Novel ANKRD26 and PDGFRB gene mutations in pediatric case of non-Langerhans cell histiocytosis: Case report and literature review.

Cutaneous non-Langerhans cell histiocytosis (NLCH) is a rare and biologically benign entity that can be broadly classified into two categories: xanthogranuloma and non-xanthogranuloma. The xanthogranuloma family is characterized by a proliferation of histiocytes with both macrophage and dendritic cell differentiation, negative BRAF mutation, and rare Touton-type giant cells. Molecular studies have reported that mutations involved in the MAPK signaling pathways are implicated in the pathophysiology of histiocytoses. While LCH is associated with the somatic mutation of BRAF v600e, however, mutations and gene fusions in NLCH cases are undefined. We hereby present a 19-month-old female with recalcitrant nodular rashes diagnosed as NLCH with associated novel genetic mutation involving ANKRD26 and PDGFRB genes, as well as PDGFRB::CD74 fusion mRNA. Immunohistochemical staining showed strong and diffuse CD68 and CD163 positivity, and negative CD1a, CD207, ALK D5F3, S100 protein, and BRAF V600E (VE1). Albeit unknown significance, this case of an ANKRD26 and PDGFRB gene mutation in cutaneous NLCH has not been reported prior in the literature. Our case highlights the advantage of pathology and genetic studies in cutaneous NLCH to increase the understanding of this heterogeneous enigmatic disorder and identify further options in management.

A Rare Case of Pediatric Xanthoma Disseminatum With Diabetes Insipidus and BRAF p.V600E Mutation.

ABSTRACT: Xanthoma disseminatum (XD) is a rare non-Langerhans cell histiocytosis characterized by xanthomatous lesions in the absence of hyperlipidemia. XD usually develops in young adults, and there are rare cases among children. BRAF mutations are frequent in Langerhans cell histiocytosis and Erdheim-Chester disease but absent or only rarely detected in other histiocytosis. Herein, we described a 6-year-old Chinese girl presented with generalized skin lesions and diabetes insipidus for 5 months. There were multiple periorbital xanthelasma with histopathological features of foamy histiocytes infiltration with Touton cells. Pituitary magnetic resonance imaging showed pituitary enlargement and pituitary stalk thickening. The presence of BRAF p.V600E mutation makes this case distinctive and also offers a potential therapeutic target. According to our review of the literature, this is the first pediatric XD with diabetes insipidus and BRAF mutation.

Reticulohistiocytoses: a revision of the full spectrum.

Reticulohistiocytoses (RH) are rare and clinically heterogeneous histiocytic disorders of dermatological interest. Three clinical entities with superimposable histopathological features are currently considered, namely solitary reticulohistiocytoma, diffuse/generalized reticulohistiocytosis and multicentric reticulohistiocytosis. Although in the last decade, RH studies have only minimally progressed, histiocytosis research has advanced considerably: the prognostic and therapeutic importance of the clinical subclassification of histiocytosis patients as well as of the detection of genetic alterations in the genes of the ERK pathway has been highlighted. According to these insights, we previously reported the presence of molecular alteration RH and described a subset of patients with disseminated multisystem involvement lacking arthritis. In the present review, we aim to update and revise the knowledge regarding RH. We first reviewed their histopathological, immunophenotypical and ultrastructural features, discussed their histopathological differential diagnosis with other conditions characterized by infiltrates made of oncocytic or epithelioid cells (with special regard to Destombes-Rosai-Dorfman disease) and finally summarized the molecular landscape of RH. We therefore tried to adjust the clinical subclassification of Langerhans cell histiocytosis to the clinical phenotypes of RH, outlining five clinically different groups of patients. Finally, we reconsidered the clinical workflow to the evaluation of RH patients, in light of the 5 different clinical groups and discussed the different therapeutic approaches and the possible role of target inhibitors.

Two siblings with PRKDC defect who presented with cutaneous granulomas and review of the literature.

V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.

Indeterminate Dendritic Cell Tumor: A Report of Two New Cases Lacking the ETV3-NCOA2 Translocation and a Literature Review.

Indeterminate dendritic cell tumor (IDCT) is a cutaneous proliferation of histiocytes that share morphologic and immunophenotypic properties with Langerhans cells. IDCT was recently included in the updated WHO classification of tumors of hematopoietic and lymphoid tissues. Recent studies have shown that some cases of IDCT demonstrate an ETV3-NCOA2 translocation, supporting the idea that IDCT is a clonal neoplasm. We report 2 new cases of IDCT at our institution lacking the ETV3-NCOA2 translocation. We also present a comprehensive review of reported cases of IDCT in the medical literature. Eighty-five cases of IDCT were reported in the literature between 1985 and 2016. The median age at diagnosis was 45 years. In contrast to Langerhans cell histiocytosis, IDCT is limited to the skin in the majority of cases (88%) and generally follows an indolent clinical course. Most reported lesions are cured with complete excision. However, the histologic features of IDCT and langerhans cell histiocytosis are similar. Conjoint immunostaining for CD1a and langerin is necessary for optimal classification.

Generalized eruptive histiocytosis associated with a novel fusion in LMNA-NTRK1.

Non-Langerhans cell histiocytosis (NLCH) is a histiocyte disorder comprised of dermal dendritic histiocytes with a characteristic staining pattern. Erdheim-Chester disease (ECD) is a subset of NLCH in which patients experience bone pain with corresponding changes on imaging. In addition, these patients show other evidence of systemic involvement, which can also be identified with imaging. This disease can occasionally present with cutaneous findings. We present a case of generalized eruptive histiocytosis (GEH), misdiagnosed as ECD, found to have an NTRK1 gene rearrangement. This is the first report of an NTRK1 kinase fusion with NLCH. The implication is unclear and further studies are warranted.

High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.

Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAF mutations have been observed in Langerhans cell histiocytosis (LCH). We investigated the frequency of BRAF mutations in several types of histiocytoses. Histology from 127 patients with histiocytoses were reviewed. Detection of BRAF(V600) mutations was performed by pyrosequencing of DNA extracted from paraffin embedded samples. Diagnoses of Erdheim-Chester disease (ECD), LCH, Rosai-Dorfman disease, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma were performed in 46, 39, 23, 12, 3, 2, 1, and 1 patients, respectively. BRAF status was obtained in 93 cases. BRAF(V600E) mutations were detected in 13 of 24 (54%) ECD, 11 of 29 (38%) LCH, and none of the other histiocytoses. Four patients with ECD died of disease. The high frequency of BRAF(V600E) in LCH and ECD suggests a common origin of these diseases. Treatment with vemurafenib should be investigated in patients with malignant BRAF(V600E) histiocytosis.

Progressive nodular histiocytosis with normal karyotypic analysis.

Non-Langerhans cell histiocytoses (NLH) comprise a spectrum of diseases that includes sinus histiocytosis with massive lymphadenopathy, hemophagocytic lymphohistiocytosis, xanthogranuloma, and reticulohistiocytoma. Progressive nodular histiocytosis (PNH) is a rare NLH that microscopically mimics juvenile xanthogranuloma but presents with disseminated persistent and progressive papulonodules in adults. Herein, we describe a case of PNH presenting as diffuse, progressively enlarging papules, nodules, and pedunculated tumors in a 38-year-old male. The diagnosis is supported microscopically by the morphologic and immunohistochemical findings. Whereas conventional cytogenetic analysis of Langerhans cell histiocytosis and juvenile xanthogranuloma has previously been described, there are no reports of the karyotype of PNH. In our patient, conventional cytogenetic analysis of the tumor revealed a normal karyotype. Although these results may represent the overgrowth of normal stromal cells rather than lesional cells, we believe this to be an important finding, indicating karyotypic analysis will not allow for distinction between PCH and other NLH or Langerhans cell histiocytoses.

Multicentric reticulohistiocytosis and urologic carcinomas: a possible paraneoplastic association.

Multicentric reticulohistiocytosis (MR) is a rare non-Langerhans histiocytosis that is characterized by cutaneous nodules and severe destructive arthritis. Although 25-30% of reported cases have been associated with internal malignancies, the pathophysiology of MR is unknown. Herein, we report two cases of MR that were associated with urologic neoplasms. Because the tumor suppressor gene p53 may play a role in the biology of other histiocytoses, we investigated its p53 immunoexpression in these two cases. Both cases were positive immunohistochemically, but it remains to be seen whether this finding is truly important in the pathogenesis of MR associated with underlying visceral neoplasms.

The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene.

About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated ( approximately 45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure-function relationships for lymphocyte perforin.

Hereditary progressive mucinous histiocytosis: first report in a male patient.

Progressive mucinous histiocytosis is a very rare, benign, non-Langerhans' cell histiocytosis limited to the skin. In total ten patients (all women) in four families and three sporadic cases have been reported. We report here the first published case of a male patient with progressive mucinous histiocytosis. The multiple red papules on the scalp and forearms were asymptomatic and had slowly increased over approximately the past 20 years. The patient's mother had similar lesions. Histological examination revealed nodules in the dermis with histiocytes and mucin deposition. The histiocytes stained positively with CD31 and negative with CD34, CAM 5.2, PGM-1 and factor XIIIa. Ultrastructurally, the histiocytes showed numerous circular myelin bodies and zebra bodies reminiscent of those seen in lysosomal storage diseases. The genetic transmission of hereditary progressive mucinous histiocytosis remains unclear; we assume an autosomal dominant transmission with some hormonal factor that makes hereditary progressive mucinous histiocytosis more likely in women.

Uncommon cutaneous non-Langerhans cell histiocytosis arising from dermal dendritic cells in adults: a clinicopathological study of five cases.

BACKGROUND: Non-Langerhans cell histiocytosis (non-LCH) is a collective term that encompasses a long list of rare "histiocytosis" that do not meet the criteria for Langerhans cell histiocytosis (LCH). Among cutaneous non-LCH, the xanthogranuloma (XG) family represents a distinct group of disorders derived from dermal dendritic cells (DDCs) at different stages of differentiation. OBJECTIVES: To investigate the clinicopathological characteristics of the XG family in adults and review the relevant literature. MATERIALS AND METHODS: We performed a retrospective clinicopathological study of five adult cases with a previous diagnosis of non-LCH. Clinicopathological features, immunophenotypes, genetic alterations and ultrastructural characteristics were analysed. RESULTS: Skin biopsies revealed that all five cases were characterized by diffuse infiltration of polymorphic cells, which were immunoreactive to factor XIIIa but negative for Langerin, CD1a, and S100. None of the cases harboured the BRAF V600E mutation. Electron microscopy of two cases exhibited abundant cytoplasmic processes with numerous lysosome-like dense bodies and electron-lucent vesicles in the cytoplasm and extracellular matrix. The overall features suggested that DDCs are the cellular origin, and these cases fulfilled the criteria for the XG family. CONCLUSION: The XG family represents a spectrum of rare diseases with different clinical presentations, a wide range of morphological appearances, and a shared common origin (DDCs). This group of disorders has been proposed as a unique entity with diagnostic challenges that should not be underestimated.

Perforin gene defects in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22, 10q21-22, or another as yet undefined locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22-linked FHL. Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation.

Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome.

Griscelli syndrome (GS) patients and the corresponding mouse model ashen exhibit defects mainly in two types of lysosome-related organelles, melanosomes in melanocytes and lytic granules in CTLs. This disease is caused by loss-of-function mutations in RAB27A, which encodes 1 of the 60 known Rab GTPases, critical regulators of vesicular transport. Here we present evidence that Rab27a function can be compensated by a closely related protein, Rab27b. Rab27b is expressed in platelets and other tissues but not in melanocytes or CTLs. Morphological and functional tests in platelets derived from ashen mice are all within normal limits. Both Rab27a and Rab27b are found associated with the limiting membrane of platelet-dense granules and to a lesser degree with alpha-granules. Ubiquitous transgenic expression of Rab27a or Rab27b rescues ashen coat color, and melanocytes derived from transgenic mice exhibit widespread peripheral distribution of melanosomes instead of the perinuclear clumping observed in ashen melanocytes. Finally, transient expression in ashen melanocytes of Rab27a or Rab27b, but not other Rab's, restores peripheral distribution of melanosomes. Our data suggest that Rab27b is functionally redundant with Rab27a and that the pathogenesis of GS is determined by the relative expression of Rab27a and Rab27b in specialized cell types.

Macrophage activation syndrome in juvenile idiopathic arthritis.

UNLABELLED: Macrophage activation syndrome (MAS) is a rare and potentially lethal complication of chronic rheumatic diseases of childhood, in particular of systemic-onset juvenile idiopathic arthritis (s-JIA), resulting from uncontrolled activation and proliferation of T lymphocytes and macrophages. The onset, acute and dramatic, may mimic a flare of the underlying disease or a severe sepsis. Diagnosis is difficult and, until now, no specific criteria have been developed. Laboratory data show pancytopenia, coagulopathy, low ESR and low concentrations of serum albumin, and high levels of ferritin, liver enzymes and triglycerides. Activated macrophages are found in various organs, particularly in bone marrow. Most hypotheses on the mechanism underlying MAS are based on the data obtained in primary haemophagocytic lymphohistiocytosis (HLH), a genetic disease very similar to MAS. Prompt diagnosis is essential because prognosis is highly related to early treatment. The first approach was to use intravenous methylprednisolone pulse therapy; cyclosporin A was proposed in patients resistant to steroids. We describe nine patients affected by haemophagocytosis: seven patients developed MAS and two patients developed HLH. A child with s-JIA developed three episodes of MAS. After the third episode, as there was no improvement with pulses of methylprednisolone and cyclosporine, he was successfully given etanercept. CONCLUSION: Our data, together with a similar, published observation, suggest that the TNF inhibitor etanercept is potentially useful for obtaining remission in children not responding to steroids and cyclosporin A.

[Hemophagocytic syndrome: diagnostic problems]. / Zespól hemofagocytarny: trudnosci diagnostyczne.

Hemophagocytic syndrome (HS) is a rare but life-threatening disease caused by inappropriate activation of T-lymphocytes and histiocytes, hipercytokinemia and hemophagocytosis. The most common symptoms are fever, hepatosplenomegaly, unspecific neurological abnormalities, pancytopenia, coagulopathy, hiperferritinemia and lipid abnormalities. HS is classified into two forms: primary, inherited (Familial Hamophagocytic Lymphohistiocytosis--FHL) and secondary (associated with infection, malignancy, autoimmune disease). In spite of the fact that diagnostic guidelines are available it often remains unrecognised. Prognosis of HS depends on the form of disease and in case of secondary HS on the underlying disease. Development of the treatment protocols (HLH-94, HLH-2004) which combine immunochemiotherapy with hematopoietic stem cell transplantation has strongly improved prognosis in HS especially in the primary form. Three-year overall survival for children with HS is now over 50%. Early diagnosis and appropriate therapy is crucial for effectiveness of the treatment. Popularisation of the knowledge about the syndrome, diagnostic guidelines and treatment protocols can contribute to more frequent appropriate recognition of HS and to improvement of the treatment results.

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms.

UNLABELLED: Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. SIGNIFICANCE: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.

Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever and hepatosplenomegaly associated with pancytopenia, hypertriglyceridemia and hypofibrinogenemia. Increased levels of cytokines and impaired natural killer activity are biological markers of HLH. HLH can be classified into two distinct forms, including primary HLH, also referred to as familial hemophagocytic lymphohistiocytosis (FHL), and secondary HLH. Although FHL is an autosomal recessive disorder typically occurring in infancy, it is important to clarify that the disease may also occur in older patients. It is now considered that FHL is a disorder of T-cell function; moreover, clonal proliferation of T lymphocytes is observed in a few FHL patients, and cytotoxicity of these T lymphocytes for target cells is usually impaired. In 1999, perforin gene (PRF1) mutation was identified as a cause of 20-30% of FHL (FHL2) cases. In Japan, two specific mutations of PRF1 were also detected. Furthermore, in 2003, MUNC13-4 mutations were identified in some non-FHL2 patients (FHL3). Identification of other genes responsible for remaining cases is a major concern. Hematopoietic stem cell transplantation (HSCT) has been established as the only accepted curative therapy for FHL. Thus, appropriate diagnosis and prompt treatment with HSCT are necessary for FHL patients. Genetic analysis for PRF1 and MUNC13-4 and functional assay of cytotoxic T lymphocytes are recommended to be performed in each patient. In those patients displaying impaired cytotoxic function but lacking genetic defects, samples should be employed for identification of unknown genes. In the near future, an entire pathogenesis should be clarified in order to establish appropriate therapies including immunotherapy, HSCT and gene therapy.