Patients may present within weeks after birth, during infancy or childhood. The clinical presentation of FM is that of extramedullary hematopoiesis and pancytopenia:

• Because of chronic bone marrow failure, hematopoiesis takes place in liver and spleen. Therefore, hepatosplenomegaly is a common finding. Enlarged liver and spleen can be palpated, but these organs should also be depicted by sonography. In neonates, an abnormally large spleen can be palpated more than 2 cm below the left costal margin. In case of hepatomegaly, the liver extends to more than 3 cm below the right costal margin of the newborn. Reference values for liver and spleen dimensions vary with the age of the patient and should be looked up in literature [1]. Hepatosplenomegaly may cause irritability, feeding difficulties, loss of appetite and weight. Children may complain about abdominal pain. Developmental delays have been reported [2].
• Anemia is one of the hallmarks of pancytopenia and is associated with fatigue, pallor, and cyanosis. Children may also be tachypneic due to hypoxia.
• Due to a lack of leukocytes, the patients' immune system is weakened, rendering them susceptible to infections. In this context, parents may inform about recurrent otitis, respiratory and gastrointestinal infections [3]. Patients suffering from any infectious disease at the time of clinical examination may have fever.
• Infants suffering from FM may show signs of progressive hemorrhagic diathesis. They are prone to bleed and parents may report abnormal bruising. Purpura may be noted in severe cases [2] [3].

• Splenomegaly

  Splenomegaly CT scan in a patient with chronic lymphocytic leukemia, showing splenomegaly. Yellow arrows point at the spleen. [en.wikipedia.org]

  Discontinuing Disease symptoms and splenomegaly with recur, sometimes rapidly Consider weaning over 7-10 days with steroid cover Splenomegaly & Extramedullary Haematopoiesis Medical management preferred but none offer sustained response Hydroxycarbamide [haembase.com]

  Newly developed JAK2 inhibitors are now first-line therapy for splenomegaly and constitutional symptoms (fever, night sweats, and weight loss). [hemonc.mhmedical.com]

  TA386 Appraisal title: Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis Section Key conclusion Ruxolitinib is recommended as an option for treating disease-related splenomegaly or symptoms in adults with primary [nice.org.uk]

  Myelofibrosis in children is usually of the acute type, presenting in infancy and running a fulminant, fatal course with minimal or mild splenomegaly. [jamanetwork.com]

• Easy Bruising

  Avoid bruising or bumping yourself. Use an electric razor, and be cautious when using nail trimmers, knives, etc. Wear hard-soled shoes, gloves, and long pants when working outside (i.e. gardening). [uihc.org]

  Bleeding and easy bruising can also occur. This is usually minor and occurs in around one quarter of all patients. [leukaemia.org.au]

  Headache Vision disturbances or silent migraines Dizziness or lightheadedness Coldness or blueness of fingers or toes Burning, redness, and pain in the hands and feet When bleeding is present as a symptom of essential thrombocythemia, it can manifest as: Easy [mpnresearchfoundation.org]

  Because platelets play an essential role in homeostasis, thrombocytopenia results in easy bruising and a propensity to bleed. [symptoma.com]

• Anemia

  Clinical manifestations depend on the type of blood cell affected and may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. [mendelian.co]

  Thus, patients suffering from myelofibrosis eventually develop anemia, leukopenia, and thrombocytopenia. [symptoma.com]

  […] or Fanconi anemia. [en.wikipedia.org]

  The paternal uncle presented in June 1996 at age 60 with anemia. The CBC showed leukoerythro-blastosis with prominent dacrocytes, mild thrombo-cytopenia but no dyspoiesis. [mdedge.com]

  The disease is characterized, classically, by anemia, mild neutrophilia, thrombocytosis, and splenomegaly. Occasional cases may present with bi- or tricytopenias (~15 percent). [hemonc.mhmedical.com]

• Fatigue

  The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international internet-based survey of 1179 MPD patients. Cancer. 2007;109:68-76. Source: Incyte Corporation Incyte Corporation Pamela M. [investor.incyte.com]

  When the bone marrow is unable to make enough healthy blood cells, the result can be severe anemia, weakness, bone pain, fatigue and increased risk of infection. [llscanada.org]

  […] signs of MF during physical examinations may include • An enlarged spleen • Pale mucous membranes, or pallor, if anemia is present • Loss of muscle mass • Cachexia, which is a wasting syndrome characterized by weight loss, muscle atrophy, weakness, and fatigue [copingmag.com]

  Symptoms of MF can include: Symptoms of anemia (low red blood count), including weakness and fatigue, shortness of breath, palpitations and pale skin Symptoms associated with an enlarged spleen, including pain and discomfort below your ribs on the left [canadianmpnnetwork.ca]

  Anemia is one of the hallmarks of pancytopenia and is associated with fatigue, pallor, and cyanosis. Children may also be tachypneic due to hypoxia. [symptoma.com]

• Fever

  Diseases related with Fever and Hepatosplenomegaly In the following list you will find some of the most common rare diseases related to Fever and Hepatosplenomegaly that can help you solving undiagnosed cases. [mendelian.co]

  Constitutional symptoms include fevers, pruritus, and the one that I find to be the most troubling is early satiety leading to weight loss. Once that starts to develop, patients tend to have a more rapid decline. [onclive.com]

  Constitutional symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi. [mpnresearchfoundation.org]

  Factors that can influence an MF prognosis are age, white blood cell counts, number of blasts (or immature blood cells) in the blood, constitutional symptoms (such as night sweats, weight loss, and fever), anemia, transfusion dependence, low platelets [copingmag.com]

• Weakness

  When the bone marrow is unable to make enough healthy blood cells, the result can be severe anemia, weakness, bone pain, fatigue and increased risk of infection. [llscanada.org]

  The deceased brother presented April 1994 with weakness at age 39. A CBC showed pancytopenia with a few blasts and nucleated rbc. [mdedge.com]

  Check with your doctor if you are experiencing: Fatigue, weakness, or shortness of breath. [cancersupportcommunity.org]

  Patients also may experience symptoms of anemia, including weakness and fatigue. A low platelet count due to MF can result in bleeding and clotting difficulties, and a low number of white blood cells can cause an increased risk of infection. [uihc.org]

  The disease, regardless of origin, can lead to bone marrow scarring and severe anemia, weakness and an enlarged spleen. The only known treatment is a hematopoietic stem cell transplant. [med.wisc.edu]

• Weight Loss

  Constitutional symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi. [mpnresearchfoundation.org]

  Common signs of MF during physical examinations may include • An enlarged spleen • Pale mucous membranes, or pallor, if anemia is present • Loss of muscle mass • Cachexia, which is a wasting syndrome characterized by weight loss, muscle atrophy, weakness [copingmag.com]

  Constitutional symptoms include fevers, pruritus, and the one that I find to be the most troubling is early satiety leading to weight loss. Once that starts to develop, patients tend to have a more rapid decline. [onclive.com]

  In turn, this causes the liver and spleen to become enlarged and creates some of the symptoms such as abdominal pain, feeling full, weight loss, fatigue, itching, bone pain, and night sweats that people diagnosed with MF may experience. [cancercare.org]

  Newly developed JAK2 inhibitors are now first-line therapy for splenomegaly and constitutional symptoms (fever, night sweats, and weight loss). [hemonc.mhmedical.com]

• Pneumonia

  […] idiyopatik interstisyel pnömoni 21 Medikal idiopathic pulmonary haemosiderosis idiyopatik pulmoner hemosiderozis 22 Medikal idiopathic chronic eosinophilic pneumonia idiyopatik kronik eozinofilik pnömoni 23 Medikal primary idiopathic amyloidosis primer [tureng.com]

  Six months after the first visit to the hospital, the patient died due to pneumonia and sepsis. Thrombotic symptoms or major bleeding events did not develop during the survival period following diagnosis of PMF. [koreamed.org]

  Symptoms of myelofibrosis may include: Fatigue and weakness Shortness of breath An unhealthy pale appearance Abdominal swelling and tenderness Bone pain Easy bruising and bleeding Loss of appetite and weight Increased risk of infection, including pneumonia [verywellhealth.com]

  NCT00045292 Phase 3 acyclovir;acyclovir sodium;valacyclovir 10 A Randomized Double-Blind Placebo-Controlled Phase III Study To Evaluate The Safety And Efficacy Of Palivizumab Combined With Aerosolized Ribavirin Compared To Ribavirin Alone To Treat RSV Pneumonia [malacards.org]

• Pleural Effusion

  Symtomatic portal hypertension and non hepatoslenic extramedullary hematopoiesis may lead to variceal bleeding, ascites, pleural effusion and/or pulmonary hypertension. Leukemic transformation is observed in approximately 20% of patients. [orpha.net]

  Myelodysplasia Dyspnea Tachycardia Pericarditis Anterior uveitis Weight loss T-cell lymphoma Impaired T cell function Lymphoproliferative disorder Aplastic anemia Refractory anemia Megakaryocyte dysplasia Arthritis Recurrent opportunistic infections Pleural [mendelian.co]

  Low‐dose irradiation remains the treatment of choice for extramedullary haematopoiesis (EMH) at other sites, including involvement of the peritoneum and pleura with resultant ascites and pleural effusions, respectively (Leinweber et al, 1991 ; Kupferschmid [onlinelibrary.wiley.com]

• Dyspnea

  Growth delay Diarrhea Failure to thrive Uveitis Episodic fever Increased serum ferritin Falls Eosinophilia Neutrophilia Joint swelling Juvenile rheumatoid arthritis Elevated C-reactive protein level Thickened calvaria Pericardial effusion Myelodysplasia Dyspnea [mendelian.co]

  Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. [en.wikipedia.org]

• Abdominal Pain

  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. [symptoma.com]

  In turn, this causes the liver and spleen to become enlarged and creates some of the symptoms such as abdominal pain, feeling full, weight loss, fatigue, itching, bone pain, and night sweats that people diagnosed with MF may experience. [cancercare.org]

  […] lymphoma Impaired T cell function Lymphoproliferative disorder Aplastic anemia Refractory anemia Megakaryocyte dysplasia Arthritis Recurrent opportunistic infections Pleural effusion Myalgia Rheumatoid arthritis Elevated erythrocyte sedimentation rate Abdominal [mendelian.co]

  FMF is characterized by 2–3 days long self-limited attacks of fever, abdominal pain, arthritis and /or pleuritis [10]. The attacks are accompanied by leukocytosis and neutrophil infiltration to synovial membranes. [ojrd.biomedcentral.com]

  However, the tip of the spleen may be palpable in a newborn baby up to three months of age.[10] Signs and symptoms[edit] Symptoms may include abdominal pain, chest pain, chest pain similar to pleuritic pain when stomach, bladder or bowels are full, back [en.wikipedia.org]

• Early Satiety

  […] with limited treatment options.1 Patients with MF suffer a high disease burden characterized by bone marrow failure, enlarged spleen (splenomegaly) and debilitating symptoms including fatigue, severe itching (pruritus), night sweats, bone pain, and early [investor.incyte.com]

  Constitutional symptoms include fevers, pruritus, and the one that I find to be the most troubling is early satiety leading to weight loss. Once that starts to develop, patients tend to have a more rapid decline. [onclive.com]

  During clinical trials, it was shown to reduce spleen size, abdominal discomfort, early satiety, bone pain, night sweats and itching in MF patients as well as the level of “pro-inflammatory cytokines” in the blood, which may cause some symptoms such as [mpnresearchfoundation.org]

  satiety due to splenic encroachment, or the symptoms of anemia due to accompanying cytopenia. [en.wikipedia.org]

  Approximately 25-50% of patients will have symptoms from an enlarged spleen at diagnosis, including pain with deep breaths, loss of appetite and feeling full after eating a small amount (called early satiety). [oncolink.org]

• Diarrhea

  Besides abdominal swelling, other symptoms such as digestive disorders (diarrhea and constipation) heartburn, and indigestion triggered by fatty foods may also appear. [aoporphan.lv]

  Jakafi may cause nausea, diarrhea, liver inflammation, reduced platelets, and increased cholesterol in some. [verywellhealth.com]

  […] of the following symptoms: Uncommon Symptoms - Between 30% and 50% cases Hypertriglyceridemia Lymphadenopathy Skin rash Rare Symptoms - Less than 30% cases Autoimmunity Inflammatory abnormality of the skin Hypofibrinogenemia Arthralgia Growth delay Diarrhea [mendelian.co]

  Diarrhea. Stages of Chronic Myeloproliferative Neoplasms Key Points There is no standard staging system for chronic myeloproliferative neoplasms. There is no standard staging system for chronic myeloproliferative neoplasms. [cancer.gov]

  Starting dose. 2)] • NCI CTCAE Grade 3 or higher diarrhea [see Warnings and Precautions (5. 24, 2018, the Food and Drug Administration granted regular approval to duvelisib (COPIKTRA, Verastem, Inc. 1)] • NCI CTCAE Grade 2 or higher in ALT and/or AST [azspirit.us]

• Loss of Appetite

  Hepatosplenomegaly may cause irritability, feeding difficulties, loss of appetite and weight. Children may complain about abdominal pain. Developmental delays have been reported. [symptoma.com]

  Side effects may include nausea, diarrhea, fatigue, loss of appetite, skin rash, and hair loss (usually temporary). [verywellhealth.com]

  […] of appetite and weight loss Symptoms associated with an enlarged liver, typically pain and discomfort in your stomach or abdomen Skin itchiness (your doctor might call this pruritus) Excessive sweating, especially at night Fever Increased risk of infection [canadianmpnnetwork.ca]

  Management of an enlarged spleen An enlarged spleen is a common symptom of MF, often leading to pain and discomfort and a feeling of fullness or loss of appetite. [mpn-mate.com]

  Approximately 25-50% of patients will have symptoms from an enlarged spleen at diagnosis, including pain with deep breaths, loss of appetite and feeling full after eating a small amount (called early satiety). [oncolink.org]

• Abdominal Distension

  distension/fluid retention (if portal hypertension or increased blood pressure within the portal vein is present) Compromised liver function Abnormal growth of blood forming cells outside of the bone marrow Routine medical examinations including complete [mpnresearchfoundation.org]

• Thrombosis

  Patients with CALR-mutated ET showed a higher platelet count (P = .017) and a lower cumulative incidence of thrombosis (P = .036) and of disease progression (P = .047) compared with those with JAK2 (V617F). [moh-it.pure.elsevier.com]

  65 without prior thrombosis have an incidence of thrombosis of 2.5 per 100 persons per year, those older than age 65 or with prior thrombosis have an incidence of 5.0 per 100 persons per year, and patients older than age 65 with prior thrombosis have [ascopubs.org]

  Among low-risk patients (defined as age ≤60 years with no prior thrombotic episodes), a retrospective review of 300 patients showed benefit for antiplatelet agents in reducing venous thrombosis in JAK2-positive cases and in reducing arterial thrombosis [uwhealth.org]

  Older patients and those with a high platelet count, or a prior history of thrombosis, may be at increased risk. A major aim of treatment in ET is to reduce your platelet count, and therefore your risk of thrombosis. [leukaemia.org.au]

  The decision to use platelet-lowering agents depends on a variety of risk factors, history of bleeding or thrombosis, vascular risk, and the severity of symptoms. [mpnresearchfoundation.org]

• Tachycardia

  Diarrhea Failure to thrive Uveitis Episodic fever Increased serum ferritin Falls Eosinophilia Neutrophilia Joint swelling Juvenile rheumatoid arthritis Elevated C-reactive protein level Thickened calvaria Pericardial effusion Myelodysplasia Dyspnea Tachycardia [mendelian.co]

  […] esophageal atresia Atelosteogenesis type I Atelosteogenesis type III Atypical teratoid tumor Autosomal dominant Larsen syndrome Autosomal recessive nonsyndromic intellectual deficit Boomerang dysplasia CLN5 disease Catecholaminergic polymorphic ventricular tachycardia [csbg.cnb.csic.es]

• Palpitations

  Symptoms of MF can include: Symptoms of anemia (low red blood count), including weakness and fatigue, shortness of breath, palpitations and pale skin Symptoms associated with an enlarged spleen, including pain and discomfort below your ribs on the left [canadianmpnnetwork.ca]

• Hepatosplenomegaly

  The illness presented with pallor, haemorrhagic symptoms, and hepatosplenomegaly, and the blood picture was that of pancytopenia and leucoerythroblastosis. Bone marrow histology showed reduced haemopoiesis with generalised fibrosis. [ncbi.nlm.nih.gov]

  Diseases related with Fever and Hepatosplenomegaly In the following list you will find some of the most common rare diseases related to Fever and Hepatosplenomegaly that can help you solving undiagnosed cases. [mendelian.co]

  Therefore, hepatosplenomegaly is a common finding. Enlarged liver and spleen can be palpated, but these organs should also be depicted by sonography. [symptoma.com]

• Hepatomegaly

  Clinical manifestations depend on the type of blood cell affected and may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. [mendelian.co]

  In some cases the liver may also be enlarged (hepatomegaly). [leukaemia.org.au]

  As the disease progresses, the liver and spleen begin to take over the production of blood to the point that the organs start swelling, leading to splenomegaly and/or hepatomegaly. [aoporphan.lv]

  […] offer sustained response Hydroxycarbamide Popular choice, limited evidence, complete response is rare Thalidomide + Pred Response in 1/3 of patients, only 8% have reduction in spleen size Cladribine Maybe useful for post-splenectomy thrombocytosis / hepatomegaly [haembase.com]

• Night Sweats

  […] fatigue, fever, night sweats and weight loss. [mpnresearchfoundation.org]

  So, malfunctioning bone marrow, anemia—low platelets in some patients—and low white cell count coupled with a very large spleen, enlargement of the liver, and very poor quality of life—bone aches and pains, night sweating, low-grade fevers, itching, night [onclive.com]

  Factors that can influence an MF prognosis are age, white blood cell counts, number of blasts (or immature blood cells) in the blood, constitutional symptoms (such as night sweats, weight loss, and fever), anemia, transfusion dependence, low platelets [copingmag.com]

  In turn, this causes the liver and spleen to become enlarged and creates some of the symptoms such as abdominal pain, feeling full, weight loss, fatigue, itching, bone pain, and night sweats that people diagnosed with MF may experience. [cancercare.org]

  Newly developed JAK2 inhibitors are now first-line therapy for splenomegaly and constitutional symptoms (fever, night sweats, and weight loss). [hemonc.mhmedical.com]

• Petechiae

  Clinical manifestations depend on the type of blood cell affected and may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension. [monarchinitiative.org]

  Clinical manifestations depend on the type of blood cell(s) affected and may include severe anemia, pallor, petechiae, ecchymosis, bleeding, thrombosis, pancytopenia, pruritus, hypermetabolic state, marked hepato/splenomegaly, and/or constitutional symptoms [orpha.net]

  […] sores that do not heal, have drainage, or are swollen, red, and warm to the touch stiff neck Bleeding symptoms easy bruising unusually heavy or prolonged bleeding bleeding for no apparent reason severe headache or visual changes stiff neck joint pain petechiae [uihc.org]

  Manifestations of disease may include, but are not limited to, the following: Pallor (anemia) Bruising, petechiae, or bleeding (thrombocytopenia) Fever Weight loss Night sweats Bone pain Left upper quadrant pain Splenomegaly (frequent), hepatomegaly, [emedicine.medscape.com]

• Urticaria

  […] kronik idiyopatik ürtikerli hasta 37 Medikal idiopathic hypersomnia idiopatik hipersomni 38 Medikal idiopathic infertility idiyopatik infertilite 39 Medikal patient with chronic idiopathic urticaria kronik idiopatik ürtikerli hasta 40 Medikal chronic [tureng.com]

  […] eruptiva perstans Typical urticaria pigmentosa Homozygous familial hypercholesterolemia Laron syndrome Short stature due to partial GHR deficiency Hyperinsulinism due to INSR deficiency Insulin-resistance syndrome type A Leprechaunism Rabson-Mendenhall [csbg.cnb.csic.es]

• Bone Pain

  It can be used to treat an enlarged spleen, bone pain or tumours that develop outside of the bone marrow. Surgery Surgery to remove the spleen (called splenectomy) may be done if an enlarged spleen is causing pain. [cancer.ca]

  In turn, this causes the liver and spleen to become enlarged and creates some of the symptoms such as abdominal pain, feeling full, weight loss, fatigue, itching, bone pain, and night sweats that people diagnosed with MF may experience. [cancercare.org]

  enlarged spleen (splenomegaly) and debilitating symptoms including fatigue, severe itching (pruritus), night sweats, bone pain, and early satiety (a feeling of fullness), leading to impaired quality of life.2 “Volunteers across the country are promoting [investor.incyte.com]

  Your haematologist will give you some medication to prevent pain, and then he or she will extract some bone marrow from your hip bone using a needle. [mpn-mate.com]

• Headache

  MPN can cause problems like an increased tendency to form blood clots, symptoms such as itching, headache, and fatigue. Also, MPN can sometimes progress to a leukemia. [wearempn.org]

  As the disease progresses, the following symptoms may appear: Blood clot Fatigue Headache Excessive sweating Blurred vision or blind spots Weakness Dizziness Itchiness, especially after a warm shower or bath Redness or a purplish appearance of skin Peptic [cancersupportcommunity.org]

  Symptoms of polycythemia vera include headaches and a feeling of fullness below the ribs on the left side. Special blood tests are used to diagnose polycythemia vera. [cancer.gov]

  […] soreness mouth or lip sores pain during urination sores that do not heal, have drainage, or are swollen, red, and warm to the touch stiff neck Bleeding symptoms easy bruising unusually heavy or prolonged bleeding bleeding for no apparent reason severe headache [uihc.org]

  Common symptoms include: headaches blurred vision fatigue weakness dizziness itchiness (pruritus) night sweats raised blood pressure (hypertension). Other symptoms experienced in MPN are a result of the affected cell involved with the MPN. [leukaemia.org.au]

• Dizziness

  A 72-year-old male visited the hospital, complaining mainly of dizziness and epistaxis. [koreamed.org]

  As the disease progresses, the following symptoms may appear: Blood clot Fatigue Headache Excessive sweating Blurred vision or blind spots Weakness Dizziness Itchiness, especially after a warm shower or bath Redness or a purplish appearance of skin Peptic [cancersupportcommunity.org]

  Common symptoms include: headaches blurred vision fatigue weakness dizziness itchiness (pruritus) night sweats raised blood pressure (hypertension). Other symptoms experienced in MPN are a result of the affected cell involved with the MPN. [leukaemia.org.au]

  Common ET Symptoms related to small vessel disturbances may include: Headache Vision disturbances or silent migraines Dizziness or lightheadedness Coldness or blueness of fingers or toes Burning, redness, and pain in the hands and feet When bleeding is [mpnresearchfoundation.org]

• Seizure

  Search for genes, diseases and other keywords, e.g. seizures, BRCA1 or therapy. Separate different terms with and, e.g. metformin and pancreas. [rareomics.healx.io]

  HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 4; FHL4 Is also known as hlh4|hplh4 Related symptoms: Seizures Global developmental delay Generalized hypotonia Anemia Hepatomegaly SOURCES: OMIM MENDELIAN More info about HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS [mendelian.co]

  […] hemophagocytic lymphohistiocytosis Fatal post-viral neurodegenerative disorder Idiopathic aplastic anemia Benign familial chorea Brain-lung-thyroid syndrome Childhood absence epilepsy Encephalopathy due to GLUT1 deficiency Epilepsy with myoclonic-astatic seizures [csbg.cnb.csic.es]

  These tumors may cause problems such as bleeding in your gastrointestinal system, coughing or spitting up of blood, compression of your spinal cord, or seizures. Bleeding complications. [drugs.com]

• Vertigo

  […] related to abdominal discomfort, fatigue, coughing, night sweats, bone pain, weight loss, inactivity, abdominal pain, pruritus, fever, and quality of life, there was an additional focus on microvascular symptoms including insomnia, sexual dysfunction, vertigo [ascopubs.org]

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 [2]. 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 [3]. 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.

• Pericardial Effusion

  […] skin Hypofibrinogenemia Arthralgia Growth delay Diarrhea Failure to thrive Uveitis Episodic fever Increased serum ferritin Falls Eosinophilia Neutrophilia Joint swelling Juvenile rheumatoid arthritis Elevated C-reactive protein level Thickened calvaria Pericardial [mendelian.co]

• Thrombocytosis

  The disease is characterized, classically, by anemia, mild neutrophilia, thrombocytosis, and splenomegaly. Occasional cases may present with bi- or tricytopenias (~15 percent). [hemonc.mhmedical.com]

  The Center for the Chronic Myeloproliferative Disorders was established in 2002 to meet the needs of patients with Polycythemia Vera, Primary Myelofibrosis, Essential Thrombocytosis, Systemic Mastocytosis or the Hypereosinophilic Syndrome, to investigate [hopkinsmedicine.org]

  Familial thrombocytosis with myeloproliferative neoplasm including chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, sporadic or familial ET... [evidence.nhs.uk]

  May control hypercatabolism, hepatosplenomegaly, leuko/thrombocytosis Options - HU, Anagrelide, IFN-Alpha Allogeneic HSCT Potentially curative with reversal of marrow fibrosis No head-to-head trials to guide best transplant practice Eligibility: simply [haembase.com]

  […] congestion, hemosiderosis, reduction in lymphoid follicles Microscopic (histologic) images Images hosted on other servers:   Bone marrow: prominent fibrosis and osteosclerosis Peripheral smear description Leukoerythroblastosis, megakaryocytic nuclei, thrombocytosis [pathologyoutlines.com]

• Neutropenia

  Patients may experience anaemia, neutropenia, and/or thrombocytopaenia. Patients may also experience pain secondary to hepatosplenomegaly. [healthengine.com.au]

  The term refractory neutropenia and refractory thrombocytopenia have sometimes been used to describe these cases. A diagnosis of MDS in patients with neutropenia or thrombocytopenia without anemia should be made with caution. [en.wikipedia.org]

  Thromboembolic Disease Hematopoietic Cell Transplantation NCCN Guidelines Pre-Transplant Recipient Evaluation Management of Graft-Versus-Host Disease Hematopoietic Growth Factors NCCN Guidelines Management of Cancer- and Chemotherapy-Induced Anemia Management of Neutropenia [nccn.org]

  Neoplasm Chronic recurrent multifocal osteomyelitis Low-grade fever Decreased mean corpuscular volume Anemia of inadequate production Microcytic anemia Psoriasiform dermatitis Portal fibrosis Bone pain Delayed skeletal maturation Flexion contracture Neutropenia [mendelian.co]

  Patients may experience anemia, neutropenia, and/or thrombocytopenia. Patients may also experience pain secondary to hepatosplenomegaly. Neutropenia may lead to opportunistic infections. Thrombocytopenia may lead to hemorrhage. [emedicine.medscape.com]

• Leukopenia

  Thus, patients suffering from myelofibrosis eventually develop anemia, leukopenia, and thrombocytopenia. [symptoma.com]

  Primary myelofibrosis is a chronic clonal myeloid neoplasm characterized by (1) anemia; (2) neutrophilia and thrombocytosis or, in a minority, thrombocytopenia and leukopenia; (3) splenomegaly; (4) immature granulocytes, increased cluster of differentiation [hemonc.mhmedical.com]

  Pathophysiology Clonal haematopoietic stem cell proliferation results in a leucoerythroblastic blood film and increased pro-inflammatory and pro-angiogenic cytokines Clinical Features Progressive anaemia, leukopenia / leukocytosis, thrombocytopenia / [haembase.com]

  […] prominently a high risk of thrombosis and a predisposition to evolve into acute myeloid leukemia or secondary myelofibrosis.6-8 Among MPNs, primary myelofibrosis has the most heterogeneous clinical presentation, including anemia, splenomegaly, leukocytosis or leukopenia [ascopubs.org]

  […] megakaryoblastic leukemia.[17][15][18] Diagnosis[edit] The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating MDS from anemia, thrombocytopenia, and leukopenia [en.wikipedia.org]

• Pleural Effusion

  Symtomatic portal hypertension and non hepatoslenic extramedullary hematopoiesis may lead to variceal bleeding, ascites, pleural effusion and/or pulmonary hypertension. Leukemic transformation is observed in approximately 20% of patients. [orpha.net]

  Myelodysplasia Dyspnea Tachycardia Pericarditis Anterior uveitis Weight loss T-cell lymphoma Impaired T cell function Lymphoproliferative disorder Aplastic anemia Refractory anemia Megakaryocyte dysplasia Arthritis Recurrent opportunistic infections Pleural [mendelian.co]

  Low‐dose irradiation remains the treatment of choice for extramedullary haematopoiesis (EMH) at other sites, including involvement of the peritoneum and pleura with resultant ascites and pleural effusions, respectively (Leinweber et al, 1991 ; Kupferschmid [onlinelibrary.wiley.com]

• Leukocytosis

  A correlation between leukocytosis and risk of acute leukemia has been recently reported in patients with PV. 24 These data indicate that PV patients with leukocytosis are at higher risk of disease evolution. [bloodjournal.org]

  Leukocytosis, anemia, thrombocytopenia, tear drop cells, nucleated RBCs, and myeloblasts were observed in both complete blood cell counts and peripheral blood smears. Bone marrow aspiration failed due to dilution with peripheral blood. [koreamed.org]

  Minor criteria include blood test for anemia, Leukocytosis, LDH level and Leukoerythroblastosis. [orpha.net]

  […] secondary to infection, autoimmune / inflammatory conditions, toxicity, hairy cell leukemia, lymphoid neoplasms or other malignancy Minor criteria: Leukoerythroblastosis Increased serum LDH (lactate dehydrogenase) Anemia Splenomegaly Laboratory Anemia, leukocytosis [pathologyoutlines.com]

Hematopoietic stem cell transplantation is curative [4]. 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 [5]. 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 [6]. 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 [7]. 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 [8].

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 [2] [9]. However, insidious onset and prolonged course have also been reported [10]. 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 [3].

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 [11], Szuber and Tefferi stated that certain genotypes had phenotypic and prognostic implications [5]. Whether their results are valid for FM remains to be seen.

Available literature supports the notion of autosomal recessive inheritance [4]. Penetrance is assumed to be incomplete and thus, the patients' family history may be unremarkable for hematological disease [3].

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 [2]. Few cases of FM have been reported to date. The disease has first been described in British siblings [2], but it has later been diagnosed in patients from Saudi Arabia, North and South America [4]. While boys and girls are affected, female preponderance has been suggested [3].

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) [5]. 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 [4]. 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 [12]. Additionally, these cytokines are known to stimulate the synthesis of extracellular matrix and its subsequent deposition in the bone marrow [12]. 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 [5]. 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 [11]. 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 [2] [9].

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 [13]. 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 [14]. This fact supports the hypothesis of an inherited predisposition to myeloproliferative disease [15]. 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.

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