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51-442: A limp is a type of asymmetric abnormality of the gait . Limping may be caused by pain, weakness, neuromuscular imbalance, or a skeletal deformity. The most common underlying cause of a painful limp is physical trauma ; however, in the absence of trauma, other serious causes, such as septic arthritis or slipped capital femoral epiphysis , may be present. The diagnostic approach involves ruling out potentially serious causes via

102-509: A gene from one chromosome that promotes cell division to a more actively transcribed area on another chromosome. The result is a cell that divides more often. An example of this includes the translocation of C-MYC , a gene that encodes a transcription factor that leads to increased cell division, next to the immunoglobulin heavy - or light-chain gene enhancers , leading to increased C-MYC expression and increased cell division. Other large changes in chromosomal structure can result in

153-731: A liver one can feel (64%), a spleen one can feel (61%), pale complexion (54%), fever (53%), and bruising (52%). Additionally, recurrent infections, feeling tired, arm or leg pain, and enlarged lymph nodes can be prominent features. The B symptoms , such as fever, night sweats, and weight loss, are often present as well. Central nervous system (CNS) symptoms such as cranial neuropathies due to meningeal infiltration are identified in less than 10% of adults and less than 5% of children, particularly mature B-cell ALL (Burkitt leukemia) at presentation. The signs and symptoms of acute lymphoblastic leukemia are variable and include: The cancerous cell in ALL

204-425: A WBC count greater than 12×10/l, fever greater than 38.5 °C (101.3 °F), ESR greater than 40 mm/h, CRP greater than 2.0 mg/dL, and refusal to walk. People with septic arthritis usually look clinically toxic or sick. Even in the absence of any of these factors, however, septic arthritis may be present. Joint aspiration is required to confirm the diagnosis. Other infections that classically lead to

255-720: A cell that divides more often, even in the absence of growth factors . Other genetic changes in B-cell ALL include changes to the number of chromosomes within the leukemic cells. Gaining at least five additional chromosomes, called high hyperdiploidy, occurs more commonly. Less often, chromosomes are lost, called hypodiploidy , which is associated with a poorer prognosis. Additional common genetic changes in B-cell ALL involve non-inherited mutations to PAX5 and IKZF1 . In T-cell ALL, LYL1 , TAL1 , TLX1 , and TLX3 rearrangements can occur. Acute lymphoblastic leukemia results when enough of these genetic changes are present in

306-627: A good prognosis while hypodiploid cases do not. For example, the most common specific abnormality in childhood B-ALL is the t(12;21) ETV6 – RUNX1 translocation, in which the RUNX1 gene, encoding a protein involved in transcriptional control of hemopoiesis , has been translocated and repressed by the ETV6 – RUNX1 fusion protein. Below is a table with the frequencies of some cytogenetic translocations and molecular genetic abnormalities in ALL. French-American-British Historically, prior to 2008, ALL

357-615: A known genetic syndrome. Rare mutations in ETV6 and PAX5 are associated with a familial form of ALL with autosomal dominant patterns of inheritance . The environmental exposures that contribute to emergence of ALL is contentious and a subject of ongoing debate. High levels of radiation exposure from nuclear fallout is a known risk factor for developing leukemia. Evidence whether lesser radiation, as from x-ray imaging during pregnancy, increases risk of disease remains inconclusive. Studies that have identified an association between x-ray imaging during pregnancy and ALL found only

408-466: A laboratory technique used to identify proteins that are expressed on their cell surface, is a key component in the diagnosis of ALL. The preferred method of immunophenotyping is through flow cytometry . In the malignant lymphoblasts of ALL, expression of terminal deoxynucleotidyl transferase (TdT) on the cell surface can help differentiate malignant lymphocyte cells from reactive lymphocytes , white blood cells that are reacting normally to an infection in

459-404: A limp include Lyme disease (a bacterial infection spread by deer ticks ) and osteomyelitis (an infection of the bone). Accidental or deliberate physical trauma may result in either a fracture, muscle bruising, or a contusion. It is the leading cause of a limp. Deliberate abuse is important to consider. Slipped capital femoral epiphysis (SCFE) is a condition in which the growth plate of

510-744: A number of years. Treatment usually also includes intrathecal chemotherapy since systemic chemotherapy can have limited penetration into the central nervous system and the central nervous system is a common site for relapse of acute lymphoblastic leukemia. Treatment can also include radiation therapy if spread to the brain has occurred. Stem cell transplantation may be used if the disease recurs following standard treatment. Additional treatments such as Chimeric antigen receptor T cell immunotherapy are being used and further studied. Acute lymphoblastic leukemia affected about 876,000 people globally in 2015 and resulted in about 111,000 deaths. It occurs most commonly in children, particularly those between

561-718: A person inherits several of these mutations together. The uneven distribution of genetic risk factors may help explain differences in disease rates among ethnic groups. For instance, the ARID5B mutation is less common in ethnic African populations. Several genetic syndrome also carry increased risk of ALL. These include: Down syndrome , Fanconi anemia , Bloom syndrome , X-linked agammaglobulinemia , severe combined immunodeficiency , Shwachman–Diamond syndrome , Kostmann syndrome , neurofibromatosis type 1 , ataxia-telangiectasia , paroxysmal nocturnal hemoglobinuria , and Li–Fraumeni syndrome . Fewer than 5% of cases are associated with

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612-453: A person with genetic risk factors. Delayed development of the immune system due to limited disease exposure may result in excessive production of lymphocytes and increased mutation rate during an illness. Several studies have identified lower rates of ALL among children with greater exposure to illness early in life. Very young children who attend daycare have lower rates of ALL. Evidence from many other studies looking at disease exposure and ALL

663-487: A refusal to walk. Hip deformities with associated muscular weakness, on the other hand, may be present with a Trendelenburg gait , with the body shifted over the affected hip. The causes of limping are many and can be either serious or non-serious. It usually results from pain, weakness, neuromuscular imbalance, or a skeletal deformity. In 30% of cases, the underlying cause remains unknown after appropriate investigations. The most common underlying cause of limping in children

714-626: A significant role. Aside from the KMT2A rearrangement, only one extra mutation is typically found. Environmental exposures are not needed to help create more mutations. Common inherited risk factors include mutations in ARID5B , CDKN2A / 2B , CEBPE , IKZF1 , GATA3 , PIP4K2A and, more rarely, TP53 . These genes play important roles in cellular development, proliferation, and differentiation. Individually, most of these mutations are low risk for ALL. Significant risk of disease occurs when

765-419: A single lymphoblast. In childhood ALL, for example, one fusion gene translocation is often found along with six to eight other ALL-related genetic changes. The initial leukemic lymphoblast copies itself into an excessive number of new lymphoblasts, none of which can develop into functioning lymphocytes. These lymphoblasts build up in the bone marrow and may spread to other sites in the body, such as lymph nodes ,

816-421: A slightly increased risk. Exposure to strong electromagnetic radiation from power lines has also been associated with a slightly increased risk of ALL. This result is questioned as no causal mechanism linking electromagnetic radiation with cancer is known. High birth weight (greater than 4000 g or 8.8 lbs) is also associated with a small increased risk. The mechanism connecting high birth weight to ALL

867-399: Is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes . Symptoms may include feeling tired, pale skin color, fever , easy bleeding or bruising, enlarged lymph nodes , or bone pain. As an acute leukemia , ALL progresses rapidly and is typically fatal within weeks or months if left untreated. In most cases, the cause

918-405: Is a degenerative disease of the head of the femur which results in bone loss and deformity. It usually presents as a chronic condition. Cancers including acute lymphocytic leukemia , osteosarcoma , and Ewing’s sarcoma may result in a gradual onset of limping in children. It is often associated with night sweating, easy bruising, weight loss, and pain most prominent at night. The diagnosis of

969-670: Is also common in persons with nervous system problems such as cauda equina syndrome , multiple sclerosis , Parkinson's disease (with characteristic Parkinsonian gait ), Alzheimer's disease , vitamin B 12 deficiency , myasthenia gravis , normal pressure hydrocephalus , and Charcot–Marie–Tooth disease . Research has shown that neurological gait abnormalities are associated with an increased risk of falls in older adults. Orthopedic corrective treatments may also manifest into gait abnormality, such as lower extremity amputation , healed fractures , and arthroplasty (joint replacement). Difficulty in ambulation that results from chemotherapy

1020-416: Is also not known. Evidence suggests that secondary leukemia can develop in individuals treated with certain types of chemotherapy, such as epipodophyllotoxins and cyclophosphamide . There is some evidence that a common infection, such as influenza , may indirectly promote the emergence of ALL. The delayed-infection hypothesis states that ALL results from an abnormal immune response to infection in

1071-490: Is generally temporary in nature, though recovery times of six months to a year are common. Likewise, difficulty in walking due to arthritis or joint pains (antalgic gait) sometimes resolves spontaneously once the pain is gone. Hemiplegic persons have circumduction gait, where the affected limb moves through an arc away from the body, and those with cerebral palsy often have scissoring gait . Acute lymphocytic leukemia Acute lymphoblastic leukemia ( ALL )

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1122-480: Is inconclusive. Some researchers have linked the hygiene hypothesis . Several characteristic genetic changes lead to the creation of a leukemic lymphoblast. These changes include chromosomal translocations , intrachromosomal rearrangements , changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes. Chromosomal translocations involve moving a large region of DNA from one chromosome to another. This move can result in placing

1173-452: Is minor physical trauma . In those with no history of trauma, 40% are due to transient synovitis and 2% are from Legg–Calvé–Perthes syndrome . Other important causes are infectious arthritis, osteomyelitis, and slipped capital femoral epiphysis in children. Septic arthritis can be difficult to separate from less serious conditions such as transient synovitis . Factors that can help indicate septic arthritis rather than synovitis include

1224-745: Is often associated with cytogenetic abnormalities (specifically, t(8;14), t (2;8), and t(8;22)), which require aggressive therapy consisting of brief, high-intensity regimens. T-cell ALL responds to cyclophosphamide-containing agents the most. Recent updates on the treatment of adult acute lymphoblastic leukemia (ALL) include advancements in immunotherapy, particularly the use of monoclonal antibodies like blinatumomab and inotuzumab ozogamicin, which target specific cancer cells and are used alongside stem cell transplantation. Additionally, tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are incorporated for Philadelphia chromosome-positive ALL, improving treatment outcomes. Radiation therapy (or radiotherapy)

1275-407: Is often needed. A large number of white blood cells and lymphoblasts in the circulating blood can be suspicious for ALL because they indicate a rapid production of lymphoid cells in the marrow. The higher these numbers typically point to a worse prognosis. While white blood cell counts at initial presentation can vary significantly, circulating lymphoblast cells are seen on peripheral blood smears in

1326-468: Is particularly valuable for classification and can in part explain the different prognoses of these groups. In regards to genetic analysis, cases can be stratified according to ploidy , a number of sets of chromosomes in the cell, and specific genetic abnormalities, such as translocations . Hyperdiploid cells are defined as cells with more than 50 chromosomes, while hypodiploid are defined as cells with less than 44 chromosomes. Hyperdiploid cases tend to carry

1377-560: Is the lymphoblast. Normal lymphoblasts develop into mature, infection-fighting B-cells or T-cells, also called lymphocytes . Signals in the body control the number of lymphocytes so neither too few nor too many are made. In ALL, both the normal development of some lymphocytes and the control over the number of lymphoid cells become defective. Acute lymphoblastic leukemia emerges when a single lymphoblast gains many mutations to genes that affect blood cell development and proliferation. In childhood ALL, this process begins at conception with

1428-406: Is treated with intrathecal administration of hydrocortisone , methotrexate, and cytarabine. Adult chemotherapy regimens mimic those of childhood ALL; however, are linked with a higher risk of disease relapse with chemotherapy alone. Two subtypes of ALL (B-cell ALL and T-cell ALL) require special considerations when it comes to selecting an appropriate treatment regimen in adults with ALL. B-cell ALL

1479-524: Is unknown. Genetic risk factors may include Down syndrome , Li–Fraumeni syndrome , or neurofibromatosis type 1 . Environmental risk factors may include significant radiation exposure or prior chemotherapy . Evidence regarding electromagnetic fields or pesticides is unclear. Some hypothesize that an abnormal immune response to a common infection may be a trigger. The underlying mechanism involves multiple genetic mutations that results in rapid cell division . The excessive immature lymphocytes in

1530-462: Is used on painful bony areas, in high disease burdens, or as part of the preparations for a bone marrow transplant (total body irradiation). In the past, physicians commonly utilized radiation in the form of whole-brain radiation for central nervous system prophylaxis, to prevent the occurrence and/or recurrence of leukemia in the brain. Recent studies showed that CNS chemotherapy provided results as favorable but with fewer developmental side effects. As

1581-400: The bone marrow interfere with the production of new red blood cells , white blood cells , and platelets . Diagnosis is typically Acute lymphoblastic leukemia based on blood tests and bone marrow examination . Acute lymphoblastic leukemia is typically treated initially with chemotherapy aimed at bringing about remission . This is then followed by further chemotherapy typically over

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1632-457: The mediastinum , the spleen , the testicles , and the brain , leading to the common symptoms of the disease. Diagnosing ALL begins with a thorough medical history, physical examination , complete blood count , and blood smears. While many symptoms of ALL can be found in common illnesses, persistent or unexplained symptoms raise suspicion of cancer. Because many features on the medical history and exam are not specific to ALL, further testing

1683-517: The World Health Organization classification of acute lymphoblastic leukemia was developed in an attempt to create a classification system that was more clinically relevant and could produce meaningful prognostic and treatment decisions. This system recognized differences in genetic, immunophenotype , molecular, and morphological features found through cytogenetic and molecular diagnostics tests. This subtyping helps determine

1734-562: The ages of two and five. In the United States it is the most common cause of cancer and death from cancer among children. Acute lymphoblastic leukemia is notable for being the first disseminated cancer to be cured. Survival for children increased from under 10% in the 1960s to 90% in 2015. Survival rates remain lower for babies (50%) and adults (35%). Initial symptoms can be nonspecific, particularly in children. Over 50% of children with leukemia had one or more of five features:

1785-465: The body-wide distribution of the malignant cells . In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs tailored to each person. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy. Must monitor closely for tumor lysis syndrome after initiating therapy Monitoring initial response to treatment is important as failure to show clearance of blood or bone marrow blasts within

1836-791: The body. On the other hand, myeloperoxidase (MPO), a marker for the myeloid lineage, is typically not expressed. Because precursor B cell and precursor T cells look the same, immunophenotyping can help differentiate the subtype of ALL and the level of maturity of the malignant white blood cells. The subtypes of ALL as determined by immunophenotype and according to the stages of maturation. An extensive panel of monoclonal antibodies to cell surface markers, particularly CD or cluster of differentiation markers, are used to classify cells by lineage. Below are immunological markers associated with B cell and T cell ALL. Cytogenetic analysis has shown different proportions and frequencies of genetic abnormalities in cases of ALL from different age groups. This information

1887-436: The cause of a limp is often made based on history, physical exam findings, laboratory tests, and radiological examination. If a limp is associated with pain it should be urgently investigated, while non-painful limps can be approached and investigated more gradually. Young children have difficulty determining the location of leg pain, thus in this population, knee pain equals hip pain . SCFE can usually be excluded by an x-ray of

1938-453: The efficacy of treatment regimens, resulting in increased survival rates. Possible treatments for acute leukemia include chemotherapy , steroids , radiation therapy , intensive combined treatments (including bone marrow or stem cell transplants), targeted therapy, and/or growth factors. Chemotherapy is the initial treatment of choice, and most people with ALL receive a combination of medications. There are no surgical options because of

1989-431: The first two weeks of therapy has been associated with a higher risk of relapse Start CNS prophylaxis and administer intrathecal chemotherapy via Ommaya reservoir or multiple lumbar punctures Central nervous system prophylaxis can be achieved via: In Philadelphia chromosome -positive ALL, the intensity of initial induction treatment may be less than has been traditionally given. Central nervous system relapse

2040-635: The head of the femur may occur. A non-painful limp may be due to a number of mechanical conditions including hip dysplasia and leg length differences. Transient synovitis is a reactive arthritis of the hip of unknown cause. People are usually able to walk and may have a low grade fever. They usually look clinically nontoxic or otherwise healthy. It may only be diagnosed once all other potential serious causes are excluded. With symptomatic care it usually resolves over one week. Juvenile rheumatoid arthritis presents gradually with early morning stiffness, fatigue, and weight loss. Legg–Calvé–Perthes syndrome

2091-418: The head of the femur slips over the underlying bone. It most commonly presents with hip pain in males during puberty and is associated with obesity . The majority of people affected have a painful limp and in half of cases both hips are affected. Nearly a quarter of people present with only knee pain. Treatment involves non-weight-bearing movement and surgery. If not identified early, osteonecrosis or death of

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2142-706: The hips. An ultrasound or x-ray guided aspiration of the hip joint maybe required to rule out an infectious process within the hip. A limp at one hospital emergency department was the presenting complaint in 4% of children. It occurs twice as commonly in boys as in girls. Gait abnormality Patients with musculoskeletal pain, weakness or limited range of motion often present conditions such as Trendelenburg's sign , limping , myopathic gait and antalgic gait . Patients who have peripheral neuropathy also experience numbness and tingling in their hands and feet. This can cause ambulation impairment, such as trouble climbing stairs or maintaining balance . Gait abnormality

2193-472: The inheritance of some of these genes. These genes, in turn, increase the risk that more mutations will occur in developing lymphoid cells. Certain genetic syndromes, like Down Syndrome , have the same effect. Environmental risk factors are also needed to help create enough genetic mutations to cause disease. Evidence for the role of the environment is seen in childhood ALL among twins, where only 10–15% of both genetically identical twins get ALL. Since they have

2244-635: The majority of cases. A bone marrow biopsy provides conclusive proof of ALL, typically with >20% of all cells being leukemic lymphoblasts. A lumbar puncture (also known as a spinal tap) can determine whether the spinal column and brain have been invaded. Brain and spinal column involvement can be diagnosed either through confirmation of leukemic cells in the lumbar puncture or through clinical signs of CNS leukemia as described above. Laboratory tests that might show abnormalities include blood count, kidney function, electrolyte, and liver enzyme tests. Pathological examination, cytogenetics (in particular

2295-693: The placement of two genes directly next to each other. The result is the combination of two usually separate proteins into a new fusion protein . This protein can have a new function that promotes the development of cancer. Examples of this include the ETV6 – RUNX1 fusion gene that combines two factors that promote blood cell development and the BCR - ABL1 fusion gene of the Philadelphia chromosome . BCR – ABL1 encodes an always-activated tyrosine kinase that causes frequent cell division. These mutations produce

2346-488: The presence of Philadelphia chromosome ), and immunophenotyping establish whether the leukemic cells are myeloblastic (neutrophils, eosinophils, or basophils) or lymphoblastic ( B lymphocytes or T lymphocytes ). Cytogenetic testing on the marrow samples can help classify disease and predict how aggressive the disease course will be. Different mutations have been associated with shorter or longer survival. Immunohistochemical testing may reveal TdT or CALLA antigens on

2397-406: The prognosis and the most appropriate treatment for each specific case of ALL. The WHO subtypes related to ALL are: The aim of treatment is to induce a lasting remission , defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells in the bone marrow) or the absence of minimal residue disease. Over the past several decades, there have been strides to increase

2448-520: The same genes, different environmental exposures explain why one twin gets ALL and the other does not. Infant ALL is a rare variant that occurs in babies less than one year old. KMT2A (formerly MLL ) gene rearrangements are most common and occur in the embryo or fetus before birth. These rearrangements result in increased expression of blood cell development genes by promoting gene transcription and through epigenetic changes. In contrast to childhood ALL, environmental factors are not thought to play

2499-466: The surface of leukemic cells. TdT is a protein expressed early in the development of pre-T and pre-B cells, whereas CALLA is an antigen found in 80% of ALL cases and also in the "blast crisis" of CML . Medical imaging (such as ultrasound or CT scanning ) can find invasion of other organs , commonly the lungs , liver, spleen, lymph nodes, brain, kidneys, and reproductive organs. In addition to cell morphology and cytogenetics, immunophenotyping ,

2550-446: The use of X-rays , blood tests , and sometimes joint aspiration . Initial treatment involves pain management . A limp is the presenting problem in about 4% of children who visit hospital emergency departments. A limp is a type of asymmetric abnormality of the gait . When due to pain it is referred to as an antalgic gait , in which the foot is in contact with the ground for a shorter duration than usual; in severe cases there may be

2601-658: Was classified morphologically using the French-American-British (FAB) system that heavily relied on morphological assessment. The FAB system takes into account information on size, cytoplasm , nucleoli , basophilia (color of cytoplasm), and vacuolation (bubble-like properties). While some clinicians still use the FAB scheme to describe tumor cell appearance, much of this classification has been abandoned because of its limited impact on treatment choice and prognostic value. World Health Organization In 2008,

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