AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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)₂D₃, 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-kB). 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-kB.

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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)

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Osteopetrosis
Gray platelet syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count: Expected findings include anemia or thrombocytopenia or both, with or without leukocytosis (with left shift). The peripheral blood smear may have an erythroblastic appearance (nucleated RBCs, teardrops, fragments, accompanied by immature myeloid cells). Platelets may be large, misshapen, or both.
• Parathyroid hormone: Hyperparathyroidism (primary or secondary to vitamin D deficiency) has been described. Among adult patients with myelofibrosis (MF), hypoparathyroidism is sometimes observed.
• Antinuclear antibodies (ANA): MF occasionally complicates systemic lupus erythematosus.
• Neutrophil alkaline phosphatase (LAP) score: A low level suggests chronic myeloid leukemia; a high level suggests chronic inflammation, as might be expected with systemic lupus erythematosus.
• BUN/creatinine test: This is performed to rule out renal dysfunction, which would suggest renal osteodystrophy as an underlying diagnosis.
• Coombs (direct antiglobulin) test, antineutrophil antibodies: MF has been observed in association with autoimmune hematologic phenomena.

Imaging Studies

• Abdominal ultrasonography or CT scanning often reveals hepatosplenomegaly, with or without adenopathy.
• MRI scanning, if performed because of particular symptoms (eg, headache), often shows diagnostic changes in marrow signal.

Other Tests

• Purified protein derivative (PPD): MF has been described as a complication of tuberculosis.

Procedures

• Bone marrow aspirate and biopsy
• • The aspirate is frequently hypocellular or shows insufficient cellularity ("dry"). An increased number of megakaryocytes that may be morphologically abnormal supports a diagnosis of primary MF. Increased blasts are often observed, but the presence of more than 25% blasts is, by definition, more  consistent with acute MF.
  • Send the bone marrow aspirate  for cytogenetic analysis.
  • Abnormalities may support a diagnosis of myelodysplasia (eg, monosomy 7) or AMKL (eg, t[1;21][p13;q13]).
  • The biopsy demonstrates increased silver (reticulin) staining.

Histologic Findings

Marrow biopsies typically exhibit marked fibrosis with pockets of cellularity that have fibroblasts and atypical megakaryoblasts. Less commonly, hyperplasia with predominance of megakaryocytic and erythroid precursors is observed, with only a slight increase in reticulin staining. The latter pattern is more typical of (adult) agnogenic myeloid metaplasia with MF and may be observed in an older pediatric patient.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

As noted, the workup of children with myelofibrosis (MF) frequently leads to a diagnosis of acute nonlymphoblastic (specifically, megakaryoblastic) leukemia or, less commonly, myelodysplastic syndrome. The treatment of these patients is not discussed here.

The identification of another treatable underlying diagnosis (eg, rickets, tuberculosis) should prompt treatment of that disorder.

Treatment should be directed at the underlying process when childhood MF is identified. Other therapeutic options include transfusion support, corticosteroids, intravenous (IV) immunoglobulin, alfa interferon, vitamin D, conventional antileukemic chemotherapy (eg, hydroxyurea), and allogeneic bone marrow transplantation (BMT). In addition, splenectomy may be palliative in selected patients.  

Treatment with imatinib mesylate (Gleevec, Novartis) is occasionally effective. Patients who do respond to imatinib sometimes exhibit increased platelet or WBC counts, which, in turn, require treatment with hydroxyurea or interferon.

One promising new agent is thalidomide, alone or in combination with prednisone.³

• Vitamin D: MF is observed in some patients with severe vitamin D deficiency. In addition, cases of MF associated with essential thrombocythemia or myelomonocytic leukemia, as well as acute (idiopathic) MF, have responded to vitamin D administration.
• Corticosteroids: Corticosteroids have been used to treat many cases of pediatric MF, with occasional apparent successes. However, one concern is that the literature does not always allow for a clear distinction between primary and secondary cases of MF. Patients with systemic lupus erythematosus or even ANLL might show a response to steroid therapy, although this would be only a temporary effect with the latter diagnosis. In particular, treatment with high-dose methylprednisolone (as outlined below) has been touted as an effective therapy; however, this recommendation is based on a published series of only 5 older pediatric patients (aged 9-14 y), at least one of whom had a positive PPD and was also treated with isoniazid.
• Thalidomide: For palliation of anemia and thrombocytopenia in adult patients with AMMM, the combination of prednisone and thalidomide appears to be reasonably effective. Among 36 patients with symptomatic AMMM who enrolled in either a trial of single-agent thalidomide (n = 15) or a trial of low-dose thalidomide (50 mg/d) combined with prednisone (n = 21), 20 (56%) showed some improvement.³ Responses included improvements in anemia (15 of 36 [42%]), thrombocytopenia (10 of 13 [77%]) and splenomegaly (5 of 30 [17%]). The combination of low-dose thalidomide and prednisone was better tolerated and more efficacious than thalidomide alone. After a median follow-up of 25 months, 10 of 36 patients (28%) showed a persistent response, including 8 patients whose protocol treatment had been discontinued for a median of 21 months.
• IV immunoglobulin: An 8-month-old girl with MF and dysgranulopoiesis responded to IV immunoglobulin (added to previous corticosteroid therapy).⁴ Her disease was unusual and was characterized by a positive Coombs test result and antineutrophil antibodies, suggesting an autoimmune etiology.
• Alfa interferon: Alfa interferon has been used to treat at least 2 adults with acute MF and one 14-year-old boy with indolent MF. The adolescent patient showed resolution of fibrosis and restoration of blood counts after 6 months of therapy with alfa interferon 3 million IU, 3 times a week.⁵ He continued to do well for at least 2 years on a maintenance dose of 2 million IU twice a week. Two adult males (aged 63 and 71 y) with acute MF (and excess blasts) were treated with subcutaneous interferon alfa-2a at doses of 1-6 million IU daily. Both showed resolution of fibrosis. The first patient was maintained on interferon for 12 weeks, but his disease progressed shortly after it was discontinued. After 4 weeks of interferon, the second patient stayed in an unmaintained remission for 4 months before dysplastic hematopoiesis recurred.
• Chemotherapy: Conventional chemotherapy, as would otherwise be used to treat acute myeloid/megakaryocytic leukemia, has been used to treat patients with C-AMF, under the assumption that C-AMF is a preleukemic condition. The details of such therapy are beyond the scope of this article and are discussed in Acute Myelocytic Leukemia.
• Bone marrow transplantation: Similarly, allogeneic BMT has been used successfully to treat patients with MF. Thirteen adult patients with MF (8 primary and 5 associated with either polycythemia vera or essential thrombocytosis) received allogeneic BMTs at the Fred Hutchinson Cancer Research Center.⁶ Preparative regimens and donors varied. Four patients died of transplant-related complications. Nine patients are apparent long-term survivors, 2 of whom experienced a relapse and are in a chronic myeloproliferative state. Published experience from Sweden demonstrates that reduced-intensity preparative regimens are often effective for treating MF and clearly have less treatment-related mortality than do myeloablative regimens.⁷
• Imatinib: In one published report, eleven adult patients with IMF (n = 8) or postpolycythemic myelofibrosis (PPMF) (n = 3) were treated with imatinib at a dose of 400 mg/d.⁸ Nine patients were in an advanced disease phase. At the time of publication, the patients had been followed for a median of 2 months. A beneficial effect of imatinib was documented in 3 patients. Leukocytosis and thrombocytosis were seen in most patients with MF during treatment with imatinib. Combination therapy with hydroxyurea or interferon seems safe and well tolerated and followed by a decrease in disease activity.

Surgical Care

Some adult patients with AMMM are candidates for splenectomy, but patient selection for this procedure is controversial. Transfusion-dependent anemia, portal hypertension, and/or symptoms of hypercatabolism are potential indications for splenectomy, but the surgery-related mortality rate may be as high as 9%. Similar statistics are not available for pediatric patients.

Placement of a central venous access device may facilitate care in patients requiring complex therapies or frequent transfusions.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treat any underlying disease (eg, rickets) as indicated for the specific disease. The medications listed here have shown some benefit in patients with idiopathic myelofibrosis (IMF).

Drug Category: Antirachitics

MF has been described in patients with severe vitamin D deficiency. In addition, some (adult) patients with MF associated with essential thrombocythemia or myelomonocytic leukemia, as well as acute (idiopathic) MF, have responded to vitamin D administration. A direct inhibitory effect on platelets has been proposed. However, other studies have not confirmed such a response in patients with idiopathic MF.

Drug Category: Corticosteroids

These agents have both immunosuppressive and cytotoxic effects. The mechanism of cytotoxicity is unknown (but apparently mediated through glucocorticoid receptors).

Drug Category: Immunomodulators

Proposed mechanisms of action are suppression of autoimmunity, enhanced immunoregulation of an abnormal clone, or both.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Supportive care with transfusions (RBC, platelets) is crucial to short-term management. Blood products should be leukodepleted (to decrease the likelihood of human leukocyte antigen [HLA] sensitization) and, ideally, cytomegalovirus (CMV) negative.
• Prophylaxis against opportunistic infections (eg, fluconazole) may be indicated for some patients with neutropenia.

Complications

• Patients with myelofibrosis (MF) but no initial evidence of myelodysplasia or leukemia may ultimately develop either of these conditions.
• As previously noted, patients can be expected to develop complications secondary to decreased blood counts (eg, anemia, hemorrhage due to thrombocytopenia, opportunistic infections due to leukopenia).
• Splenomegaly may lead to hypersplenism, thereby worsening pancytopenia.
• A single case report detailed subcutaneous lymphoma arising in a child with idiopathic MF.⁹

Prognosis

• The prognosis depends on the underlying cause of MF. With appropriate treatment for rickets, tuberculosis, systemic lupus erythematosus, and other conditions, the MF may completely resolve.
• In adult patients with myelofibrosis, several alternative prognostic scoring systems (PSSs) are available. Neither the patient's symptoms nor the percentage of circulating blasts is taken into account in the Mayo PSS (in contrast to other PSSs). A retrospective review of 334 patients with myelofibrosis showed the Mayo PSS to be more effective than other PSSs in terms of (1) identifying long-lived patients and (2) delineating an intermediate-risk disease category.¹⁰ The Mayo PSS assigns a score of 1-4 by allotting 1 point for each of the following:
• • Hemoglobin level more than 10 gm/dL
  • WBC count less than 4 or more than 30 X 10⁹/L
  • Platelet count less than 100 X 10⁹/L 
  • Absolute monocyte count equal to or more than 1 X 10⁹/L
• Idiopathic C-AMF is a fulminant disease. Without effective therapy, life expectancy is typically less than one year. Potentially effective and/or curative treatments include chemotherapy and allogeneic BMT. Treatment with high-dose corticosteroids or interferon alfa may result in a temporary amelioration of the disease (see Medication). Occasionally, pediatric patients have a more indolent course that is comparable to AMMM in adults. With supportive care alone, they may survive for many years.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Splenectomy: Some adult patients with AMMM are candidates for splenectomy, but the surgery-related mortality rate may be as high as 9%. Outcome statistics of splenectomy are not available for pediatric patients. Splenomegaly alone is not an indication for splenectomy.
• Genetic counseling: Early-onset myelofibrosis (MF) is occasionally inherited in a recessive pattern. Counsel parents about the possibility of a second affected child.
• Occult or mosaic trisomy 21: Down syndrome is a risk factor for MF. Consider chromosomal analysis in any child with onset before the age of 2 years.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• 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. 3^rd 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].

Article Last Updated: Dec 14, 2007