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1.
Pediatr Rheumatol Online J ; 22(1): 21, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38263041

RESUMO

BACKGROUND: H Syndrome is a rare genetic condition caused by biallelic pathogenic variants in the SLC29A3 gene. It is characterized by a wide range of clinical manifestations, many of which are related to the immune-rheumatological field. These include scleroderma-like skin changes, deforming arthritis, and enlarged lymph nodes. The condition also features cardiac and endocrine defects, as well as hearing loss, for which the immune pathogenesis appears less clear. Immunomodulatory medications have been shown to improve many symptoms in recent experiences. CASE PRESENTATION: A 21-year-old girl was referred to our institute after being diagnosed with H syndrome. Her medical history was characterized by the development of finger and toe deformities, which developed since the first years of life and progressively worsened with clinodactyly. At 6 years of age, she was diagnosed with diabetes mellitus without typical autoantibodies and with bilateral sensorineural hearing loss. She also complained of frequent episodes of lymphadenopathy, sometimes with colliquation and growth retardation due to pancreatic insufficiency. It wasn't until the genetic diagnosis of H syndrome that the continual increase in acute phase reactants was noticed, suggesting that an immunological pathogenesis may be the source of her problems. During her visit to our institute, she reported serious pain in both feet and hands and difficulty walking due to knee arthritis and muscle contractures. Conventional therapy with steroid injection in affected joints and methotrexate only led to partial improvement. After a thorough assessment of her inflammatory profile showing a high interferon score, the girl received treatment with baricitinib. Furthermore, based on recent data showing that SLC29A3 deficiency results in interferon production because of Toll-like Receptor 7 activation in lysosomes, hydroxychloroquine was also added. The combination of the two drugs resulted for the first time in a rapid and persistent normalization of inflammatory markers, paralleled by a dramatic improvement in symptoms. CONCLUSIONS: We describe the results of inhibiting IFN inflammation in H syndrome and discuss how JAK inhibitors and antimalarials might represent a mechanistically based treatment for this orphan drug disorder.


Assuntos
Artrite , Contratura , Perda Auditiva Neurossensorial , Histiocitose , Doenças Reumáticas , Feminino , Humanos , Adulto Jovem , Adulto , Interferons , Proteínas de Transporte de Nucleosídeos
2.
Exp Cell Res ; 434(2): 113892, 2024 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-38104646

RESUMO

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.


Assuntos
Diabetes Mellitus Tipo 2 , Histiocitose , Neoplasias , Humanos , Nucleotídeos/metabolismo , Mutação , Histiocitose/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas de Membrana Transportadoras/genética , Proteínas de Transporte de Nucleosídeos/genética , Proteínas de Transporte de Nucleosídeos/metabolismo
3.
Medicine (Baltimore) ; 102(45): e36035, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37960726

RESUMO

RATIONALE: Diagnosing intralymphatic histiocytosis can be challenging due to its rarity. We present a case of intralymphatic histiocytosis in the upper eyelid of a Korean patient. We treated the condition by surgical debulking and intralesional triamcinolone injection. PATIENT CONCERNS: A 59-year-old man was referred to our clinic with a 7-year history of unilateral swelling in the right upper eyelid. He had previously been treated with long-term oral steroids and immunosuppressants, but his eyelid swelling persisted. Unilaterally non-pitting erythematous edema was localized on the right upper eyelid without any itching or pain. His best corrected visual acuity at presentation was 20/20 for both eyes. Enhanced orbital computerized tomography revealed edematous soft tissue thickening in the right upper eyelid. In the laboratory testing, the erythrocyte sedimentation rate showed an increase of 19, and the antinuclear antibody titer was positive with a homogeneous pattern. DIAGNOSES: We diagnosed the patient with intralymphatic histiocytosis based on the histopathological findings. INTERVENTION: We attempted surgical debulking and biopsy on the right upper eyelid due to the persistent symptoms and the absence of a definitive diagnosis. OUTCOMES: The patient has demonstrated significant improvement after receiving an intralesional triamcinolone injection in the right upper eyelid following the surgery and is currently under follow-up with no signs of recurrence. LESSON: Ophthalmologists should consider intralymphatic histiocytosis in cases of persistent eyelid swelling that do not respond to treatment, even in Asian patients. Surgical debulking and intralesional triamcinolone injections may be beneficial for improvement.


Assuntos
Histiocitose , Masculino , Humanos , Pessoa de Meia-Idade , Histiocitose/diagnóstico , Pálpebras/patologia , Triancinolona/uso terapêutico , Edema/etiologia , República da Coreia
4.
Blood ; 142(20): 1679-1681, 2023 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-37971762
5.
Curr Res Transl Med ; 71(4): 103421, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38016419

RESUMO

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.


Assuntos
Histiocitose , Leucemia Mieloide Aguda , Humanos , Aberrações Cromossômicas , Análise Citogenética , Células Dendríticas/patologia , Hematologia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Histiocitose/diagnóstico , Histiocitose/genética , Histiocitose/terapia
6.
Head Neck Pathol ; 17(4): 1034-1041, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37792236

RESUMO

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare disorder which most commonly occurs in the setting of concurrent lymphoproliferative disease. Morphologically, it consists of aggregates of histiocytes containing eosinophilic crystalline material, which in most cases is composed of aggregated abnormal light chains. METHODS: Using histomorphology, immunohistochemistry and in situ hybridization, the authors characterize a rare case of orbital CSH associated with extranodal marginal zone (MALT) lymphoma and report for the first time the frozen section features of CSH. RESULTS: The frozen section featured plump histiocytes with ample weakly basophilic to grayish cytoplasm with a microvacuolated appearance and focal stippling. These features stand in contrast with the formalin-fixed, paraffin embedded histomorphological appearance of aggregates of plump histiocytes with densely eosinophilic crystalline cytoplasmic material. CONCLUSION: CSH is a challenging diagnosis to make on frozen section. The artifacts that preclude its recognition, as well as differential diagnoses of this entity in the head and neck are discussed.


Assuntos
Histiocitose , Linfoma de Zona Marginal Tipo Células B , Humanos , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/patologia , Histiocitose/complicações , Histiocitose/patologia , Secções Congeladas , Imuno-Histoquímica
7.
Front Immunol ; 14: 1260193, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37809108

RESUMO

Histiocytoses encompass a wide spectrum of diseases, all characterized by tissue infiltration by CD68+ histiocytes. Most adult histiocytoses are considered clonal diseases because they highlight recurrent somatic mutations in the MAP-kinase pathway gene, primarily BRAF. The presence of BRAF mutation is associated with widespread disease in children with Langerhans cell histiocytosis (LCH) or cardiovascular/neurological involvement in Erdheim-Chester disease (ECD). Nevertheless, few data are available on adult clonal histiocytosis. This is why we have conducted a retrospective study of all patients with clonal histiocytosis in our institution and present the data according to the presence of BRAF mutation. Among 27 adult patients (10 ECD, 10 LCH, 5 Rosai-Dorfman disease (RDD), and 3 mixed ECD/LCH), 11 (39%) have BRAF mutation with gain of function (n = 9) and deletion (n = 2). Those patients had frequent multicentric disease with risk organ involvement, especially the brain and cardiovascular system. They had frequent associated myeloid neoplasms (mostly chronic myelomonocytic leukemia) and received more frequently targeted therapy as the front-line therapy. Nevertheless, its presence did not affect the overall survival or relapse-free survival probably due to the emergence of efficient therapies. To conclude, rapid and accurate molecular establishment in adult clonal histiocytoses is crucial because BRAFV600E mutation correlates with multicentric disease with organ involvement and incomplete metabolic response.


Assuntos
Histiocitose , Proteínas Proto-Oncogênicas B-raf , Adulto , Criança , Humanos , Doença de Erdheim-Chester/genética , Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Histiocitose/metabolismo
10.
Iran J Allergy Asthma Immunol ; 22(4): 405-408, 2023 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-37767683

RESUMO

Mutations in the SLC29A3 gene cause histiocytosis-lymphadenopathy plus (H) syndrome, a rare autosomal recessive genetic condition that affects numerous systems. We present a 7-year-old Syrian patient with pericardial effusion whose acute phase reactants did not decrease despite treatment. In order to emphasize the variety and raise awareness of H syndrome in the hopes of achieving an early diagnosis and appropriate treatment, molecular investigation of SLC29A3-related disorders is crucial. H syndrome is an uncommon genetic condition with a broad spectrum of phenotypes. Therefore, early genetic testing is essential for the accurate diagnosis of patients. Doctors should be aware of this condition and its symptoms and consider autoimmune diseases as a possible alternative diagnosis in patients with suspected immunodeficiency.


Assuntos
Doenças Autoimunes , Histiocitose , Síndromes de Imunodeficiência , Linfadenopatia , Humanos , Criança , Diagnóstico Diferencial , Síndromes de Imunodeficiência/diagnóstico , Histiocitose/diagnóstico , Linfadenopatia/diagnóstico , Proteínas de Transporte de Nucleosídeos
11.
Blood ; 142(20): 1740-1751, 2023 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-37738562

RESUMO

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.


Assuntos
Histiocitose , Proteínas Quinases Ativadas por Mitógeno , Humanos , Histiocitose/genética , Histiocitose/patologia , Mutação , Receptores Toll-Like , Inflamação/genética , Proteínas de Transporte de Nucleosídeos/genética , Proteínas de Transporte de Nucleosídeos/metabolismo
14.
J Cutan Pathol ; 50(11): 991-1000, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37580954

RESUMO

BACKGROUND: Previously identified mutually-exclusive driver genes in juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG) include mutations in MAP kinase pathway genes such as MAP2K1, BRAF, ARAF, KRAS, NRAS, PIK3CD as well as fusions in BRAF and ALK, with a subset of cases with no identified driver yet. NTRK fusion has been identified in rare cases. METHODS: We identified two consecutive index cases of localized JXG or AXG with NTRK1 fusion by next-generation sequencing (NGS) and confirmed by pan-NTRK immunostain. We expanded the study to a total of 50 cases of JXG and AXG using screening by pan-NTRK immunostain. We confirmed the specificity of our approach with negative results in 5 cases of histiocytic neoplasia lacking an NTRK fusion by NGS and 14 cases of non-neoplastic histiocytic disease. RESULTS: We found 23 cases of JXG or AXG with overexpression of NTRK by immunostain, and these cases were restricted to localized disease (23 of 43 cases, 53.5%) rather than disseminated disease (zero of seven cases). CONCLUSIONS: NTRK expression is common in JXG or AXG and associated with localized rather than disseminated disease. We speculate that the potential importance of this in JXG and AXG has not been previously appreciated due to the tendency to focus sequencing studies on disseminated disease. We confirm the presence of an NTRK1 fusion in two positive cases by NGS, however, additional genetic studies are necessary to further explore this.


Assuntos
Neoplasias Hematológicas , Histiocitose , Neoplasias Cutâneas , Xantogranuloma Juvenil , Xantomatose , Adulto , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Granuloma , Xantogranuloma Juvenil/genética , Proteínas de Fusão Oncogênica/genética
15.
Indian J Pathol Microbiol ; 66(3): 655-658, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37530364

RESUMO

Crystal storing histiocytosis is a disorder characterized by local or diffuse infiltration of histiocytes containing crystalline inclusions. This entity has been reported in several organs, however the involvement of the central nervous system (CNS) is extremely rare and to date only 7 cases of crystal storing histiocytosis (CSH) of CNS have been reported in the English literature. More than 90% patients with CSH had an underlying lymphoproliferative or plasma cell disorders, especially multiple myeloma, lymphoplasmacytic lymphoma or monoclonal gammopathy. Radiologically and intraoperatively, CSH may mimic an infectious process or neoplasm, hence its histopathological confirmation is important to facilitate appropriate treatment. In this report, we describe an additional case of crystal storing histiocytosis in a 48 year old female who presented with a mass lesion in the right temporal lobe of the cerebrum.


Assuntos
Histiocitose , Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Paraproteinemias , Feminino , Humanos , Pessoa de Meia-Idade , Histiocitose/diagnóstico , Histiocitose/patologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia
16.
Front Immunol ; 14: 1061182, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37638031

RESUMO

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.


Assuntos
Contratura , Perda Auditiva Neurossensorial , Histiocitose , Feminino , Humanos , Adulto , Pré-Escolar , Histiocitose/diagnóstico , Histiocitose/tratamento farmacológico , Histiocitose/genética , Febre , Proteínas de Transporte de Nucleosídeos/genética
17.
J Exp Med ; 220(9)2023 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-37462944

RESUMO

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.


Assuntos
Histiocitose , Receptor 7 Toll-Like , Animais , Camundongos , Citocinas/genética , Histiocitose/genética , Mutação/genética , Nucleosídeos , Receptor 7 Toll-Like/genética , Receptor 8 Toll-Like/genética
19.
Med Mol Morphol ; 56(4): 297-302, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37400727

RESUMO

Crystal-storing histiocytosis (CSH) is a rare disorder that shows infiltration of histiocytes with an aberrant cytoplasmic accumulation of crystalline structures and is often accompanied by lymphoproliferative-plasma cell disorders (LP-PCD) as background diseases. The diagnosis of CSH requires identification of crystalline structures that accumulate in the infiltrating histiocytes, which may be challenging by optical microscopy alone. In this case report, we describe an atypical course of systemic CSH with multifocal fibrosclerosis of an unknown background disease that was diagnosed by ultrastructural observation, including transmission electron microscopy (TEM) and scanning electron microscopy (SEM), in pathological autopsy. In addition, crystalline structures were successfully identified by scanning electron microscopic observations using formalin-fixed and paraffin-embedded (FFPE) tissue from biopsy specimens taken before death. Since CSH was identified by SEM in a tiny biopsy specimen, observation of histiocytic infiltrative lesions by SEM using FFPE tissue may lead to early detection of and initiation of treatment for CSH.


Assuntos
Histiocitose , Humanos , Microscopia Eletrônica de Varredura , Inclusão em Parafina , Histiócitos/metabolismo , Histiocitose/diagnóstico , Histiocitose/complicações , Histiocitose/metabolismo , Formaldeído/metabolismo
20.
Zhonghua Jie He He Hu Xi Za Zhi ; 46(6): 595-598, 2023 Jun 12.
Artigo em Chinês | MEDLINE | ID: mdl-37278175

RESUMO

A 45-year-old female patient was found to have a nodule in the right lower lobe on physical examination. Chest CT showed the nodule was lobulated measuring 24 mm×23 mm, with obvious enhancement and adjacent pleural traction. As the PET-CT showed increased 18F-FDG uptake suggesting malignancy, the wedge resection of the right lower lobe was performed. Grossly, the mass was adjacent to the pleural area with indistinct boundary. On cut sections, the lesion was solid and tough, with a greyish-pink colour. Microscopically, the lesion had an ill-defined margin, and was composed of spindle and polygonoid histiocytes with rich eosinophilic cytoplasm similar to rhabdoid muscle cells. The cytoplasm of histiocytes was filled with diamond-shaped or club-shaped crystals. Immunohistochemistry (IHC) showed the histiocytes were positive for CD68, κ, λ, IgG, IgM and IgA. The patient had been followed up for 41 months and had shown neither recurrences nor new diseases. CSH is a rare non-neoplastic histiocytic proliferative disease. Pulmonary CSH should be differentiated from multiple diseases. Accurate pathological diagnosis depends on its morphology and immunophenotype. This disease is often related to potential lymphoproliferative or plasma cell disorder. After diagnosis, a systemic examination is required and long-term follow-up is recommended.


Assuntos
Histiocitose , Feminino , Humanos , Pessoa de Meia-Idade , Histiocitose/diagnóstico , Histiocitose/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Pulmão/patologia , Histiócitos/patologia
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