Myelofibrosis In Children Research Articles

Pediatric Myelofibrosis: A Rare Entity Posing a Diagnostic Challenge

Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders showing proliferation of one or more myeloid lineages. These disorders are characterized by Janus Kinase 2 (JAK2 V617F), Myeloproliferative leukemia (MPL), and Calreticulin (CALR) gene mutations and are seen more commonly in the elderly. These pathognomonic mutations are often absent in children and hence pose a diagnostic challenge. The entire onus of correct diagnosis relies heavily on detailed clinical and laboratory investigations. In the present work, we discuss 4 cases of pediatric myelofibrosis, three of which were secondary to hematolymphoid malignancies, while the remaining one had primary myelofibrosis. Pediatric primary myelofibrosis is a rare entity in children and quite different from adult primary myelofibrosis. The cases in our study show transformation into acute myeloid leukemia, which is associated with an adverse prognosis. Given the rarity of myelofibrosis in children, early and correct diagnosis helps in timely initiation of treatment, which may favorably alter the prognosis.

Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP

This retrospective study evaluated 35 children (median age 5.2 years; range 0.4–18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II–IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3–41.1) vs 58.8% (31–78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1–32.8), relapse incidence was 15.9% (5.6–30.9), progression-free survival (PFS) was 66.1% (47–79.7), GvHD-free relapse-free survival was 50% (30.6–66.7), and overall survival (OS) was 71.1% (51.4–84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3–96.1) vs 50.8% (26.3–71), p = 0.03, and 90.9% (50.8–98.7) vs 54% (28.1–74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3–53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.

Pediatric immune myelofibrosis (PedIMF) as a novel and distinct clinical pathological entity

Myelofibrosis is a rare myeloproliferative disorder. The detailed descriptions of myelofibrosis in children and adolescents is limited to a few case series and case reports describing fewer than 100 patients, thus suggesting the extreme rarity of this condition prior to adulthood. Though pediatric patients rarely present the typical features and outcomes usually observed in older people, pediatric myelofibrosis is not considered an independent entity. Here we aim to describe patients with pediatric myelofibrosis, showing different clinical and pathological features when compared to the World Health Organization 2016 Primary Myelofibrosis classification. We retrospectively collected and analyzed 14 consecutive pediatric myelofibrosis diagnosed in our Pediatric hematology outpatient clinic over a six-year period. According to clinical data and bone marrow biopsy findings, patients were classified into three subgroups: adult-like myelofibrosis, pediatric immune myelofibrosis, idiopathic myelofibrosis. Pediatric Immune Myelofibrosis was the predominant subgroup in our cohort (7/14). Pediatric Immune Myelofibrosis is characterized by peculiar bone marrow features (i.e., T lymphocyte infiltration) and a milder course compared to the other patients Pediatric Immune Myelofibrosis is a novel and distinct pathological entity. We suggest to carefully consider Pediatric Immune Myelofibrosis in case of bone marrow biopsies showing myelofibrosis that do not fulfill WHO criteria.

Congenital Thrombocytopenia and Myelofibrosis Due to Germline Mutations in G6b-B— a Megakaryocyte-Specific Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) Receptor

Unlike primary myelofibrosis (PMF) in adults, which is one of the three classical BCR-ABL-negative myeloproliferative neoplasms (MPN), myelofibrosis in children is rare, occurring most commonly in patients with acute leukemia, particularly acute megakaryoblastic leukemia. Congenital or inherited forms of myelofibrosis (cMF) are exceedingly rare, and may occur in the context of patients with inherited platelet disorders. Here we describe 3 families with inherited thrombocytopenia and cMF due to germline null mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM) receptor G6b-B.We studied 3 families with a total of 6 affected children, each of which presented with macrothrombocytopenia, mild anemia, mild leukocytosis and a distinctive pattern of bone marrow reticulin fibrosis centered around clusters of atypical megakaryocytes. The disease appeared to segregate as an autosomal recessive trait. All affected children had mild to moderate bleeding symptoms and required frequent platelet and occasional red cell transfusions. None showed evidence of extramedullary hematopoiesis, such as splenomegaly, and all were negative for MPN associated mutations in JAK2, MPL, and CALR.To identify the disease gene, we performed Affymetrix SNP 6.0 genotyping on peripheral blood DNA from three clinically affected children and 7 first and second-degree relatives from the index family, a complex consanguineous pedigree from Kuwait. Shared regions of homozygosity by descent were assessed using a custom designed platform; multiple statistically non-significant genomic loci, including the region of the major histocompatibility locus (MHC) on chromosome 6p (LOD=2.01), were identified as potential candidate genetic intervals. We focused on this region because affected individuals in the index family and one of the two other families, which were not known to be related, shared a common homozygous human leukocyte antigen (HLA) type and had congenital adrenal hyperplasia (CAH) due to the identical 21-hydroxylase (CYP21A2) mutation; the CYP21A2 and HLA loci are located at 6p21.33 and 6p21.32-6p22.1. Whole exome sequencing was performed on all three nuclear families and revealed homozygous frameshift mutations in the megakaryocyte and platelet inhibitory receptor G6b (MPIG6B, previously G6B-B, C6orf25), encoded within the candidate linkage region. We identified 5 individuals (4 affected, one previously unaffected) with a MPIG6B frameshift mutation (c.61_61+1dup; p.20fs) in two families from Kuwait. In addition we confirmed a second MPIG6B frameshift mutation at c.147insT (p.49fs) in two individuals (one proband, one mildly affected sibling) in a family from Saudi Arabia. No other homozygous mutations that segregated with the phenotype in all three families were identified. MPIG6B is a member of the immunoglobulin superfamily and is located in the MHC class III region on chromosome 6. To validate MPIG6B as a potential disease-causing gene, we evaluated G6b-B expression in bone marrow (BM) biopsy specimens from affected patient and control samples by immunohistochemical staining using a monoclonal antibody specific to G6b-B. G6b-B was strongly and selectively expressed in megakaryocytes of control BM samples, but completely absent in megakaryocytes of the clinically affected individuals.Interestingly, a murine knockout that lacks G6b-B has a strikingly similar phenotype to these patients, the animals having macrothrombocytopenia, myelofibrosis and aberrant platelet production and function. Thus, in addition to uncovering the molecular basis of this rare disease, the clinical phenotype highlights the potential importance of MPIG6B and aberrant megakaryocytic activation in mediating other forms of BM fibrosis. DisclosuresNo relevant conflicts of interest to declare.

Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice

AbstractUnlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germ line loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25, or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor.

Primary myelofibrosis in children involving the jaw: a case report

Primary myelofibrosis in children involving the jaw: a case report

Idiopathic Myelofibrosis in Children

We report 3 pediatric cases of primary/idiopathic myelofibrosis (PMF/IMF). Two cases exhibited clinical courses not typically observed in adult patients in whom this process is much more common. One of these cases exhibited spontaneous clinical and bone marrow resolution, whereas the other case achieved near resolution of myelofibrosis in response to cytoreductive therapy alone. However, the third case of IMF that met diagnostic criteria for essential thrombocythemia with a JAK2V617F mutation had central venous thrombosis that resulted in blindness. PMF/IMF, a rare finding in children, does not seem to portend the same level of risk as seen in adults with the same process, thus less aggressive management may be appropriate. However, delayed diagnosis of mutation-associated PMF or essential thrombocythemia can lead to devastating consequences. We review the literature and discuss the complexities surrounding diagnosis, risk stratification, and management of pediatric PMF/IMF.

Stem Cell Transplantation in Primary Myelofibrosis of Childhood

Fewer than 40 cases of primary myelofibrosis have been reported in children; hematopoietic stem cell transplantation is the only available curative therapy for this disease. Here, we describe the case of a female infant diagnosed with primary myelofibrosis at the age of 6 months; she underwent successful matched unrelated bone marrow transplantation with complete resolution of disease. We discuss some unique characteristics of primary myelofibrosis in children and review outcome data for children with this disease.

Primary Myelofibrosis In Children

AbstractAbstract 3079Primary myelofibrosis is a chronic myeloproliferative disorder characterized by cytopenias, leukoerythroblastosis, extramedullary hematopoiesis, hepatosplenomegaly and bone marrow fibrosis. It is a serious medical condition in adults, often requiring major interventions such as hematopoietic stem cell transplantation (HSCT) for cure. In comparison to adults, children are rarely affected by this entity; the largest case series reports on four such patients. Most of these reports suggest that the majority of affected children have spontaneous resolution of their myelofibrosis with no long term complications. To better describe the clinical characteristics and outcomes of pediatric primary myelofibrosis, we performed a retrospective chart review of children diagnosed with myelofibrosis by bone marrow pathology at our institution from 1996 to 2009. Eighteen patients with primary myelofibrosis were identified. At presentation, all patients had one or more cytopenias and only one had leukoerythroblastosis. Three of 11 patients tested (27%) had cytogenetic abnormalities, as opposed to up to two-thirds of adults with primary myelofibrosis. Eleven of 18 patients (61%) demonstrated erythroid hypoplasia in the bone marrow, which is uncommon in adults. Based on recent molecular studies of myeloproliferative disorders in adults, the World Health Organization now includes the presence of a clonal marker such as JAK2V617F as a major criterion for diagnosis of myelofibrosis in adults. In contrast to approximately half of adults (43-63%) with primary myelofibrosis, JAK2V617F mutation in the bone marrow has not been reported in children. JAK2V617F mutation analysis was negative on 16 of 18 bone marrow specimens tested. In this series, only 5 of the 18 children (27.8%) had spontaneous recovery. No child developed malignant transformation. Eight children underwent HSCT, four of whom were cured of their myelofibrosis; the remaining four children died from infections acquired during transplantation. Four children died prior to transplantation, or were identified as having myelofibrosis at autopsy. One child transferred care to another facility and thus outcome data was not available. In all children, infection was the most common cause of death. Notably, the degree of bone marrow fibrosis did not correlate with outcome. Our series demonstrates that children with primary myelofibrosis have hematologic, bone marrow and molecular features that differ from adults. In contrast to what is found in the literature, our series of pediatric patients with primary myelofibrosis, the largest reported thus far, indicates a poor outcome for the majority of these patients. Disclosures:No relevant conflicts of interest to declare.

MYELOFIBROSIS IN CHILDREN: Experience at a Single Tertiary Care Center in India

The authors describe 10 cases of myelofibrosis diagnosed and managed at their center over 16 years. There were 2 and 8 cases, respectively, of primary and secondary myelofibrosis. All patients presented with fever, pallor, hepatosplenomegaly, and/or lymphadenopathy. Hodgkin's lymphoma (n = 4), neuroblastoma (n = 1), thrombasthenic thrombopathy (n = 1), and retroperitoneal-mass (n = 1) were causal in 7 patients, whereas the diagnosis could not be established in a sole case of secondary myelofibrosis. Patients were managed with chemotherapy and appropriate care. However, outcome was poor. The authors emphasize variable clinical-laboratory spectrum of myelofibrosis, highlight management concerns, and demonstrate that prognosis/outcome depends upon appropriate management of the underlying condition.

Secondary Myelofibrosis in Children

Myelofibrosis is a rare childhood myeloproliferative disorder. It has been reported as an associated complication of certain hematologic malignancies or as an isolated idiopathic process. We describe clinical course of 6 children diagnosed over 6 years. One child each responded well to steroid and treatment of the underlying condition. Three children died because of underlying conditions and 1 child was lost to follow up. A thorough search should be made for underlying disease when myelofibrosis is first diagnosed. Trephine biopsy though giving useful information, does not have a prognostic significance.

Imaging findings of upper abdominal involvement by acute megakaryoblastic leukaemia

Acute megakaryoblastic leukaemia (AMKL), a relatively rare type of acute myeloid leukaemia, is characterized by frequent involvement of the liver, spleen and lymph nodes in addition to myelofibrosis in children. Diagnosis is difficult both clinically and pathologically, and the hepatic or lymph node involvement is not uncommonly misinterpreted as solid tumour. We report the imaging findings of upper abdominal involvement by AMKL in an infant. The hepatic lesion, initially suspected to be hepatoblastoma, showed a distinctive appearance on MRI suggesting its infiltrative nature. With the association of splenic lesion and lymphadenopathy, the imaging findings were considered indicative of a haematological disorder.

Case forum: Idiopathic myelofibrosis in children—Rare disease curable by bone marrow transplantation

Case forum: Idiopathic myelofibrosis in children—Rare disease curable by bone marrow transplantation

Myelofibrosis in Children

Myelofibrosis in Children

Myelofibrosis, myeloproliferative syndrome and monosomy C in children

We have studied six cases presenting as myeloproliferative disease with myelofibrosis in children and compared our findings with those of other investigators. Besides the classic chronic juvenile or adult type of leukemia, two groups of myeloproliferative syndrome are most often seen in pediatric practice: (1) myeloproliferative disease associated with monosomy C, which has clear-cut clinical features and a poor prognosis, with bone marrow grafting the only potentially successful treatment at this time; and, (2) idiopathic myelofibrosis with normal karyotype, which occurs less frequently and seems to have less distinct boundaries. We conclude that determination of karyotype is mandatory in these syndromes.

Metabolic consequences of trichopoliodystrophy

1. Editoral: Myelofibrosis, Lancet 1:127, 1980. 2. Say B, and Berkel t: Idiopathic myelofibrosis in an infant, J PEDIATR 64:580, 1964. 11. 3. Boxer LA, Camitta BM, Berenberg W, and Fanning JP: Myelofibrosis-myeloid metaplasia in childhood, Pediatrics 55:861, 1975. 4. Laszlo J: Myeloproliferative disorders (MPD): Myelofibro12. sis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia, Semin Hematol 12:409, 1975. 13. 5. Tobin MS, Tan C, and Argano S: Myelofibrosis in the pediatric age group, NY State J Med 1:1080, 1969. 6. Schlackman N, Green AA, and Naiman JL: Myelofibrosis 14. in children with chronic renal insufficiency, J PEDIATR 87:720, 1975. 15. 7. Crisser SD, and Chung KB: Acute myelofibrosis in progressive systemic sclerosis, Am J Med 67:151, 1979. 8. Evans DIK: Acute myelofibrosis in children with Down's syndrome, Arch Dis Child 50:458, 1975. Teasdale JM, Worth AT, and Corey MT: A missing C chromosome in the bone marrow cells of three children with myeloproliferative disease, Cancer 25:1468, 1970. Myers CE, Chabner BA, DeVita VT, and Gralnick HR: Bone marrow involvement in Hodgkin's disease: Pathology and response to MOPP chemotherapy, Blood 44:197, 1974. Smith CM, McKenna R, Hedlund B, Nesbit ME, and Krivit W: Transient myeloid metaplasia associated with an unusual hemoglobin in a newborn infant, Am J Pediatr Hematol/Oncol 1:291, 1979. Charron D, Ladislas R, Couty MC, and Binet JL: Biochemical and histological analysis of bone marrow collagen in myelofibrosis, Br J Haematol 41:151, 1979. Lewis CM, and Pegrum GD: Immune complexes in myelofibrosis: A possible guide to management, Br J Haematol 39:233, 1978. Balfanz JR, Nesbit ME, and Krivit W: Bone marrow curettage in childhood myelofibrosis, J PEDIATR 87:578, 1979. Rappeport J, Parkman R, Belli J, Levey R, Rosen F, and Nathan D: Reversibility ofmyelofibrosis after bone marrow transplantation, Blood 52(Suppl):271, 1978.

AGNOGENIC MYELOFIBROSIS IN CHILDREN

The case presented here is an 18‐month‐old female infant with agnogenic myelofibrosis. Clinically, this case was characterized by pancytopenia, bepatosplenomegaly, and rapidly fatal course, without response to steroids or other chemotherapy. Bone marrow biopsy and postmortem examination, revealed myeloid metaplasia of the liver, spleen, and lymph nodes, and conspicuous proliferation of immature cells, presumably of reticulum cells or precursors of hematopoietic cell lines, associated with prominent proliferation of reticular fibrous tissue. These morphologic features corresponded with those of agnogenic myelofibrosis, classified as a form of myeloproliferative disorder. A review of 15 cases of myelofibrosis in children collected from the literature showed a mean age of 2 years and 9 months with most cases being less than 2 years of age. There was a distinct female preponderance, while male infants with myelofibrosis were associated with Down's syndrome or C monosomy. The mean survival waa 6.7 months. Approximately 25 cases of myeloflbrosis have been reported in the English literature, while only 5 cases have been described in Japan.

Myelofibrosis in children with chronic renal insufficiency

During investigation of splenomegaly in a boy with chronic renal failure and osteodystrophy, bone marrow aspirates resulted in "dry taps," whereas biopsied material provided evidence that the marrow had been replaced by fibrous tissue. In a study of six other children with chronic renal failure, similar changes were observed. These findings suggest that the anemia of chronic renal failure may in part be a result of myelofibrosis, and the resulting reduction of functional bone marrow may limit the tolerance to immunosuppressive agents in patients who undergo renal transplantation.

Acute myelofibrosis in children with Down's syndrome.

Two boys with Down's syndrome, recognized at birth, developed acute myelogibrosis at the ages of 19 and 21 months. The disorder presented with anaemia and splenomegaly, and clinically resembled acute leukaemia, but bone marrow histology showed a bizarre pattern with generalized fibrosis, markedly increased reticulin, large reticulum cells, and giant cells resembling megakaryocytes. The children survived 6 and 11 months from diagnosis. A third case is quoted (Hillman and Forrester, 1968) which was also studied at this hospital; the features of all 3 cases are similar. There appears to be an increased incidence of acute myelofibrosis in children with Down's syndrome, which may be a further example of the instability of the haemopoietic system in the disease. In children with Down's syndrome and unusual leukaemia-like illness, histological examination of the bone marrow may be diagnostic.