Kostmann Syndrome

What Is Kostmann Syndrome?

Kostmann syndrome is a rare, severe, congenital disorder that occurs in infants due to neutropenia or low neutrophil counts, mainly characterized by a lack of mature neutrophils (neutrophils are the wide variety of white blood cells for immune defense in our body). In this neutropenia, the absolute neutrophil counts are less than 500 cells/mm3.

What Are the Clinical Features of Kostmann Syndrome?

1. Kostmann syndrome is associated with recurrent bacterial infections like otitis media, pneumonia, sinusitis, urinary tract infections, etc.

2. The abscesses of the skin or liver are also common in these infants.

3. There is an increased promyelocyte in the bone marrow.

4. Periodontal disease and neurological symptoms, such as cognitive impairment, severe neurodegeneration, and epilepsy, have been reported in some patients. This form of severe congenital neutropenia, also called SCN, may manifest as persistent or cyclic forms and can also be seen in Shwachman-Diamond syndrome (an autosomal recessive syndrome of pancreatic insufficiency). This syndrome usually can be accompanied by bone marrow dysfunction.

5. During the second episode of neutropenia, individuals can develop aphthous ulcers, gingivitis, stomatitis, and cellulitis.

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6. Death from overwhelming Clostridium perfringens infection occurs in about 10 % of patients.

7. Metaphyseal dysostosis and dwarfism are other characteristic features in these individuals in the growth phases.

8. Accessory conditions like peristomatitis, oral ulcer, pneumonia, pulmonary abscess, and perianal abscess are also reported in these individuals.

9. Patients with severe congenital neutropenia typically present with this condition in the first six months of life with frequent or severe bacterial infections.

Bone marrow biopsy may show maturation arrest at the promyelocyte stage. Even before the availability of granulocyte colony-stimulating factor (G-CSF), the mean average age of reported death was at three years, most commonly due to sepsis or pneumonia.

What Are the Pathogenesis and Genetic Inheritance Patterns of Severe Congenital Neutropenia?

Neutropenia is the term used to describe a deficient number of neutrophils in the circulation. Severe congenital neutropenia is present at birth or shortly after that; severe neutropenia (absolute neutrophil count of 0 to less than 500/mm3 is a characteristic of this syndrome. The featurette of recurrent bacterial and fungal infections and a highly reduced number of circulating neutrophils do not usually fluctuate in the count.

Physician Dr. Kostmann initially described the syndrome in 1956 when he researched several neutropenic patients in a large intermarried Swedish kinship. He observed a specific pattern of (after which this SCN syndrome is named) autosomal recessive inheritance in 24 cases by inference. In these hematologically normal parents, they had two or more neutropenic children in several families.

Recent research suggests homozygous germline HAX1 mutations have been identified in patients with SCN, including some from the original pedigree described by Dr. Kostmann, confirming the presence of an autosomal recessive inheritance in these families. Inheritance can be either autosomal recessive or autosomal dominant, and several sporadic cases have been described in the medical literature.

Affected patients usually have increased plasma concentrations of granulocyte colony-stimulating factor (G-CSF) and circulating eosinophils and monocytes. However, in severe congenital neutropenia, the neutrophil counts are low to the point of risking mortality. This is mainly due to an increase in response to exogenous G-CSF concentration despite the elevated level of G-CSF at baseline levels.

What Are the Complications Associated With Severe Congenital Neutropenia?

The genetic cause can be traced to the autosomal recessive mutations in the glucose-6-phosphatase catalytic subunit 3 (G6PC3), which occurs alongside cardiac or urogenital malformations. Research also links this condition with ethnicity, i.e., observations of dominant or spontaneous SCN having heterozygous mutations in the gene encoding neutrophil elastase (ELA2) may be responsible for this severe neutropenia.

Researchers suggest the possibility that mutations in this gene are mainly accountable for cyclic neutropenia (for example, in caucasian patients, the ELA2 mutations are responsible for more than 50 % of SCN cases). In addition, some documented cases have a possible association between epilepsy and immunological abnormalities or any reported neurological abnormalities that could be seen in the autosomal recessive inheritance of these HAX1 and G6PC3 mutations.

Abnormal mitochondrial functions could be involved as the exact hypothesis surrounding the malfunction of these genes is unclear. However, the central nervous system is usually dependent on the pathway of oxidative metabolism. Therefore, in this case of mitochondrial damage, there is subsequently decreased energy production, increased oxidative stress, and release of cellular apoptosis (cell death) factors because of which the individual’s central nervous system might be damaged, and the infant, upon growing in later stages of life may develop retardation or epilepsy complications.

A gain-of-function mutation has also been attributed in the cases of Wiskott-Aldrich syndromes, wherein the protein has been associated with an X-linked form of severe congenital neutropenia.

Severe congenital neutropenia is similarly related to reticular dysgenesis (a disorder of hematopoietic stem cells) that can primarily affect all bone marrow lineages due to mutations in the AK2gene. Research suggests that approximately 10 % of patients diagnosed with severe congenital neutropenia and Shwachman-Diamond syndrome may also develop myelodysplasia (myelogenous leukemia) or cancers (acute form). No cases are usually observed of malignant transformations in patients with either cyclic or idiopathic neutropenia.

What Are the Mainline Treatment Strategies for Severe Congenital Neutropenia?

G-CSF Therapy:

The primary treatment of any congenital neutropenia is to treat the disease with recombinant human granulocyte colony-stimulating factor (rhG-CSF). However, during the three to six days when neutrophil counts are at the lowest, if left untreated, the patient can develop a severe infection that leads to multi-organ failure and death in 10 % of cases. Hence, G-CSF therapy is recommended for emergency management to correct neutropenia and significantly reduce the incidence and duration of infectious complications by improving the neutrophil counts.

Documented cases of G-CSF recipients have been shown to survive the infection risk. Still, these cases have developed myelodysplastic syndrome or acute myeloid leukemia (a form of blood and bone marrow cancer). Therefore, individualized judgment and monitoring by the physician or healthcare provider are essential in G-CSF treatment of severe congenital neutropenia.

Bone Marrow Transplantation:

Bone marrow transplantation is also indicated for those patients who cannot respond to G-CSF treatment, but they may require sibling donors. Antibiotic treatment is not advisable as there is a high mortality rate during infancy unless G-CSF therapy improves the neutrophil count.

Conclusion:

To conclude, this syndrome, a severe inheritance, and mutated gene disorder should be managed timely by the physician to prevent the mortality risk both in infancy and in later stages of life. However, it remains a medically challenging condition.