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Introduction Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Its outcome in India is not as good as that in the western world. One of the important reasons for lesser survival rates is opportunistic infections, including invasive fungal infections (IFIs). Antifungal prophylaxis (AFP) in ALL children is routinely not followed. However, owing to its incidence in high-risk ALL, this study is focused on the use of AFP in those children. Objectives This retrospective study investigated the role of AFP in newly diagnosed children with high-risk ALL on intensive blocks of therapy on regimens B and C of the United Kingdom Acute Lymphoblastic Leukemia 2003 protocol. Materials and Methods The study was conducted in a tertiary care center from 1st December 2013 to 31st December 2019 and included children with ALL from 1 to 18 years of age. Routine AFP with voriconazole was commenced for high-risk ALL children from 1st July 2017 onward in our center. We analyzed data of all IFIs in children before and after AFP with National Cancer Institute high-risk status who had been started on regimen B induction and regimen B or C consolidation and intensification phases. Results A total of 55 children with high-risk ALL were included in the study. The median age was 4 years, with the majority being between the age of 1 and 10 years (38 out of 55; 65%) and predominantly male (36 out of 55; 69%). Total incidence of IFI in our cohort was 51% (28 out of 55). A significant number of children (16 out of 22 [70%]) who were not on prophylaxis developed IFI versus children (12 out of 33 [28%]) on prophylaxis (p = 0.008). The most common organisms isolated were Candida parapsilosis and Candida tropicalis. Children not receiving AFP were found to be 4.7 times (95% confidence interval: 1.44–15.13) more likely to get IFI than the ones receiving AFP. The presence of concurrent bacterial infection increases the risk of IFI (p = 0.04). Conclusion The incidence of IFI was high in high-risk ALL children who were not on AFP. The introduction of routine AFP reduced the incidence of IFI.

Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient’s primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis.

A 5-year-old boy presented with redness and watering in his left eye for 3 days. The child was on treatment for pre B-cell acute lymphoblastic leukaemia (ALL). At the time of diagnosis of ALL, he had presented to the hospital with fever for 2 weeks’ duration and found to have

Introduction The overall cure rate of childhood cancers is above 79% in the developed world, whereas in the developing world, like in India, it is around 50%. It is vital to know the routes of presentation and factors affecting the presentation of childhood cancers in primary, secondary, and tertiary care to design a better survival strategy in childhood cancer. Objective The aim of this study was to know the factors affecting the time to diagnosis and time to treatment in children with cancers in a single center in South India. Materials and Methods It was a retrospective cohort study of children diagnosed with cancer between January 1, 2014 and December 31, 2016 at the pediatric oncology unit, KMC Hospital Mangalore, India. The patient interval, time to diagnosis, patient's family, economic background, parental education, and referral pattern were recorded, and its impact on the time taken to diagnosis was studied. The data was analyzed using SPSS 20.0 software. Results Out of 111 children, 72 were boys (64.8%). Fifty-one (46%) children belonged to the less than 5-year age group. The most common cancer was acute lymphoblastic leukemia, diagnosed in 50% (56/111) children, followed by acute myeloid leukemia in 14/111(12.6%), brain tumors in 9 (8.1%), and neuroblastoma in 10 (9%) children. The median patient interval/patient delay was 14 days (1–90 days), referral interval was 14 days (1–150 days), and overall time to diagnosis was 41 days (1–194 days). The first contact was the pediatrician in 86/111 (77.4%). Sixty-four percent (71/111) referral came from a secondary care hospital, and the remaining from the outpatient clinics. There was no difference in sex and patient interval (p = 0.278) and overall time to diagnosis (p = 0.4169), age (p = 0.041), mother’s education (p = 0.034), and type of cancer (p = 0.013) were three critical factors that determined the time to diagnosis. Conclusion Majority of the children diagnosed with cancer presented via referral from pediatricians. An equal number of them were referred to as routine and emergency patients. Age, mother's education, and type of cancers were the crucial factors associated with the overall time taken to diagnosis.

JMML is a rare aggressive type of leukaemia seen in children. It is often seen with syndromes such as Noonan, and neurofibromatosis type 1. Rarely it can be a sporadic event. The pathogenesis of myeloproliferation in this condition is due to the activation of the MAPK-RAS pathway. We here report an association of JMML having mutations in two known disease-causing genes PTPN11 and ASXL1 in a child with neurodevelopmental delay due to chromosome 4q deletion, for the first time.

Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in children. With improved supportive care and a better understanding of the disease biology, it is now a curable cancer in the developed world. However, in low-income countries, the cure rate remains relatively poor. We report our experience on the survival of children with ALL treated on the MRD-based risk-stratified UKALL 2003 protocol, from a center in South India.All consecutive children diagnosed with ALL between years 2013 and 2019 were included in this retrospective study. All received uniform treatment as per the UKALL 2003 protocol based on NCI risk and post-induction MRD status. All the details including the type of leukemia, NCI risk status, date of diagnosis, treatment start date, the regimen, MRD status, cytogenetics, molecular genetics, and complications were captured. Analysis was done using prism GraphPad version 8.0.A total of 107 children were started on treatment during this period. The majority of them were boys (68/107). Fifty-nine of them were NCI standard risk (55%). B-ALL was the most common type (92%).Total of 56/107(52.3%) children received treatment under the government's insurance scheme for low-income bracket. The post-induction MRD was performed in 95/107 children. It was0.01% in 22% (21/95) of children. Five (4.7%) children relapsed so far with a mean follow up of 27 months from the diagnosis. There were 17 deaths (15.9%). The EFS at 3 years was 85% (95% CI 75% to 92%).It is feasible to deliver chemotherapy as per the UKALL2003 protocol without any modifications in resource-limited setting. The survival rates have significantly improved over the years in our center from 5 years EFS of 60% in 2010 and now to 3 year EFS of 85%. It is important to note that there was no treatment abandonment in our cohort.

Fanconi anemia (FA) is a rare autosomal or X-linked genetic disorder characterized by chromosomal breakages, congenital abnormalities, bone marrow failure (BMF), and cancer. There has been a discovery of 22 FANC genes known to be involved in the FA pathway. This wide number of pathway components makes molecular diagnosis challenging for FA. We present here the most comprehensive molecular diagnosis of FA subjects from India. We observed a high frequency (4.42 ± 1.5 breaks/metaphase) of chromosomal breakages in 181 FA subjects. The major clinical abnormalities observed were skin pigmentation (70.2%), short stature (46.4%), and skeletal abnormalities (43.1%), along with a few minor clinical abnormalities. The combination of Sanger sequencing and Next Generation Sequencing could molecularly characterize 164 (90.6%) FA patients and identified 12 different complementation groups [FANCA (56.10%), FANCG (16.46%), FANCL (12.80%), FANCD2 (4.88%), FANCJ (2.44%), FANCE (1.22%), FANCF (1.22%), FANCI (1.22%), FANCN (1.22%), FANCC (1.22%), FANCD1 (0.61%) and FANCB (0.61%)]. A total of 56 novel variants were identified in our cohort, including a hotspot variant: a deletion of exon 27 in the FANCA gene and a nonsense variant at c.787 C>T in the FANCG gene. Our comprehensive molecular findings can aid in the stratification of molecular investigation in the diagnosis and management of FA patients.

BackgroundSevere Combined Immune Deficiency (SCID) is an inherited defect in lymphocyte development and function that results in life-threatening opportunistic infections in early infancy. Data on SCID from developing countries are scarce.ObjectiveTo describe clinical and laboratory features of SCID diagnosed at immunology centers across India.MethodsA detailed case proforma in an Excel format was prepared by one of the authors (PV) and was sent to centers in India that care for patients with primary immunodeficiency diseases. We collated clinical, laboratory, and molecular details of patients with clinical profile suggestive of SCID and their outcomes. Twelve (12) centers provided necessary details which were then compiled and analyzed. Diagnosis of SCID/combined immune deficiency (CID) was based on 2018 European Society for Immunodeficiencies working definition for SCID.ResultsWe obtained data on 277 children; 254 were categorized as SCID and 23 as CID. Male-female ratio was 196:81. Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively. Molecular diagnosis was obtained in 162 patients - IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9), PNP (3), RFXAP (3), CIITA (2), RFXANK (2), NHEJ1 (2), CD3E (2), CD3D (2), RFX5 (2), ZAP70 (2), STK4 (1), CORO1A (1), STIM1 (1), PRKDC (1), AK2 (1), DOCK2 (1), and SP100 (1). Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%).ConclusionWe document an exponential rise in number of cases diagnosed to have SCID over the last 10 years, probably as a result of increasing awareness and improvement in diagnostic facilities at various centers in India. We suspect that these numbers are just the tip of the iceberg. Majority of patients with SCID in India are probably not being recognized and diagnosed at present. Newborn screening for SCID is the need of the hour. Easy access to pediatric HSCT services would ensure that these patients are offered HSCT at an early age.

Mendelian Susceptibility to Mycobacterial diseases (MSMD) are a group of innate immune defects with more than 17 genes and 32 clinical phenotypes identified. Defects in the IFN-γ mediated immunity lead to an increased susceptibility to intracellular pathogens like mycobacteria including attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains and non-tuberculous environmental mycobacteria (NTM), Salmonella, fungi, parasites like Leishmania and some viruses, in otherwise healthy individuals. Mutations in the IL12RB1 gene are the commonest genetic defects identified. This retrospective study reports the clinical, immunological, and molecular characteristics of a cohort of 55 MSMD patients from 10 centers across India. Mycobacterial infection was confirmed by GeneXpert, Histopathology, and acid fast bacilli staining. Immunological workup included lymphocyte subset analysis, Nitro blue tetrazolium (NBT) test, immunoglobulin levels, and flow-cytometric evaluation of the IFN-γ mediated immunity. Genetic analysis was done by next generation sequencing (NGS). Disseminated BCG-osis was the commonest presenting manifestation (82%) with a median age of presentation of 6 months due to the practice of BCG vaccination at birth. This was followed by infection with Salmonella and non-typhi Salmonella (13%), Cytomegalovirus (CMV) (11%), Candida (7%), NTM (4%), and Histoplasma (2%). Thirty-six percent of patients in cohort were infected by more than one organism. This study is the largest cohort of MSMD patients reported from India to the best of our knowledge and we highlight the importance of work up for IL-12/IL-23/ISG15/IFN-γ circuit in all patients with BCG-osis and suspected MSMD irrespective of age.

Introduction:Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility toStaphylococcalskin and pulmonary infections, eczema, raised serum IgE (>2,000 IU/ml), craniofacial anomalies, and recurrent bone fractures. Data on HIES from the Indian subcontinent is scarce and restricted to small case series and case reports. This is the first compilation of national data on HIES.Materials and Methods:A total 103 cases clinically diagnosed and treated as HIES were analyzed from nine centers. Cases with clinical and/or molecular diagnosis of DOCK8 deficiency were not included. Patients were divided into two groups: group I for whom a heterozygous rare variant of STAT3 was identified, and group II, with clinical features similar to those of AD STAT3 deficiency, but without any genetic diagnosis.Results:Genetic diagnosis was available in 27 patients (26.2%) and all harbored rare variants in the STAT3 gene. Majority of these STAT3 HIES patients presented with recurrent skin abscesses (77.7%) or pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%).Mycobacterialinfections were seen in a significant 18.5%. Mortality was seen in three subjects (11.1%). A similar trend in the clinical presentation was observed when all the 103 patients were analyzed together. Twenty percent of patients without a rare variant in the STAT3 gene had an NIH score of ≥40, whereas, 51.9% of STAT3 HIES subjects had scores below the cut off of ≥40. TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6, 16, 17, 19, 22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs*8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12.Conclusions:The report includes seven novel STAT3 variants, including a rare linker domain nonsense variant and a CC domain variant.Mycobacterialdiseases were more frequent, compared to western literature.

Ewing sarcoma is one of the rare, highly malignant neuroectodermal tumors frequently involving bones. Primary orbital Ewing sarcoma is extremely uncommon. We report a rare case of a 5-year-old boy who presented to us with painless slow-growing mass above the medial canthus of left eye, the clinical appearance of which was masquerading as internal angular dermoid. The child was subsequently diagnosed to have primary orbital Ewing sarcoma. Primary orbital Ewing sarcoma is a rare tumour with poor prognosis, poses diagnostic challenges and demands a high index of clinical suspicion.

Objectives To study the incidence, clinical manifestations, and genetic spectrum of primary immunodeficiency diseases (PID)/inborn errors of immunity (IEI) in a tertiary care hospital in Southern India. Methods A retrospective analysis of all patients with a clinical suspicion of PID/IEI seen at a tertiary care hospital was performed. All patients had at least one or more warning signs of PID. Serum immunoglobulin levels and other targeted investigations were performed as warranted by the clinical presentation. All families with suspected PID were counseled and offered genetic testing. Results A total of 225 children were evaluated for PID during the study period of 6 y. Fifty-six of them did not meet the European Society of Immunodeficiencies (ESID) criteria (working definition of clinical diagnosis) and were excluded. An IEI was found in 30/49 (61.2%) patients. The most frequent reason for referral was recurrent/unusual or serious infections (28%), or cytopenia (16%). Group IV diseases of immune dysregulation was the most common category (19%), followed by group III predominant antibody deficiencies in 23/163 (14%), as per the International Union of Immunological Societies (IUIS) classification. Conclusions This study highlights the heterogeneity of the present cohort, the underuse of genetic tests, and efforts to provide optimal care for children with possible IEI in this center.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Acute renal failure is a well-recognized complication of ALL after initiation of chemotherapy. Renal failure as the primary manifestation of ALL with no evidence of tumor lysis is rare.

Severe combined immunodeficiency (SCID) represents one of the most severe forms of primary immunodeficiency (PID) disorders characterized by impaired cellular and humoral immune responses. Here, we report the clinical, immunological, and molecular findings in 57 patients diagnosed with SCID from India. Majority of our patients (89%) presented within 6 months of age. The most common clinical manifestations observed were recurrent pneumonia (66%), failure to thrive (60%), chronic diarrhea (35%), gastrointestinal infection (21%), and oral candidiasis (21%). Hematopoietic Stem Cell Transplantation (HSCT) is the only curative therapy available for treating these patients. Four patients underwent HSCT in our cohort but had a poor survival outcome. Lymphopenia (absolute lymphocyte counts/μL

Invasive fungal infections are rare in children with acute lymphoblastic leukemia. It compromises the antileukemia therapy should it happen. Central nervous system fungal infections carry high mortality. We here report the case of a 6.5-year-old girl who developed multiple central nervous system fungal abscesses possibly due to Aspergillus infection during induction therapy for acute lymphoblastic leukemia who has been successfully managed without compromising antileukemia therapy. She has been receiving antifungal therapy and maintenance chemotherapy for 20 months from diagnosis. We reviewed literature about the optimal duration of therapy for such children as the reported cases duration ranged between 4 and 24 months.

SUMMARY: Nanjegowda CK, Kamath SP, Kamath P, Shah TD, Kulkarni V, Lashkari HP, Baliga BS. Comparison of diastolic function in children with transfusion dependent beta thalassemia major by tissue and conventional doppler imaging indices and its correlation with serum ferritin levels. Turk J Pediatr 2019; 61: 250-259. Regular blood transfusions for children with beta thalassemia major (β- TM) results in iron overload cardiomyopathy/cardiac failure. Mortality in these children is most often because of heart failure. We compared Tissue Doppler Imaging (TDI) and conventional pulse wave Doppler (PWD) indices in evaluating diastolic function in chronically transfused β-TM children and correlated the Doppler indices with mean serum ferritin levels. This was a prospective cross-sectional study conducted at tertiary teaching hospital. β-TM children aged 3 to 18 years were enrolled as per inclusion criteria. PWD parameters at the mitral inflow (E, A, E/A and DT) and TDI parameters at the medial mitral annulus (Eʹand E/Eʹ) were used for estimation of diastolic dysfunction. Of the 66 children with thalassemia, the mean age was 10.2±3.77yrs and 60.6% were boys. The E/Eʹ ratio estimated diastolic dysfunction (34/66, 51.5%) greater than four times that assessed by E/A ratio indices (8/66, 12.1%) in the subjects. Association of serum ferritin levels with E/Eʹ ratio by chi square test was significant statistically (P=0.027), however was not significant with E/A ratio. By Mann Whitney test, the median serum ferritin levels (ng/ml) were higher [4034.50, (IQR-2084-5340.25) in those with diastolic dysfunction (abnormal E/Eʹ), when compared to those with normal E/Eʹ[2037.50(1510.75- 3572.25)], with their difference being significant (p=0.011), however serum ferritin levels were not significant with E/A ratio and DT. E/Eʹ parameter had a sensitivity and specificity of 76.5% and 53.1% respectively at a mean serum ferritin cutoff level of 2076 ng/mL by ROC analysis. In conclusion, TDI is a more reliable modality for diagnosing early diastolic dysfunction when compared to PWD. Threshold level of serum ferritin greater than 2076 ng/mL is associated with increased incidence of diastolic dysfunction.

Severe hyperlipidaemia with asparaginase therapy is rare. We report six cases, four of which developed significant problems with severe hyperlipidaemia during induction therapy for ALL and lymphoblastic lymphoma. The median triglyceride level was 22.3 mmol/L and the median cholesterol level was 12.3 mmol/L. None of the patients showed signs or symptoms of pancreatitis. Three children were re-exposed with Peg asparaginase, and one with Erwinia asparaginase, without recurrence of hyperlipidaemia or other symptoms. These cases highlight the dilemma in managing such rare cases of symptomatic hypertriglyceridaemia secondary to asparaginase and steroid therapy.

Low grade gliomas (LGG) contribute to 50% of all central nervous tumors in children and 15% of all gliomas in adults. Temozolomide (TMZ) is an oral alkylating agent with activity in high and LGG. Various regimens of TMZ are currently in use. We attempted to assess the impact of different TMZ regimens on the treatment of LGG. A systematic review of the literature identified all the studies published in Pubmed, EMBASE and Cochrane databases which met the inclusion criteria. The primary outcome measure was the impact of different TMZ regimens on the 12 month progression-free survival (PFS) rates of patients diagnosed with progressive LGG. Secondary outcome measures looked at the ability of the three regimens to elicit an objective response and the associated toxicity. Statistical pooling and calculation of weighted mean average of each proportion (WMAP) was conducted using a random-effects model. 18 studies (736 patients) were analyzed. PFS at 12 months revealed a WMAP of 0.61 (95% CI 0.44-0.78) for regimen A, 0.59 (0.28-0.89) for regimen B, and 0.91 (95% CI 0.83-0.99) for regimen C (Regimen A--200 mg/m(2)/day for 5 days, repeated every 4 weeks; B--75 mg/m(2)/day for 21 days repeated every 4 weeks; C--75 mg/m(2)/day for 7 weeks with 4 weeks of every 11 weeks). In terms of objective response, WMAP were 0.19 (95% 0.13-0.25), 0.27 (95% CI 0.15-0.39) and 0.21 (95% CI 0.10-0.32) for regimen A, B, C respectively. When analyzing hematological toxicity, WMAPs were 0.14 (95% 0.11-0.18), 0.35 (0.14-0.56) and 0.23 (95% CI 0.03-0.43). The bulk of evidence originates from the standard 5 day/month regimen A but with a lack of comparative studies. Analysis revealed significant heterogeneity. Although there is possibly an indication that metronomic regimens of TMZ result in better PFS and response rate when compared to the conventional standard 5 day regimen, insufficient available data and study heterogeneity preclude any safe conclusions. Well designed randomized controlled clinical trials are needed to establish the efficacy of metronomic regimens of TMZ in LGGs.

Sertoli–Leydig cell tumors are rare ovarian neoplasms. We report two unusual cases with bilateral SLCTs suggesting evidence of genetic predisposition and at high risk of recurrence. To reduce this risk, we exploited the use of GnRH analog to lower gondadotropin and potentially directly inhibit the tumors through expressed GnRH receptors. We used it as maintenance antitumor therapy for 2 years after completion of chemotherapy, to cover the period of risk for recurrence. Both patients remain in complete remission at >2 years after completing leuprorelin therapy. Of note, both patients carry DICER1 mutations, frequently found in pleuropulmonary blastoma syndrome. Pediatr Blood Cancer 2013; 60: E16–E18. © 2012 Wiley Periodicals, Inc.

Cutis marmorata is a bluish, purplish mottling of the skin which is commonly seen in newborn babies when exposed to cold. It tends to disappear on warming. However, persistence of cutis marmorata can be seen in various conditions such as Down’s syndrome, Trisomy 18, de Lange syndrome, Neonatal lupus, congenital hypothyroidism and Adams-Oliver syndrome [1, 2]. Here we present images of a newborn baby with Adams-Oliver Syndrome.

Undifferentiated embryonal sarcoma is the uncommon malignant mesenchymal tumor of the liver seen in children and young adults. Radiologic findings reflect the solid to cystic appearances observed in the gross specimens. The discrepancy in the appearances of the mass between the ultrasound scan and computed tomography scan is the hall mark of this tumor. Ultrasonography typically show a large mass which is hyperechoic or isoechoic (solid). Computed tomography shows cystic component of the tumor. This unique radiologic feature will help in the diagnosis of the tumour.

Neuroblastoma in a known case of congenital adrenal hyperplasia has rarely been reported. The management of such a patient in the background of hormonal imbalance can be very challenging. In this report, we share our experience in managing such a child and discuss the clinical dilemma.

Chlorhexidine gluconate 2.0% w/v aqueous solution (AquiHex 2%) was used to prepare the skin before umbilical catheter insertion soon after birth in a non-identical preterm twin born at 25+4 weeks gestation. Two hours later, the skin in the right iliac fossa, right flank, the periumbilical area, perineum and groin turned erythematous. Over the subsequent 6 h, the …