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The human intestinal microbiota is a highly intricate structure with a crucial role in promoting health and preventing disease. It consists of diverse microbial communities that inhabit the gut and contribute to essential functions such as food digestion, nutrient synthesis, and immune system development. The composition and function of the gut microbiota are influenced by a variety of factors, including diet, host genetics, and environmental features. In pediatric patients, the gut microbiota is particularly dynamic and vulnerable to disruption from endogenous and exogenous factors. Recent research has focused on understanding the interaction between the gut and kidneys. In individuals with chronic kidney disease, there is often a significant disturbance in the gut microbiota. This imbalance can be attributed to factors like increased levels of harmful toxins from the gut entering the bloodstream, inflammation, and oxidative stress. This review looks at what is known about the link between a child's gut-kidney axis, how dysbiosis, or an imbalance in the microbiome, affects chronic kidney disease, and what treatments, both pharmaceutical and non-pharmaceutical, are available for this condition.

Mutations in RAS, BRAF, PIK3CA, and TP53 are well-established genetic abnormalities in metastatic colorectal cancer (mCRC). However, limited information is available for patients from Eastern Europe, including Romania. In this retrospective analysis, we investigated 104 mCRC patients from the Northeastern region of Romania to determine the frequency, distribution, coexistence, and clinicopathological and molecular correlations of these mutations. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). Patients with KRAS mutant tumors and wild-type TP53 genotype were found to have no personal history of gastrointestinal cancer ( p = 0.02, p = 0.007). KRAS mutations in exon 3 were associated with the female gender ( p = 0.02) and the absence of lymph node invasion ( p = 0.02). PIK3CA mutations were linked to the absence of lymph node invasion ( p = 0.006). TP53 mutations were associated with KRAS mutations in exon 2 ( p = 0.006), ulcerated histopathologic type ( p = 0.04), and G2 differentiation ( p = 0.01). It provides novel insights into genetic variations specific to the population from Northeastern Romania, which has been underrepresented in previous studies within Eastern Europe. Furthermore, our findings enable the development of genetic profiles in a developing country with limited access to specialized genetic tests and facilitate comparisons with other populations.

The diagnosis and management of fragile X syndrome (FXS) have significantly improved in the last three decades, although the current diagnostic techniques are not yet able to precisely identify the number of repeats, methylation status, level of mosaicism, and/or the presence of AGG interruptions. A high number of repeats (>200) in the fragile X messenger ribonucleoprotein 1 gene ( FMR1 ) results in hypermethylation of promoter and gene silencing. The actual molecular diagnosis is performed using a Southern blot, TP-PCR (Triplet-Repeat PCR), MS-PCR (Methylation-Specific PCR), and MS-MLPA (Methylation-Specific MLPA) with some limitations, with multiple assays being necessary to completely characterise a patient with FXS. The actual gold standard diagnosis uses Southern blot; however, it cannot accurately characterise all cases. Optical genome mapping is a new technology that has also been developed to approach the diagnosis of fragile X syndrome. Long-range sequencing represented by PacBio and Oxford Nanopore has the potential to replace the actual diagnosis and offers a complete characterization of molecular profiles in a single test. The new technologies have improved the diagnosis of fragile X syndrome and revealed unknown aberrations, but they are a long way from being used routinely in clinical practice.

(1) Background: Immune thrombocytopenia (ITP) is an acute autoimmune blood disorder that is the main cause of thrombocytopenia in children. It is characterized by a decrease in platelets below 100 × 10 9 /L, and limited evolution with severe complications such as intracranial hemorrhage. The chronic form is defined by the persistence of thrombocytopenia more than 12 months after diagnosis. (2) Methods: We performed a retrospective study over a period of 10 years (1 January 2011-31 December 2020) at the Emergency Clinical Hospital for Children "Sf. Maria", Iasi. The aim of the study was to describe the clinical characteristics and to determine the prognostic factors in immune thrombocytopenia in children. (3) Results: In this study we included 271 children with ITP, comprising 123 females (45.4%) and 148 males (54.6%). The remission rate was higher in males, being 68.9% compared to 56.1% in females. Children with ITP under 9 years of age had a higher remission rate. Children with a platelet count > 10 × 10 9 /L at diagnosis had a higher likelihood-of-remission rate compared to patients who presented initial platelet count below this value. (4) Conclusions: The risk factors highly suggestive for chronicity are: age at diagnosis, female sex, and the number of platelets at the onset of the disease.

Thrombotic microangiopathy can present itself in the form of several clinical entities, representing a real challenge for diagnosis and treatment in pediatric practice. Our article aims to explore the evolution of two rare cases of pediatric thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS) with extremely similar clinical pictures, which, coincidentally, presented at approximately the same time in our hospital. These cases and our literature review demonstrate the multiple facets of thrombotic microangiopathy, which can produce various determinations and salient manifestations even among the pediatric population. TTP and aHUS may represent genuine diagnostic pitfalls through the overlap of their clinical and biological findings, although they develop through fundamentally different mechanisms that require different therapeutic approaches. As a novelty, we underline that COVID-19 infection cannot be excluded as potential trigger for TTP and aHUS in our patients and we predict that other reports of such an association will follow, raising a complex question of COVID-19's implication in the occurrence and evolution of thrombotic microangiopathies. On this matter, we conducted literature research that resulted in 15 cases of COVID-19 pediatric infections associated with either TTP or aHUS. Taking into consideration the morbidity associated with TTP and aHUS, an elaborate differential diagnosis and prompt intervention are of the essence.

Over the past 40 years, the 5-years-overall survival rate of pediatric cancer reached 75-80%, and for acute lymphoblastic leukemia (ALL), exceeded 90%. Leukemia continues to be a major cause of mortality and morbidity for specific patient populations, including infants, adolescents, and patients with high-risk genetic abnormalities. The future of leukemia treatment needs to count better on molecular therapies as well as immune and cellular therapy. Advances in the scientific interface have led naturally to advances in the treatment of childhood cancer. These discoveries have involved the recognition of the importance of chromosomal abnormalities, the amplification of the oncogenes, the aberration of tumor suppressor genes, as well as the dysregulation of cellular signaling and cell cycle control. Lately, novel therapies that have already proven efficient on relapsed/refractory ALL in adults are being evaluated in clinical trials for young patients. Tirosine kinase inhibitors are, by now, part of the standardized treatment of Ph+ALL pediatric patients, and Blinatumomab, with promising results in clinical trials, received both FDA and EMA approval for use in children. Moreover, other targeted therapies such as aurora-kinase inhibitors, MEK-inhibitors, and proteasome-inhibitors are involved in clinical trials that include pediatric patients. This is an overview of the novel leukemia therapies that have been developed starting from the molecular discoveries and those that have been applied in pediatric populations.

Diamond-Blackfan anemia is a rare (6-7 million live births), inherited condition manifesting as severe anemia due to the impaired bone marrow production of red blood cells. We present the unusual case of a six month old infant with a de novo mutation of the RPS19 gene causing Diamond-Blackfan anemia who additionally suffers from severe sinus bradycardia. The infant was diagnosed with this condition at the age of four months; at the age of 6 months, she presents with severe anemia causing hypoxia which, in turn, caused severe dyspnea and polypnea, which had mixed causes (hypoxic and infectious) as the child was febrile. After correction of the overlapping diarrhea, metabolic acidosis, and severe anemia (hemoglobin < 3 g/dL), she developed severe persistent sinus bradycardia immediately after mild sedation (before central venous catheter insertion), not attributable to any of the more frequent causes, with a heart rate as low as 49 beats/min on 24 h Holter monitoring, less than the first percentile for age, but with a regular QT interval and no arrhythmia. The echocardiogram was unremarkable, showing a small interatrial communication (patent foramen ovale with left-to-right shunting), mild left ventricular hypertrophy, normal systolic and diastolic function, and mild tricuspid regurgitation. After red cell transfusion and appropriate antibiotic and supportive treatment, the child's general condition improved dramatically but the sinus bradycardia persisted. We consider this a case of well-tolerated sinus bradycardia and foresee a good cardiologic prognosis, while the hematologic prognosis remains determined by future corticoid response, treatment-related complications and risk of leukemia.

2q37 microdeletion/deletion syndrome (2q37DS) is one of the most common subtelomeric deletion disorders, caused by a 2q37 deletion of variable size. The syndrome is characterized by a broad and diverse spectrum of clinical findings: characteristic facial dysmorphism, developmental delay/intellectual disability (ID), brachydactyly type E, short stature, obesity, hypotonia in infancy, and abnormal behavior with autism spectrum disorder. Although numerous cases have been described so far, the exact mapping of the genotype and phenotype have not yet been achieved., Materials and Methods: In this study we analyzed nine newly diagnosed cases with 2q37 deletion (3 male/6 female, aged between 2 and 30 years old), and followed up at the Iasi Regional Medical Genetics Centre. All patients were tested first with MLPA using combined kits P036/P070 subtelomeric screening mix and follow-up mix P264; after, the deletion size and location were confirmed via CGH-array. We compared our findings with the data of other cases reported in the literature., Results: From nine cases, four had pure 2q37 deletions of variable sizes, and five presented deletion/duplication rearrangements (with chromosomes 2q, 9q, and 11p). In most cases, characteristic phenotypic aspects were observed: 9/9 facial dysmorphism, 8/9 global developmental delay and ID, 6/9 hypotonia, 5/9 behavior disorders, and 8/9 skeletal anomalies-especially brachydactyly type E. Two cases had obesity, one case had craniosynostosis, and four had heart defects. Other features found in our cases included translucent skin and telangiectasias (6/9), and a hump of fat on the upper thorax (5/9)., Conclusions: Our study enriches the literature data by describing new clinical features associated with 2q37 deletion, and possible genotype-phenotype correlations.

Venous thromboembolism (VTE) in children is a rare condition. An increased incidence has been observed in the last few years due to several factors, such as increased survival in chronic conditions, especially chronic kidney disease (CKD), use of catheters, and increased sensitivity of diagnostic tools. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE in children is associated with a two to six times higher mortality risk and a 5-10% prevalence of post-thrombotic syndrome. Overall, 5% of VTE episodes in children are associated with chronic kidney disease. The etiology of VTE in chronic kidney disease covers a wide range of pathologies. Various types of thrombotic complications may occur during long-term use of a chronic dialysis catheter. VTE occurs in 3% of children with nephrotic syndrome (NS). The risks for VTE and arterial thromboembolism (ATE) were particularly high in the first 6 months after the onset of NS. Other causes of VTE are graft rejection due to thrombosis of vascular anastomoses after kidney transplantation (3%) and autoimmune diseases (lupus nephritis, antiphospholipid syndrome). In this state-of-the-art overview, we have reviewed the physiologic and pathologic mechanisms underlying pediatric thrombosis and updated current diagnostic and treatment options, emphasizing personal experience as well.

While the majority of children with recently diagnosed ITP have a benign, self-limiting condition, most often with a spontaneously recovery, 40% of children with ITP progress toward persistent ITP and 10-20% goes toward chronicity. Several clinical scores have been developed with the aim to perform a better monitoring outcome or to differentiate transient vs. persistent ITP (e.g., Donato score). Our paper aims to describe and to compare the most important scores used in the management of ITP in children: bleeding severity scores and chronicity prediction scores. These scores include a combination of different already known risk factors: age, gender, presence of a previous infections or vaccination, bleeding grade, type of onset, platelet count at diagnosis. The real utility of these scores has been a matter of debate and no consensus has been reached so far as to their necessity to be implemented as compulsory tool in the care of children with ITP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Roşu, Spoială, Roşu, Ivanov, Mocanu, Munteanu, Lupu, Miron and Gavrilovici.)

Background: Colon cancer is one the most common forms of cancer in both sexes. Due to important progress in the field of early detection and effective treatment, colon and rectal cancer survivors currently account for 10% of cancer survivors worldwide. However, the effects of anti-cancer treatments, especially oxaliplatin-based chemotherapy, on the quality of life (QoL) have been less evaluated. Although the incidence of severe chemotherapy-induced neuropathy (CIPN) in clinical studies is below 20%, data from real-world studies is scarce, and CIPN is probably under-reported due to patient selection and the patients' fear that reporting side-effects might lead to treatment cessation., Aim: To determine the impact of CIPN on QoL in colorectal cancer patients with a recent history of oxaliplatin-based chemotherapy., Methods: We performed a prospective cross-sectional study in two major Romanian oncology tertiary hospitals-the Regional Institute of Oncology Iași (Iasi, Romania) and the Fundeni Clinical Oncology Institute (Bucharest, Romania). All consecutive patients with colon or rectal cancer, undergoing Oxaliplatin-based chemotherapy that consented to enroll in the study, were assessed by means of two questionnaires-the EORTC QQ-CR29 (quality of life in colon and rectal cancer patients) and the QLQ-CIPN20 (assessment of neuropathy). Several demographical, social, clinical and treatment data were also collected. Statistical analysis was performed by means of SPSS v20. The student t test was used to assess the relationship between the QLQ-CIPN20 and QLQ-CR29 results. Kaplan Meyer-curves were used to report 3-year progression-free survival (PFS) in patients that discontinued chemotherapy vs those that completed the recommended course., Results: Of the 267 patients that fulfilled the inclusion criteria in the pre-specified time frame, 101 (37.8%) agreed to participate in the clinical study. At the time of the enrolment in the study, over 50% of the patients had recently interrupted their oxaliplatin-based chemotherapy, most often due to neuropathy. Almost 85% of the responders reported having tingling or numbness in their fingers or hands, symptoms that were associated with pain in over 20% of the cases. When comparing the scores in the two questionnaires, a statistically significant relationship ( P < 0.001) was found between the presence of neuropathic symptoms and a decreased quality of life. This correlation was consistent when the patients were stratified by sex, disease stage, comorbidities and the presence of stoma or treatment type, suggesting that neuropathy in itself may be a reason for a decreased quality of life. At the 3 year final assessment, median recurrence-free survival in stage III patients was 26.88 mo. When stratified by completion of chemotherapy, median recurrence free-survival of stage III patients that completed chemotherapy was 28.27 mo vs 24.33 mo in patients that discontinued chemotherapy due to toxicity, a difference that did not reach statistical significance., Conclusion: CIPN significantly impacts QoL in colorectal cancer patients. CIPN is also the most frequent reason for treatment discontinuation. Physicians should actively assess for CIPN in order to prevent chronic neuropathy., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Abstract: Children with Down syndrome (DS) have a higher risk of developing acute leukemia than do those without DS. There are few studies in the literature about outcome, survival, and difficulties of treating patients with DS and acute leukemia in a developing country. This study aimed to analyze the outcome, response to treatment, survival, treatment complications, and causes of death in patients with DS and acute leukemia compared with those in patients with acute leukemia without DS diagnosed in the same period of time.We conducted a retrospective observational analysis including a cohort of 21 patients with DS and acute leukemia diagnosed between 2009 and 2018 in 3 hemato-oncology centers (2 pediatric centers and 1 adult hematology center). A group of patients with DS-acute lymphoblastic leukemia (DS-ALL) was analyzed and compared with a group of 165 patients with acute lymphoblastic leukemia without DS, and a group of patients with DS-acute myeloid leukemia (DS-AML) was analyzed and compared with a group of 50 patients with acute myeloid leukemia without DS, which was diagnosed during the same period of time (2009-2018) and treated under similar conditions in terms of both treatment protocols and economic resources.The overall survival rates in children with DS-ALL and DS-AML were 35.7% and 57.1%, respectively (P = .438). The overall survival rate was significantly worse in children with DS-ALL than in those with acute lymphoblastic leukemia without DS (35.71% vs 75.80%, P = .001). We noted that treatment-related mortality in the patients with DS-ALL was high (50%) (infections and toxicities related to chemotherapy); this result was significantly different from that for patients with leukemia without DS (P < .0001). The relapse rate was higher in patients with DS-ALL but not significantly higher than that in patients without DS (P = .13).In contrast, the overall survival rate was better for patients with DS-AML than for those with acute myeloid leukemia without DS (57.1% vs 45.1%, P = .47).Because of the particularities of the host, we suggest that DS-ALL and DS-AML should be considered as independent diseases and treated according to specific protocols with therapy optimization per the minimal residual disease., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Asparaginase is a basic component of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) and has played a crucial role in improving the long-term survival of this disease. The objectives of this retrospective study were to elucidate the toxicity profile associated with asparaginase in children and adolescents with ALL, to analyze the impact of each type of toxicity on long-term outcomes, and to identify risk factors. We analyzed the medical charts of 165 patients diagnosed with ALL at Sf. Maria Iasi Children's Hospital from 2010 to 2019 and treated according to a chemotherapeutic protocol containing asparaginase. The median duration of follow-up was 5 years (0.1-11.5 years). Groups of patients with specific types of toxicity were compared to groups of patients without toxicity. We found the following incidence of asparaginase-associated toxicity: 24.1% clinical hypersensitivity, 19.4% hepatotoxicity, 6.7% hypertriglyceridemia, 4.2% hyperglycemia, 3.7% osteonecrosis, 3% pancreatitis, 2.4% thrombosis, and 1.2% cerebral thrombosis. Overall, 82 patients (49.7%) had at least one type of toxicity related to asparaginase. No type of toxicity had a significant impact on overall survival or event-free survival. Being older than 14 years was associated with a higher risk of osteonecrosis ( p = 0.015) and hypertriglyceridemia ( p = 0.043) and a lower risk of clinical hypersensitivity ( p = 0.04). Asparaginase-related toxicity is common and has a varied profile, and its early detection is important for realizing efficient and appropriate management.

Otitis media (OM) represents a public health matter, being the main cause of preventable hearing loss in pediatric patients. Besides well-established risk factors for developing OM, such as craniofacial abnormalities, prematurity, low birth weight, or tobacco exposure, there is evidence that obesity could be associated with a high incidence of OM. Our aim is to perform a literature review on the state of current published research on the relationship between OM and obesity and to discuss the interconnectivity between these two entities. We conducted an electronic search in PubMed and EMBASE databases. Out of 176 references, 15 articles were included in our study. Our findings suggest that obesity and overweight might be risk factors for developing OM, and vice versa. The main mechanisms for developing OM in obese patients include alteration in cytokine profile, increased gastroesophageal reflux, and/or fat accumulation. Conversely, ear infections exposure might increase the risk of obesity, mostly by taste changes through middle ear cavity inflammation.

Background: This study evaluates the main (para)clinical aspects and outcomes in a group of Romanian children diagnosed with acute lymphoblastic leukemia (ALL), under the conditions of antileukemic treatment according to an adapted ALL IC Berlin-Frankfurt-Munster (BFM) 2002 protocol., Methods: We performed a retrospective single-center study of 125 children diagnosed with ALL between 2010 and 2016. Standard forms were used for data collection of variate clinical and paraclinical parameters., Results: The children were predominantly male (64.8%) and their median age at diagnosis was 5 years. A total of 107 patients were diagnosed with precursor B-cell acute lymphoblastic leukemia (BCP)-ALL and 18 with T-cell acute lymphoblastic leukemia T-ALL. Multiplex reverse transcription polymerase chain reaction RT-PCR assay for ETV6-RUNX1, BCR-ABL, E2A-PBX1, KMT2A-AFF1, and STIL-TAL1 fusion genes was performed in 111 patients. ETV6-RUNX1 translocation was detected in 18.9% of patients, while BCR-ABL1 and E2A-PBX1 rearrangements were seen in 2.7% and 3.6%, respectively. Complete remission at the end of induction phase was obtained in 89.6% of patients. The overall relapse rate was 11.2%, with 11 early and 3 late relapses. The 5-year overall survival rate in BCP-ALL was 81.6% and in T-ALL 71.4%., Conclusions: The 5-year overall and event-free survival rates in our study were slightly lower than those reported in developed countries, so the patients' outcomes are encouraging.

Rationale: Erythema multiforme (EM) is an immune-mediated disease with mucocutaneous localization and plurietiologic determinism. The term "multiforme" refers to the variety of aspects that the lesions can take from patient to patient and during evolution in a single patient., Patient Concerns: We have selected 2 cases of small children diagnosed with different etiology of EM to illustrate the importance of a correct and fast diagnosis. Case 1 involves a 2-year-old girl from a rural area who presented with fever and pruritic erythematous papular eruption. The onset of the symptoms was 3 days before presentation with fever and ulcerative lesions on the oral and labial mucosa, followed by the appearance of erythematous macular lesions, with progressive confluence to intense pruritic patches. The 2nd involves a 2-year-old boy with fever, loss of appetite, productive cough, and petechiae. He had corticosensible immune thrombocytopenia from the age of 6 months, with many recurrences. The patient received treatment with ampicillin/sulbactam and symptomatics for an erythemato-pultaceous angina. During the 2nd day of treatment the patient developed an erythematous macular eruption on the face, scalp, trunk, and limbs, with bullae formation., Diagnoses: The 1st patient was diagnosed based on biologic findings: positive inflammatory syndrome, elevated level of anti-Mycoplasma pneumoniae immunoglobulin M antibodies and immunoglobulin E. Histopathologic examination described papillary dermal edema, inflammatory infiltrate, and lymphocyte exocytosis. In the 2nd case, the hemoleucogram identified 12,000/mm platelets and the medulogram aspect was normal. Serology for Epstein-Barr virus was negative. The diagnosis was EM secondary to M pneumoniae infection in case 1 and secondary to administration of ampicillin/sulbactam in case 2., Interventions: In both cases, etiopathogenic treatment consisting of steroidal antiinflammatory drugs, antihistamines was administered. Because of specific etiology, the 1st case received antibiotics., Outcomes: The evolution was favorable in 10 to 14 days; the patients were discharged after etiopathogenic treatment consisting of steroidal antiinflammatory drugs, antihistamines, and/or antibiotics., Lessons: Performing a detailed clinical examination, medical history of drug use, infection or general diseases can establish a good diagnosis of EM. Histopathologic examination can help. The treatment is etiologic, pathogenic, and symptomatic. EM usually has a self-limited evolution.

Unlabelled: Acute leukemia is the most common malignancy in children, being mostly produced by such chromosomal abnormalities as translocations or inversions causing gene fusion. Different clinical studies showed that translocations identified in ALL (acute lymphoblastic leukemia) and AML (acute myeloblastic leukemia) may be used to classify patients into risk groups., Aim: To detect three fusion genes that have been proven very important in patient classification: t(9:22)p190, t(4:11) and t(12:21)., Material and Method: We conducted a prospective study on 30 patients with acute leukemia diagnosed in the interval September 2009 - September 2010 at the Iasi Hemato-Oncology Unit of Saint Mary Hospital for Children., Results: We found t(9:22)p190 in two patients, t(4:11) in two patients and t(12:21) in one patient. From the total of 30 patients, 7 were considered at high-risk, 3 were diagnosed with AML, and 20 were considered at standard-risk., Conclusions: Day 33 can still be considered the reference time in the evaluation of treatment response; patients with BCR-ABL seem to have a worse prognosis than those who do not have this translocation. The detection of fusion genes is very important in patient classification.

Langerhans cell histiocytosis is a group of idiopathic disorders characterized by the proliferation of cells of the mononuclear phagocyte system and the dendritic cell system. From the clinical point of view there are 3 forms of histiocytosis encountered in child pathology: acute, disseminated called Abt-Letterer-Siwe (it usually affects children under 2 years of age), eosinophilic granuloma and the intermediate clinical form called Hand-Schuller-Christian disease. We present the case of a premature born child that had, even from the day she was born, a rash disseminated on the entire surface of the body associated with enlarged lymph nodes, hepatosplenomegaly and thrombocytopenia. The diagnosis of Langerhans cell Histiocytosis is difficult to establish and this case is an example that confirms it. Therefore, we present the difficulties in diagnosing this case and its particular evolution.