UNDERSTANDING SEVERE CHRONIC NEUTROPENIA

Transcription

1 UNDERSTANDING SEVERE CHRONIC NEUTROPENIA A Handbook for Patients and Their Families Written for the Severe Chronic Neutropenia International Registry By: Audrey Anna Bolyard, R.N., B.S. Laurence Boxer, M.D. Tammy Cottle Carole Edwards, R.G.N/R.S.C.N., BSc. Sally Kinsey, M.D. Peter Newburger, M.D. Beate Schwinzer, Ph.D. Cornelia Zeidler, M.D. Understanding Severe Chronic Neutropenia 1

2 Contents Page Introduction 3 How Blood is Formed 3 What is Neutropenia? 4 Overview: Diagnosis & Treatment of Severe Chronic Neutropenia 5 Risk of Myelodysplastic Syndrome and Leukemia 6 Risk of Osteopenia/Osteoporosis 7 Types of Severe Chronic Neutropenia 7 Severe Congenital Neutropenia 8 Cyclic Neutropenia 8 Shwachman-Diamond Syndrome 9 Metabolic disorders with neutropenia 10 Glycogen-Storage Disease Type 1b 10 Barth Syndrome 10 Idiopathic Neutropenia 10 Autoimmune Neutropenia 10 Other Conditions Associated with Neutropenia 11 Genetics of Severe Congenital Neutropenia 11 Diagnostic Tests Used in Severe Chronic Neutropenia 12 Blood Count Monitoring 12 Other Blood Tests 12 Bone Marrow Aspirate / Trephine Biopsy 12 Cytogenetic Evaluation 12 Investigations in Other Conditions 12 Treatment for Severe Chronic Neutropenia 13 Granulocyte-Colony Stimulating Factor (G-CSF) 14 Hematopoietic Stem Cell (Bone Marrow) Transplant 15 Other Treatments 15 Long Term Management of SCN 16 Bone Marrow Monitoring 17 Pregnancy 17 Psychosocial Issues 17 The Severe Chronic Neutropenia International Registry 18 Support Groups 20 Frequently Asked Questions and Answers 20 Information Form for Schools 24 Glossary 25 Understanding Severe Chronic Neutropenia 2

3 Introduction Severe chronic neutropenia (SCN) is the name given to a group of conditions in which neutropenia is the primary problem. The severity and symptoms of the neutropenia differ widely among the various subtypes of neutropenia and even from patient to patient within each disease type. This handbook is designed to give you a better understanding of SCN. It has been written to answer many of the questions you may have about neutropenia and treatment for it. We hope that you find it useful in helping you and/or your child in coping with the disease. The purpose of this document is to give you information and to empower you to go back and ask questions of your physician. Learning about neutropenia, its causes and best treatments, is an ongoing process. Research is continually adding to what we know and recommend to patients with neutropenia and their families. Consequently, this handbook is not all-inclusive. You can update your information about neutropenia through websites sponsored by the Severe Chronic Neutropenia International Registry (termed SCNIR or Registry in this document, and the National Neutropenia Network (NNN, or through reading research papers available at Pubmed ( The staff and Advisory Board members of the SCNIR wrote this handbook. The SCNIR was established in 1994 under the sponsorship of Amgen Inc., Thousand Oaks, CA, USA. In 2000 The National Institutes of Health became the principal sponsor of the Registry. We are very grateful to Amgen for the initiation of the Registry and support we have received over the years. Since 2000, the SCNIR has continued its work on the causes, consequences and best treatments for severe chronic neutropenia with sponsorship from government sources, foundations and private gifts. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), in the U.S. currently provides major support for the SCNIR. The SCNIR depends on such grants and gifts to continue its work and will greatly appreciate your support if you find its efforts, programs and services useful to you, your family and your community. In this handbook, you refers to you/your child. Throughout the text there are words and phrases that appear in Italics, these are explained further in the glossary. How Blood is Formed The bone marrow is where all blood cell production takes place. The bone marrow, as its name indicates, is located within the bones. The skeleton of the adult human body is built of different types of bones. The bones of arms and legs are long bones with an inner cavity housing mainly fatty tissues, nerves and blood vessels. The marrow in the long bones is of yellow color and because of its fat content is referred to as yellow or fat marrow. This yellow marrow is not actively involved in the production of blood cells in an adult. The red, blood-forming marrow is located within a different type of bone that is flat like the breastbone and the pelvic bone. These bones are not hollow inside but contain a sponge-like scaffolding made from bone substance. The gaps in-between the bone structures are filled with little nests of blood-forming cells, supporting cells, and a network of nerves and small nourishing blood vessels. The medical term for blood cell formation is hematopoiesis (see Figure 1). Understanding Severe Chronic Neutropenia 3

4 There are three basic types of blood cells: The red blood cells (erythrocytes) carry oxygen from the lungs to all the tissues of the body. The platelets (thrombocytes) are essential for the clotting of the blood. The white blood cells (leukocytes) are in charge of the body s defense against infections. There are three main types of white blood cells: granulocytes, monocytes, and lymphocytes. Neutrophils normally make up the major part of the granulocytes. Figure 1. All types of blood cells are derived from one single mother cell, the pluripotent hematopoietic stem cell. Pluripotent means the cell can produce many different cell types, but not all cells and tissues, as would an embryonic stem cell. The growth and development of the blood is carefully controlled in the bone marrow to produce the correct number of each type of cell to keep the body healthy. About 3 million red and 120,000 white blood cells are produced every second. The mature cells leave the bone marrow and enter the blood stream and circulate with the blood through the body. All different blood cells are derived from a single type of cell called the hematopoietic stem cell (which is distinct from the embryonic stem cell that can produce all cells and tissues of the body). Only a very small proportion of bone marrow and blood cells are stem cells. These are the cells that need to be collected for hematopoietic stem cell transplantation (HSCT), often called bone marrow transplantation (BMT). All blood cells eventually die but their life spans vary amongst the different types of cells. Red blood cells live for about four months after they leave the bone marrow, whereas platelets live for just a few days and granulocytes (neutrophils) for only a few hours. What is Neutropenia? The term neutropenia describes the situation where the number of neutrophils in the blood is too low. Neutrophils are very important in defending the body against bacterial infections (see Figure 2) and therefore, a patient with too few neutrophils is more susceptible to bacterial infections. Neutropenia can occur for different reasons. Patients who have cancer may become neutropenic because of the chemotherapy they receive, sometimes neutropenia occurs after a viral infection. Some people are born with neutropenia, but in some cases the reasons are not known. The level of neutropenia may vary considerably. In general, the blood of healthy adults contains about 1500 to 7000 neutrophils per mm 3 ( x 10 9 /l). In children under 6 years of age the neutrophil count may be lower. To evaluate neutropenia in a child, it is important to compare the child s neutrophil counts to normal neutrophil counts of children the same age. The severity of neutropenia generally depends on the absolute neutrophil count (ANC) and is described as follows: Understanding Severe Chronic Neutropenia 4

5 Mild neutropenia, when the ANC falls below a lower limit of 1500 per mm 3 (1.500 x 10 9 /l), but remains higher than 1000 per mm 3 (1.000 x 10 9 /l). Moderate neutropenia, when the ANC falls between 500 per mm 3 and 1000 per mm 3 (0.500 x 10 9 /l x 10 9 /l). Severe neutropenia, when the ANC falls below 500 per mm 3 (0.500 x 10 9 /l). Very severe neutropenia (sometimes termed agranulocytosis ), when the ANC falls below 200 per mm 3 (0.200 x 10 9 /l). Figure 2. An artist s view of neutrophils attacking bacteria in the bloodstream. The duration of the neutropenia may be short lived, in which case, the patient is described as suffering from acute neutropenia. However, if a patient has neutropenia for a longer period, i.e., greater than three months, the patient is considered to have chronic neutropenia. The severity of symptoms usually correlates with the level of neutropenia. The lower the neutrophil count, the greater the risk of infection. This risk increases if low neutrophil counts persist for more than three days. Common types of mild infection include otitis media; tonsillitis; sore throat; mouth ulcers; gum infection and skin abscesses. Serious infections include pneumonia, peritonitis, and bloodstream infection (sepsis). Any fever (body temperature above 38.5 C/101.3 F) must be taken very seriously and the patient s nurse or physician should be informed. Severe neutropenia can lead to serious problems, which require prompt care and attention as the patient could potentially develop a bacterial, fungal or mixed infection at any time. These infections can be life threatening when the patient has persistent severe neutropenia. It is important that the patient sees a doctor as soon as possible and be treated with medications to fight the infection (such as antibiotics). Overview: Diagnosis & Treatment of Severe Chronic Neutropenia When a bone marrow sample is taken for diagnostic purposes, the cells are looked at under the microscope (see Figure 3) and often are used for other investigations, such as cytogenetics. If possible, a sample is sent to the SCNIR bone marrow cell bank to be used for research. Figure 3. A typical bone marrow of a patient with severe congenital neutropenia showing the absence of mature neutrophils (right) compared to the bone marrow of a healthy individual with neutrophils at all stages of maturation (left). Understanding Severe Chronic Neutropenia 5

6 With the cytogenetic evaluation, the chromosomes of the bone marrow are counted and studied for structural alterations. Most of the time, in the majority of patients with neutropenia, this test is completely normal. Changes in the chromosomes of cells can be harmless, but in some cases changes could indicate a possible progression towards leukemia (see Figure 4). This is the most important reason for routine annual bone marrow investigations. Figure 4. Each human cell (except for oocytes and sperms) contains two sets of 22 chromosomes and two additional sex chromosomes (females: XX, males: XY) as shown on the left side of this figure. Pre-leukemic changes may be represented e.g. by the loss of chromosome 7 as shown on the right panel of the figure, above. As soon as congenital neutropenia is diagnosed, most patients begin treatment with a hematopoietic growth factor called G-CSF (also known as filgrastim or lenograstim). Clinical trials of G-CSF treatment began at Amgen in This treatment resulted in a dramatic increase in the neutrophil count, leading to improved life expectancy and quality of life in these patients. As soon as the neutrophil counts have risen and stabilized, the patient can lead a normal life, including participation in school and sports. Before G-CSF was available, most patients died from severe bacterial infections within their first few years of life because no other treatment was able to correct their neutropenia adequately. Even antibiotic therapy could only prolong the life of these patients for a short while, because both neutrophils and antibiotics are necessary to overcome bacterial infections. G-CSF is a natural cytokine produced by the human body. A cytokine is a protein produced by cells, which is essential for the regulation of other cells. Patients with congenital neutropenia also produce G- CSF, but not in amounts adequate to correct the severe neutropenia in SCN. The lower the neutrophil count, the greater the risk of infection. Occurrence of severe bacterial infections is strongly correlated with low neutrophil counts. In most patients treated with G-CSF, bacterial infections resolve and recur less frequently once the neutrophil count stabilizes above 1000 neutrophils per mm 3 (1.000 x 10 9 /l). Individuals vary, some fight off infection with a lower neutrophil count, and others need a higher count. The response to G-CSF treatment also varies in congenital neutropenia patients. This explains the wide variation in the dose (amount) of G-CSF among the congenital neutropenia population. For more information regarding G-CSF see Treatment for severe chronic neutropenia. A very small subgroup of patients with congenital neutropenia do not respond even to very high doses of G-CSF. Patients who do not respond to G-CSF within fourteen days or require doses of more than 10 micrograms/kilogram (mcg/kg) may be evaluated for possible hematopoietic stem cell transplantation (discussed below). Risk of Myelodysplastic Syndrome and Leukemia During the last 20 years, data have been collected on more than 1100 patients with chronic neutropenia. These data indicate that patients who have severe congenital neutropenia have an increased risk of developing myelodysplastic syndrome (MDS) or leukemia, compared with healthy individuals. The risk appears to rise during the first 10 years on G-CSF therapy, then stabilizes but remains high, reaching around 20% after 15 years on treatment. In general, those who require high doses of G-CSF and still Understanding Severe Chronic Neutropenia 6

7 have low neutrophil counts (poor responders) have the highest risk, whereas those who maintain excellent neutrophil counts on lower doses of G-CSF have a risk of MDS/leukemia below that of poor responders, but still higher than the normal population. It is still not clear whether G-CSF permits survival to an age at which leukemia occurs due to the underlying bone marrow disorder or if there is an effect of G-CSF to promote the development of leukemia. In the era before G-CSF, patients with severe congenital neutropenia who survived past infancy also developed MDS and leukemia. The risk of leukemia is also high in other congenital diseases affecting blood cell formation (termed the inherited bone marrow failure syndromes). In any case, for most patients, the risk of infection without G-CSF treatment outweighs the risk of eventual leukemia. In addition, hematopoietic stem cell transplantation, the alternative to G-CSF treatment, has significant risk. Importantly, patients with cyclic neutropenia and acquired (e.g. idiopathic or autoimmune) neutropenia do NOT appear to be at risk for MDS or leukemia, whether or not they receive G-CSF therapy. The SCNIR recommends that all patients with all types of severe congenital neutropenia, except cyclic neutropenia, have a bone marrow examination and cytogenetic analysis on a yearly basis. A bone marrow examination is also recommended any time there is an apparent failure of G-CSF treatment or a worrisome change in blood counts. Transplantation should be considered if the bone marrow or chromosome pattern shows abnormalities indicating conversion to MDS or leukemia. Risk of Osteopenia/Osteoporosis Patients with chronic neutropenia on G-CSF therapy have in increased risk low bone density (osteopenia), which can lead to osteoporosis (more serious thinning of the bones). Osteoporosis may occur even in childhood in patients with severe chronic neutropenia. The risk of abnormal bone density tends to increase with G-CSF therapy, but it is still not clear whether this trend is due to the treatment or the underlying bone marrow disorder. However, very few patients actually experience clinical problems, such as pain and/or fractures due to their osteoporosis. As neither the exact cause nor the medical implications of osteoporosis are fully known, further research is underway on this problem. The SCNIR recommends monitoring of patients bone density on a regular basis with a dexascan followed by referral to an endocrinologist if the dexascan is abnormal. Types of Severe Chronic Neutropenia Severe chronic neutropenia can exist from birth (congenital neutropenia) or can occur at any time through life (acquired neutropenia). It may develop by itself or as an accompanying symptom of a different underlying disease. The following list gives examples of the different types of chronic neutropenias. Neutropenias present at birth: Severe congenital neutropenia (includes Kostmann syndrome) Cyclic neutropenia Shwachman-Diamond syndrome Metabolic diseases associated with neutropenia: Glycogen-storage disease type 1b Severe congenital neutropenia due to G6PC3 mutations Barth syndrome Understanding Severe Chronic Neutropenia 7

8 Immune disorders associated with neutropenia: Common variable immunodeficiency Myelokathexis/WHIM syndrome Wiscott-Aldrich syndrome Neutropenias that are acquired during life: Idiopathic neutropenia Autoimmune neutropenia Severe Congenital Neutropenia Severe congenital neutropenia is a rare type of neutropenia that is present at birth. It is an inherited disease and, therefore, more than one family member can be affected, but sporadic occurrence with only one patient in a family is also possible. One specific genetic form is termed Kostmann syndrome, but the name is also used at times as a general term for severe congenital neutropenia. Prenatal genetic diagnosis may be available in families in which the specific gene mutation has been identified. Congenital neutropenia is usually very severe, and neutrophils are often completely absent in the blood of these patients at the time of diagnosis. Patients who are diagnosed with congenital neutropenia usually show a maturation arrest (see Figure 5) in the early stages of neutrophil development in the bone marrow. This means that their neutrophils rarely fully mature into the cells that are capable of fighting infections. Figure 5. In healthy individuals, the maturation of neutrophilic granulocytes leads to segmented neutrophils, which leave the bone marrow and enter the blood. In congenital neutropenia patients, the maturation pathway is blocked at the stage of early precursor cells, the promyelocytes. These patients suffer from severe bacterial infections, such as omphalitis (infection of the umbilical stump), pneumonia, skin abscesses or otitis media (ear infections) during their first few months of life. Therefore, in most patients congenital neutropenia is diagnosed during infancy. A blood test and a bone marrow sample are required in order to obtain a correct diagnosis. Cyclic Neutropenia Cyclic neutropenia is another inherited type of neutropenia. As the name indicates, in this disease neutrophil counts show a cyclic pattern with a typical cycle length of 21 days. These cycles vary from patient to patient. Some individuals remain neutropenic during the whole cycle while others have low neutrophil counts for only a few days and normal blood counts during the rest of the cycle (see Figure 6). The frequency of bacterial infections depends on the length of the neutropenic period that Understanding Severe Chronic Neutropenia 8

9 the patient experiences. Those who have a longer neutropenic period within the cycle suffer more frequently from infections compared with patients who have only short neutropenic phases. If infections, fever, or aphthous stomatitis (inflammation and ulceration of the mouth) occur frequently in approximately three-week intervals, a diagnosis of cyclic neutropenia should be considered and serial differential blood counts need to be performed (at least three times per week over six weeks) to search for the cyclical pattern of blood neutrophils in this disease. Almost all patients with cyclic neutropenia have periods of severe neutropenia (ANC less than 200 per mm 3 [0.200 x 10 9 /l]) every three weeks with some symptoms almost every cycle, but significant infections (e.g., pneumonia or bloodstream infection) usually are infrequent. Cyclic neutropenia occurs because of fluctuating rates of cell production by the bone marrow stem cells. In contrast to other causes for neutropenia, in this condition the marrow changes during the cycle, from normal appearance to that of severe maturation arrest of neutrophil production, and then back again to normal. Figure 6. The absolute number of neutrophils in the blood of cyclic neutropenia patients cycles according to a typical pattern. Under G-CSF (filgrastim) therapy, the cycling is still present but the cycle length is shortened and the duration and depth of the neutropenic phase is decreased. Other blood cells, such as platelets or red cells, can also show oscillations with a cyclical pattern. Cyclic neutropenia can occur sporadically, but there are families in which cyclic neutropenia is inherited with one parent and more than one child affected. Patients with cyclic neutropenia benefit from G-CSF treatment, usually requiring lower doses than those used for severe congenital neutropenia. They appear to be at little or no risk of developing MDS or leukemia. Shwachman-Diamond Syndrome Patients who present with increased volume and frequency of fatty stools need testing for pancreatic function to rule out Shwachman-Diamond syndrome (SDS). SDS is an inherited (autosomal recessive) condition with multisystem abnormalities including pancreatic insufficiency (problems with digestion of fats in the diet resulting in large volume fatty stools), neutropenia, and short stature. At the time of diagnosis the features of SDS are extremely variable. The vast majority of patients are diagnosed in infancy, with symptoms of fatty stools and poor growth, with or without hematological abnormalities (including neutropenia). Other less common features can also be present at diagnosis. These include (extreme) short stature, skeletal abnormalities, and marked liver enlargement. SDS must be considered even if clinical symptoms of pancreatic insufficiency are absent because a significant percentage of patients do not have problems with digestion, or their symptoms may have resolved prior to the recognition of neutropenia. Understanding Severe Chronic Neutropenia 9

10 If neutropenia becomes severe, these patients also suffer from recurrent bacterial infections and treatment with G-CSF is helpful. Most G-CSF treated patients respond with an increase in blood neutrophils and reduction of infectious episodes. In SDS other blood cell numbers may also be decreased to a varying degree (potentially leading to anemia and/or thrombocytopenia). As for congenital neutropenia, patients with SDS have also an increased risk in developing leukemia and therefore it is strongly recommended to have bone marrow examination with cytogenetic testing on a yearly basis. Metabolic Disorders with Neutropenia Glycogen-storage disease type 1b is a rare metabolic disorder, which affects the glucose (sugar) metabolism. The liver, spleen and other tissues accumulate glycogen. Patients present with an enlarged liver and spleen, failure to thrive, kidney problems, hypoglycemia (low blood sugar) and recurrent infections. The presence of an enlarged spleen can be associated with low red blood cells causing anemia and thrombocytopenia, whereas neutropenia is always present. Chronic neutropenia in these patients is accompanied by a defective function of the cells that are responsible for the killing of bacteria. Patients respond to treatment with G-CSF not only with an increase in ANC but also with improvement of the activity of their neutrophils. Barth syndrome is a very rare metabolic disorder that includes not only neutropenia, which may be cyclic, but also heart muscle weakness (cardiomyopathy) and growth delay. For more information, visit Idiopathic Neutropenia The term idiopathic neutropenia describes various types of neutropenia that may occur at any point in life for unknown reasons. As already described for the other types of neutropenia, frequency and severity of infections is correlated with the neutrophil counts. Neutrophil counts and clinical problems in these patients vary considerably, but in general the more severe the neutropenia the more serious and frequent the infections. Most patients respond well to G-CSF treatment but require longterm treatment. There is no evidence for any increased risk of MDS or leukemia in patients with idiopathic neutropenia, whether or not they receive G-CSF therapy. Likely the causes of idiopathic neutropenia are multifactorial and may include autoimmune, genetic, and physiologic causes. Autoimmune Neutropenia In neutropenic children aged 6 months to 4 years the presence of neutrophil-specific antibodies can result in increased destruction of the body s own neutrophils. This process, termed autoimmune neutropenia, is the most common cause for neutropenia of this age group. Although these infants often have very low absolute neutrophil counts, they usually do not suffer from severe bacterial infections. Anti-neutrophil antibodies may be detectable by immunological blood tests that can be performed in specialized laboratories, but the absence of a positive test to these antibodies does not rule out the diagnosis of autoimmune neutropenia, nor does a positive test rule out congenital neutropenia. Patients should be kept under medical care, but may not necessarily require treatment with antibiotics or G-CSF. Depending on the frequency of infections and the neutrophil counts, prophylaxis with an oral antibiotic may be considered by the treating physician. For the few children who develop severe infections or have significant impairment of life style (e.g., frequent visits to emergency rooms), Understanding Severe Chronic Neutropenia 10

11 treatment with G-CSF is almost always effective. In most children the blood counts normalize by age 3-5 years. Autoimmune neutropenia is also seen in adults, predominantly in women. The adult form of autoimmune neutropenia is less likely to resolve spontaneously and more likely to be associated with other autoimmune disorders. There is no evidence for any increased risk of MDS or leukemia in patients with autoimmune neutropenia, whether or not they receive G-CSF therapy. Other Conditions Associated with Neutropenia There are a number of other conditions that include neutropenia as part of the symptoms. Depending on the nature of the main condition the way the neutropenia is managed may differ from the treatment of pure SCN described. The main conditions that may include neutropenia are: Severe acquired aplastic anemia Viral illnesses Post chemotherapy or radiotherapy Other drug-induced situations Fanconi anemia There are some other very rare disorders, congenital or acquired, that may be associated with neutropenia, e.g., myelokathexis, hyper IgM syndrome, or severe combined immunodeficiency. This list may be incomplete and more information about diseases associated with neutropenia is being discovered all the time. Genetics of Severe Congenital Neutropenia Recent research, much of it based on SCNIR data and materials, has identified the genetic basis of many of the inherited forms of severe chronic neutropenia, as well as genetic alterations responsible for some of the multifaceted syndromes accompanied by neutropenia. The diagnosis of these disorders, which is generally based on clinical and laboratory features, may now be supplemented by genetic testing. Under some circumstances, these tests also can be applied to prenatal diagnosis. The classification of primary neutropenias refers to disorders of neutrophil production, including cyclic neutropenia and severe congenital neutropenia. Cyclic neutropenia is inherited in an autosomal dominant fashion. It can occur sporadically as well. Both sporadic and autosomal dominant cyclic neutropenia derived from mutations in the ELANE gene (formerly termed ELA2) encoding the protein neutrophil elastase (Table 1). Severe congenital neutropenia can occur sporadically, in an autosomal dominant fashion, or as an autosomal recessive disorder (Kostmann syndrome). Mutations in the ELA2 gene are responsible for 60% of severe congenital neutropenia cases (Table 1). Additionally, very rare cases of autosomal dominant severe congenital neutropenia can arise from mutations in the genes GFI1, PRDM5, or PFAAP5. The autosomal recessive form of severe congenital neutropenia is associated with mutations in the HAX1 gene (Kostmann syndrome) or G6PC3 gene (a very rare syndrome that also includes heart, urogenital, and skin abnormalities). It is important to note that autosomal dominant disorders, even when occurring sporadically, have a 50% chance of being passed on to the children of an affected individual. Autosomal recessive disorders have a 25% chance of occurring in the siblings of an affected patient, but only a very remote chance of being passed on to the next generation. Healthy siblings of affected patients documented to have autosomal dominant neutropenia do not run the risk of transmitting neutropenia to their children. Understanding Severe Chronic Neutropenia 11

12 Genetic Classification of Neutropenia Syndromes Disorder Inheritance Gene(s) Disorder of neutrophil production Cyclic neutropenia autosomal dominant ELA2 Severe congenital neutropenia autosomal dominant ELA2, other rare genes Kostmann syndrome autosomal recessive HAX1 Disorder of the nucleus Shwachman-Diamond syndrome autosomal recessive SBDS Disorders of metabolism Glycogen storage disease, Type 1b autosomal recessive G6PT1 Barth syndrome X-linked recessive TAZ1 Disorder of Immune Function Myelokathexis (WHIM syndrome) autosomal dominant CXCR4 Much rarer causes of neutropenia include disorders affecting the nucleus or metabolism of neutrophilproducing cells, or interfering with immune function. In Shwachman-Diamond syndrome (see separate section above/below) around 90% of patients who meet the clinical criteria for this syndrome harbor mutations in the SBDS (Shwachman-Bodian-Diamond syndrome) gene, which is inherited in an autosomal recessive fashion. Another disorder of neutrophil production, glycogen storage disease Type 1b is associated with the abnormalities in the metabolism of neutrophil precursor cells. It is inherited in an autosomal recessive fashion and is associated with mutations in the gene, G6PT1. Barth syndrome, another rare disorder of metabolism, is inherited as an X-linked recessive disorder, which appears in males. In this inheritance pattern, there is a 50% chance of the same disease in a patient s brothers. The children of affected men cannot have the disease, but their daughters carry the gene and have a 50% chance of transmitting the disorder to their sons. Among the immune disorders, myelokathexis (part of the WHIM syndrome) is transmitted as an autosomal dominant disorder. The SCNIR office can provide advice on where genetic counseling and testing can be obtained. Diagnostic Tests Used in Severe Chronic Neutropenia When a diagnosis of neutropenia is suspected (e.g., with recurrent infections which may occur on a cyclical basis) physicians will begin by taking a Complete Blood Count/Full Blood Count and proceed to further tests if necessary (Complete Blood Count (CBC) or Full Blood Count (FBC), is the same thing and these terms are interchangeable). These examinations will be extended to include the bone marrow of the patient. The most important investigations performed are explained below. Blood Count Monitoring As already mentioned, the first investigation on suspicion of neutropenia is a CBC/FBC. By this procedure the neutrophil count is measured. If the neutrophil count is low it is normal to repeat the CBC/FBC to be certain that the neutropenia continues. In patients with SCN the neutrophil count may vary slightly, but it always remains at a very low level in contrast to cyclic neutropenia. If the neutrophil count is normal but at other times it is very low, the physician may suspect cyclic neutropenia. To confirm the diagnosis the physician will arrange for blood samples (CBC/FBC) to be taken three times per week for at least six weeks to see whether there is a regular cyclical pattern of neutrophil counts. Understanding Severe Chronic Neutropenia 12

13 Other Blood Tests The physician will also do a blood test to exclude autoimmune neutropenia by testing for antibodies (see section regarding autoimmune neutropenia). Bone Marrow Aspiration/Biopsy If the patient s blood tests indicate neutropenia, then it is important to do a bone marrow examination to confirm the diagnosis by looking at the marrow cells under the microscope (see Figure 4). Bone marrow cells are usually taken from the large pelvic bone, the ilium, or, sometimes also from the flat breastbone, the sternum. This is usually done with the patient asleep under general anesthetic or under local anesthetic with sedation. The actual technique may vary between treating centers. Your physician will explain exactly how the procedure will be done for you. There are two different methods to examine bone marrow. The first is a bone marrow aspirate where marrow cells can be taken out like taking a blood sample from a vein but this time from the middle of the bone. In the second method, bone marrow biopsy, a small piece of bone marrow is taken and processed differently, to look at the architecture of the marrow structure. Cytogenetic Evaluation and Molecular Testing As mentioned previously, it is important to monitor the cytogenetics of the marrow cells, as changes in the chromosome pattern may develop before any abnormalities in the appearance of bone marrow cells. There are additional techniques by which some cytogenetic changes can be monitored; your physician will explain these to you. SCN is a very rare disorder. Some treating centers are actively involved in research of SCN and may suggest other investigations. Investigations in Other Conditions To be certain about the diagnosis of conditions that are not limited to the blood system (e.g., Shwachman-Diamond syndrome, glycogen storage disease type 1b and others) investigations beyond blood tests may be necessary. Your physician will explain what further tests are required. Sometimes this may involve visits with other specialists. Treatment for Severe Chronic Neutropenia The treatments that have been tried or are being used in the management of congenital, cyclic and idiopathic neutropenia include: Granulocyte-colony stimulating factor (G-CSF) Hematopoietic stem cell transplant (HSCT; also called bone marrow transplant) Others, including: other cytokines antibiotics corticosteroids* Understanding Severe Chronic Neutropenia 13

14 immunosuppressive drugs* immunoglobulins vitamins white cell transfusions Supportive care, discussed below * treatment with these agents is generally not recommended, except for patients with rheumatological conditions (e.g., lupus), as they weaken other parts of the immune system. Treatments prescribed by your physician are extremely important to decrease the potential for infection. Good nutrition and hygiene (including good dental hygiene) are also very important. Nutritional treatments will not however raise the neutrophil count in severe chronic neutropenia. Patients should discuss specific treatment options with their physicians. These discussions should include the benefits of treatment and potential risks. Granulocyte-Colony Stimulating Factor (G-CSF, Neupogen ) G-CSF is a cytokine normally produced by the human body itself. G-CSF, which is given as treatment, is NOT from human beings but is safely manufactured (by genetic engineering) to produce an identical substance that has all the normal activity and function of the naturally-occurring cytokine. Therefore there is no risk of viral infection from G-CSF therapy. G-CSF stimulates the production of, and enhances the activity of, mature neutrophils thus improving their bacteria-killing function. It acts via a receptor localized on granulocytes that binds the G-CSF to the cell and produces a signal to tell the cell to mature, to divide or to enhance function (see Figure 3). SCN patients produce their own G-CSF, but much larger (treatment) doses of G-CSF are required to correct the neutrophil count. The dose and frequency of injection of G-CSF required to increase and maintain the neutrophil count to 1000 per mm 3 (1.000 x 10 9 /l) varies widely. For most patients, G-CSF given at 5-20 mcg/kg/day (micrograms per kilogram of body weight per day) as a daily subcutaneous injection is sufficient. But some patients need very high doses, even up to 120/mcg/kg/day (potentially injected more than once per day). Others need very low doses, as low as 0.01 mcg/kg/day. Some patients may require injections less often than daily, but short-term adjustments may be necessary if infection occurs. Treatment less often than every two or three days is rarely effective. G-CSF is usually administered by a subcutaneous injection (i.e. an injection just under the skin). Recommended sites include the abdomen below the naval, upper outer arms, and upper outer thighs (Figure 7). It is possible to self-administer G-CSF and this should be encouraged as it promotes a sense of independence and control over at least one aspect of treatment. As with any frequent and regular subcutaneous injection, rotation of the sites is recommended to prevent scarring and discomfort to the patient. The injection is not usually painful but, occasionally, a stinging sensation may be experienced for a short period of time on administration. Administration of G-CSF may result in a dramatic increase in the numbers of neutrophils in the blood and is without doubt the most effective therapy in treating SCN. Some SCN patients receiving G-CSF report bone or muscle pain and splenomegaly. Other side effects are infrequent but a few patients have experienced thrombocytopenia, injection site reactions, rash, enlarged liver, joint pain, Understanding Severe Chronic Neutropenia 14

15 Figure 7. Where and how to apply G-CSF. osteoporosis, rash, blood or protein in the urine, hair loss and exacerbation of some pre-existing skin disorders (e.g., psoriasis). If these or other side effects occur, the patient s doctor should be notified. In addition, cytogenetic abnormalities, transformation to myelodysplasia (MDS) and leukemia have been observed in patients with congenital neutropenia treated with G-CSF (this issue is discussed in detail above). Hematopoietic Stem Cell Transplant HSCT is the only curative treatment option for SCN. It may be considered for failure to respond to treatment, or for patients who develop MDS or leukemia in the course of their disease. Due to the higher risk of MDS and leukemia in SCN with a poor response to high doses of G-CSF (see Risk of MDS/Leukemia), some individuals in this group may also be considered for HSCT. Transplantation is a very intensive procedure, carrying serious risks and is therefore not recommended as first choice treatment. It is important for the patient and physician to discuss in detail the risks and benefits of this procedure. The HSCT procedure includes chemotherapy to eliminate the abnormal bone marrow, and then infusion of the donor s bone marrow through an intravenous (IV) catheter, much like a blood transfusion; no surgery is involved. Often, long-term medical management is necessary after transplant to treat or prevent complications of the procedure. The donor, who may be a close relative or a matched volunteer, provides the necessary hematopoietic stem cells from bone marrow (multiple needle punctures, under anesthesia) or blood (run from one vein, through a cell separator, and returned to another vein by a process called pheresis). Hematopoietic stem cells can also be obtained from frozen, stored umbilical cord blood units, which also need to be matched to the patient s tissue type. Hematopoietic stem cells are distinct cells, capable of reconstituting the blood and immune systems, but different from embryonic stem cells that could theoretically form an entire organism. Other Treatments Corticosteroids: In some conditions steroids have long been effective at increasing neutrophil counts in the blood. Steroids work by encouraging neutrophils to leave the bone marrow and enter the blood stream. However, they do not induce the production of new neutrophils in the bone marrow and they may decrease the function of neutrophils and the number of other types of white cells, thus increasing the risk of infection. In general, steroids have not proven useful for patients with SCN, except for some patients with neutropenia associated with lupus or other chronic rheumatologic conditions. In addition to the unwanted side effects of increasing the risk of infection, long-term use of steroids has many other side effects, e.g., it may induce the development of diabetes mellitus. Understanding Severe Chronic Neutropenia 15

16 White cell transfusions: White blood cell transfusions are rarely used. They are generally reserved for severe lifethreatening infections. The replacement of neutrophils by transfusion is not feasible in the long term for various reasons. The collection of these cells is quite difficult, the mature neutrophil has quite a short life span and the cell cannot be stored for more than a few hours. Even more than with other blood products, there are also risks of severe reactions to the transfusion. Supportive Treatment There are a variety of supportive therapies; only the most important are addressed below: Mouth care: this should include regular dental checkups. Excellent oral hygiene is very important and the use of an antibacterial mouthwash is recommended. Immunizations and vaccinations: people with SCN have an intact immune system that allows them to make normal antibodies protecting from the devastating effects of viral illnesses. Therefore all routine immunizations according to the standard vaccination schedule of your country are recommended. Influenza vaccine should also be administered if recommended for the patient s age group. Monitoring temperature: in the case of a fever above 38.5 C/101.3 F the patient must seek medical attention. Good general hygiene including thorough hand washing. Oral prophylaxis: antibiotics/antifungals, either oral or intravenous, may be given to SCN patients but this is very much based on individual physician choice. Prompt contact of physician/hospital/clinic: it is important to have these contact telephone numbers easily accessible. Foreign travel: concerns should be raised with your physician, as special precautions, emergencies and contact telephone numbers need discussion. A list of the neutropenia experts in different European countries cooperating with the SCNIR is located at the website Long Term Management of Severe Chronic Neutropenia The key issue in the treatment of SCN is normalization of life and the promotion of a normal life for you. This includes schooling, vacations, family life and social life. Administering G-CSF allows a neutropenic patient to continue daily life tasks without the risk of dangerously low levels of neutrophils. A CBC/FBC evaluation gives the physician the information needed to monitor your ANC. Monitoring the ANC alerts the physician to the need to adjust the G-CSF dosing. When G-CSF treatment is initiated, your doctor will follow your ANC closely, generally for the first 4 to 10 weeks to assure that the dose of G-CSF is correct for you. The Registry suggests that when the dose has been stabilized, severe congenital neutropenia patients should still be monitored with a monthly CBC/FBC. For patients on a daily administration of G-CSF, blood should be drawn approximately 18 hours after dosing. Patients taking G-CSF on a less frequent program should have the CBC/FBC done just prior to the next administration of the medication. This allows the physician to monitor the ANC at its lowest point. (See neutropenia health tips on the website, check out CBCs, nice table, may want to include) Understanding Severe Chronic Neutropenia 16

17 Bone Marrow Monitoring Bone marrow aspirate and biopsy procedures are done to help the physician diagnose the patient s medical condition. The bone marrow evaluation will help confirm if the patient has congenital neutropenia or another form of neutropenia. After the diagnosis is confirmed, the Registry suggests that patients with congenital neutropenia be followed on a yearly basis with bone marrow and cytogenetic evaluations to monitor for changes in their bone marrow. Early detection of MDS or leukemia through bone marrow monitoring can lead to more successful therapy. SCN patients with types of neutropenia other than congenital neutropenia (such as cyclic, idiopathic, or autoimmune) may have annual bone marrow testing at the discretion of their physician. Pregnancy The SCNIR collects information on SCN patients and pregnancy; however, the number of pregnancies reported to date is relatively small and thus little information is known about the potential effects of G-CSF during pregnancy. Therefore, the use of G-CSF during pregnancy should be evaluated on an individual basis with your primary physician, who can weigh the currently-known risks and benefits of the treatment in the context of your individual situation. Because the safety of G-CSF administration during pregnancy is not yet established, the current recommendation given by the experts of the SCNIR is that if possible, G-CSF should be avoided or minimized during the first trimester. You should discuss this issue with your physician well in advance of any decisions regarding pregnancy. It will then be possible for your physician to review the current pregnancy data with you and develop a plan for G-CSF dosing. Psychosocial Issues Family dynamics, school and employment all can be affected by the increased stress caused by the chronic illness of a family member. Families and patients with SCN may experience similar stresses to those found in families with a family member with diabetes, epilepsy, cystic fibrosis, or other longterm conditions. Children with SCN will experience the normal milestones of childhood along with the added stress caused by having a chronic condition. After the diagnosis of SCN the patient and family may experience the common feelings of confusion, bewilderment and possibly anger. SCN is difficult to diagnose. Some patients will have life threatening infections, others constant infections, while some experience only intermittent infections. There may be disruptions to normal family life because the untreated SCN patient may have unpredictable illnesses. Vacations or travel may be avoided or delayed because of the unpredictable nature of infections that may occur. Families may feel isolated from friends and community, needing to speak with other families that are dealing with this rare problem. Joining support groups, family- or professionally-led, will help with these feelings. Listed below are support groups dedicated to helping families and patients whose lives have been impacted by neutropenia. All pre-school children s developmental milestones include the mastery of their environment. Children with SCN need to be involved in their health care as is appropriate for their age. This may include learning to clean cuts and scrapes, proper hand washing, and helping with the administration of the G-CSF. At this age it may be beneficial for a child to be given a doll to care for that also is neutropenic allowing the child to act as the doll s caregiver. The treated SCN child may want to act out giving the doll medication. This allows the child to act out the frustrations he/she is feeling regarding the neutropenia and to begin the process of learning necessary coping mechanisms. All school-aged children utilize school for socialization and academic development. This development is essential to help the child move through the milestones of childhood. The SCN child Understanding Severe Chronic Neutropenia 17

18 will need all caregivers (such as school teachers, school nurses, day-care providers, coaches, etc.) to understand SCN. The SCNIR website has letters explaining SCN that you can share with providers. Adolescence is a difficult time for most children. Children with SCN will realize, often for the first time that they are different from their peers. This may be the first time the child understands that he/she will have SCN for the rest of their life. The adolescent may feel that SCN affects school or relationships with peers. It is not uncommon for the adolescent to respond with denial and/or resentment of their condition. They may develop behaviors such as not caring for skin infections, lack of good oral hygiene or stopping the administration of the G-CSF. At this stage the adolescent is struggling to maintain a positive self-image. The child may struggle against anything that appears to label them negatively. It is important for the parent to be alert to signs of change in habits or patterns that might indicate signs of depression or unusual anger (such as decreased interest in school or extreme behavior). Parents need to trust their intuition and knowledge of the child s normal behavior. If a parent observes concerning changes in the adolescent s behavior, they should contact the child s primary health care provider to discuss their concerns. The Severe Chronic Neutropenia International Registry The Severe Chronic Neutropenia International Registry (SCNIR) was established in 1994 to monitor the clinical course, treatment, and disease outcomes in patients with severe chronic neutropenia (SCN). The Registry has the largest collection of long-term data on patients with this condition in the world. Participation in the Registry benefits patients, their families and the physicians who treat them by providing the most up-to-date information on the natural history of SCN and its treatment options. Patients qualify for the Registry if: Their ANCs are under 500 per mm 3 (0.500 X 10 9 /L) on at least three occasions in the three months prior to applying for the Registry (if currently treated, three ANC s under 500 per mm 3 [0.500 X 10 9 /L] prior to the start of G-CSF therapy) with the exception of patients with Shwachman-Diamond syndrome, glyogen-storage disease type 1b and Barth syndrome who are enrolled with higher ANC s or even no neutropenia at all. There is a history of recurrent infections. Patients do not qualify for the Registry if: Their neutropenia is known to be drug-induced. The patient has any one of the following conditions: Thrombocytopenia (SDS and GSD-1b patients are an exception to this exclusion) Myelodysplastic syndrome Aplastic anemia HIV positive Known immune diseases such as rheumatoid arthritis The patient has had chemotherapy for cancer within the past 5 years. For patients qualifying for the Registry the following basic examinations are required: A bone marrow evaluation has been completed that confirms the diagnosis of SCN. Understanding Severe Chronic Neutropenia 18

19 A cytogenetic evaluation has been completed, if G-CSF treatment has been considered or initiated. The patient has signed a formal consent to allow the anonymous use of his/her data. The objectives of the SCNIR are to: Document the clinical course of SCN and monitor clinically significant changes e.g., primary treatment response over time and long-term safety. Study the incidence and/or outcome of the following previously identified adverse events: osteoporosis, splenomegaly, vasculitis, thrombocytopenia, cytogenetic abnormalities, myelodysplastic syndrome, and leukemia. Establish a physician network to increase the understanding of SCN. Establish a demographic database to allow for current and future research. Collect bone marrow samples of patients at different time points for current and future research. The SCNIR Advisory Board of expert physicians/hematologists list can be found on the SCNIR web site: A panel of European physicians/hematologists called the Local Liaison Physicians located throughout the European countries can be found on the web site Information concerning the SCNIR can be obtained from the web site: In the USA In Europe Severe Chronic Neutropenia International Registry University of Washington, Seattle Phone +1(206) * or (800) (inside the U.S.) FAX +1(206) * Severe Chronic Neutropenia International Registry Medizinische Hochschule Hannover Kinderklinik D Hannover, Germany Phone +49 (511) * FAX +49 (511) * Severe Chronic Neutropenia International Registry Web Sites United States Germany Understanding Severe Chronic Neutropenia 19

20 Support Groups Support groups can provide assistance with linking families to others who have a family member with SCN. These contacts can help alleviate the alienation families often feel when one of their members is chronically ill. USA National Neutropenia Network Lee Reeves Phone ( ) Canada Europe Schwachman-Diamond Syndrome Foundation Lorna Stevens Phone (877) (inside the U.S. only) Barth Foundation Linda Stundis Phone: (617) Neutropenia Support Association Inc. Phone (800) Interessengemeinschaft Neutropenie Hannover Phone +49 (4441) * *The + preceding the country code represents the local predial code for international calls. Frequently Asked Questions and Answers Why does my child have SCN? Nobody truly knows how and why SCN develops. It is often, but not always, genetically inherited. Cyclic neutropenia and most cases of congenital neutropenia are inherited in an autosomal dominant manner. This is where one parent actually suffered to some extent from the condition himself or herself due to a gene that was dominant over its partner gene. There is a 50% possibility that other children in the family could be affected and that your child will pass the disorder onto his/her children. Rare congenital neutropenia cases with a mutation in the HAX1 gene (Kostmann syndrome) are inherited as an autosomal recessive disorder. This means that the affected patient s parents are carriers of the gene responsible for the disorder, and both passed that gene to their child. The only way your child can pass the disorder on to his/her children is if he/she married somebody else with a carrier gene. However, in all subtypes of inherited neutropenia exceptions to the above mentioned pathway are possible, e.g., that in some cases the disease can occur for the first time in a family without having a parent carrying the gene. Understanding Severe Chronic Neutropenia 20

21 Autoimmune and idiopathic neutropenia are not inherited and are very unlikely to be passed on to future children. Autoimmune neutropenia may be associated with other autoimmune disorders, for which your physician may wish to perform additional testing. Will my child with chronic neutropenia develop normally, especially in their growth and development? Children with chronic neutropenias develop in the usual way. However, some children with congenital neutropenia may tend to be smaller than individuals with other chronic neutropenias or those without neutropenia. My child is due some vaccinations, is it safe for her/him to have them? In general, it is safe for your child to have vaccinations (including yearly influenza immunization) and all routine vaccinations are recommended to be given at the standard time intervals. Your physician should discuss any limitations based on your child s diagnosis. My child recently had an extremely bad case of flu, which my doctor did not treat with antibiotics; however, when my son cut himself after falling over the doctor did treat him with antibiotics. My doctor told me the difference was that flu was a different type of infection in which antibiotics would not be successful. I am now extremely confused as to what type of infections I should be looking out for. Can you please explain? Neutrophils are the most important cells against bacterial and fungal infections. Your child has a reduced number of neutrophils and hence is at greater risk of developing bacterial infections. Skin cuts, abrasions, ulcers etc., are at risk of becoming infected by bacteria. Bacterial infections are treatable by antibiotic therapy. In contrast, viruses cause most colds, flu and other childhood illnesses such as chickenpox. Antibiotics cannot treat these diseases. Viruses are eliminated by lymphocytes, which usually are not reduced in your child s blood, so neutropenia patients usually have normal immune responses to viral infections. If you have any doubt about the type of infection your child has, you should take him to his physician. What is the life expectancy of a child with chronic neutropenia? Before the availability of G-CSF, people with chronic neutropenia had many problems with infection. In some individuals, these infections were life threatening and some died from infection at a young age. Patients who are treated with G-CSF and have a near-normal ANC as a result, should be able to have a normal life expectancy. However, some patients with congenital neutropenia develop life-threatening complications such as MDS or leukemia. When should my child commence G-CSF? Your child should start G-CSF therapy if he/she is suffering from frequent mouth ulcers or infections that limit quality of life. People differ: the same neutrophil count in different individuals may result in different numbers of infections. The important thing is to reduce the number and seriousness of infections in your child whatever the baseline neutrophil count is. Is there a safe limit to the amount of time you can take G-CSF? The SCNIR has information on many individuals who have received long term G-CSF treatment since the late 1980s. It indicates that long term G-CSF therapy is safe and remains effective. Understanding Severe Chronic Neutropenia 21

22 Can you take G-CSF orally? G-CSF cannot be taken orally because it is a protein that would be destroyed by the stomach and intestines during the digestive process. Is it safe to have surgery while on G-CSF? Yes, it is OK to have surgery as long as the surgeon is made fully aware of your condition and G- CSF treatment. You should obtain medical clearance from your hematologist prior to elective surgery and receive advice regarding your G-CSF dosing and schedule. My daughter, who is aged 7, wants to attend a camp with her school. As she has severe congenital neutropenia and is receiving daily G-CSF that I administer to her, I am reluctant for her to attend but I also do not want her to miss out on these opportunities. Have you any advice? Your daughter should be encouraged to participate in all activities with children of her own age. Going away to camp will need special arrangements for storage and administration of G-CSF that can be arranged with the camp doctor/nurse. Alternatively, many pediatric hematology/oncology centers have summer camps in which physicians or nursing staff is able to administer medications. My son has been receiving G-CSF since he was diagnosed with severe congenital neutropenia three months ago. While he is a lot better he still tends to get breakthrough mouth ulcers, which cause him a lot of discomfort. Is there anything we can do to help alleviate his suffering? Children may benefit from good mouth care including flossing and regular dental checkups. If the neutrophil count is low, he may also benefit from mouthwashes such as chlorhexidine (Peridex and other brand names) or benzydamine (Difflam). It also may be useful to see your physician to discuss the dose of G-CSF; it may be that the dose needs modifying which could mean an increase. I am 27 years old and have cyclic neutropenia. For this, I receive G-CSF three times a week. My boyfriend and I are getting married in a few months and soon after we would like to start trying for a family. Can you give me any advice on a.) the chances of our child having cyclic neutropenia and b.) any special precautions I should take while pregnant? The chance of your child also having cyclic neutropenia is 50% as long as your partner does not have cyclic neutropenia as well. This is because cyclic neutropenia is inherited in an autosomal dominant pathway. It would therefore be advisable to see a geneticist to discuss your individual risk. As G-CSF can cross the placenta to the fetus, it is best to discuss with your physician before you are pregnant the G-CSF dosing options and develop a plan to deal with infections that may occur. At this present time, we do not usually recommend the use of G-CSF in the first trimester, if possible. If you are currently pregnant, you should discuss what the dosing should be and what conditions caused by neutropenia would require you to contact your physician (such as fever or an infection). Will a certain diet improve my disease? A good balanced diet will be beneficial for your family s overall health as it will provide essential nutrients and vitamins to ensure good health and promotion of normal growth and development. Understanding Severe Chronic Neutropenia 22

23 There are no known vitamins, herb supplements or special diets that help raise the neutrophil level. Can my child participate in school activities? Yes, providing that your child does not have a significantly enlarged spleen, low platelets or other restricting medical condition, he/she should be able to participate in all sports and other activities in the usual way. The school should be aware of your child s neutropenia and report any injuries to the parent. What advice should I give to teachers at my child s school? Explain about your child s diagnosis and ask them to be vigilant for any fever or infections your child may develop. Ensure that they are aware that neutropenia is not contagious and that your child is able to fully participate in all school activities and should be treated differently from any other child. (See below for a letter that can serve as an example). Where and how can I get in contact with other patients? Listed below is contact information for patient support groups including websites and phone numbers. Your physician may be able to help you by looking at the SCNIR web page or, contacting the appropriate office in Australia, Germany, the United Kingdom or the USA (see above). Where can I find more literature on the disease? The SCNIR web page has a reference list; in addition you can obtain literature by contacting the offices of the Registry (see above). Understanding Severe Chronic Neutropenia 23

24 Information for Schools Regarding Severe Chronic Neutropenia To: From: Severe chronic neutropenia (SCN) is the name given to a group of conditions in which neutropenia is the primary problem. The term neutropenia describes the situation where the numbers of neutrophils in the blood is too low. The neutrophils are very important in defending the body against bacterial infections and therefore, a patient with too few neutrophils is more susceptible to bacterial infections. This condition is not contagious and cannot be spread from one person to another. It is a genetic blood disorder. Neutropenia is treated with injections of a cytokine called G-CSF or Neupogen. This helps the body create neutrophils to fight infection. Please help us to fight infections by cleaning minor cuts with an antibacterial soap or Betadine. Please notify me the day of the injury so that I may monitor the wound. For wounds that may need special care please notify me immediately. For fever above 101 F (38 C) please call me immediately. If you have concerns about my child s health, you may reach me at the following telephone numbers:. For more information regarding neutropenia, please visit the following websites: SCNIR or the National Neutropenia Network; or contact my child s physician at:.. Understanding Severe Chronic Neutropenia 24

25 Glossary ANC (absolute neutrophil count), determined by adding the percentage of neutrophils in the blood with the percentage of bands in the blood, multiplying that number by the white blood count and dividing the product by 100. This number represents the amount of neutrophils that are available for defending the body at the time of the blood test. A normal ANC is generally within the range of Acute myeloid leukemia (AML), an acute form of leukemia, a malignant disease of the white blood cells affecting monocytes or granulocytes. It is characterized by the appearance of immature, abnormal cells in the bone marrow and peripheral blood. Alopecia, loss of hair. Anemia, too few red blood cells. Antibodies, proteins made by a subgroup of white blood cells the lymphocytes that are responsible for the body s defense. Antibodies are normally directed against foreign structures like bacteria or viruses. However, sometimes they also may be directed against structures and cells of their own body, e.g., in the case of anti-neutrophil antibodies where the antibodies recognize and destroy the patient s own neutrophils. Aplastic anemia, a deficiency of all types of blood cells, representing a failure of the bone marrow to produce these cells. Arthralgia, painful joints. Arthritis, inflammation of joints. Autosomal dominant, a particular type of genetic inheritance. In a disorder with a dominant inheritance pattern, such as cyclic neutropenia, a child will have the disease if one parent passes on the affected gene. Usually that parent will also have the disorder. Autosomal refers to the fact that the inheritance is independent of the child s sex. Autosomal recessive, a particular type of genetic inheritance. In a disorder with a recessive inheritance pattern, such as Kostmann syndrome, a child will have the disease only if both parents pass on an affected gene. The parents usually show no sign of the disorder. Autosomal refers to the fact that the inheritance is independent of the child s sex. Bands, juvenile neutrophils. These are usually counted as neutrophils and contribute to the absolute neutrophil count (ANC). They may also be called stabs on a differential count. Basophils, a subgroup of granulocytes, which may increase after splenectomy. Bone marrow, the spongy material located in the center of our bones. It is the home of our stem cells, which reproduce to create our blood, including white blood cells, red blood cells, platelets, B- and T- lymphocytes and macrophages. Bone marrow transplantation (BMT), see hematopoietic stem cell transplantation. CBC (Complete Blood Count), a determination of the numbers of all types of cells present in the blood; same as FBC. Chemotherapy, a drug treatment to destroy cancer cells. Understanding Severe Chronic Neutropenia 25

26 Chromosomes, carry all genetic information and are located in the cell nuclei. Changes of the chromosomes may indicate the development of a disease. They are counted and examined by cytogenetic testing. Cutaneous, concerning the skin. Cytogenetics, a method by which chromosomes are counted and analyzed under the microscope. Differential blood count, a form of blood count that specifies the number of each type of white blood cell. Erythrocytes, red blood cells. FBC (Full Blood Count), a determination of the numbers of all types of cells present in the blood; same as CBC. Filgrastim, the international non-proprietary name for recombinant human G-CSF. G-CSF, granulocyte colony-stimulating factor, a protein that stimulates the production and function of granulocytes. G-CSF receptor, a structure on the surface of a cell to which G-CSF binds. Binding of G-CSF to its receptor, provides information to the cell on how to proceed, (e.g., grow, divide, mature, etc.). Genetic engineering, a method by which a gene can be changed in structure or reproduced in the laboratory. Examples include gene cloning, production of recombinant proteins (such as G-CSF), and gene therapy. Glycogen, a large molecule that serves as a storage form of glucose (sugar). Granulocyte, a type of leukocyte. The category includes not only neutrophils, but also eosinophils and basophils. However, granulocyte, neutrophil, and polymorphonuclear leukocyte are often used interchangeably. Hematopoiesis, the formation of blood. Hematopoietic growth factor, a protein stimulating the production (growth) of blood cells. Hematopoietic stem cells, very rare bone marrow or blood cells that have the potential to develop into any type of mature blood cell (e.g., red cells, white cells, platelets). These cells are NOT the same as embryonic stem cells. Hematopoietic stem cell transplantation (HSCT), the transfer of blood-forming stem cells from one individual (the donor) to another (the recipient), leading to permanent replacement of the recipient s bone marrow, blood, and immune system with donor cells. The stem cells may come from the donor s blood or bone marrow. In the latter case, the procedure is termed bone marrow transplantation (BMT). Hematuria, the occurrence of blood in the urine. Hepatomegaly, enlargement of the liver. HIV, human immunodeficiency virus. Understanding Severe Chronic Neutropenia 26

27 Incidence, the number of new cases of a certain disease in a certain time period. Kostmann syndrome, a specific type of severe congenital neutropenia with autosomal recessive inheritance, due to mutations in both copies of the HAX1 gene. Lenograstim, the international non-proprietary name for one form of G-CSF. Leukemia, a malignant disease of the white blood cells. Leukocytes, a general term for all white blood cells, including granulocytes, monocytes and lymphocytes. Lymphocytes, subgroup of leukocytes which are responsible for the body s defense against viruses (T lymphocytes) and the production of antibodies (B lymphocytes). Metabolic, refers to the balance between uptake, degradation and utilization of food. Monocytes, a subgroup of leukocytes, which eliminate infectious particles and infected cells by eating and digesting them. Morphological, refers to the physical shape and size. Myelodysplastic syndrome (MDS), a syndrome characterized by decreased blood counts, the appearance of abnormal cells in the bone marrow, and changes in the chromosomes of bone marrow cells. MDS can progress to leukemia. Myelokathexis, a very rare form of congenital neutropenia that is characterized by the inability of the neutrophils to leave the bone marrow and enter the blood. Neutrophils, a subgroup of granulocytes defending the body against bacteria and fungi. Neutrophils are also known as segs, polys or segmented neutrophils. Osteopenia, mildly demineralized bone substance. Osteoporosis, severely demineralized bone substance. Platelets, a subgroup of blood cells responsible for clotting; also called thrombocytes. Polymorphonuclear leukocyte or poly, a neutrophil with a multi-lobed nucleus, also called a PMN. The terms poly, granulocyte, and neutrophil are often used interchangeably. Promyelocytes, precursors of granulocytes in the bone marrow. Prophylaxis, any procedure to avoid undesired events e.g. the development of infections. Proteinuria, the occurrence of protein in the urine. Psoriasis, a disease characterized by scaly skin. Rheumatoid arthritis, chronic inflammation of several joints also referred to as polyarthritis. Splenectomy, surgical removal of the spleen. Splenomegaly, the enlargement of the spleen. Understanding Severe Chronic Neutropenia 27

28 Sporadic, the new occurrence of a dominant condition in a family in which the condition has never occurred before, caused by a mutation that arises prior to conception, only in the egg or the sperm of a parent. Stem cells, rare cells found in most tissues, with the abilities both to renew themselves by cell division and to produce a wide range of mature, specialized cell types. See hematopoietic stem cells for the type specific to blood formation. Subcutaneous, under the skin. Syndrome, a complex of various disease characteristics. Thrombocytes, a subgroup of blood cells responsible for clotting which are also referred to as platelets. Thrombocytopenia, the decreased number of platelets in the blood (< 150,000 per mm 3 ). Vasculitis, inflammation of small blood vessels. WHIM syndrome, a genetic disorder encompassing warts, Hypogammaglobulinemia (low levels of antibody in the blood), infections, and myelokathexis. White blood count, the total number of leukocytes in the blood. White blood cells, a subgroup of blood cells consisting of monocytes, granulocytes and lymphocytes which together build the immune system and defend the body against infection. Understanding Severe Chronic Neutropenia 28

29 WINTER 2015 A Letter from Lee The 2015 Family Conference was a weekend of firsts. It was the first time Audrey Anna Bolyard, clinical manager of the SCNIR, was able to join us for the entire weekend. It was the first time we videoed the educational sessions to make them available to all patients via the internet. It was the first time we had our own official t-shirts for sale. It was the first time we hosted a session on transitioning from pediatric to adult hematology, and for many it was their first Family Conference. The new features and first-time attendees are an important aspect of the Conference, but something else caught my attention this year, there was a core of visitors who have returned repeatedly over the years. For them the Conference has become a warm hearth, a place where they can be themselves, where they can talk about their struggles with neutropenia without fear of judgement, without having to explain to puzzled faces how their bone marrow doesn t work. When we started hosting the Conference over a decade ago, I wanted to create the kind of experience I could only dream of as the mother of a child with severe congenital neutropenia in the 1980s. I wanted to give patients and families a chance to meet and get to know each other, a chance to ease the pain and stigma that comes from having a disease virtually unknown to the rest of the world. We have done that but I never could have imagined the ties that would form among patients and families, the deep camaraderie that would grow and strengthen over the years a second family bonded together by a rare disease. It s a welcoming family, an open hearted one where new visitors can feel immediate trust and comfort. One family that has been integral in fostering a hospitable atmosphere is the extended family of Conference coordinator, Mara Lim who has spent countless hours working to assure the event runs smoothly and meets visitors expectations. Her mother Charlene Teel has volunteered for several years. We are especially grateful that Charlene agreed to spearhead the successful new ConnectCare clubhouse on Saturday afternoon. Mara s brother, Mat Solomon, volunteered this year, and found himself inspired by the chance to share time with others who have neutropenia. In past years Mat has not seen much WHAT S INSIDE benefit of discussing his neutropenia, but this year he found 2016 Conference Basics...2 his voice, talking about his struggles and sharing coping Practical Wisdom from Audrey Anna mechanisms he has developed over the four decades he Olivia s Story...6 has lived with neutopenia. Mat hopes to come back in the future and to continue to make a difference by sharing his Ron s Story...7 own story and listening to others. Mat started a Facebook Vanessa s Story page called, Neutropenia for Dudes and Everyone Else. Australian Family Conference In addition to families returning year after year, we are fortunate to have a core of physicians who join us regularly: Laurence Boxer MD, Maryann Bonilla MD, David Dale MD, Peter Newburger MD, Akiko Shimimura MD. They share their expertise in formal presentations and private consultations, they join participants during meals and informal times. We are so fortunate to Cont. on page 2 national neutropenia network awareness, education, research and support A Fun Event for Our Cause...11 The National Neutropenia Network newsletter is published several times a year. Lee Reeves, NNN Executive Director: lee@neutropenianet.org P.O. Box 1693 Brighton, MI neutropenianet.org Many thanks to Mariel Lewis, Owner of Trapdoor Design and NNN board member, for the donation of her graphic design services to help create this newsletter. Thank you to Peter Newburger MD for proofing this newsletter. Thank you to the wonderful staff at the SCNIR for mailing this newsletter.

30 A Letter from Lee Cont. have such a dedicated knowledgeable group of physicians willing to freely share their expertise and time, a rarity in today s world. Another facet of the Conference that gives it a family feeling is the presentations from individuals with neutropenia. For many years Shay Jones MA LPC who has congenital neutropenia has headed up popular sessions that address the psychological and emotional challenges of living with neutropenia. This year we added a talk on Integrative Medicine Therapies for Better Living with Neutropenia, presented by Galie Jean-Louis who began her presentation by sharing the challenges she has faced living with idiopathic neutropenia. We heard from Kristin McGuinness, founder of Ella Jewell Foundation who talked of her journey as the mother of a child with congenital neutropenia, and Olivia Schroder who shared her experience growing up with neutropenia. I cannot close an article about the family feeling at the Conference without noting the feature nearest and dearest to my heart, Neutropenia Kids Kamp. I know how much it would have meant to my daughter to go to a camp with children who lived under the constant threat of life-threatening infections as she did. Even in today s world where neutropenia is far better managed than it was thirty years ago, children still experience feelings of isolation, of not being normal, but at Neutropenia Kids Kamp for the first time in their lives, they are among peers. They spend happy active time with other children who also must take shots and get bone marrow aspirations. They learn about their disease in a safe open atmosphere where having fun is a priority. It is a joy to see their happy faces, and to watch their friendships form and grow. This I believe is the most life-changing aspects of the Neutropenia Family Conference. It is what inspires me. On the weekend of July 8, 2016 we will once again welcome many returning friends to Ann Arbor and they will reach out to make the newcomers feel at ease and part of the family. I hope you can make it Conference Basics The 2016 Neutropenia Family Conference will be held July 8-10 at the beautiful Marriott Eagle Crest The National Neutropenia Network has reserved a block of rooms at a discounted price of $114 plus tax, per room. We recommend reserving as early as possible. Conference fees are inclusive. They include all presentations, handouts, children programs, and meals: Friday reception, breakfast, lunch and dinner on Saturday and Sunday breakfast. Early Bird (Before April 1): $175 each for 12 years and up; $100 each 4 to 11 years Regular Registration (April 1 and later): $195 each for 12 years and up; $120 each 4 years to 11 years Visit neutropenianet.org, and click on the Conference tab to register. Registration and hotel booking will be available after December 14. How about asking for help with Conference attendance as a Christmas gift! Important: There will be NO Family Conference is Patient Assistance Grants As in past years we will award grants to patients and families who cannot attend the Neutropenia Family Conference without financial assistance. The grants generally only cover partial costs of attendance. Preference is given to those who have not attended a Conference. We do not yet know how much funding will be available. We depend entirely on donations from friends and family who understand what it means to live with neutropenia. Donors may contribute to the NNN through neutropenianet.org or the National Neutropenia Network PO BOX 1693, Brighton, MI Donations are tax deductible. Check our website in early spring for more information on Patient Assistance Grants. 2

31 Kampers create their own planet Dr. Dale talks about the SCNIR Dr. Newburger talks about staying healthy Kids Kampers 2015 Shay jones facilitates group discussion Taylor Carlton, Shay Jones, Mat Solomon 3

32 Practical Wisdom from Audrey Anna Audrey Anna Bolyard, the Clinical Manager of the SCNIR (Severe Chronic Neutropenia International Registry), has witnessed a lot of firsts during her 37-year association with neutropenia. In 1988 she joined the clinical trial team at the University of Washington, headed by Dr. David Dale that first tested neutropenic patients response to Neupogen given daily to manage severe chronic neutropenia. In 1994, she was involved with the creation of the Registry for severe chronic neutropenia patients, establishing a global database of treatment and disease-related outcomes for persons diagnosed with SCN. The Registry tracks members medical data for use in research related to the causes and treatment of the blood disorder. I started working at the University in 1978, in those early years working as a research nurse on the wards I met the person who would become the first person to take long-term Neupogen therapy, Bolyard said. She became the Registry s clinical manager in 1994, a position she holds today. It seems fitting, then, that she experienced another first this past summer at the 2015 NNN Family Conference in Seattle when she met, face-to-face, Registry patients whom she had known for years, but only by telephone or through the Internet. It was great to meet people for the first time that I ve known for years through the Registry, Bolyard said. We get to know each other over the phone, so it was like meeting an old friend. One woman said she remembers me when I had long red hair and was surprised to find that it is gray now! It was just lovely to meet people I ve actually known for years. Her role as clinical manager has evolved since 1994, when the Registry was started, Bolyard said. It was the first registry at the University, so we didn t have a model or know how to create a registry. We developed systems about how to collect data from people over years and years. It was much like a clinical trial in the beginning. Now, she said, the Registry also is heavily involved in outreach, providing expertise to help doctors, patients and their families to learn about neutropenia. It s rare for most physicians to understand what it is, she said. When they find that a patient has a low blood count, the first thing they assume is leukemia. They are not even aware that there s another possible diagnosis. A focus of the Registry is to increase awareness about and understanding of neutropenia, among both patients and the medical establishment. We also publish a great deal, Bolyard said, adding that the SCNIR website at washington.edu/registry includes a comprehensive bibliography of publications covering the period from For more focused information on pertinent publications, interested patients and other individuals can contact Bolyard at bolyard@uw.edu. Bolyard s job description expanded as the Registry grew, said Lee Reeves, director of the National Neutropenia Network (NNN). If someone is having trouble with their dose, she talks to them. She has probably talked to more patients than anyone else over the years. Everybody loves her. She is an icon in this world. Although neutropenia is a relatively uncommon condition, more than 1400 patients are registered on the SCNIR, Bolyard said. That figure represents only a portion of the total population of those who have neutropenia because there are several forms of the blood disorder and many patients are undiagnosed at this point. 4

33 The most important thing that people who have or suspect they have neutropenia can do is to get educated, Bolyard said Find out everything you can. Do your homework. Get online. Find out what the current thought is about medication. You may have to educate your doctor about neutropenia. We let people know that there are other pathways, Bolyard said. The most important part of this story is that there IS help with rare conditions, and the work is generally done by the family and the patients. The world is very small now, thanks to the Internet. You can find local, national and international experts. Once you locate the experts, she said, you CAN get help. But first and foremost, she said, get educated! The Spit Test seeks clues As part of ongoing research into the causes of neutropenia, Audrey Anna Bolyard collected saliva from neutropenic participants who attended the 2015 Family Conference in Seattle. We collected samples of DNA in the easiest way possible (by having people spit into a test tube), Bolyard said. DNA also can be collected through samples of blood, bone marrow and skin. This collection is a sub-study of the Repository Study, whose goal is determining causes of neutropenia specifically through DNA samples, Bolyard said. We are looking at a large group of people who have long term neutropenia, focusing on neutropenic patients that do not have a known genetic mutation. Our goal is to discover if there are other genetic causes for neutropenia. The collection was so popular that Bolyard ran out of tubes to test everyone who wanted to donate their saliva, she said. Audrey Anna has been instrumental to the Registry s success. She has supported hundreds of patients with thoughtful guidance and compassion. Her value to the neutropenic patient community is beyond measure. David C. Dale MD Applying for the Registry Tips provided by Audrey Anna Bolyard, clinical manager of the Severe Chronic Neutropenia International Registry (SCNIR) 1. The process may be initiated by the patient or the doctor. 2. The patient s registration form will include requests for the following: 3. 3 or more CBCs with ANC less than 0.5 x 109 within 3 months before the initial dose of G-CSF (Neupogen). If cyclic neutropenia, then provide 3x/week for 6 weeks. 4. Bone marrow and cytogenetic evaluations done prior to enrollment. This includes one stained and one unstained bone marrow slide if available. 5. Bone density evaluation if available. 6. Genetic testing if available: Common tests are ELANE, HAX1, GSD 1b, SBDS, and TAZ. 7. Autoimmune testing if available: common names for tests are Anti-Neutrophil Antibodies, Granulocyte Antibodies, and ANA. Obtaining the medical records from the procedures and tests can be time consuming. Keeping copies of tests will help when you apply to enroll in the Registry. 5

34 Olivia s Story Olivia Schroeder is lovely, vivacious, talented and, she likes to say, a normal 20-year-old who enjoys soaking up the sun in the still warm days of fall, writing poems, designing her own clothing and walking her puppy. She has attended the Art Institute of Chicago and is currently working on developing her art. She has also lived with neutropenia for all of her life. It can be difficult, Schroeder said, but I m still living a happy life. Those words were the focus of her talk about living with neutropenia at this past summer s NNN Family Conference in Seattle, emphasizing the positive aspects of her struggle with the bone-marrow disorder. It was an incredible experience to speak at the Conference, said Schroeder, who said she believes she was at the first NNN Family Conference ever held. I think I had something to say that needed to be addressed, she said. I live a very normal life and had a very normal childhood. I think a lot of parents don t realize that their children can be normal, successful and happy. She advises parents not to be afraid of their children going to a playground, or to daycare or a public swimming pool. I wanted them to know their kids can be happy. Schroeder s father also has neutropenia, which she said has made it easier for her to deal with it. I was lucky to grow up with another neutropenic person, my dad, so that helps me normalize, she said. My parents have always been very supportive. Indeed, said Network founder Lee Reeves, her entire family has been supportive of Schroeder and of the Network, as well. Three generations of her family were at the Conference this year, she said. Olivia s grandmother was one of the first to donate to the Network. When I saw Olivia go up to the podium (at the Conference), I was proud and happy, said her grandmother, Mary Schroeder. There was my granddaughter, who I had seen grow up living with neutropenia, and she was about to share her experiences with people who she hardly knew. Many of them were just getting used to either their diagnosis of neutropenia or that of their children, she said. I felt sure that Olivia could give them a true message of how living with the ups and downs of the disease could still enable you to have a full, rich life. She could give them that hope. Yes, I was proud of Olivia! Attending the annual NNN Family Conferences nearly every year since she was 8 years old, Schroeder has had the opportunity to meet many others who have neutropenia. It helps to know you are not alone, she said, and that having neutropenia doesn t make you a freak. Yes, she said, there are times when it gets her down, but since starting Neupogen in 1996, she has had fewer illnesses. I have had bone pain, from the medication, but I can live with it, she said. For a while, I didn t realize bone pain wasn t normal. I m pretty darn functional and I rarely have to go to bed because of the pain. So, sometimes, living with neutropenia can be a challenge, Schroder said, adding, My disease does not make me any less human, and it does not stop me from pursuing and achieving my goals. You ve got to be tenacious. I had to separate the neutropenia from my self-worth. Once I did that, my future was limitless! Olivia a Conference presentation is available on the NNN website under Conference Highlights. To follow Olivia Schroeder and her art, check out her new website at oschroederisthenucleus.tumblr.com 6

35 Ron s Story We are losing her! said the doctor on a fateful summer evening nearly 30 years ago. His daughter s organs were shutting down, and Ron Bloxham stayed with Lucy as doctors rushed her by helicopter to Good Samaritan Hospital in Phoenix, Ariz. After two weeks in hospitals and innumerable tests, 8-year-old Lucy inexplicably began to recover. Subsequent testing determined that she had had toxic shock. And so began a roller coaster of illness followed by complete recovery that put Bloxham and his wife on a quest to find the cause of their daughter s frequent illnesses and high fevers. In 1989, a Las Vegas physician referred them to a new program at the University of Washington overseen by Dr. David C. Dale, Dr. William Hammond and Audrey Anna Bolyard. The whole family underwent tests, and it was determined that Lucy had cyclic neutropenia, and she began treatment with Neupogen immediately. Ron also was found to have neutropenia, but none of Lucy s siblings or her mother had the bone marrow disorder. Some 26 years later, two of Lucy s three children have neutropenia. In 2012 Ron attended his first Family Conference in Phoenix. The experience brought home the profound impact neutropenia has had on his daughter s life. Meeting other families and hearing from the experts gave him a greater understanding of the disease and the struggles that come with it. After the Conference he accompanied Lucy as she revisited the hospital where she almost died twenty years earlier. It was an emotional experience for the whole family, and Ron resolved he wanted to do something to make a difference. Several weeks later he called Lee Reeves and offered to serve on the board of directors for the National Neutropenia Network. Lee Reeves said she was very pleased when Ron called. Lucy s is serving her final term on the board. She had served as chairperson and was pivotal in revitalizing the flagging organization in Lucy was instrumental in helping to revive the Network over ten years ago. I don t know what I would have done without her help and encouragement. She was always available. Reeves said. Now her Father has stepped in with dedication and support. This kind of family commitment is important for an organization like ours. After Phoenix, Ron attended two more Conferences with his wife, Vicki, who fully supports Ron s work with the NNN. They make a point of getting to know other families who attend the Conference and they make themselves available to volunteer as needed. This past year they committed funds to help underwrite the cost of videoing the educational sessions in Seattle. Ron, who retired in 2011, was a prosecutor for the Clark County District Attorney s office in Las Vegas for 34 years. He worked his way through college by writing for a newspaper and put himself through law school by working as a welfare hearing referee, also working for his law school. He currently engages in church service missions in the Family History Center of the Church of Jesus Christ of Latter Day Saints. He also works with Brigham Young University-Idaho. In addition, he sits on the Nevada State Bar disciplinary committee. Having witnessed the difficulties Lucy experienced as a child with neutropenia in a world where there was no Network, no Family Conference, no Registry, Ron understands the value of these services. I want to express my appreciation for all the great work that has been done on behalf of myself and my family, he said. I also appreciate the wonderful work done by Dr. Dale and Audrey Anna and the help of Amgen in providing medicine that has saved lives and helped so many people. 7

36 Vanessa s Story 8 It was 2008, I think. I was 31, married, and I went for a regular medical check-up that showed that my numbers were very off. Something was not right. That was the beginning of a very long and difficult journey for Vanessa Enrizo, one which took her to doctor after doctor, through dozens of tests and bloodwork, and resulted in diagnoses ranging from infectious mononucleosis to anemia, from leukemia to lymphoma. It was all very scary, Enrizo said. It was several years of craziness. But I felt like I needed to survive to be there for my son. Eventually, a doctor sent the Miami resident, now 38, for a bone marrow biopsy. But it took two hours, Enrizo said. And they couldn t get in on the first try. I have an incredible threshold for pain, but it was really awful. What kept me going was thinking about little kids who have much worse things. If they can do it, how could I not? Another thing that helped her through the unpleasant process was repeating a prayer that her father prayed when he was in the military in Cuba. I took it everywhere I went and would repeat it during that difficult time, she said. She promised that, if her illnesses were caused by something she could live with and be with her son, she would never complain. I m a very tough person, and it s difficult to explain that vulnerable moment, but I didn t feel alone. After this long process of elimination, Enrizo finally found an interventional radiologist who was able to do a painless bone marrow biopsy and correctly diagnose her problem: chronic severe idiopathic neutropenia. He said to me, I have good news and bad news. The good news is that you do not have lymphoma or leukemia. The bad news is that you have neutropenia, and we don t know very much about it. She said to herself, I m not going to cry about this. I m going to do whatever it takes to learn more about it and figure it out. And so began years of research and learning to live with neutropenia. Enrizo spent a lot of time on the Internet, reading about the condition. I didn t get sick often, but when I did, it was bad. I would be in the hospital for a week. In all of this time, Enrizo rarely shared information about her medical situation with friends or work colleagues. I didn t want my family to worry, she said, although they were very supportive. I was afraid people would feel sorry for me. I look completely normal, but when anyone in the office had a cold, I d spray Lysol all around. Only my boss knew. She was essentially living a double life, Enrizo said. She took a year-long leave of absence from her job while she tried to find answers. Her job as a business manager at a large Florida university was stressful, with constant deadlines. I felt I didn t have the patience to deal with work because I didn t know what was going on with my health, Enrizo said, adding that her boss has been very supportive. She s been amazing. In the course of her research, she came across the National Neutropenia Network and Lee Reeves, one of its founders. Lee encouraged her to attend a Family Conference, but Vanessa didn t feel she could afford it at the time. I looked fine, despite getting sick once or twice a year, Enrizo said. But I had to accept the fact that there was something going on. In May of this year (2015), she was hospitalized with a cold, so weak she couldn t get out of bed. Lee called me and urged me to attend the Conference, Enrizo said. She said it could be life-changing for me. I decided it was time to give the Conference a shot. So, she and her brother, Orlando Enrizo, an interventional radiologist, traveled to the NNN 2015 Family Conference in Seattle. Lee was right; it changed my life, Vanessa Enrizo said. For the first time, I was able to talk with people who have what I have. I couldn t stop crying, there were so

37 many emotions. It was such a relief. I learned so much and now, I can educate my doctors about neutropenia. In addition, her brother is now able to share information about neutropenia with the medical community, which is largely unaware of this rare blood disorder. I m proud of Vanessa for not just accepting [the incorrect diagnoses] that some of the physicians gave her, said Dr. Enrizo, who first learned about neutropenia when his sister was correctly diagnosed with chronic severe idiopathic neutropenia. It was Vanessa who discovered the National Neutropenic Network online. Her brother said he learned a great deal during the conference. It opened my eyes, Dr. Enrizo said. I learned from these expert physicians how to treat it, and I saw some interesting trends. It s the same disease process and the same treatment for all types of neutropenia. Dr. Enrizo said a take-away for him is becoming an advocate to help educate other oncologists and physicians. When I see an oncologist at my hospital, I say Do you know about neutropenia? My sister has it. That question can open the door to increased awareness of this rare disorder, something that the neutropenic community knows is necessary. The first thing that most doctors will think of when they see these numbers is HIV, or leukemia or other bone marrow abnormality, Dr. Enrizo said. He said he has sent articles about neutropenia to oncologists and other doctors at his hospital to help raise awareness. He also noted that a preponderance of the patients he spoke informally with at the conference said that their bone marrow biopsies, like his sister s, were very painful. But, as done by interventional radiologists and using CT scan imagery, bone marrow biopsies can be pain-free, so patients might want to discuss procedural options with their doctors before having their biopsies. Since the conference, Vanessa Enrizo is in the process of getting on the Registry, she said. Once that is accomplished, she will qualify for daily Neupogen and will likely see fewer neutropenia-related illnesses in the future. That certainly is the hope, her brother said. One of the biggest lessons I learned at the Conference is that it s okay to ask for help, Vanessa Enrizo said. After years of carrying the burden of her neutropenia largely alone, she has found a new source of support in the NNN and the people she met at the Conference. I learned that you don t always have to be the strong one. Conference Videos Online We know that many cannot take the time or spend the resources on Conference attendance. With that in mind this year we videotaped many of the presentations. Visit neutropenianet.org and click on Conference Highlights. You will find the following videos of: The SCNIR How it Works and How to Make it Work for You, Audrey Anna Bolyard RN Life Management for Those Who Live with Chronic Neutropenia, Audrey Anna Bolyard RN Kristin McGuinness Shares the Story of her Journey with Congenital Neutropenia Olivia Schroeder Shares the Story of her Journey with Cyclical Neutropenia My Beloved Neutrophil, Laurence Boxer MD The Registry Past, Present and Future, David Dale MD Living with (and without) Neutropenia, Peter Newburger, MD Integrative Medicine Therapies for Better Living with Neutropenia, Galie Jean-Louis LAC EAMP RYT 9

38 Australian Family Conference 10 The Henry family, of Sydney, Australia, has been dealing with neutropenia since their son, Sam, 21, was diagnosed at 8 months of age. This past summer, they flew 7,750 miles from Sydney to Seattle, Washington, to attend the 2015 NNN Family Conference, in part so they could learn how to structure a similar conference in Australia. Kath Henry, Sam s mother, said she and her husband, Phil, decided to put together a Neutropenia Family Conference in Australia, modeled on the American conference. Their intent is to provide an accessible opportunity for Australians who are dealing with neutropenia to learn more about the rare blood disorder and latest treatment information from the experts. It will also afford an opportunity to get questions answered and to meet and network with other neutropenic individuals and their families Planning for the Australian Family Conference is well underway, with the dates set for Sept. 30 and Oct. 1, 2016, at the Quality Hotel in the Sydney suburb of Mascot, a shuttlebus ride from the airport. The keynote speaker will be David C. Dale, MD, professor of medicine at the University of Washington and co-director of the Severe Chronic Neutropenia International Registry (SCNIR). She is hoping to set up a session for Dr. Dale to speak to the medical community, as well. There will be presentations by Sam and a young woman in her 20s about what it s like growing up with neutropenia. A Q&A session will allow families to ask questions and get one-on-one information. Audrey Anna Bolyard, clinical manager of the SCNIR, may do a presentation via Skype. A children s program is also in the planning stages, Henry said. I want the families to be able to come, which was one of the wonderful things about the American conference, she said. You could just see it was so helpful for the young ones. So far, she is aware of just 10 families in Australia who have a neutropenic member in their midst, but hopes that more might be found through the SCNIR. Professor Frank Firkin, an honorary professor at Melbourne University and Vincent s Hospital in Melbourne, is investigating the possibility of starting a registry in Australia to help locate more patients in that country and to provide education about the disease and allow researchers a vehicle for studying it in Australia. He will also participate in the Conference. Kath Henry, with encouragement and support from her husband and son, is now working on the administrative details of the Australian conference. The main thing I m trying to figure out now is how to responsibly cover the costs, she said. The management of the hotel has been very accommodating and cooperative and we are looking at other options to help offset the costs, she said. Henry hasn t decided yet what the cost to attend will be. That will depend on how much the other costs amount to, but right now, she is looking at $300 per adult and $50 per child, but she hopes to bring that down. This will be a chance for Australians to hear from some of the top specialists in the field of neutropenia, Henry said. Accessibility to specialists is greater in the States, she said. It s not just that they have incredible knowledge, although the bulk of the research has been done in America, but they have a great compassion because of their personal interest. Henry hopes that holding a neutropenia conference in her country will provide the access to expertise that is not generally available there, and therefore, raise the level of understanding of the disorder. The trip from Australia to Seattle is long about 17 hours by air and expensive, but one that the family undertook because they felt it would be worthwhile. It was so important for Sam because, for the first time, he was able to talk to people who have the same thing he has. It was so encouraging for him. I met someone with neutropenia, and someone my age, as well! That was awesome. said Sam

39 A Fun Event for Our Cause Henry, who is in his last year of collegiate IT studies, currently spending 6 months at Loughborough University near London, England. Also, it was great to be honest and open about dealing with the emotional side of it. It gives you perspective. His cyclic neutropenia was difficult to diagnose because it is usually inherited, but no hereditary link could be found. It s an expensive trip to the States, he continued. My family was blessed to be able to go [to the American Conference], Sam Henry said. Having a conference in Australia will be great for families who don t have the money to travel to the States and for patients who are too sick to travel. The template for an Australian Family Conference was, of course, provided by the American conference, Kath Henry said. We are so grateful to Lee Reeves, the Director of the National Neutropenia Network, and to the team who put the conference together in the States. They were so welcoming to us coming from Australia. It s a gift we can never repay. In summing up the experience and the planning for an Australian conference, Phil Henry expressed some of the excitement shared by his family: Going to Seattle was fantastic, he said. Kath is doing very well in planning the conference; I m her enthusiastic supporter. The idea of Dr. Dale coming out to Australia is just spectacular. Kath added, We just want to be a blessing to people. Join friends and families across America for the third annual Bowling for Neutrophils fundraiser event sponsored by Ella Jewell Foundation. Proceeds benefit neutropenia research through EJF and patient support through the NNN. If you ve always wanted to do something to support our cause but have been unsure of what to do, this may be the perfect opportunity for you. Kristin has made it a turnkey operation. All that is needed to set up a team is: four to six players, access to a bowling alley, a date between January 15 and March 30, some friends and family willing to support the effort and the desire to make a difference for those who live with severe chronic neutropenia. Registration begins on December 1. For more information and step by step details on how to start your own team visit More Ways to Make a Difference While shopping online this holiday season all Amazon purchases can benefit our cause. An Amazon Smile link is posted on every page of our website neutropenianet.org. When a shopper clicks that link and makes a purchase a percentage of the purchase will be donated to the National Neutropenia Network. Here s an idea for a holiday gift. We have the official National Neutropenia Network t-shirt for sale on our website. It s an great way to tell our story and support the NNN. For more details on the Austrailian Conference, contact Kath Henry at: kath@northridge.org.au 11