Familial myelofibrosis (FM) is a rare variant of primary myelofibrosis. It is a myeloproliferative disorder caused by germline mutations affecting the maturation, differentiation, and function of hematopoietic stem cells. As a consequence of excess release of certain growth factors, hematopoietic tissue is progressively replaced by fibrous connective tissue. Although bone marrow functions are partially assumed by liver and spleen, FM patients eventually develop pancytopenia, which may lead to death within months or years. Hematopoietic stem cell transplantation is curative but implicates high risks.
Blood count analysis and peripheral blood smear examination are essential first steps to diagnosing FM. Blood counts generally reveal normocytic, normochromic anemia, leukopenia, and thrombocytopenia. At the same time, the number of immature cells in peripheral blood is increased. Immature granulocytes, reticulocytes, normoblasts, and dacrocytes can be observed under the microscope. Pancytopenia and leukoerythroblastosis require further clarification and should prompt a bone marrow biopsy. Usually, only a few cells can be obtained by bone marrow aspiration as it results in a dry tap. The histological examination of bone marrow samples reveals hypocellularity and reduced hematopoiesis as well as generalized fibrosis . Cytogenetic studies and sequencing of genes JAK2, CALR, and MPL should subsequently be carried out to identify the underlying chromosomal or gene aberration. However, such studies frequently yield negative results . The identification of so-called driver mutations is thus not an exclusion criterion for FM. It is, however, mandatory to rule out possible causes of secondary myelofibrosis, e.g., infectious disease and malignancy.
Hematopoietic stem cell transplantation is curative . Due to the risks implied by this procedure, it is reserved for high-risk patients and alternative options for treatment must be considered in the remainder of affected individuals. Unfortunately though, considerable knowledge gaps regarding the etiology and pathogenesis of FM complicate the search for causal treatment options and clinical trials on the efficacy of molecular targeted therapies in FM have not been carried out. Distinct compounds have, however, been tested in cases of other myeloproliferative disorders including primary myelofibrosis due to somatic mutations. More than 50% of patients suffering from primary myelofibrosis present JAK2 mutation V617F and thus, they may respond to treatment with JAK inhibitors . One of those JAK inhibitors is ruxolitinib, a compound that has been approved for the treatment of intermediate or high-risk myelofibrosis, with many others still being under development . Major side effects of ruxolitinib treatment comprise anemia and thromobocytopenia, which limit the use and dose of the drug. Furthermore, patients may develop resistance to ruxolitinib . A conservative approach to therapy is recommended for patients of low or intermediate risk who are unsuitable for therapy with JAK inhibitors or don't respond to it .
The clinical course is highly variable. While distinct scoring systems have been developed to predict the outcome in adult patients with primary myelofibrosis, it is not known whether these can be applied to FM. In contrast to primary myelofibrosis in the elder adult, FM has repeatedly been described to follow an acute or even fulminant course, leading to death within a short period of time  . However, insidious onset and prolonged course have also been reported . Children who don't undergo hematopoietic stem cell transplantation may survive for up to ten years, but if such a procedure is carried out, the disease may be cured .
Only a few cases of FM have been reported to date and little is known about the germline mutations underlying primary myelofibrosis in infants and young children. It is currently assumed that mutations of genes JAK2, CALR, and MPL may trigger FM. Such mutations have been identified in non-familial primary myelofibrosis. They encode for Janus kinase 2, calreticulin, and myeloproliferative leukemia virus oncogene.
Although data regarding FM are scarce, studies have been carried out on possible genotype-phenotype correlations in adults suffering from primary myelofibrosis. While Beauverd and colleagues didn't observe any significant differences in hematological and clinical phenotypes between patients carrying mutations in genes JAK2, CALR, or MPL, and those who tested negative for all of them , Szuber and Tefferi stated that certain genotypes had phenotypic and prognostic implications . Whether their results are valid for FM remains to be seen.
Available literature supports the notion of autosomal recessive inheritance . Penetrance is assumed to be incomplete and thus, the patients' family history may be unremarkable for hematological disease .
In general, myelofibrosis is a disease of the elder adult, but this does not apply to FM: Here, germline mutations interfere with hematopoiesis in the bone marrow and trigger acute and rapidly progressive bone marrow failure in infants and young children . Few cases of FM have been reported to date. The disease has first been described in British siblings , but it has later been diagnosed in patients from Saudi Arabia, North and South America . While boys and girls are affected, female preponderance has been suggested .
Mutations of genes JAK2, CALR or MPL are considered driver mutations in primary myelofibrosis. They are often mutually exclusive and demonstrate the clonal nature of the disease. All driver mutations known to date trigger the constitutive
activation of Janus kinase-signal transducers and activators of transcription (JAK-STAT) . The JAK-STAT signaling pathway transmits extracellular signals from the cell surface to the nucleus. Under physiological conditions, binding of cytokines and growth factors to membrane-bound receptors triggers the transcription of genes required for cell growth, differentiation, and proliferation. By contrast, mutations associated with primary myelofibrosis invalidate the JAK-STAT regulatory mechanism and favor an abnormal proliferation of cellular bone marrow components.
In this context, excess megakaryocyte proliferation is a key feature of myelofibrosis. According to current knowledge, uncontrolled cytokine release by megakaryocytes leads to stromal proliferation . In detail, degenerated megakaryocytes may secrete increased amounts of basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor β, and vascular endothelial growth factor, and thereby enhance fibroblast proliferation . Additionally, these cytokines are known to stimulate the synthesis of extracellular matrix and its subsequent deposition in the bone marrow . Accordingly, bone marrow fibrosis is an epiphenomenon to hematopoietic stem cell mutation. And while the underlying mutation may interfere with hematopoiesis, the space-occupying process of myelofibrosis does increasingly disturb intramedullar blood production.
Because the triggers of germline mutations in genes involved in hematopoiesis remain unknown, no recommendations can be given to prevent FM.
Myelofibrosis refers to the progressive replacement of functional bone marrow by connective tissue. It may be triggered by radiation, pathogens like mycobacteria, human immunodeficiency virus, and fungi, but myelofibrosis may also arise from polycythemia vera, essential thrombocythemia, leukemia, lymphoma, and myeloma. In these cases, myelofibrosis develops secondary to other conditions. By contrast, primary myelofibrosis is caused by mutations of genes JAK2, CALR, and MPL, among others . There is no underlying condition that interfered with bone marrow function: Gene aberrations affect growth, differentiation, and maturation of hematopoietic stem cells and surrounding fibroblasts. In the vast majority of cases, the causal mutations are somatic mutations. They are acquired in mid- to late adulthood and result in clinical disease beyond the age of 50 years . Germline mutations inducing primary myelofibrosis have rarely been described and thus, the incidence of FM, as this variant is called, is assumed to be very low. FM becomes symptomatic in infancy or early childhood and tends to follow an acute to fulminant, often lethal course  .
Of note, the term FM is occasionally used to refer to an inherited predisposition to myelofibrosis. For instance, polycythemia vera may be inherited in an autosomal dominant manner and predisposes to myelofibrosis . Even in the absence of a pathological condition like polycythemia vera, first-degree relatives of patients with myeloproliferative disorders have a 7-fold increased risk of developing such a disease . This fact supports the hypothesis of an inherited predisposition to myeloproliferative disease . Nevertheless, this article will focus on myelofibrosis due to germline mutations affecting hematopoiesis.
The term myelofibrosis describes the progressive replacement of functional bone marrow by fibrous connective tissue. Hematopoiesis is one of the main functions of the bone marrow, i.e., stem cells in the bone marrow differentiate into erythrocytes, leukocytes, and platelets, thereby ensuring the continuous renewal of blood cells throughout life. If hematopoiesis in the bone marrow is disturbed, the body tries to compensate by enhancing extramedullary blood production. It takes place in liver and spleen but it is usually insufficient to maintain adequate cell counts. Thus, patients suffering from myelofibrosis eventually develop anemia, leukopenia, and thrombocytopenia. Lack of red blood cells manifests in fatigue, pallor, and cyanosis, while white blood cell deficiencies result in an increased susceptibility to infection. Affected individuals are particularly prone to otitis, respiratory and gastrointestinal infections. Because platelets play an essential role in homeostasis, thrombocytopenia results in easy bruising and a propensity to bleed. Because of extramedullary hematopoiesis, myelofibrosis is usually associated with enlarged liver and spleen, which may cause abdominal pain, nausea, loss of appetite and weight.
Myelofibrosis may have distinct causes. On the one hand, it may be triggered by radiation, infection, and hematological diseases like polycythemia vera, essential thrombocythemia, and leukemia. If there is an underlying condition causing myelofibrosis, the patient is diagnosed with secondary myelofibrosis. On the other hand, myelofibrosis may be induced by mutations in genes involved in hematopoietic stem cell differentiation and growth. In the vast majority of cases, these mutations are acquired in mid- to late adulthood for as-of-yet unknown reasons. In rare cases though, such mutations may be present at birth. They may then be inherited from one generation to the next. Patients suffering from this type of myelofibrosis are diagnosed with familial myelofibrosis, a rare form of primary myelofibrosis. Familial myelofibrosis manifests in infancy or early childhood.
The course of the disease is highly variable. It may be acute or even fulminant and lead to death within months, but familial myelofibrosis may also have an insidious onset and follow a prolonged course. Hematopoietic stem cell transplantation is the only chance of cure. Due to the risks implied by this procedure, it is reserved for high-risk patients, though. Patients may survive for years without undergoing hematopoietic stem cell transplantation. Alternative treatment options are currently under development.