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At a glance

This is a rare blood disorder characterized by severe chronic neutropenia as a result of bone marrow primary insufficiency. Symptoms associated with this severe chronic neutropenia include recurring infections, severe fever, mouth ulcerations, and periodontitis. Life-threatening recurrent infections are common complications that may last for months or years and can affect both children and adults.

Synonyms

Kostmann Disease; Severe Neutropenia Syndrome; Infantile Agranulocytosis; Congenital autosomal dominant (or sporadic) neutropenia.

History

Rolf Kostmann first described this medical condition in 1956 when he studied, for his doctoral thesis, 14 affected children from an inbred family living in the province of Norrbotten, Sweden. It is characterized by severe neutropenia and the clinical manifestation of severe bacterial infections early in life. He reported that the neutropenia was accompanied by “a primary insufficiency of the bone marrow” and that the disease was determined by a “single recessive gene difference.” Fifty years later, homozygous mutations in the gene encoding the mitochondrial protein HCLS1-associated X1 (HAX1) have been identified in affected descendants of the original Kostmann family.

Classification:

The three main forms are congenital, idiopathic, and cyclic neutropenia:

  • Congenital Forms: Typically apparent at birth or during early childhood and are considered the most severe form.

  • Chronic Idiopathic Neutropenia: Usually affects only adults. However, in some cases, the disorder has been demonstrated during childhood, but clinically remains undetected until adulthood.

  • Cyclic Neutropenia: Most cases are thought to be present at birth. However, in some cases, symptoms may not become apparent until childhood, adolescence, or even early adulthood. The disorder may also be acquired.

Incidence

The exact incidence remains unknown worldwide. However, it is estimated in the United States alone that it affects approximately 2,000 to 5,000 individuals.

Genetic inheritance

Severe chronic neutropenia may be inherited as an autosomal dominant or an autosomal recessive genetic trait. It can be acquired or may be idiopathic for unknown reasons. It affects males and females equally. Both children and adults can be affected.

Clinical aspects

  • Congenital Forms of Severe Chronic Neutropenia: Characterized by fevers, recurrent pneumonia, ear infections, gingivitis, and stomatitis. Periodontitis is often present. Recurrent oral ulcerations are common. Bacterial infections often affect the skin, gastrointestinal tract, and respiratory system and can be life-threatening. The most severe form of congenital neutropenia is known as Kostmann Syndrome. Treatment of Kostmann Syndrome consists of G-CSF for life. Some patients unfortunately may progress to myelodysplastic syndrome or acute myelogenous leukemia under this G-CSF therapy.

  • Chronic Idiopathic Neutropenia: Symptoms are less severe than those observed with congenital neutropenia; however, infections may also be life-threatening.

  • Cyclic Neutropenia: Severe chronic decrease of neutrophils, presenting as episodes recurring on an average every 21 days and lasting for approximately 3 to ...

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