Kostmann Disease Clinical Presentation

Updated: Aug 24, 2017
  • Author: Peter N Huynh, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Presentation

History

Neutropenic patients are usually infected by organisms of their endogenous flora, the resident bacteria of the mouth and oropharynx, gastrointestinal tract, and skin. A cardinal feature of these infections is a lack of purulence. By age 2 years, oral ulcers and tooth decay are almost always present. The stomatologic disorders are distinguished by erosive, hemorrhagic, and painful gingivitis associated with papules on the tongue and the cheek mucosa, as well as perirectal inflammation or cellulitis. Abscesses, pneumonia, and septicemia may also occur.

The most common microbes seen are S aureus and gram-negative organisms. Patients with severe congenital neutropenia also are at risk for significant bacterial infections such as otitis media, bronchitis, pneumonia, osteomyelitis, or cellulitis. In addition, patients can also experience diffuse gastrointestinal lesions leading to abdominal pain and diarrhea that can mimic Crohn disease. They are not initially predisposed to other fungal, parasitic, or viral infections, but have a higher risk of fungal infection with prolonged neutropenia or extended antibiotic use. [5, 3]

Severe congenital neutropenia patients also may experience a variety of extrahematopoietic manifestations depending on their genetic abnormalities, such as neurologic involvement in HAX1 mutations, dermatologic manifestations in G6PC3 mutations, or monocytopenia in WASp mutations.

Before the introduction of granulocyte colony-stimulating factor (G-CSF), patients would often die during the first year of life. After the introduction of G-CSF, patients survive into adulthood but are at significant risk of leukemia or myelodysplasia. [15] On the basis of national averages of premature deliveries in the general population, an estimated 8% of patients with Kostmann disease are delivered prematurely and admitted to neonatal intensive care units. Although neutropenia is common in ill preterm infants and severe congenital neutropenia is relatively rare, severe congenital neutropenia should be considered if other etiologies for the neutropenia are not found. Therapy with G-CSF can save lives in this clinical setting because of the innate risks of infection in a preterm infant.

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Physical

Signs and symptoms of Kostmann disease include the following:

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Causes

Although the first description of severe congenital neutropenia was reported in 1956 by Rolf Kostmann, the underlying genetic defect was not elucidated until 50 years later. [1, 17] Today, the condition initially described by Kostmann is referred to as Kostmann disease. However, it is now apparent that severe congenital neutropenia is a genetically heterogeneous group of related disorders. Our evolving understanding of severe congenital neutropenia parallels the explosion of new genetic discoveries. Below in chronological order based on date of discovery, some of the mutations responsible for severe congenital neutropenia and recent advances are highlighted. The underlying genetic cause remains elusive in about 40% of patients with severe congenital neutropenia, and future discoveries will certainly yield new insights.

Excess neutrophil apoptosis is a central mechanism in the pathogenesis of severe congenital neutropenia. Several of the mutations associated with severe congenital neutropenia result in increased apoptosis, including those involving neutrophil elastase (ELANE), WASp, HAX1, and, potentially, GFI1. This suggests that errors in trafficking and the unfolded protein response (UPR) may be triggers for premature neutrophil cell death.

CSF3R mutation (1999) (acquired)

The most critical myeloid cytokine for neutrophil production, differentiation, and survival is G-CSF. Since 1987, G-CSF has been used for the treatment of severe congenital neutropenia. Therefore, mutations in the G-CSF receptor (CSF3R gene) were initially suggested to be the cause of severe congenital neutropenia. [18] It was subsequently realized that these mutations were acquired during the lifetime of severe congenital neutropenia patients.

Two classes of CSF3R mutations have been recognized, resulting in hyporesponsive and hyperresponsive forms of the G-CSF receptor. [8] 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. Patients with this mutation have a strong predisposition for myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). G-CSFRhyper enhances stat-5 activation, which seems to provide a selective advantage to hematopoietic stem cells with this mutation. Hence, this mutation may be an early step in leukemogenesis. Acquired G-CSFR mutations have been detected in approximately 80% of severe congenital neutropenia patients who develop AML/MDS.

The second mutation class is a hyporesponsive form of the receptor, G-CSFRhypo, which is seen in severe congenital neutropenia patients who are unresponsive to G-CSF therapy. These mutations act in a dominant fashion over wild-type receptors and prevent normal ligand binding. Although 10% of severe congenital neutropenia patients are refractory to G-CSF, it is not known what percentage of patients harbor the G-CSFRhypo mutation. As G-CSF receptor mutations (CSF3R) are not present at birth, they do not represent the underlying defect for severe congenital neutropenia.

Neutrophil elastase mutations (ELA2) (2000) (autosomal dominant)

ELANE (previously ELA2) mutations account for about 50-60% of patients with severe congenital neutropenia. Gene expression is autosomal dominant. The mutation is in the gene for neutrophil elastase, which is a serine protease made primarily at the promyelocytic stage of neutrophil production. The ELANE gene has been implicated as a cause of severe congenital neutropenia, as well as cyclic neutropenia. More than 40 mutations have been identified.

It is not understood why the same ELANE mutations can result in either cyclic neutropenia or severe congenital neutropenia. Some experts consider cyclic neutropenia and severe congenital neutropenia due to ELANE mutations along the same spectrum of disease. The molecular mechanisms whereby neutrophil elastase mutations disrupt neutrophil production are not entirely understood. One hypothesis is that neutrophil elastase mutations may lead to disruptions in intracellular trafficking. This, in turn, may lead to activation of the UPR and, ultimately, apoptosis of granulocytic precursors. [19, 5]

WASp gain-of-function mutation (2001) (X-linked recessive)

The Wiskott-Aldrich syndrome protein (WASp) regulates actin polymerization in hematopoietic cells. Actin polymerization is required for cell signaling, cell-to-cell interactions, and cell motility. Wiskott-Aldrich syndrome is an X-linked immunodeficiency associated with congenital microthrombocytopenia and eczema. There are almost 150 different WASp mutations leading to Wiskott-Aldrich syndrome, including missense and splice mutations, short deletions, and nonsense mutations, all of which result in loss of protein function.

In contrast, X-linked severe congenital neutropenia has been linked to gain-of-function WASp mutations. These mutations lead to constitutional-active protein forms and consequently unregulated actin polymerization. The 3 mutations seen (L270P, 1294T and S27OP) are thought to disrupt the autoinhibitory domain of this protein. [11] These patients have defective mitosis and cytokinesis, which leads to decreased proliferation and increased apoptosis in myeloid progenitors. [8]

GFI1 mutation (2003) (autosomal dominant)

In 2003, Person et al screened GFI1 as a candidate gene for patients affected with severe congenital neutropenia. [20] GFI1 is a proto-oncogene that encodes a zinc finger transcription factor. Dominant negative zinc finger mutations result in disabled transcriptional repressor activity. It is hypothesized that GFI1 mutations cause overexpression of neutrophil elastase. The up-regulation of neutrophil elastase activates the UPR and induces neutrophil apoptosis.

Bcl-2 expression (2004)

Carlsson et al noted that the Kostmann disease patients they studied had elevated apoptosis in the bone marrow. [21] They also found an abnormally low number of B-cell lymphoma-2 (Bcl-2) in biopsies from patients with severe congenital neutropenia prior to initiation of G-CSF therapy. The primary function of Bcl-2 is prevention of mitochondrial release of cytochrome c, which initiates apoptosis, into the cells. After G-CSF administration, Bcl-2 levels appeared normalized and apoptosis of the cells decreased.

HAX1 mutations (2006) (autosomal recessive)

Although Kostmann disease was first described in 1956, the underlying genetic mutation was not elucidated until recently. HAX-1 deficiency is now known to be responsible for Kostmann disease, an autosomal recessive type of severe congenital neutropenia. Members of the original Swedish “Kostmann” family members were found to have mutations in HAX1 gene. [17] This gene is on chromosome 1 and encodes HAX-1 or HCLS-1–associated protein X, which is a mitochondria-targeted protein member of the Bcl-2 family of apoptosis-regulating proteins. [21]

Increased apoptosis is seen in HAX-1–deficient neutrophils. There is also increased release of cytochrome c from mitochondria in myeloid progenitor cells, suggesting HAX-1 helps in stabilizing the mitochondrial membrane potential. Mitochondrial control of apoptosis seems to be a mechanism in humans of regulating myeloid cell homeostasis.

Homozygous HAX1 mutations have been found in autosomal-recessive severe congenital neutropenia, and compound heterozygous HAX1 mutations have also been identified. All mutations described inactivate the HAX-1 protein. A mutation affecting transcript variant 1 of HAX-1 is associated with congenital neutropenia alone, but mutations affecting both transcripts caused congenital and neurological symptoms. [16] Isoform B also may affect neuronal function. [10]

G6PC3 mutation (2009) (autosomal recessive)

In 2009, Boztug et al described a congenital neutropenia syndrome with biallelic mutations in G6PC3, a gene encoding glucose-6-phosphatase, catalytic subunit 3. [22] Like patients with mutations in ELA2 or HAX1, peripheral-blood neutrophils had increased rates of spontaneous apoptosis in the absence of G6PC3. Therefore, G6PC3 is required to maintain neutrophil viability. It is hypothesized that increased neutrophil apoptosis in G6PC3 deficiency involves increased endoplasmic reticulum stress, which is seen in deficient protein folding in the endoplasmic reticulum.

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