Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2019

Open Access 01-12-2019 | Myelodysplastic Syndrome | Research

Hematopoietic stem cell transplantation in a patient with type 1 mosaic variegated aneuploidy syndrome

Authors: Alexandra Laberko, Dmitry Balashov, Elena Deripapa, Olga Soldatkina, Elena Raikina, Alexei Maschan, Galina Novichkova, Anna Shcherbina

Published in: Orphanet Journal of Rare Diseases | Issue 1/2019

Login to get access

Abstract

Background

Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal instability disorder that leads to aneuploidies of different chromosomes in various tissues. Type 1 MVA (MVA1) is caused by mutations in the budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) gene. The main clinical features of MVA1 syndrome are growth and mental retardation, central nervous system anomalies, microcephaly, and predisposition to cancers. There have been no reports of hematopoietic stem cell transplantation (HSCT) in MVA patients.

Results

We report an 11-year old boy diagnosed with MVA1 syndrome. The BUB1B gene mutations c.498_505delAAACTTTA and c.1288 + 5G > A were detected using the next generation sequencing (NGS) method. The patient presented with cytopenia soon after birth, but remained stable until 9 years of age, when he developed myelodysplastic syndrome associated with monosomy of chromosome 7. Due to severe dependence on blood transfusions, a TCRαβ+/CD19+ depleted HSCT was performed from a matched unrelated donor (MUD) using a treosulfan-based reduced intensity conditioning (RIC) regimen. The engraftment occurred, and no severe toxicity was observed soon after the HSCT, but on day + 47, graft rejection was detected. It was followed by prolonged pancytopenia and sepsis with multi-organ Enterococcus faecium infection, which led to the patient’s death on day + 156 after HSCT.

Conclusions

In conclusion, we demonstrate that RIC HSCT with TCRαβ+/CD19+ depletion was well tolerated and resulted in complete hematologic recovery in our MVA1 patient, but, unfortunately, it was followed by rapid graft rejection. This fact needs to be taken into consideration for HSCT in other MVA patients.
Literature
1.
Hanks S, Coleman K, Reid S, Plaja A, Firth H, FitzPatrick D, et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet. 2004 Nov;36(11):1159–61.CrossRefPubMed
2.
Sudakin V, Chan GKT, Yen TJ. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol. 2001 Sep 3;154(5):925–36.CrossRefPubMedPubMedCentral
3.
Bohers E, Sarafan-Vasseur N, Drouet A, Paresy M, Latouche J-B, Flaman J-M, et al. Gradual reduction of BUBR1 protein levels results in premature sister-chromatid separation then in aneuploidy. Hum Genet. 2008 Dec;124(5):473–8.CrossRefPubMed
4.
Wang Q. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood. 2003 Oct 23;103(4):1278–85.CrossRefPubMed
5.
Matsuura S, Matsumoto Y, Morishima K, Izumi H, Matsumoto H, Ito E, et al. MonoallelicBUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome. Am J Med Genet A. 2006 Feb 15;140A(4):358–67.CrossRef
6.
Kato M, Kato T, Hosoba E, Ohashi M, Fujisaki M, Ozaki M, et al. PCS/MVA syndrome caused by an Alu insertion in the BUB1B gene. Hum Genome Var. 2017 Jun 8;4:17021.CrossRefPubMedPubMedCentral
7.
García-Castillo H, Vásquez-Velásquez AI, Rivera H, Barros-Núñez P. Clinical and genetic heterogeneity in patients with mosaic variegated aneuploidy: delineation of clinical subtypes. Am J Med Genet A. 2008 Jul 1;146A(13):1687–95.CrossRefPubMed
8.
Jacquemont S, Bocéno M, Rival JM, Méchinaud F, David A. High risk of malignancy in mosaic variegated aneuploidy syndrome: high risk of malignancy in MVA syndrome. Am J Med Genet. 2002 Apr 15;109(1):17–21.CrossRefPubMed
9.
Hanks S, Coleman K, Summersgill B, Messahel B, Williamson D, Pritchard-Jones K, et al. Comparative genomic hybridization and BUB1B mutation analyses in childhood cancers associated with mosaic variegated aneuploidy syndrome. Cancer Lett. 2006 Aug;239(2):234–8.CrossRefPubMed
10.
Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JKV, Markowitz SD, et al. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998 Mar;392(6673):300–3.CrossRefPubMed
11.
Roberts NJ, Norris AL, Petersen GM, Bondy ML, Brand R, Gallinger S, et al. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic Cancer. Cancer Discov. 2016 Feb 1;6(2):166–75.CrossRefPubMed
12.
Shindo K, Yu J, Suenaga M, Fesharakizadeh S, Cho C, Macgregor-Das A, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol. 2017 Oct 20;35(30):3382–90.CrossRefPubMedPubMedCentral
13.
Rooney D, Czepulkowski B. Human cytogenetics: a practical approach: IRL Press; 1992. p. 1–25.
14.
Munker R, Editor. The BMT data book: including cellular therapy. 3rd ed. Cambridge ; New York: Cambridge University Press; 2013. 543 p.
15.
Weltgesundheitsorganisation. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. Lyon: International Agency for Research on Cancer; 2017. 585 p. (World Health Organization classification of tumours).
16.
Wlodarski MW, Hirabayashi S, Pastor V, Stary J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016 Mar 17;127(11):1387–97.CrossRefPubMed
17.
18.
Ebens CL, MacMillan ML, Wagner JE. Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations. Expert Rev Hematol. 2017 Jan 2;10(1):81–97.CrossRefPubMed
19.
Balashov D, Shcherbina A, Maschan M, Trakhtman P, Skvortsova Y, Shelikhova L, et al. Single-center experience of unrelated and Haploidentical stem cell transplantation with TCRαβ and CD19 depletion in children with primary immunodeficiency syndromes. Biol Blood Marrow Transplant. 2015 Nov;21(11):1955–62.CrossRefPubMed
20.
Deripapa E, Balashov D, Rodina Y, Laberko A, Myakova N, Davydova NV, et al. Prospective study of a cohort of Russian Nijmegen breakage syndrome patients demonstrating predictive value of low kappa-deleting recombination excision circle (KREC) numbers and beneficial effect of hematopoietic stem cell transplantation (HSCT). Front Immunol [Internet]. 2017 Jul 24 [cited 2017 Sep 24];8. Available from: http://​journal.​frontiersin.​org/​article/​10.​3389/​fimmu.​2017.​00807/​full.
21.
Pfau SJ, Silberman RE, Knouse KA, Amon A. Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo. Genes Dev. 2016 Jun 15;30(12):1395–408.CrossRefPubMedPubMedCentral
22.
23.
24.
Slack J, Albert MH, Balashov D, Belohradsky BH, Bertaina A, Bleesing J, et al. Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders. J Allergy Clin Immunol. 2018 Jan;141(1):322–328.e10.CrossRefPubMed
Metadata
Title
Hematopoietic stem cell transplantation in a patient with type 1 mosaic variegated aneuploidy syndrome
Authors
Alexandra Laberko
Dmitry Balashov
Elena Deripapa
Olga Soldatkina
Elena Raikina
Alexei Maschan
Galina Novichkova
Anna Shcherbina
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2019
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-019-1073-x

Other articles of this Issue 1/2019

Orphanet Journal of Rare Diseases 1/2019 Go to the issue

Research

Comparison of structural progression between ciliopathy and non-ciliopathy associated with autosomal recessive retinitis pigmentosa

Research

Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial

Research

Predictors of paravalvular aortic regurgitation after surgery for Behcet’s disease-related severe aortic regurgitation

Research

Primary hypertrophic osteoarthropathy related gastrointestinal complication has distinctive clinical and pathological characteristics: two cases report and review of the literature

Review

Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

Research

Arabidopsis thaliana alternative dehydrogenases: a potential therapy for mitochondrial complex I deficiency? Perspectives and pitfalls