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From www.bloodjournal.org by guest on November 24, 2014. For personal use only.
2014 123: 4002-4004
doi:10.1182/blood-2014-02-553685
Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by
Xq28 deletions encompassing F8 and BRCC3 genes
Szymon Janczar, Anna Fogtman, Marta Koblowska, Dobromila Baranska, Agata Pastorczak, Olga
Wegner, Magdalena Kostrzewska, Pawel Laguna, Maciej Borowiec and Wojciech Mlynarski
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BLOOD, 19 JUNE 2014 x VOLUME 123, NUMBER 25
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displayed significant cell death after exposure to neutrophils in the
presence of either RTX or OFA, but not to either agent alone. The
addition of DPI rescued NK cells, strongly suggesting NADPH
oxidase– and ROS-dependent NK cell death (Figure 1E). During
the course of these experiments we did not have access to the
glycoengineered antibody obinituzumab, but given its profound
capacity to stimulate neutrophils, it is likely to share the ROStriggering characteristics of RTX and OFA.
Collectively, our findings raise the question of whether
oxygen radical release from aCD20-exposed neutrophils may
inactivate NK cells also in vivo and thus limit the efficacy of
therapeutic mAbs in CLL. More studies are warranted to investigate whether neutrophils or neutrophil-derived ROS are important effector arms in antibody treatment of CLL, and whether it
may be beneficial to supplement aCD20 therapy with antioxidative strategies to unravel the full effector function of NK cells
in CLL.
Approval was obtained from the Ethical Review Board of
Gothenburg for these experiments. Informed consent was provided
according to the Declaration of Helsinki.
Olle Werlenius
Sahlgrenska Cancer Center and Department of Hematology,
The Sahlgrenska Academy, University of Gothenburg,
Gothenburg, Sweden
Rebecca E. Riise
Sahlgrenska Cancer Center and Department of Infectious Diseases,
The Sahlgrenska Academy, University of Gothenburg,
Gothenburg, Sweden
Maria Simpanen
Sahlgrenska Cancer Center and Department of Hematology,
The Sahlgrenska Academy, University of Gothenburg,
Gothenburg, Sweden
Johan Aurelius
Sahlgrenska Cancer Center and Department of Infectious Diseases,
The Sahlgrenska Academy, University of Gothenburg,
Gothenburg, Sweden
Fredrik B. Thoren
´
Sahlgrenska Cancer Center and Department of Infectious Diseases,
The Sahlgrenska Academy, University of Gothenburg,
Gothenburg, Sweden
Acknowledgments: This work was supported by the Goteborg
¨
Medical
Society, the Wilhelm and Martina Lundgren Foundation, the Assar Gabrielsson
Foundation, and the Swedish Cancer Society.
Contribution: O.W., R.E.R., and M.S. performed experiments; O.W. analyzed
results and made the figure; and O.W., J.A., and F.B.T. designed the research
and wrote the letter.
Conflict-of-interest disclosure: The authors declare no competing financial
interests.
Correspondence: Olle Werlenius, Sahlgrenska Cancer Center, University of
Gothenburg, Box 425, 405 30 Gothenburg, Sweden; e-mail: olle.werlenius@
gu.se.
References
1. Golay J, Da Roit F, Bologna L, et al. Glycoengineered CD20 antibody
obinutuzumab activates neutrophils and mediates phagocytosis through CD16B
more efficiently than rituximab. Blood. 2013;122(20):3482-3491.
2. Bylund J, Bjornsdottir
¨
H, Sundqvist M, Karlsson A, Dahlgren C. Measurement of
respiratory burst products, released or retained, during activation of professional
phagocytes. Methods Mol Biol. 2014;1124:321-338.
3. Dall’Ozzo S, Tartas S, Paintaud G, et al. Rituximab-dependent cytotoxicity by
natural killer cells: influence of FCGR3A polymorphism on the concentrationeffect relationship. Cancer Res. 2004;64(13):4664-4669.
4. Golay J, Manganini M, Facchinetti V, et al. Rituximab-mediated antibodydependent cellular cytotoxicity against neoplastic B cells is stimulated strongly by
interleukin-2. Haematologica. 2003;88(9):1002-1012.
5. Hellstrand K, Asea A, Dahlgren C, Hermodsson S. Histaminergic regulation of
NK cells. Role of monocyte-derived reactive oxygen metabolites. J Immunol.
1994;153(11):4940-4947.
6. Thoren
´ FB, Romero AI, Hermodsson S, Hellstrand K. The CD16-/CD56bright
subset of NK cells is resistant to oxidant-induced cell death. J Immunol.
2007;179(2):781-785.
© 2014 by The American Society of Hematology
To the editor:
Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions
encompassing F8 and BRCC3 genes
A 10-year-old boy with severe hemophilia A and no other obvious
morbidity arrived at the hospital with focal neurological signs and a
suspected intracranial hemorrhage. Surprisingly, radiological studies
demonstrated an ischemic stroke. Neither active thromboembolism
nor genetic predisposition to thrombosis was found. Neuroimaging
demonstrated severe narrowing of internal carotid arteries and their
branches and development of a collateral vascular network, diagnostic
of moyamoya syndrome (Figure 1). Further clinical workup revealed
mild facial dysmorphia, hypertension, osteopenia, and duplication
of the right renal artery, a phenotype likely caused by a genetic
aberration. Next-generation sequencing followed by long-range
polymerase chain reaction (Figure 1 and supplemental Materials)
demonstrated a large Xq28 deletion of ;150 kbp encompassing
exons 1 to 6 of F8, as well as the FUNDC2, MTCP1NB, MTCP1,
and BRCC3 genes. BRCC3 was recently identified as a familial
moyamoya gene.1 We demonstrate that both centromeric and telomeric
breakage sites of the deletion are located in nearly identical repetitive
Alu sequences that could be mutational hotspots. The patient’s sister
and mother are heterozygous for the same deletion. At the age of 18,
the sister presented a mild phenotype including low levels of factor
VIII (22%), aortic coarctation, and hypertension, but she has no signs
of moyamoya angiopathy.
A review of the literature yields 3 more likely individuals/families
with this novel severe hemophilia and moyamoya (SHAM) syndrome:
1 clinical description in a Japanese patient2 and 2 descriptions of
Xq28 rearrangements in hemophilia A patients that disrupt BRCC3
and bear striking clinical similarity to Xq28-linked familial moyamoya, although no neuroimaging data are available to confirm the
diagnosis.3,4 There is also a genetic report of BRCC3 deletion in
a hemophilia patient without phenotype data.5 The ratio of BRCC3
inactivation in hemophilia A is unknown because the regions
telomeric to F8 are rarely subjected to genetic diagnostics. We
accessed the Centers for Disease Control Hemophilia A mutation
project database that contains .2000 pathological F8 mutations
From www.bloodjournal.org by guest on November 24, 2014. For personal use only.
BLOOD, 19 JUNE 2014 x VOLUME 123, NUMBER 25
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4003
Figure 1. The radiological and genetic diagnosis of Xq28 linked moyamoya in hemophilia A patient. (A) MRI angiography, the arrows show truncation of the internal
carotid arteries. (B) Long-range PCR products in 4 members of the family. (C) NGS trace (the location shown on chromosome ideogram) below genes located within the
region, which corresponds to the long-range PCR-confirmed Xq28 deletion in a SHAM patient (indicated with red box).
reported worldwide. This reports 5.9% of cases with large structural
variation among hemophilia A patients, with a rate of large deletions
of 4.7% and a rate of deletions affecting exon 1 of 1.1%. It has not
been determined how many of these lesions extend to other genes.
It must be considered, however, that in some patients, hemophilia
A comorbidity, including well-documented osteopenia, hypertension, and reduced growth velocity,6-8 might be exacerbated by
genomic disruption or defective regulation of genes other than F8. We
conclude hemophilia A may be associated with moyamoya angiopathy, and the patients with SHAM syndrome are at risk of ischemic
stroke.
Because of features of cerebral circulation insufficiency, our
patient underwent neurosurgical intervention (indirect bypass
revascularization) and is clinically stable with no ischemic episodes at 2.5 years after surgery. The prognosis is poor because of
multiorgan abnormalities expected in familial moyamoya linked
to Xq28.1
Szymon Janczar
Department of Pediatrics, Oncology, Hematology, and Diabetology,
Medical University of Lodz,
Lodz, Poland
Anna Fogtman
Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics,
Polish Academy of Sciences,
Warsaw, Poland
Marta Koblowska
Faculty of Biology, University of Warsaw,
Warsaw, Poland
Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics,
Polish Academy of Sciences,
Warsaw, Poland
Dobromila Baranska
Department of Pediatric Radiology, University Hospital No 4,
Lodz, Poland
Agata Pastorczak
Department of Pediatrics, Oncology, Hematology, and Diabetology,
Medical University of Lodz,
Lodz, Poland
Olga Wegner
Department of Pediatrics, Oncology, Hematology, and Diabetology,
Medical University of Lodz,
Lodz, Poland
Magdalena Kostrzewska
Department of Pediatrics, Oncology, Hematology, and Diabetology,
Medical University of Lodz,
Lodz, Poland
Pawel Laguna
Department of Pediatrics, Hematology and Oncology,
Medical University of Warsaw,
Warsaw, Poland
Maciej Borowiec
Department of Pediatrics, Oncology, Hematology, and Diabetology,
Medical University of Lodz,
Lodz, Poland
From www.bloodjournal.org by guest on November 24, 2014. For personal use only.
4004
CORRESPONDENCE
Wojciech Mlynarski
Department of Pediatrics, Oncology, Hematology, and Diabetology,
Medical University of Lodz,
Lodz, Poland
The online version of this article contains a data supplement.
Contribution: A.F., M. Koblowska, A.P., D.B., O.W., M. Kostrazewska, P.L., and.
M.B. performed experiments and analyzed results; and S.J. and W.M. designed
the research, performed experiments, analyzed results, and wrote the paper.
Conflict-of-interest disclosure: The authors declare no competing financial
interests.
Correspondence: Wojciech Mlynarski, Department of Pediatrics, Oncology,
Hematology and Diabetology, Medical University of Lodz, 36/50 Sporna Str,
91-738 Lodz, Poland; e-mail: [email protected].
References
1. Miskinyte S, Butler MG, Herve´ D, et al. Loss of BRCC3 deubiquitinating enzyme
leads to abnormal angiogenesis and is associated with syndromic moyamoya.
Am J Hum Genet. 2011;88(6):718-728.
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2. Matsuda M, Enomoto T, Yanaka K, Nose T. Moyamoya disease associated with
hemophilia A. Case report. Pediatr Neurosurg. 2002;36(3):157-160.
3. Fujita J, Miyawaki Y, Suzuki A, et al. A possible mechanism for Inv22-related
F8 large deletions in severe hemophilia A patients with high responding factor
VIII inhibitors. J Thromb Haemost. 2012;10(10):2099-2107.
4. Kenwrick S, Levinson B, Taylor S, Shapiro A, Gitschier J. Isolation and sequence
of two genes associated with a CpG island 59 of the factor VIII gene. Hum Mol
Genet. 1992;1(3):179-186.
5. Kim HJ, Kim DK, Yoo KY, et al. Heterogeneous lengths of copy number
mutations in human coagulopathy revealed by genome-wide high-density SNP
array. Haematologica. 2012;97(2):304-309.
6. Barnes C, Wong P, Egan B, et al. Reduced bone density among children with
severe hemophilia. Pediatrics. 2004;114(2):e177-e181.
7. Fransen van de Putte DE, Fischer K, Makris M, et al. Increased prevalence of
hypertension in haemophilia patients. Thromb Haemost. 2012;108(4):750-755.
8. Donfield SM, Lynn HS, Lail AE, Hoots WK, Berntorp E, Gomperts ED;
Hemophilia Growth and Development Study Group. Delays in maturation among
adolescents with hemophilia and a history of inhibitors. Blood. 2007;110(10):
3656-3661.
© 2014 by The American Society of Hematology