 1821 2098
GLUCOSE 137 71
UREA 14 20 24
CREATININE 0.49 0.49 0.48
VANILMANDELLIC ACID 7.19 mg/24 h

42 Year XVII • No. 64 (4/2021)


aspiration which revealed richly cellulated pleomorphic
aspect, with hyperplasic erythropoiesis, hypergranular
elements in granulopoiesis, and normoplastic megakary-
opoiesis with platelets in pile.
After a few days with a slight amelioration of the
general status, we could perform a tumor biopsy which
revealed corticosuprarenal gland carcinoma. In Figure 3,
we present the typical aspect with necrosis and tumoral
proliferation, in HE coloration, followed by the immuno-
histochemical exam which revealed the specific cellular
marker for this type of tumor.
Figure 3. Necrosis and tumor proliferation, HEx100.
Collection of Dr. Doina Mihăilă from the “Sf. Maria”
Emergency Clinical Hospital for Children, Iaşi
Figure 5. Synapto x 100. Collection of Dr. Doina Mihăilă
from the “Sf. Maria” Emergency Clinical Hospital for
Children, Iaşi
Figure 7. Melan A x 200. Collection of Dr. Doina Mihăilă
from the “Sf. Maria” Emergency Clinical Hospital for
Children, Iaşi
Year XVII • No. 64 (4/2021)
pediatru
After these investigations, we had a certitude diag-
nosis: adrenocortical carcinoma in a child.
Unfortunately, the patient’s general condition dete-
riorated rapidly due to severe hypertension, develop-
ing signs of pulmonary vascular overload, which ne-
cessitated the transfer to the intensive care unit, with
the diagnosis of Cushing syndrome, acute respiratory
failure, and malignant hypertension. The patient per-
formed a chest X-ray which showed accentuated and
thickened intercleidohilar drawing, diffuse veiling
of the left hemithorax and the diaphragmatic cost
Figure 4. Numerous cytonuclear atypia, HEx200.
Collection of Dr. Doina Mihăilă from the “Sf. Maria”
Emergency Clinical Hospital for Children, Iaşi
Figure 6. S100 x 100. Collection of Dr. Doina Mihăilă
from the “Sf. Maria” Emergency Clinical Hospital for
Children, Iaşi
Figure 8. EMA x 100. Collection of Dr. Doina Mihăilă
from the “Sf. Maria” Emergency Clinical Hospital for
Children, Iaşi
43
case report
Figure 9. Chromogranin x 100. Collection of Dr. Doina
Mihăilă from the “Sf. Maria” Emergency Clinical Hospital
for Children, Iaşi
sinus. Heart displayed on the diaphragm with the
transverse diameter increased at the expense of the
lower left arch. The aspect was suggestive for acute
pulmonary oedema.
Because of the poor general condition, with aggravat-
ing dyspnea, polypnea (30 respiration/min), tachycar-
dia (144/min), malignant high blood pressure (200/144
mmHg), the patient was retransferred to the intensive
care unit (ICU). He maintained the severe respiratory
failure (SaO2 87-97%), but he suddenly developed heart
failure, with hypotension (94/54 mmHg) and tachycar-
dia (122-145/min). In the 18th day after admission, he
suffered a cardiorespiratory arrest that did not respond
to the resuscitation maneuvers.
The final diagnosis was left adrenocortical carcinoma,
hepatic and lung metastases, cardiorespiratory failure,
Figure 11. Chest X-ray – acute pulmonary edema
44
Figure 10. Vimentin x 100 . Collection of Dr. Doina
Mihăilă from the “Sf. Maria” Emergency Clinical Hospital
for Children, Iaşi
severe secondary high blood pressure, acute pulmonary
edema, left pleurisy, renal and inferior vena cava throm-
bosis, severe mental retardation, early puberty. Due to
the religious affiliation of the parents, necropsy evalu-
ation was not possible.
Discussion
A very important step in the diagnosis process is
represented by the tumor biopsy and the immunohis-
tochemical exam of the resection piece, adding the mo-
lecular analysis (NGS panel for the genetical diagnosis).
Suggestive findings for the diagnosis are: abdominal or
suprarenal gland mass, virilization syndrome, Cushing
or adrenogenital syndrome, primary hyperaldosteron-
ism. Almost 50% of the adrenocortical carcinomas pro-
duce cortisol, aldosterone and dehydroepiandrosterone.
The pathological diagnosis of adrenocortical carcinoma,
still challenging for its rarity, is based on the recognition
at light microscopy of at least three among nine morpho-
logical parameters, according to the Weiss scoring sys-
tem, introduced 27 years ago(3). The metastatic disease
is more common in children aged above 12 years old,
and the most common sites of metastases are the liver
and the lungs(4). In our case, the metastases were proven
from the first moment, in the lung and liver, just like the
literature mentions. There are some genetic syndromes
recognized to determine CSC in children in their evolu-
tion. Li-Fraumeni syndrome is a rare condition in which
the mutation of p53 gene can determine corticosuprare-
nal tumors. Beckwith-Widemann syndrome associates
macroglossia, macrosomia, organomegaly, and some-
times mass formation (neuroblastoma, Wilms tumor,
hepatoblastoma, masses in the adrenal cortex). Another
entity is familial adenomatous polyposis which implies
multiple polyps localized in the large intestine mucous
which can develop colorectal cancer and suprarenal
gland tumors. The syndrome MEN1 implies parathyroid
tumors, pancreatic tumors and pituitary gland tumors.
In 30-50% of cases they can associate suprarenal gland
masses and in some cases the masses are malignant(5).
Unfortunately, in our case we didn’t have enough time
to performed genetic studies, but the initial anamnesis
didn’t confirm hereditary diseases in the family. The
Year XVII • No. 64 (4/2021)
 pediatru

treatment consists in surgery – elective at the diagnosis
(if possible), chemotherapy (doxorubicin, etoposide, cis-
platin), arterial embolization, and radiotherapy(6). The
rapid fatal evolution of our patient prevented the initia-
tion of any specific oncological therapy, but the place-
ment of the case in the final stage from the beginning,
with systemic metastases, signed a severe prognosis.
Conclusions
Adrenocortical carcinoma is a very rare pediatric on-
cologic pathology, in association with early puberty and
secondary severe untreated high blood pressure. The
respiratory and vascular complications of the secondary
high blood pressure, next to lung and liver metastases,
made impossible the treatment of this case, with a ful-
minant evolution. n
Acknowledgment: Our thanks go to Dr. Doina
Mihăilă for her contribution in the preparation and
interpretation of the biopsy, an essential step in the
diagnosis of this case. Also, we want to thank Lecturer
Bogdan Stana for his guidance in writing this paper.
Conflict of interests: The authors declare no con­
flict of interests.

1. McAteer JP, Huaco JA, Gow KW. Predictors of survival in pediatric adrenocortical Clinic from 1950 to 2017. Horm Res Paediatr. 2018;90:8-18.
References

carcinoma: a Surveillance, Epidemiology, and End Results (SEER) program study.
J Pediatr Surg. 2013 May;48(5):1025-31.
2. Grisanti S, Cosentini D, Laganà M, Turla A, Berruti A. Different management of
adrenocortical carcinoma in children compared to adults: is it time to share
guidelines? Endocrine. 2021 Dec;74(3):475-477.
3. Papotti M, Libè R, Duregon E, Volante M, Bertherat J, Tissier F. The Weiss score
and beyond – histopathology for adrenocortical carcinoma. Horm Cancer. 2011
Dec;2(6):333-40.
4. Gupta N, Rivera M, Novotny P, Rodriguez V, Bancos I, Lteif A. Adrenocortical
Carcinoma in Children: A Clinicopathological Analysis of 41 Patients at the Mayo
5. Wang JG, Mo DC. Regarding the Children’s Oncology Group ARAR0332 Protocol
for Pediatric Adrenocortical Carcinoma. J Clin Oncol. 2021 Sep 20;39(27):3087-
3088.
6. Rodriguez-Galindo C, Krailo MD, Pinto EM, Pashankar F, Weldon CB, Huang L,
Caran EM, Hicks J, McCarville MB, Malkin D, Wasserman JD, de Oliveira Filho
AG, LaQuaglia MP, Ward DA, Zambetti G, Mastellaro MJ, Pappo AS, Ribeiro RC.
Treatment of Pediatric Adrenocortical Carcinoma With Surgery, Retroperitoneal
Lymph Node Dissection, and Chemotherapy: The Children’s Oncology Group
ARAR0332 Protocol. J Clin Oncol. 2021 Aug 1;39(22):2463-2473.

PREZENTARE DE PRODUS
Până la 40% dintre sugari suferă episoade de indigestie nespecifică
(flatulenţă, colici, constipaţie) în primele luni de viaţă(1).

HiPP Comfort, Formulă de lapte specială

HiPP Comfort, Formulă de lapte specială, a fost concepută pentru
a acoperi nevoile nutriționale particulare ale copiilor cu burtici sensibile,
care suferă de balonare, colici și constipație. Compoziția particulară a
HiPP Comfort, Formulă de lapte specială, reglează digestia și în-
moaie scaunul copilului. Această formulă este potrivită pentru regimul
dietetic al colicilor de 3 luni „induse de lactoză”/balonare şi constipaţie
ale sugarilor:
n potrivită de la naştere, ca hrană unică, precum şi de la 6 luni, ca parte
a unei diete mixte;
n proteine hidrolizate, care sunt astfel mai uşor digerate şi reduc epi-
soadele de plâns;
n conţinut redus de lactoză, pentru o digestie îmbunătăţită în cazul
unui deficit temporar de lactază(2,3,4);
Reclamă PED(64)0208

n grăsimi cu structură specială – cu proporţie mare de beta-palmitat,

în mod particular ușor digerabile(5,6);
n combinaţia unică de probiotice (Lactobacillus fermentum) şi prebiotice
(galacto-oligozaharide), pentru susţinerea florei intestinale. n
1. Iacono G et al. Dig Liver Dis 2005; 37: 432-8; Lucassen PLBJ et al. Arch Dis Child. 2001;84:398-403.
2. Arikan D et al. Jclin Nursing. 2008;17:1754-61.
3. Kanabat D et al. J Hum Nutr Diet. 2001;14:359-63.
4. Kearnez PJ et al. J Hum Nutr Diet. 1998;11:281-5.
5. Kennedy D et al. J Clin Nursing. 2008;17:1754-61.
6. Quinlan PT et al. JPGN. 1995;20:81-90.

Year XVII • No. 64 (4/2021)

45
 case report
Rectal bleeding in children –
case report
Iulia Florentina Abstract
Ţincu1,2,
Andrei Intestinal polyps are tumoral masses protruding in the
gas­tro­in­tes­tinal lumen, with various histopathological
Zamfirescu1,2, pat­terns, either as neoplastic or non-neoplastic type, and
Cristian Ioan epi­th­e­lial or non-epithelial type. The classical form of cli­ni­
Nedelcu2,3, cal presentation is rectal bleeding, with or without mu­cus,
Anca Ioana in a normal appearing stool, and only in a minority of cases
Avram2, there is lower abdominal pain. The standard pro­ce­dure
for diagnosis and management of pediatrics co­lo­rec­tal
Doina Anca po­lyps is full colonoscopy. Recent studies have re­vealed
Pleşca1,2 high levels of fecal calprotectin in patients with in­tes­ti­nal
1. Department of Pediatrics, po­lyps and modern sonography empowered the detection
“Carol Davila” University rate of colonic polyps before performing co­lo­no­sco­py. We
of Medicine and Pharmacy,
Bucharest, Romania re­port the case of a 5-year-old boy who was refereed to
2. “Dr. Victor Gomoiu”
our gastroenterology unit with a history of one month of
Clinical Hospital for Children, in­ter­mit­tent rectal bleeding and mild ab­do­mi­nal pain,
Bucharest, Romania with an unremarkable medical history, and with nor­mal
3. “Dr. Carol Davila” Central phy­si­cal and biochemical exam. The abdominal ultra­sound
Military Emergency Hospital, showed abundant blood flow signal in a round pe­dun­­cu­
Bucharest, Romania
la­ted shaped intraluminal mass situated in the lower left
Corresponding author: ab­do­men area, measuring 20/15 mm. The co­lo­no­sco­py
Iulia Florentina Ţincu
E-mail: if_boian@yahoo.com re­vealed a pedunculated left colon polyp that was re­moved
using electroresection. The aim of this report is to draw at­
ten­tion to the importance of hematochezia in chil­dren and
to the need for adherence to actual guidelines re­gar­ding
the endoscopic evaluation of the gastrointestinal tract in
chil­dren.
Keywords: colonic polyp, colonoscopy, hematochezia
Submission date:
26.11.2021 Sângerarea rectală la copii – prezentare de caz
Acceptance date: Suggested citation for this article: Ţincu IF, Zamfirescu A, Nedelcu CI, Avram AI, Pleşca DA. Rectal bleeding in children – case report.
6.12.2021 Pediatru.ro. 2021;64(4):46-50.
Introduction
The intestinal polyp is defined as a tumoral mass
protruding in the gastrointestinal lumen, with various
histopathological patterns, either as neoplastic or non-
neoplastic type, and epithelial or non-epithelial type(1).
In the pediatric population, the main type consists in
single or sporadic epithelial polyps; as many as 84% to 97%
of these are juvenile polyps, with a peak age incidence of
2 to 6 years old, being more prevalent in boys than girls(2).
In terms of malignant transformation, the progression
and recurrence of any type of non-neoplastic epithelial
tumors is highly inexistent(3,4). Rarely, children develop
neoplastic polyps, like an adenomatous one, classified as
tubule-villous adenoma, tubular adenoma, and villous
adenoma(5).
The standard procedure for the diagnosis and manage-
ment of pediatric colorectal polyps is full colonoscopy(6).
46
Rezumat
Polipii intestinali reprezintă mase tumorale proeminente în
lu­me­nul gastrointestinal, cu diverse aspecte histopatologice,
de tip neoplazic sau non-neoplazic, epiteliale sau non­epi­te­lia­
le. Forma clasică de prezentare clinică este sângerarea rec­ta­lă,
cu sau fără mucus, într-un scaun cu aspect normal și doar în
unele cazuri rare asociază și durere abdominală. Pro­ce­du­
ra standard pentru diagnosticul și managementul polipilor
co­­l­o­­rec­­tali pediatrici este reprezentată de colonoscopia
com­­­ple­­tă. Studii recente au evidențiat niveluri ridicate ale
cal­­pro­­tec­­ti­­nei fe­ca­le la pacienții cu polipi intestinali, iar eco­
gra­fia mo­der­nă a crescut rata de detectare a acestora anterior
exa­­mi­­nă­­rii endoscopice. Prezentăm cazul unui copil de sex
mas­­cu­­li­n, în vârstă de 5 ani, adresat departamentului de
gas­­tro­­en­­te­­­ro­­­lo­­­gie pediatrică, având un istoric de scaune cu
sân­ge proas­păt debutate în urmă cu o lună, la care asociază
și du­reri abdominale moderare, fără a avea un istoric medical
re­­mar­­ca­­bil. Examenul clinic şi investigațiile de laborator au
fost în limite normale. Ecografia abdominală a evidențiat o
masă intraluminală rotund-ovalară, având semnal vascular
pre­­zent, situată în cadranul abdominal inferior stâng, cu
di­­men­­siuni de 20/15 mm. Colonoscopia a evidențiat un polip
pe­­dun­­cu­­lat al colonului stâng pentru care s-a practicat elec­
tro­­re­zec­ţie. Scopul acestei comunicări este de a atrage aten­ția
asupra importanței hematocheziei la copii și asupra ne­ce­si­tă­
ții aderării la ghidurile actuale privind evaluarea endoscopică
a tractului gastrointestinal la această vârstă.
Cuvinte-cheie: polip colonic, colonoscopie, hematochezie
Nowadays, modern sonography empowered the detec-
tion rate of colonic polyps before performing colono­
scopy, as a revolutionary screening tool, dependent of
colonic preparation(7).
Case presentation
A previously healthy 5-year-old boy was refereed to
our gastroenterology unit with a history of one month
of intermittent rectal bleeding and mild abdominal pain.
The pain was inconstant, located to the inferior left side
of his abdomen. Rectal bleeding was described as bright
red blood passing through rectum, with a normal stool,
although initially there was a five-day history of diar-
rhea, vomiting and fever. Initially, he had a medical visit
in a local unit and took medication for an infectious
diarrhea, with intestinal antiseptics, antidiarrheal and
probiotics, but the symptoms did not improve and in the
Year XVII • No. 64 (4/2021)
 pediatru

past three weeks he had daily normal bowel movements,

stools appearing as Bristol 4, covered by fresh appear-
ing blood every after day (Figure 1), with no fever or
any other acute illness, with no contact with unhealthy
people, and no history of travel. Colonoscopy revealed a
pedunculated polyp located 20 cm above the anal orifice.
There was no accompanying complains like vomiting,
wight loss, dehydration or fever in the present. This was
the first bleeding event for the patient, and blood in stool
gradually increased. In the meantime, he had normal
food ingestion, no family history for coagulopathies, in-
flammatory bowel disease or polyps. The medical history
was also negative for adenocarcinoma of the digestive
tract or for any family medical records of breast tumor,
brain tumor or ovarian tumor.
On admission day, vital signs showed normal blood
pressure (101/60 mmHg), heart rate 88 beats per minute,
respiratory rate 24 breaths per minute, and temperature
36.5°C. He weighed 16.4 kg. The clinical examination
revealed a well-nourished and hydrated patient, with no
particular skin signs. The abdomen was soft and nondis-
tended, with no pain during superficial palpation and
only a mild tenderness on deep palpation; the perirectal
examination did not reveal any lesions or skin tags. A
surgical examination with digital rectal exam did not
show any palpable mass.
The biological investigation showed minor dropping
in patient’s hemoglobin level (12.5 mg/dl) one month
ago to 10.9 mg/dl on admission. White blood cell count
was 9.4×10 6/μL and platelet count was 366×103/μL.
The screening for electrolytes, renal and liver function
tests were within normal ranges, as well as inflamma-
tory signs (C reactive protein: 1.3 mg/dL, erythrocyte
sedimentation rate: 6 mm/h). Coagulopathies were in-
firmed since international normalized ratio and partial
thromboplastin time were all normal (1.05 and 34.6 s,
respectively). There was a positive determination of fe-
cal calprotectin performed by parents in the ambulatory
(1420 μg/g, normal: <50 μg/g), but other biochemical and
stool cultures were negative. Figure 1. Stool covered by fresh blood

Figure 2. Abdominal
ultrasound showing
intraluminal blood flow
signal mass

Year XVII • No. 64 (4/2021)

47
case report
Figure 3. Endoscopic visualization and the resection of the polyp
An abdominal ultrasound demonstrated no evidence
of intussusception, but an abundant blood flow signal
in a round pedunculated shaped intraluminal mass situ-
ated in the lower left abdomen area, measuring 20/15
mm (Figure 2).
Taking into account the possibility of a colonic juvenile
polyp, the decision for colonoscopy was presented to legal
guardians and we performed endoscopic exploration of
the lower digestive tract, using an an electronic video
Figure 4. Macroscopically aspect of the polyp after
excision
48
endoscope (type CF-Q165L, Olympus Optical, Tokyo,
Japan), under deep sedation performed by the anesthe-
siologist. The colonoscopy revealed a pedunculated polyp
located 20 cm above the anal orifice (Figure 3). This soli-
tary mass was covered by a smooth, bright red and friable
epithelium.
Saline solution was used to lift the submucosal layer and
the mass was removed using electroresection with poly­
pectomy snare, with no bleeding signs of the underlaying
mucosa. The entire exploration of the colon, including the
terminal ileum in the last 10 cm, revealed a normal mu-
cosa with no additional polyps. The recovered polyp was a
21/14/11 mm mass (Figure 4) addressed to the pathology
service, resulting in a light microscopy examination as a
typically aspect of juvenile polyp with large tubular and
cystic lakes over a flattened epithelium.
The patient had a benign evolution, without remarkable
gastrointestinal signs. There were no complications after
polypectomy, and we discharged the patient one day later.
The one-month follow-up visit revealed normal stool and
the decrease level of fecal calprotectin to less than 50 μg/g.
Discussion
Juvenile polyps represent benign hamartomas, with an
incidence according to age between 2 and 10 years old, and
a peak considered at 3-4 years old. Usually, there are no
more than one or two polyps in 80% of cases(8). The classi-
cal form of clinical presentation is rectal bleeding, with or
without mucus, in a normal appearing stool, and no pain
associated(9). Only in a minority of cases there is lower
abdominal pain, indicating the implantation place and
the traction of the colonic tract. The majority of juvenile
polyps are pedunculated, and some of them are sessile; the
patients may experience massive rectal bleeding due to
Year XVII • No. 64 (4/2021)

autoamputation. Bright red blood exteriorized with stool
passage occurs when fecal bolus mechanically traumatizes
the polyp during bowel movement. Depending on its loca-
tion in the colonic segments, the blood tends to be darker
and located in the middle of the evacuated stool. Rectosig-
moid is the elective place of polyps’ location, implicated
in as much as 60-80% of cases; thus, rectal examination
reveals the luminal mass and sometimes there is a pro-
lapsed tissue outside the anus in low rectal polyps(8,10).
Histologically, in children and adolescents, juvenile
polyps (hamartomas) represent up to 85% of all cases, less
than 10 % are adenomas, and only 3 % are hyperplastic(11).
When an adenomatous polyp occurs during histology ex-
amination, mainly in older children and adolescents, one
should take into account the actual guidelines for evalu-
ation, management and follow-up, as part of a careful
evaluation of polyposis syndrome(12,13).
The best way to evaluate colonic polyp in children
is colonoscopy under deep sedation that enables in the
meantime the safe removal and subsequently the micro-
scopic analysis(14). Recurrent colonic polyps are regarded
as rare in children, only 17% of single polyps having a
relapse in the following years(15). Only patients having
more than three juvenile polyps and a positive family his-
tory of colonic polyposis should be evaluated every two or
pediatru
three years in terms of colorectal cancer; even though the
polyp itself is not malignant, the syndrome is associated
with a higher incidence of colorectal neoplasia(12). The use
of colonoscopy in young children takes into account the
risk of sedation side effects and the particular narrow size
of the colonic lumen that makes a great burden for the
endoscopist. Previous experience showed that predicting
the polyp’s location before colonoscopy helps the success
of the procedure. This is why abdominal ultrasonogra-
phy has been attributing an important role as a primary
screening test for predicting the polyps’ location in the
intestinal tract, being both safe and accurate(7). Most of
the false-negative ultrasonographic results are explained
by small polyp size, examinator experience and training,
and by the rectal localization of the polyps. The rate of de-
tection is increased if the exam is performed after colonic
enema preparation, with an ultrasonographic diagnosis in
up to 97% cases; our patient underwent abdominal ultra-
sonography after the initiation of the bowel preparation
for colonoscopy and the polyp was successfully detected
prior to colonoscopy.
Fecal calprotectin (FC) is a protein located in the cy-
toplasm of neutrophils, additionally distributed in the
cytoplasm of monocytes, macrophages and granulocytes,
known for its antimicrobial role(16,17). The most important
Reclamă PED(64)0209
case report
clinical role is in the screening and management of in-
flammatory bowel diseases patients, who release cal-
protectin in the gastrointestinal tract due to leukocyte
recruitment and to activation in the process of inflamma-
tion located in the bowel mucosa through proinflamma-
tory chemokines(18). As a consequence, the destructions of
implicated cells release calprotectin extracted to feces and
thus measurable, in various conditions, such as infectious
diarrhea, eosinophilic colitis, colorectal malignancies and
drugs enteropathies(19,20). Recent studies have revealed
high levels of fecal calprotectin in patients with intestinal
polyps, considered as a part of the highly inflammatory
process within the polyp cells. FC levels are less high than
in inflammatory bowel disease patients, as shown in the
1. Kleinman E, Goulet OJ, Giorgina MV, Sanderson IR, Sherman P, Shneider BL.
References
Walker’s Pediatric Gastrointestinal Disease, Hamilton, Ontario, Canada, 6th edition,
2018.
2. Waitayakul S, Singhavejsakul J, Ukarapol N. Clinical Characteristics of colorectal
polyp in Thai children: a retrospective study. Journal of the Medical Association of
Thailand. 2004 Jan;87(1):41-6.
3. Hood B, Bigler S, Bishop P, Liu H, Ahmad N, Renault M, Nowicki M. Juvenile polyps
and juvenile polyp syndromes in children: a clinical and endoscopic survey. Clin
Pediatr (Phila). 2011 Oct;50(10):910-5.
4. Heiss KF, Schaffner D, Ricketts RR, Winn K. Malignant risk in juvenile polyposis
coli: increasing documentation in the pediatric age group. J Pediatr Surg. 1993
Sep;28(9):1188-93.
5. Tam YH, Lee KH, Chan KW, Sihoe JD, Cheung ST, Mou JW. Colonoscopy in Hong
Kong Chinese children. World J Gastroenterol. 2010 Mar 7;16(9):1119-22.
6. Baek MD, Jackson CS, Lunn J, et al. Endocuff assisted colonoscopy significantly
increases sessile serrated adenoma detection in veterans. J Gastrointest Oncol.
2017;8:636–42;
7. Qu NN, Liu RH, Shi L, Cao XL, Yang YJ, Li J. Sonographic diagnosis of colorectal
polyps in children: Diagnostic accuracy and multi-factor combination evaluation.
Medicine (Baltimore). 2018;97(39):e12562.
8. Lee BG, Shin SH, Lee YA, Wi JH, Lee YJ, Park JH. Juvenile polyp and colonoscopic
polypectomy in childhood. Pediatr Gastroenterol Hepatol Nutr. 2012;15(4):250-255.
9. Campbell AM, Sugarman I. Does painless rectal bleeding equate to a colonic
polyp? Arch Dis Child. 2017 Nov;102(11):1049-1051.
10. Balkan E, Kiriştioğlu I, Gürpinar A, et al. Sigmoidoscopy in minor lower
gastrointestinal bleeding. Arch Dis Child. 1998;78(3):267-8.
11. Thakkar K, Alsarraj A, Fong E, et al. Prevalence of colorectal polyps in pediatric
colonoscopy. Dig Dis Sci. 2012 Apr;57(4):1050-5.
50
Olafsdottir et al. study(21), but the exact value is related
to the size and number of polyps(22). We can benefit today
of noninvasive screening tools like fecal calprotectin and
well-trained ultrasonography(23).
Conclusions
The aim of this report was to draw the attention to
the importance of hematochezia in children and to the
need for adherence to actual guidelines regarding the
endoscopic evaluation of the gastrointestinal tract in
children. n
Conflict of interests: The authors declare no con­
flict of interests.
12. Kay M, Eng K, Wyllie R. Colonic polyps and polyposis syndromes in pediatric
patients. Curr Opin Pediatr. 2015 Oct;27(5):634-41.
13. Kay M, Wyllie R. Pediatric Colonoscopic Polypectomy Technique. J Pediatr
Gastroenterol Nutr. 2020 Mar;70(3):280-284.
14. Latt TT, Nicholl R, Domizio P, et al. Rectal bleeding and polyps. Arch Dis Child. 1993
Jul;69(1):144-7.
15. Fox VL, Perros S, Jiang H, Goldsmith JD. Juvenile polyps: recurrence in patients
with multiple and solitary polyps. Clin Gastroenterol Hepatol. 2010 Sep;8(9):795-9.
16. Roca M, Rodriguez Varela A, Carvajal E, Donat E, Cano F, Armisen A, et al. Fecal
calprotectin in healthy children aged 4-16 years. Sci Rep. 2020 Nov 25;10(1):20565.
17. Rugtveit J, Brandtzaeg P, Halstensen TS, Fausa O, Scott H. Increased macrophage
subset in inflammatory bowel disease: apparent recruitment from peripheral
blood monocytes. Gut. 1994;35(5):669–74.
18. Nisapakultorn K, Ross KF, Herzberg MC. Calprotectin expression inhibits bacterial
binding to mucosal epithelial cells. Infect Immun. 2001;69(6):3692–6.
19. Voganatsi A, Panyutich A, Miyasaki KT, Murthy RK. Mechanism of extracellular
release of human neutrophil calprotectin complex. J Leukoc Biol. 2001;70(1):130–4;
20. Chen CC, Huang JL, Chang CJ, Kong MS. Fecal calprotectin as a correlative marker
in clinical severity of infectious diarrhea and usefulness in evaluating bacterial or
viral pathogens in children. J Pediatr Gastroenterol Nutr. 2012;55(5):541–7.
21. Olafsdottir I, Nemeth A, Lorinc E, Toth E, Agardh D. Value of fecal calprotectin as a
biomarker for juvenile polyps in children investigated with colonoscopy. J Pediatr
Gastroenterol Nutr. 2016;62(1):43–6.
22. Khan F, Mani H, Chao C, Hourigan S. Fecal calprotectin as a future screening tool
for large juvenile polyps. Glob Pediatr Health. 2015;2:2333794X15623716.
23. Di Nardo G, Esposito F, Ziparo C, et al. Faecal calprotectin and ultrasonography
as non-invasive screening tools for detecting colorectal polyps in children with
sporadic rectal bleeding: a prospective study. Ital J Pediatr. 2020;46:66.
Reclamă PED(64)0110
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