Acute lymphoblastic leukemia (ALL) is a monoclonal hematological malignancy characterized by infiltration of the bone marrow by more than 20% of hematopoietic cells with blocked differentiation called blasts belonging to the lymphoblastic lineage of lymphoid nature (B or T lymphoblasts) [1] . Around 40% of childhood cancers are leukemias, and 85% of these are ALL [2] . In France, it affects between 400 and 500 children annually, making it the most common paediatric cancer [3] . Epidemiological data on the overall prevalence of osteoarticular involvement in pediatric lymphoblastic leukemia are still poorly known. Nevertheless, in Europe, the study by Pêcheux et al., in Belgium, carried out over a period of 30 years, found 104 cases with 85% pre-B ALL and 12% T ALL, with 67% of patients having osteoarticular involvement, an average age of 5.9 years and a sex ratio of 1.6. [4] In Brazil, Teresa Robazzi reported 313 cases of leukemia over a 20-year period, with 54.7% osteoarticular involvement, a mean age of 6.8 years, and a sex ratio of 1.4 [5] . The first descriptions of osteoarticular (OA) involvement as an inaugural manifestation date back to 1913 with August Strauch. Nevertheless, this mode of presentation remains a diagnostic challenge, as the signs of such involvement are not specific to leukemias [6] . The onset of AO involvement in ALL is multifactorial: patient-, disease- or treatment-related [2] . Depending on their chronology, they may be inaugural, leading to erroneous and delayed diagnosis, as they are often confused with juvenile idiopathic arthritis or infectious causes. Or they may occur during or after treatment, mainly due to the toxicity of anti-leukemic drugs and corticosteroids. The mainstay of OA management is the etiological treatment of leukemia [7] , but intra-articular corticosteroid infiltration, calcium, and vitamin D supplementation, the use of biphosphates in osteoporosis, and orthopedic and/or surgical treatment may also be used, especially in the case of osteonecrosis [2] .

The aim of this study is to describe an isolated case of ALL with osteoarticular manifestations and to review the literature in order to establish pathophysiological mechanisms.

A 14-year-old adolescent with no specific pathological history was referred to us from the pediatric department for the etiological investigation of chronic peripheral polyarthritis, which had been progressively evolving for about seven weeks. Clinical examination revealed chronic peripheral polyarthritis, polysynovitis, deforming but not ankylosing, with involvement of the knees, shoulders, wrists, and proximal interphalangeal (PIP) and dactylitis ( Figure 1 ), associated with a leukemic facies (facial puffiness and periorbital erythema). ( Figure 2 )

Biological investigations revealed a non-specific inflammatory syndrome with a VS of 60 mm in the first hour and CRP increased to 45mg/l (N ≤ 6 mg/l). The blood count showed hyperleukocytosis at 25,600/mm³ with lymphocyte predominance at 18,660/mm³, normocytic normochromic anemia with hemoglobin at 11 g/dl and hyperplakettosis at 510,000/mm³. The blood smear showed 37% blasts confirmed on the medullogram, with over 20% blastic invasion and a common B-type lymphocytic predominance on immunophenotyping with negative Philadelphia. Renal (uremia, creatininemia and 24-hour proteinuria) and hepatic (blood glucose, lipids, uricemia, infectious diseases) tests were unremarkable. Hand X-rays ( Figure 3 ) and abdominal ultrasound for organomegaly were also unremarkable. The diagnosis of B-type lymphocytic leukemia was made on the basis of these clinical and paraclinical arguments after eliminating: juvenile idiopathic arthritis, with negative immunological findings (rheumatoid factors, anti-CCP antibodies, antinuclear antibodies, and ASLO); paraneoplastic arthritis, with a normal thoraco-abdominopelvic CT scan and, above all, improvement after local infiltration with delayed corticosteroids and initiation of multidrug therapy within the first few weeks of treatment. The patient also received phosphocalcic supplementation in accordance with his needs.

The osteoarticular manifestations of pediatric acute lymphoblastic leukemia are of physiopathological, epidemiological, diagnostic and therapeutic interest.

The hematopoietic system is organized hierarchically, with hematopoietic stem cells (HSCs) at the top, possessing self-renewal capacities and generating the progenitors of all mature blood elements [8] . As they differentiate, the differentiation potential of the progenitors is restricted until only one type of mature cell is generated [9] . If they are transformed, they acquire or retain self-renewal properties and resistance to apoptosis, with a modified response to proliferative and anti-proliferative signals. Schematically, there is an initiation phase, followed by promotion, progression and then metastasis. In leukemia, this translates into a block in differentiation. The result of a multi-stage transformation process is an accumulation of genetic alterations affecting the main oncogenic/tumor suppressor pathways, blocking maturation, proliferation and survival. The genetic basis of cancers is already accepted, but it is a fact that in leukemia, the phenomena of recurrent acquired chromosomal translocations are to the fore. The cloning of chromosomal translocation breakpoints associated with human leukemias has identified fusion genes, including the BCR-ABL1 gene responsible for the Philadelphia chromosome, which are involved in the pathogenesis of the disease [10] . Several other genetic mutations have also been identified ( Table 1 and Table 2 ). Environmental factors underlie all chromosomal lesions, including exposure (benzene, pesticides, etc.), ionizing radiation, chemotherapy (alkylating agents, VP16), radiotherapy and infectious diseases (HIV, Epstein Barr Virus, HTLV1) [11] . The so-called de Novo primary in the absence of several identified causes.

In the pathophysiology of osteoarticular damage in leukemia, we haven’t found a single cause established by the authors. Nevertheless, there are individualized gene mutations ( Table 1 and Table 2 ) [9] , the most frequent of which is BCR ABL1, but what interests us most in this table is that of the RUNX genes involved in chromosomal translocations. They are involved in mesenchymal cell differentiation and control of B lymphopoiesis differentiation [9] . The crucial importance of this gene has been highlighted by experiments on mice [12] . In CBFβ-deficient mice, fetal hepatic hematopoiesis is absent before birth, and dwarfism, skeletal malformation, reduced calcification, and delayed ossification occur, hence its role in skeletal and mesenchymal cell development. Mice specifically deleting the Runx1 gene also show reduced ossification, bone density and mandibular defects, indicating an osteoporotic phenotype. Deletion of Runx1 impairs fracture healing. Core-binding factor β (CBFβ) is an essential binding partner for Runx1 [13] , stabilizing Runx1 by forming heterodimers without which Runx1 can barely be detected. CBFβ provides Runx1 proteins with an inhibitory domain and enhances their DNA binding. Both act in different processes ( Table 3 ) [12] , most notably in cartilage and bone formation. As a working model, we have highlighted the particular role of Runx1 in bone formation and inhibition of adipogenesis at early stages, with late activation by RUNX 2 ( Figure 4 ) [14] .

This is achieved via signaling pathways aided by Smad proteins. Smad proteins are transcription factors to the cell nucleus, modulating target gene expression through Smad DNA-complex binding. Runx1 is a central regulator of osteogenesis and bone homeostasis, orchestrating the BMP, Wnt/β-catenin and TGF-beta signaling pathways, regulating early osteoblast differentiation and inhibiting Runx2 expression at later stages of osteoblast differentiation. Runx1 has great potential for the emergence of hematopoietic stem cells and for osteoblastic differentiation. At a much later stage of bone differentiation, we found a role for Runx2 with this modem overexpression in breast cancer-mediated bone metastases. High Runx2 expression was associated with higher metastatic risk and poorer overall survival, and activated osteoclasts ( Figure 5 ) [15] .

So, it’s easy to see how mutations in the Runx gene can lead to disturbances in both hematopoiesis and osteogenesis, which are at the root of the various osteoarticular disorders. This leads to a variety of radiological presentations. In our case study, the x-rays of the hands performed are normal, but several authors have found images of bone destruction [16] - [20] .

Leukemic bone damage is linked to the pressure exerted by bone marrow infiltration on the periosteum, cytokine-mediated stimulation of osteoclasts, and weakening of the bone matrix, leading to fractures or vertebral compression. In addition to leukemic infiltration of the synovium or leukemic arthritis. Secondary non-specific arthritis, blastic infiltration of the juxtaarticular bone, subcapsular or intra-articular haemorrhage, complex immune deposits, microcrystalline or septic arthritis may also occur [2] .

The growing skeleton can be weakened by bone toxicity of treatments, particularly glucocorticoids, which directly affect bone, modify the hormonal axis, and alter intestinal calcium absorption and renal calcium excretion. Glucocorticoids have also been incriminated in the pathogenesis of TAN by promoting the hypertrophy of medullary fat cells, generating an increase in intra-osseous pressure, compressing blood vessels and sinuses in the more fragile epiphyseal zones [21] .

Epidemiologically, in Europe, we have the studies by Mathilde Louvigné and colleagues in France [4] , Pécheux L and colleagues in Belgium [22] , and Brix Nina and colleagues in Denmark [23] , with 49, 104, and 286 cases, respectively. The annual incidence was higher in Denmark (12.4) than in Belgium (3.4). T-type lymphocytic leukemia was predominant in all studies, with a mean age ranging from 7.3 in France to 4.4 in Belgium and a male predominance in all studies. In America, the studies by Isaias [5] in Missouri and Teresa [24] in Brazil, with 74 and 313 cases, respectively, showed a higher annual incidence in Brazil (15.6), with myeloid leukemia predominating in the Isaias study, which explains the later age of onset and the lower percentage of osteoarticular involvement than in the Brazilian study. In North Africa, S. El aichaoui [25] and Latifa Harzallah [26] reported more individual cases, with a later mean age, a predominance of males, and the disease being found in all cases. West Africa Paul Eloundou in Cameroon described an association of Still’s disease with acute lymphoblastic leukemia [27] . Our case is a 14-year-old male. The clinicobiological data are in line with the literature.

Diagnostically, the circumstances of discovery were inaugural in the Pecheux, Teresa Robazzi and Ninna Birix studies, with 50%, 88%, and 100%, respectively. In the Pêcheux study, osteoarticular involvement was found during chemotherapy and 28% and 37% after treatment. The clinical course of leukemia is polymorphous, and osteoarticular disorders are diverse. After clinical suspicion, we look for hyperleukocytosis, sometimes associated with anemia, thrombocytopenia, and an inflammatory syndrome. Blood smears, medullograms, and cerebrospinal fluid studies confirm blastosis. Ultrasound-guided synovial biopsy with anapathic examination and examination of joint fluid also reveal blastosis. Imaging is used to explore osteoarticular damage through radiology, joint ultrasound, bone magnetic resonance imaging, and bone densitometry. Table 3 summarizes the osteoarticular disorders found in the literature. [22] [26] [28] [29] .

Therapeutically, intra-articular corticosteroid infiltrations have failed, according to the literature. Calcium and vitamin supplementation and the use of biphosphates are used mainly during and after treatment in conjunction with corticosteroid therapy. Orthopedic and surgical treatment are more common in the management of sequelae. In all cases, etiological treatment is the cornerstone in the management of osteoarticular disorders [22] [29] . Our patient benefited from polychemotherapy for the induction, consolidation, and intensification phases in an appropriate clinical hematology department. We performed infiltrations in the large joints, with improvement in joint pain and synovitis with adequate phosphocalcium intake. As part of our screening for treatment-related complications, we plan to carry out bone densitometry one year after the start of chemotherapy, and to use magnetic resonance imaging of painful joints to detect epiphyseal osteonecrosis at an early stage. He is currently waiting for a donor. Our case presents certain limitations linked to the sometimes precarious diagnostic tools available in our developing countries. We are particularly interested in synovial biopsy and genetic testing to identify mutations in the RUNX gene.

Leukemia is a diagnostic and therapeutic emergency. Osteoarticular involvement is often the initial presentation linked to the patient, the disease, or the treatments. They may also reveal a relapse of acute leukemia, or the accusation of chronic leukemia, which requires multidisciplinary management.