New Congenital Neutropenia Syndrome And Causative Gene Mutation Identified By Scientists

http://www.medicalnewstoday.com/articles/134370.php

New Congenital Neutropenia Syndrome And Causative Gene Mutation Identified By Scientists

"Our discovery will help facilitate genetic diagnosis in this newly defined group of severe congenital neutropenia patients," said Christoph Klein, M.D., Ph.D., Hannover Medical School, the principal investigator of the study. "Knowledge about the underlying genetic defect is an important first step in developing a targeted therapy."



For more information on Shwachman-Diamond Syndrome, please see Shwachman-Diamond America

Medications that Cause Neutropenia

Here is a link to a site that lists medications that can cause neutropenia:

http://www.globalrph.com/neutropenia.htm



For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Merck Neutropenia Article

Merck Neutropenia Article

Great article on Neutropenia, causes and degrees. Talks about inflammation of response (when ANC is below 200, inflammation response can be gone). Very detailed!


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Neutrophil Dysfunction Classification

Neutrophil Dysfunction

Numerous disorders may cause neutropenia, which is defined as an absolute reduction in the number of circulating neutrophils.
The link above takes you to a page with the classification and diganosis info.

Prevalence of Neutropenia in the U.S. Population: Age, Sex, Smoking Status, and Ethnic Differences

Prevalence of Neutropenia in the U.S. Population: Age, Sex, Smoking Status, and Ethnic Differences

Interesting article on Neutropenia! Includes several interesting charts.

Neutropenia: A Patient's Guide

Neutropenia: A Patient's Guide

This is an 8 page handout that is wonderful for Teachers,Schools, Patients and Parents!

Article: Chronic idiopathic neutropenias and SCN

Just got the full-text of this one & it is very interesting.

Chronic idiopathic neutropenias and severe congenital neutropenia.


Departments of Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. jan.palmblad@ki.se
PURPOSE OF REVIEW: Chronic idiopathic and severe congenital neutropenias are rare disorders for which recent discoveries have highlighted mechanisms and consequences. RECENT FINDINGS: An inflammatory bone marrow milieu has been shown to be a major contributor to the pathophysiology of chronic idiopathic neutropenia. Activated T-lymphocytes with myelosuppressive properties and pro-apoptotic mediators, such as IFNgamma, TNFalpha, Fas-ligand and TGFbeta1 result in accelerated apoptosis of granulocytic progenitor cells. Decreased levels of the anti-inflammatory cytokine IL-10 further disturb the balance between survival and pro-apoptotic mediators in chronic idiopathic neutropenia. Mutations in the HAX1 gene are associated with most cases of recessive autosomal severe congenital neutropenia, while ELA2 mutations are found in most cases of autosomal dominant and sporadic cases. The role of HAX-1 protein as a regulatory step in apoptosis provides further evidence for severe congenital neutropenia as a disorder of programmed cell death. The preleukemic character of severe congenital neutropenia, particularly for patients with need for high granulocyte colony stimulating factor dosage, was recently emphasized. SUMMARY: Chronic idiopathic (or as recent data suggest, immunologic) and severe congenital neutropenias provide intriguing models for better understanding of regulation of myelopoiesis. Similarities and differences between the two disorders might help to dissect these regulatory events.

Discovering Early Molecular Determinants of Leukemogenesis

Link to the full text of this article can be found here: http://www.shwachmandiamondamerica.org/SDSarticles.html

Discovering early molecular determinants of leukemogenesis.

Departments of Medicine and Molecular and Medical Genetics, Oregon Health and Sciences University, and Northwest Veterans Affairs Cancer Research Center, Portland, Oregon, USA.
Truncating mutations of the G-CSF receptor are found during disease course in nearly half of all patients with severe congenital neutropenia. In this issue of the JCI, Liu et al. demonstrate that these mutations confer a competitive clonal advantage upon HSCs in mice and that the advantage is conditional because it is observed only in the presence of the ligand G-CSF (see the related article, doi:10.1172/JCI32704). Once activated, the mutant receptor requires the function of Stat5 in order to effect clonal expansion of this stem cell population. The results support the notion that early molecular steps in this and other neoplastic processes represent adaptations in which, through somatic mutations, "unfit" stem cells gain a measure of fitness by altering their relationships with their microenvironment.

SCN-HAX1 article

Link to full text of this article can be found here: http://www.shwachmandiamondamerica.org/medicalarticles.html

Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency.
Matsubara K, Imai K, Okada S, Miki M, Ishikawa N, Tsumura M, Kato T, Ohara O, Nonoyama S, Kobayashi M.
Department of Pediatrics, Nishi-Kobe Medical Center, Japan. kskmatsu@s4.dion.ne.jp
HAX1 deficiency has recently been identified as a cause of severe congenital neutropenia (SCN), but little is known about the phenotype. We described an SCN patient with a homozygous 256C-to-T transition causing an R86X mutation in the HAX1 gene. Notably, the patient has been complicated by epilepsy and severe delay of motor, cognitive, and intellectual development; each developmental quotient was 21-26 at 7 years old. Growth failure and dental development delay were also noted. Neurodevelopmental delay in this patient expands the clinical phenotype of HAX1 deficiency and suggests an important role of HAX1 on neural development as well as myelopoiesis.

Neutropenia Article Links

http://www.realnurseed.com/t1000.htm


http://www.emedicine.com/med/topic1640.htm


http://www.medicinenet.com/neutropenia/article.htm

Infections in Neutropenics

From Nathan and Oski's Hematology of Infancy and Childhood 5th Edition:

"The most frequent types of pyogenic infections in patients with significant neutropenia are cutaneous cellulitis, superficial or deep cutaneous abscesses, furunculosis, pneumonia, and septicemia. Stomatitis, gingivitis, periodontitis, perirectal inflammation, and otitis media (especially in children) occur as well. However, neutropenia in and of itself does not heighten susceptibility of patients to viral, fungal, and parasitic infections or to bacterial meningitis. the most commonly isolated organisims from neutropenic patients are S. aureus and gram-negative bacteria. The usual signs and symptoms of local infection--such as exudates, fluctuation, ulceration, and regional adenopathy--are much less evident in neutropenic patients than they are in non-neutropenic individuals."

What Decreases the Neutrophil Count?

NEUTROPHILS ARE DECREASED BY:

Bone marrow depression due to radiation or cytotoxic drugs

Infections: Typhoid, tularemia, brucellosis, hepatitis, influenza, measles, mumps, rubella, infectious mononucleosis

Hypersplenism: hepatic disease and storage diseases

Collagen vascular diseases, such as systemic lupus erythematosus

Deficiency of folic acid or Vitamin B12

*Second Edition of Diagnostic Tests by Springhouse

What Increases the Neutrophil Count?

Neutrophils are increased by:

Infections: osteomyelitis. otitis media, salpingitis, septicemia, gonorrhea, endocarditis, smallpox, chickenpox, herpes,Rocky Mountain spotted fever

Ischemic necrosis due to myocardial infarction, burns, or cancer

Metabolic disorders: diabetic acidosis, eclampsia, uremia, thyrotoxicosis

Stress response due to acute hemorrhage, surgery, excessive exercise, emotional distress, third trimester of pregnancy, or childbirth

Inflammatory diseases: rheumatic fever, rheumatoid arthritis, acute gout, vasculitis, myositis

*This comes from the Second Addition of Diagnostic Tests

Neutrophil Chemotaxis- Neutrophil Function

If you read anything about Shwachman-Diamond Syndrome, chances are you'll read about poor neutrophil function or defective neutrophil chemotaxis.

What is neutrophil chemotaxis?

Chemotaxis can be defined as the ability of the neutrophils to move to the site of infection. If neutrophils are unable to migrate (move) to the site of infection, a person is said to have a neutrophil chemotaxis defect. Medical literature suggests that most Shwachman-Diamond Syndrome patients have some level of neutrophil chemotaxis defect. For instance, my two SDS boys were tested at two different labs (using two different techniques) and were found to have neutrophil chemotaxis dysfunction. In one of the studies, only 17% of J's neutrophils moved toward the bacteria, while 33% of S's moved toward the bacteria. The control that was sent along with their samples had 100% of her neutrophils move toward the bacteria.

Neutrophils also produce enzymes that kill invading bacteria, which also helps neutrophils to kill these foreign pathogens.

The following comes from a diagnostics textbook 5th edition:

Normal neutrophils--the body's primary defense against bacterial invasion--engulf and destroy bacteria and foreign particles by a process known as phagocytosis. In patients who have repeated bacterial infections, neutrophil function tests may reveal the inability of neutrophils to kill a target bacteria or to migrate to the bacterial site (chemotaxis).

Neutrophil killing ability can be evaluated by the nitroblue tetrazolium (NBT) test, which relies on neutrophil generation of bactericidal enzymes and toxins during killing. This action results in increased oxygen consumption and glucose metabolism, which reduces colorless NBT to blue formazan. The reduced dye is then extracted with pyridine and measured photometrically; the level of reduction indicates phagocytic activity.

Neutrophil killing activity can also be evaluated by noting the neutrophils' chemiluminescence--ability to emit light. After a neutrophil phagocytizes a microorganism, oxygen-containing substances form within the phagocytic vacuoles. As the cell is stimulated, it emits light in proportion to the amount of oxygen-containing substances that are formed, providing an indirect measurement of phagocytosis.

Chemotaxis can be assessed in vitro by placing bacteria in the lower half of a two-part chamber and phagocytic neutrophils in the upper half. After incubation, migrating cells are counted microscopically and compared to standard values."

Calculating an ANC

After calculating an ANC for so many years, it seems like second nature to me. Neutropenia is the most common hematological abnormality in Shwachman-Diamond Syndrome. Many of the familys that contact Shwachman-Diamond America ask , "How do you calculate ANC?"

I have a page on our family website dedicated to neutropenia. I built this page many years ago in hopes that it would help people surfing the web to understand what neutropenia is, what causes neutropenia and how to figure out what a person's absolute neutrophil count is. Visit the hyper links in this post for more information on neutropenia and its causes. Here is the basic formula for calculating the absolute neutrophil count:

To obtain the Absolute count, one must multiply the relative value of each type of cell (neutrophils in our case) by the total WBC count. If a person has a total WBC of 6,000 and his differential shows 30% neutrophils, to figure the Absolute Neutrophil Count (ANC) we multiply 6,000 by 30% to arrive at an ANC of 1800.