Kostmann Disease

Updated: Aug 31, 2015
  • Author: Peter N Huynh, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Overview

Background

Kostmann disease was first described in 1956 as an autosomal recessive disorder characterized by severe neutropenia and onset of severe bacterial infections early in life. [1] In his pivotal doctoral thesis, Rolf Kostmann studied 14 affected children from an inbred family from the province of Norrbotten, Sweden. He reported that the neutropenia was accompanied by "a primary insufficiency of the bone marrow" and that the disease is determined by a "single recessive gene difference." Fifty years later, homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1 (HAX1) were found in affected descendants of the original Kostmann family. [2]

Today, the condition initially described by Kostmann is referred to as Kostmann disease. However, it is now apparent that congenital neutropenia is a genetically heterogeneous group of related disorders and, therefore, is designated as severe congenital neutropenia. Severe congenital neutropenia demonstrates several modes of inheritance, including autosomal recessive, autosomal dominant, sporadic, and X-linked forms.

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Pathophysiology

Neutrophils are the most prevalent type of white blood cell and are an essential part of the innate immune system. They act as initial responders to inflammation and ingest, or phagocytize, microorganisms or particles. A phagosome is formed around the ingested microbes, and an oxidative burst is generated in the phagosome. They also release neutrophil granules that kill the invading microorganism. Neutrophils undergo apoptosis and are then cleared by macrophages or other phagocytic cells, which clear the toxic contents. [3, 4]

Neutropenia is a disorder characterized by an abnormally low absolute number of neutrophils in the blood. Mild neutropenia is classified as less than 1500 granulocytes/μL, moderate is less than 1000/μL, severe is less than 500/μL, and very severe is less than 200/μL. Severe congenital neutropenia usually presents in infancy with an absolute neutrophil count of less than 200/μL. [5, 6]

Several genetic causes of severe congenital neutropenia have been identified, but a common thread among the variants is excessive neutrophil apoptosis. A decrease in the production or shorter half-life of neutrophils results in fewer cells in the periphery.

The unfolded protein response (UPR) has been recently proposed as a potential explanation for increased apoptosis seen in severe congenital neutropenia. Increased endoplasmic reticulum stress leads to the activation of the UPR. When an accumulation of unfolded or misfolded proteins occurs in the lumen of the endoplasmic reticulum, the UPR works to protect the cell against the damage caused by these improperly folded proteins. The goals of the UPR are to maintain homeostasis in the cell by arresting protein translation and promoting signaling pathways that lead to increased production of molecular chaperones to help with protein folding. If this does not happen, the UPR initiates apoptosis. [7, 8, 9, 10]

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Epidemiology

Frequency

International

Epidemiological data are limited given the overlapping case definitions of congenital neutropenia and few patient registries.

According to International Neutropenia Registry data from 2003 covering areas with a total population of 700 million in United States, Canada, Australia, and Europe (excluding France), 731 cases were reported, with a prevalence of about 1 case per million people.

A French registry reported an incidence as high as 6 cases per million people. Of the patients from the French survey, 30% had ELANE mutations (20% with severe congenital neutropenia and 10% with cyclic neutropenia), 30% had Shwachman-Diamond syndrome (SBDS), 5% had glycogen storage disease type 1b, and 35% had other disorders (1 or 2% each). [5]

In another study from the North American Severe Chronic Neutropenia Tissue Repository, mutations in ELANE genes were found in 90 (55.6%) of 162 patients. Of 72 patients with normal ELANE genes, 45 had sufficient DNA to undergo throughput sequencing to determine prevalence of other mutations(HAX1, -WASp, SBDS, GFI1, and G6PC3). Five of these patients were found to have mutations: G6PC3 in 2, GFI1 in 1, SBDS in 1, and WASp in 1. In 40% of patients, a genetic etiology for severe congenital neutropenia was unknown. [11]

Mortality/Morbidity

The mortality rate is 70% within the first year of life in the absence of medical intervention with granulocyte colony-stimulating factor (G-CSF), bone marrow transplantation, or peripheral blood stem cell transplantation. [12]

Patients with severe congenital neutropenia are at an increased risk of bacterial and fungal infections, with most frequent infections involving the skin, mucosa, ears, nose, throat, and lungs. Stomatitis starts after age 2 years with erosive hemorrhagic gingivitis and painful aphthouslike papules on the tongue and cheeks, contributing significantly to morbidity. Chronic periodontal disease has been attributed to deficiency in a defensin, the antimicrobial peptide LL-37. [13] Diffuse gastrointestinal lesions may cause abdominal pain and diarrhea, resembling bacterial enteritis. Bacterial infections involve Staphylococcus aureus and Staphylococcus epidermidis, streptococci, enterococci, pneumococci, Pseudomonas aeruginosa, gram-negative bacilli, and fungal infections with Candida or Aspergillus species.

About 1 in 5 patients with severe congenital neutropenia develop secondary malignancies. The incidence of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in severe congenital neutropenia after 10 years of G-CSF treatment is 21%. Acquired mutations in G-CSF receptor CSF3R are a highly predictive marker for the progression of severe congenital neutropenia to leukemia. [14] Of patients with severe congenital neutropenia, 20-30% have acquired mutations in the CSF3R gene, which produce C-terminally truncated hyperresponsive forms of the G-CSFRhyper and a strong predisposition for MDS and AML.

Race

No major differences likely exist in prevalence across countries. However, certain mutations are linked to geographic origin, such as HAX1 in Kurdistan and Sweden and G6PC3 in Arameans. [5]

Sex

As the name implies, X-linked severe congenital neutropenia due to WASpmutations are only seen in boys. No sexual predilection is associated with the other causes of severe congenital neutropenia.

Age

Patients are diagnosed shortly after birth with recurrent bacterial infections within the first few months of life.

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