Conect4children (c4c) and the Greek network of pediatric clinical studies HELPNet Maria Kouti, Vasiliki Toumpoulidou, Elias Iosifidis, Nikos Karantaglis, Varvara Noutsou, Emmanuel Roilides
154
REVIEW ARTICLES
Kingella kingae as a pathogenic agent of pediatric infections
Varlamis Sotirios, Kyriazidi Maria Anna, Mitka Stella, Mavridou Maria, Chatzidimitriou Maria
166
Bone age: A Key Diagnostic Tool in Pediatric Endocrinology
Eugenia Chalari, Sofia Spirakou, Garyfalia Mageira, Iliana Bani, Anastasios Serbis
182
Immunopeptidomics of major histocompatibility complex-MHC in pediatrics
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192
CASE REPORT
Microprolactinoma presenting as galactorrhea in an adolescent: diagnostic and therapeutic approach
Phenotypic and molecular characterization of Streptococcus pyogenes isolates from pediatric infections using next-generation sequencing
Elizabeth-Barbara Tatsi,
Maria-Myrto Dourdouna, George Paradeisis, Angeliki Stathi, Theano Georgakopoulou, Foteini Koutouzi, Anastassios Doudoulakakis, George Kalogeras, Levantia Zachariadou, Christos Hadjichristodoulou, Athanasios Michos
Abstract
Elizabeth-Barbara Tatsi
Maria-Myrto Dourdouna Foteini Koutouzi
Athanasios Michos
Infectious Diseases and Chemotherapy Research Laboratory, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital
George Paradeisis
Angeliki Stathi
Levantia Zachariadou
Department of Microbiology, "Aghia Sophia" Children's Hospital
Theano Georgakopoulou
Christos Hadjichristodoulou
National Public Health Organization
Anastassios Doudoulakakis
George Kalogeras
Department of Microbiology, "P. & A. Kyriakou" Children's Hospital
Introduction: An increase in Group A Streptococcus (GAS) infection after the peak of the COVID-19 pandemic raised concerns regarding a potential shift in GAS virulence. The study aimed to assess the phenotypic and molecular characteristics of GAS isolated from Greek children with streptococcal infections.
Methods: GAS isolates were prospectively collected from children aged 0-16 years with invasive GAS (iGAS) and non-iGAS infections in 2023-2024. Antimicrobial susceptibility testing with disk-diffusion method and Etest, emm-typing, and study of virulence factor (VF) and antimicrobial resistance genes with next generation sequencing (NGS) were performed.
Results: This study included 867 isolates collected from children (506/867, 58.4% boys) with median age of 5.7(IQR:3.7-8.0) years. From these isolates, 53/867(6.1%) were iGAS. The most common emm-types were emm1(251/867, 29.0%) and emm12(228/867, 26.3%). Antimicrobial resistance to erythromycin was 9.9%(86/867) and to clindamycin 4.6%(40/867). Emm1 was associated with iGAS(p-value<0.001) and fatal outcome(p-value=0.001). NGS was performed in 53 iGAS και 42 non-iGAS isolates. Τhe majority (30/39, 76.9%) of emm1 isolates belonged to the Μ1UK lineage. Statistically significant differences were noted in the VF genes cpa, sda, SpeA, SpeJ, sic, which were more frequent in iGAS and in prtF2, sfbI/prtF1, sfbII/sof, sfbx, mf2, sdn, enn, mrp, SpeC, ssa, rib, which were more frequent in non-iGAS. ErmB was associated with erythromycin (p-value=0.003) and clindamycin (pvalue=0.021) resistance.
Conclusions: Εmm1 and emm12 are prevalent in our country. Εmm1 has been associated with invasive disease and fatal outcome of GAS infections. The M1UK is the main prevalent genetic subtype, as it has been described in other European countries.
Keywords: Streptococcuspyogenes, Group A Streptococcus, Invasive infection, Next-Generation Sequencing (NGS)
cpa: Collagen binding protein of group A streptococci gene
SPSS 28 (IBM, Νew York, USA). Το επίπεδο στατιστικής σημαντικότητας ορίστηκε στο 0,05 (p-value<0,05).
Αποτελέσματα Κατά την περίοδο 1/1/2023-31/12/2024, συλλέχθηκαν 867 στελέχη GAS τα οποία απομονώθηκαν από παιδιά [506/867 (58,4%) αγόρια, διάμεση (IQR) ηλικία:5,7 (3,7-8,0) έτη] με
(53/867, 6,1%) και μη
(8/53, 15,1%),
(165/814, 20,3%).
(814/867, 93,9%)
(10/867,
(31/53, 58,5%) και
Emm Τυποποίηση
Συνολικά, στα 867 στελέχη ανιχνεύτηκαν 40 διαφορετικοί emm-τύποι. Οι επικρατέστεροι emm-τύποι ήταν ο emm1 (251/867, 29,0%), ο emm12 (228/867, 26,3%), ο emm89 (76/867, 8,8%) και ο emm28 (58/867, 6,7%). Στα διεισδυτικά στελέχη, ανιχνεύτηκαν 11 διαφορετικοί emm-τύποι. Οι συχνότεροι τύποι ήταν οι emm1 (31/53, 58,5%), και emm12 (10/53, 18,9%). Στα μη διεισδυτικά στελέχη, ανιχνεύτηκαν 38 διαφορετικοί emm-τύποι και οι επικρατέστεροι ήταν οι emm1 (220/814, 27,0%), emm12 (218/814, 26,8%) και emm89 (74/814, 9,1%). O emm1 ήταν πιο συχνός στις διεισδυτικές
(31/53, 58,5%),
(220/814, 27,0%) (p-value<0,001). O emm12 δεν συσχετίστηκε με τη διεισδυτικότητα (p-value=0,260).
Οι emm τύποι των στελεχών από τα
emm1 (8/10, 80,0%) και emm12 (2/10, 20,0%). O emm1 συσχετίστηκε με την θανατηφόρο έκβαση (p-value=0,001).
(10/95).
και ermA (n=1/6)]
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Το conect4children (c4c)
HELPnet
conect4children Stichting (c4c-S).
Innovative Medicines Initiative 2 (Horizon 2020, Grant Agreement 777389).
Correspondence
Emmanuel Roilides
Konstantinoupoleos 49, 54642 Thessaloniki
Τ. +30 2310 892444
M. +30 6937442644
e-mail: roilides@auth.gr
conect4children (c4c) and the Greek network of pediatric clinical studies HELPNet
Maria Kouti, Vasiliki Toumpoulidou, Elias Iosifidis, Nikos Karantaglis, Varvara Noutsou, Emmanuel Roilides
Abstract
Background: Despite significant legislative progress such as the Pediatric Regulation in the EU and the Pediatric Research Equity Act in the US, almost half of medicines used in children remain off-label. Ethical and methodological challenges, combined with the limited market incentives for pediatric research, continue to hinder the development of safe and effective therapies for the pediatric population.
Objective: To present the European pediatric clinical research network conect4children (c4c) and its Greek National Hub, HELPnet, highlighting their role in strengthening and harmonizing pediatric clinical trials in Europe, as well as the transition to the new sustainable entity conect4children Stichting (c4c-S).
Methods: The c4c initiative, funded by the Innovative Medicines Initiative 2 (Grant Agreement 777389), established a pan-European public–private partnership involving 46 organizations across 21 countries. Through the creation of 20 National Hubs, including HELPnet in Greece, the network connected national pediatric centers with the European central point of contact and provided training, feasibility advice, and data standardization tools.
Results: The project strengthened the conduct of multinational pediatric clinical trials by developing an integrated infrastructure of research centers, expert networks, and harmonized operational processes. Over 450 experts contributed to the Strategic Feasibility Advice service, and a dedicated Training Academy promoted education in pediatric pharmacology and clinical research. The Greek HELPnet enhanced visibility and participation of national research sites in European studies.
Conclusions: The c4c network has transformed pediatric research in Europe into a coordinated, sustainable structure. The establishment of c4c-S ensures long-term continuity, providing a single-entry point for efficient and ethically robust pediatric drug development.
Keywords: Pediatric clinical trials; conect4children Stichting; off-label; European research networks; pediatric drug development
Maria Kouti
Vasiliki Toumpoulidou
Elias Iosifidis
Nikos Karantaglis
Varvara Noutsou
Emmanuel Roilides
Unit of Coordination and Conduct of Clinical Studies, 3rd Department of Pediatrics, Aristotle University of Thessaloniki
το c4c στο conect4children Stichting
(c4c-S)
Βιβλιογραφία
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Kingella kingae as a pathogenic agent of pediatric infections
Varlamis Sotirios, Kyriazidi Maria Anna, Mitka Stella, Mavridou Maria, Chatzidimitriou Maria
Abstract
Kingella kingae is increasingly recognized as a significant etiological agent of invasive infections in early childhood, particularly among children aged 6 to 36 months. Once considered a rare pathogen, its identification has markedly improved over recent decades due to the development of advanced culture techniques and the application of sensitive molecular diagnostic methods. K. kingae is a Gram-negative, facultatively anaerobic coccobacillus, classified within the HACEK group, and commonly colonizes the oropharynx of young children. Transmission occurs through respiratory secretions. Today, K. kingae is acknowledged as a leading cause of osteoarticular infections in children. It has also been detected in cases of bacteremia, endocarditis, and, less frequently, in infections of the respiratory tract, central nervous system, and soft tissues. Except for endocarditis, clinical presentations are typically mild, with a moderate inflammatory response, which can complicate diagnosis. Endocarditis caused by K. kingae is characterized by high-grade fever and elevated inflammatory markers. Endocarditis may be complicated by embolic events, posing a risk of serious neurological deficits. Isolation of the pathogen from synovial fluid cultures is enhanced when blood culture bottles are used. Molecular techniques, such as real-time PCR, significantly improve detection rates, particularly in culture-negative cases, and allow for timely therapeutic intervention. Lack of clinical suspicion and failure to apply appropriate diagnostic methods may result in underdiagnosis and delayed treatment.
της K. kingae περιλαμβάνουν τη συμβατική PCR (conventional PCR) (61), τη RealTime PCR (RT-PCR) (62,63) και τη multiplex PCR (64),
K. kingae με
Haldar et al. (64) αναζήτησαν
K.kingae
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Correspondence
Anastasios Serbis
Τ. +30 2651099602
Μ. +30 6973303018
e-mail: aserbis@uoi.gr
Eugenia Chalari
Sofia Spirakou
Garyfalia Mageira
Iliana Bani
Anastasios Serbis
Pediatric Clinic, Department of Medicine, University of Ioannina
REVIEW ARTICLES
Bone age: A Key Diagnostic Tool in Pediatric Endocrinology
Eugenia Chalari, Sofia Spirakou, Garyfalia Mageira, Iliana Bani, Anastasios Serbis
Abstract
Introduction: Bone age (BA) assessment is a fundamental tool in the daily practice of Pediatric Endocrinology, used to evaluate skeletal maturation across a wide range of physiological and pathological conditions. Moreover, in recent years, it has found applications beyond the clinical setting. The aim of this review is to provide a concise overview of the physiological and pathological factors influencing BA, the available methods for its assessment, and its contemporary applications in pediatric endocrinology.
Methods: Following a comprehensive review of the relevant literature, the physiological determinants of skeletal maturation and both traditional and novel methods of BA assessment are presented. The clinical advantages and limitations of these methods are also discussed, along with the conditions and disorders associated with delayed or advanced BA. Results: The review highlights the pivotal role of BA assessment in the diagnosis and follow-up of conditions such as precocious and delayed puberty, congenital adrenal hyperplasia, thyroid disorders, obesity, and other endocrine diseases. The use of BA in non-clinical contexts, such as age estimation in migrants or athletes, is accompanied by significant limitations due to the lack of validated methods across diverse populations.
Conclusions: BA remains a key diagnostic and prognostic tool in Pediatric Endocrinology, with its use being expanded by emerging technologies such as artificial intelligence algorithms. However, its application requires caution and critical interpretation, both in clinical and non-clinical settings, due to inherent scientific, technical, and ethical limitations.
Keywords: bone age, pediatric endocrinology, growth, endocrine disorders
Κατάλογος
ACTH: Adrenocorticotropic Hormone
AI: Artificial Intelligence
BA: Bone Age
CASAS: Computer Aided Skeletal Age Scoring
CNNs: Convolutional Neural Networks
GH: Growth hormone
GnRH: Gonadotropin Releasing Hormone
GP: Greulich-Pyle
IGF: Insulin-like Growth Factor
MRI: Magnetic Resonance Imaging
ROIs: Regions of interest
SGA: Small for Gestational Age
TSH: Thyroid Stimulating Hormone
TW: Tanner-Whitehouse
ΟΗ:
1.
2.
Οιστρογόνα
Σ. McCune-Albright
Σ. Sotos
Σ. Beckwith- Wiedemann
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(Major Histocompatibility Complex - MHC)
e-mail: alexis.mavroudis@
Correspondence
Alexios Mavroudis
MD,MSc.
Syntagmatarchou Davaki 11 Kallithea 17672
T. +30 6978699611
e-mail: alexis.mavroudis@ yahoo.gr
Immunopeptidomics of major histocompatibility complex-MHC in pediatrics
Alexios Mavroudis
Introduction: The major histocompatibility system is a biological process of antigen recognition and gene expression associated with the body’s defense.
Purpose: Study of the mechanisms of molecular conformation (MHC) at the cellular level and genetic interaction in the manifestation of diseases.
Material: An international literature search was conducted in the electronic databases Google Scholar and PubMed.
Method: The method followed is secondary as it draws on data from research and expert studies highlighting the immunopeptidome of the Major Histocompatibility Complex - MHC) in pediatrics.
Results: The immune system functions uniquely in each individual, with variations in the quantity and quality of antibodies produced against specific antigens, as well as in the ability to respond to pathogens. This individualization of the immune response is influenced by the genetic diversity of molecules expressed on the surface of cells in each organism. At the same time, separate pathways of expression of class I and II immunopeptides are reported, resulting in the activation of unique reactions in the differential diagnosis of diseases.
Conclusions: Immunopeptidomics is a modern field of disease recognition and progression with a particular function in the molecular identification of diseases according to the standards of personalized medicine.
. Marek Wieczorek, Esam T Abualrous, Jana Sticht, Miguel Álvaro-Benito, Sebastian Stolzenberg, Frank Noé et al.Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Front Immunol. 2017 Mar 17:8:292. (8)
ΤΑΡ: Τransporter associated with antigen processing
TSA: Τumor Specific Antigens
DQA1*05:01, DQA1*02:01, DQA1*03 και DQB1*03:02
DQB1*0302, DQB1*0201 και DQB1*0602
Αντιγόνα όρχεως/καρκίνου NY-ES01
Αντιγόνα σχετιζόμενα με πρωτεΐνες του θερμικού στρες. HSPPC-96
Αδόκιμη έκφραση σε κύτταρα όγκων. Δεν ευρίσκονται σε φυσιολογικούς, πλήρως διαφοροποιημένους ιστούς
Παθολογικά αναδιπλωμένες πρωτεΐνες
που
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IV σε μασχάλες-μαστούς-εφήβαιο, ΒΣ = 55,8Kg(50-85η ΕΘ), Υ = 161,3cm(50η ΕΘ)], πλην
Πραγματοποιήθηκε
(PRL): 138ng/ml (0 min), 132ng/ ml (20 min)
Correspondence
Elpis-Athina Vlachopapadopoulou
Thivon & Levadeias, Athens 11527, Greece
T. +30 213 2009851
M. +30 6932247228
e-mail: elpis.vl@gmail.com
Microprolactinoma presenting as galactorrhea in an adolescent: diagnostic and therapeutic approach
Background: Prolactinomas account for more than 50% of anterior pituitary tumors, are usually benign and rare in adolescence (1-10/100,000). Clinically, they present with galactorrhea, delayed puberty, menstrual disturbances and infertility. Diagnosis relies on measurement of prolactin (PRL) levels and pituitary MRI with contrast. First-line treatment is cabergoline.
Methods: We report a 15-year-old girl with a 7-month history of galactorrhea. Menarche occurred at 1110/12 years, with regular menses lasting 4–6 days every 25–28 days. Physical examination was unremarkable [Tanner stage IV for axillae-breasts-pubic area, Weight=55.8 kg(50–85th pc), Height=161.3 cm(50th pc)], except for milky nipple discharge.
Maria-Konstantina
Georgiadou
Anastasia Konidari
2nd Department of Pediatrics, “P. & A. Kyriakou” Children’s Hospital, Athens
Maria-Margarita Rossolatou
Elpis-Athina Vlachopapadopoulou
Department of Endocrinology, “P. & A. Kyriakou” Children’s Hospital, Athens
Nikolaos Siskas
Private Radiologist, “Magnetic Tomography of Lesvos,” Mytilene
Results: Extensive laboratory evaluation was normal, except for elevated morning levels in two occasions PRL: 138ng/ml (0 min), 132ng/ml (20 min) and repeat 110.5ng/ml (ref. 1.8–29.2ng/ml), confirming hyperprolactinemia. Nipple discharge cytology was negative. Pituitary MRI revealed a hypovascular lesion measuring 6×5×7 mm, consistent with adenoma. The diagnosis of microprolactinoma was established and cabergoline was initiated at 0.5 mg/week. After one month, PRL decreased but remained above normal, while galactorrhea persisted. Consequently, the cabergoline was escalated to 0.5mg twice weekly maintained to date. Over a two-year follow-up period, patient remained asymptomatic, with normal PRL levels and progressive reduction of the microprolactinoma on annual MRI scans. Conclusions: Galactorrhea in adolescence is abnormal requiring endocrinological evaluation. Elevated PRL levels and MRI findings support the diagnosis of prolactinoma. Cabergoline is effective and well-tolerated. Long-term monitoring (PRL, MRI, clinical) is necessary to detect recurrence and assess remission. Prognosis is excellent, especially in microprolactinomas with good compliance.
φυσιολογικά, με ΑΠ = 108/50mmHg και Σφ = 67/min. Στην αντικειμενική
υπήρξαν παθολογικά ευρήματα, πλην γαλακτώδους εκκρίματος θηλών. Πραγματοποιήθηκε εκτενής εργαστηριακός έλεγχος ορού, συμπεριλαμβανομένων ορμονών που ήταν φυσιολογικός (Πίνακας 1), πλην αυξημένων επιπέδων PRL: 138ng/ml (στα 0 min) και 132ng/ml (στα 20 min), η οποία επανελήφθη και ανευρέθη 110,5ng/ml (στα 0 min) (με φ.τ = 1,8-29,2ng/ml), συμβατή με διάγνωση υπερπρολακτιναιμίας. Για τη διερεύνηση
ΕΘ:
Σφ:
FDA:
MRI: Magnetic Resonance
PEG-test: PolyEthylene
Glycol precipitation test
PRL: Prolactin (Προλακτίνη)
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2. Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, et al. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 2, specific diseases. Nat Rev Endocrinol. 2024 May 1;20(5):290–309.
3. Yang Y, Ke X, Duan L, Yang H, Gong F, Pan H, et al. Clinical Characteristics and Outcomes of Prolactinomas in Children and Adolescents: A Large Retrospective Cohort Study. Journal of Clinical Endocrinology and Metabolism. 2024 Sep 1;109(9):e1741–9.
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Patient With Prolactinoma. Journal of Clinical Endocrinology and Metabolism. 2023 Sep 1;108(9):2400–23.
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ΣΥΝΑΔΕΛΦΙΚΑ
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2.
3. Βραβευμένες
4. Ερευνητικές μελέτες
5.
6.
7. Επίκαιρα θέματα
τραπεζών
8. Θέματα εκπαίδευσης και οργάνωσης υγείας
9. Ενδιαφέρουσες περιπτώσεις
10. Σύντομα νέα
11. Βραχείες δημοσιεύσεις
12. Επιστολές προς τη σύνταξη
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14.
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