Lymphoblastic lymphoma (LBL) is a rare, aggressive malignancy comprising T-cell (T-LBL) and B-cell (B-LBL) subtypes. While outcomes for LBL have improved, comprehensive national data on clinical and biological features remain limited. We conducted a retrospective review of children and adolescents with LBL in Ireland over 20 years (2004-2023). Data on demographics, clinical presentation, tumour characterization, treatment protocols, and outcomes were analysed. The cohort included 52 patients: 79% with T-LBL and 21% with B-LBL. T-LBL cases predominantly affected males (2.2:1) and presented with advanced disease, including mediastinal masses (98%) and high lactate dehydrogenase levels. B-LBL cases had a female predominance (0.4:1) and localized disease (82%). Survival outcomes were excellent for B-LBL, with 5-year event-free survival (EFS) and overall survival (OS) of 100%. For T-LBL, 5-year EFS and OS were 85%. Relapsed/refractory disease occurred in 4% (T-LBL only). Genetic, Minimal Disseminated Disease and Minimal Residual Disease analyses were limited. LBL outcomes in Ireland align with international reports, highlighting favourable survival but underscoring the need for improved risk stratification and genetic profiling, particularly for T-LBL.

Figure S1. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Click to increase image sizeClick to decrease image size AcknowledgementsThe authors to acknowledge all the staff involved in the care of these patients and of course the patients and families themselves.Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementThe data that support the findings of this study are available on request from the corresponding author, AT. The data are not publicly available due to their containing information that could compromise the privacy of research participants.Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.

Quinn, Shauna; Kavanagh, Karl; McArdle, Linda; Betts, David; Lynch, Sally-Ann Author Information

Abstract Nicolaides–Baraitser syndrome is a rare, neuro-developmental disorder caused by heterozygous pathogenic variants in the SMARCA2 gene, involved with chromatin regulation. Cardinal features include intellectual disability, short stature, microcephaly, triangular facies, sparse hair, brachydactyly, prominent interphalangeal joints and seizures. Genetic testing demonstrated a loss within SMARCA2 at 9p24.3 inclusive of basepairs 2094861_2141830 (hg19) in our patient. This case highlights a child with Nicolaides–Baraiter syndrome, a SMARCA2 gene deletion and a novel association of hypertrophic obstructive cardiomyopathy.

Anaplastic large cell lymphoma (ALCL) accounts for 10–15% of pediatric and adolescent lymphomas [1]. ALCL is a T or null cell lymphoma characterized by malignant expression of CD30 [2]. The majorit...

Letter to Blood| December 9, 2021 Association of unbalanced translocation der(1;7) with germline GATA2 mutations Emilia J. Kozyra, Emilia J. Kozyra Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, andFaculty of Biology, University of Freiburg, Freiburg, Germany; https://orcid.org/0000-0003-1107-8818 Search for other works by this author on: This Site PubMed Google Scholar Gudrun Göhring, Gudrun Göhring Department of Human Genetics, Hannover Medical School, Hannover, Germany; Search for other works by this author on: This Site PubMed Google Scholar Dennis D. Hickstein, Dennis D. Hickstein Immune Deficiency–Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Search for other works by this author on: This Site PubMed Google Scholar Katherine R. Calvo, Katherine R. Calvo Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; Search for other works by this author on: This Site PubMed Google Scholar Courtney D. DiNardo, Courtney D. DiNardo Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX; https://orcid.org/0000-0001-9003-0390 Search for other works by this author on: This Site PubMed Google Scholar Michael Dworzak, Michael Dworzak St. Anna Childreńs Hospital and Cancer Research Institute, Pediatric Clinic, Medical University of Vienna, Vienna, Austria; Search for other works by this author on: This Site PubMed Google Scholar Valerie de Haas, Valerie de Haas Dutch Childhood Oncology Group (DCOG), Utrecht, The Netherlands; https://orcid.org/0000-0003-0339-6816 Search for other works by this author on: This Site PubMed Google Scholar Jan Starý, Jan Starý Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic; Search for other works by this author on: This Site PubMed Google Scholar Henrik Hasle, Henrik Hasle Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark; Search for other works by this author on: This Site PubMed Google Scholar Akiko Shimamura, Akiko Shimamura Dana-Farber and Boston Children's Cancer and Blood Disorders Center, Boston, MA; https://orcid.org/0000-0002-4683-9958 Search for other works by this author on: This Site PubMed Google Scholar Mark D. Fleming, Mark D. Fleming Department of Pathology, Boston Children's Hospital, Boston, MA; https://orcid.org/0000-0003-0948-4024 Search for other works by this author on: This Site PubMed Google Scholar Hiroto Inaba, Hiroto Inaba Department of Oncology and Search for other works by this author on: This Site PubMed Google Scholar Sara Lewis, Sara Lewis Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN; Search for other works by this author on: This Site PubMed Google Scholar Amy P. Hsu, Amy P. Hsu Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; https://orcid.org/0000-0001-6841-2122 Search for other works by this author on: This Site PubMed Google Scholar Steven M. Holland, Steven M. Holland Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Search for other works by this author on: This Site PubMed Google Scholar Danielle E. Arnold, Danielle E. Arnold Immune Deficiency–Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD; https://orcid.org/0000-0001-7501-806X Search for other works by this author on: This Site PubMed Google Scholar Cristina Mecucci, Cristina Mecucci Department of Medicine, Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy; https://orcid.org/0000-0002-1623-0148 Search for other works by this author on: This Site PubMed Google Scholar Siobán B. Keel, Siobán B. Keel Department of Medicine, Division of Hematology, University of Washington, Seattle, WA; Search for other works by this author on: This Site PubMed Google Scholar Alison A. Bertuch, Alison A. Bertuch Department of Pediatrics/Hematology-Oncology, Baylor College of Medicine, Houston, TX; Search for other works by this author on: This Site PubMed Google Scholar Kiran Tawana, Kiran Tawana Department of Haematology, Addenbrooke's Hospital, Cambridge, United Kingdom; Search for other works by this author on: This Site PubMed Google Scholar Shlomit Barzilai, Shlomit Barzilai Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petah-Tikva, Israel;Sackler Faculty of Medicine, Tel Aviv University, Israel; Search for other works by this author on: This Site PubMed Google Scholar Shinsuke Hirabayashi, Shinsuke Hirabayashi Department of Pediatrics and https://orcid.org/0000-0001-7961-0968 Search for other works by this author on: This Site PubMed Google Scholar Masahiro Onozawa, Masahiro Onozawa Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan; https://orcid.org/0000-0001-9267-2864 Search for other works by this author on: This Site PubMed Google Scholar Shaohua Lei, Shaohua Lei Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN; Search for other works by this author on: This Site PubMed Google Scholar Helena Alaiz, Helena Alaiz Hematology Department, Oncology Institute Francisco Gentil, Lisbon, Portugal; Search for other works by this author on: This Site PubMed Google Scholar Hajnalka Andrikovics, Hajnalka Andrikovics Laboratory of Molecular Diagnostics, Central Hospital of Southern Pest, Budapest, Hungary; Search for other works by this author on: This Site PubMed Google Scholar David Betts, David Betts National Children's Cancer Service, Children's Health Ireland at Crumlin, Dublin, Ireland; Search for other works by this author on: This Site PubMed Google Scholar Berna H. Beverloo, Berna H. Beverloo Dutch Childhood Oncology Group (DCOG), Utrecht, The Netherlands;Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Search for other works by this author on: This Site PubMed Google Scholar Jochen Buechner, Jochen Buechner Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway; https://orcid.org/0000-0001-5848-4501 Search for other works by this author on: This Site PubMed Google Scholar Martin Čermák, Martin Čermák Department of Genetics, The National Institute of Oncology, Bratislava, Slovakia; https://orcid.org/0000-0002-9949-0163 Search for other works by this author on: This Site PubMed Google Scholar José Cervera, José Cervera Department of Hematology, Genetics Unit, Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Hospital Universitario y Politécnico La Fe, Valencia, Spain; Search for other works by this author on: This Site PubMed Google Scholar Olga Haus, Olga Haus Department of Clinical Genetics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland; Search for other works by this author on: This Site PubMed Google Scholar Kirsi Jahnukainen, Kirsi Jahnukainen New Children's Hospital, Pediatric Research Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland;Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden; Search for other works by this author on: This Site PubMed Google Scholar Kalliopi N. Manola, Kalliopi N. Manola Department of Biodiagnostic Sciences and Technologies, The Institute of Nuclear & Radiological Sciences and Technology, Energy & Safety (INRASTES), National Centre for Research 'Demokritos', Athens, Greece; Search for other works by this author on: This Site PubMed Google Scholar Karin Nebral, Karin Nebral Labdia Labordiagnostik GmbH, Clinical Genetics, Vienna, Austria; https://orcid.org/0000-0002-0548-541X Search for other works by this author on: This Site PubMed Google Scholar Francesco Pasquali, Francesco Pasquali Medical Genetics, Department of Medicine and Surgery, University of Insubria, Varese, Italy; Search for other works by this author on: This Site PubMed Google Scholar Joelle Tchinda, Joelle Tchinda Laboratory for Oncology, University Children's Hospital Zürich, Zürich, Switzerland; Search for other works by this author on: This Site PubMed Google Scholar Dominik Turkiewicz, Dominik Turkiewicz Department of Pediatrics, Section of Pediatric Oncology, Hematology, Immunology and Nephrology, Skåne University Hospital, Lund, Sweden; Search for other works by this author on: This Site PubMed Google Scholar Nadine Van Roy, Nadine Van Roy Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Search for other works by this author on: This Site PubMed Google Scholar Zuzana Zemanova, Zuzana Zemanova Center of Oncocytogenomics, Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine of Charles University, Prague, Czech Republic; and Search for other works by this author on: This Site PubMed Google Scholar Victor B. Pastor, Victor B. Pastor Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, and Search for other works by this author on: This Site PubMed Google Scholar Brigitte Strahm, Brigitte Strahm Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, and https://orcid.org/0000-0002-6086-130X Search for other works by this author on: This Site PubMed Google Scholar Peter Noellke, Peter Noellke Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, and https://orcid.org/0000-0002-0281-4732 Search for other works by this author on: This Site PubMed Google Scholar Charlotte M. Niemeyer, Charlotte M. Niemeyer Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, andGerman Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany https://orcid.org/0000-0003-3856-7937 Search for other works by this author on: This Site PubMed Google Scholar Brigitte Schlegelberger, Brigitte Schlegelberger Department of Human Genetics, Hannover Medical School, Hannover, Germany; https://orcid.org/0000-0001-5256-1270 Search for other works by this author on: This Site PubMed Google Scholar Ayami Yoshimi, Ayami Yoshimi Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, and Search for other works by this author on: This Site PubMed Google Scholar Marcin W. Wlodarski Marcin W. Wlodarski Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, andDepartment of Hematology, St Jude Children’s Research Hospital, Memphis, TN; https://orcid.org/0000-0001-6638-9643 Search for other works by this author on: This Site PubMed Google Scholar Blood (2021) 138 (23): 2441–2445. https://doi.org/10.1182/blood.2021012781 Article history Submitted: June 4, 2021 Accepted: August 5, 2021 First Edition: September 1, 2021 Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Request Permissions Cite Icon Cite Search Site Citation Emilia J. Kozyra, Gudrun Göhring, Dennis D. Hickstein, Katherine R. Calvo, Courtney D. DiNardo, Michael Dworzak, Valerie de Haas, Jan Starý, Henrik Hasle, Akiko Shimamura, Mark D. Fleming, Hiroto Inaba, Sara Lewis, Amy P. Hsu, Steven M. Holland, Danielle E. Arnold, Cristina Mecucci, Siobán B. Keel, Alison A. Bertuch, Kiran Tawana, Shlomit Barzilai, Shinsuke Hirabayashi, Masahiro Onozawa, Shaohua Lei, Helena Alaiz, Hajnalka Andrikovics, David Betts, Berna H. Beverloo, Jochen Buechner, Martin Čermák, José Cervera, Olga Haus, Kirsi Jahnukainen, Kalliopi N. Manola, Karin Nebral, Francesco Pasquali, Joelle Tchinda, Dominik Turkiewicz, Nadine Van Roy, Zuzana Zemanova, Victor B. Pastor, Brigitte Strahm, Peter Noellke, Charlotte M. Niemeyer, Brigitte Schlegelberger, Ayami Yoshimi, Marcin W. Wlodarski; Association of unbalanced translocation der(1;7) with germline GATA2 mutations. Blood 2021; 138 (23): 2441–2445. doi: https://doi.org/10.1182/blood.2021012781 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBlood Search Subjects: Myeloid Neoplasia TO THE EDITOR: GATA2 deficiency is an autosomal dominant disorder predisposing to myeloid neoplasia and immunodeficiency.1-4 GATA2-related myelodysplastic syndrome (MDS) may present early in life and is commonly associated with monosomy 7 and trisomy 8 karyotypes.5,6 Der(1;7)(q10;p10), henceforth der(1;7), is an unbalanced whole-arm chromosomal translocation resulting in trisomy 1q and deletion 7q (del(7q)) (Figure 1A).7 This translocation has been recurrently reported in adults with primary and therapy-related hematopoietic malignancies, whereas in children it is associated with primary MDS.6,8-10 Previously, we and others reported single cases of GATA2 deficiency that carry der(1;7).4,6,11–15 Building on this intriguing observation, we aimed to define the prevalence of der(1;7) in pediatric MDS according to germline GATA2 mutation (GATA2mut) status and describe the features of this unique subgroup. We evaluated 1620 children and adolescents with primary MDS consecutively enrolled in the registries of the European... REFERENCES 1.Hsu AP, Sampaio EP, Khan J, et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood. 2011;118(10):2653-2655.Google ScholarCrossrefSearch ADS PubMed 2.Dickinson RE, Griffin H, Bigley V, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011;118(10):2656-2658.Google ScholarCrossrefSearch ADS PubMed 3.Hahn CN, Chong CE, Carmichael CL, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43(10):1012-1017.Google ScholarCrossrefSearch ADS PubMed 4.Pasquet M, Bellanné-Chantelot C, Tavitian S, et al. 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PURPOSE:In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS:Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS:Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. CONCLUSION:Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.

Acute megakaryoblastic leukaemia (AMKL) is a subtype of myeloid leukaemia and is the most common leukaemia type in children with Down syndrome (DS) under 4 years of age. AMKL is often preceded by a transient neonatal pre-leukaemic syndrome, transient myeloproliferative disorder (TMD). Although TMD often spontaneously resolves, 20–30% of these patients subsequently develop AMKL within the first 4 years of life. To perform a retrospective consecutive national audit of all documented cases of childhood TMD and AMKL-DS from 1990 to 2018 at Our Lady’s Children’s Hospital, Crumlin (OLCHC), Ireland. All patients with a diagnosis of AMKL treated consecutively at (OLCHC) between 1990 and 2018 were reviewed. Kaplan-Meier survival curves were constructed. Twenty-seven patients with AMKL-DS were identified. A prior neonatal diagnosis of TMD was described in 10 patients (37%). Nineteen patients (70%) are alive and well, in complete remission, at a median follow-up of 11.4 years. Overall survival (OS) of this cohort has risen from 54% from those treated between the years 1990 and 2004 (n = 13) to 93% for those treated between the years 2005 and 2018 (n = 14). High cure rates are observed in AMKL-DS using current polychemotherapy protocols. The finding of a low platelet count at time of diagnosis is in keeping with the knowledge that AMKL-DS is a malignancy of platelet progenitor cells.

Background Both trisomy 9p and partial trisomy 13q have been recognised in past with characteristics clinical anomaly, our case is the first reported case of combined partial double trisomy involving chromosome 9p and 13q. Phenotypic Characteristics vary based on the regions of the chromosome involved and the gene dosages effect. Characteristics of our index case would not only help clinician in genotype-phenotype correlation of any such future cases but would also add up to the already described consequences in offspring of balanced reciprocal translocations in either parents Case report A female infant was born at 41 weeks gestation by normal delivery with birth weight 3.3 kgs. The pregnancy was uneventful. Baby had an episode of hypoglycaemia during very first day of life. Physical examination of the baby revealed profound central hypotonia, head lag, low set ears, depressed nasal bridge and increased nuchal pad of fat. Cardiac examination revealed soft systolic murmur of grade 2/6 which subsequently on echocardiography was noted to arise from a small atrial septal defect. Remainder systemic examination was within normal limits. Further course in the special care baby unit was complicated by recurrent apneas, desaturations and poor feeding. She also developed symptoms of cow milk protein’s intolerance and gastro oesophageal reflux later on in life. Cranial ultrasound, Electroencephalography, MRI of the brain, renal ultrasound, sleep study, Laryngo bronchoscopy, chest and thoracic inlet X-rays were all normal. Array comparative genomic hybridisation, using a 60K Agilent chip showed a gain of chromosome 9 material of approximately 30.9Mb at bands 9p24.3–9p21.1 between base pair coordinates 204193 and 31104204, and an another gain of chromosome 13 material of approximately 11.2Mb at bands 13q12.11–13q12.3 between base pair coordinates 20407295 and 31578124, with the former representing the most proximal probe on this platform. Subsequent analysis of G banded metaphase chromosomes demonstrated an abnormal female karyotype with an additional chromosome consistent with a der(13)t(9;13)(p21.1;q12). Karyotypic analysis of the parents showed that the mother carried a balanced t(9;13) translocations. Therefore the transferred genetic defect in the index case was a product of 3:1 segregation error of maternal reciprocal translocation t(9;13)(p21;q12). Conclusion Balanced reciprocal translocations in either parents can amplify and produce unbalanced gamets leading to defective conceptus. Prenatal diagnosis is strongly recommended where balanced translocation is found in parent. Clinical features of the affected conceptus depends largely on the regions of chromosome involved.

A patient was referred in consequence of an abnormal microarray finding. The background history was of Left Congenital Diaphragmatic hernia, coarctation of Aorta and PDA. Examined at 5 weeks by Consultant Clinical Geneticist, she was non-dysmorphic, her head circumference was on 25th percentile. Neurological examination was age appropriate. ACGH showed a mosaic chromosomal imbalance involving chromosome 2q in the form of a ∼46.7Mb gain of 2q26.1–q31.2 and a ∼17.6Mb loss of 2q36.2–qter, which was estimated to be present in approximate 50% of cells. In contrast G-band karyotype analysis of phytohaemoglutinin stimulated and cultured cells showed no evidence of the abnormal cell line, with only apparently normal female 46, XX metaphases seen. So, there was a data mismatch. Parental karyotypes were both normal. Due to the peripheral blood karyotype result a skin biopsy was taken for culture and karyotyping, together with a buccal smear for FISH analysis. In addition, a second peripheral blood sample was taken to allow FISH analysis on non-cultured cells. These FISH analyses indicated the presence of an abnormal cell line in 19% (buccal smear) and 35% (whole blood) of the 200 cells analysed. Conversely cultured fibroblasts only resulted in cells with a normal female karyotype. Hence, these results indicate that the level of mosaicism varies dramatically between different cell lineages. The absence of the abnormal cell line in the cultured cells would support that this cell line is not present in the T-lymphocytes. A FBC and film showed normal white cell counts and morphology. The findings with the cultured fibroblasts may be reflective of either the absence or scarcity of the abnormal cell line in the biopsy. This most unusual case illustrates that the understanding of how test results are generated and potential limitations of each test is crucial when considering the clinical features of the patient. Further it demonstrates how mosaicism may be unequally distributed between cell types or indeed absent in the actual cell type that is being tested. It is reassuring that the patient is neurologically age appropriate. The management with clinical and developmental observation are warranted to monitor her progress.

The spectrum of phenotypes associated with heterozygous deletions of neurexin-1 (NRXN1) is diverse and includes: autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, seizures, schizophrenia, mood disorders and congenital malformations. Reduced penetrance and variable expressivity of deletions in this gene remain a challenge for genetic counselling. We clinically reviewed 67 NRXN1 deletions from 34 families to document the phenotype and determine odds ratio. Thirty-four probands (5 adults, 29 children (<16 years)) were initially identified from a cohort clinically referred for arrayCGH. A further 33 NRXN1 deletions (16 with established phenotype) from the families were identified following cascade screening. Speech and language delay was a consistent clinical presentation. Pedigree analysis of the inherited group revealed numerous untested relatives with a history of mental health and developmental issues, most notably in the NRXN1β isoform patients. Our study highlights the complex nature of the NRXN1 phenotype in this population.

The cover image, by James J. O'Byrne et al., is based on the Clinical Report Bicoronal and metopic craniosynostosis in association with a de novo unbalanced t(2;7) chromosomal translocation, DOI: 10.1002/ajmg.a.38001.

We report the case of a developmentally appropriate infant male with a de novo unbalanced chromosome translocation involving bands 2q32.1 and 7p21.3. The child was noted to have metopic and bicoronal craniosynostosis with closely spaced eyes, turricephaly, and flattening of the forehead. © 2016 Wiley Periodicals, Inc.

Transient abnormal myelopoiesis (TAM) is a transient neonatal leukaemia that occurs in infants with Down Syndrome (DS) including trisomy 21 (T21) mosaicism. There are reported cases of TAM occurring in constitutionally normal children in whom T21 is present in the leukaemia cells (Richards et al, 1998). Monozygotic (MZ) twins are frequently referred to as ‘identical’. Identical twins with concordant leukaemia, although rare, are well described (Greaves et al, 2003). Concordance for leukaemia in MZ twins is explained by a single origin of leukaemia in one twin in utero with spread by intraplacental anastomoses to the other twin. We present MZ twins concordant for TAM but discordant for T21. One twin died in utero. In the surviving twin, after resolution of leukaemia, there was no evidence of constitutional T21, even at mosaic level. The deceased twin was mosaic T21. A 41-year old primigravida conceived a monochorionic diamniotic twin pregnancy following in vitro fertilization. The development of maternal pre-eclampsia and foetal hydrops in one twin necessitated urgent caesarean section at 28 weeks’ gestation. The hydropic foetus died in utero shortly prior to delivery. Twin I was a live born female weighing 1·14 kg. Full blood count showed haemoglobin (Hb) of 114 g/l, white cell count 126 × 109/l comprising 80% blasts and platelet count of 124 × 109/ll. Biochemistry revealed a hyperuricaemia, hyperkalaemia and grossly elevated lactate dehydrogenase (LDH). These were felt to be secondary to hyperleucocytosis as no other cause was identified. Blood film and flow cytometry confirmed the diagnosis of TAM with undifferentiated blasts comprising 80% of white cells. Blasts were positive for the megakaryocytic marker CD61. Fluorescence in situ hybridization (FISH) confirmed the presence of an extra copy of chromosome 21 in all cells examined. A GATA1 mutation in exon 2 was identified, in keeping with a diagnosis of TAM. The leukaemia resolved over 10 weeks with supportive management including red cell and platelet transfusions and the use of rasburicase to manage hyperuricaemia. Initial karyotype, carried out on peripheral blood 7 d after birth, showed T21 karyotype. However, FISH analysis on a buccal smear showed T21 in just 4% of cells. The follow-up karyotype, after resolution of TAM, at 22 weeks of age confirmed a normal female 46,XX karyotype. At age 3 years there is no evidence of disease recurrence, and karyotype is normal 46,XX. Twin 2, also female, was stillborn, weighing 1·8 kg. Post mortem findings showed a markedly hydropic female. There was generalized oedema. There were pleural, pericardial and peritoneal effusions. The liver was markedly enlarged (4·5 times the normal size), as was the spleen. Sections taken through multiple organs including heart, lungs, liver, uterus, fallopian tubes and ovaries, kidneys, thyroid, pituitary, adrenals and thymus showed an infiltrate comprising large blasts. Some blasts had granular cytoplasm and resembled atypical megakaryoblasts with platelet budding. Others were undifferentiated. Blasts were positive for myeloperoxidase and CD61, in keeping with megakaryoblastic leukaemia. The karyotype of Twin 2, performed by fibroblast monolayer, showed 47,XX,+21(9)/46,XX(21). This was verified in two independent skin fibroblast cultures and was consistent with a female with T21 mosaicism. GATA1 analysis was not performed in Twin 2. Placental examination confirmed monochorionicity and the placental karyotype was normal 46,XX. Monozygosity of the twins was confirmed by microsatellite analysis. The occurrence of TAM in twins is rare but has been previously described (Shimada et al, 2004). However, in that case report, unlike ours, the affected twins were concordant for T21. It is likely that TAM arose in Twin 2, who was mosaic T21, and spread to Twin 1 via vascular anastomoses. Vascular anastomoses occur in 70% of monochorionic twins (van Dijk et al, 1996). It is uncertain why the same disease process led to such different outcomes in the twins; despite a white cell count of over 100 × 109/l, [previously identified as a risk factor for early death (Massey et al, 2006)], Twin 1 had no identifiable cardiac or hepatic compromise secondary to her TAM, and went on to complete remission with supportive therapy only. Potential explanations include a briefer duration of disease in Twin 1 with briefer exposure to TAM blast-derived cytokines, e.g., platelet-derived growth factor or transforming growth factor-beta, which are implicated in the development of fibrosis (Hattori et al, 2001). Prenatal TAM is associated with high mortality rates (Roy et al, 2013). Attempts at prenatal treatment have been reported with inconsistent results (Tamblyn et al, 2016). While it is often assumed that monozygotic twins are ‘identical’ this is not the case. Post-zygotic genetic and epigenetic changes occur. These may be clinically silent or in extreme cases can result in discordance for trisomy, as in this case. In considering prenatal diagnosis and intervention, the possibility of discordant karyotypes within a monozygotic pair should be noted. This case presents us with an extreme example of discordance in so-called ‘identical’ twins – one mosaic T21 with in utero lethal outcome, the other karyotypically normal with a transient leukaemia and favourable outcome. No honorarium, grant or other payment was received. There are no prior publications or submissions with any overlapping information, including studies and patients. GB wrote the manuscript and was the neonatal registrar with clinical responsibility for the patient. KF and MG were responsible for prenatal and perinatal care. ED was the pathologist involved in the post-mortem analysis of the deceased twin. DB was the chief scientist involved in the laboratory diagnosis of TAM. AF was the consultant neonatologist in charge of the patient. AOM and MC were the haematologists involved in diagnosis and management and MC has responsibility for long-term follow-up.

Background Chromosomal trisomies are associated with advancing maternal age. In Ireland, information on the total prevalence and outcome of trisomy affected pregnancies is unavailable. This study aimed to ascertain more precise data on Trisomies 21, 18 and 13 in a large Irish region during the period 2011-2013. Methods Multiple information sources were used in case finding, including a regional congenital anomaly register, all maternity and paediatric hospitals in the region and the regional Department of Clinical Genetics. Results There were 394 trisomy cases from 80894 total births, of which 289 were Trisomy 21, 75 were Trisomy 18 and 30 were Trisomy 13. The total prevalence rate was 48.9/10000 births, 35.7, 9.3 and 3.7 for Trisomies 21, 18 and 13, respectively. Over 90% of Trisomies 18/13 and 47% of Trisomy 21 were diagnosed prenatally; 61% of Trisomy 21 cases and nearly 30% of Trisomies 18/13 were live births; 38% all trisomy affected pregnancies ended in a termination. Conclusions This study provides precise data on the total prevalence and outcome of trisomy affected pregnancies in the East of Ireland. Total prevalence rates were higher than previously reported. Prenatal diagnosis had a significant impact on outcome. These data provide a better basis for planning of services for live-born children affected by trisomy.

Mosaic Turner syndrome (TSM) commonly occurs in the form of 45,X/46,XX and 45,X/46,X,i(X)(q10). Mosaicism for a Y chromosome, 45,X/46,XY, has been well documented and is associated with increased risk of gonadoblastoma (GB). To date, there are only six reported cases of TSM with a trisomy 18 karyotype, and only two of these were phenotypically female with 45,X/47,XY,+18 karyotype. We present the case of a phenotypically female infant born with dysmorphic features. G-banded karyotype and interphase FISH of blood showed 45,X in 95% and 47,XY,+18 (trisomy 18) in 5% of cells analysed. However, interphase FISH of buccal cells showed only the presence of the 45,X cell line. Due to the presence of Y chromosome material, elective gonadectomy was performed at 13 months of age. There were bilateral streak ovaries with early evidence of GB bilaterally, a rudimentary uterus and bilateral fallopian tubes with unilateral ectopic adrenal tissue identified histologically. Interphase FISH of the gonadal tissue was similar to the blood findings with 45,X in 86% of cells and 47,XY,+18 in 14% of cells analysed. This case highlights a rare karyotype of TSM and trisomy 18 in the same patient and is the first reporting the associated finding of bilateral GB.

HaemophiliaVolume 22, Issue 1 p. e51-e54 Letter to the Editor X-linked moyamoya syndrome associated with severe haemophilia A M. Lavin, M. Lavin Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this authorP. V. Jenkins, Corresponding Author P. V. Jenkins Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, Ireland Correspondence: Dr. Vince Jenkins, National Centre for Hereditary Coagulation Disorders, St. James's Hospital, Dublin 8, Ireland. Tel.: +353 (1) 416 2141; fax: +353 (1) 410 3570; e-mail: [email protected]Search for more papers by this authorC. Keenan, C. Keenan National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this authorB. White, B. White Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this authorD. R. Betts, D. R. Betts Department of Clinical Genetics, Our Lady's Children's Hospital, Dublin, IrelandSearch for more papers by this authorJ. S. O'Donnell, J. S. O'Donnell Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this authorN. M. O'Connell, N. M. O'Connell Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this author M. Lavin, M. Lavin Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this authorP. V. Jenkins, Corresponding Author P. V. Jenkins Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, Ireland Correspondence: Dr. Vince Jenkins, National Centre for Hereditary Coagulation Disorders, St. James's Hospital, Dublin 8, Ireland. Tel.: +353 (1) 416 2141; fax: +353 (1) 410 3570; e-mail: [email protected]Search for more papers by this authorC. Keenan, C. Keenan National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this authorB. White, B. White Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this authorD. R. Betts, D. R. Betts Department of Clinical Genetics, Our Lady's Children's Hospital, Dublin, IrelandSearch for more papers by this authorJ. S. O'Donnell, J. S. O'Donnell Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this authorN. M. O'Connell, N. M. O'Connell Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Trinity College Dublin, Dublin, Ireland National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, IrelandSearch for more papers by this author First published: 30 September 2015 https://doi.org/10.1111/hae.12806Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1Rallapalli PM, Kemball-Cook G, Tuddenham EG, Gomez K, Perkins SJ. Factor VIII mutation database, 2014. Available at http://www.factorviii-db.org/. Accessed May 1, 2015. 2Miskinyte S, Butler MG, Hervé D et al. Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am J Hum Genet 2011; 88: 718–28. 3Janczar S, Fogtman A, Koblowska M et al. Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 genes. Blood 2014; 123: 4002–4. 4Winter P, Egan H, McNulty O, Jones FG, O'Donnell J, Jenkins PV. A recurrent F8 mutation in Irish haemophilia A patients: evidence for a founder effect. Haemophilia 2008; 14: 394–5. Citing Literature Volume22, Issue1January 2016Pages e51-e54 ReferencesRelatedInformation