eMedicine Specialties > Pediatrics: General Medicine > Hematology

Myelofibrosis

Author: J Martin Johnston, MD, Director of Pediatric Hematology/Oncology, Backus Children's Hospital, Memorial Health University Medical Center
Contributor Information and Disclosures

Updated: Dec 14, 2007

Introduction

Background

Myelofibrosis (MF), bone marrow fibrosis, is an uncommon condition in children. Fewer than 100 cases have been described in the medical literature. Most cases arise secondary to other disease processes. For example, MF is frequently associated with malignancy (eg, acute megakaryoblastic leukemia [AMKL]). MF may be observed prior to a clear diagnosis of acute leukemia, at the time of diagnosis of leukemia, or as a late event in patients previously treated for leukemia. Numerous nonmalignant diseases have also been reported in association with MF (see Causes).

Cases of primary or idiopathic MF (IMF) are also described. These are chronic myeloproliferative disorders, which occasionally are familial. Among adults, 2 broad classes of primary MF are recognized. Agnogenic myeloid metaplasia with myelofibrosis (AMMM) is an indolent myeloproliferative syndrome characterized by clonal hematopoiesis, splenomegaly, and an erythroblastic peripheral blood smear (as defined below). Median age at diagnosis is about 60 years, and median life expectancy from onset of symptoms is 10 years. In contrast, acute MF in adulthood is a rapidly fatal disorder in which splenomegaly is not usually observed; bone marrow examination typically reveals numerous bizarre megakaryocytes and blasts.

Occasional pediatric cases of MF, especially in older adolescents, are indistinguishable from AMMM. However, so-called acute myelofibrosis of childhood (C-AMF) combines features of the 2 adult MF syndromes. C-AMF is usually a fulminant disease (survival <1 y), but most patients do exhibit splenomegaly and erythroblastosis. This condition overlaps with AMKL in terms of both clinical findings and population at risk (ie, younger children with Down syndrome). In fact, many investigators now consider C-AMF to be a variant (potential precursor) of AMKL.

The prognosis of childhood MF varies depending on the clinical context in which it occurs.

Pathophysiology

The hallmark of MF is increased reticulin staining. The fibrous network observed in MF is collagenous and contains fibronectin; the reticulin (silver or Gomori) stain reacts with a protein that is intimately associated with type III collagen and is generally considered to be a form of procollagen.

Fibrosis of the bone marrow presumably reflects overgrowth of the normal marrow matrix. As previously noted, this can be observed in association with many diseases (see Causes). Matrix homeostasis results from a balance between its deposition and its removal. The former is regulated by various growth factors, most notably platelet-derived growth factor (PDGF), whereas the latter presumably reflects the activity of collagenase-expressing monocytes, macrophages, and granulocytes. Thus, the diseases associated with MF can be classified according to whether the basic defect is matrix overproduction, underresorption, or both. The last of these is typified by vitamin D deficiency because 1,25(OH)2 D3, the active metabolite of vitamin D3, inhibits the proliferation of megakaryocytes and encourages monocyte/macrophage differentiation.

In cases of C-AMF, MF may be secondary to the release of a granules by abnormal megakaryocytes (see Histologic Findings). In addition to PDGF, these granules contain transforming growth factor b (TGF-b) and epidermal growth factor, both of which can stimulate proliferation of fibroblasts. TGF-b synthesis appears to be regulated by nuclear factor kappaB (NF-k B). Interestingly, the overexpression of an immunophilin, FK506 binding protein 51, has been observed in MF megakaryocytes, and this protein appears, in turn, to activate NF-k B.

Some investigators believe that the abnormal fibrotic marrow stroma directly enhances the circulation and dissemination of hematopoietic precursors by an unknown mechanism. This leads to extramedullary hematopoiesis in the liver, spleen, lymph nodes, or (occasionally) kidneys, which causes myeloid metaplasia in these organs, which then become enlarged. On occasion, hypersplenism may also contribute to cytopenias.

Among adults with IMF, conventional cytogenetic analysis of the marrow reveals an abnormal clone in approximately one third of patients. Using a comparative genomic hybridization technique, Al-Assar et al studied IMF marrow specimens and found chromosomal imbalances in 21 of 25 cases.1 Gains of 9p, 13q, 2q, 3p, and 12q were among the most commonly seen abnormalities.

The gain-of-function V617F mutation in the JAK2 gene (on chromosome 9p) is seen in many adult patients with IMF. Its presence correlates with a shift from thrombopoiesis toward increased erythropoiesis and may also predict progression to massive splenomegaly and leukemic transformation.

Frequency

United States

Fewer than 100 cases of pediatric MF have been reported worldwide. This is likely an underrepresentation because cases associated with AML (the most common association) are not generally reportable. Of the roughly 500 new cases of pediatric acute nonlymphoid leukemia (ANLL) in the United States annually, approximately 5% are megakaryoblastic (M7 subtype, AMKL). If as few as 20% of these patients have a significant degree of MF, this would yield roughly 5 new cases per year. Other cases of MF (ie, not associated with AMKL) likely total only a handful per year, as well.

International

Cases of pediatric MF have been described in association with tuberculosis (in Pakistan) and visceral leishmaniasis (in Sudan). Thus, MF is presumably more common in areas of endemicity for these 2 diseases. Epidemiological data are not available.

A recent report suggests that autosomal recessive familial MF is more common among children from Saudi Arabia.2

Mortality/Morbidity

MF causes, or accompanies conditions that cause, disruption of hematopoiesis. Patients may experience anemia, neutropenia, and/or thrombocytopenia. Patients may also experience pain secondary to hepatosplenomegaly.

  • Neutropenia may lead to opportunistic infections, such as bacterial sepsis, oral thrush, or systemic fungal infections.
  • Thrombocytopenia may lead to hemorrhage.
  • The prognosis for individual patients with MF depends on the underlying disease process and its potential for treatment. Most cases of C-AMF have eventually ended in death; the course is usually fulminant.

Race

As noted above, an autosomal recessive form of MF appears to be more common among children from Saudi Arabia.2

Sex

In published cases of pediatric MF, females outnumber males by a ratio of approximately 2:1.

Age

Approximately half of published cases of pediatric MF occurred in children younger than 3 years. These younger patients are more likely to have Down syndrome, rickets, or a familial (possibly autosomal recessive) form of MF. Among older patients, ANLL, systemic lupus erythematosus, and tuberculosis are the most common associations.

Clinical

History

Patients typically present with a fairly insidious onset of pallor and fatigue, with or without fever (about one third of cases), bruising, bone pain, or left upper quadrant abdominal pain.

  • Down syndrome, systemic lupus erythematosus, or histiocytosis may have been previously diagnosed.
  • Rarely, myelofibrosis (MF) may appear long after successful treatment for acute leukemia.
  • A history of radiation exposure may be noted.
  • Look for a history of similar illness in siblings, especially if onset is in infancy. Parental consanguinity may suggest an autosomal recessive form of the disease.
  • Patients may have been exposed to tuberculosis.

Physical

  • Physical findings reflect the blood counts.
    • Pallor (anemia)
    • Bruising or bleeding (thrombocytopenia)
    • Oral thrush (neutropenia)
    • Splenomegaly (frequent) or hepatomegaly or lymphadenopathy (less common)
  • Stigmata of Down syndrome may be present.
  • Multiple hemangiomas have been described in one affected pair of siblings with IMF.

Causes

Classification of myelofibrosis in children

  • Primary (idiopathic) C-AMF
  • Secondary (malignant) C-AMF
    • Acute megakaryoblastic (M7) leukemia
    • Acute myeloid leukemia
    • Acute lymphoblastic leukemia
    • Chronic myelogenous leukemia
    • Non-Hodgkin lymphoma
    • Essential thrombocythemia
    • Hodgkin disease (reported cases in adults only)
  • Secondary (nonmalignant) C-AMF
    • Langerhans cell histiocytosis
    • Hemophagocytic lymphohistiocytosis
    • Sickle cell disease (a single case report)
    • Fanconi anemia
    • Vitamin D deficiency
    • Infectious causes - Tuberculosis, visceral leishmaniasis, histoplasmosis (reported cases in adults only)
    • Renal osteodystrophy
    • Systemic lupus erythematosus
    • Juvenile rheumatoid arthritis
    • Gray platelet syndrome
    • Osteopetrosis
    • Hyperparathyroidism
    • Hypoparathyroidism (reported cases in adults only)
    • Pernicious anemia (reported cases in adults only)
    • Gaucher disease (reported cases in adults only)
    • Exposure to radiation, thorium dioxide, benzene (reported cases in adults only)

More on Myelofibrosis

Overview: Myelofibrosis
Differential Diagnoses & Workup: Myelofibrosis
Treatment & Medication: Myelofibrosis
Follow-up: Myelofibrosis
References
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References

  1. Al-Assar O, Ul-Hassan A, Brown R. Gains on 9p are common genomic aberrations in idiopathic myelofibrosis: a comparative genomic hybridization study. Br J Haematol. Apr 2005;129(1):66-71. [Medline].

  2. Rossbach HC. Familial infantile myelofibrosis as an autosomal recessive disorder: preponderance among children from Saudi Arabia. Pediatr Hematol Oncol. Jul 2006;23(5):453-4. [Medline].

  3. Mesa RA, Elliott MA, Schroeder G. Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia. Mayo Clin Proc. Jul 2004;79(7):883-9. [Medline].

  4. Pilorget H, Bangui A, Adam M. [Myelofibrosis regressing under corticotherapy and intravenous immunoglobulins in an infant(in French)]. Arch Pediatr. Jan 1996;3(1):40-3. [Medline].

  5. Domingues MA, Haepers AT, Massaut IH, Vassallo J, Lorand-Metze I. Reversal of bone marrow fibrosis in idiopathic myelofibrosis after treatment with alpha-interferon. Haematologica. Dec 1998;83(12):1124-5. [Medline].

  6. Soll E, Massumoto C, Clift RA. Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment. Blood. Dec 15 1995;86(12):4667-73. [Medline].

  7. Merup M, Lazarevic V, Nahi H. Different outcomes of allogeneic transplantation in myelofibrosis using conventional or reduced-intensity conditioning regimens. Br J Haematol. Nov 2006;135(3):367-73. [Medline].

  8. Tefferi A, Mesa RA, Gray LA. Phase 2 trial of imatinib mesylate in myelofibrosis with myeloid metaplasia. Blood. May 15 2002;99(10):3854-6. [Medline].

  9. Hung IJ, Kuo TT, Sun CF. Subcutaneous panniculitic T-cell lymphoma developing in a child with idiopathic myelofibrosis. J Pediatr Hematol Oncol. Jan-Feb 1999;21(1):38-41. [Medline].

  10. Tefferi A, Huang J, Schwager S. Validation and comparison of contemporary prognostic models in primary myelofibrosis: analysis based on 334 patients from a single institution. Cancer. May 2007;109(10):2083-8. [Medline].

  11. Abla O, Ye CC. Acute lymphoblastic leukemia with massive myelofibrosis. J Pediatr Hematol Oncol. Sep 2006;28(9):633-4. [Medline].

  12. Anderson JE, Sale G, Appelbaum FR. Allogeneic marrow transplantation for primary myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocytosis. Br J Haematol. Sep 1997;98(4):1010-6. [Medline].

  13. Arlet P, Nicodeme R, Adoue D. Clinical evidence for 1,25-dihydroxycholecalciferol action in myelofibrosis. Lancet. May 5 1984;1(8384):1013-4. [Medline].

  14. Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood. Dec 1 2007;110(12):4030-6. [Medline].

  15. Boxer LA, Camitta BM, Berenberg W. Myelofibrosis-myeloid metaplasia in childhood. Pediatrics. Jun 1975;55(6):861-5. [Medline].

  16. Brovall C, Mitchell H, Saral R. Acute myelofibrosis in a child. J Pediatr. Jul 1983;103(1):91-3. [Medline].

  17. Cohn SL, Cohn RA, Chou P. Infantile myelofibrosis with nephromegaly secondary to myeloid metaplasia. Clin Pediatr (Phila). Jan 1991;30(1):59-61. [Medline].

  18. Evans DI. Acute myelofibrosis in children with Down's syndrome. Arch Dis Child. Jun 1975;50(6):458-62. [Medline].

  19. Fernbach SK, Feinstein KA. Extramedullary hematopoiesis in the kidneys in infant siblings with myelofibrosis. Pediatr Radiol. 1992;22(3):211-2. [Medline].

  20. Hashim MS, Kordofani AY, el Dabi MA. Tuberculosis and myelofibrosis in children: a report. Ann Trop Paediatr. Mar 1997;17(1):61-5. [Medline].

  21. Hasselbalch HC, Bjerrum OW, Jensen BA, et al. Imatinib mesylate in idiopathic and postpolycythemic myelofibrosis. Am J Hematol. Dec 2003;74(4):238-42. [Medline].

  22. Inoue S, Limsuwan A, McQueen R. Spontaneous resolution of myelofibrosis and pancytopenia followed by the development of acute myeloid leukemia with an extramedullary mass. J Pediatr Hematol Oncol. May-Jun 1998;20(3):268-70. [Medline].

  23. Ivanyi JL, Mahunka M, Papp A. Prognostic significance of bone marrow reticulin fibres in idiopathic myelofibrosis: evaluation of clinicopathological parameters in a scoring system. Haematologia (Budap). 1994;26(2):75-86. [Medline].

  24. Kerbauy DM, Gooley TA, Sale GE. Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. Biol Blood Marrow Transplant. Mar 2007;13(3):355-65. [Medline].

  25. Komura E, Tonetti C, Penard-Lacronique V. Role for the nuclear factor kappaB pathway in transforming growth factor-beta1 production in idiopathic myelofibrosis: possible relationship with FK506 binding protein 51 overexpression. Cancer Res. Apr 15 2005;65(8):3281-9. [Medline].

  26. Lewis DS. Association between megakaryoblastic leukaemia and Down syndrome. Lancet. Sep 26 1981;2(8248):695. [Medline].

  27. Maj JS, Roslan K, Fic-Sikorska B. Acute myelofibrosis in children: report on two cases. Acta Haematol Pol. 1996;27(1):79-84. [Medline].

  28. Manoharan A. Idiopathic myelofibrosis: a clinical review. Int J Hematol. Dec 1998;68(4):355-62. [Medline].

  29. Manoharan A, Horsley R, Pitney WR. The reticulin content of bone marrow in acute leukaemia in adults. Br J Haematol. 1979;43(2):185-90. [Medline].

  30. McCarthy DM. Annotation. Fibrosis of the bone marrow: content and causes. Br J Haematol. Jan 1985;59(1):1-7. [Medline].

  31. Mesa RA, Nagorney DS, Schwager S. Palliative goals, patient selection, and perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic. Cancer. Jul 2006;107(2):361-70. [Medline].

  32. Ozsoylu S, Ruacan S. High-dose intravenous corticosteroid treatment in childhood idiopathic myelofibrosis. Acta Haematol. 1986;75(1):49-51. [Medline].

  33. Paquette RL, Meshkinpour A, Rosen PJ. Autoimmune myelofibrosis. A steroid-responsive cause of bone marrow fibrosis associated with systemic lupus erythematosus. Medicine (Baltimore). May 1994;73(3):145-52. [Medline].

  34. Rao SP, Miller ST, Thelmo W. Myelofibrosis in a child with sickle cell anemia. Am J Pediatr Hematol Oncol. Winter 1991;13(4):487-9. [Medline].

  35. Reilly JT. Idiopathic myelofibrosis: pathogenesis, natural history and management. Blood Rev. Dec 1997;11(4):233-42. [Medline].

  36. Richard C, Mazorra F, Iriondo A. The usefulness of 1,25-dihydroxy-vitamin D3(1,25(OH)2vitD3) in the treatment of idiopathic myelofibrosis. Br J Haematol. Feb 1986;62(2):399-400. [Medline].

  37. Rudzki Z, Sacha T, Stoj A. The gain-of-function JAK2 V617F mutation shifts the phenotype of essential thrombocythemia and chronic idiopathic myelofibrosis to more "erythremic" and less "thrombocythemic": a molecular, histologic, and clinical study. Int J Hematol. Aug 2007;86(2):130-6. [Medline].

  38. Saleem M, Anwar M, Khan AH. Myelofibrosis in visceral leishmaniasis. Br J Haematol. Aug 1991;78(4):573-4. [Medline].

  39. Schwartz CL, Cohen H. Myeloproliferative and myelodysplastic syndromes. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, PA: JB Lippincott Company; 1997:512-4.

  40. Sekhar M, Prentice HG, Popat U. Idiopathic myelofibrosis in children. Br J Haematol. May 1996;93(2):394-7. [Medline].

  41. Stephan JL, Galambrun C, Dutour A. Myelofibrosis: an unusual presentation of vitamin D-deficient rickets. Eur J Pediatr. Oct 1999;158(10):828-9. [Medline].

  42. Tefferi A. Treatment approaches in myelofibrosis with myeloid metaplasia: the old and the new. Semin Hematol. Jan 2003;40(1 Suppl 1):18-21. [Medline].

  43. Tefferi A, Mesa RA, Nagorney DM. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood. Apr 1 2000;95(7):2226-33. [Medline].

  44. Uysal Z, Ileri T, Gozdasoglu S. Reversible myelofibrosis associated with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. Jul 2007;49(1):108-9. [Medline].

  45. Walka MM, Daumling S, Hadorn HB. Vitamin D dependent rickets type II with myelofibrosis and immune dysfunction. Eur J Pediatr. Jul 1991;150(9):665-8. [Medline].

  46. Wolf BC, Neiman RS. Myelofibrosis with myeloid metaplasia: pathophysiologic implications of the correlation between bone marrow changes and progression of splenomegaly. Blood. Apr 1985;65(4):803-9. [Medline].

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Further Reading

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Keywords

myelofibrosis, MF, bone marrow fibrosis, myelosclerosis, osteomyelofibrotic syndrome, agnogenic myeloid metaplasia with myelofibrosis, AMMM, acute myelofibrosis of childhood, C-AMF, primary MF, idiopathic MF, IMF, fibrosis of the bone marrow, acute megakaryoblastic leukemia, AMKL, chronic myeloproliferative disorders, clonal hematopoiesis, splenomegaly, erythroblastic peripheral blood smear, myeloid metaplasia, thrombopoiesis, tuberculosis, visceral leishmaniasis, anemia, neutropenia, thrombocytopenia, hepatosplenomegaly, bacterial sepsis, rickets, systemic lupus erythematosus, histiocytosis, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin disease, Langerhans cell histiocytosis, sickle cell disease, Fanconi anemia, vitamin D deficiency, osteodystrophy, juvenile rheumatoid arthritis, osteopetrosis, hyperparathyroidism, hypoparathyroidism, pernicious anemia, Gaucher disease

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Contributor Information and Disclosures

Author

J Martin Johnston, MD, Director of Pediatric Hematology/Oncology, Backus Children's Hospital, Memorial Health University Medical Center
J Martin Johnston, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

Medical Editor

Sharada A Sarnaik, MD, Director of Sickle Cell Program, Department of Pediatrics, Professor, Children's Hospital of Michigan and Wayne State University
Sharada A Sarnaik, MD is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

James L Harper, MD, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center
James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Clinical Oncology, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

 
 
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