Kostmann syndrome

Overview

Kostmann syndrome, also known as severe congenital neutropenia (SCN), is a rare genetic disorder characterized by a deficiency of neutrophils—a type of white blood cell essential for fighting bacterial infections. It typically presents in infancy with recurrent, life-threatening bacterial infections. The condition was first described by Swedish pediatrician Rolf Kostmann in 1956. Without early diagnosis and treatment, Kostmann syndrome can lead to severe infections, sepsis, and even death. However, with appropriate medical intervention, patients can live significantly longer and healthier lives.

Causes

Kostmann syndrome is most commonly caused by mutations in the HAX1 gene, which plays a crucial role in the survival of neutrophil precursors in the bone marrow. The condition is inherited in an autosomal recessive pattern, meaning both copies of the gene must be mutated for a child to be affected. Other gene mutations such as ELANE, G6PC3, and CSF3R may also be involved in related forms of congenital neutropenia. The genetic mutation leads to failure of neutrophil maturation, resulting in extremely low neutrophil counts (neutropenia) in the bloodstream.

Symptoms

Symptoms of Kostmann syndrome usually appear within the first few months of life and are primarily related to increased susceptibility to bacterial infections. Common signs and symptoms include:

• Recurrent skin infections (boils, abscesses, cellulitis)

• Pneumonia and respiratory tract infections

• Mouth ulcers and gingivitis

• Fever and failure to thrive

• Sepsis (a potentially life-threatening body-wide infection)

• Delayed wound healing

Despite these infections, affected infants often show no major abnormalities at birth. The hallmark laboratory finding is an absolute neutrophil count (ANC) persistently below 500 cells/µL.

Diagnosis

Diagnosis of Kostmann syndrome involves a combination of clinical evaluation, laboratory testing, and genetic analysis. Diagnostic steps include:

• Complete blood count (CBC): Reveals severe neutropenia with ANC < 500 cells/µL

• Bone marrow biopsy: Shows maturation arrest of neutrophil precursors at the promyelocyte/myelocyte stage

• Genetic testing: Confirms mutations in the HAX1 gene or other associated genes

• Family history: May reveal consanguinity or affected siblings

Early diagnosis is critical for prompt initiation of therapy and prevention of severe infections.

Treatment

The primary goal of treatment for Kostmann syndrome is to increase neutrophil counts and prevent infections. Management includes:

• Granulocyte colony-stimulating factor (G-CSF): A medication like filgrastim is used to stimulate neutrophil production

• Antibiotics: Prompt treatment of bacterial infections and prophylactic antibiotics in some cases

• Hematopoietic stem cell transplantation (HSCT): Considered for patients who do not respond to G-CSF or develop bone marrow failure or myelodysplastic changes

• Regular monitoring: Routine blood counts and infection surveillance

• Genetic counseling: For affected families to understand inheritance and reproductive risks

Prognosis

The prognosis for individuals with Kostmann syndrome has significantly improved with the use of G-CSF. Most patients respond well to this therapy and can lead relatively normal lives with careful management. However, a subset of patients may develop complications such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Early diagnosis, consistent treatment, and regular follow-up are essential to improving long-term outcomes and minimizing risks.