- Genotype-Phenotype Correlation of Hereditary Erythrocytosis Mutations, a single center experience. [Journal Article]
- AJAm J Hematol 2018 May 23
- Hereditary erythrocytosis is associated with high oxygen affinity hemoglobin variants (HOAs), 2,3-bisphosphoglycerate deficiency and abnormalities in EPOR and the oxygen-sensing pathway proteins PHD,...
Hereditary erythrocytosis is associated with high oxygen affinity hemoglobin variants (HOAs), 2,3-bisphosphoglycerate deficiency and abnormalities in EPOR and the oxygen-sensing pathway proteins PHD, HIF2α, and VHL. Our laboratory has 40 years of experience with hemoglobin disorder testing and we have characterized HOAs using varied protein and molecular techniques including functional assessment by p50 analysis. In addition, we have more recently commenced adding the assessment of clinically relevant regions of the VHL, BPGM, EPOR, EGLN1 (PHD2), and EPAS1 (HIF2A) genes in a more comprehensive hereditary erythrocytosis panel of tests. Review of our experience confirms a wide spectrum of alterations associated with erythrocytosis which we have correlated with phenotypic and clinical features. Through generic hemoglobinopathy testing we have identified 762 patients with 81 distinct HOA Hb variants (61 β, 20 α), including 12 that were first identified by our laboratory. Of the 1192 cases received for an evaluation specific for hereditary erythrocytosis, approximately 12% had reportable alterations: 85 pathogenic/likely pathogenic mutations and 58 variants of unknown significance. Many have not been previously reported. Correlation with clinical and phenotypic data supports an algorithmic approach to guide economical evaluation; although, testing is expanded if the suspected causes are negative or of uncertain significance. Clinical features are similar and range from asymptomatic to recurrent headaches, fatigue, restless legs, chest pain, exertional dyspnea and thrombotic episodes. Many patients were chronically phlebotomized with reported relief of symptoms. This article is protected by copyright. All rights reserved.
- Distinctive CD8+ T cell and MHC class I signatures in polycythemia vera patients. [Journal Article]
- AHAnn Hematol 2018 May 22
- Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by overproduction of red blood cells. We have performed a comprehensive characterization of blood immune cells for expression of ...
Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by overproduction of red blood cells. We have performed a comprehensive characterization of blood immune cells for expression of naïve and memory receptors as well as β2m-associated and β2m-free MHC class I heavy chains, also known as closed and open conformers, respectively, in PV patients and age-matched controls (CTR). We show that the peripheral CD3+CD8+ T cell pool in PV patients is clearly divided into two discrete populations, a more granular CD3+CD8high T cell population enriched in effector-memory CD45RA+ T cells (CD8+ TEMRA) when compared to CTR (P < 0.001), and a less granular CD3+CD8int T cell population that is completely absent in the CTR group (78 vs. 0%, P < 0.001) and is a mixture of naïve (CD8+ TN) and CD8+ TEMRA cells expressing intermediate levels of CD28, i.e., CD3+CD8intCD28int. While the percentage of CD3+CD8int TN cells correlated positively with the number of erythrocytes, the percentage of CD3+CD8int TEMRA correlated negatively with the number of platelets. Finally, we report that PV patients' lymphocytes and monocytes display lower levels of closed (W6/32+) MHC-I conformers at the cell surface while exhibiting increased amounts of open (HC-10+) MHC-I conformers. The implications of this distinctive immune signature are discussed.
- Functioning Mediastinal Paraganglioma Associated with a Germline Mutation of von Hippel-Lindau Gene. [Journal Article]
- JCJ Clin Med 2018 May 23; 7(6)
- We report the case of a 21-year old woman presenting with high blood pressure and raised normetanephrine levels. Indium-111-pentetreotide single photon-emission computed tomography with computed tomo...
We report the case of a 21-year old woman presenting with high blood pressure and raised normetanephrine levels. Indium-111-pentetreotide single photon-emission computed tomography with computed tomography (SPECT/CT) and 2-deoxy-2-[fluorine-18]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging showing isolated tracer-uptake by a 2 cm tumor close to the costovertebral angle of the third thoracic vertebra. Thoracic surgery led to normalization of normetanephrine levels. Histological findings were consistent with the presence of a paraganglioma. Mutations in SDHA, SDHB, SDHC, SDHD, RET, SDHAF2, TMEM127, MAX, NF1, FH, MDH2, and EPAS1 were absent, but a heterozygous missense mutation, c.311G > T, was found in exon 1 of the von Hippel-Lindau gene, VHL, resulting in a glycine to valine substitution in the VHL protein at position 104, p.Gly104Val. This same mutation was found in both the mother and the 17-year old sister in whom a small retinal hemangioblastoma was also found. We diagnose an unusual functional mediastinal paraganglioma in this young patient with a germline VHL gene mutation, a mutation previously described as inducing polycythemia and/or pheochromocytoma but not paraganglioma or retinal hemangioblastoma.
- Sustained Regression of Hydroxycarbamide Induced Actinic Keratoses after Switching to Anagrelide. [Journal Article]
- CRCase Rep Dermatol Med 2018; 2018:2874012
- Hydroxycarbamide (HC) is the first-line treatment for certain myeloproliferative neoplasms, such as polycythemia vera and essential thrombocytosis (ET). In a subset of these patients long-term treatm...
Hydroxycarbamide (HC) is the first-line treatment for certain myeloproliferative neoplasms, such as polycythemia vera and essential thrombocytosis (ET). In a subset of these patients long-term treatment with HC can result in the development of confluent actinic keratoses (AK) followed by invasive keratinocytic carcinomas ("squamous dysplasia"), preferentially on sun-exposed skin. Discontinuation or dose reduction of HC may result in partial improvement. A 59-year-old farmer after 14 years on HC (2 gr/d) and acetylsalicylic acid (100 mg/d) for ET, was referred for numerous, hyperkeratotic AK on face, scalp, and hands that could not be controlled with repeated (N = 15) cryosurgery sessions in the previous 3 years. Acitretin (0.32 mg/kg daily) and topical treatments (cryosurgery with ingenol mebutate) were initiated with only marginal improvement after 3 months. Acitretin dose was doubled and HC was switched to anagrelide (0.5 mg twice daily). Within a month the AK load regressed significantly and, at 3 months follow-up, complete clinical remission was achieved and acitretin was discontinued. Twenty months later the patient is clear from AK. In conclusion, the impressive and sustainable AK remission under anagrelide draws attention to a possible role of the phosphodiesterase 3 pathway, the major pharmacological target of anagrelide, as a potential therapeutic target for keratinocytic cancers.
- A Review of Fabry Disease. [Journal Article]
- STSkin Therapy Lett 2018; 23(3):5-9
- The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an im...
The class of medications known as Janus kinase inhibitors block cytokine-mediated signaling via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, which plays an important role in immunoregulation and normal cell growth. This class includes the drugs tofacitinib, approved for the treatment of rheumatoid arthritis, and ruxolitinib, approved for the treatment of myelofibrosis and polycythemia rubra vera. The most common adverse events (AEs) reported in patients taking tofacitinib are infections, whereas the most common AEs in patients taking ruxolitinib are anemia and thrombocytopenia. Both first and second generation Janus kinase inhibitors have become promising treatment modalities for dermatologic conditions such as psoriasis, atopic dermatitis, alopecia areata, vilitigo, dermatomyositis, and graft-versus-host disease. Future promising areas of investigation include treatment of cutaneous lupus, cutaneous T-cell lymphoma, melanoma, allergic contact dermatitis, and lichen planus.
- Difficulty distinguishing essential thrombocythaemia from polycythaemia vera in children with JAK2 V617F-positive myeloproliferative neoplasms. [Letter]
- BJBr J Haematol 2018 May 16
- Serum ferritin as a biomarker of polycythemia vera? [Editorial]
- EEJIFCC 2018; 29(1):94-95
- Sudden hemichorea and frontal lobe syndrome: a rare presentation of unbalanced polycythaemia vera. [Journal Article]
- BCBMJ Case Rep 2018 May 14; 2018
- Polycythaemia vera (PV) is an haematological neoplasm that frequently presents neurological symptoms. However, chorea is a rare complication of this disease, occurring in less than 5% of the patients...
Polycythaemia vera (PV) is an haematological neoplasm that frequently presents neurological symptoms. However, chorea is a rare complication of this disease, occurring in less than 5% of the patients. Cognitive impairment related to PV unbalanced is also a rare complication, and it can improve with proper treatment. We present a 96-year-old-man with acute-onset hemichorea and frontal lobe syndrome with no vascular pathology in the basal ganglia or frontal region. A clear relationship was observed between the onset of involuntary movements and the cognitive impairment and worsening of haematological parameters in the patient. After causal and symptomatic treatment, the patient's clinical status improved. In the elderly, PV must be considered as a cause of acute chorea and sudden cognitive impairment, as early diagnosis leads to effective treatment and prevention of complications.
- StatPearls [BOOK]
- BOOKStatPearls Publishing: Treasure Island (FL)
- Anemia is a common sign found in both inpatient and outpatient management. Although it is routinely listed as a "freestanding" diagnosis, it is a sign (like tachycardia or rash) that needs to be work...
Anemia is a common sign found in both inpatient and outpatient management. Although it is routinely listed as a "freestanding" diagnosis, it is a sign (like tachycardia or rash) that needs to be worked up and further elucidated. Anemia is a prevalent condition that by some estimates is under-recognized and undertreated. It has both the obvious, primary, direct, negative consequences of diminished tissue oxygenation and a secondary indirect negative consequence of complicating the progression of many coexisting diseases. Despite the gravity of the diagnosis of the sign anemia, there remains clinical discordance in both the formal definition of anemia and in the protocols to screen for it. Symptoms of anemia include fatigue, weakness, lightheadedness, headache, pallor/jaundice, tachycardia/palpitations, chest pain, dyspnea, and cold distal extremities, and claudication. These symptoms can be quite limiting and are primary negative consequences of anemia. The cause of the anemia modulates the presence and magnitude of these symptoms. The greater the lethal underlying pathology, the more dramatic the symptomatology. The presence of anemia in conjunction with other pathology adds additional concern. Anemia frequently complicates diabetes, various cancers, chronic kidney disease, cardiovascular disease, hepatitis C, HIV/AIDS, inflammatory bowel disease, rheumatoid arthritis and, despite compensatory polycythemia, chronic obstructive pulmonary disease (COPD). It is universally agreed that anemia is a decrease in the relative number of circulating erythrocytes (red blood cell mass) with a consequent diminished ability to deliver oxygen to tissues. Opinions diverge on the subject of absolute numbers and concentrations to diagnose individuals of various genders, ethnicities, and ages as being anemic. In addition, opinions differ on who is to be routinely screened for anemia and who is to be tested on a "need to know" basis. Finally, the threshold for treatment and the final targets of treatment are subject to variation according to discipline and medical condition. The World Health Organization anemia standard of 2010 is a Hb less than 12 g/dl in premenopausal females and 13 g/dl in postmenopausal females and men of all ages. The Journal Blood disagreed citing the paucity of WHO data and methods and set down standards divided by race, gender and decade of life. Their standards concluded that the standard in white men from 20 to 60 years of age was 13.7 g/dl and after 60 declined to 13.2 g/dl and women of all ages were considered anemic at 12.2 g/dl. This noted a significant difference in Hb in black men and women but did not cite standards. At this point, the majority of the literature utilizes the WHO standards for consistency. There is similar discordance concerning screening for anemia between the US Preventative Services Task Force, and various individual medical academies and, what is done in the day-to-day practice of medicine. For example, the USPTF issued a statement on screening for iron deficiency anemia in asymptomatic children 6 to 24 months of age. The conclusion was that there was insufficient evidence on the benefits and harms of screening for anemia in children of this age. At the same time, the American Academy of Family Practice released their position statement: "Universal screening for anemia should be performed at 12 months of age, with measurement of hemoglobin levels and an assessment of risk factors associated with iron deficiency and iron deficiency anemia." The issue of screening in pregnant women presented a similar discordance. "The USPTF concludes that the evidence of the effect of routine screening for iron deficiency anemia in asymptomatic pregnant women on maternal health and birth outcomes is insufficient...and the balance of benefits and harms cannot be determined." The American Academy of Family Practice voiced agreement with the USPSTF. The American College of Obstetrics and Gynecology in Practice Bulletin No. 95 issued the position statement, "all pregnant women should be screened for anemia and treated if necessary." At present, there are no recommendations for routine anemia screening of non-gravid, well adults.
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- Methods for Studying Iron Regulatory Protein 1: An Important Protein in Human Iron Metabolism. [Journal Article]
- MEMethods Enzymol 2018; 599:139-155
- Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by regulating the expression of genes involved in iron metabolism. IRPs respond to ...
Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by regulating the expression of genes involved in iron metabolism. IRPs respond to cellular iron deficiency by binding to iron-responsive elements (IREs) found in the mRNAs of iron metabolism transcripts, enhancing iron import, and reducing iron storage, utilization, and export. IRP1, a bifunctional protein, exists in equilibrium between a [Fe4S4] cluster containing cytosolic aconitase, and an apoprotein that binds to IREs. At high cellular iron levels, this equilibrium is shifted more toward iron-sulfur cluster containing aconitase, whereas IRP2 undergoes proteasomal degradation by an E3 ubiquitin ligase complex that contains an F-box protein, FBXL5. Irp1-/- mice develop polycythemia and pulmonary hypertension, whereas Irp2-/- mice develop microcytic anemia and progressive neurodegeneration, indicating that Irp1 has important functions in the erythropoietic and pulmonary systems, and Irp2 has essential roles in supporting erythropoiesis and nervous system functions. Mice lacking both Irp1 and Irp2 die during embryogenesis, suggesting that functions of Irp1 and Irp2 are redundant. In this review, we will focus on the methods for studying IRP1 activities and function in cells and animals.