85 results on '"Histiocytosis genetics"'
Search Results
2. ALK-positive histiocytosis in 12 Asian children.
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Feng X, Tao J, He N, Wang J, He L, and Zhang N
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- Child, Child, Preschool, Female, Humans, Infant, Male, Oncogene Proteins, Fusion genetics, Retrospective Studies, Treatment Outcome, Tyrosine Kinase Inhibitors therapeutic use, Anaplastic Lymphoma Kinase genetics, Asian People, Histiocytosis pathology, Histiocytosis genetics
- Abstract
Anaplastic lymphoma kinase-positive histiocytosis, first reported in 2008, is a rare, novel type of neoplasm. To date, no more than 100 cases of anaplastic lymphoma kinase-positive histiocytosis have been reported. In this retrospective study, 12 cases of anaplastic lymphoma kinase-positive histiocytosis, including clinical symptoms, histological features, molecular pathology, treatment, and prognosis, in children were analyzed to gain a deeper understanding of the disease. All patients were Asian children, aged 2 months to 8 years and 2 months (mean 3.1 years), and the male-to-female ratio was 5:7. All patients were followed up closely. One patient died during the follow-up period, seven (case 1-7) had focal anaplastic lymphoma kinase-positive histiocytosis, and five (case 8-12) had multisystem anaplastic lymphoma kinase-positive histiocytosis. In addition, we report the case of a patient who benefited from anaplastic lymphoma kinase-targeted therapy and a patient with the rare EML4-ALK fusion gene. The current study is expected to substantially contribute to increasing the awareness of anaplastic lymphoma kinase-positive histiocytosis., Competing Interests: Declaration of competing interest All the authors have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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3. Clinical phenotype of adult-onset systemic histiocytosis harboring BRAF in-frame deletions.
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Papo M, Razanamahéry J, Da Silva M, Hélias-Rodzewicz Z, Potapenko V, Bota S, Leguy-Seguin V, Dominique S, Lhote R, Moyon Q, Taïeb D, Abrassart T, Campana M, Keo V, Rivière E, Lucidarme O, Cohen-Aubart F, Amoura Z, Haroche J, and Emile JF
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- Humans, Adult, Male, Female, Histiocytosis genetics, Histiocytosis pathology, Histiocytosis diagnosis, Middle Aged, Sequence Deletion, Age of Onset, Proto-Oncogene Proteins B-raf genetics, Phenotype
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- 2024
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4. A novel start-loss mutation of the SLC29A3 gene in a consanguineous family with H syndrome: clinical characteristics, in silico analysis and literature review.
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Rezaie N, Mansour Samaei N, Ghorbani A, Gholipour N, Vosough S, Rafigh M, and Amini A
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- Humans, Female, Male, Adolescent, Child, Mutation, Histiocytosis genetics, Histiocytosis pathology, Computer Simulation, Hypertrichosis genetics, Exome Sequencing, Contracture, Hearing Loss, Sensorineural, Nucleoside Transport Proteins genetics, Consanguinity, Pedigree
- Abstract
Background: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene., Methods: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing., Results: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein., Conclusion: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition., (© 2024. The Author(s).)
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- 2024
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5. Localised ALK-positive histiocytosis in lung with EML4::ALK fusion.
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Zou L, Lu T, Li M, Wang A, Zhang Z, Pan B, and Sun J
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- Humans, Male, Lung pathology, Anaplastic Lymphoma Kinase genetics, Anaplastic Lymphoma Kinase metabolism, Female, Middle Aged, Oncogene Proteins, Fusion genetics, Histiocytosis pathology, Histiocytosis genetics, Histiocytosis metabolism, Histiocytosis diagnosis
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- 2024
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6. [ALK positive histiocytosis with multiple system involvement: report of a case].
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Yao S, Zhang F, Chen Y, and Liu YH
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- Humans, Female, Adult, In Situ Hybridization, Fluorescence, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Breast Neoplasms pathology, Breast Neoplasms genetics, Breast Neoplasms metabolism, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Anaplastic Lymphoma Kinase genetics, Anaplastic Lymphoma Kinase metabolism, Histiocytosis pathology, Histiocytosis metabolism, Histiocytosis genetics, CD68 Molecule, Receptors, Cell Surface
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- 2024
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7. Equilibrative nucleotide transporter ENT3 (SLC29A3): A unique transporter for inherited disorders and cancers.
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Ma H, Qu J, Liao Y, Liu L, Yan M, Wei Y, Xu W, Luo J, Dai Y, Pang Z, and Qu Q
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- Humans, Nucleotides metabolism, Mutation, Membrane Transport Proteins genetics, Nucleoside Transport Proteins genetics, Nucleoside Transport Proteins metabolism, Histiocytosis genetics, Diabetes Mellitus, Type 2, Neoplasms drug therapy, Neoplasms genetics
- Abstract
As a crucial gene associated with diseases, the SLC29A3 gene encodes the equilibrative nucleoside transporter 3 (ENT3). ENT3 plays an essential regulatory role in transporting intracellular hydrophilic nucleosides, nucleotides, hydrophilic anticancer and antiviral nucleoside drugs, energy metabolism, subcellular localization, protein stability, and signal transduction. The mutation and inactivation of SLC29A3 are intimately linked to the occurrence, development, and prognosis of various human tumors. Moreover, many hereditary human diseases, such as H syndrome, pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome, Faisalabad histiocytosis (FHC), are related to SLC29A3 mutations. This review explores the mechanisms of SLC29A3 mutations and expression alterations in inherited disorders and cancers. Additionally, we compile studies on the inhibition of ENT3, which may serve as an effective strategy to potentiate the anticancer activity of chemotherapy. Thus, the synopsis of genetics, permeant function and drug therapy of ENT3 provides a new theoretical and empirical foundation for the diagnosis, prognosis of evaluation and treatment of various related diseases., Competing Interests: Declaration of competing interest The authors declare they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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8. Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.
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Shiloh R, Lubin R, David O, Geron I, Okon E, Hazan I, Zaliova M, Amarilyo G, Birger Y, Borovitz Y, Brik D, Broides A, Cohen-Kedar S, Harel L, Kristal E, Kozlova D, Ling G, Shapira Rootman M, Shefer Averbuch N, Spielman S, Trka J, Izraeli S, Yona S, and Elitzur S
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- Humans, Mutation, Toll-Like Receptors, Inflammation genetics, Nucleoside Transport Proteins genetics, Nucleoside Transport Proteins metabolism, Mitogen-Activated Protein Kinases, Histiocytosis genetics, Histiocytosis pathology
- Abstract
Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation., (© 2023 by The American Society of Hematology.)
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- 2023
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9. Letter to the Editor Regarding "Local ALK-Positive Histiocytosis with Unusual Morphology and Novel TRIM33::ALK Gene Fusion" by Tran et al.
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Soylemez Akkurt T, Dur Karasayar AH, Gurbuz BC, Altınay S, Yuzkan S, and Baskan F
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- Humans, Receptor Protein-Tyrosine Kinases, Gene Fusion, Oncogene Proteins, Fusion genetics, Transcription Factors genetics, Histiocytosis diagnosis, Histiocytosis genetics, Lung Neoplasms genetics
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Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2023
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10. Cytogenetics in the management of acute myeloid leukemia and histiocytic/dendritic cell neoplasms: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).
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Bidet A, Quessada J, Cuccuini W, Decamp M, Lafage-Pochitaloff M, Luquet I, Lefebvre C, and Tueur G
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- Humans, Chromosome Aberrations, Cytogenetic Analysis, Dendritic Cells pathology, Hematology, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Histiocytosis diagnosis, Histiocytosis genetics, Histiocytosis therapy
- Abstract
Genetic data are becoming increasingly essential in the management of hematological neoplasms as shown by two classifications published in 2022: the 5th edition of the World Health Organization Classification of Hematolymphoid Tumours and the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. Genetic data are particularly important for acute myeloid leukemias (AMLs) because their boundaries with myelodysplastic neoplasms seem to be gradually blurring. The first objective of this review is to present the latest updates on the most common cytogenetic abnormalities in AMLs while highlighting the pitfalls and difficulties that can be encountered in the event of cryptic or difficult-to-detect karyotype abnormalities. The second objective is to enhance the role of cytogenetics among all the new technologies available in 2023 for the diagnosis and management of AML., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
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- 2023
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11. TLR7/8 stress response drives histiocytosis in SLC29A3 disorders.
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Shibata T, Sato R, Taoka M, Saitoh SI, Komine M, Yamaguchi K, Goyama S, Motoi Y, Kitaura J, Izawa K, Yamauchi Y, Tsukamoto Y, Ichinohe T, Fujita E, Hiranuma R, Fukui R, Furukawa Y, Kitamura T, Takai T, Tojo A, Ohtsuki M, Ohto U, Shimizu T, Ozawa M, Yoshida N, Isobe T, Latz E, Mukai K, Taguchi T, Hemmi H, Akira S, and Miyake K
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- Animals, Mice, Cytokines genetics, Mutation genetics, Nucleosides, Toll-Like Receptor 8 genetics, Histiocytosis genetics, Toll-Like Receptor 7 genetics
- Abstract
Loss-of-function mutations in the lysosomal nucleoside transporter SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs. However, little is known about the mechanism by which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was shown to depend on Toll-like receptor 7 (TLR7), which senses a combination of nucleosides and oligoribonucleotides (ORNs). TLR7 increased phagocyte numbers by driving the proliferation of Ly6Chi immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Downstream of TLR7, FcRγ and DAP10 were required for monocyte proliferation. Histiocytosis is accompanied by inflammation in SLC29A3 disorders. However, TLR7 in nucleoside-laden splenic monocytes failed to activate inflammatory responses. Enhanced production of proinflammatory cytokines was observed only after stimulation with ssRNAs, which would increase lysosomal ORNs. Patient-derived monocytes harboring the G208R SLC29A3 mutation showed enhanced survival and proliferation in a TLR8-antagonist-sensitive manner. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders., (© 2023 Shibata et al.)
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- 2023
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12. H syndrome treated with Tocilizumab: two case reports and literature review.
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Jacquot R, Jouret M, Valentin MG, Richard M, Jamilloux Y, Rousset F, Emile JF, Haroche J, Steinmüller L, Zekre F, Phan A, Belot A, and Seve P
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- Female, Humans, Adult, Child, Preschool, Fever, Nucleoside Transport Proteins genetics, Hearing Loss, Sensorineural, Contracture, Histiocytosis diagnosis, Histiocytosis drug therapy, Histiocytosis genetics
- Abstract
H syndrome is a rare autosomal recessive genetic disorder characterized by the following clinical features: cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, hyperglycemia, fixed flexion contractures of the toe joints, and the proximal interphalangeal joints. In rare cases, autoinflammatory and lymphoproliferative manifestations have also been reported. This disorder is due to loss-of-function mutations in SLC29A3 gene, which encode the equilibrative nucleoside transporter ENT3. This deficiency leads to abnormal function and proliferation of histiocytes. H syndrome is part of the R-group of histiocytosis. We report two different cases, one was diagnosed in adulthood and the other in childhood. The first case reported is a 37-year-old woman suffering from H syndrome with an autoinflammatory systemic disease that begins in adulthood (fever and diffuse organ's infiltration) and with cutaneous, articular, auditory, and endocrinological manifestations since childhood. The second case reported is a 2-year-old girl with autoinflammatory, endocrine, and cutaneous symptoms (fever, lymphadenopathy, organomegaly, growth delay, and cutaneous hyperpigmentation). Homozygous mutations in SLC29A3 confirmed the diagnosis of H syndrome in both cases. Each patient was treated with Tocilizumab with a significant improvement for lymphoproliferative, autoinflammatory, and cutaneous manifestations. Both cases were reported to show the multiple characteristics of this rare syndrome, which can be diagnosed either in childhood or in adulthood. In addition, an overview of the literature suggested Tocilizumab efficiency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author AB declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Jacquot, Jouret, Valentin, Richard, Jamilloux, Rousset, Emile, Haroche, Steinmüller, Zekre, Phan, Belot and Seve.)
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- 2023
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13. CSF1R inhibition for histiocytic neoplasm with CBL mutations refractory to MEK1/2 inhibition.
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Diamond EL, Francis JH, Lacouture ME, Rotemberg V, Yabe M, Petrova-Drus K, Ulaner GA, Reddy R, Abdel-Wahab O, and Durham BH
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- Humans, Mutation, Receptor Protein-Tyrosine Kinases genetics, Histiocytosis genetics, Hematologic Neoplasms
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- 2023
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14. Multisystem ALK-positive histiocytosis: a multi-case study and literature review.
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Liu W, Liu HJ, Wang WY, Tang Y, Zhao S, Zhang WY, Yan JQ, and Liu WP
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- Adult, Child, Preschool, Humans, Infant, Male, Middle Aged, Histiocytes pathology, Liver pathology, Prognosis, Receptor Protein-Tyrosine Kinases, Histiocytosis genetics, Histiocytosis pathology
- Abstract
Background: Anaplastic lymphoma kinase (ALK)-positive histiocytosis, a novel rare histiocytic proliferation, was first described in 2008; it occurs in early infancy with liver and hematopoietic involvement. The spectrum was subsequently broadened to include localized diseases in older children and young adults. However, its full clinicopathological features and molecular lineage have not been fully elucidated., Results: Here, we report four cases of multisystem ALK-positive histiocytosis without hematopoietic involvement. Clinically, three patients were adults aged between 32 and 51 years. Two patients', whose main manifestations were intracranial mass and numerous micronodules in the thoracoabdominal cavity organs and skin papules respectively, had a partial response to ALK inhibitors after surgery. One patient presented with mediastinal neoplasm without surgical treatment, and progressive disease occurred after two years of ALK inhibitor therapy. The fourth patient was a 17-month-old male with a large intracranial mass and presented with a poor response to ALK inhibitor and chemoradiotherapy; he died eight months after surgery. Pathologically, the histiocytes were large, with abundant eosinophilic cytoplasm, and mixed with variable numbers of foamy cells and Touton giant cells. Interstitial fibrosis was also observed. Histiocytes were positive for macrophage markers (CD68 and CD163) and ALK. KIF5B-ALK fusions were detected in two cases, EML4-ALK in one, and both DCTN1-ALK and VRK2-ALK fusions were detected in one case., Conclusions: We observed that ALK inhibitors present robust and durable responses in adult patients but a poor response in young children with central nervous system involvement. There is no consensus on the optimal treatment regimen and long-term prognosis requires further observation. Moreover, every unusual histiocytic proliferative lesion, especially unresectable and multisystem involvement, should be routinely tested for ALK immunohistochemical staining to identify this rare disease., (© 2023. The Author(s).)
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- 2023
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15. Atypical comorbidities in a child considered to have type 1 diabetes led to the diagnosis of SLC29A3 spectrum disorder.
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Besci Ö, Patel KA, Yıldız G, Tüfekçi Ö, Acinikli KY, Erbaş İM, Abacı A, Böber E, Bayram MT, Yılmaz Ş, and Demir K
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- Child, Contracture, Hearing Loss, Sensorineural, Humans, Male, Nucleoside Transport Proteins genetics, Diabetes Mellitus, Type 1 complications, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 genetics, Histiocytosis complications, Histiocytosis genetics, Hypertrichosis complications, Hypertrichosis genetics, Hypertrichosis pathology
- Abstract
Introduction: SLC29A3 spectrum disorder is an autosomal, recessively inherited, autoinflammatory, multisystem disorder characterized by distinctive cutaneous features, including hyperpigmentation or hypertrichosis, hepatosplenomegaly, hearing loss, cardiac anomalies, hypogonadism, short stature, and insulin-dependent diabetes., Case Presentation: Herein, we report a 6-year-old boy who presented with features resembling type 1 diabetes mellitus, but his clinical course was complicated by IgA nephropathy, pure red cell aplasia, and recurrent febrile episodes. The patient was tested for the presence of pathogenic variants in 53 genes related to monogenic diabetes and found to be compound heterozygous for two SLC29A3 pathogenic variants (p. Arg386Gln and p. Leu298fs)., Conclusion: This case demonstrated that SLC29A3 spectrum disorder should be included in the differential diagnosis of diabetes with atypical comorbidities, even when the distinctive dermatological hallmarks of SLC29A3 spectrum disorder are entirely absent., (© 2022. Hellenic Endocrine Society.)
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- 2022
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16. An Atypical Myelomonocytic Cell Infiltrate: Use of Next-Generation Sequencing to Diagnose Indeterminate Cell Histiocytosis.
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Belina ME, Kwock JT, Al-Rohil R, and Fresco A
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- Female, High-Throughput Nucleotide Sequencing, Histiocytes pathology, Humans, Middle Aged, Skin pathology, Dendritic Cell Sarcoma, Interdigitating, Histiocytosis diagnosis, Histiocytosis genetics, Histiocytosis pathology, Histiocytosis, Langerhans-Cell, Histiocytosis, Non-Langerhans-Cell pathology
- Abstract
Abstract: Indeterminant cell histiocytosis (ICH) is a rare lymphoproliferative disorder that demonstrates features of Langerhans and non-Langerhans cell histiocytoses and diagnosis can be challenging. We present a case of a 62 year old woman with a generalized eruption of erythematous papules on the face, trunk and extremities. Skin biopsies demonstrated a dermal mononuclear cell infiltrate with monocytic (CD4, CD33), histiocytic (CD68, CD163), and dendritic cell (CD1a) immunophenotype but negative for Langerhans' cell marker (CD207). The differential diagnosis included leukemia cutis and ICH, and further workup revealed a normal bone marrow biopsy. To confirm the diagnosis of ICH, next generation sequencing with ETV3-NCOA2 gene fusion was performed and was positive. The patient's condition improved with methotrexate and narrow band UVB phototherapy. Our case adds to the existing literature supporting the use of next-generation sequencing to test for ETV3-NCOA2 gene fusion in suspected cases of ICH., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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17. Case report of H-syndrome with a review from a rheumatological perspective.
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Yadav S and Canchi B
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- Contracture, Female, Hearing Loss, Sensorineural, Humans, Nucleoside Transport Proteins genetics, Syndrome, Histiocytosis genetics, Rheumatic Diseases
- Abstract
A woman in her 20s, symptomatic since the age of 4 with short stature, hearing loss, skin hyperpigmentation and induration over the medial aspect of the thigh, hypertrichosis, histiocytes on biopsy, lymphadenopathy, dilated scleral vessels, pancreatic exocrine deficiency, pericardial thickening, swelling of the eyelids and resistant retroperitoneal fibrosis. Whole-genome sequencing showed a mutation in SLC29A3, confirming 'H'-syndrome. She is on steroids and methotrexate. This case highlights the rheumatological mimics of this rare disorder., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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18. Immunometabolic activation of macrophages leads to cytokine production in the pathogenesis of KRAS-mutated histiocytosis.
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Ferrero E, Villa A, Stefanoni D, Nemkov T, D'Alessandro A, Tengesdal I, Belloni D, Molteni R, Vergani B, De Luca G, Grassini G, Cangi MG, Dagna L, Doglioni C, Cavalli G, and Ferrarini M
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- Cytokines metabolism, Gene Expression, Humans, Macrophages metabolism, Mutation, Histiocytosis genetics, Histiocytosis pathology, Proto-Oncogene Proteins p21(ras) genetics
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- 2022
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19. Distinct Clinicopathologic Features and Possible Pathogenesis of Localized ALK-positive Histiocytosis of the Breast.
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Osako T, Kurisaki-Arakawa A, Dobashi A, Togashi Y, Baba S, Shiozawa S, Ishigame H, Ishige H, Ohno S, Ishikawa Y, and Takeuchi K
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- Adult, Anaplastic Lymphoma Kinase genetics, Biomarkers metabolism, Breast Diseases genetics, Breast Diseases metabolism, Breast Diseases pathology, Female, Gene Rearrangement, Genetic Markers, Histiocytosis genetics, Histiocytosis metabolism, Histiocytosis pathology, Humans, Oncogene Proteins, Fusion metabolism, Anaplastic Lymphoma Kinase metabolism, Breast Diseases diagnosis, Histiocytosis diagnosis, Oncogene Proteins, Fusion genetics
- Abstract
Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare emerging entity characterized by systemic or localized proliferation of histiocytes harboring ALK rearrangements. Breasts are reportedly affected by ALK-positive histiocytosis. Here, we evaluated 2 localized cases of breast ALK-positive histiocytosis through a comprehensive clinicopathologic, molecular, and genomic analysis to further delineate this entity and better understand its pathogenesis. The cases involved 2 undiagnosed ALK-positive spindle-cell breast lesions. Both cases were Asian women aged 30s to 40s who underwent excisions for asymptomatic breast masses. Macroscopically, both lesions were well-circumscribed, solid masses. Microscopically, both lesions were predominantly composed of fascicles with uniform, bland spindle cells, admixed with epithelioid histiocyte-like cells and lymphoid aggregates. Immunohistochemically, the spindle and epithelioid cells coexpressed ALK and histiocytic markers (eg, CD68, CD163). Genetically, both lesions harbored KIF5B-ALK, confirmed by fluorescence in situ hybridization and polymerase chain reaction-direct sequencing analyses. Combining these results, both cases were successfully diagnosed as ALK-positive histiocytosis. Furthermore, no common or previously annotated somatic alterations were identified by whole-exome sequencing. One case harbored clonal immunoglobulin gene rearrangements according to the polymerase chain reaction-based BIOMED-2 protocol. Therefore, ALK-positive histiocytosis can be accurately diagnosed through a combination of morphologic, immunohistochemical, and molecular analyses. In this entity, breast cases may have distinct clinicopathologic features: Asian women aged 30s to 40s, asymptomatic masses, and predominant spindled morphology. For pathogenesis, ALK rearrangements could be the driver alteration, and a subset of ALK-positive histiocytosis may harbor a lymphoid lineage. These findings can be utilized to improve the diagnosis of ALK-positive histiocytosis and better understand its pathogenesis., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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20. Diverse kinase alterations and myeloid-associated mutations in adult histiocytosis.
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Chen J, Zhao AL, Duan MH, Cai H, Gao XM, Liu T, Sun J, Liang ZY, Zhou DB, Cao XX, and Li J
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- Adult, Aged, Case-Control Studies, Female, Follow-Up Studies, Histiocytosis classification, Histiocytosis genetics, Humans, Male, Middle Aged, Myeloid Cells metabolism, Prognosis, Retrospective Studies, Survival Rate, Biomarkers, Tumor genetics, Histiocytosis pathology, MAP Kinase Kinase 1 genetics, Mutation, Myeloid Cells pathology, Proto-Oncogene Proteins B-raf genetics
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- 2022
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21. Phenotypic intrafamilial variability including H syndrome and Rosai-Dorfman disease associated with the same c.1088G > A mutation in the SLC29A3 gene.
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Chouk H, Ben Rejeb M, Boussofara L, Elmabrouk H, Ghariani N, Sriha B, Saad A, H'Mida D, and Denguezli M
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- Contracture, Hearing Loss, Sensorineural, Humans, Mutation, Nucleoside Transport Proteins genetics, Histiocytosis genetics, Histiocytosis, Sinus genetics, Histiocytosis, Sinus pathology
- Abstract
Background: Mutations in the SLC29A3 gene, which encodes the nucleoside transporter hENT3, have been implicated in syndromic forms of histiocytosis including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, Faisalabad histiocytosis and Familial Rosai-Dorfman disease (RDD). Herein, we report five new patients from a single family who present with phenotypes that associate features of H syndrome and Familial Rosai-Dorfman disease., Methods: We investigated the clinical, biochemical, histopathological and molecular findings in five Tunisian family members' diagnosed with Familial RDD and/or H syndrome. The solute carrier family 29 (nucleoside transporters), member 3 (SLC29A3) gene was screened for molecular diagnosis using direct Sanger sequencing., Results: Genetic analysis of all affected individuals revealed a previously reported missense mutation c.1088 G > A [p.Arg363Gln] in exon 6 of the SLC29A3 gene. Four affected members presented with clinical features consistent with the classical H syndrome phenotype. While their cousin's features were in keeping with Familial Rosai-Dorfman disease diagnosis with a previously undescribed cutaneous RDD presenting as erythematous nodular plaques on the face. This report underlines the clinical variability of SLC29A3 disorders even with an identical mutation in the same family., Conclusion: We report a rare event of 5 Tunisian family members' found to be homozygous for SLC29A3 gene mutations but showing a different phenotype severity. Our study reveals that despite a single mutation, the clinical expression of the SLC29A3 disorders may be significantly heterogeneous suggesting a poor genotype-phenotype correlation for the disease., (© 2021. The Author(s).)
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- 2021
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22. Local ALK-Positive Histiocytosis With Unusual Morphology and Novel TRIM33-ALK Gene Fusion.
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Tran TAN, Chang KTE, Kuick CH, Goh JY, and Chang CC
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- Female, Histiocytosis genetics, Histiocytosis pathology, Histiocytosis surgery, Humans, Mesentery diagnostic imaging, Mesentery surgery, Tomography, X-Ray Computed, Young Adult, Anaplastic Lymphoma Kinase genetics, Histiocytosis diagnosis, Mesentery pathology, Oncogene Proteins, Fusion genetics, Transcription Factors genetics
- Abstract
ALK-positive histiocytosis was first described in 2008 as a systemic histiocytic disorder involving young infants and neonates. Subsequently, cases of local ALK-positive histiocytosis as well as clinical presentation in adult patients have been increasingly reported in the literature. The current case documented the hitherto largest local ALK-positive histiocytosis lesion involving the mesentery of a 20-year-old female patient, a clinical presentation that has not been previously reported in the medical literature. Of note was the presence of numerous lymphocytes, plasma cells, and eosinophils as well as the formation of lymphoid follicles in the lesion, mimicking an inflammatory myofibroblastic tumor. Other unique histologic aspects of the current case included the nested arrangement of the histiocytes, intravascular extension of the histiocytic proliferation into a large vein, and tumor necrosis. Notably, molecular studies revealed a novel TRIM33 (exon 12) -ALK (exon 20) gene fusion. Therefore, ALK-positive histiocytosis with TRIM33-ALK gene fusion expands the clinical, histologic, and molecular spectrum of local ALK-positive histiocytosis. Since ALK-positive histiocytosis associated with a significant inflammatory component can pose considerable diagnostic challenges, increased awareness of this peculiar variant of ALK-positive histiocytosis is essential to minimize the risk of misdiagnosis.
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- 2021
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23. ALK-positive Histiocytosis of the Breast: A Clinicopathologic Study Highlighting Spindle Cell Histology.
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Kashima J, Yoshida M, Jimbo K, Izutsu K, Ushiku T, Yonemori K, and Yoshida A
- Subjects
- Adolescent, Adult, Anaplastic Lymphoma Kinase antagonists & inhibitors, Anaplastic Lymphoma Kinase genetics, Biomarkers analysis, Breast Diseases genetics, Breast Diseases pathology, Breast Diseases therapy, Chemotherapy, Adjuvant, Female, Gene Rearrangement, Histiocytosis genetics, Histiocytosis pathology, Histiocytosis therapy, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Kinesins genetics, Mastectomy, Middle Aged, Protein Kinase Inhibitors therapeutic use, Treatment Outcome, Anaplastic Lymphoma Kinase analysis, Breast Diseases enzymology, Histiocytosis enzymology
- Abstract
Originally described as a systemic self-limiting disease in infancy, the spectrum of ALK-positive histiocytosis has recently been broadened to include localized diseases in older children and young adults. Despite different manifestations, these tumors share histologic characteristics and a highly recurrent KIF5B-ALK fusion. ALK-positive histiocytosis is poorly characterized in the breast. In this study, we report 3 cases of ALK-positive histiocytosis of the breast. The patients were Asian women, aged 16 to 45 years. Two patients presented with an isolated breast mass, while 1 exhibited multiorgan involvement. The latter patient received ALK inhibitor after surgery, which led to complete remission. Histologically, well-circumscribed tumors displayed fascicular and storiform growth of uniform, nonatypical spindle cells admixed with lymphocytic infiltrates. Fewer conventional epithelioid histiocytes with lobulated or clefted nuclei were observed within the same breast tumors in 2 cases or within a concomitant brain tumor in the third case. Touton-type giant cells were focally present in 2 cases. Immunohistochemically, tumor spindle, and epithelioid cells were diffusely positive for CD163 and ALK in all cases and focally positive for S100 protein in 1 of the cases. CD1a and langerin were negative. Actin-positive myofibroblasts were admixed within the tumor in 2 cases, and their reactive nature was highlighted using double immunostaining. Break-apart fluorescence in situ hybridization assay demonstrated gene rearrangements involving KIF5B and ALK in all the 3 cases. ALK-positive histiocytosis rarely occurs as a spindle cell breast tumor, and should be distinguished from other diseases such as inflammatory myofibroblastic tumors and spindled histiocytic reaction., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by JSPS Grant-in-Aid for Young Scientists 18K15108 (A.Y.). K.I. received research grants and honoraria from Chugai Pharmaceutical Co. Ltd that are not related to this study. K.Y. served as an advisor for Chugai Pharmaceutical Co. Ltd, but not related to this study. For the remaining authors none were declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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24. Identification of Critical Transcriptomic Signaling Pathways in Patients with H Syndrome and Rosai-Dorfman Disease.
- Author
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Lara-Reyna S, Poulter JA, Vasconcelos EJR, Kacar M, McDermott MF, Tooze R, Doffinger R, and Savic S
- Subjects
- Adolescent, Adult, Autoimmune Diseases genetics, Biomarkers metabolism, Cytokines genetics, Female, Gene Expression genetics, Histiocytes metabolism, Humans, Inflammation genetics, Macrophages metabolism, Male, Middle Aged, Monocytes metabolism, Nucleoside Transport Proteins genetics, Young Adult, Contracture genetics, Hearing Loss, Sensorineural genetics, Histiocytosis genetics, Histiocytosis, Sinus genetics, Signal Transduction genetics, Transcriptome genetics
- Abstract
Biallelic mutations in SLC29A3 cause histiocytosis-lymphadenopathy plus syndrome, also known as H syndrome (HS). HS is a complex disorder, with ~ 25% of patients developing autoinflammatory complications consisting of unexplained fevers, persistently elevated inflammatory markers, and unusual lymphadenopathies, with infiltrating CD68
+ , S100+ , and CD1a- histiocytes, resembling the immunophenotype found in Rosai-Dorfman disease (RDD). We investigated the transcriptomic profiles of monocytes, non-activated (M0), classically activated (M1), and alternatively activated macrophages (M2) in two patients with HS, one without autoinflammatory (HS1) and one with autoinflammatory complications (HS2). RNA sequencing revealed a dysregulated transcriptomic profile in both HS patients compared to healthy controls (HC). HS2, when compared to HS1, had several differentially expressed genes, including genes associated with lymphocytic-histiocytic predominance (e.g. NINL) and chronic immune activation (e.g. B2M). The transcriptomic and cytokine profiles of HS patients were comparable to patients with SAID with high levels of TNF. SERPINA1 gene expression was found to be upregulated in all patients studied. Moreover, higher levels of IFNγ were found in the serum of both HS patients when compared to HC. Gene ontology (GO) enrichment analysis of the DEGs in HS patients revealed the terms "type I IFN," "IFNγ signaling pathway," and "immune responses" as the top 3 most significant terms for monocytes. Gene expression analysis of lymph node biopsies from sporadic and H syndrome-associated RDD suggests common underlying pathological process. In conclusion, monocytes and macrophages from both HS patients showed transcriptomic profiles similar to SAIDs and also uniquely upregulated IFNγ signature. These findings may help find better therapeutic options for this rare disorder.- Published
- 2021
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25. ALK-Positive Histiocytosis: A Case Report and Literature Review.
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Jaber OI, Jarrah DA, Hiasat M, and Hussaini MA
- Subjects
- Adult, Gene Fusion, Histiocytosis genetics, Histiocytosis pathology, Histiocytosis surgery, Humans, Immunohistochemistry, Male, Oncogene Proteins, Fusion genetics, Real-Time Polymerase Chain Reaction, Treatment Outcome, Activin Receptors, Type II analysis, Histiocytosis metabolism
- Abstract
ALK positive histiocytosis is a relatively new histiocytic proliferation disease with a characteristic gene translocation involving fusion of the ALK gene with different partners, mostly KIF5B. We report a case of ALK-positive histiocytosis with literature review. A 27-year-old male patient presented mainly with progressive lower limb weakness. Imaging studies showed an intradural extramedullary enhancing lesion at the L3 level. A 1.5 cm mass was excised from the sensory nerve root in the filum terminale at the level of L3. Histologic examination showed infiltration of the nerve by numerous histiocytes with moderate to abundant eosinophilic to clear-foamy and variably-vacuolated cytoplasm with irregular-to-smooth contoured nuclei. The histiocytes were positive for CD68 and ALK1 and negative for S100 and CD1a. KIF5B-ALK fusion was detected by real time-polymerase chain reaction. The patient is asymptomatic nine months after surgical excision. This is the first reported localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestations of this disease. An integrated histological, immunohistochemical and molecular approach is recommended for diagnosis. We recommend performing ALK1 immunohistochemical stain on all histiocytosis cases to increase awareness and detection of this newly described entity.
- Published
- 2021
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26. Inherited disorders of lysosomal membrane transporters.
- Author
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Huizing M and Gahl WA
- Subjects
- Amino Acid Transport Systems, Neutral genetics, Amino Acid Transport Systems, Neutral metabolism, Cystinosis genetics, Cystinosis pathology, Histiocytosis genetics, Histiocytosis pathology, Humans, Lysosomal Storage Diseases genetics, Membrane Transport Proteins genetics, Nucleoside Transport Proteins genetics, Nucleoside Transport Proteins metabolism, Organic Anion Transporters genetics, Organic Anion Transporters metabolism, Sialic Acid Storage Disease genetics, Sialic Acid Storage Disease pathology, Symporters genetics, Symporters metabolism, Lysosomal Storage Diseases pathology, Lysosomes metabolism, Membrane Transport Proteins metabolism
- Abstract
Disorders caused by defects in lysosomal membrane transporters form a distinct subgroup of lysosomal storage disorders (LSDs). To date, defects in only 10 lysosomal membrane transporters have been associated with inherited disorders. The clinical presentations of these diseases resemble the phenotypes of other LSDs; they are heterogeneous and often present in children with neurodegenerative manifestations. However, for pathomechanistic and therapeutic studies, lysosomal membrane transport defects should be distinguished from LSDs caused by defective hydrolytic enzymes. The involved proteins differ in function, localization, and lysosomal targeting, and the diseases themselves differ in their stored material and therapeutic approaches. We provide an overview of the small group of disorders of lysosomal membrane transporters, emphasizing discovery, pathomechanism, clinical features, diagnostic methods and therapeutic aspects. We discuss common aspects of lysosomal membrane transporter defects that can provide the basis for preclinical research into these disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)
- Published
- 2020
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27. Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect.
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Çağdaş D, Sürücü N, Tan Ç, Kayaoğlu B, Özgül RK, Akkaya-Ulum YZ, Aydınoğlu AT, Aytaç S, Gümrük F, Balci-Hayta B, Balci-Peynircioğlu B, Özen S, Gürsel M, and Tezcan İ
- Subjects
- Adolescent, Contracture drug therapy, Contracture immunology, Contracture pathology, Glucocorticoids therapeutic use, Hearing Loss, Sensorineural drug therapy, Hearing Loss, Sensorineural immunology, Hearing Loss, Sensorineural pathology, Histiocytosis drug therapy, Histiocytosis immunology, Histiocytosis pathology, Humans, Immunoglobulins, Intravenous therapeutic use, Immunologic Deficiency Syndromes drug therapy, Immunologic Deficiency Syndromes immunology, Immunologic Deficiency Syndromes pathology, Inflammasomes immunology, Lysosomes immunology, Lysosomes pathology, Male, Mitochondria immunology, Mitochondria pathology, Treatment Outcome, Autoimmunity genetics, Contracture genetics, Hearing Loss, Sensorineural genetics, Histiocytosis genetics, Immunologic Deficiency Syndromes genetics, Nucleoside Transport Proteins genetics
- Abstract
Introduction: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS)., Aim: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect., Patient and Methods: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide., Results: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1β and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient., Conclusion: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
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28. Homozygosity for a novel large deletion in SLC29A3 in a patient with H syndrome.
- Author
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Shankar SG, Rangarajan S, Priyadarshini A, Swaminathan A, and Sundaram M
- Subjects
- Adolescent, Humans, Male, Contracture diagnosis, Contracture genetics, Hearing Loss, Sensorineural diagnosis, Hearing Loss, Sensorineural genetics, Histiocytosis diagnosis, Histiocytosis genetics, Homozygote, Mutation genetics, Nucleoside Transport Proteins genetics
- Abstract
H syndrome (OMIM 6027820) is a novel form of histiocytosis affecting multiple organs with peculiar cutaneous manifestations. It is an autosomal recessive genodermatosis caused by pathogenic mutations in SLC29A3 that encodes the human equilibrative nucleoside transporter, hENT3. The cutaneous manifestations can mimic other sclerodermoid conditions. We present a 15-year-old boy diagnosed with H syndrome with typical clinical features and homozygosity for a novel pathogenic mutation., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2020
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29. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms.
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Durham BH, Lopez Rodrigo E, Picarsic J, Abramson D, Rotemberg V, De Munck S, Pannecoucke E, Lu SX, Pastore A, Yoshimi A, Mandelker D, Ceyhan-Birsoy O, Ulaner GA, Walsh M, Yabe M, Petrova-Drus K, Arcila ME, Ladanyi M, Solit DB, Berger MF, Hyman DM, Lacouture ME, Erickson C, Saganty R, Ki M, Dunkel IJ, Santa-María López V, Mora J, Haroche J, Emile JF, Decaux O, Geissmann F, Savvides SN, Drilon A, Diamond EL, and Abdel-Wahab O
- Subjects
- Adolescent, Adult, Aminopyridines pharmacology, Benzothiazoles pharmacology, Child, Child, Preschool, Female, Genome, Human, Hematologic Neoplasms drug therapy, Hematologic Neoplasms genetics, Hematologic Neoplasms pathology, Histiocytosis drug therapy, Histiocytosis pathology, Humans, Infant, Male, Mutation, Picolinic Acids pharmacology, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology, Pyridines pharmacology, Pyrroles pharmacology, Receptor Protein-Tyrosine Kinases genetics, Twins, Monozygotic, Exome Sequencing, Young Adult, Anaplastic Lymphoma Kinase genetics, Histiocytosis genetics, Proto-Oncogene Proteins c-ret genetics, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor genetics
- Abstract
Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.
- Published
- 2019
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30. ALK-positive histiocytosis with KIF5B-ALK fusion in an adult female.
- Author
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Gupta GK, Xi L, Pack SD, Jones JB, Pittaluga S, Raffeld M, and Jaffe ES
- Subjects
- Adult, Age Factors, Biomarkers, Child, Preschool, Diagnosis, Differential, Female, Genetic Association Studies methods, Humans, Immunohistochemistry, Infant, Middle Aged, Anaplastic Lymphoma Kinase genetics, Genetic Predisposition to Disease, Histiocytosis diagnosis, Histiocytosis genetics, Oncogene Proteins, Fusion genetics
- Published
- 2019
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31. H syndrome - the first report in Malaysia.
- Author
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Low DE, Tang MM, Surana U, Lee JY, Pramano ZAD, and Leong KF
- Subjects
- Contracture genetics, Contracture pathology, DNA Mutational Analysis, Hearing Loss, Sensorineural genetics, Hearing Loss, Sensorineural pathology, Histiocytosis genetics, Histiocytosis pathology, Humans, Malaysia, Male, Pedigree, Skin pathology, Young Adult, Contracture diagnosis, Hearing Loss, Sensorineural diagnosis, Histiocytosis diagnosis, Nucleoside Transport Proteins genetics
- Published
- 2019
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32. A novel homozygous frame-shift mutation in the SLC29A3 gene: a new case report and review of literature.
- Author
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Noavar S, Behroozi S, Tatarcheh T, Parvini F, Foroutan M, and Fahimi H
- Subjects
- Adult, Base Sequence, Connexin 26, Connexin 30 genetics, Connexins genetics, Diabetes Mellitus, Type 1 genetics, Exons, Female, Genetic Association Studies, Humans, Iran, Male, Middle Aged, Pedigree, Contracture genetics, Frameshift Mutation, Genetic Predisposition to Disease genetics, Hearing Loss, Sensorineural genetics, Histiocytosis genetics, Homozygote, Nucleoside Transport Proteins genetics
- Abstract
Background: The SLC29A3 gene, encoding a nucleoside transporter protein, is found in intracellular membranes. Based on the literatures, mutations in this gene cause a wide range of clinical manifestations including H syndrome, pigmented hypertrichosis with insulin dependent diabetes, Faisalabad histiocytosis, and dysosteosclerosis. However, all these disorders with their different names and terminologies are actually the same entity termed H syndrome., Case Presentation: We report four GJB2 and GJB6 negative deaf patients from two Iranian related families who present the associated symptoms of SLC29A3-disorder. Whole Exome Sequencing (WES) using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in one of studied patients. A novel homozygous frame-shift mutation c.307-308delTT (p.Phe103fs) in exon 3 of SLC29A3 gene was identified in a 35 years old man with profound hearing loss, camptodactyly, rheumatoid arthritis and delayed puberty without any skin changes, short stature and insulin dependent diabetes mellitus. The mutation found was also confirmed by Sanger sequencing in other studied patients and their healthy parents. In compared to proband, however the clinical manifestations of these patients were different, indicating variable expressivity of mutant SLC29A3 gene as well as possible involvement of other modifier genes., Conclusion: The present study uncovered a rare novel homozygous frame-shift mutation c.307-308delTT in SLC29A3 gene of four related patients with various manifestation of SLC29A3-disorder. Such studies can help to conduct genetic counseling and subsequently, prenatal diagnosis more accurately for individuals at the high risk of these types of genetic disorders.
- Published
- 2019
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33. ALK-positive histiocytosis with KIF5B-ALK fusion in the central nervous system.
- Author
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Lucas CG, Gilani A, Solomon DA, Liang X, Maher OM, Chamyan G, Kleinschmidt-Demasters BK, and Perry A
- Subjects
- Brain Diseases complications, Brain Diseases diagnostic imaging, Brain Diseases surgery, Cerebellar Diseases diagnostic imaging, Cerebellar Diseases genetics, Cerebellar Diseases surgery, Cerebellar Neoplasms diagnosis, Child, Diagnosis, Differential, Female, Foam Cells pathology, Histiocytosis complications, Histiocytosis diagnostic imaging, Histiocytosis surgery, Humans, Magnetic Resonance Imaging, Medulloblastoma diagnosis, Neoplasm Proteins analysis, Neuroimaging, Oncogene Proteins, Fusion analysis, Seizures etiology, Brain Diseases genetics, Histiocytosis genetics, Neoplasm Proteins genetics, Oncogene Proteins, Fusion genetics
- Published
- 2019
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34. Skin-limited H syndrome in a Chinese man.
- Author
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Wang X and Sun J
- Subjects
- Humans, Male, Middle Aged, Contracture genetics, Contracture pathology, Hearing Loss, Sensorineural genetics, Hearing Loss, Sensorineural pathology, Histiocytosis genetics, Histiocytosis pathology
- Published
- 2019
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- View/download PDF
35. ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion.
- Author
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Chang KTE, Tay AZE, Kuick CH, Chen H, Algar E, Taubenheim N, Campbell J, Mechinaud F, Campbell M, Super L, Chantranuwat C, Yuen ST, Chan JKC, and Chow CW
- Subjects
- Adolescent, Adult, Child, Preschool, Crizotinib therapeutic use, Female, Genetic Predisposition to Disease, Histiocytes pathology, Histiocytosis drug therapy, Histiocytosis enzymology, Histiocytosis pathology, Hong Kong, Humans, Infant, Infant, Newborn, Male, Phenotype, Protein Kinase Inhibitors therapeutic use, Singapore, Treatment Outcome, Victoria, Cell Proliferation drug effects, Gene Fusion, Histiocytes enzymology, Histiocytosis genetics, Oncogene Proteins, Fusion genetics
- Abstract
In 2008, we presented three cases of ALK-positive histiocytosis as a novel systemic histiocytic proliferation of early infancy with hepatosplenomegaly and dramatic hematological disturbances. This series of 10 cases (including the original three cases) describes an expanded clinicopathological spectrum and the molecular findings of this histiocytic proliferation. Six patients had disseminated disease: five presented in early infancy with eventual disease resolution, and the sixth presented at 2 years of age and died of intestinal, bone marrow, and brain involvement. The other four patients had localized disease involving nasal skin, foot, breast, and intracranial cavernous sinus - the first three had no recurrence after surgical resection, while the cavernous sinus lesion showed complete resolution with crizotinib therapy. The lesional histiocytes were very large, with irregularly folded nuclei, fine chromatin, and abundant eosinophilic cytoplasm, sometimes with emperipolesis. There could be an increase in foamy histiocytes and Touton giant cells with time, resembling juvenile xanthogranuloma. Immunostaining showed that the histiocytes were positive for ALK, histiocytic markers (CD68, CD163) and variably S100, while being negative for CD1a, CD207, and BRAF-V600E. Next-generation sequencing-based anchored multiplex PCR (Archer® FusionPlex®) performed in six cases identified KIF5B-ALK gene fusion in five and COL1A2-ALK fusion in one. There was no correlation of gene fusion type with disease localization or dissemination. The clinicopathological spectrum of ALK-positive histiocytosis is broader than originally described, and this entity is characterized by frequent presence of KIF5B-ALK gene fusion. We recommend that every unusual histiocytic proliferative disorder, especially disseminated lesions, be tested for ALK expression because of the potential efficacy of ALK inhibitor therapy in unresectable or disseminated disease.
- Published
- 2019
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36. Complement receptor-associated CD163 + /CD18 + /CD11c + /CD206 - /CD209 - expression profile in chronic histiocytic intervillositis of the placenta.
- Author
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Hussein K, Stucki-Koch A, Müller AM, Arnold R, Kreipe H, and Feist H
- Subjects
- Adult, Antigens, CD genetics, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic genetics, Antigens, Differentiation, Myelomonocytic metabolism, CD11c Antigen metabolism, CD18 Antigens metabolism, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Chorionic Villi immunology, Chorionic Villi metabolism, Chorionic Villi pathology, Chronic Disease, Female, Fetal Growth Retardation genetics, Fetal Growth Retardation immunology, Fetal Growth Retardation pathology, Gene Expression Regulation, Gestational Age, Histiocytes immunology, Histiocytes metabolism, Histiocytes pathology, Histiocytosis immunology, Histiocytosis metabolism, Histiocytosis pathology, Humans, Lectins, C-Type genetics, Lectins, C-Type metabolism, Mannose Receptor, Mannose-Binding Lectins genetics, Mannose-Binding Lectins metabolism, Placenta immunology, Placenta pathology, Placenta Diseases immunology, Placenta Diseases metabolism, Placenta Diseases pathology, Pregnancy, Receptors, Cell Surface genetics, Receptors, Cell Surface metabolism, Receptors, Complement metabolism, Retrospective Studies, Transcriptome, Young Adult, CD11c Antigen genetics, CD18 Antigens genetics, Histiocytosis genetics, Placenta metabolism, Placenta Diseases genetics, Receptors, Complement genetics
- Abstract
Introduction: Chronic histiocytic intervillositis of unknown etiology (CIUE) is a non-infectious, most probably immunologic placenta lesion. CIUE is associated with recurrent miscarriage, intrauterine growth restriction and stillbirth. Among the pathologic-anatomic defined placental lesions this entity displays the highest risk of recurrence in following pregnancies (about 67-100%). The histiocytic cells accumulate in the placental blood space but do not infiltrate into the villi or decidua. Sparsely known is the expression profile of these intervillous cells regarding histiocytic markers., Methods: We analysed 5-22 markers by immunohistochemistry in a total of 41 placenta samples and evaluated decidual, villous and intervillous histiocytic cells., Results: In CIUE, intervillous CD163
+ histiocytes over-express CD11c/CD18 and down-regulate CD206/CD209, while CD163+ decidual and Hofbauer cells show low CD11c/CD18 and higher CD206/CD209 protein expressions., Discussion: CD163 expression indicates a M2-like polarisation. CD11c and CD18 form the complement receptor 4 which could be related to a complement mediated trigger for aberrant cell accumulation in CIUE., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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37. Efficacy of MEK inhibition in patients with histiocytic neoplasms.
- Author
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Diamond EL, Durham BH, Ulaner GA, Drill E, Buthorn J, Ki M, Bitner L, Cho H, Young RJ, Francis JH, Rampal R, Lacouture M, Brody LA, Ozkaya N, Dogan A, Rosen N, Iasonos A, Abdel-Wahab O, and Hyman DM
- Subjects
- Azetidines pharmacology, Histiocytic Disorders, Malignant genetics, Histiocytic Disorders, Malignant pathology, Histiocytosis genetics, Histiocytosis pathology, Humans, MAP Kinase Kinase 1 antagonists & inhibitors, MAP Kinase Kinase 2 antagonists & inhibitors, MAP Kinase Kinase 2 genetics, MAP Kinase Signaling System drug effects, Mutation, Piperidines pharmacology, Progression-Free Survival, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-raf genetics, Azetidines therapeutic use, Histiocytic Disorders, Malignant drug therapy, Histiocytic Disorders, Malignant enzymology, Histiocytosis drug therapy, Histiocytosis enzymology, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Piperidines therapeutic use
- Abstract
Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway
1,2 . For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5 , RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7 . However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.- Published
- 2019
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38. Highly sensitive methods are required to detect mutations in histiocytoses.
- Author
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Melloul S, Hélias-Rodzewicz Z, Cohen-Aubart F, Charlotte F, Fraitag S, Terrones N, Riller Q, Chazal T, Héritier S, Moreau A, Kambouchner M, Copin MC, Donadieu J, Taly V, Amoura Z, Haroche J, and Emile JF
- Subjects
- Humans, Reproducibility of Results, Sensitivity and Specificity, Biomarkers, DNA Mutational Analysis methods, DNA Mutational Analysis standards, Genetic Predisposition to Disease, Histiocytosis diagnosis, Histiocytosis genetics, Mutation
- Published
- 2019
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- View/download PDF
39. Atypical Histiocytic Lesion Preceding a Peripheral T-Cell Lymphoma Involving the Skin Exhibiting the Same Molecular Alterations.
- Author
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Machan S, Córdoba R, Carvajal N, Requena L, Piris MÁ, Facchetti F, and Rodríguez-Pinilla SM
- Subjects
- Aged, 80 and over, Female, GTP Phosphohydrolases genetics, Histiocytosis genetics, Humans, Laryngeal Diseases genetics, Lymphoma, T-Cell, Peripheral genetics, Membrane Proteins genetics, Mutation, Nose Neoplasms genetics, Skin Neoplasms genetics, Histiocytosis pathology, Laryngeal Diseases pathology, Lymphoma, T-Cell, Peripheral pathology, Nose Neoplasms pathology, Skin Neoplasms pathology
- Abstract
Peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS) is a diagnosis of exclusion, showing extreme cytological and phenotypic heterogeneity. Skin involvement of PTCL may be primary or secondary. Diagnosis of histiocytosis may be difficult, requiring clinical-pathological correlation. We describe a laryngeal atypical histiocytic lesion (AHL) and a nasal PTCL, NOS with cutaneous involvement in the same patient presenting with peculiar histopathologic and immunophenotypic features. The laryngeal neoplasm showed morphological and immunophenotypic evidence of histiocytic differentiation and does not fit any other category of the WHO classification nor the revised classification of histiocytosis. The nasal and cutaneous lesions presented features close to natural killer/T-cell lymphoma and gamma-delta T-cell lymphoma but did not meet accurately the WHO criteria. A somatic activating Q61K mutation was found on exon 3 of the NRAS gene in both AHL and PTCL, NOS. The mutation on NRAS gene in both AHL and PTCL, NOS may suggest a common origin from a precursor cell.
- Published
- 2019
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40. Imaging of Histiocytosis in the Era of Genomic Medicine.
- Author
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Park H, Nishino M, Hornick JL, and Jacobsen ED
- Subjects
- Female, Genomics, Histiocytosis genetics, Histiocytosis pathology, Histiocytosis therapy, Humans, Male, Mutation, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Histiocytosis diagnostic imaging, Precision Medicine
- Abstract
Histiocytosis describes a group of diseases that have long been considered enigmatic in the history of medicine. Recently, novel genomic analyses have identified somatic oncogenic driver mutations responsible for the pathogenesis of these entities. These discoveries have led to the recharacterization of histiocytoses as neoplastic diseases and have opened a new era of precision medicine approaches for treatment. The histiocytic disorders demonstrate a variety of imaging manifestations involving multiple organ systems, and radiologists play a major role in diagnosis and monitoring. An up-to-date knowledge of the novel genomic discoveries and their implications is essential for radiologists to understand the new approaches to treating histiocytic disorders and to contribute as key members of the multidisciplinary treatment team. This article provides a cutting-edge review of the novel concepts in histiocytosis, with a focus on recent genomic discoveries and precision medicine approaches to treating the disease, and describes imaging manifestations with correlative histologic and genomic findings, with an emphasis on adult-onset cases and uncommon subtypes.
© RSNA, 2018.- Published
- 2019
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41. Clinical, Histochemical, and Molecular Study of Three Turkish Siblings Diagnosed with H Syndrome, and Literature Review.
- Author
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Simsek E, Simsek T, Eren M, Yilmaz E, Arik D, Cilingir O, Ceylaner S, and Harmancı K
- Subjects
- Adolescent, Adult, Child, DNA Mutational Analysis, Exons, Family, Female, Humans, Male, Syndrome, Turkey, Contracture diagnosis, Contracture genetics, Contracture metabolism, Contracture pathology, Hearing Loss, Sensorineural diagnosis, Hearing Loss, Sensorineural genetics, Hearing Loss, Sensorineural metabolism, Hearing Loss, Sensorineural pathology, Histiocytosis diagnosis, Histiocytosis genetics, Histiocytosis metabolism, Histiocytosis pathology, Hyperpigmentation diagnosis, Hyperpigmentation genetics, Hyperpigmentation metabolism, Hyperpigmentation pathology, Hypertrichosis diagnosis, Hypertrichosis genetics, Hypertrichosis metabolism, Hypertrichosis pathology, Mutation, Nucleoside Transport Proteins genetics, Nucleoside Transport Proteins metabolism, Siblings
- Abstract
Background: The term "H syndrome" was coined to denote the major clinical findings, which include hyperpigmentation, hypertrichosis, hearing loss, hepatosplenomegaly, hyperglycaemia, hypogonadism, hallux flexion contractures, and short height., Objective: To report the clinical, endocrinological, histochemical, and genetic findings of three siblings., Methods: Skin and liver biopsies were taken to investigate the histochemical characteristics of hyperpigmented hypertrichotic skin lesions and massive hepatomegaly. The levels of basal serum thyroid hormones, oestradiol, total testosterone, follicle-stimulating hormone, luteinising hormone, and stimulated growth hormone (GH) were measured to investigate the endocrine aspects of the syndrome. Mutation analysis was carried out in all six exons and exon-intron boundaries of SLC29A3 by direct sequencing., Results: Physical examination of the patients revealed common charac-teristic findings of H syndrome. Additional clinical findings were sectorial iris atrophy in the younger sister. Laboratory evaluation revealed microcytic anaemia, markedly increased erythrocyte sedimentation rate and C-reactive protein levels, and humoral immune deficiency in the younger siblings, who presented with recurrent fever and sinopulmonary infection. Two different GH stimulation tests revealed GH deficiency in the younger sister with short stature. Liver and skin biopsies revealed polyclonal lymphohistiocytic and plasma cell infiltration. Sequencing of SLC29A3 in the three siblings revealed a novel homozygous mutation in exon 6, which caused the transition of arginine to tryptophan., Conclusion: This study not only extended the clinical and mutation spectrum of SLC29A3 in H syndrome, but also showed that short children should be assessed according to the guidelines for short stature in children., (© 2019 S. Karger AG, Basel.)
- Published
- 2019
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42. Histiocytic cell neoplasms involving the bone marrow: summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016.
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Tzankov A, Kremer M, Leguit R, Orazi A, van der Walt J, Gianelli U, and Hebeda KM
- Subjects
- Amino Acid Substitution, Congresses as Topic, Europe, Humans, MAP Kinase Signaling System genetics, Mutation, Missense, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Bone Marrow Neoplasms genetics, Bone Marrow Neoplasms metabolism, Bone Marrow Neoplasms pathology, Bone Marrow Neoplasms therapy, Hematology, Histiocytosis genetics, Histiocytosis metabolism, Histiocytosis pathology, Histiocytosis therapy, Societies, Medical
- Abstract
The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAF
V600E mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.- Published
- 2018
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43. H syndrome: Clinical, histological and genetic investigation in Tunisian patients.
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Jaouadi H, Zaouak A, Sellami K, Messaoud O, Chargui M, Hammami H, Jones M, Jouini R, Chadli Debbiche A, Chraiet K, Fenniche S, Mrad R, Mokni M, Turki H, Benkhalifa R, and Abdelhak S
- Subjects
- Adult, Child, Preschool, Contracture diagnosis, Contracture pathology, Exons genetics, Female, Frameshift Mutation, Genetic Testing, Hearing Loss, Sensorineural diagnosis, Hearing Loss, Sensorineural pathology, Histiocytosis diagnosis, Histiocytosis pathology, Humans, Male, Pedigree, Rare Diseases diagnosis, Rare Diseases pathology, Skin pathology, Tunisia, Young Adult, Contracture genetics, Hearing Loss, Sensorineural genetics, Histiocytosis genetics, Nucleoside Transport Proteins genetics, Rare Diseases genetics
- Abstract
H syndrome is a rare autosomal recessive disorder with characteristic dermatological findings consisting of hyperpigmentation and hypertrichosis patches mainly located on the inner thighs and multisystemic involvement including hepatosplenomegaly, hearing loss, heart abnormalities and hypogonadism. The aim of this study was to conduct a clinical and genetic investigation in five unrelated Tunisian patients with suspected H syndrome. Hence, genetic analysis of the SLC29A3 gene was performed for four patients with a clinical diagnosis of H syndrome. We identified a novel frame-shift mutation in the SLC29A3 gene in a female patient with a severe clinical presentation. Furthermore, we report two mutations previously described, the p.R363Q mutation in a male patient and the p.P324L mutation in two patients of different age and sex. This paper extends the mutation spectrum of H syndrome by reporting a novel frame-shift mutation, the p.S15Pfs*86 in exon 2 of SLC29A3 gene and emphasizes the relevance of genetic testing for its considerable implications in early diagnosis and clinical management., (© 2018 Japanese Dermatological Association.)
- Published
- 2018
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44. Tocilizumab for the Treatment of SLC29A3 Mutation Positive PHID Syndrome.
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Rafiq NK, Hussain K, and Brogan PA
- Subjects
- Adolescent, Contracture diagnosis, Female, Hearing Loss, Sensorineural diagnosis, Histiocytosis diagnosis, Humans, Syndrome, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Contracture drug therapy, Contracture genetics, Hearing Loss, Sensorineural drug therapy, Hearing Loss, Sensorineural genetics, Histiocytosis drug therapy, Histiocytosis genetics, Mutation genetics, Nucleoside Transport Proteins genetics
- Abstract
Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) is associated with recessive mutations in SLC29A3 , encoding the equilibrative nucleoside transporter hENT3 expressed in mitochondria, causing PHID and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy-plus syndrome. Autoinflammation is increasingly recognized in these syndromes. We previously reported a 16-year-old girl with PHID syndrome associated with severe autoinflammation that was recalcitrant to interleukin-1 and tumor necrosis factor-α blockade. Tocilizumab is a humanized, monoclonal, anti-human interleukin-6 receptor antibody routinely used to treat arthritis in children and adults. Herein we report the first case of successful treatment of PHID syndrome using tocilizumab. Before commencing tocilizumab, there was evidence of significant systemic inflammation, and progressive sclerodermatous changes (physician global assessment [PGA] 7/10). Twelve weeks after starting tocilizumab (8 mg/kg every 2 weeks, intravenously) systemic inflammatory symptoms improved, and acute phase response markers normalized; serum amyloid A reduced from 178 to 8.4 mg/L. After a dose increase to 12 mg/kg every 2 weeks her energy levels, appetite, fevers, and night sweats further improved. Less skin tightness (PGA 5/10) was documented 12 months later. This excellent clinical and serological response was sustained over 48 months, and cutaneous sclerosis had improved further (PGA 3/10). Her height remained well below the 0.4th centile, and tocilizumab also had no impact on her diabetes or exocrine pancreatic insufficiency. Although the mechanism of autoinflammation of PHID remains uncertain, we suggest that tocilizumab should be the first choice when considering treatment of the autoinflammatory or cutaneous manifestations of this genetic disease., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Brogan has received institutional grant funding and consultancy fees from Roche; Drs Rafiq and Hussain have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)
- Published
- 2017
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45. Special variant of histiocytosis.
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Quint KD, Cleven AH, and Vermeer MH
- Subjects
- Aged, Diagnosis, Differential, Histiocytosis radiotherapy, Humans, Male, Proto-Oncogene Proteins c-ets genetics, Rare Diseases, Translocation, Genetic, Treatment Outcome, Histiocytosis genetics, Histiocytosis pathology, Nuclear Receptor Coactivator 2 genetics, Ultraviolet Therapy methods
- Abstract
Indeterminate cell histiocytosis is a rare variant of histiocytosis. The diagnosis is currently based on presence and absence of immunohistochemical markers. The current case described an indeterminate cell histiocytosis with ETV3-NCOA2 translocation., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)
- Published
- 2017
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46. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease.
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Mass E, Jacome-Galarza CE, Blank T, Lazarov T, Durham BH, Ozkaya N, Pastore A, Schwabenland M, Chung YR, Rosenblum MK, Prinz M, Abdel-Wahab O, and Geissmann F
- Subjects
- Animals, Clone Cells enzymology, Clone Cells metabolism, Clone Cells pathology, Disease Models, Animal, Erythroid Precursor Cells enzymology, Erythroid Precursor Cells metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Histiocytosis enzymology, Histiocytosis genetics, Histiocytosis metabolism, Histiocytosis pathology, Humans, Macrophages enzymology, Macrophages metabolism, Macrophages pathology, Male, Mice, Microglia enzymology, Microglia metabolism, Microglia pathology, Mosaicism, Myeloid Progenitor Cells enzymology, Myeloid Progenitor Cells metabolism, Neurodegenerative Diseases enzymology, Neurodegenerative Diseases metabolism, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Erythroid Precursor Cells pathology, MAP Kinase Signaling System, Mutation, Myeloid Progenitor Cells pathology, Neurodegenerative Diseases genetics, Neurodegenerative Diseases pathology, Proto-Oncogene Proteins B-raf genetics
- Abstract
The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses and demonstrate that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases.
- Published
- 2017
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47. Autoinflammatory Diseases in Pediatric Dermatology-Part 2: Histiocytic, Macrophage Activation, and Vasculitis Syndromes.
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Hernández-Ostiz S, Xirotagaros G, Prieto-Torres L, Noguera-Morel L, and Torrelo A
- Subjects
- Autoimmune Diseases of the Nervous System genetics, Autoimmune Diseases of the Nervous System immunology, Child, Disease Management, Histiocytosis genetics, Histiocytosis immunology, Humans, Interferon-alpha physiology, Macrophage Activation, Vasculitis genetics, Vasculitis immunology, Hereditary Autoinflammatory Diseases classification, Hereditary Autoinflammatory Diseases immunology, Skin Diseases, Genetic classification, Skin Diseases, Genetic immunology
- Abstract
The discovery of new autoinflammatory syndromes and novel mutations has advanced at breakneck speed in recent years. Part 2 of this review focuses on vasculitis syndromes and the group of histiocytic and macrophage activation syndromes. We also include a table showing the mutations associated with these autoinflammatory syndromes and treatment alternatives., (Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)
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- 2017
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48. Localized pulmonary crystal-storing histiocytosis complicating pulmonary mucosa-associated lymphoid tissue lymphoma presenting with multiple mass lesions.
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Kokuho N, Terasaki Y, Kunugi S, Onda N, Urushiyama H, Terasaki M, Hino M, Gemma A, Hatori T, and Shimizu A
- Subjects
- Adult, Biomarkers, Tumor genetics, Chromatography, Liquid, Crystallization, Female, Gene Rearrangement, Genes, Immunoglobulin Heavy Chain, Histiocytes ultrastructure, Histiocytosis genetics, Histiocytosis pathology, Humans, Immunohistochemistry, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms ultrastructure, Lymphoma, B-Cell, Marginal Zone genetics, Lymphoma, B-Cell, Marginal Zone ultrastructure, Microscopy, Electron, Polymerase Chain Reaction, Positron-Emission Tomography, Tandem Mass Spectrometry, Tomography, X-Ray Computed, Biomarkers, Tumor analysis, Histiocytes immunology, Histiocytosis immunology, Immunoglobulin kappa-Chains analysis, Lung Neoplasms immunology, Lymphoma, B-Cell, Marginal Zone immunology
- Abstract
Crystal-storing histiocytosis (CSH) is an uncommon finding in lymphoplasmacytic disorders that presents histiocytes with abnormal intralysosomal accumulations of immunoglobulin light chains as crystals of unknown etiology. A 38-year-old woman with antiphospholipid syndrome had a surgical lung biopsy because of multiple lung mass lesions. In a right middle lobe lesion, lymphoplasmacytic cells had a monocytoid appearance, destructive lymphoepithelial lesions, and positive immunoglobulin heavy chain (IGH) gene rearrangements. A right upper lobe lesion manifested proliferating rounded histiocytes with abundant, deeply eosinophilic cytoplasm and negative IGH gene rearrangements. Electron microscopy and mass spectrometry revealed a case of pulmonary CSH: abnormal proliferation of the immunoglobulin κ chain of a variable region that may be crystallized within plasma cells and histiocytes. We report a rare case of localized pulmonary CSH complicating pulmonary mucosa-associated lymphoid tissue lymphoma with multiple mass lesions. We demonstrate advances in the understanding of the pathogenesis of CSH by various analyses of these lesions., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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49. Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes.
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Lee LH, Gasilina A, Roychoudhury J, Clark J, McCormack FX, Pressey J, Grimley MS, Lorsbach R, Ali S, Bailey M, Stephens P, Ross JS, Miller VA, Nassar NN, and Kumar AR
- Subjects
- 3T3 Cells, Adult, Animals, Drug Resistance, Neoplasm, Female, Histiocytosis genetics, Histiocytosis pathology, Humans, Imidazoles administration & dosage, Imidazoles therapeutic use, Infant, Male, Mice, Mutation, Oximes administration & dosage, Oximes therapeutic use, Prospective Studies, Protein Kinase Inhibitors therapeutic use, Pyridones administration & dosage, Pyridones therapeutic use, Pyrimidinones administration & dosage, Pyrimidinones therapeutic use, Treatment Outcome, Young Adult, Anaplastic Lymphoma Kinase genetics, Histiocytosis drug therapy, MAP Kinase Kinase 1 genetics, Protein Kinase Inhibitors administration & dosage, Proto-Oncogene Proteins B-raf genetics, Sequence Analysis, DNA methods, Sequence Analysis, RNA methods
- Abstract
Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known BRAF V600E mutation, and 11 patients (15%) carried various mutations in MAP2K1 , which we confirm induce constitutive activation of extracellular signal-regulated kinase (ERK) and were sensitive to inhibitors of mitogen-activated protein kinase kinase (MEK, the product of MAP2K1 ). We also identified recurring ALK rearrangements, and 4 LCH patients with an uncommon in-frame deletion in BRAF (N486_P490del or N486_T491>K), resulting in constitutive activation of ERK with resistance to V600E-specific inhibitors. We subsequently describe clinical cases where patients with aggressive multisystem LCH experience dramatic and sustained responses to monotherapy with either dabrafenib or trametinib. These findings support our conclusion that comprehensive genomic profiling should be regularly applied to these disorders at diagnosis, and can positively impact clinical care., Competing Interests: S. Ali, M. Bailey, P. Stephens, V.A. Miller, and J.S. Ross are employees of Foundation Medicine Inc.
- Published
- 2017
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50. [Histiocytoses: General classification and molecular criteria].
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Emile JF, Charlotte F, Chassagne-Clement C, Copin MC, Fraitag S, Mokhtari K, and Moreau A
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- Diagnosis, Differential, Histiocytosis genetics, Humans, Mutation, Terminology as Topic, Histiocytes pathology, Histiocytosis classification, Histiocytosis pathology
- Abstract
Histiocytoses are rare and heterogeneous disease sharing histology, characterized by accumulation of histiocytes. They may be inherited or sporadic, and related to the accumulation of endo- or exogenous material in macrophages or to macrophage activation. Recent discoveries have shown that some histiocytoses, such as Langerhans cell histiocytosis or Erdheim-Chester disease, previously considered as idiopathic or inflammatory were clonal myeloid proliferations. This review presents the general classification of histiocytoses, and describes diagnostic and molecular criteria of idiopathic histiocytoses and histiocytic neoplasms., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2017
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