A Novel MECOM Variant Associated with Congenital Amegakaryocytic Thrombocytopenia and Radioulnar Synostosis Hanan Al-Abboh1, Akmal Zahra1 and Adekunle Adekile1,2Pediatric Hematology Unit, Mubarak Hospital1 and Department of Pediatrics, Faculty of Medicine, Kuwait University2, Kuwait Address Correspondence to: Professor Adekunle Adekile Department of Pediatrics Faculty of Medicine Kuwait University PO Box 24923 Safat 13110 Kuwait Email: [email protected] Tel: +96525319486To the EditorCongenital radioulnar synostosis (RUS) is a rare developmental anomaly of proximal fusion of the radius and ulna, resulting in limited pronation and supination of the forearm. It may accompany other abnormalities in the skeleton, kidney, heart and aneuploidy syndromes1,2. A subset of patients with RUS present with bone marrow failure (BMF) syndromes, characterized by amegakaryocytic thrombocytopenia (RUSAT), progressing to myelodysplasia and pancytopenia2,3. The hematological manifestations are quite variable, with some presenting with severe BMF in childhood, while others are mild and may not present until adulthood.Heterozygous germline variants in the homeobox A11 (HOXA11) gene were the first to be associated with RUS and designated RUSAT14, but lately, several families have been described with variants in the MDS1 and EVI1 complex (MECOM) locus, and referred to as RUSAT22,5,6. Many of these variants appear de novo , while others follow an autosomal dominant inheritance. We, hereby, report the case of a Kuwaiti patient who presented with congenital amegakaryocytic thrombocytopenia (CAMT) in the neonatal period and later noticed to have RUS. Whole exome sequencing revealed a novel MECOM variant.A.A. is a male Kuwaiti, the first child of consanguineous parents and was first seen at the age of 36 days, following antenatal ultrasound diagnosis of bilateral hydronephrosis and right renal cyst. He was a product of induced vaginal delivery with a birth weight of 2.3 kg. After delivery, he was kept under observation in the neonatal intensive care unit. His CBC showed isolated thrombocytopenia (Plt 34 x109/L). He received several platelet transfusions, as well as IVIG twice. Postnatal abdominal ultrasound showed multicystic right kidney, in addition to bilateral hydronephrosis. The mother had no history of thrombocytopenia during pregnancy and there was no other pertinent family history.Physical examination at presentation showed 2 café-au-lait spots, one on the back, measuring 1x2 cm and another over the left leg, that was less than 0.6 cm. There were no obvious dysmorphic features and other systems were unremarkable. CBC showed WBC 11.2 x109/L Hb 10.4 g/dL, MCV 83fl, Plt 49 x109/L, ANC 1.8 x109/L. Renal function tests were normal. Blood film showed no abnormal cells; there was true thrombocytopenia with giant forms. Antiplatelet antibody was negative. Abdominal ultrasound at age 1 month showed complete replacement of the right kidney by cystic changes with left moderate hydronephrosis. Skeletal survey was reportedly normal.Bone marrow biopsy showed normal distribution of granulocytic and erythroid precursors, with severe suppression of megakaryocytosis, consistent with a bone marrow failure syndrome. Chromosomal breakage study was normal. The patient was diagnosed with right undescended testis, as well as right inguinal hernia that were operated at age 1 year and 10 months. At the age 2 and a half years, A.A. was noticed to have limited bilateral arm movement supination and pronation. The mother volunteered that she has a similar defect. X-rays confirmed that the child had bilateral radioulnar synostosis. Whole exome sequencing showed that the patient is heterozygous for a previously-unreported MECOM gene, c.2282A>G mutation. Unfortunately, the parents have not been screened for these mutations.The patient has been under follow up for 4 years, his platelet count has been stable, ranging between 40-50 x109/L, with no bleeding tendency. In spite of his limited arm rotation, he currently functions normally in his daily activities, however, his hand writing skills and ability to engage in sports are yet to be observed since he is still pre-school age. Platelet transfusion is reserved only for severe bleeding, which he has not had. Bone marrow transplant may be considered in future if his bone marrow failure worsens and/or his marrow shows dysplastic changes.Dokal et al3 were the first to report an association between RUS and late-onset BMF, while Thompson et al described its association with CAMT and linked it to the c.872delA ,p.Asn291Thrfs3 variant of the HOXA11gene4,7. More recently, several germline mutations in the MECOM locus have been reported and appear to be the more common cause of RUSAT. Indeed, no other cases of HOXA11 mutations linked to RUSAT have been described since the initial report. Niihori et al8 reported the first 3 heterozygous MECOMmutations in 3 sporadic patients. These variants and those subsequently reported by Walne et al2 are in a highly conserved cluster within 10 amino acids (aa750-760) and impact on either the highly conserved Cys2His2 zinc finger motif (zinc finger 8, aa733-755) or the adjacent linker motif (aa756-760). It has been shown that removal of the 8th zinc finger causes granulopoiesis arrest while mutations and deletions in other parts of the complex, outside the 8th and 9th fingers, are associated with hematological disorders without RUS9.MECOM codes for a zinc finger transcription factor with important roles in normal development and oncogenesis and is involved in the regulation of embryonic development and hematopoietic stem-cell renewal. Hence the phenotype in individuals with these mutations is very variable ranging from BMF to different skeletal, cardiac, renal malformations, B cell deficiency and sensorineural deafness.Our patient showed a previously unreported variant in the region of the 8th zinc finger of the MECOM locus. This c.2282A>G missense variant results in the tyrosine to cysteine substitution at codon 761 (p.Tyr761Cys). The amino acid is in the Zinc finger, C2H2 and Zinc finger, C2H2-like protein domains and is highly evolutionarily conserved. Unfortunately, the parents were not screened for the mutation, however, the mother shows RUS, with normal blood counts. This is consistent with the marked variability in the clinical phenotype. The father is also physically and hematologically normal.Apart from thrombocytopenia, our patient also had renal abnormalities – hydronephrosis and multicystic kidney disease. The natural history of his condition is that he may develop pancytopenia and/or myelodysplasia in the future. He is under close follow up and will be considered for bone marrow transplantation if his condition worsens. In the meantime, he remains hypomegakaryocytic with a platelet count at 30 – 50 x 109/l while other blood cellular elements are normal. His renal function and hearing are being monitored, but still remain normal.AcknowledgementsWe thank the patient’s family for allowing us to report this case. The whole exome sequencing was done at the Laboratory of Genetics and Genomics, Cincinnati Children’s Hospital, Cincinnati, Ohio.References1. Rizzo R, Pavone V, Corsello G, Sorge G, Neri G, Opitz JM. Autosomal dominant and sporadic radio-ulnar synostosis. Am J Med Genet.1997;68(2):127-134.2. Walne A, Tummala H, Ellison A, et al. Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease. Haematologica. 2018;103(7):e284-e287.3. Dokal I, Ganly P, Riebero I, et al. Late onset bone marrow failure associated with proximal fusion of radius and ulna: a new syndrome.Br J Haematol. 1989;71(2):277-280.4. Thompson AA, Nguyen LT. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet. 2000;26(4):397-398.5. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586-596.6. Ripperger T, Hofmann W, Koch JC, et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica. 2018;103(2):e55-e58.7. Thompson AA, Woodruff K, Feig SA, Nguyen LT, Schanen NC. Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome.Br J Haematol. 2001;113(4):866-870.8. Niihori T, Ouchi-Uchiyama M, Sasahara Y, et al. Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. Am J Hum Genet.2015;97(6):848-854.9. Nielsen M, Vermont CL, Aten E, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia. J Med Genet.2012;49(9):598-600.

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni Syndrome (LFS), resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) have been associated with a high rate of germline TP53 PVs. This study provides an updated estimate of the prevalence of TP53 germline PVs from a large cohort of patients (n=239) enrolled in five Children’s Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in anRMS patients in this series is much lower than previously reported, this prevalence remains significantly elevated. Germline genetic evaluation for TP53 PVs should be strongly considered in patients with anRMS.

Social determinants of health (SDoH) are associated with stark disparities in cancer outcomes, but systematic SDoH data collection is currently absent from oncology clinical trials. Trial-based SDoH data are essential to ensure representation of marginalized populations, contextualize outcomes, and identify health-equity intervention opportunities. We report the feasibility of the first pediatric oncology multicenter trial-embedded SDoH investigation. Among 448 trial participants, 392 (87.5%) opted-in to the embedded SDoH study; 375 (95.7%) completed baseline surveys, with high longitudinal response rates (87.2-92.8%) over 24-months of therapy. Trial-embedded SDoH data collection is feasible and acceptable, and must be consistently included within future oncology trials.

Erythroid sarcoma is very rare form of pure erythroid leukemia with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case.

Purpose: Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard-of-care has not been established due to a paucity of data. Methods: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. Results: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n=13; 31.7%), followed by posterior fossa (n=7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, one from pneumonia and one from Moyamoya following radiation-therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types – 62% germinomas, 79% for NGGCTs, and 53% for teratomas. Conclusion: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae.

Nonprofit organizations (NPOs) play critical roles as funding sources, research partners, and disseminators of emerging drug developments in pediatric cancer, yet the literature offers limited understanding or guidance of ethical best practices and processes. We conducted a systematic search for peer reviewed articles, commentaries, newsletters, and white papers indexed in the PubMed and Web of Science databases to identify the ethical, legal, and social responsibilities of NPOs to i) patients/families, ii) researchers, iii) sponsors, and iv) donors when funding clinical trials. Fifty-four articles met the inclusion criteria. Minimizing conflicts of interest, ensuring transparent reporting of trial endpoints, and communicating with families about trial opportunities emerged as key themes. We identified critical gaps in the literature related to negotiating research partnerships, setting trial priorities and establishing best ethical practices in the emerging field of venture philanthropy. Results informed points to consider for NPOs when funding pediatric cancer clinical trials going forward.

Background and objectives: To investigate the feasibility and safety of ultrasound-guided totally implantable venous access ports (TIVAPs) via the right brachiocephalic vein (BCV) in pediatric patients. Methods: A single institutional retrospective review was performed on 35 pediatric patients with hematological malignancies who underwent TIVAPs implantation via ultrasound-guided right BCV approach from July 2018 to June 2021. Technical success rate, procedural information and TIVAP related complications were evaluated. Results: All the pediatric TIVAP devices were successfully implanted via right BCV access. Venous access was successful by first attempt in 32 children (91.42%); two cases (5.71%) required a second attempt; one patient (2.86%) required a third attempt. The mean procedural time was 44.63 ± 6.41 mins (range, 34-62 mins). No intraoperative complications occurred. The average TIVAP indwelling time was 563.51 ± 208.47 days (range, 193-1014 days) with a cumulative 19,723 catheter-days. The incidence of postoperative complications was 11.43% (4/35), corresponding to a rate of 0.20 complications per 1000 catheter-days. Two cases of local hematoma and two catheter dysfunctions occurred in three patients. No other complications such as wound dehiscence, delayed incision healing, catheter-related thrombosis (CRT), catheter malposition/fracture, surgical site infection, catheter-related bloodstream infection (CRBSI), pinch-off syndrome and drug extravasation were observed during follow-up. Conclusions: Ultrasound-guided right BCV access for TIVAPs placement in pediatric patients appears to be technically feasible, safe and effective. Further large-sample, prospective studies are warranted.

To the editor: Is it possible to achieve long-term survival in relapsed Intracranial Non-Germinomatous Germ Cell Tumours?

Title: Posterior Reversible Encephalopathy Syndrome and Necrotizing Enterocolitis in a Pediatric Patient with Medulloblastoma Infected with COVID-19

Background: Flow artifact, intrinsic to Magnetic Resonance Angiography (MRA), is dependent on technical parameters and can lead to overinterpretation of stenosis. Degree of cerebrovascular stenosis in pediatric patients with sickle cell anemia (SCA) informs need for chronic transfusion therapy, which may have significant risks. The primary objective of this study was to document any change in stroke prevention therapy that could be attributed to the implementation of a standardized MRA scanning protocol. Procedure: A standardized MRA scanning protocol with an echo time of <5 msec was implemented at Montefiore Medical Center in May 2016. Retrospective chart review identified 29 patients ≤ 21 years with SCA cerebral vasculopathy and an MRA head pre- and post-May 2016. Level of arterial stenosis on MRA, echo time, and treatment plans were documented both pre- and post-implementation. McNemar analysis determined the significance of change in treatment plans before and after implementation of the standardized scanning protocol. Results: Previously seen stenosis was re-classified to a lower degree in 12/29 patients (41%). Notably, 6 patients had a reclassification of vasculopathy leading to discontinuation of chronic transfusion therapy whereas 0 patients required escalation of therapy to chronic transfusions. McNemar analysis showed this difference to be statistically significant (p = 0.042). Conclusion: Minimizing flow artifact with echo time <5msec improves accurate interpretation of true cerebrovascular disease and ensures appropriate treatment plans are in place for stroke prevention. This is especially important when trying to implement “TCD With Transfusions Changing to Hydroxyurea (TWiTCH)” clinical trial results in the real-world setting.

A document by H Shafeeq Ahmed. Click on the document to view its contents.

A document by Bilawal Nadeem. Click on the document to view its contents.

High-dose methotrexate (HD-MTX) with rigorous supportive care is essential to the treatment of pediatric non-Hodgkin lymphomas (NHL). We describe the safety and tolerability of HD-MTX in patients with NHL treated at our center. In our cohort of 46 patients, the majority had at least one course of delayed clearance and/or creatinine elevation. Additionally, more than one-third of patients experienced an episode of grade ≥3 mucositis. Creatinine elevations and delayed clearance were independently associated with subsequent grade ≥3 mucositis. We advocate for greater availability of methotrexate monitoring to allow dose escalation of this essential modality around the world.

Comment on: Standardizing the surgical management of benign ovarian tumors in children and adolescents: A best practice Delphi consensus statement.Matthew J. Murray1,2, Nigel J. Hall3, Sara Stoneham4, Anthony Penn5, Mark Brougham6, James C. Nicholson1,7; on behalf of the Children’s Cancer and Leukaemia Group (CCLG) Germ Cell Tumour (GCT) Special Interest Group (SIG).1 Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK2 Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK3 University Surgery Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK4 Department of Paediatrics and Child Health, University College Hospital London NHS Foundation Trust, London, UK5 Department of Paediatric Oncology, Royal Manchester Children’s Hospital, Oxford Road, Manchester, M13 9WL, UK6 Department of Paediatric Oncology, Royal Hospital for Children & Young People, 50 Little France Crescent, Edinburgh bio Quarter, Edinburgh, EH16 4TJ, UK7 Department of Paediatrics, University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UKConflict of interest statement : the authors declare no conflicts of interest.We read with interest the article from Braungart and colleagues, discussing management of young females with benign ovarian tumors [1]. This is important and timely, and we agree with the need for clarity in management of this under-investigated group. As the authors note, published evidence to support decisions is limited, so in certain areas, guidance may have to rely on expert opinion. The authors emphasize the importance of multidisciplinary team (MDT) discussion to optimise management and risk-stratification [1]. They highlight the importance and safety of ovarian-sparing-surgery in benign tumors, to preserve fertility and avoid long-term effects including premature ovarian failure [1].However, important aspects of their methodology are unclear. The denominator (number of experts approached to be involved) and response rate is not stated. The standard thresholds for accepting Delphi statements is >70% votes in support from >60% of experts in each voting round [2], as used in Delphi studies undertaken by the authors here [3,4]. Furthermore, there is no indication of level of support for statement(s) not reaching the 70% threshold. Moreover, they list specialties involved without defining numbers in each group, preventing assessment of the work’s objectivity and relative representation. Frequent criticisms of Delphi method work are poor questionnaire/statement design, compounded by inadequate definition/ selection of experts [5]. For example, ‘the inclusion of other clinicians… may be appropriate to provide an alternative clinical view, particularly when the study is expected to have an impact beyond a particular specialist field’ [5]. Of particular note, the study states that a ‘…. Delphi panel was instigated that included… pediatric oncologists representing CCLG Germ Cell Tumour Group’ [1]. Unfortunately, there was no pediatric oncologist involvement from the group in formulating the statements for discussion. Subsequently, only one was invited to participate in the Delphi itself, once the statements had been finalized. Furthermore, there was no patient/parent representation in the Delphi process, crucial to involve for a benign disease, with issues regarding surgical approach, fertility, and the burden of proposed ultrasound follow-up.The surgical guidance is useful; however, a size cut-off for minimally invasive surgery is specified, without supportive evidence [1]. Another incongruity is for tumor marker follow-up (section 2.3, bullet 7) if they were elevated preoperatively; by definition this group should have had normal markers at diagnosis (section 2.1, first paragraph) [1]. In the follow-up section (2.3), bullet-points 3-5 are most contentious as no evidence is presented for dictating time-interval to scan, and a recent systematic review looking at this indication, which concluded, based on available evidence, that ‘routine surveillance… should certainly be considered’ and suggested annual ultrasound [6], was overlooked. In addition, no reference is provided here to existing guidelines [7]. The recommended two-year interval between ultrasounds [1] is therefore neither evidence-based nor considers the patient/parent opinion. Furthermore, there is no justification for gynecologic fertility referral following ovarian-sparing-surgery where subsequent ultrasound shows normal ovarian reserve bilaterally. Consequently, terms relating to specific aspects that ‘should’ include/be undertaken/performed are inappropriate. Suggesting that ‘a reasonable strategy that could be considered might be as follows…’ would be a better approach.In summary, attempts to improve the management of young females with benign ovarian tumors are laudable. Some of the surgical recommendations made should help to streamline care. However, a representative group of key stakeholders were not included in the Delphi method and most of the follow-up recommendations cannot be justified based on use of a limited group of experts with limited supporting evidence. What is required is a wider collaborative approach, including GCT, surgical, gynecologic, radiology, and importantly patient groups, to answer these questions more robustly, preferably with international collaboration. This will also ensure appropriate clinician engagement, minimise inconsistencies in management and optimise outcomes for this patient group.

The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT) consists of a collaboration between the Children’s Oncology Group (COG) Soft Tissue Sarcoma Committee, the European pediatric Soft-Tissue Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to provide consensus expert opinions for clinical treatment of pediatric soft tissue sarcoma, we sought to provide updated, evidenced-based consensus guidelines for local treatment of parameningeal rhabdomyosarcoma using both existing literature as well as recommendations from the relevant cooperative group clinical trials. Overall, parameningeal rhabdomyosarcoma represents a distinctly challenging disease to treat given its location near many critical structures in the head and neck, frequently advanced local presentation, and predilection for local failure. Definitive chemoradiation remains the standard treatment approach for parameningeal rhabdomyosarcoma, with surgery often limited to biopsy or salvage therapy for recurrent disease. In this consensus paper, we specifically discuss consensus guidelines and evidence for definitive local management with radiotherapy, with a focus on imaging for radiotherapy planning, dose and timing of radiation, approach for nodal irradiation, various radiation techniques including proton therapy, and the limited role of surgical resection.

A document by Patrick Reeves. Click on the document to view its contents.

A document by Gauthier Toutain. Click on the document to view its contents.

AIMS This study analysed the clinical features of children with intracranial germ cell tumours (IC-GCTs) treated at two European centres. We retrospectively reviewed timelag between symptoms onset, clinic-radiological findings, diagnosis and outcomes. METHODS Symptoms at diagnosis were divided into four groups: 1)raised intracranial pressure (RICP); 2)visual impairment; 3)endocrinopathy; 4)other. Total diagnostic interval (TDI), defined as the interval between symptom onset (including retrospective recall of symptoms) and definitive diagnosis of IC-GCT, was calculated and compared to survival rates. RESULTS Our cohort included 55 children with a median follow-up of 78.9 months (0.5-249.9). The majority (63.6%) had germinomas and 10.9% were metastatic at diagnosis. IC-GCTs were suprasellar (41.8%), pineal (36.4%), bifocal (12.7%) or in atypical sites (9.1%). The most common presenting symptoms were related to RICP (43.6%); however, by the time of tumour diagnosis, 50.9% of the patients had developed endocrine dysfunctions. All pineal GCTs manifested with RICP or visual impairment. All suprasellar GCTs presented with endocrinopathies. TDI ranged between 0.25-58.5 months (median 4 months). Pineal GCTs had the shortest TDI (median TDI 1 month versus 24 months in suprasellar GCTs, p<0.001). TDI >6 months was observed in 47.3% of patients and was significantly associated with endocrine presenting symptoms. No statistically significant difference was found in progression-free survival and overall survival between patients with TDI >6 months and with TDI 6 months. CONCLUSION Approximately half of our patients had TDI >6 months, mostly with endocrine deficiencies as presenting symptoms. TDI >6 months was not associated with increased relapse rate or mortality.