A Family with Hemoglobin I

Hemoglobin I was recently found in a Negro family. The amino acidsubstitution was shown to occur in the sixteenth residue of the chain (lys asp) and to be identical with hemoglobin I described by Murayama.¹⁰ Theminor component, I₂, was demonstrated by agar gel electrophoresis.

Submitted on January 9, 1963 Accepted on April 3, 1963     

How I manage children with neutropenia

Neutropenia, usually defined as a blood neutrophil count <1·5 × 10⁹/l, is a common medical problem for children and adults. There are many causes for neutropenia, and at each stage in life the clinical pattern of causes and consequences differs significantly. I recommend utilizing the age of the child and clinical observations for the preliminary diagnosis and primary management. In premature infants, neutropenia is quite common and contributes to the risk of sepsis with necrotizing enterocolitis. At birth and for the first few months of life, neutropenia is often attributable to isoimmune or alloimmune mechanisms and predisposes to the risk of severe bacterial infections. Thereafter when a child is discovered to have neutropenia, often associated with relatively minor symptoms, it is usually attributed to autoimmune disorder or viral infection. The congenital neutropenia syndromes are usually recognized when there are recurrent infections, the neutropenia is severe and there are congenital anomalies suggesting a genetic disorder. This review focuses on the key clinical finding and laboratory tests for diagnosis with commentaries on treatment, particularly the use of granulocyte colony‐stimulating factor to treat childhood neutropenia.     

How I manage children with Diamond-Blackfan anaemia

Diamond-Blackfan anaemia (DBA) is a rare inherited marrow failure disorder, characterized by hypoplastic anaemia, congenital anomalies and a predisposition to cancer as a result of ribosomal dysfunction. Historically, treatment is based on glucocorticoids and/or blood transfusions, which is accompanied by significant toxicity and long-term sequelae. Currently, stem cell transplantation is the only curative option for the haematological DBA phenotype. Whereas this procedure has been quite successful in the last decade in selected patients, novel therapies and biological insights are still warranted to improve clinical care for all DBA patients. In addition to paediatric haematologists, other physicians (e.g. endocrinologist, gynaecologist) should ideally be involved in the care of this chronic condition from an early age, to improve lifelong management of haematological and non-haematological symptoms, and screen for DBA-associated malignancies. Here we provide an overview of current knowledge and recommendations for the day-to-day care of DBA patients.     

How I manage patients with Fanconi anaemia

Fanconi Anaemia is a rare, genetic heterogeneous multisystem disease that is the most common congenital syndrome of marrow failure. Twenty genes have been reported to cause the disease. Remarkable progress has been made over the last 20 years in the understanding of the genetic and pathophysiological mechanisms. Unfortunately, these advances have not been completely paralleled by advances in medical treatment, where the most important component remains stem cell transplantation. This therapy, although contributing to long‐term negative effects, such as increased occurrence of late malignancies, is the only current option capable of prolonging the survival of patients. In spite of relevant recent progress in matched unrelated donor transplants, the largest studies with longer follow‐up still show a superiority of matched sibling donor transplants with a success rate, in selected cohorts, of over 90%. This article reviews different aspects of the disease, including genetics, diagnosis and treatment options, with special focus on stem cell transplantation, comprehensive post‐diagnosis management, decision‐making processes and long‐term follow‐up.     

Glutaric aciduria type I presenting with hypoglycaemia

We present a child with glutaryl CoA-dehydrogenase deficiency (type I glutaric aciduria) who presented with bilateral subdural hydromas, and progressive choreoathetosis and dysarthria. The diagnosis was made when she was investigated for hypoglycaemia at the age of 3.5 years. Temporary adrenocortical insufficiency was also noted. Three years after diagnosis the adrenal insufficiency and hypoglycaemia have resolved and treatment with riboflavin and lioresal, a GABA analogue, has prevented any further neurological deterioration.     

Troponin I levels in patients with preeclampsia

Introduction

Preeclampsia involves a diffuse inflammatory state and elevated levels of troponins in patients with preeclampsia have been anecdotally reported. It is, however, unknown whether it is attributable to the preeclampsia.

Objective

We sought to determine the troponin I levels at the time of delivery in pregnant women with and without preeclampsia.

Methods

Plasma samples were obtained at the time of delivery and serum troponin I was measured by ELISA method.

Results

Thirty-nine women were included (20 with preeclampsia and 19 without). Mean troponin I level was 0.008 ng/mL in patients with preeclampsia and 0.01 ng/mL in controls (P =.59). The highest troponin I level was 0.04 ng/mL for both patients with and without preeclampsia.

Conclusions

Preeclampsia was not associated with a rise in troponin I levels in our study. Patients with preeclampsia and elevated troponin levels should have further cardiac investigations.     

How I treat patients with polycythemia vera

The clinical course of polycythemia vera (PV) is marked by a high incidence of thrombotic complications; fibrotic and leukemic disease transformations are additional causes of morbidity and mortality. Major predictors of vascular events are increasing age and previous thrombosis; leukocytosis and high JAK2 V617F allele burden are currently being investigated for additional prognostic value in this regard. Myelosuppressive drugs can reduce the rate of thrombosis, but there is concern that their use raises the risk of transformation into acute leukemia. To tackle this dilemma, a risk-oriented management strategy is recommended. Low-risk patients should be treated with phlebotomy and low-dose aspirin. Cytotoxic therapy is indicated in high-risk patients, and the drug of choice is hydroxyurea because of its efficacy in preventing thrombosis and low leukemogenicity. Interferon-alpha should be reserved for selected categories of patients due to high cost and toxicity. The demonstration of JAK2 V617F mutation in the vast majority of PV patients opens the avenue for the development of promising new molecularly targeted drugs.     

How I manage patients with follicular lymphoma

Recent advances in the treatment of follicular lymphoma (FL) have provided insight into molecular and biological influences on pathogenesis and prognosis. Additionally, numerous available treatment strategies for both newly diagnosed and relapsed disease require thoughtful consideration of patient selection to avoid the burden of overtreatment and toxicities. This review provides a broad overview on our approach to managing patients with low grade FL.     

How I manage patients with grey zone lymphoma

Since grey zone lymphoma (GZL) was originally included in the 2008 World Health Organization classification as a B‐cell lymphoma unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL), new biological and clinical knowledge have been learned. It is important to highlight that diagnosis of this entity is complex and involvement by haematopathologists with expertise in this disease is recommended. It is recognized now that patients with GZL may present clinically with primary mediastinal localization or systemic disease without mediastinal involvement. Regardless of clinical presentation, patients with GZL have relatively high relapse rates, especially compared with primary mediastinal DLBCL or cHL. Interestingly, relapsed/refractory GZL patients appear to be salvaged fairly successfully, especially with haematopoietic stem cell transplantation (HSCT). Off of a clinical trial, we recommend R‐CHOP (rituximab, cyclophosphamide, doxorubicin, oncovin, prednisolone) or dose‐adjusted EPOCH‐R (etoposide, prednisolone, oncovin, cyclophosphamide, doxorubicin, rituximab) for frontline treatment of GZL. Additionally, we advocate use of consolidative radiotherapy for localized and/or bulky disease. For patients with relapsed/refractory GZL, salvage chemotherapy followed by consolidative autologous HSCT should be considered. Finally, continued biological and pathologic examination of this unique disease entity is warranted as well as exploration towards the integration of targeted therapeutic agents (e.g., brentuximab vedotin, programmed cell death 1inhibitors, B‐cell receptor inhibitors, proteasome inhibitors, etc.) into the treatment paradigm of GZL.     

How I manage patients with atypical microcytic anaemia

Microcytic hypochromic anaemias are a result of defective iron handling by erythroblasts that decrease the haemoglobin content per red cell. Recent advances in our knowledge of iron metabolism and its homeostasis have led to the discovery of novel inherited anaemias that need to be distinguished from common iron deficiency or other causes of microcytosis. These atypical microcytic anaemias can be classified as: (i) defects of intestinal iron absorption (ii) disorders of the transferrin receptor cycle that impair erythroblast iron uptake (iii) defects of mitochondrial iron utilization for haem or iron sulphur cluster synthesis and (iv) defects of iron recycling. A careful patient history and evaluation of laboratory tests may enable these rare conditions to be distinguished from the more common iron deficiency anaemia. Molecular studies allow distinction of the different types, a prerequisite for differentiated therapy.     

Clostridial-Induced Type I Polyagglutinability with Associated Intravascular Hemolysis

A woman with a clostridial septicemia manifested in vivo type I polyagglutinability of her erythrocytes, presumably due to activation of the latent T-receptor. A filtrate of the Clostridium culture was capable of causing T-activation of erythrocytes in vitro and bacterial products probably caused the T-activation in vivo . Moreover, there was evidence that anti-T in donor plasma caused lysis of T-active red cells.     

Pulmonary hypertension in patients with neurofibromatosis type I

Neurofibromatosis type I (NF1) is a rare genetic disease caused by mutations in the NF1 gene, which codes for tumor suppressor neurofibromin. NF1 is transmitted as an autosomal dominant and fully penetrant trait with no sex predominance. Precapillary pulmonary hypertension (PH) is a severe complication of NF1, initially described in patients with advanced parenchymal lung disease, which may complicate the course of NF1. We conducted this study to describe clinical, functional, radiologic, and hemodynamic characteristics and outcome of patients with NF1-associated PH. We identified 8 new cases of NF1-associated PH in patients carrying a NF1 gene mutation. No bone morphogenic protein receptor 2 (BMPR2) point mutation or large size rearrangements were identified. Seven female patients and 1 male patient were reported, suggesting a possible female predominance. PH occurred late in the course of the disease (median age, 62 yr; range, 53-68 yr). Dyspnea and signs of right heart failure were the major symptoms leading to the diagnosis of PH. At diagnosis, patients had severe hemodynamic impairment with low cardiac index (median, 2.3 L/min per m2; range, 1.9-4.7) and elevated indexed pulmonary vascular resistance (median, 15.1 mm Hg/L/min per m2; range, 4.5-25.9). All patients were in New York Heart Association functional class III with severe exercise limitation (median 6-min walk distance, 180 m; range, 60-375 m). Most patients had associated parenchymal lung disease, but some had no or mild lung involvement with disproportionate pulmonary vascular disease. Overall, the impact of PH therapy was limited and outcomes were poor. In conclusion, PH represents a rare but severe complication of NF1, characterized by female predominance, late onset in the course of NF1, and severe functional and hemodynamic impairment. Because of poor outcome and limited impact of specific PH therapy, eligible patients require early referral for lung transplantation. Further studies are needed to better understand the pathophysiology and the role, if any, of neurofibromin in NF1-associated PH.