Accumulation Of Histiocytes Research Articles

Morphological features of pilonidal cysts of the sacrococcygeal region.

Despite the fact that the pilonidal cyst of the sacrococcygeal region is a long-known disease, the mechanism of accumulation or absence of hair in the cyst remains unclear, which affects the accuracy of the name of the disease, as well as understanding of its pathogenesis. Aim to perform morphological examination of pilonidal cysts of the sacrococcygeal region, to determine the nature of the cysts, the frequency of hair in the cyst cavity and to determine the causes and mechanism of its accumulation in cysts. A morphological study of skin areas with altered tissues of the sacrococcygeal region after radical surgical treatment of 235 patients with a coccygeal cyst of the sacrococcygeal region was carried out. The gender distribution of patients with pilonidal cysts was as follows: 220 (93.4%) male patients, 15 female patients (6.6%). Among 235 patients who underwent radical surgical treatment, the absence of hair shafts was recorded in 112 (46.8%) cases, hair in the cyst structure - in 123 male patients (53.2%), both visually and under a microscope, and in 4 of them (0.9%) only under a microscope. Among 15 patients, hair in the cyst cavity was found in 1 case (0.4%), in 14 patients they were not detected either visually or by microscopic examination. Having observed the formation of foreign body granuloma and the accumulation of polynuclear histiocytes of foreign bodies around the hair in the pilonidal cyst cavity, a proportional increase in histiocytes depending on the number of hairs, that is, the body's reaction to the foreign body was registered. However, multinucleated histiocytes in lower numbers were also observed in cases in which hair shafts were not found either microscopically or macroscopically, which may indicate both completed phagocytosis and formation of a cyst without a hair component, registering the reaction of histiocytes to inflammatory changes in the cyst cavity. The detection of atypically located pilonidal cysts (cheek, navel) provides additional confirmation of the formation of pilonidal cyst as a result of disturbance of hair growth through the hair funnel due to inflammatory changes in the hair follicle and their accumulation subcutaneously.

Langerhans Cell Histiocytosis in Paediatric Zygoma Swelling.

Langerhans cell histiocytosis (LCH) is a rare neoplasm characterized by accumulation of histiocytes in various tissues. It has a wide clinical spectrum and its presentation may mimic clinical features of common diseases. High level of suspicion is required for early diagnosis. Here is a rare case of a rapidly aggressive LCH which first presented with right zygomatic swelling.

Images in Breast Oncology: Extra-Nodal Rosai–Dorfman Disease Mimicking Metastatic Breast Malignancy on PET CT

Rosai–Dorfman disease is a rare disorder wherein there is excessive production and accumulation of histiocytes in the lymph nodes. This excessive deposition may occur in other areas like the skin, central nervous system, kidney, and digestive tract. Also referred to as extra-nodal RDD, these may mimic other diseases in these organs. A postmenopausal lady was referred to us for breast biopsy from another centre. PET CT images taken already were concerning for metastatic breast malignancy. Rosai–Dorfman disease was diagnosed on histopathology based on samples taken from the right breast mass. This case highlighted the rare occurrence of Rosai–Dorfman disease affecting breast and mimicking a metastatic breast primary in the presence of loco-regional nodal disease and numerous lytic lesions in the bone.

High frequency of clonal hematopoiesis in Erdheim-Chester disease

AbstractErdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38− BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD.

A Case Report: Rosai Dorfman Disease

Rosai-Dorfman Disease (RDD) is a rare disorder which usually associated with enlargement various superficial or deep lymph nodes. Clinical course of this disease is prolonged with exacerbation and remission phases occasionally. Over-production and accumulation of a specific type of white blood cell called histiocyte occurred in the lymph nodes of the body, mostly on the the neck. Other lymph node groups and in some cases, extra nodal abnormal accumulation of histiocytes may occur in other areas of the body that is more common in the head and neck region. Here we discussed a patient with extra-nodal involvement who presented with bilateral orbital mass.

Lanthanum deposition in the gastric mucosa

Lanthanum carbonate is a phosphate binding agent used for the management of hyperphosphataemia in patients with chronic renal failure. Cases of lanthanum deposition within the gastrointestinal tract, first recognised in gastric mucosa, have been reported since 2015. However, lanthanum deposition remains a relatively novel entity with potential for under-recognition and confusion with a variety of other processes. This case study reports a case of lanthanum deposition involving the gastric mucosa in a renal transplant patient. Biopsies taken from the gastric antrum demonstrated appearances of reactive gastropathy together with an accumulation of histiocytes, including occasional multinucleated forms, containing deposits of amphophilic to brown finely granular to coarse material within the superficial lamina propria. The differential diagnosis included gastric mucosal calcinosis, iron therapy-induced gastric injury, an infectious aetiology, or the accumulation of exogenous materials related to medications including resins/crystalloids. Investigation of the patient’s medication history revealed oral lanthanum carbonate use; this finding taken in conjunction with the morphologic findings was most in keeping with lanthanum deposition. The identification of lanthanum deposition in gastric biopsies is important as the long-term consequences are currently unknown, and the use of this medication is increasing.

Non-infectious granulomatous dermatoses.

Granulomatous dermatoses comprise a wide range of etiologically and clinically distinct skin diseases that share a common histology characterized by the accumulation of histiocytes include macrophages. While the pathogenesis of these disorders is not fully understood, the underlying mechanism is thought to involve a reaction pattern caused by an immunogenic stimulus. Antigen-presenting cells and the effect of various cytokines play a key role. Our understanding of granulomatous reaction patterns has been advanced by insights drawn from observations of such reactions in patients on immunomodulatory therapy and in individuals with genetic immunodeficiency. Traditionally, a distinction is made between infectious and non-infectious granulomatous dermatoses. The present CME article addresses granulomatous skin diseases for which there is no evidence of a causative infectious agent. Common representatives include granuloma annulare, necrobiosis lipoidica and cutaneous sarcoidosis. Granulomatous dermatoses may be part of the clinical spectrum of various systemic disorders or may be associated therewith. Some neoplastic disorders may mimic granulomatous dermatoses histologically. Given the pathogenetic diversity involved, the clinical presentation, too, is quite varied. Overall, however, each disorder is characterized by typical clinical features. The diagnosis always requires thorough clinicopathologic correlation. Treatment is preferably based on the underlying pathogenesis and frequently involves anti-inflammatory agents. In most cases, however, there is insufficient study data. The dermal nature of these disorders frequently poses a therapeutic challenge, especially with respect to topical treatment.

A scale for patient-reported symptom assessment for patients with Erdheim-Chester disease

AbstractErdheim-Chester disease (ECD) is an ultra-rare hematologic neoplasm characterized by somatic mutations of the MAPK pathway and by accumulation of lesional histiocytes within tissues. Clinical phenotypes and sites of disease involvement are heterogenous in ECD, and no tool exists for systematic and comprehensive assessment of ECD symptomatology. We describe a collaborative effort among ECD specialists, patient-reported outcome (PRO) methodologists, and ECD patients to develop the Erdheim-Chester Disease Symptom Scale (ECD-SS): a symptom inventory for clinical ECD care and evaluation of ECD therapies. Methodologically rigorous focus groups led to the identification of 63 ECD symptoms in 6 categories, incorporated into the ECD-SS with respect to both severity and frequency. Among 50 ECD patients participating in a prospective registry study completing the ECD-SS, 46 (92%) reported neurological/psychological symptoms, 29 (58%) reported pain, and at least one-half reported mood symptoms, memory problems, or fatigue. Symptoms were highly frequent or almost constant regardless of their severity. The ECD-SS is a rigorously developed, patient-centered tool that demonstrates the wide and previously unappreciated burden of symptomatology experienced by ECD patients. Further studies will refine the symptom inventory and define its psychometric properties and role in clinical care and investigation in the context of ECD.

Atteintes ostéoarticulaires au cours des histiocytoses

Histiocytoses are heterogeneous diseases characterized by the accumulation of histiocytes in various organs. The detection of somatic molecular alterations in some of these led to a new classification, published in 2016. In this review, we describe bone involvement of L-group histiocytosis (Langerhans-cell histiocytosis (LCH) and Erdheim-Chester disease (ECD)), and Destombes-Rosai-Dorfman disease (RDD). The osseous lesions of LCH consist of unilateral or multifocal, hypermetabolic lesions on bone C-computed tomography (CT)-scan or 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), mainly affecting flat bones and vertebrae, and more rarely long bones, with a risk of fracture. ECD bone involvement is characterized by metaphyso-diaphyseal sclerotic, hypermetabolic lesions, present in more than 90 % of cases, and constituting an iconic feature of this disease. Limbs bone pain may be suggestive of ECD, and is sometimes the first sign of the disease. RDD is characterized by multifocal bone involvement of the limbs or spine, associated in typical forms with node involvement. Treatments options vary for these 3 types of histiocytoses, and range from abstention to chemotherapy in LCH, from immunomodulatory treatments to targeted therapies in ECD, and from abstention, corticosteroid therapy, immunosuppressive drugs, to chemotherapies in RDD.

PD-1/ PD-L1 Expression Is Associated with Tissue Inflammation and BRAF Status in Erdheim-Chester Disease

Rationale: In patients with Erdheim-Chester disease (ECD), accumulation of foamy histiocytes leads to multi-systemic disease with various organs involvement. The fact that BRAFV600E mutation is found in as much as 70% of ECD tissues, led to the reclassification of ECD as a myeloid neoplasm and has already greatly improved therapy for adults with histiocytoses. Despite these advances, there is still a need to further improve therapy for ECD patients as targeted therapies may cause morbidity and late treatment effects from such regimens and as patients almost systematically relapse when these therapies are stopped. In 2015, Galatica et al reported an increased expression of PD-L1 in 4/4 ECD cases tested all of which were BRAFV600E mutated. We thus decided to analyze a larger case series of patients as this could represent rationale for addition of immune check-point inhibitors in treatment of multisystemic and/or refractory histiocytoses.Patients and Methods: We included 36 ECD patients for which BRAF status was determined. Biopsy samples were re-read in all cases. The density of inflammatory cells (lymphocytes and plasma cells) other than histiocytes was evaluated as mild (+), moderate (++), or marked (+++). Immunostaining was performed to detect PD-L1 (QR1Clone) in histiocytes and PD-1 (NAT105 clone) in lymphocytes. PD-L1 was assessed as percentage of positive histiocytes. The positivity of PD-L1 was defined as ≥ 5%. PD-1 immunostaining was evaluated as mild (+), moderate (++), or marked (+++).Results: Overall, BRAFV600E was present in 19 patients (52.8%), MAP2K1 in 2 (5.5%) and NRAS in 1 (2.8 %). PD-L1 was positive in 15 patients (41.7%), PD-1 in 23 (63.8%) and both were found in 13 (36.1%). The intensity of inflammation in 21 patients (58.3%) was mild, moderate in 9 (25%) and high in 6 (16.7%). Among the 23 PD-1 positive cases, 15 (65.2%) were mild and 8 (34.8%) moderate. We found a strong association between PD-L1 positivity and intensity of inflammation: 13 PD-L1 positive patients were moderate/marked, vs 2 PD-L1 positive being mild; only 2 PD-L1 negative patients were moderate/marked, vs 19 PD-L1 negative being mild (p<0.001). The same association was seen between PD1 positivity and level of inflammation: 14 PD-1 positive patients had moderate/marked inflammation, vs 9 PD-1 positive patients with mild inflammation; 1 PD-1 negative patient had moderate/marked inflammation, vs 12 PD-1 negative with mild inflammation (p<0.01). We found a negative association between PD-L1 positivity and BRAFV600E mutation: 4 PD-L1 + patients were mutated vs 11 PD-L1 + being BRAFV600E Wild Type (WT); 15 PD-L1 - patients were mutated vs 6 PD-L1- being WT (p<0.01). No association was found between PD-1 postivity and BRAFV600E mutation. 80 % of patients which were PD-L1 - PD-1 + were BRAFV600E mutated. In the contrary, all patients PD-L1 + PD-1 - were WT.Conclusions: We found a negative association between PD-L1 positivity and BRAFV600E mutation. Eleven patients only (30.5%) of ECD patients were PD-L1 and PD-1 negative. The recent success of immune checkpoint blockade therapy in some cancer types combined with the expression of immune checkpoint antigens in ECD samples suggests that such therapies should be investigated for refractory ECD. DisclosuresNo relevant conflicts of interest to declare.

Gastric crystal-storing histiocytosis without any underlying disorders: Report of a case

Crystal-storing histiocytosis (CSH) is a rare phenomenon in which crystalline material accumulates in the cytoplasm of histiocytes. Localized gastric CSH is an extremely rare condition. We report a case of localized gastric CSH in a 72-year-old female who presented with diffuse granular mucosa in the gastric fundus and body endoscopically. Biopsy specimens from the stomach showed accumulation of crystal-storing histiocytes, and the crystalline material was immunohistochemically positive for kappa light chains and polyclonal heavy chains. There were no crystal-storing histiocytes in other organs. For the past 5 years, the gastric CSH lesion has remained without any change, and no neoplastic or lymphoproliferative disease has developed. Once the diagnosis of CSH is established, it is necessary to check for an underlying lymphoplasmacytic disorder. However, some cases of localized gastric CSH are not associated with lymphoplasmacytic neoplasia, and these tend to have a good prognosis.

Verruciform Xanthoma, a Rare Lesion Located on the Left Lateral Border of the Tongue: a Case Report

Verruciform xanthoma is a benign mucocutaneous lesion of unknown etiology characterized by the accumulation of histiocytes filled with lipids, below the epithelium; it may represent an unusual reaction or immune response to trauma or local epithelial damage. It typically affects the oral cavity, specifically the gum region and alveolar mucosa. The aim of this study was to report the case of a 58-year-old man with leukoderma with a circumscribed papillary lesion with verruciform surface and yellowish-color, located on the left lateral border of the tongue, in the region of the foliaceous papillae, of approximately 1 cm in diameter. During anamnesis, the patient reported habits of alcoholism and smoking in the past, with a history of cold sore and squamous papilloma in the oral cavity. The initial diagnostic hypothesis of oral lymphoepithelial cyst was replaced, after excisional biopsy, with an anatomopathological report of verruciform xanthoma, which is considered a rare lesion.

Rosai-Dorfman disease as a rare cause of cervical lymphadenopathy - case report and literature review.

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare, benign clinical entity of unknown cause. RDD is characterised by the overproduction and accumulation of histiocytes, primarily in the lymph nodes, although it may affect every organ and system. It predominantly affects children and young adults. Typically, patients are in good general condition, with massive cervical lymphadenopathy and fever. In about 40% of cases extranodal localisation of RDD is diagnosed. In laboratory tests the most common abnormalities are increased erythrocyte sedimentation rate (ESR), leukocytosis with neutrophilia, normocytic anaemia, and hypergammaglobulinaemia. Histopathological examination remains the mainstay of diagnosis – lymph nodes have massive sinusoidal dilation, containing histiocytes positive for S-100 and CD68, and negative for CD1a. Most patients do not require treatment as spontaneous remissions are observed. We present a brief review of the literature and the case of a six-year-old boy with cervical lymphadenopathy diagnosed with RDD. So far, the patient has not required systemic treatment and has been kept under observation.

Gastric Xanthoma (GX) as an Incidental Endoscopic Finding: A Report of 2 Cases

Gastric xanthomas (GXs) are yellow mucosal lesions characterized by the accumulation of lipid-laden histiocytes in the lamina propria. It is usually an incidental endoscopic finding of unclear clinical significance. It has a quite variable incidence that increases with age. GX was reported to be associated with chronic gastritis, hyperplastic polyps, gastric cancer and H.pylori infection. It has been hypothesized that GX could be related to gastric injury, which was supported by the higher prevalence of gastric atrophy among reported cases. Surprisingly, no correlation between GX and hyperlipidemia was found. Case 1: A 54 year-old Caucasian female with a history of primary pulmonary hypertension and ESRD post renal and bilateral lung transplant, admitted to the hospital with epigastric pain. Vital signs were normal, physical examination was significant for mild epigastric tenderness. Laboratory work and Imaging studies were inconclusive. EGD was remarkable for a single 5 mm sessile in the gastric fundus, complete resection was accomplished. (Figure 1) Pathology results revealed GX with focal active inflammation and erosion, No Helicobacter pylori organisms identified. There was no evidence of malignancy.FigureCase 2: This is an 82 year-old male with a significant history of DM II and renal cell carcinoma, who presented to our hospital with melena. On physical examination, he looked pale and tired. Vital signs were stable, his labs were remarkable only for normocytic anemia (HB: 7.9 g/dL, MCV: 92 fL). EGD was performed next day and it revealed a mass in the gastric body and a small gastric antral polyp (Figure 2), both biopsied. Subsequently, pathology results showed clear cell carcinoma consistent with metastatic renal cell carcinoma (the mass). Gastric antral polyp biopsy was suggestive of gastric xanthoma, confirmed by immunohistochemical staining for CD68. Eventually, laparoscopic partial gastrectomy was performed successfully. GX is a rare condition of unknown etiology, there is increasing evidence on the association between GX and gastric injury. GX should be considered as a warning sign, to look for other concomitant serious conditions, most importantly gastric cancer. In our reported cases, there was no evidence of H. pylori infection or primary gastric cancer, lipid profile was normal. However, the second patient endoscopy revealed a metastatic gastric mass. We think it is prudent to look for GX gastric partners and always send for histologic confirmation.Figure

LANGERHANS CELL HISTIOCYTOSIS OF THE SCAPULA - DIAGNOSIS &amp; TREATMENT OPTIONS

ABSTRACT Langerhans cell histiocytosis (LCH) is characterised by an abnormal histiocytic accumulation in tissues such as the lung, spleen, bone marrow, skin, central nervous system, liver and lymph nodes, causing focal or systemic effects. No specific clinical &amp; radiographic presentation of LCH is described in literature. This poses a diagnostic dilemma for surgeons. The scapula is the site of 3% of bone tumours, while for LCH it is the least common site. In a 10-year-old boy with isolated lesion of the scapula with no other systemic involvement, and no specific finding in MRI or CT scan of scapula, diagnosis was confirmed on biopsy. Division into single and multi-system disease is paramount in treatment, given that it is a single system disease. The patient improved clinically on follow-up of 2 years. The scapula is one of the rarest site of LCH, and because various lesions mimic each other, a biopsy is always required, with immunohistochemistry for CD68 &amp; S-100. This was only a single system disease, so conservative management was performed, and the patent improved clinically.

An unusual case of interstitial lung disease in a patient with cardiopulmonary syndrome as the initial presentation of Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a very rare disorder with only approximately 600 cases reported in the literature. ECD has been recently reclassified as a histiocytic dendritic cell neoplasm. The clinical...

Histiocytose mucineuse progressive sporadique

Progressive mucinous histiocytosis is a very rare, benign, non-Langerhans' cell histiocytosis limited to the skin. This disorder has been observed solely in women, with the exception of three cases in male patients, and most cases are hereditary. The hereditary forms begin in childhood, with sporadic cases occurring later, and it is characterized by numerous papules of slow progression. The aetiology and mode of genetic transmission remain unclear. We report one sporadic case of progressive mucinous histiocytosis. A 33-year-old woman presented with a 15-year history of multiple small purplish asymptomatic papules on the outside of both legs. There was no history of similar cases in her family. The dermatologists she consulted suggested a diagnosis of lichen planus. A punch biopsy was performed and revealed dermal accumulation of histiocytes with abundant mucin deposition. Seventeen hereditary cases in seven families, all of which concerned women except for three males, and five sporadic cases have been described to date. The clinical and histological presentation is typical. Histopathology shows dermal accumulation of histiocytes with abundant mucin deposition. The ultrastructural aspect (intracytoplasmic phospholipid deposits) and progressive extension suggest a disorder similar to that observed in lysosomal diseases. However, primary proliferation of macrophages in response to an unknown stimulus cannot be ruled out. At present, there is no treatment.

Juvenile Xanthogranuloma

The histiocytoses are a heterogenous group of diseases that are characterized by the accumulation of reactive or neoplastic histiocytes in various tissues. Juvenile Xanthogranuloma is a member of the non-Langerhans cell group of histiocytic proliferative disorders. This present case report describes a juvenile xanthogranuloma in a twenty-month old male baby.Nepal Journal of Dermatology, Venereology &amp; Leprology, Vol.14(1) 2016, pp.56-58

Clinicopathologic analysis of extranodal Rosai-Dorfman disease of breast: a report of 12 cases

To investigate the clinicopathologic features, diagnosis and differential diagnosis of extranodal Rosai-Dorfman disease(RDD)of the breast. Twelve cases of extranodal RDD of the breast were analyzed using hematoxylin-eosin stain and immunohistochemical staining.The morphological features and immunophenotype were observed by light microscopy, accompanied with a review of the literature. Twelve cases of extranodal RDD of the breast are presented. The patients were women and their ages ranged from 15 to 55 years (mean =37 years). Except one patient with involvement of the right breast and ipsilateral axillary lymph nodes, other eleven patients' disease confined to the breast. Seven cases located in the right breast, the other five cases in the left breast. Microscopically, it showed a typical morphology, characterized by diffuse infiltration of large histiocytes, lymphocytes and plasmocytes that formed irregular nodular structure with light and dark appearance under microscope. Spindling of histiocytosis often arranged in a vague storiform with prominent fibrosis, accumulation of foamy histiocytes and scattered atypical nuclei. The characteristic histocytes and emperipolesis could not be seen obviously in extranodal RDD of the breast.Immunohistochemical staining showed histocytes were strongly positive for S-100 protein, CD68 and CD163, while negative for CD1a. Extranodal RDD of the breast is very rare. Because of unconspicuous emperipolesis and lack of specificity in clinic and images, extranodal RDD of the breast is easy to be misdiagnosed as other histiocytosis. The microscopic differential diagnosis includes idiopathic granulomatous mastitis, infective granulomas, langerhans cell histiocytosis, IgG4 related sclerosing disease, Erdheim-Chester disease, benign fibrous histiocytoma, malignant fibrous histiocytoma and Hodgkin Lymphoma. Light and dark appearance under microscope is the important clue in diagnosis of extranodal RDD in breast. Immunohistochemistry is also helpful.

Erdheim-Chester Disease with Emperipolesis: A Unique Case Involving the Heart

Histiocytosis is an uncommon disease characterized by excessive accumulation of histiocytes. Here, we report a rare case of non-Langerhans-cell histiocytosis in a 51-year-old woman who presented with severe symptoms of pericardial effusion. Radiologic investigation also detected multiple bone (lower limbs, vertebrae, ribs, and ilium) lesions. Resected pericardium showed abundant mono- or multi-nucleated non-foamy histiocytes (CD68+/CD163+/S-100+/CD1α−/langerin−) in a fibroinflammatory background. The histiocytes demonstrated emperipolesis of lymphocytes, a hallmark feature of Rosai-Dorfman disease (RDD). However, molecular analysis revealed a BRAF V600E mutation of the proliferating histiocytes, highlighting the neoplastic features frequently observed in another non-Langerhans-cell histiocytosis known as Erdheim-Chester Disease (ECD). We consider this case to be a unique presentation of ECD harboring some RDD-like cells with emperipolesis, but not a case of RDD with a BRAF mutation concerning its clinical manifestation (involvement of the heart and bones) and neoplastic features.