La sindrome di Chediak-Higashi a esordio tardivo

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the CHS1/LYST gene, encoding for LYST protein, involved in lysosomal trafficking. It is characterized by recurrent bacterial infections, oculocutaneous albinism, silver hair, haematological and neurological alterations and a possible evolution towards the socalled accelerated phase (haemophagocytic lymphohistiocytosis). It is classified in a classic form, with infantile onset, lethal if bone marrow transplantation is not promptly performed, and in an atypical form, with adolescent/adult onset, for which a more conservative approach may be possible. The paper describes a case of hypertrophic-hyperplastic gingivopathy associated with leuko-neutropenia. The evaluation of the bone marrow smear raised the suspicion of CHS and the analysis of the clinical history highlighted the presence of suggestive criteria for atypical CHS. The genetic investigation confirmed the diagnosis.

Download Full-text

Novel HeterogenousCHS1Mutations Identified in Five Japanese Patients with Chediak-Higashi Syndrome

Case Reports in Medicine ◽

10.1155/2010/464671 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5 ◽

Cited By ~ 6

Author(s):

Fuminori Tanabe ◽

Hirotake Kasai ◽

Michiko Morimoto ◽

Shigeharu Oh ◽

Hidetoshi Takada ◽

...

Keyword(s):

Bacterial Infections ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Japanese Patients ◽

Visual Disturbance ◽

Oculocutaneous Albinism ◽

Neurological Dysfunction ◽

Nonsense Mutations ◽

Chediak Higashi Syndrome ◽

Exon 10

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by oculocutaneous albinism, recurrent bacterial infections and progressive neurological dysfunction. We demonstrate novel heterogenous mutations ofCHS1, the responsive gene of CHS, identified in five Japanese patients with CHS. Patients 1, 2, and 3 were siblings, and they had albinism of the skin and hair. They all had a heterogenous two-base deletion (c.5541-5542 del AA, p.Q1847fsX1850) in exon 18. Patient 4 had a heterogenous single-base insertion (c.3944-3945 ins C, p.T1315fsX1331) in exon 10. The patient exhibited severe early-onset phenotype and suffered from hemophagocytic lymphohistiocytosis. Patient 5 had two heterogenous nonsense mutations; c.7982C>G, p.S2661X in exon 30 and c.8281A>T, p.R2761X in exon 31. The patient suffered from infections in childhood and had visual disturbance and albinism of the skin and hair. TheCHS1mutations described here have not been reported previously.

Download Full-text

Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia

Blood ◽

10.1182/blood-2006-01-010249 ◽

2006 ◽

Vol 108 (7) ◽

pp. 2182-2189 ◽

Cited By ~ 153

Author(s):

Phil J. Ancliff ◽

Michael P. Blundell ◽

Giles O. Cory ◽

Yolanda Calle ◽

Austen Worth ◽

...

Keyword(s):

Bone Marrow ◽

Bacterial Infections ◽

Killer Cell ◽

Significant Proportion ◽

Congenital Neutropenia ◽

Gene Encoding ◽

Wiskott Aldrich Syndrome ◽

Immunologic Function ◽

Syndrome Protein

Abstract Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent bacterial infections, and maturation arrest in the bone marrow. Although many cases have mutations in the ELA2 gene encoding neutrophil elastase, a significant proportion remain undefined at a molecular level. A mutation (Leu270Pro) in the gene encoding the Wiskott-Aldrich syndrome protein (WASp) resulting in an X-linked SCN kindred has been reported. We therefore screened the WAS gene in 14 young SCN males with wild-type ELA2 and identified 2 with novel mutations, one who presented with myelodysplasia (Ile294Thr) and the other with classic SCN (Ser270Pro). Both patients had defects of immunologic function including a generalized reduction of lymphoid and natural killer cell numbers, reduced lymphocyte proliferation, and abrogated phagocyte activity. In vitro culture of bone marrow progenitors demonstrated a profound reduction in neutrophil production and increased levels of apoptosis, consistent with an intrinsic disturbance of normal myeloid differentiation as the cause of the neutropenia. Both mutations resulted in increased WASp activity and produced marked abnormalities of cytoskeletal structure and dynamics. Furthermore, these results also suggest a novel cause of myelodysplasia and that male children with myelodysplasia and disturbance of immunologic function should be screened for such mutations.

Download Full-text

Periodontitis in Chédiak-Higashi Syndrome: An Altered Immunoinflammatory Response

JDR Clinical & Translational Research ◽

10.1177/2380084417724117 ◽

2017 ◽

Vol 3 (1) ◽

pp. 35-46 ◽

Cited By ~ 4

Author(s):

V. Thumbigere Math ◽

P. Rebouças ◽

P.A. Giovani ◽

R.M. Puppin-Rontani ◽

R. Casarin ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Marrow Transplantation ◽

Critical Role ◽

Autosomal Recessive Disorder ◽

Aggressive Periodontitis ◽

Cytokine Expression ◽

Gingival Fibroblasts ◽

Chediak Higashi Syndrome ◽

Periodontal Phenotype

Chédiak-Higashi syndrome (CHS), a rare autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator gene (LYST), is associated with aggressive periodontitis. It is suggested that LYST mutations affect the toll-like receptor (TLR)–mediated immunoinflammatory response, leading to frequent infections. This study sought to determine the periodontal status of patients with classic (severe) and atypical (milder) forms of CHS and the immunoregulatory functions of gingival fibroblasts in CHS patients. In contrast to aged-matched healthy controls, atypical (n = 4) and classic (n = 3) CHS patients presented with mild chronic periodontitis with no evidence of gingival ulceration, severe tooth mobility, or premature exfoliation of teeth. As a standard of care, all classic CHS patients had undergone bone marrow transplantation (BMT). Primary gingival fibroblasts obtained from atypical and BMT classic CHS patients displayed higher protein expression of TLR-2 (1.81-fold and 1.56-fold, respectively) and decreased expression of TLR-4 (−2.5-fold and −3.85-fold, respectively) at baseline when compared with healthy control gingival fibroblasts. When challenged with whole bacterial extract of Fusobacterium nucleatum, both atypical and classic CHS gingival fibroblasts failed to up-regulate TLR-2 and TLR-4 expression when compared with their respective untreated groups and control cells. Cytokine multiplex analysis following F. nucleatum challenge showed that atypical CHS gingival fibroblasts featured significantly increased cytokine expression (interleukin [IL]–2, IL-4, IL-5, IL-6, IL-10, IL-12, interferon-γ, tumor necrosis factor–α), whereas classic CHS cells featured similar/decreased cytokine expression when compared with treated control cells. Collectively, these results suggest that LYST mutations in CHS patients affect TLR-2 and TLR-4 expression/function, leading to dysregulated immunoinflammatory response, which in turn may influence the periodontal phenotype noted in CHS patients. Furthermore, our results suggest that atypical CHS patients and classic CHS patients who undergo BMT early in life are less susceptible to aggressive periodontitis and that hematopoietic cells play a critical role in mitigating the risk of aggressive periodontitis in CHS. Knowledge Transfer Statement: Results from this study can be used to create awareness among clinicians and researchers that not all CHS patients exhibit historically reported aggressive periodontitis, especially if they have atypical CHS disease or have received bone marrow transplantation. LYST mutations in CHS patients may affect TLR-2 and TLR-4 expression/function leading to dysregulated immunoinflammatory response, which in turn may influence the periodontal phenotype noted in CHS patients.

Download Full-text

Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation

Human Molecular Genetics ◽

10.1093/hmg/ddab040 ◽

2021 ◽

Author(s):

Eleonora Panfili ◽

Giada Mondanelli ◽

Ciriana Orabona ◽

Maria L Belladonna ◽

Marco Gargaro ◽

...

Keyword(s):

Er Stress ◽

Mononuclear Cells ◽

Autosomal Recessive Disorder ◽

Wolfram Syndrome ◽

Therapeutic Interventions ◽

T Helper 17 ◽

Gene Encoding ◽

Peripheral Blood Mononuclear ◽

Inflammatory State ◽

Wfs1 Gene

Abstract Mutations in the WFS1 gene, encoding wolframin (WFS1), cause endoplasmic reticulum (ER) stress and are associated with a rare autosomal-recessive disorder known as Wolfram syndrome (WS). WS is clinically characterized by childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus and neurological signs. We identified two novel WFS1 mutations in a patient with WS, namely, c.316-1G > A (in intron 3) and c.757A > T (in exon 7). Both mutations, located in the N-terminal region of the protein, were predicted to generate a truncated and inactive form of WFS1. We found that although the WFS1 protein was not expressed in peripheral blood mononuclear cells (PBMCs) of the proband, no constitutive ER stress activation could be detected in those cells. In contrast, WS proband’s PBMCs produced very high levels of proinflammatory cytokines (i.e. TNF-α, IL-1β, and IL-6) in the absence of any stimulus. WFS1 silencing in PBMCs from control subjects by means of small RNA interference also induced a pronounced proinflammatory cytokine profile. The same cytokines were also significantly higher in sera from the WS patient as compared to matched healthy controls. Moreover, the chronic inflammatory state was associated with a dominance of proinflammatory T helper 17 (Th17)-type cells over regulatory T (Treg) lymphocytes in the WS PBMCs. The identification of a state of systemic chronic inflammation associated with WFS1 deficiency may pave the way to innovative and personalized therapeutic interventions in WS.

Download Full-text

Bone marrow aspirate in Chédiak-Higashi syndrome

American Journal of Hematology ◽

10.1002/ajh.22123 ◽

2011 ◽

Vol 87 (1) ◽

pp. 100-100 ◽

Cited By ~ 4

Author(s):

Abbas Hashim Abdulsalam ◽

Nafila Sabeeh ◽

Barbara J. Bain

Keyword(s):

Bone Marrow ◽

Bone Marrow Aspirate ◽

Chediak Higashi Syndrome

Download Full-text

THE UTILITY OF BLOOD AND BONE MARROW FILMS AND TREPHINE BIOPSY SECTIONS IN THE DIAGNOSIS OF PARASITIC INFECTIONS

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2015.039 ◽

2015 ◽

Vol 7 ◽

pp. e2015039 ◽

Cited By ~ 2

Author(s):

Clare Miller ◽

Barbara Bain

Keyword(s):

Bone Marrow ◽

Iron Deficiency Anaemia ◽

Parasitic Infection ◽

Clinical History ◽

Bone Marrow Examination ◽

Accurate Diagnosis ◽

Parasitic Infections ◽

Trephine Biopsy ◽

Deficiency Anaemia ◽

Blood Examination

The laboratory haematologist has a role in the diagnosis of parasitic infections. Peripheral blood examination is critical in the diagnosis of malaria, babesiosis, filariasis and trypanosomiasis. Bone marrow examination is important in the diagnosis of leishmaniasis and occasionally leads to the diagnosis of other parasitic infections. The detection of eosinophilia or iron deficiency anaemia can alert the laboratory haematologist or physician to the possibility of parasitic infection. In addition to morphological skills, an adequate clinical history is important for speedy and accurate diagnosis, particularly in non-endemic areas.

Download Full-text

Chediak-Higashi syndrome: reversal of increased susceptibility to infection by bone marrow transplantation

Blood ◽

10.1182/blood.v47.4.555.bloodjournal474555 ◽

1976 ◽

Vol 47 (4) ◽

pp. 555-559

Author(s):

JA Kazmierowski ◽

RJ Elin ◽

HY Reynolds ◽

WA Durbin ◽

SM Wolff

Keyword(s):

Bone Marrow ◽

Candida Albicans ◽

Bone Marrow Transplantation ◽

Human Disease ◽

Marrow Transplantation ◽

Normal Bone Marrow ◽

Susceptibility To Infection ◽

Normal Bone ◽

Chediak Higashi Syndrome ◽

Increased Susceptibility

Transplantation of normal bone marrow to mice with the Chediak-Higashi syndrome (CHS) resulted in normal granulopoiesis and a reversal of their increased susceptibility to challenge with intravenous Candida albicans. These findings suggest that (1) the leukocyte defect in CHS can be reversed by marrow transplantation and (2) the mechanism for increased susceptibility to infection in these animals is due to a bone- marrow-derived cellular defect. Because of similarities between murine and human CHS, bone marrow transplantation might be considered as a mode of therapy in selected cases of the human disease.

Download Full-text

Correction of symptoms of platelet storage pool deficiency in animal models for Chediak-Higashi syndrome and Hermansky-Pudlak syndrome

Blood ◽

10.1182/blood.v66.5.1196.bloodjournal6651196 ◽

1985 ◽

Vol 66 (5) ◽

pp. 1196-1201

Author(s):

EK Novak ◽

MP McGarry ◽

RT Swank

Keyword(s):

Bone Marrow ◽

Animal Models ◽

Dense Granule ◽

Whole Body ◽

Inherited Disorders ◽

Humoral Factors ◽

Storage Pool ◽

Platelet Storage ◽

Hermansky Pudlak Syndrome ◽

Chediak Higashi Syndrome

Two human diseases of platelet storage pool deficiency (SPD), Hermansky- Pudlak syndrome and Chediak-Higashi syndrome, are recessively inherited disorders characterized by hypopigmentation, prolonged bleeding, and normal platelet counts accompanied by a reduction in dense granule number. We have recently described seven independent recessive mutations in the mouse regulated by separate genes which are likely animal models for human SPD. Reciprocal bone marrow transplants were carried out between normal C57BL/6J mice and two of these mutants, beige and pallid, in order to test whether the platelet defects are due to a defect in platelet progenitor cells or to humoral factors. Normal and congenic mutant mice were transplanted with marrow after 950 rad whole body radiation. The long bleeding times and low serotonin concentrations of the two mutants were converted to normal values after transplantation with normal marrow. Likewise, normal mice displayed symptoms of SPD when transplanted with mutant marrow. These studies demonstrate that with each of the two mutations, platelet SPD results from a defect in bone marrow precursor cells. Also, the studies suggest that in severe cases, platelet SPD may be successfully treated by bone marrow transplantation.

Download Full-text

The Evolution in The Treatment of Multiple Myeloma Towards Targeted Magnetic Molecularly Imprinted Nanomedicines

Edelweiss: Cancer Open Access ◽

10.33805/2689-6737.101 ◽

2015 ◽

pp. 1-2

Author(s):

Edgar Pérez-Herrero

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bacterial Infections ◽

Plasma Cells ◽

The Body ◽

Western World ◽

Bone Lesions ◽

Non Hodgkin Lymphoma ◽

Clonal Proliferation ◽

Tract Infections

Multiple myeloma is the second more frequently haematological cancer in the western world, after non-Hodgkin lymphoma, being about the 1-2 % of all the cancers cases and the 10-13% of hematologic diseases. The disease is caused by an uncontrolled clonal proliferation of plasma cells in the bone marrow that accumulate in different parts of the body, usually in the bone marrow, around some bones, and rarely in other tissues, forming tumor deposits, called plasmocytomas. This uncontrolled clonal proliferation of plasma cells produces the secretion of an abnormal monoclonal immunoglobulin (paraprotein or M-protein) and prevents the formation of the other antibodies produced by the normal plasma cells that are destroyed. The anormal secretion of paraproteins unbalance the osteoblastosis and osteoclastosis processes, leading to bone lesions that cause lytic bone deposits and the release of calcium from bones (hypercalcemia) that may produce renal failure. Regions affected by bone lesions are the skull, spine, ribs, sternum, pelvis and bones that form part of the shoulders and hips. The substitution of the healthy bone marrow by infiltrating malignant cells and the inhibition of the normal production of red blood cells produce anaemia, thrombocytopenia and leukopenia. Multiple myeloma patients are immunosuppressed because of leukopenia and the abnormal immunoglobulin production caused by the uncontrolled clonal proliferation of plasma cells, being susceptible to bacterial infections, like pneumonias and urinary tract infections. The interaction of immunoglobulin with hemostatic mechanisms may lead to haemorrhagic diathesis or thrombosis. Also, disorders of the central and peripheral nervous system are part of the disease, being the more common neurological manifestations the spinal cord compressions and the peripheral neuropathies.

Download Full-text

Chediak-Higashi Syndrome in Accelerated Phase, a Case Report

10.53902/sojmccr.2021.01.000502 ◽

2021 ◽

Vol 1 (1) ◽

Author(s):

Artriz R

Keyword(s):

Hemophagocytic Syndrome ◽

Respiratory Infections ◽

Autosomal Recessive Inheritance ◽

Oculocutaneous Albinism ◽

Clinical Findings ◽

Genetic Abnormalities ◽

History Of ◽

Chediak Higashi Syndrome ◽

Lysosomal Transport ◽

Pro Inflammatory Cytokines

Chediak-Higashi syndrome corresponds to a series of genetic abnormalities in lysosomal transport, of autosomal recessive inheritance, characterized by partial oculocutaneous albinism and recurrent infections,1 usually between 7 and 10 years of age the accelerated phase of the disease, where developing hemophagocytic syndrome, given by a set of clinical findings, laboratory and histological studies where phagocytosis is prominent,2 with a failure in the regulation of the immune system due to an excessive production of pro-inflammatory cytokines that coexists with a dysfunction of natural killer cells and T lymphocytes, which leads to lethal development. We present a case of a 13-month-old patient, natural and from Pregonero, with a family history of consanguinity, recurrent respiratory infections, and a characteristic phenotype of Chediak-Higashi syndrome, without prior diagnosis or controls for this pathology, who presents with hemophagocytic syndrome leading to its death in 20 days.

Download Full-text