International Journal of Hematology

, Volume 110, Issue 1, pp 95–101 | Cite as

First case of neutropenia and thrombocytopenia in the setting of cerebral cavernous malformation 3

  • Clay Travis CohenEmail author
  • Katie Lee Bergstrom
  • Rui Xiao
  • Mohamed Tarek Elghetany
  • Ionela Iacobas
  • Ghadir Sasa
Case Report


Cerebral cavernous malformation 3 (CCM3) is a vascular malformation disorder causing brain slow-flow vascular parenchymal lesions. These lesions are the result of variants in the Programmed Cell Death Protein 10 (PDCD10) gene, located on 3q26.1. We report an 8-month-old patient who was presented with seizures and intracranial abscesses and was found to have a variant of PDCD10 on whole exome sequencing, representing, to our knowledge, the youngest case of CCM3 described in the literature. Her clinical course was complicated by the development of neutropenia, requiring granulocyte colony-stimulating factor, and thrombocytopenia, requiring intermittent platelet transfusions, with later development of B acute lymphoblastic leukemia 2 years after initial presentation. This case represents the first description in the literature of hematologic complications in the setting of CCM3. We hypothesize that these hematological manifestations are the result of alterations in the actin and microtubule cytoskeleton, affecting the process of hematopoiesis in a similar fashion to the documented effect of the PDCD10 variant on neuronal migration.


Cerebral cavernous malformation 3 Neutropenia Thrombocytopenia Pancytopenia Vascular malformation 



The authors are grateful to the patient and her family as well as the clinical staff at Texas Children’s Hospital Hematology and Cancer Centers for their participation.

Author Contributions

C. T. Cohen and K. L. Bergstrom prepared the initial draft of the manuscript. Revision and editing of the manuscript were done by C. T. Cohen, K. L. Bergstrom, G. Sasa, M. T. Elghetany, R. Xiao, and I. Iacobas.

Compliance with ethical standards

Conflict of interest

C. T. Cohen has research funding from Bayer Consumer Care AG, unrelated to above case report. R. Xiao works in the Department of Molecular and Human Genetics at Baylor College of Medicine which receives revenue from clinical genetic testing done at Baylor Genetics. K. L. Bergstrom, M. T. Elghetany, G. Sasa, and I. Iacobas declare that they have no conflict of interest.

Ethics statement

The patient’s parents have provided verbal consent for participation in this publication. This report was reviewed by the Baylor College of Medicine institutional review board and deemed exempt from review.


  1. 1.
    Carlsson G, Fasth A, Berglof E, Lagerstedt-Robinson K, Nordenskjold M, Palmblad J, et al. Incidence of severe congenital neutropenia in Sweden and risk of evolution to myelodysplastic syndrome/leukaemia. Br J Haematol. 2012;158(3):363–9.CrossRefGoogle Scholar
  2. 2.
    Tsangaris E, Klaassen R, Fernandez CV, Yanofsky R, Shereck E, Champagne J, et al. Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations. J Med Genet. 2011;48(9):618–28.CrossRefGoogle Scholar
  3. 3.
    Donadieu J, Beaupain B, Mahlaoui N, Bellanne-Chantelot C. Epidemiology of congenital neutropenia. Hematol Oncol Clin N Am. 2013;27(1):1–17 (vii).CrossRefGoogle Scholar
  4. 4.
    Schelonka RL, Yoder BA, desJardins SE, Hall RB, Butler J. Peripheral leukocyte count and leukocyte indexes in healthy newborn term infants. J Pediatr. 1994;125(4):603–6.CrossRefGoogle Scholar
  5. 5.
    Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6:26.CrossRefGoogle Scholar
  6. 6.
    Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral cavernous malformations: review of the genetic and protein-protein interactions resulting in disease pathogenesis. Front Surg. 2016;3:60.CrossRefGoogle Scholar
  7. 7.
    Riant F, Cecillon M, Saugier-Veber P, Tournier-Lasserve E. CCM molecular screening in a diagnosis context: novel unclassified variants leading to abnormal splicing and importance of large deletions. Neurogenetics. 2013;14(2):133–41.CrossRefGoogle Scholar
  8. 8.
    Liquori CL, Berg MJ, Squitieri F, Ottenbacher M, Sorlie M, Leedom TP, et al. Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat. 2006;27(1):118.CrossRefGoogle Scholar
  9. 9.
    Bonilla MA, Gillio AP, Ruggeiro M, Kernan NA, Brochstein JA, Abboud M, et al. Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N Engl J Med. 1989;320(24):1574–80.CrossRefGoogle Scholar
  10. 10.
    Sutcliffe MJ, Shuster JJ, Sather HN, Camitta BM, Pullen J, Schultz KR, et al. High concordance from independent studies by the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children’s Oncology Group (COG) initiative. Leukemia. 2005;19(5):734–40.CrossRefGoogle Scholar
  11. 11.
    Louvi A, Nishimura S, Gunel M. Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration. Development. 2014;141(6):1404–15.CrossRefGoogle Scholar
  12. 12.
    Zhu Y, Zhao K, Prinz A, Keyvani K, Lambertz N, Kreitschmann-Andermahr I, et al. Loss of endothelial programmed cell death 10 activates glioblastoma cells and promotes tumor growth. Neuro Oncol. 2016;18(4):538–48.CrossRefGoogle Scholar
  13. 13.
    Lauenborg B, Kopp K, Krejsgaard T, Eriksen KW, Geisler C, Dabelsteen S, et al. Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosis. Apmis. 2010;118(10):719–28.CrossRefGoogle Scholar
  14. 14.
    Cigoli MS, Avemaria F, De Benedetti S, Gesu GP, Accorsi LG, Parmigiani S, et al. PDCD10 gene mutations in multiple cerebral cavernous malformations. PLoS One. 2014;9(10):e110438.CrossRefGoogle Scholar
  15. 15.
    Spiegler S, Najm J, Liu J, Gkalympoudis S, Schroder W, Borck G, et al. High mutation detection rates in cerebral cavernous malformation upon stringent inclusion criteria: one-third of probands are minors. Mol Genet Genomic Med. 2014;2(2):176–85.CrossRefGoogle Scholar
  16. 16.
    Riant F, Bergametti F, Fournier HD, Chapon F, Michalak-Provost S, Cecillon M, et al. CCM3 mutations are associated with early-onset cerebral hemorrhage and multiple meningiomas. Mol Syndromol. 2013;4(4):165–72.Google Scholar
  17. 17.
    Moulding DA, Moeendarbary E, Valon L, Record J, Charras GT, Thrasher AJ. Excess F-actin mechanically impedes mitosis leading to cytokinesis failure in X-linked neutropenia by exceeding Aurora B kinase error correction capacity. Blood. 2012;120(18):3803–11.CrossRefGoogle Scholar
  18. 18.
    Ancliff PJ, Blundell MP, Cory GO, Calle Y, Worth A, Kempski H, et al. Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia. Blood. 2006;108(7):2182–9.CrossRefGoogle Scholar
  19. 19.
    Thrasher AJ. WASp in immune-system organization and function. Nat Rev Immunol. 2002;2(9):635–46.CrossRefGoogle Scholar
  20. 20.
    He Y, Zhang H, Yu L, Gunel M, Boggon TJ, Chen H, et al. Stabilization of VEGFR2 signaling by cerebral cavernous malformation 3 is critical for vascular development. Sci Signal. 2010;3(116):ra26.CrossRefGoogle Scholar
  21. 21.
    Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. Embo J. 1999;18(14):3964–72.CrossRefGoogle Scholar
  22. 22.
    Nanjundan M, Nakayama Y, Cheng KW, Lahad J, Liu J, Lu K, et al. Amplification of MDS1/EVI1 and EVI1, located in the 3q26.2 amplicon, is associated with favorable patient prognosis in ovarian cancer. Cancer Res. 2007;67(7):3074–84.CrossRefGoogle Scholar
  23. 23.
    Juranovic T, O’Suoji CC, Sivakumaran TA, Zhang K, Estallila OC, Jelic TM. Hematogones in the peripheral blood of a 5(1/2)-month-old boy with cyclic neutropenia due to heterozygous, novel ELANE gene mutation p.Q97P, c.290 A> C. Pediatr Dev Pathol. 2014;17(5):393–9.CrossRefGoogle Scholar
  24. 24.
    Bussolino F, Wang JM, Defilippi P, Turrini F, Sanavio F, Edgell CJ, et al. Granulocyte- and granulocyte-macrophage-colony stimulating factors induce human endothelial cells to migrate and proliferate. Nature. 1989;337(6206):471–3.CrossRefGoogle Scholar
  25. 25.
    Bussolino F, Ziche M, Wang JM, Alessi D, Morbidelli L, Cremona O, et al. In vitro and in vivo activation of endothelial cells by colony-stimulating factors. J Clin Invest. 1991;87(3):986–95.CrossRefGoogle Scholar
  26. 26.
    Lee M, Aoki M, Kondo T, Kobayashi K, Okumura K, Komori K, et al. Therapeutic angiogenesis with intramuscular injection of low-dose recombinant granulocyte-colony stimulating factor. Arterioscler Thromb Vasc Biol. 2005;25(12):2535–41.CrossRefGoogle Scholar
  27. 27.
    Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013;369(16):1502–11.CrossRefGoogle Scholar
  28. 28.
    Lin FY, Bergstrom K, Person R, Bavle A, Ballester LY, Scollon S, et al. Integrated tumor and germline whole-exome sequencing identifies mutations in MAPK and PI3K pathway genes in an adolescent with rosette-forming glioneuronal tumor of the fourth ventricle. Cold Spring Harb Mol Case Stud. 2016;2(5):a001057.CrossRefGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, Section of Hematology-Oncology, Texas Children’s Cancer and Hematology Center, Baylor College of MedicineTexas Children’s HospitalHoustonUSA
  2. 2.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  3. 3.Department of Pathology and Immunology, Baylor College of MedicineTexas Children’s HospitalHoustonUSA

Personalised recommendations